David G. Mutch, MD

As the proportion of the elderly in the US population continues to increase, with life expectancy trending upward, we can expect to see more gynecologic cancers in our patients.^1,2 At present, the most effective approach to these cancers commonly includes aggressive surgical resection with chemotherapy and, in some cases, radiation. It remains unclear whether elderly patients should be managed the same as younger patients, with minimal data to guide physicians. Some evidence suggests an increased risk of surgical complications in 
older adults.³

To optimize surgical care in our elderly patients, we need to understand the risks of perioperative mortality and morbidity in this population. For example, the current standard of care for advanced epithelial ovarian cancer is aggressive cytoreductive surgery followed by adjuvant chemotherapy,⁴ although neoadjuvant chemotherapy is gaining utility and popularity in certain circumstances. During pretreatment counseling, it is imperative that we communicate patient-specific outcomes so that patients and their families can make educated decisions in line with their goals. What should we know about age-dependent outcomes when counseling our patients?

To optimize surgical care in this population, we also need to develop and use new methods of surgical decision making. Although some data suggest that age is an independent risk factor for postoperative complications, not all elderly patients are the same in terms of comorbidities and functional status. In order to truly assess risks, we need to identify additional preoperative risk factors. Are there accurate scoring tools or predictors of outcomes available to help us assess the risks of postoperative mortality and morbidity?

In this article, we highlight recent developments in surgical treatment of the elderly, focusing on:

• postoperative mortality and morbidity in patients older than 80 years
• adjuncts to preoperative assessment for oncogeriatric surgical patients.

Risks rise sharply in older patients undergoing treatment for ovarian Ca

Moore KN, Reid MS, Fong DN, et al. Ovarian cancer in the octogenarian: does the paradigm of aggressive cytoreductive surgery and chemotherapy still apply? 
Gynecol Oncol. 2008;110(2):133–139.

Mahdi H, Wiechert A, Lockhart D, Rose PG. Impact of age on 30-day mortality and morbidity in patients undergoing surgery for ovarian cancer. Int J Gynecol 
Cancer. 2015;25(7):1216–1223.

The cornerstone of optimal survival from certain gynecologic cancers, such as advanced ovarian cancer, is aggressive debulking surgery. However, older adults are classically under-represented in clinical trials that guide this standard of care.

To determine whether patients aged 80 years or older respond differently from younger patients to conventional ovarian cancer management, Moore and colleagues retrospectively reviewed their institutional experience. They found that postoperative mortality increased from 5.4% in patients aged 80 to 84 years to 9.1% in those aged 85 to 89 and 14.4% in those older than 90. The rates for younger patients were 0.6% for patients younger than 60 years, 2.8% for those aged 60 to 69 years, and 2.5% for those aged 70 to 
79 years (P<.001).

Notably, 13% of patients aged 80 years or older who underwent primary surgery died during their primary hospitalization. Of those who survived, 50% were discharged to skilled nursing facilities. Of patients who underwent cytoreductive surgery, 13% were unable to undergo any intended adjuvant therapy, and only 57% completed more than 3 cycles of chemotherapy, either due to demise or toxicities. Two-month survival for patients 80 years or older was comparable between patients who underwent primary surgery and those who had primary chemotherapy (20% and 26%, respectively).

With a similar objective, Mahdi and colleagues identified 2,087 patients with ovarian cancer who underwent surgery. After adjusting for confounders with multivariable analyses, they found that octogenarians whose initial management was surgery were 9 times more likely than younger patients to die and 70% more likely to develop complications within 30 days. Among patients who underwent neoadjuvant chemotherapy, there were no significant differences between older and younger patients in 30-day postoperative mortality or morbidity.

When evaluating elderly patients for surgery, the use of multiple risk-assessment strategies may improve accuracy

Huisman MG, Audisio RA, Ugolini G, et al. Screening for predictors of adverse outcome in onco-geriatric surgical patients: a multicenter prospective cohort study. Eur J Surg Oncol. 2015;41(7):844–851.

Uppal S, Igwe E, Rice L, Spencer R, Rose SL. Frailty index predicts severe complications in gynecologic oncology patients. Gynecol Oncol. 2015;137(1):98–101.

The National Comprehensive Cancer 
Network recommends that clinicians determine baseline life expectancy for older adults with cancer to aid in management decision making. The use of tools such as www.eprognosis.com, developed to determine anticipated life expectancy independent of cancer, can prove useful in determining a patient’s risk of dying or suffering from their cancer before dying of another cause.⁵

When it comes to the determination of risk related to a patient’s cancer diagnosis and selection of potential management options, many argue that the subgroup of elderly patients is not homogenous and that the use of age alone to guide management decisions may be unfair. Preoperative evaluation ideally should incorporate a global assessment of predictive risk factors.

Three assessment tools are 
especially useful

Huisman and colleagues set out to identify accurate preoperative assessment methods in elderly patients undergoing oncologic surgery. They prospectively recruited 328 patients aged 70 years or older and evaluated patients preoperatively using 11 well-known geriatric screening tools. They compared these evaluations with outcomes to determine which tools best predict the occurrence of major postoperative complications. They found the strongest correlation with outcomes when combining gender and type of surgery with the following 3 assessment tools:

• Timed Up and Go (TUG)—a walking test to measure functional status
• American Society of Anesthesiologists scale—a scoring system that quantifies preoperative physical status and estimates anesthetic risk
• Nutritional Risk Screening—an assessment of nutritional risk based on recent weight loss, overall condition, and reduction of food intake.

All 3 are simple and short screening tools. When used together, they can provide clinicians with accurate risk estimations.

The findings of Huisman and colleagues reinforce the importance of a global assessment of the patient’s comorbidities, functional status, and nutritional status when determining candidacy for oncologic surgery.

Functional index predicts need 
for postoperative ICU care 
and risk of death

Uppal and colleagues set out to quantify the predictive value of the modified Functional Index (mFI) in assessing the need for postoperative critical care support and/or the risk of death within 30 days after gynecologic cancer surgery. The mFI can be calculated by adding 1 point for each variable listed in the TABLE, with a score of 4 or higher representing a high-frailty cohort.

Of 6,551 patients who underwent gynecologic surgery, 188 were admitted to the intensive care unit (ICU) or died within 
30 days after surgery. The mFI was calculated, with multivariate analyses of additional variables. An mFI score of 3 or higher was predictive of the need for critical care support and the risk of 30-day mortality and was associated with a significantly higher number of complications (P<.001).

Predictors significant for postoperative critical care support or death were:

• preoperative albumin level less than 3 g/dL (odds ratio [OR] = 6.5)
• operative time (OR = 1.003 per minute of increase)
• nonlaparoscopic surgery (OR = 3.3)
• mFI score, with a score of 0 serving as the reference (OR for a score of 1 = 1.26; score of 2 = 1.9; score of 3 = 2.33; and score of 4 or higher = 12.5).

When they combined the mFI and albumin scores—both readily available in the preoperative setting—Uppal and colleagues were able to develop an algorithm to determine patients who were at “low risk” versus “high risk” for ICU admission and/or death postoperatively (FIGURE).

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Bottom line

Older patients are more commonly affected by multiple medical comorbidities, as well as functional, cognitive, and nutritional deficiencies, which contribute to their increased risk of morbidity and mortality after surgery. The elderly experience greater morbidity with noncardiac surgery in general.

Clearly, the decision to operate on an elderly patient should be approached with caution, and a critical assessment of the patient’s risk factors should be performed to inform counseling about the patient’s management options. Future randomized prospective data will help us better understand the relationship between age and surgical outcomes.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

As the proportion of the elderly in the US population continues to increase, with life expectancy trending upward, we can expect to see more gynecologic cancers in our patients.^1,2 At present, the most effective approach to these cancers commonly includes aggressive surgical resection with chemotherapy and, in some cases, radiation. It remains unclear whether elderly patients should be managed the same as younger patients, with minimal data to guide physicians. Some evidence suggests an increased risk of surgical complications in 
older adults.³

To optimize surgical care in our elderly patients, we need to understand the risks of perioperative mortality and morbidity in this population. For example, the current standard of care for advanced epithelial ovarian cancer is aggressive cytoreductive surgery followed by adjuvant chemotherapy,⁴ although neoadjuvant chemotherapy is gaining utility and popularity in certain circumstances. During pretreatment counseling, it is imperative that we communicate patient-specific outcomes so that patients and their families can make educated decisions in line with their goals. What should we know about age-dependent outcomes when counseling our patients?

To optimize surgical care in this population, we also need to develop and use new methods of surgical decision making. Although some data suggest that age is an independent risk factor for postoperative complications, not all elderly patients are the same in terms of comorbidities and functional status. In order to truly assess risks, we need to identify additional preoperative risk factors. Are there accurate scoring tools or predictors of outcomes available to help us assess the risks of postoperative mortality and morbidity?

In this article, we highlight recent developments in surgical treatment of the elderly, focusing on:

• postoperative mortality and morbidity in patients older than 80 years
• adjuncts to preoperative assessment for oncogeriatric surgical patients.

Risks rise sharply in older patients undergoing treatment for ovarian Ca

Moore KN, Reid MS, Fong DN, et al. Ovarian cancer in the octogenarian: does the paradigm of aggressive cytoreductive surgery and chemotherapy still apply? 
Gynecol Oncol. 2008;110(2):133–139.

Mahdi H, Wiechert A, Lockhart D, Rose PG. Impact of age on 30-day mortality and morbidity in patients undergoing surgery for ovarian cancer. Int J Gynecol 
Cancer. 2015;25(7):1216–1223.

The cornerstone of optimal survival from certain gynecologic cancers, such as advanced ovarian cancer, is aggressive debulking surgery. However, older adults are classically under-represented in clinical trials that guide this standard of care.

To determine whether patients aged 80 years or older respond differently from younger patients to conventional ovarian cancer management, Moore and colleagues retrospectively reviewed their institutional experience. They found that postoperative mortality increased from 5.4% in patients aged 80 to 84 years to 9.1% in those aged 85 to 89 and 14.4% in those older than 90. The rates for younger patients were 0.6% for patients younger than 60 years, 2.8% for those aged 60 to 69 years, and 2.5% for those aged 70 to 
79 years (P<.001).

Notably, 13% of patients aged 80 years or older who underwent primary surgery died during their primary hospitalization. Of those who survived, 50% were discharged to skilled nursing facilities. Of patients who underwent cytoreductive surgery, 13% were unable to undergo any intended adjuvant therapy, and only 57% completed more than 3 cycles of chemotherapy, either due to demise or toxicities. Two-month survival for patients 80 years or older was comparable between patients who underwent primary surgery and those who had primary chemotherapy (20% and 26%, respectively).

With a similar objective, Mahdi and colleagues identified 2,087 patients with ovarian cancer who underwent surgery. After adjusting for confounders with multivariable analyses, they found that octogenarians whose initial management was surgery were 9 times more likely than younger patients to die and 70% more likely to develop complications within 30 days. Among patients who underwent neoadjuvant chemotherapy, there were no significant differences between older and younger patients in 30-day postoperative mortality or morbidity.

When evaluating elderly patients for surgery, the use of multiple risk-assessment strategies may improve accuracy

Huisman MG, Audisio RA, Ugolini G, et al. Screening for predictors of adverse outcome in onco-geriatric surgical patients: a multicenter prospective cohort study. Eur J Surg Oncol. 2015;41(7):844–851.

Uppal S, Igwe E, Rice L, Spencer R, Rose SL. Frailty index predicts severe complications in gynecologic oncology patients. Gynecol Oncol. 2015;137(1):98–101.

The National Comprehensive Cancer 
Network recommends that clinicians determine baseline life expectancy for older adults with cancer to aid in management decision making. The use of tools such as www.eprognosis.com, developed to determine anticipated life expectancy independent of cancer, can prove useful in determining a patient’s risk of dying or suffering from their cancer before dying of another cause.⁵

When it comes to the determination of risk related to a patient’s cancer diagnosis and selection of potential management options, many argue that the subgroup of elderly patients is not homogenous and that the use of age alone to guide management decisions may be unfair. Preoperative evaluation ideally should incorporate a global assessment of predictive risk factors.

Three assessment tools are 
especially useful

Huisman and colleagues set out to identify accurate preoperative assessment methods in elderly patients undergoing oncologic surgery. They prospectively recruited 328 patients aged 70 years or older and evaluated patients preoperatively using 11 well-known geriatric screening tools. They compared these evaluations with outcomes to determine which tools best predict the occurrence of major postoperative complications. They found the strongest correlation with outcomes when combining gender and type of surgery with the following 3 assessment tools:

• Timed Up and Go (TUG)—a walking test to measure functional status
• American Society of Anesthesiologists scale—a scoring system that quantifies preoperative physical status and estimates anesthetic risk
• Nutritional Risk Screening—an assessment of nutritional risk based on recent weight loss, overall condition, and reduction of food intake.

All 3 are simple and short screening tools. When used together, they can provide clinicians with accurate risk estimations.

The findings of Huisman and colleagues reinforce the importance of a global assessment of the patient’s comorbidities, functional status, and nutritional status when determining candidacy for oncologic surgery.

Functional index predicts need 
for postoperative ICU care 
and risk of death

Uppal and colleagues set out to quantify the predictive value of the modified Functional Index (mFI) in assessing the need for postoperative critical care support and/or the risk of death within 30 days after gynecologic cancer surgery. The mFI can be calculated by adding 1 point for each variable listed in the TABLE, with a score of 4 or higher representing a high-frailty cohort.

Of 6,551 patients who underwent gynecologic surgery, 188 were admitted to the intensive care unit (ICU) or died within 
30 days after surgery. The mFI was calculated, with multivariate analyses of additional variables. An mFI score of 3 or higher was predictive of the need for critical care support and the risk of 30-day mortality and was associated with a significantly higher number of complications (P<.001).

Predictors significant for postoperative critical care support or death were:

• preoperative albumin level less than 3 g/dL (odds ratio [OR] = 6.5)
• operative time (OR = 1.003 per minute of increase)
• nonlaparoscopic surgery (OR = 3.3)
• mFI score, with a score of 0 serving as the reference (OR for a score of 1 = 1.26; score of 2 = 1.9; score of 3 = 2.33; and score of 4 or higher = 12.5).

When they combined the mFI and albumin scores—both readily available in the preoperative setting—Uppal and colleagues were able to develop an algorithm to determine patients who were at “low risk” versus “high risk” for ICU admission and/or death postoperatively (FIGURE).

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and modified Functional Index","field_file_image_credit[und][0][value]":"6"},"type":"media","attributes":{"height":"316","width":"665","class":"media-element file-medstat-image-full-text"}}]]
Bottom line

Older patients are more commonly affected by multiple medical comorbidities, as well as functional, cognitive, and nutritional deficiencies, which contribute to their increased risk of morbidity and mortality after surgery. The elderly experience greater morbidity with noncardiac surgery in general.

Clearly, the decision to operate on an elderly patient should be approached with caution, and a critical assessment of the patient’s risk factors should be performed to inform counseling about the patient’s management options. Future randomized prospective data will help us better understand the relationship between age and surgical outcomes.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

As the proportion of the elderly in the US population continues to increase, with life expectancy trending upward, we can expect to see more gynecologic cancers in our patients.^1,2 At present, the most effective approach to these cancers commonly includes aggressive surgical resection with chemotherapy and, in some cases, radiation. It remains unclear whether elderly patients should be managed the same as younger patients, with minimal data to guide physicians. Some evidence suggests an increased risk of surgical complications in 
older adults.³

To optimize surgical care in our elderly patients, we need to understand the risks of perioperative mortality and morbidity in this population. For example, the current standard of care for advanced epithelial ovarian cancer is aggressive cytoreductive surgery followed by adjuvant chemotherapy,⁴ although neoadjuvant chemotherapy is gaining utility and popularity in certain circumstances. During pretreatment counseling, it is imperative that we communicate patient-specific outcomes so that patients and their families can make educated decisions in line with their goals. What should we know about age-dependent outcomes when counseling our patients?

To optimize surgical care in this population, we also need to develop and use new methods of surgical decision making. Although some data suggest that age is an independent risk factor for postoperative complications, not all elderly patients are the same in terms of comorbidities and functional status. In order to truly assess risks, we need to identify additional preoperative risk factors. Are there accurate scoring tools or predictors of outcomes available to help us assess the risks of postoperative mortality and morbidity?

In this article, we highlight recent developments in surgical treatment of the elderly, focusing on:

• postoperative mortality and morbidity in patients older than 80 years
• adjuncts to preoperative assessment for oncogeriatric surgical patients.

Risks rise sharply in older patients undergoing treatment for ovarian Ca

Moore KN, Reid MS, Fong DN, et al. Ovarian cancer in the octogenarian: does the paradigm of aggressive cytoreductive surgery and chemotherapy still apply? 
Gynecol Oncol. 2008;110(2):133–139.

Mahdi H, Wiechert A, Lockhart D, Rose PG. Impact of age on 30-day mortality and morbidity in patients undergoing surgery for ovarian cancer. Int J Gynecol 
Cancer. 2015;25(7):1216–1223.

The cornerstone of optimal survival from certain gynecologic cancers, such as advanced ovarian cancer, is aggressive debulking surgery. However, older adults are classically under-represented in clinical trials that guide this standard of care.

To determine whether patients aged 80 years or older respond differently from younger patients to conventional ovarian cancer management, Moore and colleagues retrospectively reviewed their institutional experience. They found that postoperative mortality increased from 5.4% in patients aged 80 to 84 years to 9.1% in those aged 85 to 89 and 14.4% in those older than 90. The rates for younger patients were 0.6% for patients younger than 60 years, 2.8% for those aged 60 to 69 years, and 2.5% for those aged 70 to 
79 years (P<.001).

Notably, 13% of patients aged 80 years or older who underwent primary surgery died during their primary hospitalization. Of those who survived, 50% were discharged to skilled nursing facilities. Of patients who underwent cytoreductive surgery, 13% were unable to undergo any intended adjuvant therapy, and only 57% completed more than 3 cycles of chemotherapy, either due to demise or toxicities. Two-month survival for patients 80 years or older was comparable between patients who underwent primary surgery and those who had primary chemotherapy (20% and 26%, respectively).

With a similar objective, Mahdi and colleagues identified 2,087 patients with ovarian cancer who underwent surgery. After adjusting for confounders with multivariable analyses, they found that octogenarians whose initial management was surgery were 9 times more likely than younger patients to die and 70% more likely to develop complications within 30 days. Among patients who underwent neoadjuvant chemotherapy, there were no significant differences between older and younger patients in 30-day postoperative mortality or morbidity.

When evaluating elderly patients for surgery, the use of multiple risk-assessment strategies may improve accuracy

Huisman MG, Audisio RA, Ugolini G, et al. Screening for predictors of adverse outcome in onco-geriatric surgical patients: a multicenter prospective cohort study. Eur J Surg Oncol. 2015;41(7):844–851.

Uppal S, Igwe E, Rice L, Spencer R, Rose SL. Frailty index predicts severe complications in gynecologic oncology patients. Gynecol Oncol. 2015;137(1):98–101.

The National Comprehensive Cancer 
Network recommends that clinicians determine baseline life expectancy for older adults with cancer to aid in management decision making. The use of tools such as www.eprognosis.com, developed to determine anticipated life expectancy independent of cancer, can prove useful in determining a patient’s risk of dying or suffering from their cancer before dying of another cause.⁵

When it comes to the determination of risk related to a patient’s cancer diagnosis and selection of potential management options, many argue that the subgroup of elderly patients is not homogenous and that the use of age alone to guide management decisions may be unfair. Preoperative evaluation ideally should incorporate a global assessment of predictive risk factors.

Three assessment tools are 
especially useful

Huisman and colleagues set out to identify accurate preoperative assessment methods in elderly patients undergoing oncologic surgery. They prospectively recruited 328 patients aged 70 years or older and evaluated patients preoperatively using 11 well-known geriatric screening tools. They compared these evaluations with outcomes to determine which tools best predict the occurrence of major postoperative complications. They found the strongest correlation with outcomes when combining gender and type of surgery with the following 3 assessment tools:

• Timed Up and Go (TUG)—a walking test to measure functional status
• American Society of Anesthesiologists scale—a scoring system that quantifies preoperative physical status and estimates anesthetic risk
• Nutritional Risk Screening—an assessment of nutritional risk based on recent weight loss, overall condition, and reduction of food intake.

All 3 are simple and short screening tools. When used together, they can provide clinicians with accurate risk estimations.

The findings of Huisman and colleagues reinforce the importance of a global assessment of the patient’s comorbidities, functional status, and nutritional status when determining candidacy for oncologic surgery.

Functional index predicts need 
for postoperative ICU care 
and risk of death

Uppal and colleagues set out to quantify the predictive value of the modified Functional Index (mFI) in assessing the need for postoperative critical care support and/or the risk of death within 30 days after gynecologic cancer surgery. The mFI can be calculated by adding 1 point for each variable listed in the TABLE, with a score of 4 or higher representing a high-frailty cohort.

Of 6,551 patients who underwent gynecologic surgery, 188 were admitted to the intensive care unit (ICU) or died within 
30 days after surgery. The mFI was calculated, with multivariate analyses of additional variables. An mFI score of 3 or higher was predictive of the need for critical care support and the risk of 30-day mortality and was associated with a significantly higher number of complications (P<.001).

Predictors significant for postoperative critical care support or death were:

• preoperative albumin level less than 3 g/dL (odds ratio [OR] = 6.5)
• operative time (OR = 1.003 per minute of increase)
• nonlaparoscopic surgery (OR = 3.3)
• mFI score, with a score of 0 serving as the reference (OR for a score of 1 = 1.26; score of 2 = 1.9; score of 3 = 2.33; and score of 4 or higher = 12.5).

When they combined the mFI and albumin scores—both readily available in the preoperative setting—Uppal and colleagues were able to develop an algorithm to determine patients who were at “low risk” versus “high risk” for ICU admission and/or death postoperatively (FIGURE).

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and modified Functional Index","field_file_image_credit[und][0][value]":"6"},"type":"media","attributes":{"height":"316","width":"665","class":"media-element file-medstat-image-full-text"}}]]
Bottom line

Older patients are more commonly affected by multiple medical comorbidities, as well as functional, cognitive, and nutritional deficiencies, which contribute to their increased risk of morbidity and mortality after surgery. The elderly experience greater morbidity with noncardiac surgery in general.

Clearly, the decision to operate on an elderly patient should be approached with caution, and a critical assessment of the patient’s risk factors should be performed to inform counseling about the patient’s management options. Future randomized prospective data will help us better understand the relationship between age and surgical outcomes.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Ovarian cancer remains the deadliest gynecologic malignancy in the United States, with more than 22,000 women newly diagnosed and more than 14,000 deaths each year. We have made slow progress in terms of survival with new drugs and applications, such as intraperitoneal chemotherapy combined with more aggressive cytoreductive efforts. Five-year survival rates have increased—from 36% to 44%—since the late 1970s.¹ To make the leap from molecular genetics to successful screening, early diagnosis, and targeted treatment, we must first:

• Enhance our understanding of the changes that lead to ovarian cancer. Currently, malignant transformation of the fallopian tube epithelium is thought to result in high-grade papillary serous cancer.² If this is indeed the pathologic origin of ovarian cancers, then early detection or even detection in the premalignant phase may be possible using tests of vaginal fluid. Are early detection, and even screening, possible and how would it effect treatment and survival?
• Develop new and powerful tools to detect molecular changes that might impact treatment and survival. Just a few years ago, initial sequencing of the human genome cost more than $100 million, but DNA sequencing technologies have evolved rapidly, with current estimates at less than a few thousand dollars per genome.³ Knowing the mutations responsible for an individual’s cancer would allow for targeted, individualized treatment plans. Would one patient benefit from neoadjuvant therapy while another needs primary surgical debulking?

In this article, we highlight the historical basis and recent developments in the field of ovarian cancer, focusing on:

What mutations are we looking for?

Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609−615.

In last year’s Update, we discussed the role of The Cancer Genome Atlas (TCGA) project in endometrial cancer.⁴ For ovarian cancer, TCGA analyzed messenger RNA expression, microRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumors.

Almost all tumors (96%) were characterized by mutations of the gene encoding TP53 in addition to statistically recurrent mutations in nine other loci, including NF1, BRCA1, BRCA2, RB1, and CDK12, although these were of low prevalence. Analyses also brought new insight regarding the survival impact of tumors containing BRCA1 or BRCA2 and CCNE1 mutations. Findings included NOTCH and FOXM1 signaling involvement in serous ovarian cancer pathophysiology as well as defective homologous recombination in approximately half of the tumors studied.

What this evidence means for practiceWith these mutations as our targets, we can screen vaginal secretions as well as blood for markers of ovarian cancer.

Ovarian and endometrial cancer cells detected in the vagina

Kinde I, Bettegowda C, Wang Y, et al. Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers. Sci Transl Med. 2013;5(167):167ra4.

Erickson BK, Kinde I, Dobbin AC, et al. Detection of somatic TP53 mutations in tampons of patients with high-grade serous ovarian cancer [published online ahead of print October 2014]. Obstet Gynecol. 2014;124(5).

Ruth Graham, Papanicolaou’s cytology technician in the 1940s, first described ovarian cancer cells detected in vaginal/cervical cytology obtained from vaginal secretions.⁵ Current  studies now demonstrate that we have technology capable of more than simple cytologic detection. We can isolate and evaluate these cancer cells in very small numbers.

Ovarian and endometrial cancer DNA identified in Pap specimenKinde and colleagues assembled a catalog of common mutations previously found in ovarian cancer as well as new data on 22 endometrial tumors. They tested 24 endometrial and 22 ovarian samples from patients with endometrial or ovarian cancers and confirmed that all 46 harbored at least some component of the common genetic changes in their catalog. Hypothesizing that the cancers likely shed cells from their surfaces, they sought to determine whether they could detect these cells among the cervical cells in a Pap smear.

These investigators used massively parallel sequencing to test DNA collected in modern liquid-based cytologic specimens for the same mutations found in the cancer cells. They found that 100% of the endometrial cancers and 41% of ovarian cancers were detectable by this method.

TP53 mutations in ovarian cancer cells detected in vaginally placed tamponWith similar technology, but a different collection method, Erickson and colleagues sought to detect tumor cells in the vagina of women with serous ovarian cancer by TP53 analysis of DNA samples collected via vaginal tampon.

Thirty-three women with pelvic masses suspicious for malignancy and scheduled to undergo diagnostic or therapeutic surgery were enrolled. Of the 25 patients who placed the tampon 8 to 12 hours prior to surgery; 13 had benign disease; three had nonovarian malignancies; and nine had serous adenocarcinoma of ovarian, tubal, or primary peritoneal origin. DNA from tumor specimens of eight patients with serous carcinoma and adequate DNA samples were analyzed for TP53 mutations. The corresponding DNA extracted from the tampon was then probed for the mutation identified in the tumor.

Mutational analysis of the tampon specimen DNA revealed no mutations in the tampon DNA of the three patients who had previously undergone tubal ligation, while mutations were observed in three of the five patients with intact tubes—producing a sensitivity of 60%. The fraction of mutant alleles in the tampon DNA was extremely low at 0.01% to 0.07%, requiring ultra-deep sequencing and increasing the importance of paired primary tumor specimens.

What this evidence means for practiceWhile sensitivity in a population of high-risk patients with intact tubes was found to be 60%, it is unclear what it would be in patients with less advanced disease. The ability of the test to detect mutations at exceptionally low limits is impressive; however, it increases the risk that a variant represents a sequencing error or a sample-to-sample contamination. This study is novel in its approach to diagnosis of ovarian cancer and is a stride toward screening, providing an opportunity to further validate the technology prior to widespread use and clinical application.

                     Circulating tumor cells—the future of cancer management?

Obermayr E, Castillo-Tong DC, Pils D, et al. Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance: a study of the OVCAD consortium. Gynecol Oncol. 2013;128(1):15−21.

Similar in concept to noninvasive prenatal testing for fetal aneuploidy, high circulating tumor cell (CTC) numbers have been correlated with aggressive disease, increased metastasis, and decreased time to relapse. As with cancer cells in vaginal secretions, CTCs also may provide an opportunity for early detection and targeted treatment.⁶

While many CTC studies have used epithelial cell adhesion molecule (EpCAM)−based CTC detection, results have been found to be highly variable between tumor subtypes and phase of disease.⁷ Therefore, Obermayer and colleagues sought to identify novel markers for CTCs in patients with epithelial ovarian cancer and elucidate their impact on outcome.

Details of the studyMatched ovarian cancer tissues and peripheral blood leukocytes of 35 patients underwent microarray analysis to identify novel CTC markers. Gene expression of the novel markers as well as EpCAM were analyzed using blood samples taken from 39 healthy females and from 216 patients with ovarian cancer before primary treatment and 6 months after adjuvant chemotherapy. Overexpression of at least one gene, compared with the healthy control group, was considered CTC positivity.

CTCs were detected in 24.5% of the baseline and 20.4% of the follow-up samples, of which two-thirds showed overexpression of the cyclophilin C gene (PPIC), and just a few by EpCAM overexpression. PPIC-positive CTCs during follow-up were detected significantly more often in the platinum resistant group, and indicated poor outcome even when controlling for classical prognostic parameters.

What this evidence means for practiceThe study authors found that molecular characterization of CTC is superior to CTC enumeration. Ultimately, CTC diagnostics may lead to earlier detection and more personalized treatment of ovarian cancer.

Therefore, this technology could have great impact on screening for and the survival of a large subset of patients with ovarian cancer. In addition, the cells obtained preoperatively could help assess the risk of malignancy in an ovarian mass prior to surgery, or even help in treatment planning, as we enter an era in which we have the ability to assess cancers for prognosis and features of treatment response.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com.

Ovarian cancer remains the deadliest gynecologic malignancy in the United States, with more than 22,000 women newly diagnosed and more than 14,000 deaths each year. We have made slow progress in terms of survival with new drugs and applications, such as intraperitoneal chemotherapy combined with more aggressive cytoreductive efforts. Five-year survival rates have increased—from 36% to 44%—since the late 1970s.¹ To make the leap from molecular genetics to successful screening, early diagnosis, and targeted treatment, we must first:

• Enhance our understanding of the changes that lead to ovarian cancer. Currently, malignant transformation of the fallopian tube epithelium is thought to result in high-grade papillary serous cancer.² If this is indeed the pathologic origin of ovarian cancers, then early detection or even detection in the premalignant phase may be possible using tests of vaginal fluid. Are early detection, and even screening, possible and how would it effect treatment and survival?
• Develop new and powerful tools to detect molecular changes that might impact treatment and survival. Just a few years ago, initial sequencing of the human genome cost more than $100 million, but DNA sequencing technologies have evolved rapidly, with current estimates at less than a few thousand dollars per genome.³ Knowing the mutations responsible for an individual’s cancer would allow for targeted, individualized treatment plans. Would one patient benefit from neoadjuvant therapy while another needs primary surgical debulking?

In this article, we highlight the historical basis and recent developments in the field of ovarian cancer, focusing on:

What mutations are we looking for?

Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609−615.

In last year’s Update, we discussed the role of The Cancer Genome Atlas (TCGA) project in endometrial cancer.⁴ For ovarian cancer, TCGA analyzed messenger RNA expression, microRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumors.

Almost all tumors (96%) were characterized by mutations of the gene encoding TP53 in addition to statistically recurrent mutations in nine other loci, including NF1, BRCA1, BRCA2, RB1, and CDK12, although these were of low prevalence. Analyses also brought new insight regarding the survival impact of tumors containing BRCA1 or BRCA2 and CCNE1 mutations. Findings included NOTCH and FOXM1 signaling involvement in serous ovarian cancer pathophysiology as well as defective homologous recombination in approximately half of the tumors studied.

What this evidence means for practiceWith these mutations as our targets, we can screen vaginal secretions as well as blood for markers of ovarian cancer.

Ovarian and endometrial cancer cells detected in the vagina

Kinde I, Bettegowda C, Wang Y, et al. Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers. Sci Transl Med. 2013;5(167):167ra4.

Erickson BK, Kinde I, Dobbin AC, et al. Detection of somatic TP53 mutations in tampons of patients with high-grade serous ovarian cancer [published online ahead of print October 2014]. Obstet Gynecol. 2014;124(5).

Ruth Graham, Papanicolaou’s cytology technician in the 1940s, first described ovarian cancer cells detected in vaginal/cervical cytology obtained from vaginal secretions.⁵ Current  studies now demonstrate that we have technology capable of more than simple cytologic detection. We can isolate and evaluate these cancer cells in very small numbers.

Ovarian and endometrial cancer DNA identified in Pap specimenKinde and colleagues assembled a catalog of common mutations previously found in ovarian cancer as well as new data on 22 endometrial tumors. They tested 24 endometrial and 22 ovarian samples from patients with endometrial or ovarian cancers and confirmed that all 46 harbored at least some component of the common genetic changes in their catalog. Hypothesizing that the cancers likely shed cells from their surfaces, they sought to determine whether they could detect these cells among the cervical cells in a Pap smear.

These investigators used massively parallel sequencing to test DNA collected in modern liquid-based cytologic specimens for the same mutations found in the cancer cells. They found that 100% of the endometrial cancers and 41% of ovarian cancers were detectable by this method.

TP53 mutations in ovarian cancer cells detected in vaginally placed tamponWith similar technology, but a different collection method, Erickson and colleagues sought to detect tumor cells in the vagina of women with serous ovarian cancer by TP53 analysis of DNA samples collected via vaginal tampon.

Thirty-three women with pelvic masses suspicious for malignancy and scheduled to undergo diagnostic or therapeutic surgery were enrolled. Of the 25 patients who placed the tampon 8 to 12 hours prior to surgery; 13 had benign disease; three had nonovarian malignancies; and nine had serous adenocarcinoma of ovarian, tubal, or primary peritoneal origin. DNA from tumor specimens of eight patients with serous carcinoma and adequate DNA samples were analyzed for TP53 mutations. The corresponding DNA extracted from the tampon was then probed for the mutation identified in the tumor.

Mutational analysis of the tampon specimen DNA revealed no mutations in the tampon DNA of the three patients who had previously undergone tubal ligation, while mutations were observed in three of the five patients with intact tubes—producing a sensitivity of 60%. The fraction of mutant alleles in the tampon DNA was extremely low at 0.01% to 0.07%, requiring ultra-deep sequencing and increasing the importance of paired primary tumor specimens.

What this evidence means for practiceWhile sensitivity in a population of high-risk patients with intact tubes was found to be 60%, it is unclear what it would be in patients with less advanced disease. The ability of the test to detect mutations at exceptionally low limits is impressive; however, it increases the risk that a variant represents a sequencing error or a sample-to-sample contamination. This study is novel in its approach to diagnosis of ovarian cancer and is a stride toward screening, providing an opportunity to further validate the technology prior to widespread use and clinical application.

                     Circulating tumor cells—the future of cancer management?

Obermayr E, Castillo-Tong DC, Pils D, et al. Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance: a study of the OVCAD consortium. Gynecol Oncol. 2013;128(1):15−21.

Similar in concept to noninvasive prenatal testing for fetal aneuploidy, high circulating tumor cell (CTC) numbers have been correlated with aggressive disease, increased metastasis, and decreased time to relapse. As with cancer cells in vaginal secretions, CTCs also may provide an opportunity for early detection and targeted treatment.⁶

While many CTC studies have used epithelial cell adhesion molecule (EpCAM)−based CTC detection, results have been found to be highly variable between tumor subtypes and phase of disease.⁷ Therefore, Obermayer and colleagues sought to identify novel markers for CTCs in patients with epithelial ovarian cancer and elucidate their impact on outcome.

Details of the studyMatched ovarian cancer tissues and peripheral blood leukocytes of 35 patients underwent microarray analysis to identify novel CTC markers. Gene expression of the novel markers as well as EpCAM were analyzed using blood samples taken from 39 healthy females and from 216 patients with ovarian cancer before primary treatment and 6 months after adjuvant chemotherapy. Overexpression of at least one gene, compared with the healthy control group, was considered CTC positivity.

CTCs were detected in 24.5% of the baseline and 20.4% of the follow-up samples, of which two-thirds showed overexpression of the cyclophilin C gene (PPIC), and just a few by EpCAM overexpression. PPIC-positive CTCs during follow-up were detected significantly more often in the platinum resistant group, and indicated poor outcome even when controlling for classical prognostic parameters.

What this evidence means for practiceThe study authors found that molecular characterization of CTC is superior to CTC enumeration. Ultimately, CTC diagnostics may lead to earlier detection and more personalized treatment of ovarian cancer.

Therefore, this technology could have great impact on screening for and the survival of a large subset of patients with ovarian cancer. In addition, the cells obtained preoperatively could help assess the risk of malignancy in an ovarian mass prior to surgery, or even help in treatment planning, as we enter an era in which we have the ability to assess cancers for prognosis and features of treatment response.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com.

Ovarian cancer remains the deadliest gynecologic malignancy in the United States, with more than 22,000 women newly diagnosed and more than 14,000 deaths each year. We have made slow progress in terms of survival with new drugs and applications, such as intraperitoneal chemotherapy combined with more aggressive cytoreductive efforts. Five-year survival rates have increased—from 36% to 44%—since the late 1970s.¹ To make the leap from molecular genetics to successful screening, early diagnosis, and targeted treatment, we must first:

• Enhance our understanding of the changes that lead to ovarian cancer. Currently, malignant transformation of the fallopian tube epithelium is thought to result in high-grade papillary serous cancer.² If this is indeed the pathologic origin of ovarian cancers, then early detection or even detection in the premalignant phase may be possible using tests of vaginal fluid. Are early detection, and even screening, possible and how would it effect treatment and survival?
• Develop new and powerful tools to detect molecular changes that might impact treatment and survival. Just a few years ago, initial sequencing of the human genome cost more than $100 million, but DNA sequencing technologies have evolved rapidly, with current estimates at less than a few thousand dollars per genome.³ Knowing the mutations responsible for an individual’s cancer would allow for targeted, individualized treatment plans. Would one patient benefit from neoadjuvant therapy while another needs primary surgical debulking?

In this article, we highlight the historical basis and recent developments in the field of ovarian cancer, focusing on:

What mutations are we looking for?

Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609−615.

In last year’s Update, we discussed the role of The Cancer Genome Atlas (TCGA) project in endometrial cancer.⁴ For ovarian cancer, TCGA analyzed messenger RNA expression, microRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumors.

Almost all tumors (96%) were characterized by mutations of the gene encoding TP53 in addition to statistically recurrent mutations in nine other loci, including NF1, BRCA1, BRCA2, RB1, and CDK12, although these were of low prevalence. Analyses also brought new insight regarding the survival impact of tumors containing BRCA1 or BRCA2 and CCNE1 mutations. Findings included NOTCH and FOXM1 signaling involvement in serous ovarian cancer pathophysiology as well as defective homologous recombination in approximately half of the tumors studied.

What this evidence means for practiceWith these mutations as our targets, we can screen vaginal secretions as well as blood for markers of ovarian cancer.

Ovarian and endometrial cancer cells detected in the vagina

Kinde I, Bettegowda C, Wang Y, et al. Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers. Sci Transl Med. 2013;5(167):167ra4.

Erickson BK, Kinde I, Dobbin AC, et al. Detection of somatic TP53 mutations in tampons of patients with high-grade serous ovarian cancer [published online ahead of print October 2014]. Obstet Gynecol. 2014;124(5).

Ruth Graham, Papanicolaou’s cytology technician in the 1940s, first described ovarian cancer cells detected in vaginal/cervical cytology obtained from vaginal secretions.⁵ Current  studies now demonstrate that we have technology capable of more than simple cytologic detection. We can isolate and evaluate these cancer cells in very small numbers.

Ovarian and endometrial cancer DNA identified in Pap specimenKinde and colleagues assembled a catalog of common mutations previously found in ovarian cancer as well as new data on 22 endometrial tumors. They tested 24 endometrial and 22 ovarian samples from patients with endometrial or ovarian cancers and confirmed that all 46 harbored at least some component of the common genetic changes in their catalog. Hypothesizing that the cancers likely shed cells from their surfaces, they sought to determine whether they could detect these cells among the cervical cells in a Pap smear.

These investigators used massively parallel sequencing to test DNA collected in modern liquid-based cytologic specimens for the same mutations found in the cancer cells. They found that 100% of the endometrial cancers and 41% of ovarian cancers were detectable by this method.

TP53 mutations in ovarian cancer cells detected in vaginally placed tamponWith similar technology, but a different collection method, Erickson and colleagues sought to detect tumor cells in the vagina of women with serous ovarian cancer by TP53 analysis of DNA samples collected via vaginal tampon.

Thirty-three women with pelvic masses suspicious for malignancy and scheduled to undergo diagnostic or therapeutic surgery were enrolled. Of the 25 patients who placed the tampon 8 to 12 hours prior to surgery; 13 had benign disease; three had nonovarian malignancies; and nine had serous adenocarcinoma of ovarian, tubal, or primary peritoneal origin. DNA from tumor specimens of eight patients with serous carcinoma and adequate DNA samples were analyzed for TP53 mutations. The corresponding DNA extracted from the tampon was then probed for the mutation identified in the tumor.

Mutational analysis of the tampon specimen DNA revealed no mutations in the tampon DNA of the three patients who had previously undergone tubal ligation, while mutations were observed in three of the five patients with intact tubes—producing a sensitivity of 60%. The fraction of mutant alleles in the tampon DNA was extremely low at 0.01% to 0.07%, requiring ultra-deep sequencing and increasing the importance of paired primary tumor specimens.

What this evidence means for practiceWhile sensitivity in a population of high-risk patients with intact tubes was found to be 60%, it is unclear what it would be in patients with less advanced disease. The ability of the test to detect mutations at exceptionally low limits is impressive; however, it increases the risk that a variant represents a sequencing error or a sample-to-sample contamination. This study is novel in its approach to diagnosis of ovarian cancer and is a stride toward screening, providing an opportunity to further validate the technology prior to widespread use and clinical application.

                     Circulating tumor cells—the future of cancer management?

Obermayr E, Castillo-Tong DC, Pils D, et al. Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance: a study of the OVCAD consortium. Gynecol Oncol. 2013;128(1):15−21.

Similar in concept to noninvasive prenatal testing for fetal aneuploidy, high circulating tumor cell (CTC) numbers have been correlated with aggressive disease, increased metastasis, and decreased time to relapse. As with cancer cells in vaginal secretions, CTCs also may provide an opportunity for early detection and targeted treatment.⁶

While many CTC studies have used epithelial cell adhesion molecule (EpCAM)−based CTC detection, results have been found to be highly variable between tumor subtypes and phase of disease.⁷ Therefore, Obermayer and colleagues sought to identify novel markers for CTCs in patients with epithelial ovarian cancer and elucidate their impact on outcome.

Details of the studyMatched ovarian cancer tissues and peripheral blood leukocytes of 35 patients underwent microarray analysis to identify novel CTC markers. Gene expression of the novel markers as well as EpCAM were analyzed using blood samples taken from 39 healthy females and from 216 patients with ovarian cancer before primary treatment and 6 months after adjuvant chemotherapy. Overexpression of at least one gene, compared with the healthy control group, was considered CTC positivity.

CTCs were detected in 24.5% of the baseline and 20.4% of the follow-up samples, of which two-thirds showed overexpression of the cyclophilin C gene (PPIC), and just a few by EpCAM overexpression. PPIC-positive CTCs during follow-up were detected significantly more often in the platinum resistant group, and indicated poor outcome even when controlling for classical prognostic parameters.

What this evidence means for practiceThe study authors found that molecular characterization of CTC is superior to CTC enumeration. Ultimately, CTC diagnostics may lead to earlier detection and more personalized treatment of ovarian cancer.

Therefore, this technology could have great impact on screening for and the survival of a large subset of patients with ovarian cancer. In addition, the cells obtained preoperatively could help assess the risk of malignancy in an ovarian mass prior to surgery, or even help in treatment planning, as we enter an era in which we have the ability to assess cancers for prognosis and features of treatment response.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com.

Endometrial cancer is the most common malignancy of the female reproductive tract in the United States, and its incidence continues to rise, with an estimated 49,560 new cases predicted for 2013.¹ If we are to successfully traverse the pathway from molecular cell genetics to the development of targeted therapies and personalized cancer care, we need to meet a few benchmarks:

• We need to enhance our understanding of the molecular changes that lead to endometrial cancer. Of particular interest are nonendometrioid tumors. Increased mortality from endometrial cancer appears to be related to the growing number of uterine papillary serous carcinomas and clear-cell cancers. Although these cancers constitute less than 10% of all endometrial cancers, they account for a disproportionately high number of recurrences and cancer-related deaths.^2,3 Do recent studies validate the original classification of endometrial cancers as Type I (endometrioid) or Type II (serous and clear cell), or is there more heterogeneity than was originally thought? How do recent studies affect treatment options?
• We need to establish a genomic characterization of endometrial cancer to supplement clinical research data. The identification of novel mutations specific to each histologic type has the potential to improve adjuvant therapy. How close are we to performing a comprehensive genomic analysis of endometrial cancer?
• We need to develop new adjuvant treatment options for recurrent and advanced disease. When clinical symptoms of endometrial cancer are overt, as they often are, early diagnosis is possible, with a 5-year survival rate of 80% to 90%. The prognosis declines dramatically in women with advanced-stage disease or high-risk histologies, with a 5-year survival rate of 57% and 19% for Stage III and Stage IV disease, respectively.¹ Adjuvant treatment options are limited in the setting of recurrent or advanced disease. Do any biologic agents increase survival?

In this article, we highlight the historical foundation and newest advances in the field of endometrial cancer, focusing on:

• histologic classification
• etiologic heterogeneity and molecular biology
• genome-guided clinical trials involving targeted therapy, with the ultimate goal of achieving individualized cancer care.

Should we reclassify endometrial cancers to reflect molecular characteristics of tumors?

Brinton LA, Felix AS, McMeekin DS, et al. Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial. Gynecol Oncol. 2013;129(2):277–284.

Cancer Genome Atlas Research Network, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

Uterine papillary serous carcinoma (UPSC) was first established as a distinct subtype of endometrial cancer in the early 1980s, when teams led by Lauchlan4 and Hendrickson5 described it as histologically similar to serous epithelial ovarian carcinoma. Shortly thereafter, Bokhman proposed two broad categories of endometrial carcinoma characterized by distinct microscopic appearance, epidemiology, and endocrine and metabolic functioning (TABLE, page 28).6

More recently, research has focused on expanding this histologic classification system to encompass molecular differences. Brinton and colleagues conducted a study within Gynecologic Oncology Group 210, investigating the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologies. They found that risk factors for aggressive endometrial cancers, including Grade 3 endometrioid and nonendometrioid tumors, appear to differ from those of lower-grade endometrioid carcinomas.

Details of the study by Brinton and colleagues
A total of 3,434 women were included, representing endometrioid (78%) and serous (9%) carcinomas. Grade 3 endometrioid tumors resembled Type II endometrial cancers more closely than did Grade 1–2 endometrioid tumors. Patients with Grade 3 endometrioid and Type II cancers were diagnosed at a significantly older age than patients with Grades 1–2 endometrioid cancers (eg, diagnosis of serous cancers: median age, 67.4 years; Grade 3 endometrioid cancers: median age, 61.9 years; Grade 1–2 endometrioid cancers: median age, 59.6 years). They also were more likely to be nonwhite than patients with Grades 1–2 endometrioid histology. Specifically, black patients were rarely diagnosed with Grades 1–2 endometrioid cancers (5% vs 9% for Grade 3 endometrioid cancers; 20% for serous cancers, 23% for carcinosarcomas, and 12% for clear-cell cancers).

After adjustments for age, enrollment year, and race, patients with Type II tumors (serous, carcinosarcomas, or clear-cell tumors) were much more likely to be multiparous or smokers or to have a history of breast cancer treated with tamoxifen, compared with women with Grade 1–2 endometrioid cancers. An adequately powered subanalysis of serous carcinomas and Grades 1–2 endometrioid cancers revealed that associations persisted between serous carcinomas and multiparity, body mass index, and a history of breast cancer treated with tamoxifen.

Related article: The future of the Pap test: Identifying endometrial and ovarian cancers (Janelle Yates, August 2013)

Overall, this study provides some of the strongest epidemiologic support we have that endometrial cancers are heterogeneous, with evidence to suggest that we might classify Grade 3 endometrioid carcinomas as Type II cancers. These findings paved the way for molecular profiling of endometrial cancers.

Details of the study by the Cancer Genome Atlas Research Network
The Cancer Genome Atlas Research Network recently published an integrated genomic, transcriptomic, and proteomic ­characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. The goal was to provide better insight into disease biology and tumor classification to help guide clinical trials and drug development, with the ultimate goal of achieving personalized cancer care.

The group classified endometrial cancers into four new categories:

• polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
• microsatellite instability (MSI) hypermutated
• somatic copy number alterations (SCNA) low
• SCNA high.

Most endometrioid tumors had few SCNA or P53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS genes. Novel mutations also were discovered in the SWI/SNF chromatin remodeling complex gene ARID5B. About 10% of endometrioid tumors had markedly increased transversion mutations and newly identified mutations in POLE, a gene involved in nuclear DNA replication and repair.

As expected, serous tumors had significantly worse progression-free survival (PFS) than endometrioid tumors (P = .003, log-rank). A subset (25%) of high-grade endometrioid tumors had SCNAs and mutation spectra similar to those of uterine serous carcinomas, suggesting that patients with such tumors might benefit from treatment options that parallel those for serous tumors.

Other overlapping treatment paradigms existed between different organ systems. For example, some molecular features were similar in uterine serous carcinomas, basal-like breast carcinomas, and high-grade serous ovarian carcinomas. All three carcinomas displayed a high frequency of P53 mutations, very low frequency of PTEN mutations, similar focal SCNA patterns, and minimal DNA methylation changes. However, investigators also found several mutations that are unique to uterine serous carcinomas (eg, PIK3CA, FBXW7, PPP2R1A, and ARID1A), providing potential opportunities for targeted pharmacotherapy.

What this evidence means for practice
These studies highlight the etiologic heterogeneity of endometrial cancer. The histologic groundwork laid by Bokhman was not only correct but provided a foundation for molecular characterization of endometrial cancers to drive translational science into targeted therapeutics.

The similar molecular phenotypes of high-grade endometrioid carcinomas and serous endometrial carcinomas strengthens existing evidence that chemotherapy may be preferable to adjuvant radiotherapy for patients with highly mutated endometrioid cancers (eg, SCNA). Current chemotherapy regimens for serous endometrial cancers remain appropriate, given the compelling similarities between these cancers and serous ovarian and basal-like breast cancers. However, the identification of unique molecular features not shared by breast or ovarian cancer may expand standard options to include more targeted therapy.

Overall, this type of research, which encompasses proper histologic classification refined by genomics, has the potential to achieve personalized cancer care.

How we are achieving individualized cancer care: 3 genome-guided clinical trials

Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–3285.

Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259–2265.

Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–27.

Women with locally recurrent, advanced, or metastatic endometrial cancer have limited options for treatment. Hormonal therapies have modest effects at best, with a median survival rate of 7 to 12 months.^7–9 To address this lack of options, researchers have begun to focus on targeted therapies directed at molecular pathways of cellular proliferation. These therapies include but are not limited to inhibitors of:

• mammalian target of rapamycin (mTOR)
• human epidermal growth factor receptor 2
• epidermal growth factor receptor
• vascular endothelial growth factor (VEGF).

Several studies have produced promising findings in recent years. They involve ­investigations of temsirolimus and bevacizumab as single agents in two independent clinical trials, and a study of the drugs in combination in women with recurrent or persistent endometrial carcinoma.

mTOR inhibitors elicited a greater response in chemotherapy-naïve women
Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene more commonly associated with endometrioid endometrial cancers (26%–80%) than with Type II cancers.¹⁰ Loss of PTEN expression leads to deregulated signaling of the phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway. Disruption of this pathway is thought to provide cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell-cycle progression.¹⁰

Temsirolimus is an mTOR inhibitor recently explored by Oza and colleagues. They performed a multicenter, Phase II study involving 62 patients with recurrent and/or metastatic endometrial cancer as part of the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Patients were divided into two groups on the basis of their treatment history:

• chemotherapy-naïve women, with no more than one prior hormonal treatment (n = 33)
• chemotherapy-treated women (n = 27).

Temsirolimus was given weekly in 4-week cycles at an intravenous (IV) dose of 25 mg over 30 minutes.

The drug elicited a response regardless of the histologic type of cancer. That response was more pronounced in chemotherapy-naïve women and not limited to patients with PTEN loss. In the chemotherapy-naïve group, four women (14%) had a partial response, 20 (69%) had stable disease, and five (18%) had progressive disease. Median PFS was 7.33 months (95% confidence interval [CI], 3.61–9.86), compared with 3.25 months (95% CI, 1.97–3.84) in chemotherapy-treated women. Among chemotherapy-treated women, one (4%) had a partial response and 12 (48%) had stable disease.

An angiogenesis inhibitor alone was well tolerated
VEGF is the principal growth factor responsible for angiogenesis, initiating the process of neovascularization. Bevacizumab is a humanized monoclonal antibody that binds to circulating VEGF-A, stimulating clinical effects in multiple tumor types, including persistent or recurrent ovarian and cervical cancers.

Aghajanian and colleagues conducted a Phase II trial of single-agent bevacizumab in women with recurrent or persistent endometrial cancer to assess the drug’s activity and tolerability. Eligible patients had histologic confirmation by central pathology review, recurrent or persistent disease after one or two cytotoxic regimens, and a Gynecologic Oncology Group performance score of 2 or lower. They received IV bevacizumab 15 mg/kg every 3 weeks until the disease progressed or toxicity became prohibitive. Fifty-two women participated.

Seven women (13.5%) experienced a clinical response (one complete response and six partial responses), and 21 (40%) had PFS of at least 6 months. Median PFS and overall survival were 4.2 and 10.5 months, respectively.

Combined with temsirolimus, bevacizumab increased overall survival

Alvarez and colleagues conducted a Phase II trial of combination bevacizumab and temsirolimus in women with recurrent or persistent endometrial carcinoma. Forty-nine patients participated.

These women had undergone earlier treatment with one (82%) or two (18%) chemotherapy regimens and radiation (41%). Median PFS and overall survival were 5.6 and 16.9 months, respectively. Toxicity was significant, with 38.8% of women withdrawn from the study due to toxicity.  

What this evidence means for practice
Given the findings regarding temsirolimus and bevacizumab as single agents, their use in combination was expected to produce a robust effect. The 6-month PFS rate is similar for all three regimens, but for overall survival, combination therapy had a 6.4-month advantage over bevacizumab alone.

Given the significant toxicity associated with the combination of bevacizumab and temsirolimus, further study is needed to develop biomarkers to predict response and toxicity. Other areas meriting future research include optimal timing of angiogenesis and mTOR pathway inhibitors, different combinations of agents, and the identification, through genomic analysis, of patient populations most likely to benefit from these drugs with minimal toxicity.

The studies presented here show promise in the area of genomics and represent the beginning of our movement toward personalized cancer care.

We want to hear from you!  Tell us what you think.

Endometrial cancer is the most common malignancy of the female reproductive tract in the United States, and its incidence continues to rise, with an estimated 49,560 new cases predicted for 2013.¹ If we are to successfully traverse the pathway from molecular cell genetics to the development of targeted therapies and personalized cancer care, we need to meet a few benchmarks:

• We need to enhance our understanding of the molecular changes that lead to endometrial cancer. Of particular interest are nonendometrioid tumors. Increased mortality from endometrial cancer appears to be related to the growing number of uterine papillary serous carcinomas and clear-cell cancers. Although these cancers constitute less than 10% of all endometrial cancers, they account for a disproportionately high number of recurrences and cancer-related deaths.^2,3 Do recent studies validate the original classification of endometrial cancers as Type I (endometrioid) or Type II (serous and clear cell), or is there more heterogeneity than was originally thought? How do recent studies affect treatment options?
• We need to establish a genomic characterization of endometrial cancer to supplement clinical research data. The identification of novel mutations specific to each histologic type has the potential to improve adjuvant therapy. How close are we to performing a comprehensive genomic analysis of endometrial cancer?
• We need to develop new adjuvant treatment options for recurrent and advanced disease. When clinical symptoms of endometrial cancer are overt, as they often are, early diagnosis is possible, with a 5-year survival rate of 80% to 90%. The prognosis declines dramatically in women with advanced-stage disease or high-risk histologies, with a 5-year survival rate of 57% and 19% for Stage III and Stage IV disease, respectively.¹ Adjuvant treatment options are limited in the setting of recurrent or advanced disease. Do any biologic agents increase survival?

In this article, we highlight the historical foundation and newest advances in the field of endometrial cancer, focusing on:

• histologic classification
• etiologic heterogeneity and molecular biology
• genome-guided clinical trials involving targeted therapy, with the ultimate goal of achieving individualized cancer care.

Should we reclassify endometrial cancers to reflect molecular characteristics of tumors?

Brinton LA, Felix AS, McMeekin DS, et al. Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial. Gynecol Oncol. 2013;129(2):277–284.

Cancer Genome Atlas Research Network, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

Uterine papillary serous carcinoma (UPSC) was first established as a distinct subtype of endometrial cancer in the early 1980s, when teams led by Lauchlan4 and Hendrickson5 described it as histologically similar to serous epithelial ovarian carcinoma. Shortly thereafter, Bokhman proposed two broad categories of endometrial carcinoma characterized by distinct microscopic appearance, epidemiology, and endocrine and metabolic functioning (TABLE, page 28).6

More recently, research has focused on expanding this histologic classification system to encompass molecular differences. Brinton and colleagues conducted a study within Gynecologic Oncology Group 210, investigating the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologies. They found that risk factors for aggressive endometrial cancers, including Grade 3 endometrioid and nonendometrioid tumors, appear to differ from those of lower-grade endometrioid carcinomas.

Details of the study by Brinton and colleagues
A total of 3,434 women were included, representing endometrioid (78%) and serous (9%) carcinomas. Grade 3 endometrioid tumors resembled Type II endometrial cancers more closely than did Grade 1–2 endometrioid tumors. Patients with Grade 3 endometrioid and Type II cancers were diagnosed at a significantly older age than patients with Grades 1–2 endometrioid cancers (eg, diagnosis of serous cancers: median age, 67.4 years; Grade 3 endometrioid cancers: median age, 61.9 years; Grade 1–2 endometrioid cancers: median age, 59.6 years). They also were more likely to be nonwhite than patients with Grades 1–2 endometrioid histology. Specifically, black patients were rarely diagnosed with Grades 1–2 endometrioid cancers (5% vs 9% for Grade 3 endometrioid cancers; 20% for serous cancers, 23% for carcinosarcomas, and 12% for clear-cell cancers).

After adjustments for age, enrollment year, and race, patients with Type II tumors (serous, carcinosarcomas, or clear-cell tumors) were much more likely to be multiparous or smokers or to have a history of breast cancer treated with tamoxifen, compared with women with Grade 1–2 endometrioid cancers. An adequately powered subanalysis of serous carcinomas and Grades 1–2 endometrioid cancers revealed that associations persisted between serous carcinomas and multiparity, body mass index, and a history of breast cancer treated with tamoxifen.

Related article: The future of the Pap test: Identifying endometrial and ovarian cancers (Janelle Yates, August 2013)

Overall, this study provides some of the strongest epidemiologic support we have that endometrial cancers are heterogeneous, with evidence to suggest that we might classify Grade 3 endometrioid carcinomas as Type II cancers. These findings paved the way for molecular profiling of endometrial cancers.

Details of the study by the Cancer Genome Atlas Research Network
The Cancer Genome Atlas Research Network recently published an integrated genomic, transcriptomic, and proteomic ­characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. The goal was to provide better insight into disease biology and tumor classification to help guide clinical trials and drug development, with the ultimate goal of achieving personalized cancer care.

The group classified endometrial cancers into four new categories:

• polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
• microsatellite instability (MSI) hypermutated
• somatic copy number alterations (SCNA) low
• SCNA high.

Most endometrioid tumors had few SCNA or P53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS genes. Novel mutations also were discovered in the SWI/SNF chromatin remodeling complex gene ARID5B. About 10% of endometrioid tumors had markedly increased transversion mutations and newly identified mutations in POLE, a gene involved in nuclear DNA replication and repair.

As expected, serous tumors had significantly worse progression-free survival (PFS) than endometrioid tumors (P = .003, log-rank). A subset (25%) of high-grade endometrioid tumors had SCNAs and mutation spectra similar to those of uterine serous carcinomas, suggesting that patients with such tumors might benefit from treatment options that parallel those for serous tumors.

Other overlapping treatment paradigms existed between different organ systems. For example, some molecular features were similar in uterine serous carcinomas, basal-like breast carcinomas, and high-grade serous ovarian carcinomas. All three carcinomas displayed a high frequency of P53 mutations, very low frequency of PTEN mutations, similar focal SCNA patterns, and minimal DNA methylation changes. However, investigators also found several mutations that are unique to uterine serous carcinomas (eg, PIK3CA, FBXW7, PPP2R1A, and ARID1A), providing potential opportunities for targeted pharmacotherapy.

What this evidence means for practice
These studies highlight the etiologic heterogeneity of endometrial cancer. The histologic groundwork laid by Bokhman was not only correct but provided a foundation for molecular characterization of endometrial cancers to drive translational science into targeted therapeutics.

The similar molecular phenotypes of high-grade endometrioid carcinomas and serous endometrial carcinomas strengthens existing evidence that chemotherapy may be preferable to adjuvant radiotherapy for patients with highly mutated endometrioid cancers (eg, SCNA). Current chemotherapy regimens for serous endometrial cancers remain appropriate, given the compelling similarities between these cancers and serous ovarian and basal-like breast cancers. However, the identification of unique molecular features not shared by breast or ovarian cancer may expand standard options to include more targeted therapy.

Overall, this type of research, which encompasses proper histologic classification refined by genomics, has the potential to achieve personalized cancer care.

How we are achieving individualized cancer care: 3 genome-guided clinical trials

Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–3285.

Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259–2265.

Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–27.

Women with locally recurrent, advanced, or metastatic endometrial cancer have limited options for treatment. Hormonal therapies have modest effects at best, with a median survival rate of 7 to 12 months.^7–9 To address this lack of options, researchers have begun to focus on targeted therapies directed at molecular pathways of cellular proliferation. These therapies include but are not limited to inhibitors of:

• mammalian target of rapamycin (mTOR)
• human epidermal growth factor receptor 2
• epidermal growth factor receptor
• vascular endothelial growth factor (VEGF).

Several studies have produced promising findings in recent years. They involve ­investigations of temsirolimus and bevacizumab as single agents in two independent clinical trials, and a study of the drugs in combination in women with recurrent or persistent endometrial carcinoma.

mTOR inhibitors elicited a greater response in chemotherapy-naïve women
Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene more commonly associated with endometrioid endometrial cancers (26%–80%) than with Type II cancers.¹⁰ Loss of PTEN expression leads to deregulated signaling of the phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway. Disruption of this pathway is thought to provide cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell-cycle progression.¹⁰

Temsirolimus is an mTOR inhibitor recently explored by Oza and colleagues. They performed a multicenter, Phase II study involving 62 patients with recurrent and/or metastatic endometrial cancer as part of the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Patients were divided into two groups on the basis of their treatment history:

• chemotherapy-naïve women, with no more than one prior hormonal treatment (n = 33)
• chemotherapy-treated women (n = 27).

Temsirolimus was given weekly in 4-week cycles at an intravenous (IV) dose of 25 mg over 30 minutes.

The drug elicited a response regardless of the histologic type of cancer. That response was more pronounced in chemotherapy-naïve women and not limited to patients with PTEN loss. In the chemotherapy-naïve group, four women (14%) had a partial response, 20 (69%) had stable disease, and five (18%) had progressive disease. Median PFS was 7.33 months (95% confidence interval [CI], 3.61–9.86), compared with 3.25 months (95% CI, 1.97–3.84) in chemotherapy-treated women. Among chemotherapy-treated women, one (4%) had a partial response and 12 (48%) had stable disease.

An angiogenesis inhibitor alone was well tolerated
VEGF is the principal growth factor responsible for angiogenesis, initiating the process of neovascularization. Bevacizumab is a humanized monoclonal antibody that binds to circulating VEGF-A, stimulating clinical effects in multiple tumor types, including persistent or recurrent ovarian and cervical cancers.

Aghajanian and colleagues conducted a Phase II trial of single-agent bevacizumab in women with recurrent or persistent endometrial cancer to assess the drug’s activity and tolerability. Eligible patients had histologic confirmation by central pathology review, recurrent or persistent disease after one or two cytotoxic regimens, and a Gynecologic Oncology Group performance score of 2 or lower. They received IV bevacizumab 15 mg/kg every 3 weeks until the disease progressed or toxicity became prohibitive. Fifty-two women participated.

Seven women (13.5%) experienced a clinical response (one complete response and six partial responses), and 21 (40%) had PFS of at least 6 months. Median PFS and overall survival were 4.2 and 10.5 months, respectively.

Combined with temsirolimus, bevacizumab increased overall survival

Alvarez and colleagues conducted a Phase II trial of combination bevacizumab and temsirolimus in women with recurrent or persistent endometrial carcinoma. Forty-nine patients participated.

These women had undergone earlier treatment with one (82%) or two (18%) chemotherapy regimens and radiation (41%). Median PFS and overall survival were 5.6 and 16.9 months, respectively. Toxicity was significant, with 38.8% of women withdrawn from the study due to toxicity.  

What this evidence means for practice
Given the findings regarding temsirolimus and bevacizumab as single agents, their use in combination was expected to produce a robust effect. The 6-month PFS rate is similar for all three regimens, but for overall survival, combination therapy had a 6.4-month advantage over bevacizumab alone.

Given the significant toxicity associated with the combination of bevacizumab and temsirolimus, further study is needed to develop biomarkers to predict response and toxicity. Other areas meriting future research include optimal timing of angiogenesis and mTOR pathway inhibitors, different combinations of agents, and the identification, through genomic analysis, of patient populations most likely to benefit from these drugs with minimal toxicity.

The studies presented here show promise in the area of genomics and represent the beginning of our movement toward personalized cancer care.

We want to hear from you!  Tell us what you think.

Endometrial cancer is the most common malignancy of the female reproductive tract in the United States, and its incidence continues to rise, with an estimated 49,560 new cases predicted for 2013.¹ If we are to successfully traverse the pathway from molecular cell genetics to the development of targeted therapies and personalized cancer care, we need to meet a few benchmarks:

• We need to enhance our understanding of the molecular changes that lead to endometrial cancer. Of particular interest are nonendometrioid tumors. Increased mortality from endometrial cancer appears to be related to the growing number of uterine papillary serous carcinomas and clear-cell cancers. Although these cancers constitute less than 10% of all endometrial cancers, they account for a disproportionately high number of recurrences and cancer-related deaths.^2,3 Do recent studies validate the original classification of endometrial cancers as Type I (endometrioid) or Type II (serous and clear cell), or is there more heterogeneity than was originally thought? How do recent studies affect treatment options?
• We need to establish a genomic characterization of endometrial cancer to supplement clinical research data. The identification of novel mutations specific to each histologic type has the potential to improve adjuvant therapy. How close are we to performing a comprehensive genomic analysis of endometrial cancer?
• We need to develop new adjuvant treatment options for recurrent and advanced disease. When clinical symptoms of endometrial cancer are overt, as they often are, early diagnosis is possible, with a 5-year survival rate of 80% to 90%. The prognosis declines dramatically in women with advanced-stage disease or high-risk histologies, with a 5-year survival rate of 57% and 19% for Stage III and Stage IV disease, respectively.¹ Adjuvant treatment options are limited in the setting of recurrent or advanced disease. Do any biologic agents increase survival?

In this article, we highlight the historical foundation and newest advances in the field of endometrial cancer, focusing on:

• histologic classification
• etiologic heterogeneity and molecular biology
• genome-guided clinical trials involving targeted therapy, with the ultimate goal of achieving individualized cancer care.

Should we reclassify endometrial cancers to reflect molecular characteristics of tumors?

Brinton LA, Felix AS, McMeekin DS, et al. Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial. Gynecol Oncol. 2013;129(2):277–284.

Cancer Genome Atlas Research Network, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

Uterine papillary serous carcinoma (UPSC) was first established as a distinct subtype of endometrial cancer in the early 1980s, when teams led by Lauchlan4 and Hendrickson5 described it as histologically similar to serous epithelial ovarian carcinoma. Shortly thereafter, Bokhman proposed two broad categories of endometrial carcinoma characterized by distinct microscopic appearance, epidemiology, and endocrine and metabolic functioning (TABLE, page 28).6

More recently, research has focused on expanding this histologic classification system to encompass molecular differences. Brinton and colleagues conducted a study within Gynecologic Oncology Group 210, investigating the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologies. They found that risk factors for aggressive endometrial cancers, including Grade 3 endometrioid and nonendometrioid tumors, appear to differ from those of lower-grade endometrioid carcinomas.

Details of the study by Brinton and colleagues
A total of 3,434 women were included, representing endometrioid (78%) and serous (9%) carcinomas. Grade 3 endometrioid tumors resembled Type II endometrial cancers more closely than did Grade 1–2 endometrioid tumors. Patients with Grade 3 endometrioid and Type II cancers were diagnosed at a significantly older age than patients with Grades 1–2 endometrioid cancers (eg, diagnosis of serous cancers: median age, 67.4 years; Grade 3 endometrioid cancers: median age, 61.9 years; Grade 1–2 endometrioid cancers: median age, 59.6 years). They also were more likely to be nonwhite than patients with Grades 1–2 endometrioid histology. Specifically, black patients were rarely diagnosed with Grades 1–2 endometrioid cancers (5% vs 9% for Grade 3 endometrioid cancers; 20% for serous cancers, 23% for carcinosarcomas, and 12% for clear-cell cancers).

After adjustments for age, enrollment year, and race, patients with Type II tumors (serous, carcinosarcomas, or clear-cell tumors) were much more likely to be multiparous or smokers or to have a history of breast cancer treated with tamoxifen, compared with women with Grade 1–2 endometrioid cancers. An adequately powered subanalysis of serous carcinomas and Grades 1–2 endometrioid cancers revealed that associations persisted between serous carcinomas and multiparity, body mass index, and a history of breast cancer treated with tamoxifen.

Related article: The future of the Pap test: Identifying endometrial and ovarian cancers (Janelle Yates, August 2013)

Overall, this study provides some of the strongest epidemiologic support we have that endometrial cancers are heterogeneous, with evidence to suggest that we might classify Grade 3 endometrioid carcinomas as Type II cancers. These findings paved the way for molecular profiling of endometrial cancers.

Details of the study by the Cancer Genome Atlas Research Network
The Cancer Genome Atlas Research Network recently published an integrated genomic, transcriptomic, and proteomic ­characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. The goal was to provide better insight into disease biology and tumor classification to help guide clinical trials and drug development, with the ultimate goal of achieving personalized cancer care.

The group classified endometrial cancers into four new categories:

• polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
• microsatellite instability (MSI) hypermutated
• somatic copy number alterations (SCNA) low
• SCNA high.

Most endometrioid tumors had few SCNA or P53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS genes. Novel mutations also were discovered in the SWI/SNF chromatin remodeling complex gene ARID5B. About 10% of endometrioid tumors had markedly increased transversion mutations and newly identified mutations in POLE, a gene involved in nuclear DNA replication and repair.

As expected, serous tumors had significantly worse progression-free survival (PFS) than endometrioid tumors (P = .003, log-rank). A subset (25%) of high-grade endometrioid tumors had SCNAs and mutation spectra similar to those of uterine serous carcinomas, suggesting that patients with such tumors might benefit from treatment options that parallel those for serous tumors.

Other overlapping treatment paradigms existed between different organ systems. For example, some molecular features were similar in uterine serous carcinomas, basal-like breast carcinomas, and high-grade serous ovarian carcinomas. All three carcinomas displayed a high frequency of P53 mutations, very low frequency of PTEN mutations, similar focal SCNA patterns, and minimal DNA methylation changes. However, investigators also found several mutations that are unique to uterine serous carcinomas (eg, PIK3CA, FBXW7, PPP2R1A, and ARID1A), providing potential opportunities for targeted pharmacotherapy.

What this evidence means for practice
These studies highlight the etiologic heterogeneity of endometrial cancer. The histologic groundwork laid by Bokhman was not only correct but provided a foundation for molecular characterization of endometrial cancers to drive translational science into targeted therapeutics.

The similar molecular phenotypes of high-grade endometrioid carcinomas and serous endometrial carcinomas strengthens existing evidence that chemotherapy may be preferable to adjuvant radiotherapy for patients with highly mutated endometrioid cancers (eg, SCNA). Current chemotherapy regimens for serous endometrial cancers remain appropriate, given the compelling similarities between these cancers and serous ovarian and basal-like breast cancers. However, the identification of unique molecular features not shared by breast or ovarian cancer may expand standard options to include more targeted therapy.

Overall, this type of research, which encompasses proper histologic classification refined by genomics, has the potential to achieve personalized cancer care.

How we are achieving individualized cancer care: 3 genome-guided clinical trials

Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–3285.

Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259–2265.

Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–27.

Women with locally recurrent, advanced, or metastatic endometrial cancer have limited options for treatment. Hormonal therapies have modest effects at best, with a median survival rate of 7 to 12 months.^7–9 To address this lack of options, researchers have begun to focus on targeted therapies directed at molecular pathways of cellular proliferation. These therapies include but are not limited to inhibitors of:

• mammalian target of rapamycin (mTOR)
• human epidermal growth factor receptor 2
• epidermal growth factor receptor
• vascular endothelial growth factor (VEGF).

Several studies have produced promising findings in recent years. They involve ­investigations of temsirolimus and bevacizumab as single agents in two independent clinical trials, and a study of the drugs in combination in women with recurrent or persistent endometrial carcinoma.

mTOR inhibitors elicited a greater response in chemotherapy-naïve women
Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene more commonly associated with endometrioid endometrial cancers (26%–80%) than with Type II cancers.¹⁰ Loss of PTEN expression leads to deregulated signaling of the phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway. Disruption of this pathway is thought to provide cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell-cycle progression.¹⁰

Temsirolimus is an mTOR inhibitor recently explored by Oza and colleagues. They performed a multicenter, Phase II study involving 62 patients with recurrent and/or metastatic endometrial cancer as part of the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Patients were divided into two groups on the basis of their treatment history:

• chemotherapy-naïve women, with no more than one prior hormonal treatment (n = 33)
• chemotherapy-treated women (n = 27).

Temsirolimus was given weekly in 4-week cycles at an intravenous (IV) dose of 25 mg over 30 minutes.

The drug elicited a response regardless of the histologic type of cancer. That response was more pronounced in chemotherapy-naïve women and not limited to patients with PTEN loss. In the chemotherapy-naïve group, four women (14%) had a partial response, 20 (69%) had stable disease, and five (18%) had progressive disease. Median PFS was 7.33 months (95% confidence interval [CI], 3.61–9.86), compared with 3.25 months (95% CI, 1.97–3.84) in chemotherapy-treated women. Among chemotherapy-treated women, one (4%) had a partial response and 12 (48%) had stable disease.

An angiogenesis inhibitor alone was well tolerated
VEGF is the principal growth factor responsible for angiogenesis, initiating the process of neovascularization. Bevacizumab is a humanized monoclonal antibody that binds to circulating VEGF-A, stimulating clinical effects in multiple tumor types, including persistent or recurrent ovarian and cervical cancers.

Aghajanian and colleagues conducted a Phase II trial of single-agent bevacizumab in women with recurrent or persistent endometrial cancer to assess the drug’s activity and tolerability. Eligible patients had histologic confirmation by central pathology review, recurrent or persistent disease after one or two cytotoxic regimens, and a Gynecologic Oncology Group performance score of 2 or lower. They received IV bevacizumab 15 mg/kg every 3 weeks until the disease progressed or toxicity became prohibitive. Fifty-two women participated.

Seven women (13.5%) experienced a clinical response (one complete response and six partial responses), and 21 (40%) had PFS of at least 6 months. Median PFS and overall survival were 4.2 and 10.5 months, respectively.

Combined with temsirolimus, bevacizumab increased overall survival

Alvarez and colleagues conducted a Phase II trial of combination bevacizumab and temsirolimus in women with recurrent or persistent endometrial carcinoma. Forty-nine patients participated.

These women had undergone earlier treatment with one (82%) or two (18%) chemotherapy regimens and radiation (41%). Median PFS and overall survival were 5.6 and 16.9 months, respectively. Toxicity was significant, with 38.8% of women withdrawn from the study due to toxicity.  

What this evidence means for practice
Given the findings regarding temsirolimus and bevacizumab as single agents, their use in combination was expected to produce a robust effect. The 6-month PFS rate is similar for all three regimens, but for overall survival, combination therapy had a 6.4-month advantage over bevacizumab alone.

Given the significant toxicity associated with the combination of bevacizumab and temsirolimus, further study is needed to develop biomarkers to predict response and toxicity. Other areas meriting future research include optimal timing of angiogenesis and mTOR pathway inhibitors, different combinations of agents, and the identification, through genomic analysis, of patient populations most likely to benefit from these drugs with minimal toxicity.

The studies presented here show promise in the area of genomics and represent the beginning of our movement toward personalized cancer care.

We want to hear from you!  Tell us what you think.

A majority of ovarian cancers are diagnosed at an advanced stage, requiring extensive surgical cytoreductive procedures.¹ Because the presence of residual macroscopic disease correlates highly with decreased survival,² these procedures can be lengthy, complicated, and risky for the patient. Many patients who undergo cytoreduction will be left with a suboptimal result despite surgery.

Better identification and improved treatment of patients who are at high risk of a suboptimal result are clearly needed. One treatment option is neoadjuvant chemotherapy, the administration of chemotherapy prior to the main treatment. Although early data suggested that it was associated with worse outcomes, recent studies have yielded new information:

• Neoadjuvant chemotherapy followed by interval debulking surgery is not inferior to primary debulking surgery followed by chemotherapy for patients who have bulky stage III or IV ovarian cancer
• In patients who have advanced ovarian cancer, neoadjuvant chemotherapy followed by surgical cytoreduction is associated with improved perioperative outcomes
• Postoperative intraperitoneal chemotherapy after neoadjuvant chemotherapy has not yet proved to be associated with improved survival.

Several questions prompted by these findings include:

• Will neoadjuvant chemotherapy improve surgical outcomes in patients who have advanced ovarian cancer and, thus, improve survival?
• Is neoadjuvant chemotherapy a better strategy for all patients?
• Will neoadjuvant chemotherapy reduce the surgical effort necessary to achieve an optimal result?
• What is the role of intraperitoneal chemotherapy in patients who undergo neoadjuvant chemotherapy?

Further national (or international) data are needed to confirm a survival advantage for patients who receive neoadjuvant chemotherapy, compared with those who undergo primary surgery before the administration of chemotherapy.

Neoadjuvant chemotherapy is an acceptable alternative to primary surgical cytoreduction

Vergote I, Tropé CG, Amant F, et al; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–953.

Historically, the standard of care in ovarian cancer treatment has been surgical cytoreduction followed by chemotherapy.^3-6 However, data from prospective randomized trials to support this practice are limited. Neoadjuvant chemotherapy is an alternative strategy that has been explored as a way to improve outcomes from interval surgical debulking in patients who have ovarian cancer in whom suboptimal cytoreduction is otherwise expected. Vergote and coworkers attempted to determine which strategy is better through a randomized trial of 632 patients.

Participants had to have biopsy-proven stage IIIc or IV ovarian, fallopian tube, or primary peritoneal cancer. The two treatment arms were:

• primary debulking surgery followed by at least 6 cycles of platinum-based chemotherapy
• 3 cycles of platinum-based neoadjuvant chemotherapy followed by interval debulking surgery in responders and those who had stable disease. These patients then received an additional 3 cycles of platinum-based chemotherapy post-operatively.

All surgical procedures were completed by qualified gynecologic oncologists, and all patients were evaluated for eligibility before randomization, with no additional selection criteria.

Postoperative death occurred in 2.5% of patients in the primary-surgery group, compared with 0.7% of patients in the neoadjuvant-chemotherapy group. Grade 3 or 4 hemorrhage occurred in 7.4% of patients after primary debulking, compared with 4.1% of patients after interval debulking. Patients who received neoadjuvant chemotherapy experienced a lower rate of infection (1.7% versus 8.1%) and venous complications (0% versus 2.6%).

Overall and progression-free survival rates were similar between the two groups. After multivariate analysis, the strongest predictors of survival were absence of residual disease after surgery (P<.001), small tumor size before randomization (P=.001), and endometrioid histology (P=.001)

Neoadjuvant chemotherapy improves perioperative outcomes

Milam MR, Tao X, Coleman RL, et al. Neoadjuvant chemotherapy is associated with prolonged primary treatment intervals in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2011;21(1):66–71.

Milam and coworkers investigated chemotherapy-associated morbidity and timing in two groups of patients who had advanced epithelial ovarian cancer:

• those undergoing neoadjuvant chemotherapy followed by maximal cytoreductive surgery
• those undergoing primary surgery followed by chemotherapy.

Their retrospective study involved 263 consecutive patients who were treated at MD Anderson Cancer Center from 1993 to 2005. In this cohort, 47 women (18%) received neoadjuvant chemotherapy. These patients experienced less blood loss (400 mL versus 750 mL) and a shorter hospital stay (6 versus 8 days). Time to the initiation of chemotherapy from the date of diagnosis did not differ between groups, and the amount of residual disease and rate of survival were also similar between arms. However, patients who received neoadjuvant chemotherapy underwent more cycles of chemotherapy over a longer treatment period.

In the pipeline: Data on intraperitoneal chemotherapy after neoadjuvant chemotherapy

Le T, Latifah H, Jolicoeur L, et al. Does intraperitoneal chemotherapy benefit optimally debulked epithelial ovarian cancer patients after neoadjuvant chemotherapy? Gynecol Oncol. 2011;121(3):451–454.

Although several studies have demonstrated that intraperitoneal (IP) chemotherapy provides a survival advantage, compared with intravenous (IV) chemotherapy, after primary surgical debulking, it remains unclear whether IP chemotherapy would provide a similar superior survival outcome following neoadjuvant chemotherapy (FIGURE).

Intraperitoneal chemotherapy: How efficacious?
The jury is still out on whether intraperitoneal chemotherapy improves survival after neoadjuvant chemotherapy and interval debulking in stages III and IV ovarian cancer.The authors of this paper attempted to answer this question through a retrospective review of 71 patients. All patients were treated with neoadjuvant chemotherapy followed by interval debulking and either IP or IV chemotherapy. Overall, 17 patients (24%) received IP chemotherapy, and 54 patients (76%) received IV chemotherapy. The median number of cycles given prior to and after surgery was the same for both groups (3 for both neoadjuvant chemotherapy and chemotherapy following surgery).

Although patients who received IP chemotherapy had a higher overall response rate (82% versus 67%), there were no differences between groups in terms of progression-free (P=.42) and overall survival (P=.72).

One important limitation of this study was its small sample size and lack of statistical power. In addition, more patients in the IP group had macroscopic residual disease than in the IV group (71% versus 52%; P=.17).

A phase II/III study is under way to evaluate the use of IP chemotherapy following neoadjuvant chemotherapy in ovarian cancer patients.⁷ The two-stage randomized trial will compare IV chemotherapy with platinum-based IP chemotherapy in women who have undergone optimal surgical debulking (>1 cm) after 3 to 4 cycles of platinum-based neoadjuvant chemotherapy. This study is led by the US National Cancer Institute in collaboration with the Society of Gynecologic Oncologists of Canada, the UK National Cancer Research Institute, the Spanish Ovarian Cancer Research Group, and the US Southwest Oncology Group.

We want to hear from you! Tell us what you think.

A majority of ovarian cancers are diagnosed at an advanced stage, requiring extensive surgical cytoreductive procedures.¹ Because the presence of residual macroscopic disease correlates highly with decreased survival,² these procedures can be lengthy, complicated, and risky for the patient. Many patients who undergo cytoreduction will be left with a suboptimal result despite surgery.

Better identification and improved treatment of patients who are at high risk of a suboptimal result are clearly needed. One treatment option is neoadjuvant chemotherapy, the administration of chemotherapy prior to the main treatment. Although early data suggested that it was associated with worse outcomes, recent studies have yielded new information:

• Neoadjuvant chemotherapy followed by interval debulking surgery is not inferior to primary debulking surgery followed by chemotherapy for patients who have bulky stage III or IV ovarian cancer
• In patients who have advanced ovarian cancer, neoadjuvant chemotherapy followed by surgical cytoreduction is associated with improved perioperative outcomes
• Postoperative intraperitoneal chemotherapy after neoadjuvant chemotherapy has not yet proved to be associated with improved survival.

Several questions prompted by these findings include:

• Will neoadjuvant chemotherapy improve surgical outcomes in patients who have advanced ovarian cancer and, thus, improve survival?
• Is neoadjuvant chemotherapy a better strategy for all patients?
• Will neoadjuvant chemotherapy reduce the surgical effort necessary to achieve an optimal result?
• What is the role of intraperitoneal chemotherapy in patients who undergo neoadjuvant chemotherapy?

Further national (or international) data are needed to confirm a survival advantage for patients who receive neoadjuvant chemotherapy, compared with those who undergo primary surgery before the administration of chemotherapy.

Neoadjuvant chemotherapy is an acceptable alternative to primary surgical cytoreduction

Vergote I, Tropé CG, Amant F, et al; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–953.

Historically, the standard of care in ovarian cancer treatment has been surgical cytoreduction followed by chemotherapy.^3-6 However, data from prospective randomized trials to support this practice are limited. Neoadjuvant chemotherapy is an alternative strategy that has been explored as a way to improve outcomes from interval surgical debulking in patients who have ovarian cancer in whom suboptimal cytoreduction is otherwise expected. Vergote and coworkers attempted to determine which strategy is better through a randomized trial of 632 patients.

Participants had to have biopsy-proven stage IIIc or IV ovarian, fallopian tube, or primary peritoneal cancer. The two treatment arms were:

• primary debulking surgery followed by at least 6 cycles of platinum-based chemotherapy
• 3 cycles of platinum-based neoadjuvant chemotherapy followed by interval debulking surgery in responders and those who had stable disease. These patients then received an additional 3 cycles of platinum-based chemotherapy post-operatively.

All surgical procedures were completed by qualified gynecologic oncologists, and all patients were evaluated for eligibility before randomization, with no additional selection criteria.

Postoperative death occurred in 2.5% of patients in the primary-surgery group, compared with 0.7% of patients in the neoadjuvant-chemotherapy group. Grade 3 or 4 hemorrhage occurred in 7.4% of patients after primary debulking, compared with 4.1% of patients after interval debulking. Patients who received neoadjuvant chemotherapy experienced a lower rate of infection (1.7% versus 8.1%) and venous complications (0% versus 2.6%).

Overall and progression-free survival rates were similar between the two groups. After multivariate analysis, the strongest predictors of survival were absence of residual disease after surgery (P<.001), small tumor size before randomization (P=.001), and endometrioid histology (P=.001)

Neoadjuvant chemotherapy improves perioperative outcomes

Milam MR, Tao X, Coleman RL, et al. Neoadjuvant chemotherapy is associated with prolonged primary treatment intervals in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2011;21(1):66–71.

Milam and coworkers investigated chemotherapy-associated morbidity and timing in two groups of patients who had advanced epithelial ovarian cancer:

• those undergoing neoadjuvant chemotherapy followed by maximal cytoreductive surgery
• those undergoing primary surgery followed by chemotherapy.

Their retrospective study involved 263 consecutive patients who were treated at MD Anderson Cancer Center from 1993 to 2005. In this cohort, 47 women (18%) received neoadjuvant chemotherapy. These patients experienced less blood loss (400 mL versus 750 mL) and a shorter hospital stay (6 versus 8 days). Time to the initiation of chemotherapy from the date of diagnosis did not differ between groups, and the amount of residual disease and rate of survival were also similar between arms. However, patients who received neoadjuvant chemotherapy underwent more cycles of chemotherapy over a longer treatment period.

In the pipeline: Data on intraperitoneal chemotherapy after neoadjuvant chemotherapy

Le T, Latifah H, Jolicoeur L, et al. Does intraperitoneal chemotherapy benefit optimally debulked epithelial ovarian cancer patients after neoadjuvant chemotherapy? Gynecol Oncol. 2011;121(3):451–454.

Although several studies have demonstrated that intraperitoneal (IP) chemotherapy provides a survival advantage, compared with intravenous (IV) chemotherapy, after primary surgical debulking, it remains unclear whether IP chemotherapy would provide a similar superior survival outcome following neoadjuvant chemotherapy (FIGURE).

Intraperitoneal chemotherapy: How efficacious?
The jury is still out on whether intraperitoneal chemotherapy improves survival after neoadjuvant chemotherapy and interval debulking in stages III and IV ovarian cancer.The authors of this paper attempted to answer this question through a retrospective review of 71 patients. All patients were treated with neoadjuvant chemotherapy followed by interval debulking and either IP or IV chemotherapy. Overall, 17 patients (24%) received IP chemotherapy, and 54 patients (76%) received IV chemotherapy. The median number of cycles given prior to and after surgery was the same for both groups (3 for both neoadjuvant chemotherapy and chemotherapy following surgery).

Although patients who received IP chemotherapy had a higher overall response rate (82% versus 67%), there were no differences between groups in terms of progression-free (P=.42) and overall survival (P=.72).

One important limitation of this study was its small sample size and lack of statistical power. In addition, more patients in the IP group had macroscopic residual disease than in the IV group (71% versus 52%; P=.17).

A phase II/III study is under way to evaluate the use of IP chemotherapy following neoadjuvant chemotherapy in ovarian cancer patients.⁷ The two-stage randomized trial will compare IV chemotherapy with platinum-based IP chemotherapy in women who have undergone optimal surgical debulking (>1 cm) after 3 to 4 cycles of platinum-based neoadjuvant chemotherapy. This study is led by the US National Cancer Institute in collaboration with the Society of Gynecologic Oncologists of Canada, the UK National Cancer Research Institute, the Spanish Ovarian Cancer Research Group, and the US Southwest Oncology Group.

We want to hear from you! Tell us what you think.

A majority of ovarian cancers are diagnosed at an advanced stage, requiring extensive surgical cytoreductive procedures.¹ Because the presence of residual macroscopic disease correlates highly with decreased survival,² these procedures can be lengthy, complicated, and risky for the patient. Many patients who undergo cytoreduction will be left with a suboptimal result despite surgery.

Better identification and improved treatment of patients who are at high risk of a suboptimal result are clearly needed. One treatment option is neoadjuvant chemotherapy, the administration of chemotherapy prior to the main treatment. Although early data suggested that it was associated with worse outcomes, recent studies have yielded new information:

• Neoadjuvant chemotherapy followed by interval debulking surgery is not inferior to primary debulking surgery followed by chemotherapy for patients who have bulky stage III or IV ovarian cancer
• In patients who have advanced ovarian cancer, neoadjuvant chemotherapy followed by surgical cytoreduction is associated with improved perioperative outcomes
• Postoperative intraperitoneal chemotherapy after neoadjuvant chemotherapy has not yet proved to be associated with improved survival.

Several questions prompted by these findings include:

• Will neoadjuvant chemotherapy improve surgical outcomes in patients who have advanced ovarian cancer and, thus, improve survival?
• Is neoadjuvant chemotherapy a better strategy for all patients?
• Will neoadjuvant chemotherapy reduce the surgical effort necessary to achieve an optimal result?
• What is the role of intraperitoneal chemotherapy in patients who undergo neoadjuvant chemotherapy?

Further national (or international) data are needed to confirm a survival advantage for patients who receive neoadjuvant chemotherapy, compared with those who undergo primary surgery before the administration of chemotherapy.

Neoadjuvant chemotherapy is an acceptable alternative to primary surgical cytoreduction

Vergote I, Tropé CG, Amant F, et al; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–953.

Historically, the standard of care in ovarian cancer treatment has been surgical cytoreduction followed by chemotherapy.^3-6 However, data from prospective randomized trials to support this practice are limited. Neoadjuvant chemotherapy is an alternative strategy that has been explored as a way to improve outcomes from interval surgical debulking in patients who have ovarian cancer in whom suboptimal cytoreduction is otherwise expected. Vergote and coworkers attempted to determine which strategy is better through a randomized trial of 632 patients.

Participants had to have biopsy-proven stage IIIc or IV ovarian, fallopian tube, or primary peritoneal cancer. The two treatment arms were:

• primary debulking surgery followed by at least 6 cycles of platinum-based chemotherapy
• 3 cycles of platinum-based neoadjuvant chemotherapy followed by interval debulking surgery in responders and those who had stable disease. These patients then received an additional 3 cycles of platinum-based chemotherapy post-operatively.

All surgical procedures were completed by qualified gynecologic oncologists, and all patients were evaluated for eligibility before randomization, with no additional selection criteria.

Postoperative death occurred in 2.5% of patients in the primary-surgery group, compared with 0.7% of patients in the neoadjuvant-chemotherapy group. Grade 3 or 4 hemorrhage occurred in 7.4% of patients after primary debulking, compared with 4.1% of patients after interval debulking. Patients who received neoadjuvant chemotherapy experienced a lower rate of infection (1.7% versus 8.1%) and venous complications (0% versus 2.6%).

Overall and progression-free survival rates were similar between the two groups. After multivariate analysis, the strongest predictors of survival were absence of residual disease after surgery (P<.001), small tumor size before randomization (P=.001), and endometrioid histology (P=.001)

Neoadjuvant chemotherapy improves perioperative outcomes

Milam MR, Tao X, Coleman RL, et al. Neoadjuvant chemotherapy is associated with prolonged primary treatment intervals in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2011;21(1):66–71.

Milam and coworkers investigated chemotherapy-associated morbidity and timing in two groups of patients who had advanced epithelial ovarian cancer:

• those undergoing neoadjuvant chemotherapy followed by maximal cytoreductive surgery
• those undergoing primary surgery followed by chemotherapy.

Their retrospective study involved 263 consecutive patients who were treated at MD Anderson Cancer Center from 1993 to 2005. In this cohort, 47 women (18%) received neoadjuvant chemotherapy. These patients experienced less blood loss (400 mL versus 750 mL) and a shorter hospital stay (6 versus 8 days). Time to the initiation of chemotherapy from the date of diagnosis did not differ between groups, and the amount of residual disease and rate of survival were also similar between arms. However, patients who received neoadjuvant chemotherapy underwent more cycles of chemotherapy over a longer treatment period.

In the pipeline: Data on intraperitoneal chemotherapy after neoadjuvant chemotherapy

Le T, Latifah H, Jolicoeur L, et al. Does intraperitoneal chemotherapy benefit optimally debulked epithelial ovarian cancer patients after neoadjuvant chemotherapy? Gynecol Oncol. 2011;121(3):451–454.

Although several studies have demonstrated that intraperitoneal (IP) chemotherapy provides a survival advantage, compared with intravenous (IV) chemotherapy, after primary surgical debulking, it remains unclear whether IP chemotherapy would provide a similar superior survival outcome following neoadjuvant chemotherapy (FIGURE).

Intraperitoneal chemotherapy: How efficacious?
The jury is still out on whether intraperitoneal chemotherapy improves survival after neoadjuvant chemotherapy and interval debulking in stages III and IV ovarian cancer.The authors of this paper attempted to answer this question through a retrospective review of 71 patients. All patients were treated with neoadjuvant chemotherapy followed by interval debulking and either IP or IV chemotherapy. Overall, 17 patients (24%) received IP chemotherapy, and 54 patients (76%) received IV chemotherapy. The median number of cycles given prior to and after surgery was the same for both groups (3 for both neoadjuvant chemotherapy and chemotherapy following surgery).

Although patients who received IP chemotherapy had a higher overall response rate (82% versus 67%), there were no differences between groups in terms of progression-free (P=.42) and overall survival (P=.72).

One important limitation of this study was its small sample size and lack of statistical power. In addition, more patients in the IP group had macroscopic residual disease than in the IV group (71% versus 52%; P=.17).

A phase II/III study is under way to evaluate the use of IP chemotherapy following neoadjuvant chemotherapy in ovarian cancer patients.⁷ The two-stage randomized trial will compare IV chemotherapy with platinum-based IP chemotherapy in women who have undergone optimal surgical debulking (>1 cm) after 3 to 4 cycles of platinum-based neoadjuvant chemotherapy. This study is led by the US National Cancer Institute in collaboration with the Society of Gynecologic Oncologists of Canada, the UK National Cancer Research Institute, the Spanish Ovarian Cancer Research Group, and the US Southwest Oncology Group.

We want to hear from you! Tell us what you think.

Because ovarian cancer is usually diagnosed at an advanced stage—when prognosis is much worse than earlier in its course—a great deal of effort has been directed toward developing strategies to detect it early. These strategies include screening by a woman’s primary gynecologist with 1) a test of the serum CA-125 level and 2) transvaginal ultrasonography (TVU).

But how useful are the results of those screening tests? How should they be interpreted?

The answers aren’t clear.

Recent studies have yielded new information about ovarian cancer screening and detection. We discuss them in this Update:

• Screening with serial testing of the CA-125 level and TVU still is not recommended by the US Preventive Services Task Force or by ACOG
• Initial preliminary data from a prevalence screen of more than 50,000 subjects in the United Kingdom are encouraging, and show that new screening strategies may be feasible
• Using a patient’s report of her symptoms to trigger medical evaluation for ovarian cancer is not an effective screening tool
• Women who have an adnexal mass and a serum CA-125 level >35 U/mL and abnormal sonographic findings have an increased likelihood of ovarian cancer. They should be referred directly to a specialist.

The effect of screening on ovarian cancer mortality remains unknown

Partridge E, Greenlee RT, Xu J-L, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol. 2009;113(4):775–782.

The potential benefit of an effective screening program for ovarian cancer is great; the disease is the most lethal of all common gynecologic malignancies and carries significant individual and societal costs.¹ Furthermore, diagnosis at an early stage is associated with improved survival.

To date, however, studies have not shed light on whether screening with CA-125 testing or TVU has an impact on morbidity or mortality from ovarian cancer. In a large, multicenter trial of more than 30,000 women, Partridge and colleagues attempted to answer this question.

Investigators sought to determine whether this cohort of healthy women, ranging in age from 55 to 74 years, experienced a reduction in mortality from ovarian cancer when subjects were screened annually with a combination of CA-125 testing and TVU. The study was part of a larger trial (the Prostate, Lung, Colorectal and Ovarian [PLCO] Cancer Screening Trial²).

Subjects were randomized 1:1 to 1) the screening arm or 2) their customary gynecologic care without screening. The regimen in the screening arm comprised:

• annual measurement of the CA-125 in Years 1 through 6
• annual TVU in Years 1 through 4
• evaluation and follow-up of positive screening tests at the discretion of each subject’s treating physician.

Distribution of staging was unaffected. Overall, the positive predictive value of the screening regimen was relatively constant—and quite low—across the screening years (1.1% in Year 1 [95% confidence interval (CI), 0.6–1.6]; 1.0% in Year 2 [95% CI, 0.4–1.5]; 1.1% in Year 3 [95% CI, 0.5–1.7]; and 1.3% in Year 4 [95% CI, 0.6–2.0]).

Of 3,388 women who had at least one positive result on either screening test, 1,170 (34.5%) underwent biopsy at some point. Of those, 60 (5.1%) had invasive cancer—yielding a surgery-to-detected-cancer ratio of 19.5:1.

Approximately 70% of cancers detected by screening were a Stage-III or -IV tumor. As such, the screening effort did not change the expected distribution of staging from what would be expected in an unscreened population.

Is it feasible to screen for ovarian cancer on a large scale?

Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009;10(4):327–340.

The low prevalence of ovarian cancer presents a significant challenge to anyone hoping to devise a useful screening program: A screening test designed to detect a low-prevalence disease must have exceptionally high sensitivity and specificity to achieve a clinically useful positive predictive value—especially when the intervention is relatively risky (surgical removal of the ovaries) and has known harmful health implications.

With that requirement in mind, researchers have refined ovarian cancer screening methods. One of these refinements is a risk-of-ovarian-cancer algorithm by which clinicians would be able to interpret serial CA-125 results.^3,4

Interim results from a prevalence screen. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) evaluated these new screening methods in a multicenter, randomized, controlled trial in an effort that assessed not only mortality but also cost, acceptance by patients, and the physical and psychosocial morbidities associated with screening. At this point, investigators are reporting the results of a prevalence screen.

The team evaluated more than 200,000 low-risk women who were randomized to either 1) no screening, 2) multimodal screening (MMS), or 3) annual TVU screening, in, respectively, a 2:1:1 ratio. Multimodal screening comprised:

• annual CA-125 testing (interpreted using a risk-of-ovarian-cancer algorithm) and
• TVU as a second-line test.

Follow-up algorithms for women in both groups were determined a priori, based on a risk score (“normal,” “intermediate,” and “high”) from initial screening results. An initial, basic level-1 sonogram was performed on all women; a subsequent, more focused level-2 sonogram was performed only if indicated.

Among women assigned to screening, the following was noted:

• fewer women in the MMS group (0.3%) required clinical evaluation than in the TVU group (3.9%)
• fewer women in the MMS group (0.2%) required surgery than in the TVU group (1.8%)
• a similar number of cancers was detected in the two groups (MMS, 42; TVU, 45)
• more borderline tumors were detected in the TVU group than in the MMS group.

MMS had higher specificity and positive predictive value than TVU (respectively: 99.8% and 98.2%; 43.3% and 5.35%). Almost 50% of cancers detected on the initial screen were Stage I or II.

Symptoms are not predictive of the risk of ovarian cancer

Rossing MA, Wicklund KG, Cushing-Haugen KL, Weiss NS. Predictive value of symptoms for early detection of ovarian cancer. J Natl Cancer Inst. 2010;102(4):222–229.

Evaluation of symptoms has been suggested as a way of identifying women who may be at risk of ovarian cancer. In a 2007 consensus statement on the topic, contributors note that certain symptoms—bloating, pelvic or abdominal pain, difficulty eating, early satiety—are more common in women who have ovarian cancer than they are in the general population.⁵ They recommend that women who have these symptoms consult their physician for prompt evaluation.

But concerns have been raised about the true utility of these symptoms as a tool for detecting ovarian cancer at an earlier stage and, therefore, improving survival.

Linking symptom onset to time of diagnosis. Using a population-based registry that is part of the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the investigators conducted a large, population-based study to examine the occurrence and timing of symptoms in 1) women who have ovarian cancer and 2) controls. They identified women in a 13-county area of western Washington State, ranging from 35 to 74 years old, who were given a diagnosis of epithelial ovarian cancer or had a borderline epithelial ovarian tumor over a 3-year period.

Of 1,058 eligible women who had ovarian cancer, the team interviewed 812. An additional 1,313 controls (providing a 69% response rate) were interviewed.

Results showed that most case patients who had symptoms often associated with ovarian cancer experienced those symptoms only within 5 months before their initial diagnosis. Symptoms were also less likely to occur in early-stage ovarian cancer than in late-stage disease.

The positive predictive value for the symptom index was extremely low (<0.5% in early-stage disease and 0.6%–1.1% in late-stage disease).

Ultrasonography in combination with serum CA-125 can facilitate early referral to a subspecialist

McDonald JM, Doran S, DeSimone CP, et al. Predicting risk of malignancy in adnexal masses. Obstet Gynecol. 2010;115(4):687–694.

The finding of an adnexal mass is a common clinical scenario in gynecology. Any number of benign causes may be responsible, but it is important to identify which of those masses present a high likelihood of malignancy because complete surgical resection, along with adjuvant therapy administered in a timely manner, will maximize survival.

For that reason, an individualized risk profile in patients who have an adnexal mass confirmed by ultrasonography (US) would assist clinicians in making early referral to a cancer specialty care center.

Researchers evaluated 399 women who had been referred because of an adnexal mass on pelvic examination. Their objective was to estimate the accuracy of the following combination in predicting the risk of malignancy:

• patient demographics
• tumor morphology on US
• the serum CA-125 level.

The serum CA-125 level correlated directly with risk of malignancy in women who had an adnexal mass: Only 7.7% of women whose serum CA-125 level was within the normal range had ovarian cancer, compared with 34.2% women whose CA-125 level was 35–59 U/mL, and 86.8% whose level was 60–120 U/mL (P < .001). Multivariate analysis revealed that the most accurate significant predictor of a high risk of malignancy in patients who have an adnexal mass with complex or solid morphology is a serum CA-125 level >35 U/mL. This cutoff yielded a sensitivity of 77.3% for early stage ovarian cancer and 98.6% for advanced stage disease.

In summary

To repeat: As we await results of the UKCTOCS and the PLCO trial, do not screen patients routinely for ovarian cancer. Women who have an adnexal mass, an elevated CA-125 level, and troubling US findings should be referred—early—to a specialist.

Because ovarian cancer is usually diagnosed at an advanced stage—when prognosis is much worse than earlier in its course—a great deal of effort has been directed toward developing strategies to detect it early. These strategies include screening by a woman’s primary gynecologist with 1) a test of the serum CA-125 level and 2) transvaginal ultrasonography (TVU).

But how useful are the results of those screening tests? How should they be interpreted?

The answers aren’t clear.

Recent studies have yielded new information about ovarian cancer screening and detection. We discuss them in this Update:

• Screening with serial testing of the CA-125 level and TVU still is not recommended by the US Preventive Services Task Force or by ACOG
• Initial preliminary data from a prevalence screen of more than 50,000 subjects in the United Kingdom are encouraging, and show that new screening strategies may be feasible
• Using a patient’s report of her symptoms to trigger medical evaluation for ovarian cancer is not an effective screening tool
• Women who have an adnexal mass and a serum CA-125 level >35 U/mL and abnormal sonographic findings have an increased likelihood of ovarian cancer. They should be referred directly to a specialist.

The effect of screening on ovarian cancer mortality remains unknown

Partridge E, Greenlee RT, Xu J-L, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol. 2009;113(4):775–782.

The potential benefit of an effective screening program for ovarian cancer is great; the disease is the most lethal of all common gynecologic malignancies and carries significant individual and societal costs.¹ Furthermore, diagnosis at an early stage is associated with improved survival.

To date, however, studies have not shed light on whether screening with CA-125 testing or TVU has an impact on morbidity or mortality from ovarian cancer. In a large, multicenter trial of more than 30,000 women, Partridge and colleagues attempted to answer this question.

Investigators sought to determine whether this cohort of healthy women, ranging in age from 55 to 74 years, experienced a reduction in mortality from ovarian cancer when subjects were screened annually with a combination of CA-125 testing and TVU. The study was part of a larger trial (the Prostate, Lung, Colorectal and Ovarian [PLCO] Cancer Screening Trial²).

Subjects were randomized 1:1 to 1) the screening arm or 2) their customary gynecologic care without screening. The regimen in the screening arm comprised:

• annual measurement of the CA-125 in Years 1 through 6
• annual TVU in Years 1 through 4
• evaluation and follow-up of positive screening tests at the discretion of each subject’s treating physician.

Distribution of staging was unaffected. Overall, the positive predictive value of the screening regimen was relatively constant—and quite low—across the screening years (1.1% in Year 1 [95% confidence interval (CI), 0.6–1.6]; 1.0% in Year 2 [95% CI, 0.4–1.5]; 1.1% in Year 3 [95% CI, 0.5–1.7]; and 1.3% in Year 4 [95% CI, 0.6–2.0]).

Of 3,388 women who had at least one positive result on either screening test, 1,170 (34.5%) underwent biopsy at some point. Of those, 60 (5.1%) had invasive cancer—yielding a surgery-to-detected-cancer ratio of 19.5:1.

Approximately 70% of cancers detected by screening were a Stage-III or -IV tumor. As such, the screening effort did not change the expected distribution of staging from what would be expected in an unscreened population.

Is it feasible to screen for ovarian cancer on a large scale?

Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009;10(4):327–340.

The low prevalence of ovarian cancer presents a significant challenge to anyone hoping to devise a useful screening program: A screening test designed to detect a low-prevalence disease must have exceptionally high sensitivity and specificity to achieve a clinically useful positive predictive value—especially when the intervention is relatively risky (surgical removal of the ovaries) and has known harmful health implications.

With that requirement in mind, researchers have refined ovarian cancer screening methods. One of these refinements is a risk-of-ovarian-cancer algorithm by which clinicians would be able to interpret serial CA-125 results.^3,4

Interim results from a prevalence screen. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) evaluated these new screening methods in a multicenter, randomized, controlled trial in an effort that assessed not only mortality but also cost, acceptance by patients, and the physical and psychosocial morbidities associated with screening. At this point, investigators are reporting the results of a prevalence screen.

The team evaluated more than 200,000 low-risk women who were randomized to either 1) no screening, 2) multimodal screening (MMS), or 3) annual TVU screening, in, respectively, a 2:1:1 ratio. Multimodal screening comprised:

• annual CA-125 testing (interpreted using a risk-of-ovarian-cancer algorithm) and
• TVU as a second-line test.

Follow-up algorithms for women in both groups were determined a priori, based on a risk score (“normal,” “intermediate,” and “high”) from initial screening results. An initial, basic level-1 sonogram was performed on all women; a subsequent, more focused level-2 sonogram was performed only if indicated.

Among women assigned to screening, the following was noted:

• fewer women in the MMS group (0.3%) required clinical evaluation than in the TVU group (3.9%)
• fewer women in the MMS group (0.2%) required surgery than in the TVU group (1.8%)
• a similar number of cancers was detected in the two groups (MMS, 42; TVU, 45)
• more borderline tumors were detected in the TVU group than in the MMS group.

MMS had higher specificity and positive predictive value than TVU (respectively: 99.8% and 98.2%; 43.3% and 5.35%). Almost 50% of cancers detected on the initial screen were Stage I or II.

Symptoms are not predictive of the risk of ovarian cancer

Rossing MA, Wicklund KG, Cushing-Haugen KL, Weiss NS. Predictive value of symptoms for early detection of ovarian cancer. J Natl Cancer Inst. 2010;102(4):222–229.

Evaluation of symptoms has been suggested as a way of identifying women who may be at risk of ovarian cancer. In a 2007 consensus statement on the topic, contributors note that certain symptoms—bloating, pelvic or abdominal pain, difficulty eating, early satiety—are more common in women who have ovarian cancer than they are in the general population.⁵ They recommend that women who have these symptoms consult their physician for prompt evaluation.

But concerns have been raised about the true utility of these symptoms as a tool for detecting ovarian cancer at an earlier stage and, therefore, improving survival.

Linking symptom onset to time of diagnosis. Using a population-based registry that is part of the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the investigators conducted a large, population-based study to examine the occurrence and timing of symptoms in 1) women who have ovarian cancer and 2) controls. They identified women in a 13-county area of western Washington State, ranging from 35 to 74 years old, who were given a diagnosis of epithelial ovarian cancer or had a borderline epithelial ovarian tumor over a 3-year period.

Of 1,058 eligible women who had ovarian cancer, the team interviewed 812. An additional 1,313 controls (providing a 69% response rate) were interviewed.

Results showed that most case patients who had symptoms often associated with ovarian cancer experienced those symptoms only within 5 months before their initial diagnosis. Symptoms were also less likely to occur in early-stage ovarian cancer than in late-stage disease.

The positive predictive value for the symptom index was extremely low (<0.5% in early-stage disease and 0.6%–1.1% in late-stage disease).

Ultrasonography in combination with serum CA-125 can facilitate early referral to a subspecialist

McDonald JM, Doran S, DeSimone CP, et al. Predicting risk of malignancy in adnexal masses. Obstet Gynecol. 2010;115(4):687–694.

The finding of an adnexal mass is a common clinical scenario in gynecology. Any number of benign causes may be responsible, but it is important to identify which of those masses present a high likelihood of malignancy because complete surgical resection, along with adjuvant therapy administered in a timely manner, will maximize survival.

For that reason, an individualized risk profile in patients who have an adnexal mass confirmed by ultrasonography (US) would assist clinicians in making early referral to a cancer specialty care center.

Researchers evaluated 399 women who had been referred because of an adnexal mass on pelvic examination. Their objective was to estimate the accuracy of the following combination in predicting the risk of malignancy:

• patient demographics
• tumor morphology on US
• the serum CA-125 level.

The serum CA-125 level correlated directly with risk of malignancy in women who had an adnexal mass: Only 7.7% of women whose serum CA-125 level was within the normal range had ovarian cancer, compared with 34.2% women whose CA-125 level was 35–59 U/mL, and 86.8% whose level was 60–120 U/mL (P < .001). Multivariate analysis revealed that the most accurate significant predictor of a high risk of malignancy in patients who have an adnexal mass with complex or solid morphology is a serum CA-125 level >35 U/mL. This cutoff yielded a sensitivity of 77.3% for early stage ovarian cancer and 98.6% for advanced stage disease.

In summary

To repeat: As we await results of the UKCTOCS and the PLCO trial, do not screen patients routinely for ovarian cancer. Women who have an adnexal mass, an elevated CA-125 level, and troubling US findings should be referred—early—to a specialist.

Because ovarian cancer is usually diagnosed at an advanced stage—when prognosis is much worse than earlier in its course—a great deal of effort has been directed toward developing strategies to detect it early. These strategies include screening by a woman’s primary gynecologist with 1) a test of the serum CA-125 level and 2) transvaginal ultrasonography (TVU).

But how useful are the results of those screening tests? How should they be interpreted?

The answers aren’t clear.

Recent studies have yielded new information about ovarian cancer screening and detection. We discuss them in this Update:

• Screening with serial testing of the CA-125 level and TVU still is not recommended by the US Preventive Services Task Force or by ACOG
• Initial preliminary data from a prevalence screen of more than 50,000 subjects in the United Kingdom are encouraging, and show that new screening strategies may be feasible
• Using a patient’s report of her symptoms to trigger medical evaluation for ovarian cancer is not an effective screening tool
• Women who have an adnexal mass and a serum CA-125 level >35 U/mL and abnormal sonographic findings have an increased likelihood of ovarian cancer. They should be referred directly to a specialist.

The effect of screening on ovarian cancer mortality remains unknown

Partridge E, Greenlee RT, Xu J-L, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol. 2009;113(4):775–782.

The potential benefit of an effective screening program for ovarian cancer is great; the disease is the most lethal of all common gynecologic malignancies and carries significant individual and societal costs.¹ Furthermore, diagnosis at an early stage is associated with improved survival.

To date, however, studies have not shed light on whether screening with CA-125 testing or TVU has an impact on morbidity or mortality from ovarian cancer. In a large, multicenter trial of more than 30,000 women, Partridge and colleagues attempted to answer this question.

Investigators sought to determine whether this cohort of healthy women, ranging in age from 55 to 74 years, experienced a reduction in mortality from ovarian cancer when subjects were screened annually with a combination of CA-125 testing and TVU. The study was part of a larger trial (the Prostate, Lung, Colorectal and Ovarian [PLCO] Cancer Screening Trial²).

Subjects were randomized 1:1 to 1) the screening arm or 2) their customary gynecologic care without screening. The regimen in the screening arm comprised:

• annual measurement of the CA-125 in Years 1 through 6
• annual TVU in Years 1 through 4
• evaluation and follow-up of positive screening tests at the discretion of each subject’s treating physician.

Distribution of staging was unaffected. Overall, the positive predictive value of the screening regimen was relatively constant—and quite low—across the screening years (1.1% in Year 1 [95% confidence interval (CI), 0.6–1.6]; 1.0% in Year 2 [95% CI, 0.4–1.5]; 1.1% in Year 3 [95% CI, 0.5–1.7]; and 1.3% in Year 4 [95% CI, 0.6–2.0]).

Of 3,388 women who had at least one positive result on either screening test, 1,170 (34.5%) underwent biopsy at some point. Of those, 60 (5.1%) had invasive cancer—yielding a surgery-to-detected-cancer ratio of 19.5:1.

Approximately 70% of cancers detected by screening were a Stage-III or -IV tumor. As such, the screening effort did not change the expected distribution of staging from what would be expected in an unscreened population.

Is it feasible to screen for ovarian cancer on a large scale?

Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009;10(4):327–340.

The low prevalence of ovarian cancer presents a significant challenge to anyone hoping to devise a useful screening program: A screening test designed to detect a low-prevalence disease must have exceptionally high sensitivity and specificity to achieve a clinically useful positive predictive value—especially when the intervention is relatively risky (surgical removal of the ovaries) and has known harmful health implications.

With that requirement in mind, researchers have refined ovarian cancer screening methods. One of these refinements is a risk-of-ovarian-cancer algorithm by which clinicians would be able to interpret serial CA-125 results.^3,4

Interim results from a prevalence screen. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) evaluated these new screening methods in a multicenter, randomized, controlled trial in an effort that assessed not only mortality but also cost, acceptance by patients, and the physical and psychosocial morbidities associated with screening. At this point, investigators are reporting the results of a prevalence screen.

The team evaluated more than 200,000 low-risk women who were randomized to either 1) no screening, 2) multimodal screening (MMS), or 3) annual TVU screening, in, respectively, a 2:1:1 ratio. Multimodal screening comprised:

• annual CA-125 testing (interpreted using a risk-of-ovarian-cancer algorithm) and
• TVU as a second-line test.

Follow-up algorithms for women in both groups were determined a priori, based on a risk score (“normal,” “intermediate,” and “high”) from initial screening results. An initial, basic level-1 sonogram was performed on all women; a subsequent, more focused level-2 sonogram was performed only if indicated.

Among women assigned to screening, the following was noted:

• fewer women in the MMS group (0.3%) required clinical evaluation than in the TVU group (3.9%)
• fewer women in the MMS group (0.2%) required surgery than in the TVU group (1.8%)
• a similar number of cancers was detected in the two groups (MMS, 42; TVU, 45)
• more borderline tumors were detected in the TVU group than in the MMS group.

MMS had higher specificity and positive predictive value than TVU (respectively: 99.8% and 98.2%; 43.3% and 5.35%). Almost 50% of cancers detected on the initial screen were Stage I or II.

Symptoms are not predictive of the risk of ovarian cancer

Rossing MA, Wicklund KG, Cushing-Haugen KL, Weiss NS. Predictive value of symptoms for early detection of ovarian cancer. J Natl Cancer Inst. 2010;102(4):222–229.

Evaluation of symptoms has been suggested as a way of identifying women who may be at risk of ovarian cancer. In a 2007 consensus statement on the topic, contributors note that certain symptoms—bloating, pelvic or abdominal pain, difficulty eating, early satiety—are more common in women who have ovarian cancer than they are in the general population.⁵ They recommend that women who have these symptoms consult their physician for prompt evaluation.

But concerns have been raised about the true utility of these symptoms as a tool for detecting ovarian cancer at an earlier stage and, therefore, improving survival.

Linking symptom onset to time of diagnosis. Using a population-based registry that is part of the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the investigators conducted a large, population-based study to examine the occurrence and timing of symptoms in 1) women who have ovarian cancer and 2) controls. They identified women in a 13-county area of western Washington State, ranging from 35 to 74 years old, who were given a diagnosis of epithelial ovarian cancer or had a borderline epithelial ovarian tumor over a 3-year period.

Of 1,058 eligible women who had ovarian cancer, the team interviewed 812. An additional 1,313 controls (providing a 69% response rate) were interviewed.

Results showed that most case patients who had symptoms often associated with ovarian cancer experienced those symptoms only within 5 months before their initial diagnosis. Symptoms were also less likely to occur in early-stage ovarian cancer than in late-stage disease.

The positive predictive value for the symptom index was extremely low (<0.5% in early-stage disease and 0.6%–1.1% in late-stage disease).

Ultrasonography in combination with serum CA-125 can facilitate early referral to a subspecialist

McDonald JM, Doran S, DeSimone CP, et al. Predicting risk of malignancy in adnexal masses. Obstet Gynecol. 2010;115(4):687–694.

The finding of an adnexal mass is a common clinical scenario in gynecology. Any number of benign causes may be responsible, but it is important to identify which of those masses present a high likelihood of malignancy because complete surgical resection, along with adjuvant therapy administered in a timely manner, will maximize survival.

For that reason, an individualized risk profile in patients who have an adnexal mass confirmed by ultrasonography (US) would assist clinicians in making early referral to a cancer specialty care center.

Researchers evaluated 399 women who had been referred because of an adnexal mass on pelvic examination. Their objective was to estimate the accuracy of the following combination in predicting the risk of malignancy:

• patient demographics
• tumor morphology on US
• the serum CA-125 level.

The serum CA-125 level correlated directly with risk of malignancy in women who had an adnexal mass: Only 7.7% of women whose serum CA-125 level was within the normal range had ovarian cancer, compared with 34.2% women whose CA-125 level was 35–59 U/mL, and 86.8% whose level was 60–120 U/mL (P < .001). Multivariate analysis revealed that the most accurate significant predictor of a high risk of malignancy in patients who have an adnexal mass with complex or solid morphology is a serum CA-125 level >35 U/mL. This cutoff yielded a sensitivity of 77.3% for early stage ovarian cancer and 98.6% for advanced stage disease.

In summary

To repeat: As we await results of the UKCTOCS and the PLCO trial, do not screen patients routinely for ovarian cancer. Women who have an adnexal mass, an elevated CA-125 level, and troubling US findings should be referred—early—to a specialist.

Dr. Mutch reports that he has received grant or research support from Lilly and Genentech. He serves as a speaker for GSK, Lilly, and Merck. Dr. Rimel reports no financial relationships relevant to this article.

Endometrial cancer is a great concern in industrialized nations, where it is the most common gynecologic cancer—with incidence increasing every year. Survival is generally very good for women who have low-grade disease confined to the uterus. However, for patients who have high-grade disease, an aggressive histologic type, or other features that suggest a poor prognosis, the cure rate approaches 75%.¹

Primary surgery is the mainstay of initial treatment and basis of FIGO staging ( TABLE ), which requires:

• total hysterectomy
• bilateral salpingo-oophorectomy
• complete examination of the abdomen
• pelvic washings
• lymph-adenectomy (anatomic boundaries and node counts aren’t specified).

Controversy clouds our understanding of the optimal type of surgery, utility of pelvic lymphadenectomy, and possible benefit of adjuvant radiation therapy. During the past year, fuel has been added to this debate:

• Two randomized, controlled trials of surgery with and without pelvic lymphadenectomy in early-stage patients demonstrated no survival benefit. Earlier studies investigating the benefits of lymphadenectomy in endometrial cancer have been largely retrospective, and results have varied.
• A concurrent randomized, controlled trial of external-beam radiotherapy for women who have intermediate- or high-risk disease showed no improvement in overall survival, although local control increased by 3%.

TABLE

FIGO surgical staging for endometrial cancer

No survival advantage to pelvic lymphadenectomy—but it has other benefits

ASTEC study group, Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373:125–136.

Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100:1707–1716.

Among the arguments for lymphadenectomy in endometrial cancer staging are:

• It aids in the selection of women for radiation or other adjuvant treatment
• It may have a direct survival benefit, as suggested by retrospective studies.

But lymphadenectomy is time-consuming, requires a specialized gynecologic surgeon, and is associated with some increase in the risk of morbidity—namely, lymphedema, lymphocyst formation, deep-vein thrombosis (DVT), and blood loss.

The much-anticipated report of the 85-center, multinational ASTEC trial [ A S urgical T rial of E ndometrial C ancer], published earlier this year, offers further insight into the practice of lymphadenectomy. ASTEC involved two randomizations: The first, to pelvic lymphadenectomy; the second, to radiation therapy.

Details of the ASTEC trial

The ASTEC trial enrolled 1,408 women who had histologically confirmed endometrial carcinoma that was believed to be confined to the uterus. How this determination was made was not specified. Patients who had enlarged lymph nodes corroborated by computed tomography or magnetic resonance imaging were not excluded.

Participants were randomized to either of the following treatment groups:

• traditional surgery with total hysterectomy and bilateral salpingo-oophorectomy, pelvic washings, and palpation of para-aortic nodes
• the same surgery plus systematic lymphadenectomy of the iliac and obturator nodes.

If any para-aortic nodes were suspicious, biopsy or lymphadenectomy was performed at the discretion of the surgeon ( FIGURE ).

FIGURE Nodes reveal when cancer has spread

Women in the ASTEC trial were randomized to traditional surgery (total hysterectomy and bilateral salpingo-oophorectomy), pelvic washings, and palpation of para-aortic nodes or to the same surgery plus lymphadenectomy of the iliac and obturator nodes.

Operative findings determined a patient’s level of risk

After surgery, patients were categorized as having one of the following:

• low-risk, early-stage disease. This group included patients who had disease classified as stage IA or IB, grade 1 or 2. They were deemed to have a suitably low risk of recurrence to be offered further treatment according to their physician’s standard practice.
• intermediate- or high-risk, early-stage disease. These patients were randomized to the ASTEC radiation-therapy trial, which compared external-beam radiotherapy with no external-beam radiotherapy. The authors assert that this second randomization was necessary to prevent over- or undertreatment of patients who had unknown node status, which might alter survival outcomes.
• advanced disease. These patients were referred to their physician for further treatment.

In both surgical groups (with and without lymphadenectomy), approximately 80% of patients had disease confined to the uterus. Nodes were harvested in 91% of the patients in the lymphadenectomy group, compared with 5% of patients in the traditional-surgery group. Nine percent of women in the lymphadenectomy group had positive nodes.

The authors observe that more women had deeply invasive disease and adverse histologic types in the group that underwent lymphadenectomy. There were no differences between the two groups in overall survival; disease-specific survival; recurrence-free survival; or recurrence-free, disease-specific survival, after adjustment for baseline differences. Subgroup analysis for low-risk, high-risk, and advanced disease also failed to demonstrate differences in overall survival and recurrence-free survival.

Study from Italy produces similar findings

An independent randomized, controlled trial examining survival outcomes for endometrial cancer patients with and without lymphadenectomy was released by the Italian group in late 2008. In this study, 537 patients who had histologically confirmed endometrial carcinoma believed to be confined to the uterus were randomized to total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without pelvic lymphadenectomy.

Anatomic boundaries of the pelvic lymph-node dissection were clearly defined, and a minimum lymph-node count of 20 was specified for inclusion. Intraoperative frozen section was utilized to exclude patients who had grade-1 disease that was less than 50% invasive. The option of para-aortic lymph-node dissection or sampling was left to the discretion of the surgeon. If pelvic nodes were larger than 1 cm, they were removed or sampled regardless of randomization.

Unlike the ASTEC trial, this study did not attempt to control adjuvant treatment. Patients were treated according to the discretion of the physician. Most patients received no further therapy; only 20% underwent radiation therapy, and 7% received chemotherapy.

Women in the lymphadenectomy group were more likely to have stage-IIIC disease, which is directly attributable to histologic evaluation of the lymph nodes in this group. The authors point out that these patients had more accurate assessment of their prognosis, allowing for the tailoring of adjuvant treatment.

The overall survival and disease-free survival curves for the two experimental groups were similar, consistent with data from the ASTEC trial. This proved to be true for both the intention-to-treat and according-to-protocol groups. The authors note that their results are similar to those of the ASTEC trial, despite the significant difference in the number of nodes removed in each trial.

Some aspects of the trials hamper interpretation and comparison

Outcomes are improved when surgery is performed by a trained gynecologic oncologist. In the ASTEC trial, each lymphadenectomy was performed by a specialized gynecologic surgeon who was “skilled in the procedure.” In the Italian study, the type of surgeon was not specified, but the specific anatomic boundaries of the dissection and the minimum node count were. More specific data are needed before any conclusions can be drawn about the effect of surgical skill on outcome in these trials.

In the ASTEC trial, 9% of patients in the lymphadenectomy group had no nodes removed, and more than 60% of patients would not have met criteria for inclusion in the lymphadenectomy arm of the Italian study—suggesting that the majority of women in the ASTEC trial had inadequate lymphadenectomy. Para-aortic lymphadenectomy was left to the discretion of the attending surgeon, and some patients did have resection of these nodes. The data do not include information about whether these patients were treated in the para-aortic region based on the histology of these nodes.

Randomization in a prospective study is supposed to equalize the risks between groups. In the ASTEC trial, despite randomization, there were 10% more patients who had deeply invasive disease in the lymphadenectomy group, along with 3% more adverse histologies and high-grade (grade-3) tumors. Given the higher incidence of positive nodes and poorer outcome in these cases, this difference may have had a significant impact on the evaluation of the groups for overall or disease-specific survival.

External-beam radiotherapy reduces local recurrence of endometrial Ca but does not improve survival

ASTEC/EN.5 Study Group, Blake P, Swart AM, Orton J, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet. 2009;373:137–146.

Radiation therapy has been a standard treatment for endometrial cancer when there is high risk of recurrence. This report combines two independent randomized, controlled trials investigating the benefit of postoperative adjuvant pelvic radiation in women who had early-stage disease and who met histologic criteria for high risk of recurrence and death. The trials are the EN.5 trial from Canada, and the radiation-therapy randomization of the ASTEC trial). Neither found a benefit in terms of overall survival, disease-specific survival, or recurrence-free survival, although local recurrence was reduced by 2.9% The authors also provide a review of the literature and a meta-analysis of other randomized, controlled trials on this subject.

Details of the EN.5 and ASTEC radiation-therapy trials

Criteria for enrollment were similar for the two trials, which focused on women who had histologically confirmed endometrial cancer and an intermediate or high risk of recurrence. This included women who had FIGO stage IA or stage IB (grade 3), stage IC (all grades), or papillary serous or clear-cell histology (all stages).

Lymphadenectomy was not required for patients enrolled in EN.5, but was part of the surgical randomization for ASTEC. This distinction could confound the results of the combined trials, as the investigators were trying to answer two questions within one patient population.

In both the EN.5 and ASTEC trials, women were randomized to observation or external-beam radiotherapy, with these parameters:

• Radiation therapy was to begin no later than 12 weeks after surgery (most patients began radiation therapy 6 to 8 weeks after surgery)
• For ASTEC, the target dosage was 40–46 Gy in 20–26 daily fractions to the pelvis, with treatment five times each week. For EN.5, the dosage and timing were very similar: 45 Gy, 25 daily fractions, five times weekly
• In both trials, vaginal brachytherapy was allowed if it was the local practice or the center’s policy
• Women were classified as being at intermediate risk or high risk, based on the likelihood of distant recurrence, as defined by GOG99 and PORTEC1 studies. Intermediate risk included all patients who had stage-IA or -IB (grade-3) or stage-IC or -IIA (grade-1 or -2) disease. Women who had papillary serous or clear-cell histology, stage-IC or -IIA (grade-3) disease, or any stage-IIB disease were considered at high risk.

The primary outcome evaluated for both trials was overall survival. Secondary endpoints were:

• disease-specific survival
• recurrence-free survival
• locoregional recurrence
• treatment toxicity.

A total of 905 women were enrolled in the ASTEC and EN.5 trials, with most patients having endometrial histology (83%) and being categorized as at intermediate risk (75%). Approximately half the patients in both trials received brachytherapy, which was allowed according to local practice. Only 47% of the observation group actually received no treatment.

Findings were remarkably similar in EN.5 and ASTEC

Here are the main findings:

• no difference between groups in overall survival, disease-specific survival, and recurrence-free survival
• significantly fewer isolated vaginal or pelvic initial recurrences in the external-beam radiotherapy group, with an absolute difference of 2.9%. (Only 35% of all recurrences were isolated recurrences)
• no significant difference between groups in distant or local and distant recurrences
• as expected, higher toxicity in the group receiving external-beam radiotherapy, including life-threatening toxicity (acute toxicity, 3% vs <1%; late toxicity, 1% vs 0%).

Subgroup analysis comparing overall survival in intermediate- and high-risk patients demonstrated no improvement with external-beam radiotherapy. Nor was overall survival altered by lymphadenectomy. The authors performed a meta-analysis using data from GOG99, PORTEC1, and this combined trial, and found no significant difference in overall survival or disease-specific survival, regardless of histologic risk group.

Trial has notable strengths and weaknesses

This large prospective trial has significant strengths: its size and its multi-institutional nature. The authors also evaluated their data in combination with other randomized, controlled trials to further investigate the effect of external-beam radiotherapy on survival. However, allowing brachytherapy somewhat confounds the true effect of external-beam radiotherapy on local recurrence. (There were few local recurrences, and the authors did not evaluate whether women who had an isolated vaginal recurrence received vaginal brachytherapy.) Moreover, 15% of women who were randomized to external-beam radiotherapy did not complete it.

In addition, secondary randomization of patients in the intermediate-risk and high-risk categories to external-beam radiotherapy versus no treatment may have significantly confounded the results of the entire ASTEC trial. Because women were, or were not, randomized to treatment regardless of node status, some patients who had positive nodes failed to receive adjuvant treatment. This may have had a significant effect on overall survival, as positive lymph nodes are a negative prognostic factor.

Dr. Mutch reports that he has received grant or research support from Lilly and Genentech. He serves as a speaker for GSK, Lilly, and Merck. Dr. Rimel reports no financial relationships relevant to this article.

Endometrial cancer is a great concern in industrialized nations, where it is the most common gynecologic cancer—with incidence increasing every year. Survival is generally very good for women who have low-grade disease confined to the uterus. However, for patients who have high-grade disease, an aggressive histologic type, or other features that suggest a poor prognosis, the cure rate approaches 75%.¹

Primary surgery is the mainstay of initial treatment and basis of FIGO staging ( TABLE ), which requires:

• total hysterectomy
• bilateral salpingo-oophorectomy
• complete examination of the abdomen
• pelvic washings
• lymph-adenectomy (anatomic boundaries and node counts aren’t specified).

Controversy clouds our understanding of the optimal type of surgery, utility of pelvic lymphadenectomy, and possible benefit of adjuvant radiation therapy. During the past year, fuel has been added to this debate:

• Two randomized, controlled trials of surgery with and without pelvic lymphadenectomy in early-stage patients demonstrated no survival benefit. Earlier studies investigating the benefits of lymphadenectomy in endometrial cancer have been largely retrospective, and results have varied.
• A concurrent randomized, controlled trial of external-beam radiotherapy for women who have intermediate- or high-risk disease showed no improvement in overall survival, although local control increased by 3%.

TABLE

FIGO surgical staging for endometrial cancer

No survival advantage to pelvic lymphadenectomy—but it has other benefits

ASTEC study group, Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373:125–136.

Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100:1707–1716.

Among the arguments for lymphadenectomy in endometrial cancer staging are:

• It aids in the selection of women for radiation or other adjuvant treatment
• It may have a direct survival benefit, as suggested by retrospective studies.

But lymphadenectomy is time-consuming, requires a specialized gynecologic surgeon, and is associated with some increase in the risk of morbidity—namely, lymphedema, lymphocyst formation, deep-vein thrombosis (DVT), and blood loss.

The much-anticipated report of the 85-center, multinational ASTEC trial [ A S urgical T rial of E ndometrial C ancer], published earlier this year, offers further insight into the practice of lymphadenectomy. ASTEC involved two randomizations: The first, to pelvic lymphadenectomy; the second, to radiation therapy.

Details of the ASTEC trial

The ASTEC trial enrolled 1,408 women who had histologically confirmed endometrial carcinoma that was believed to be confined to the uterus. How this determination was made was not specified. Patients who had enlarged lymph nodes corroborated by computed tomography or magnetic resonance imaging were not excluded.

Participants were randomized to either of the following treatment groups:

• traditional surgery with total hysterectomy and bilateral salpingo-oophorectomy, pelvic washings, and palpation of para-aortic nodes
• the same surgery plus systematic lymphadenectomy of the iliac and obturator nodes.

If any para-aortic nodes were suspicious, biopsy or lymphadenectomy was performed at the discretion of the surgeon ( FIGURE ).

FIGURE Nodes reveal when cancer has spread

Women in the ASTEC trial were randomized to traditional surgery (total hysterectomy and bilateral salpingo-oophorectomy), pelvic washings, and palpation of para-aortic nodes or to the same surgery plus lymphadenectomy of the iliac and obturator nodes.

Operative findings determined a patient’s level of risk

After surgery, patients were categorized as having one of the following:

• low-risk, early-stage disease. This group included patients who had disease classified as stage IA or IB, grade 1 or 2. They were deemed to have a suitably low risk of recurrence to be offered further treatment according to their physician’s standard practice.
• intermediate- or high-risk, early-stage disease. These patients were randomized to the ASTEC radiation-therapy trial, which compared external-beam radiotherapy with no external-beam radiotherapy. The authors assert that this second randomization was necessary to prevent over- or undertreatment of patients who had unknown node status, which might alter survival outcomes.
• advanced disease. These patients were referred to their physician for further treatment.

In both surgical groups (with and without lymphadenectomy), approximately 80% of patients had disease confined to the uterus. Nodes were harvested in 91% of the patients in the lymphadenectomy group, compared with 5% of patients in the traditional-surgery group. Nine percent of women in the lymphadenectomy group had positive nodes.

The authors observe that more women had deeply invasive disease and adverse histologic types in the group that underwent lymphadenectomy. There were no differences between the two groups in overall survival; disease-specific survival; recurrence-free survival; or recurrence-free, disease-specific survival, after adjustment for baseline differences. Subgroup analysis for low-risk, high-risk, and advanced disease also failed to demonstrate differences in overall survival and recurrence-free survival.

Study from Italy produces similar findings

An independent randomized, controlled trial examining survival outcomes for endometrial cancer patients with and without lymphadenectomy was released by the Italian group in late 2008. In this study, 537 patients who had histologically confirmed endometrial carcinoma believed to be confined to the uterus were randomized to total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without pelvic lymphadenectomy.

Anatomic boundaries of the pelvic lymph-node dissection were clearly defined, and a minimum lymph-node count of 20 was specified for inclusion. Intraoperative frozen section was utilized to exclude patients who had grade-1 disease that was less than 50% invasive. The option of para-aortic lymph-node dissection or sampling was left to the discretion of the surgeon. If pelvic nodes were larger than 1 cm, they were removed or sampled regardless of randomization.

Unlike the ASTEC trial, this study did not attempt to control adjuvant treatment. Patients were treated according to the discretion of the physician. Most patients received no further therapy; only 20% underwent radiation therapy, and 7% received chemotherapy.

Women in the lymphadenectomy group were more likely to have stage-IIIC disease, which is directly attributable to histologic evaluation of the lymph nodes in this group. The authors point out that these patients had more accurate assessment of their prognosis, allowing for the tailoring of adjuvant treatment.

The overall survival and disease-free survival curves for the two experimental groups were similar, consistent with data from the ASTEC trial. This proved to be true for both the intention-to-treat and according-to-protocol groups. The authors note that their results are similar to those of the ASTEC trial, despite the significant difference in the number of nodes removed in each trial.

Some aspects of the trials hamper interpretation and comparison

Outcomes are improved when surgery is performed by a trained gynecologic oncologist. In the ASTEC trial, each lymphadenectomy was performed by a specialized gynecologic surgeon who was “skilled in the procedure.” In the Italian study, the type of surgeon was not specified, but the specific anatomic boundaries of the dissection and the minimum node count were. More specific data are needed before any conclusions can be drawn about the effect of surgical skill on outcome in these trials.

In the ASTEC trial, 9% of patients in the lymphadenectomy group had no nodes removed, and more than 60% of patients would not have met criteria for inclusion in the lymphadenectomy arm of the Italian study—suggesting that the majority of women in the ASTEC trial had inadequate lymphadenectomy. Para-aortic lymphadenectomy was left to the discretion of the attending surgeon, and some patients did have resection of these nodes. The data do not include information about whether these patients were treated in the para-aortic region based on the histology of these nodes.

Randomization in a prospective study is supposed to equalize the risks between groups. In the ASTEC trial, despite randomization, there were 10% more patients who had deeply invasive disease in the lymphadenectomy group, along with 3% more adverse histologies and high-grade (grade-3) tumors. Given the higher incidence of positive nodes and poorer outcome in these cases, this difference may have had a significant impact on the evaluation of the groups for overall or disease-specific survival.

External-beam radiotherapy reduces local recurrence of endometrial Ca but does not improve survival

ASTEC/EN.5 Study Group, Blake P, Swart AM, Orton J, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet. 2009;373:137–146.

Radiation therapy has been a standard treatment for endometrial cancer when there is high risk of recurrence. This report combines two independent randomized, controlled trials investigating the benefit of postoperative adjuvant pelvic radiation in women who had early-stage disease and who met histologic criteria for high risk of recurrence and death. The trials are the EN.5 trial from Canada, and the radiation-therapy randomization of the ASTEC trial). Neither found a benefit in terms of overall survival, disease-specific survival, or recurrence-free survival, although local recurrence was reduced by 2.9% The authors also provide a review of the literature and a meta-analysis of other randomized, controlled trials on this subject.

Details of the EN.5 and ASTEC radiation-therapy trials

Criteria for enrollment were similar for the two trials, which focused on women who had histologically confirmed endometrial cancer and an intermediate or high risk of recurrence. This included women who had FIGO stage IA or stage IB (grade 3), stage IC (all grades), or papillary serous or clear-cell histology (all stages).

Lymphadenectomy was not required for patients enrolled in EN.5, but was part of the surgical randomization for ASTEC. This distinction could confound the results of the combined trials, as the investigators were trying to answer two questions within one patient population.

In both the EN.5 and ASTEC trials, women were randomized to observation or external-beam radiotherapy, with these parameters:

• Radiation therapy was to begin no later than 12 weeks after surgery (most patients began radiation therapy 6 to 8 weeks after surgery)
• For ASTEC, the target dosage was 40–46 Gy in 20–26 daily fractions to the pelvis, with treatment five times each week. For EN.5, the dosage and timing were very similar: 45 Gy, 25 daily fractions, five times weekly
• In both trials, vaginal brachytherapy was allowed if it was the local practice or the center’s policy
• Women were classified as being at intermediate risk or high risk, based on the likelihood of distant recurrence, as defined by GOG99 and PORTEC1 studies. Intermediate risk included all patients who had stage-IA or -IB (grade-3) or stage-IC or -IIA (grade-1 or -2) disease. Women who had papillary serous or clear-cell histology, stage-IC or -IIA (grade-3) disease, or any stage-IIB disease were considered at high risk.

The primary outcome evaluated for both trials was overall survival. Secondary endpoints were:

• disease-specific survival
• recurrence-free survival
• locoregional recurrence
• treatment toxicity.

A total of 905 women were enrolled in the ASTEC and EN.5 trials, with most patients having endometrial histology (83%) and being categorized as at intermediate risk (75%). Approximately half the patients in both trials received brachytherapy, which was allowed according to local practice. Only 47% of the observation group actually received no treatment.

Findings were remarkably similar in EN.5 and ASTEC

Here are the main findings:

• no difference between groups in overall survival, disease-specific survival, and recurrence-free survival
• significantly fewer isolated vaginal or pelvic initial recurrences in the external-beam radiotherapy group, with an absolute difference of 2.9%. (Only 35% of all recurrences were isolated recurrences)
• no significant difference between groups in distant or local and distant recurrences
• as expected, higher toxicity in the group receiving external-beam radiotherapy, including life-threatening toxicity (acute toxicity, 3% vs <1%; late toxicity, 1% vs 0%).

Subgroup analysis comparing overall survival in intermediate- and high-risk patients demonstrated no improvement with external-beam radiotherapy. Nor was overall survival altered by lymphadenectomy. The authors performed a meta-analysis using data from GOG99, PORTEC1, and this combined trial, and found no significant difference in overall survival or disease-specific survival, regardless of histologic risk group.

Trial has notable strengths and weaknesses

This large prospective trial has significant strengths: its size and its multi-institutional nature. The authors also evaluated their data in combination with other randomized, controlled trials to further investigate the effect of external-beam radiotherapy on survival. However, allowing brachytherapy somewhat confounds the true effect of external-beam radiotherapy on local recurrence. (There were few local recurrences, and the authors did not evaluate whether women who had an isolated vaginal recurrence received vaginal brachytherapy.) Moreover, 15% of women who were randomized to external-beam radiotherapy did not complete it.

In addition, secondary randomization of patients in the intermediate-risk and high-risk categories to external-beam radiotherapy versus no treatment may have significantly confounded the results of the entire ASTEC trial. Because women were, or were not, randomized to treatment regardless of node status, some patients who had positive nodes failed to receive adjuvant treatment. This may have had a significant effect on overall survival, as positive lymph nodes are a negative prognostic factor.

Dr. Mutch reports that he has received grant or research support from Lilly and Genentech. He serves as a speaker for GSK, Lilly, and Merck. Dr. Rimel reports no financial relationships relevant to this article.

Endometrial cancer is a great concern in industrialized nations, where it is the most common gynecologic cancer—with incidence increasing every year. Survival is generally very good for women who have low-grade disease confined to the uterus. However, for patients who have high-grade disease, an aggressive histologic type, or other features that suggest a poor prognosis, the cure rate approaches 75%.¹

Primary surgery is the mainstay of initial treatment and basis of FIGO staging ( TABLE ), which requires:

• total hysterectomy
• bilateral salpingo-oophorectomy
• complete examination of the abdomen
• pelvic washings
• lymph-adenectomy (anatomic boundaries and node counts aren’t specified).

Controversy clouds our understanding of the optimal type of surgery, utility of pelvic lymphadenectomy, and possible benefit of adjuvant radiation therapy. During the past year, fuel has been added to this debate:

• Two randomized, controlled trials of surgery with and without pelvic lymphadenectomy in early-stage patients demonstrated no survival benefit. Earlier studies investigating the benefits of lymphadenectomy in endometrial cancer have been largely retrospective, and results have varied.
• A concurrent randomized, controlled trial of external-beam radiotherapy for women who have intermediate- or high-risk disease showed no improvement in overall survival, although local control increased by 3%.

TABLE

FIGO surgical staging for endometrial cancer

No survival advantage to pelvic lymphadenectomy—but it has other benefits

ASTEC study group, Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373:125–136.

Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100:1707–1716.

Among the arguments for lymphadenectomy in endometrial cancer staging are:

• It aids in the selection of women for radiation or other adjuvant treatment
• It may have a direct survival benefit, as suggested by retrospective studies.

But lymphadenectomy is time-consuming, requires a specialized gynecologic surgeon, and is associated with some increase in the risk of morbidity—namely, lymphedema, lymphocyst formation, deep-vein thrombosis (DVT), and blood loss.

The much-anticipated report of the 85-center, multinational ASTEC trial [ A S urgical T rial of E ndometrial C ancer], published earlier this year, offers further insight into the practice of lymphadenectomy. ASTEC involved two randomizations: The first, to pelvic lymphadenectomy; the second, to radiation therapy.

Details of the ASTEC trial

The ASTEC trial enrolled 1,408 women who had histologically confirmed endometrial carcinoma that was believed to be confined to the uterus. How this determination was made was not specified. Patients who had enlarged lymph nodes corroborated by computed tomography or magnetic resonance imaging were not excluded.

Participants were randomized to either of the following treatment groups:

• traditional surgery with total hysterectomy and bilateral salpingo-oophorectomy, pelvic washings, and palpation of para-aortic nodes
• the same surgery plus systematic lymphadenectomy of the iliac and obturator nodes.

If any para-aortic nodes were suspicious, biopsy or lymphadenectomy was performed at the discretion of the surgeon ( FIGURE ).

FIGURE Nodes reveal when cancer has spread

Women in the ASTEC trial were randomized to traditional surgery (total hysterectomy and bilateral salpingo-oophorectomy), pelvic washings, and palpation of para-aortic nodes or to the same surgery plus lymphadenectomy of the iliac and obturator nodes.

Operative findings determined a patient’s level of risk

After surgery, patients were categorized as having one of the following:

• low-risk, early-stage disease. This group included patients who had disease classified as stage IA or IB, grade 1 or 2. They were deemed to have a suitably low risk of recurrence to be offered further treatment according to their physician’s standard practice.
• intermediate- or high-risk, early-stage disease. These patients were randomized to the ASTEC radiation-therapy trial, which compared external-beam radiotherapy with no external-beam radiotherapy. The authors assert that this second randomization was necessary to prevent over- or undertreatment of patients who had unknown node status, which might alter survival outcomes.
• advanced disease. These patients were referred to their physician for further treatment.

In both surgical groups (with and without lymphadenectomy), approximately 80% of patients had disease confined to the uterus. Nodes were harvested in 91% of the patients in the lymphadenectomy group, compared with 5% of patients in the traditional-surgery group. Nine percent of women in the lymphadenectomy group had positive nodes.

The authors observe that more women had deeply invasive disease and adverse histologic types in the group that underwent lymphadenectomy. There were no differences between the two groups in overall survival; disease-specific survival; recurrence-free survival; or recurrence-free, disease-specific survival, after adjustment for baseline differences. Subgroup analysis for low-risk, high-risk, and advanced disease also failed to demonstrate differences in overall survival and recurrence-free survival.

Study from Italy produces similar findings

An independent randomized, controlled trial examining survival outcomes for endometrial cancer patients with and without lymphadenectomy was released by the Italian group in late 2008. In this study, 537 patients who had histologically confirmed endometrial carcinoma believed to be confined to the uterus were randomized to total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without pelvic lymphadenectomy.

Anatomic boundaries of the pelvic lymph-node dissection were clearly defined, and a minimum lymph-node count of 20 was specified for inclusion. Intraoperative frozen section was utilized to exclude patients who had grade-1 disease that was less than 50% invasive. The option of para-aortic lymph-node dissection or sampling was left to the discretion of the surgeon. If pelvic nodes were larger than 1 cm, they were removed or sampled regardless of randomization.

Unlike the ASTEC trial, this study did not attempt to control adjuvant treatment. Patients were treated according to the discretion of the physician. Most patients received no further therapy; only 20% underwent radiation therapy, and 7% received chemotherapy.

Women in the lymphadenectomy group were more likely to have stage-IIIC disease, which is directly attributable to histologic evaluation of the lymph nodes in this group. The authors point out that these patients had more accurate assessment of their prognosis, allowing for the tailoring of adjuvant treatment.

The overall survival and disease-free survival curves for the two experimental groups were similar, consistent with data from the ASTEC trial. This proved to be true for both the intention-to-treat and according-to-protocol groups. The authors note that their results are similar to those of the ASTEC trial, despite the significant difference in the number of nodes removed in each trial.

Some aspects of the trials hamper interpretation and comparison

Outcomes are improved when surgery is performed by a trained gynecologic oncologist. In the ASTEC trial, each lymphadenectomy was performed by a specialized gynecologic surgeon who was “skilled in the procedure.” In the Italian study, the type of surgeon was not specified, but the specific anatomic boundaries of the dissection and the minimum node count were. More specific data are needed before any conclusions can be drawn about the effect of surgical skill on outcome in these trials.

In the ASTEC trial, 9% of patients in the lymphadenectomy group had no nodes removed, and more than 60% of patients would not have met criteria for inclusion in the lymphadenectomy arm of the Italian study—suggesting that the majority of women in the ASTEC trial had inadequate lymphadenectomy. Para-aortic lymphadenectomy was left to the discretion of the attending surgeon, and some patients did have resection of these nodes. The data do not include information about whether these patients were treated in the para-aortic region based on the histology of these nodes.

Randomization in a prospective study is supposed to equalize the risks between groups. In the ASTEC trial, despite randomization, there were 10% more patients who had deeply invasive disease in the lymphadenectomy group, along with 3% more adverse histologies and high-grade (grade-3) tumors. Given the higher incidence of positive nodes and poorer outcome in these cases, this difference may have had a significant impact on the evaluation of the groups for overall or disease-specific survival.

External-beam radiotherapy reduces local recurrence of endometrial Ca but does not improve survival

ASTEC/EN.5 Study Group, Blake P, Swart AM, Orton J, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet. 2009;373:137–146.

Radiation therapy has been a standard treatment for endometrial cancer when there is high risk of recurrence. This report combines two independent randomized, controlled trials investigating the benefit of postoperative adjuvant pelvic radiation in women who had early-stage disease and who met histologic criteria for high risk of recurrence and death. The trials are the EN.5 trial from Canada, and the radiation-therapy randomization of the ASTEC trial). Neither found a benefit in terms of overall survival, disease-specific survival, or recurrence-free survival, although local recurrence was reduced by 2.9% The authors also provide a review of the literature and a meta-analysis of other randomized, controlled trials on this subject.

Details of the EN.5 and ASTEC radiation-therapy trials

Criteria for enrollment were similar for the two trials, which focused on women who had histologically confirmed endometrial cancer and an intermediate or high risk of recurrence. This included women who had FIGO stage IA or stage IB (grade 3), stage IC (all grades), or papillary serous or clear-cell histology (all stages).

Lymphadenectomy was not required for patients enrolled in EN.5, but was part of the surgical randomization for ASTEC. This distinction could confound the results of the combined trials, as the investigators were trying to answer two questions within one patient population.

In both the EN.5 and ASTEC trials, women were randomized to observation or external-beam radiotherapy, with these parameters:

• Radiation therapy was to begin no later than 12 weeks after surgery (most patients began radiation therapy 6 to 8 weeks after surgery)
• For ASTEC, the target dosage was 40–46 Gy in 20–26 daily fractions to the pelvis, with treatment five times each week. For EN.5, the dosage and timing were very similar: 45 Gy, 25 daily fractions, five times weekly
• In both trials, vaginal brachytherapy was allowed if it was the local practice or the center’s policy
• Women were classified as being at intermediate risk or high risk, based on the likelihood of distant recurrence, as defined by GOG99 and PORTEC1 studies. Intermediate risk included all patients who had stage-IA or -IB (grade-3) or stage-IC or -IIA (grade-1 or -2) disease. Women who had papillary serous or clear-cell histology, stage-IC or -IIA (grade-3) disease, or any stage-IIB disease were considered at high risk.

The primary outcome evaluated for both trials was overall survival. Secondary endpoints were:

• disease-specific survival
• recurrence-free survival
• locoregional recurrence
• treatment toxicity.

A total of 905 women were enrolled in the ASTEC and EN.5 trials, with most patients having endometrial histology (83%) and being categorized as at intermediate risk (75%). Approximately half the patients in both trials received brachytherapy, which was allowed according to local practice. Only 47% of the observation group actually received no treatment.

Findings were remarkably similar in EN.5 and ASTEC

Here are the main findings:

• no difference between groups in overall survival, disease-specific survival, and recurrence-free survival
• significantly fewer isolated vaginal or pelvic initial recurrences in the external-beam radiotherapy group, with an absolute difference of 2.9%. (Only 35% of all recurrences were isolated recurrences)
• no significant difference between groups in distant or local and distant recurrences
• as expected, higher toxicity in the group receiving external-beam radiotherapy, including life-threatening toxicity (acute toxicity, 3% vs <1%; late toxicity, 1% vs 0%).

Subgroup analysis comparing overall survival in intermediate- and high-risk patients demonstrated no improvement with external-beam radiotherapy. Nor was overall survival altered by lymphadenectomy. The authors performed a meta-analysis using data from GOG99, PORTEC1, and this combined trial, and found no significant difference in overall survival or disease-specific survival, regardless of histologic risk group.

Trial has notable strengths and weaknesses

This large prospective trial has significant strengths: its size and its multi-institutional nature. The authors also evaluated their data in combination with other randomized, controlled trials to further investigate the effect of external-beam radiotherapy on survival. However, allowing brachytherapy somewhat confounds the true effect of external-beam radiotherapy on local recurrence. (There were few local recurrences, and the authors did not evaluate whether women who had an isolated vaginal recurrence received vaginal brachytherapy.) Moreover, 15% of women who were randomized to external-beam radiotherapy did not complete it.

In addition, secondary randomization of patients in the intermediate-risk and high-risk categories to external-beam radiotherapy versus no treatment may have significantly confounded the results of the entire ASTEC trial. Because women were, or were not, randomized to treatment regardless of node status, some patients who had positive nodes failed to receive adjuvant treatment. This may have had a significant effect on overall survival, as positive lymph nodes are a negative prognostic factor.

EXPERT COMMENTARY

When it comes to cervical cancer prevention, screening and diagnostic tests have limits to their accuracy. Cancer-prevention strategies work because we assess patients over time and because we accept a small number of false positives as necessary to minimize the loss of sensitivity; in that way, we also minimize cancer-related morbidity.¹

Link between high-risk HPV and cancer is a given

Cervical cancer is invariably linked to high-risk HPV. Women who are not truly infected with high-risk HPV are believed to have no risk for cervical cancer.² Assay-based endpoints such as HPV DNA testing have good accuracy indices, whereas cytologic and histologic endpoints are subject to greater human error.

A CIN 3 lesion should never occur in a woman who is negative for high-risk HPV DNA. When the combination is found, which is rare, one of two mechanisms is involved:

• a falsely negative HPV test
  
• a falsely positive diagnosis of CIN 3.
  

In ALTS, falsely positive histology was probably to blame

The CIN 3 detected in women who tested negative for high-risk HPV DNA (i.e., after borderline cytology rather than because of a high-grade squamous intraepithelial lesion [HSIL]) was probably associated with falsely positive histology rather than falsely negative HPV testing.

CIN 3 in women who tested negative for high-risk HPV DNA was more likely to be:

• diagnosed at exit
  
• from a center where CIN 3 diagnoses were not confirmed by the Pathology
  

• associated with a referral Pap test classified as LSIL than as ASCUS
  
• associated with an enrollment Pap test classified as HSIL
  
• symptomatic
  
• associated with high-grade Cervigrams.
  These women also were likely to test negative for HPV DNA using Linear Array.
  

In reviewing cases of CIN 3 in the 33 women who tested negative for high-risk HPV DNA, investigators found only 8 cases attributable to falsely-negative HPV testing, whereas 12 were related to incident HPV infection. Eight cases were caused by histologic overcall; 5 represented non–high-risk HPV that was unlikely to progress to cancer.

EXPERT COMMENTARY

When it comes to cervical cancer prevention, screening and diagnostic tests have limits to their accuracy. Cancer-prevention strategies work because we assess patients over time and because we accept a small number of false positives as necessary to minimize the loss of sensitivity; in that way, we also minimize cancer-related morbidity.¹

Link between high-risk HPV and cancer is a given

Cervical cancer is invariably linked to high-risk HPV. Women who are not truly infected with high-risk HPV are believed to have no risk for cervical cancer.² Assay-based endpoints such as HPV DNA testing have good accuracy indices, whereas cytologic and histologic endpoints are subject to greater human error.

A CIN 3 lesion should never occur in a woman who is negative for high-risk HPV DNA. When the combination is found, which is rare, one of two mechanisms is involved:

• a falsely negative HPV test
  
• a falsely positive diagnosis of CIN 3.
  

In ALTS, falsely positive histology was probably to blame

The CIN 3 detected in women who tested negative for high-risk HPV DNA (i.e., after borderline cytology rather than because of a high-grade squamous intraepithelial lesion [HSIL]) was probably associated with falsely positive histology rather than falsely negative HPV testing.

CIN 3 in women who tested negative for high-risk HPV DNA was more likely to be:

• diagnosed at exit
  
• from a center where CIN 3 diagnoses were not confirmed by the Pathology
  

• associated with a referral Pap test classified as LSIL than as ASCUS
  
• associated with an enrollment Pap test classified as HSIL
  
• symptomatic
  
• associated with high-grade Cervigrams.
  These women also were likely to test negative for HPV DNA using Linear Array.
  

In reviewing cases of CIN 3 in the 33 women who tested negative for high-risk HPV DNA, investigators found only 8 cases attributable to falsely-negative HPV testing, whereas 12 were related to incident HPV infection. Eight cases were caused by histologic overcall; 5 represented non–high-risk HPV that was unlikely to progress to cancer.

EXPERT COMMENTARY

When it comes to cervical cancer prevention, screening and diagnostic tests have limits to their accuracy. Cancer-prevention strategies work because we assess patients over time and because we accept a small number of false positives as necessary to minimize the loss of sensitivity; in that way, we also minimize cancer-related morbidity.¹

Link between high-risk HPV and cancer is a given

Cervical cancer is invariably linked to high-risk HPV. Women who are not truly infected with high-risk HPV are believed to have no risk for cervical cancer.² Assay-based endpoints such as HPV DNA testing have good accuracy indices, whereas cytologic and histologic endpoints are subject to greater human error.

A CIN 3 lesion should never occur in a woman who is negative for high-risk HPV DNA. When the combination is found, which is rare, one of two mechanisms is involved:

• a falsely negative HPV test
  
• a falsely positive diagnosis of CIN 3.
  

In ALTS, falsely positive histology was probably to blame

The CIN 3 detected in women who tested negative for high-risk HPV DNA (i.e., after borderline cytology rather than because of a high-grade squamous intraepithelial lesion [HSIL]) was probably associated with falsely positive histology rather than falsely negative HPV testing.

CIN 3 in women who tested negative for high-risk HPV DNA was more likely to be:

• diagnosed at exit
  
• from a center where CIN 3 diagnoses were not confirmed by the Pathology
  

• associated with a referral Pap test classified as LSIL than as ASCUS
  
• associated with an enrollment Pap test classified as HSIL
  
• symptomatic
  
• associated with high-grade Cervigrams.
  These women also were likely to test negative for HPV DNA using Linear Array.
  

In reviewing cases of CIN 3 in the 33 women who tested negative for high-risk HPV DNA, investigators found only 8 cases attributable to falsely-negative HPV testing, whereas 12 were related to incident HPV infection. Eight cases were caused by histologic overcall; 5 represented non–high-risk HPV that was unlikely to progress to cancer.

The authors report no financial relationships relevant to this article.

Postmenopausal bleeding is a symptom evaluated often by general gynecologists. It necessitates assessment of the endometrium, most often by tissue sampling. When endometrial cancer is confirmed by biopsy, management becomes complex. Should the patient be referred to a gynecologic oncologist? What kind of surgery does she need? What kind of adjuvant treatment will be offered? Could the diagnosis be part of a genetic cancer syndrome?

Recent studies have yielded new information:

• Preoperative, intraoperative, and postoperative care by a gynecologic oncologist significantly lowers the cost of health care
• Lymphadenectomy for endometrial cancer remains controversial, and may be unnecessary in low-risk patients
• Chemotherapy plays an expanding role in the treatment of endometrial cancer. Adjuvant therapy with doxorubicin, cisplatin, and paclitaxel is the treatment of choice for patients who have advanced-stage disease
• Nine percent of women who are given a diagnosis of endometrial cancer before 50 years of age have a germ-line Lynch syndrome-associated mutation, which demonstrates that heredity is an important aspect of endometrial cancer and should be considered at all times.

It’s good economics to refer patients to gyn oncology sooner, not later

Hoekstra A, Singh DK, Garb M, Arekapudi S, Rademaker A, Lurain JR. Participation of the general gynecologist in the surgical staging of endometrial cancer: analysis of cost and perioperative outcomes. Gynecol Oncol. 2006;103:897–901.

Early-stage endometrial cancer is often curable with surgery alone because a full 88% of endometrial cancers present as clinical stage I.¹ The role of the general gynecologist in surgical management of these cases is controversial; at some institutions, the practice is to call in the gynecologic oncologist for lymph-node sampling or when gross disease is identified; at others, the standard is to refer the patient to gynecologic oncology as soon as malignancy is diagnosed by endometrial biopsy. Hoekstra and colleagues have attempted to shed light on this issue with a retrospective chart review of 121 patients who were treated at one institution from 1998 to 2000.

Costs of early treatment by a gynecologic oncologist were lower than without referral

The authors performed a retrospective analysis of a group of women with clinical stage-I endometrial cancer who were treated surgically at Prentice Women’s Hospital in Chicago.

The cohort was divided in two:

• Group 1 comprised patients who underwent surgery with a general gynecologist, who consulted a gynecologic oncologist intraoperatively
• Group 2 comprised patients who were referred to a gynecologic oncologist before surgery and underwent the procedure with a gynecologic oncologist.

Overall, subjects in both groups were similar in age, distribution of surgical stage, need for lymphadenectomy, and length of follow-up.

Group 2 had a significantly shorter operative time overall, and shorter total time in the operating room. Cost per procedure was also significantly lower in this group, in terms of cost to the payer and the physician’s charge. Perioperative costs were also lower in Group 2.

No difference was observed in postoperative outcome. Total hospital costs and lengths of stay were also similar.

Recommendation for practice

With health-care costs rising, be aware of referral strategies that promote cost containment. Women who have endometrial cancer may benefit from the early involvement of a gynecologic oncologist.

Is lymphadenectomy necessary when risk of metastasis is low?

Mariani A, Dowdy S, Cliby W, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11–18.

The need for surgical staging of endometrial cancer has been recognized since surgical staging criteria were adopted by the International Federation of Gynecology and Obstetrics (FIGO) in 1988. Staging includes hysterectomy, bilateral salpingo-oophorectomy, and biopsy of any gross disease. Clear guidelines on the assessment of lymphatic dissemination and the anatomic extent of this assessment are, however, still lacking.

Proponents of systematic pelvic and para-aortic lymph-node dissection for patients with endometrial cancer cite:

• the 15% risk of lymph-node metastasis in women who have tumors 2 cm or larger in diameter²
• poor correlation between frozen-section grade and myometrial invasion with final pathology³
• the potential therapeutic benefit of the procedure.⁴

Opponents of such lymph-node dissection argue that women who have grade-1, stage-I disease will be overtreated if standardized lymphadenectomy is adopted.

Several retrospective studies have explored this question, with varying results. A large, prospective, randomized trial evaluating lymphadenectomy in clinical stage-I patients (ASTEC trial) has been completed, but is yet to be published.

When lymphadenectomy may (or may not) be necessary

After prospectively studying more than 300 endometrial cancer patients treated at the Mayo Clinic between 1984 and 1996,⁵ Mariani and colleagues launched a new study to assess a novel pattern of surgical management that aims to reduce the number of low-risk patients receiving lymphadenectomy. According to this pattern, the following types of women were able to bypass lymphadenectomy:

• those who had type-I, grades-1 and -2 tumors
• those with myometrial invasion ≤50%
• those with a primary tumor ≤2 cm in diameter.

Women who had endometrial cancer that did not meet these criteria underwent complete lymphadenectomy to the level of the renal vessels. Histologic assessment of the uterus to determine grade, depth of invasion, and primary tumor diameter was performed by frozen-section analysis in all cases.

The study included 422 women from January 2004 to December 2006. According to the guidelines of the study, 112 patients did not require lymphadenectomy. However, 22 (20%) women in this group did undergo the procedure because of palpable lymphadenopathy, initiation of dissection before the frozen-section report was received, or physician preference. All nodes were negative in these patients.

Of the women who met criteria for lymphadenectomy, 29 (9%) did not undergo dissection; among the reasons were disseminated disease, comorbid conditions, and advanced age. Of the women defined as at-risk who did undergo lymphadenectomy, 22% had lymph-node metastases.

Most positive para-aortic nodes lay above the inferior mesenteric artery

Information regarding the anatomic location of para-aortic nodal metastases was available for a small subset of women in the study. Seventy-seven percent of these women had para-aortic nodal metastasis above the inferior mesenteric artery. In addition, 71% of these patients had ipsilateral pelvic nodes that were free of disease. However, these patients had a poorer prognosis, and many would have received adjuvant therapy based on their hysterectomy specimen alone.

Recommendation for practice

This study suggests that there is a subset of patients who have endometrial cancer that is very low in risk and, because of this, they may forego lymph-node dissection without harm. In addition, a significant number of periaortic nodal metastases occur above the inferior mesenteric artery and in the absence of pelvic node involvement.

One of the limitations of this study is the need for intraoperative uterine assessment by frozen section by an expert pathologist—a service that is not widely available.

Taken together, these data suggest that, if the uterus can be assessed by frozen section at the time of surgery, a subset of clinical stage-I patients can be spared lymphadenectomy and its attendant risks.

Patients undergoing lymphatic assessment should undergo full systematic lymphnode dissection, not sampling. The dissection should include the region above the inferior mesenteric artery.

Removal of lymph nodes in endometrial cancer remains complex and controversial, a fact that strengthens the argument that an experienced gynecologic oncologist should be involved in the care of patients who have this disease.

Chemotherapy is warranted in advanced or recurrent disease

Homesley H, Filiaci V, Gibbons S, et al. Randomized phase III trial in advanced endometrial carcinoma of surgery and volume-directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Abstract presented at the Society of Gynecologic Oncologists, March 2008.

Adjuvant therapy for advanced-stage endometrial cancer has varied considerably over the years, and treatment of these patients remains somewhat controversial. Clinical trials comparing chemotherapy with radiation, and chemotherapy regimens with each other, have led to an era in which chemotherapy is used to treat more women than ever before.

In 2006, the Gynecologic Oncology Group (GOG) published the results of a prospective randomized study (GOG 122) that compared whole-abdomen radiation to doxorubicin and cisplatin in stage-III or -IV endometrial cancer. The investigators determined that chemotherapy was superior to whole-abdomen radiation in this trial.⁶

This finding was quickly followed by another trial (GOG 177) in which doxorubicin plus cisplatin was compared with a regimen of doxorubicin, cisplatin, and paclitaxel. Women in this trial had stage-III or -IV or recurrent disease. A history of radiation treatment did not disqualify patients from the study, and the treatment groups were well balanced in randomization. The doxorubicin–cisplatin–paclitaxel arm improved progression-free and overall survival, making this combination the preferred treatment.⁷

After volume-directed radiation, paclitaxel does not add benefit

Several retrospective analyses of radiation versus chemotherapy have shown improvement with radiation or combination therapy.⁸ Most recently, the GOG released data from a trial comparing chemotherapy regimens after radiation treatment. GOG 184 evaluated surgically debulked, stage-III or -IV patients who had received volume-directed radiation; subjects were randomized into either of two chemotherapy regimens:

• doxorubicin plus cisplatin
• doxorubicin, cisplatin, and paclitaxel.

In these patients, there was no improvement in survival when paclitaxel was added to the chemotherapeutic regimen, compared with doxorubicin plus cisplatin. Morbidity increased, however, with the addition of paclitaxel.

Patients in this trial underwent surgical resection of all gross disease, with no residual tumor larger than 2 cm. The role of optimal cytoreduction in endometrial cancer has been debated, however. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter (FIGURE).^9-11 GOG 184 inclusion criteria required surgical resection of gross disease to ≤2 cm in diameter. It is possible that the therapeutic benefit of surgical debulking may have improved outcome in these patients—to the extent that the addition of paclitaxel did not provide appreciable benefit.

FIGURE Debulk gross disease?

The role of optimal cytoreduction in endometrial cancer has been debated. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter.

Recommendation for practice

Data on adjuvant therapy for endometrial cancer remains conflicting. Women who have advanced-stage or recurrent endometrial cancer should receive chemotherapy—either with doxorubicin, cisplatin, and paclitaxel, or a platinum taxane regimen. The addition of paclitaxel in surgically debulked patients who have undergone radiation treatment does not appear to improve survival.

There is, however, a clear recommendation for paclitaxel in radiation-naïve patients and those who have gross residual disease. Further studies are needed to elucidate the role of radiation therapy in an era of volume-directed radiation.

Look for Lynch syndrome in young women with endometrial cancer

Lu K, Schorge J, Rodabaugh K, et al. Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol. 2007;25:5158–5164.

Endometrial cancer is part of the spectrum of Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). Patients with this autosomal-dominant hereditary cancer susceptibility syndrome may present with colorectal cancer, endometrial cancer, or, more rarely, ovarian cancer. Lynch syndrome derives from germline mutations in DNA mismatch repair genes, most often MLH1, MSH2, and MSH6.¹² Genetic testing for all three genes is available for clinical use.

In the past, screening for Lynch syndrome focused on colorectal cancer, but it is now clear that women who have this disorder have a lifetime risk of developing endometrial cancer that exceeds 40%.¹³

In Lynch syndrome, gynecologic cancer often precedes colon cancer

Women with Lynch syndrome-associated endometrial cancer typically present at a younger age than their syndrome-free counterparts (48 compared with 60 years).¹⁴ Previous retrospective studies demonstrated that 50% of women with Lynch syndrome-associated colon and gynecologic cancers had gynecologic cancer preceding the colon cancer. The average was 11 years earlier for endometrial cancer, which suggests that, if these women could be identified at the time they are given their diagnosis of endometrial cancer, more intensive screening for colon cancer could then be initiated.¹⁵

9% of women who develop endometrial cancer before age 50 have Lynch syndrome

One of the screening criteria for Lynch syndrome-associated colon cancer is age <50 years. In this recent prospective, multicenter study involving 100 women who were diagnosed with endometrial cancer at less than 50 years of age, germline Lynch syndrome mutations were identified in 9% of patients. (In this study, germline mutation testing was performed for MLH1, MSH2, and MSH6 genes by full sequencing, and immunohistochemistry was performed for all three genes. Microsatellite analysis was performed on 95 patients, with five women having insufficient tumor for DNA extraction.)

All women who had a germline mutation had a first-degree relative with Lynch syndrome-associated cancer. The combination of a negative family history for Lynch syndrome and a body mass index greater than 30 was highly predictive of having no Lynch syndrome mutation, with a negative predictive value of 96%.

Recommendation for practice

Patients who have an hereditary cancer syndrome such as Lynch syndrome can begin cancer-prevention screening—and be engaged in that screening—when the syndrome is recognized early. Because women who have endometrial cancer that was diagnosed before they were 50 years old are at significant risk of a germline mutation, they should be offered genetic counseling and testing.

The authors report no financial relationships relevant to this article.

Postmenopausal bleeding is a symptom evaluated often by general gynecologists. It necessitates assessment of the endometrium, most often by tissue sampling. When endometrial cancer is confirmed by biopsy, management becomes complex. Should the patient be referred to a gynecologic oncologist? What kind of surgery does she need? What kind of adjuvant treatment will be offered? Could the diagnosis be part of a genetic cancer syndrome?

Recent studies have yielded new information:

• Preoperative, intraoperative, and postoperative care by a gynecologic oncologist significantly lowers the cost of health care
• Lymphadenectomy for endometrial cancer remains controversial, and may be unnecessary in low-risk patients
• Chemotherapy plays an expanding role in the treatment of endometrial cancer. Adjuvant therapy with doxorubicin, cisplatin, and paclitaxel is the treatment of choice for patients who have advanced-stage disease
• Nine percent of women who are given a diagnosis of endometrial cancer before 50 years of age have a germ-line Lynch syndrome-associated mutation, which demonstrates that heredity is an important aspect of endometrial cancer and should be considered at all times.

It’s good economics to refer patients to gyn oncology sooner, not later

Hoekstra A, Singh DK, Garb M, Arekapudi S, Rademaker A, Lurain JR. Participation of the general gynecologist in the surgical staging of endometrial cancer: analysis of cost and perioperative outcomes. Gynecol Oncol. 2006;103:897–901.

Early-stage endometrial cancer is often curable with surgery alone because a full 88% of endometrial cancers present as clinical stage I.¹ The role of the general gynecologist in surgical management of these cases is controversial; at some institutions, the practice is to call in the gynecologic oncologist for lymph-node sampling or when gross disease is identified; at others, the standard is to refer the patient to gynecologic oncology as soon as malignancy is diagnosed by endometrial biopsy. Hoekstra and colleagues have attempted to shed light on this issue with a retrospective chart review of 121 patients who were treated at one institution from 1998 to 2000.

Costs of early treatment by a gynecologic oncologist were lower than without referral

The authors performed a retrospective analysis of a group of women with clinical stage-I endometrial cancer who were treated surgically at Prentice Women’s Hospital in Chicago.

The cohort was divided in two:

• Group 1 comprised patients who underwent surgery with a general gynecologist, who consulted a gynecologic oncologist intraoperatively
• Group 2 comprised patients who were referred to a gynecologic oncologist before surgery and underwent the procedure with a gynecologic oncologist.

Overall, subjects in both groups were similar in age, distribution of surgical stage, need for lymphadenectomy, and length of follow-up.

Group 2 had a significantly shorter operative time overall, and shorter total time in the operating room. Cost per procedure was also significantly lower in this group, in terms of cost to the payer and the physician’s charge. Perioperative costs were also lower in Group 2.

No difference was observed in postoperative outcome. Total hospital costs and lengths of stay were also similar.

Recommendation for practice

With health-care costs rising, be aware of referral strategies that promote cost containment. Women who have endometrial cancer may benefit from the early involvement of a gynecologic oncologist.

Is lymphadenectomy necessary when risk of metastasis is low?

Mariani A, Dowdy S, Cliby W, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11–18.

The need for surgical staging of endometrial cancer has been recognized since surgical staging criteria were adopted by the International Federation of Gynecology and Obstetrics (FIGO) in 1988. Staging includes hysterectomy, bilateral salpingo-oophorectomy, and biopsy of any gross disease. Clear guidelines on the assessment of lymphatic dissemination and the anatomic extent of this assessment are, however, still lacking.

Proponents of systematic pelvic and para-aortic lymph-node dissection for patients with endometrial cancer cite:

• the 15% risk of lymph-node metastasis in women who have tumors 2 cm or larger in diameter²
• poor correlation between frozen-section grade and myometrial invasion with final pathology³
• the potential therapeutic benefit of the procedure.⁴

Opponents of such lymph-node dissection argue that women who have grade-1, stage-I disease will be overtreated if standardized lymphadenectomy is adopted.

Several retrospective studies have explored this question, with varying results. A large, prospective, randomized trial evaluating lymphadenectomy in clinical stage-I patients (ASTEC trial) has been completed, but is yet to be published.

When lymphadenectomy may (or may not) be necessary

After prospectively studying more than 300 endometrial cancer patients treated at the Mayo Clinic between 1984 and 1996,⁵ Mariani and colleagues launched a new study to assess a novel pattern of surgical management that aims to reduce the number of low-risk patients receiving lymphadenectomy. According to this pattern, the following types of women were able to bypass lymphadenectomy:

• those who had type-I, grades-1 and -2 tumors
• those with myometrial invasion ≤50%
• those with a primary tumor ≤2 cm in diameter.

Women who had endometrial cancer that did not meet these criteria underwent complete lymphadenectomy to the level of the renal vessels. Histologic assessment of the uterus to determine grade, depth of invasion, and primary tumor diameter was performed by frozen-section analysis in all cases.

The study included 422 women from January 2004 to December 2006. According to the guidelines of the study, 112 patients did not require lymphadenectomy. However, 22 (20%) women in this group did undergo the procedure because of palpable lymphadenopathy, initiation of dissection before the frozen-section report was received, or physician preference. All nodes were negative in these patients.

Of the women who met criteria for lymphadenectomy, 29 (9%) did not undergo dissection; among the reasons were disseminated disease, comorbid conditions, and advanced age. Of the women defined as at-risk who did undergo lymphadenectomy, 22% had lymph-node metastases.

Most positive para-aortic nodes lay above the inferior mesenteric artery

Information regarding the anatomic location of para-aortic nodal metastases was available for a small subset of women in the study. Seventy-seven percent of these women had para-aortic nodal metastasis above the inferior mesenteric artery. In addition, 71% of these patients had ipsilateral pelvic nodes that were free of disease. However, these patients had a poorer prognosis, and many would have received adjuvant therapy based on their hysterectomy specimen alone.

Recommendation for practice

This study suggests that there is a subset of patients who have endometrial cancer that is very low in risk and, because of this, they may forego lymph-node dissection without harm. In addition, a significant number of periaortic nodal metastases occur above the inferior mesenteric artery and in the absence of pelvic node involvement.

One of the limitations of this study is the need for intraoperative uterine assessment by frozen section by an expert pathologist—a service that is not widely available.

Taken together, these data suggest that, if the uterus can be assessed by frozen section at the time of surgery, a subset of clinical stage-I patients can be spared lymphadenectomy and its attendant risks.

Patients undergoing lymphatic assessment should undergo full systematic lymphnode dissection, not sampling. The dissection should include the region above the inferior mesenteric artery.

Removal of lymph nodes in endometrial cancer remains complex and controversial, a fact that strengthens the argument that an experienced gynecologic oncologist should be involved in the care of patients who have this disease.

Chemotherapy is warranted in advanced or recurrent disease

Homesley H, Filiaci V, Gibbons S, et al. Randomized phase III trial in advanced endometrial carcinoma of surgery and volume-directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Abstract presented at the Society of Gynecologic Oncologists, March 2008.

Adjuvant therapy for advanced-stage endometrial cancer has varied considerably over the years, and treatment of these patients remains somewhat controversial. Clinical trials comparing chemotherapy with radiation, and chemotherapy regimens with each other, have led to an era in which chemotherapy is used to treat more women than ever before.

In 2006, the Gynecologic Oncology Group (GOG) published the results of a prospective randomized study (GOG 122) that compared whole-abdomen radiation to doxorubicin and cisplatin in stage-III or -IV endometrial cancer. The investigators determined that chemotherapy was superior to whole-abdomen radiation in this trial.⁶

This finding was quickly followed by another trial (GOG 177) in which doxorubicin plus cisplatin was compared with a regimen of doxorubicin, cisplatin, and paclitaxel. Women in this trial had stage-III or -IV or recurrent disease. A history of radiation treatment did not disqualify patients from the study, and the treatment groups were well balanced in randomization. The doxorubicin–cisplatin–paclitaxel arm improved progression-free and overall survival, making this combination the preferred treatment.⁷

After volume-directed radiation, paclitaxel does not add benefit

Several retrospective analyses of radiation versus chemotherapy have shown improvement with radiation or combination therapy.⁸ Most recently, the GOG released data from a trial comparing chemotherapy regimens after radiation treatment. GOG 184 evaluated surgically debulked, stage-III or -IV patients who had received volume-directed radiation; subjects were randomized into either of two chemotherapy regimens:

• doxorubicin plus cisplatin
• doxorubicin, cisplatin, and paclitaxel.

In these patients, there was no improvement in survival when paclitaxel was added to the chemotherapeutic regimen, compared with doxorubicin plus cisplatin. Morbidity increased, however, with the addition of paclitaxel.

Patients in this trial underwent surgical resection of all gross disease, with no residual tumor larger than 2 cm. The role of optimal cytoreduction in endometrial cancer has been debated, however. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter (FIGURE).^9-11 GOG 184 inclusion criteria required surgical resection of gross disease to ≤2 cm in diameter. It is possible that the therapeutic benefit of surgical debulking may have improved outcome in these patients—to the extent that the addition of paclitaxel did not provide appreciable benefit.

FIGURE Debulk gross disease?

The role of optimal cytoreduction in endometrial cancer has been debated. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter.

Recommendation for practice

Data on adjuvant therapy for endometrial cancer remains conflicting. Women who have advanced-stage or recurrent endometrial cancer should receive chemotherapy—either with doxorubicin, cisplatin, and paclitaxel, or a platinum taxane regimen. The addition of paclitaxel in surgically debulked patients who have undergone radiation treatment does not appear to improve survival.

There is, however, a clear recommendation for paclitaxel in radiation-naïve patients and those who have gross residual disease. Further studies are needed to elucidate the role of radiation therapy in an era of volume-directed radiation.

Look for Lynch syndrome in young women with endometrial cancer

Lu K, Schorge J, Rodabaugh K, et al. Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol. 2007;25:5158–5164.

Endometrial cancer is part of the spectrum of Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). Patients with this autosomal-dominant hereditary cancer susceptibility syndrome may present with colorectal cancer, endometrial cancer, or, more rarely, ovarian cancer. Lynch syndrome derives from germline mutations in DNA mismatch repair genes, most often MLH1, MSH2, and MSH6.¹² Genetic testing for all three genes is available for clinical use.

In the past, screening for Lynch syndrome focused on colorectal cancer, but it is now clear that women who have this disorder have a lifetime risk of developing endometrial cancer that exceeds 40%.¹³

In Lynch syndrome, gynecologic cancer often precedes colon cancer

Women with Lynch syndrome-associated endometrial cancer typically present at a younger age than their syndrome-free counterparts (48 compared with 60 years).¹⁴ Previous retrospective studies demonstrated that 50% of women with Lynch syndrome-associated colon and gynecologic cancers had gynecologic cancer preceding the colon cancer. The average was 11 years earlier for endometrial cancer, which suggests that, if these women could be identified at the time they are given their diagnosis of endometrial cancer, more intensive screening for colon cancer could then be initiated.¹⁵

9% of women who develop endometrial cancer before age 50 have Lynch syndrome

One of the screening criteria for Lynch syndrome-associated colon cancer is age <50 years. In this recent prospective, multicenter study involving 100 women who were diagnosed with endometrial cancer at less than 50 years of age, germline Lynch syndrome mutations were identified in 9% of patients. (In this study, germline mutation testing was performed for MLH1, MSH2, and MSH6 genes by full sequencing, and immunohistochemistry was performed for all three genes. Microsatellite analysis was performed on 95 patients, with five women having insufficient tumor for DNA extraction.)

All women who had a germline mutation had a first-degree relative with Lynch syndrome-associated cancer. The combination of a negative family history for Lynch syndrome and a body mass index greater than 30 was highly predictive of having no Lynch syndrome mutation, with a negative predictive value of 96%.

Recommendation for practice

Patients who have an hereditary cancer syndrome such as Lynch syndrome can begin cancer-prevention screening—and be engaged in that screening—when the syndrome is recognized early. Because women who have endometrial cancer that was diagnosed before they were 50 years old are at significant risk of a germline mutation, they should be offered genetic counseling and testing.

The authors report no financial relationships relevant to this article.

Postmenopausal bleeding is a symptom evaluated often by general gynecologists. It necessitates assessment of the endometrium, most often by tissue sampling. When endometrial cancer is confirmed by biopsy, management becomes complex. Should the patient be referred to a gynecologic oncologist? What kind of surgery does she need? What kind of adjuvant treatment will be offered? Could the diagnosis be part of a genetic cancer syndrome?

Recent studies have yielded new information:

• Preoperative, intraoperative, and postoperative care by a gynecologic oncologist significantly lowers the cost of health care
• Lymphadenectomy for endometrial cancer remains controversial, and may be unnecessary in low-risk patients
• Chemotherapy plays an expanding role in the treatment of endometrial cancer. Adjuvant therapy with doxorubicin, cisplatin, and paclitaxel is the treatment of choice for patients who have advanced-stage disease
• Nine percent of women who are given a diagnosis of endometrial cancer before 50 years of age have a germ-line Lynch syndrome-associated mutation, which demonstrates that heredity is an important aspect of endometrial cancer and should be considered at all times.

It’s good economics to refer patients to gyn oncology sooner, not later

Hoekstra A, Singh DK, Garb M, Arekapudi S, Rademaker A, Lurain JR. Participation of the general gynecologist in the surgical staging of endometrial cancer: analysis of cost and perioperative outcomes. Gynecol Oncol. 2006;103:897–901.

Early-stage endometrial cancer is often curable with surgery alone because a full 88% of endometrial cancers present as clinical stage I.¹ The role of the general gynecologist in surgical management of these cases is controversial; at some institutions, the practice is to call in the gynecologic oncologist for lymph-node sampling or when gross disease is identified; at others, the standard is to refer the patient to gynecologic oncology as soon as malignancy is diagnosed by endometrial biopsy. Hoekstra and colleagues have attempted to shed light on this issue with a retrospective chart review of 121 patients who were treated at one institution from 1998 to 2000.

Costs of early treatment by a gynecologic oncologist were lower than without referral

The authors performed a retrospective analysis of a group of women with clinical stage-I endometrial cancer who were treated surgically at Prentice Women’s Hospital in Chicago.

The cohort was divided in two:

• Group 1 comprised patients who underwent surgery with a general gynecologist, who consulted a gynecologic oncologist intraoperatively
• Group 2 comprised patients who were referred to a gynecologic oncologist before surgery and underwent the procedure with a gynecologic oncologist.

Overall, subjects in both groups were similar in age, distribution of surgical stage, need for lymphadenectomy, and length of follow-up.

Group 2 had a significantly shorter operative time overall, and shorter total time in the operating room. Cost per procedure was also significantly lower in this group, in terms of cost to the payer and the physician’s charge. Perioperative costs were also lower in Group 2.

No difference was observed in postoperative outcome. Total hospital costs and lengths of stay were also similar.

Recommendation for practice

With health-care costs rising, be aware of referral strategies that promote cost containment. Women who have endometrial cancer may benefit from the early involvement of a gynecologic oncologist.

Is lymphadenectomy necessary when risk of metastasis is low?

Mariani A, Dowdy S, Cliby W, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11–18.

The need for surgical staging of endometrial cancer has been recognized since surgical staging criteria were adopted by the International Federation of Gynecology and Obstetrics (FIGO) in 1988. Staging includes hysterectomy, bilateral salpingo-oophorectomy, and biopsy of any gross disease. Clear guidelines on the assessment of lymphatic dissemination and the anatomic extent of this assessment are, however, still lacking.

Proponents of systematic pelvic and para-aortic lymph-node dissection for patients with endometrial cancer cite:

• the 15% risk of lymph-node metastasis in women who have tumors 2 cm or larger in diameter²
• poor correlation between frozen-section grade and myometrial invasion with final pathology³
• the potential therapeutic benefit of the procedure.⁴

Opponents of such lymph-node dissection argue that women who have grade-1, stage-I disease will be overtreated if standardized lymphadenectomy is adopted.

Several retrospective studies have explored this question, with varying results. A large, prospective, randomized trial evaluating lymphadenectomy in clinical stage-I patients (ASTEC trial) has been completed, but is yet to be published.

When lymphadenectomy may (or may not) be necessary

After prospectively studying more than 300 endometrial cancer patients treated at the Mayo Clinic between 1984 and 1996,⁵ Mariani and colleagues launched a new study to assess a novel pattern of surgical management that aims to reduce the number of low-risk patients receiving lymphadenectomy. According to this pattern, the following types of women were able to bypass lymphadenectomy:

• those who had type-I, grades-1 and -2 tumors
• those with myometrial invasion ≤50%
• those with a primary tumor ≤2 cm in diameter.

Women who had endometrial cancer that did not meet these criteria underwent complete lymphadenectomy to the level of the renal vessels. Histologic assessment of the uterus to determine grade, depth of invasion, and primary tumor diameter was performed by frozen-section analysis in all cases.

The study included 422 women from January 2004 to December 2006. According to the guidelines of the study, 112 patients did not require lymphadenectomy. However, 22 (20%) women in this group did undergo the procedure because of palpable lymphadenopathy, initiation of dissection before the frozen-section report was received, or physician preference. All nodes were negative in these patients.

Of the women who met criteria for lymphadenectomy, 29 (9%) did not undergo dissection; among the reasons were disseminated disease, comorbid conditions, and advanced age. Of the women defined as at-risk who did undergo lymphadenectomy, 22% had lymph-node metastases.

Most positive para-aortic nodes lay above the inferior mesenteric artery

Information regarding the anatomic location of para-aortic nodal metastases was available for a small subset of women in the study. Seventy-seven percent of these women had para-aortic nodal metastasis above the inferior mesenteric artery. In addition, 71% of these patients had ipsilateral pelvic nodes that were free of disease. However, these patients had a poorer prognosis, and many would have received adjuvant therapy based on their hysterectomy specimen alone.

Recommendation for practice

This study suggests that there is a subset of patients who have endometrial cancer that is very low in risk and, because of this, they may forego lymph-node dissection without harm. In addition, a significant number of periaortic nodal metastases occur above the inferior mesenteric artery and in the absence of pelvic node involvement.

One of the limitations of this study is the need for intraoperative uterine assessment by frozen section by an expert pathologist—a service that is not widely available.

Taken together, these data suggest that, if the uterus can be assessed by frozen section at the time of surgery, a subset of clinical stage-I patients can be spared lymphadenectomy and its attendant risks.

Patients undergoing lymphatic assessment should undergo full systematic lymphnode dissection, not sampling. The dissection should include the region above the inferior mesenteric artery.

Removal of lymph nodes in endometrial cancer remains complex and controversial, a fact that strengthens the argument that an experienced gynecologic oncologist should be involved in the care of patients who have this disease.

Chemotherapy is warranted in advanced or recurrent disease

Homesley H, Filiaci V, Gibbons S, et al. Randomized phase III trial in advanced endometrial carcinoma of surgery and volume-directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Abstract presented at the Society of Gynecologic Oncologists, March 2008.

Adjuvant therapy for advanced-stage endometrial cancer has varied considerably over the years, and treatment of these patients remains somewhat controversial. Clinical trials comparing chemotherapy with radiation, and chemotherapy regimens with each other, have led to an era in which chemotherapy is used to treat more women than ever before.

In 2006, the Gynecologic Oncology Group (GOG) published the results of a prospective randomized study (GOG 122) that compared whole-abdomen radiation to doxorubicin and cisplatin in stage-III or -IV endometrial cancer. The investigators determined that chemotherapy was superior to whole-abdomen radiation in this trial.⁶

This finding was quickly followed by another trial (GOG 177) in which doxorubicin plus cisplatin was compared with a regimen of doxorubicin, cisplatin, and paclitaxel. Women in this trial had stage-III or -IV or recurrent disease. A history of radiation treatment did not disqualify patients from the study, and the treatment groups were well balanced in randomization. The doxorubicin–cisplatin–paclitaxel arm improved progression-free and overall survival, making this combination the preferred treatment.⁷

After volume-directed radiation, paclitaxel does not add benefit

Several retrospective analyses of radiation versus chemotherapy have shown improvement with radiation or combination therapy.⁸ Most recently, the GOG released data from a trial comparing chemotherapy regimens after radiation treatment. GOG 184 evaluated surgically debulked, stage-III or -IV patients who had received volume-directed radiation; subjects were randomized into either of two chemotherapy regimens:

• doxorubicin plus cisplatin
• doxorubicin, cisplatin, and paclitaxel.

In these patients, there was no improvement in survival when paclitaxel was added to the chemotherapeutic regimen, compared with doxorubicin plus cisplatin. Morbidity increased, however, with the addition of paclitaxel.

Patients in this trial underwent surgical resection of all gross disease, with no residual tumor larger than 2 cm. The role of optimal cytoreduction in endometrial cancer has been debated, however. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter (FIGURE).^9-11 GOG 184 inclusion criteria required surgical resection of gross disease to ≤2 cm in diameter. It is possible that the therapeutic benefit of surgical debulking may have improved outcome in these patients—to the extent that the addition of paclitaxel did not provide appreciable benefit.

FIGURE Debulk gross disease?

The role of optimal cytoreduction in endometrial cancer has been debated. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter.

Recommendation for practice

Data on adjuvant therapy for endometrial cancer remains conflicting. Women who have advanced-stage or recurrent endometrial cancer should receive chemotherapy—either with doxorubicin, cisplatin, and paclitaxel, or a platinum taxane regimen. The addition of paclitaxel in surgically debulked patients who have undergone radiation treatment does not appear to improve survival.

There is, however, a clear recommendation for paclitaxel in radiation-naïve patients and those who have gross residual disease. Further studies are needed to elucidate the role of radiation therapy in an era of volume-directed radiation.

Look for Lynch syndrome in young women with endometrial cancer

Lu K, Schorge J, Rodabaugh K, et al. Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol. 2007;25:5158–5164.

Endometrial cancer is part of the spectrum of Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). Patients with this autosomal-dominant hereditary cancer susceptibility syndrome may present with colorectal cancer, endometrial cancer, or, more rarely, ovarian cancer. Lynch syndrome derives from germline mutations in DNA mismatch repair genes, most often MLH1, MSH2, and MSH6.¹² Genetic testing for all three genes is available for clinical use.

In the past, screening for Lynch syndrome focused on colorectal cancer, but it is now clear that women who have this disorder have a lifetime risk of developing endometrial cancer that exceeds 40%.¹³

In Lynch syndrome, gynecologic cancer often precedes colon cancer

Women with Lynch syndrome-associated endometrial cancer typically present at a younger age than their syndrome-free counterparts (48 compared with 60 years).¹⁴ Previous retrospective studies demonstrated that 50% of women with Lynch syndrome-associated colon and gynecologic cancers had gynecologic cancer preceding the colon cancer. The average was 11 years earlier for endometrial cancer, which suggests that, if these women could be identified at the time they are given their diagnosis of endometrial cancer, more intensive screening for colon cancer could then be initiated.¹⁵

9% of women who develop endometrial cancer before age 50 have Lynch syndrome

One of the screening criteria for Lynch syndrome-associated colon cancer is age <50 years. In this recent prospective, multicenter study involving 100 women who were diagnosed with endometrial cancer at less than 50 years of age, germline Lynch syndrome mutations were identified in 9% of patients. (In this study, germline mutation testing was performed for MLH1, MSH2, and MSH6 genes by full sequencing, and immunohistochemistry was performed for all three genes. Microsatellite analysis was performed on 95 patients, with five women having insufficient tumor for DNA extraction.)

All women who had a germline mutation had a first-degree relative with Lynch syndrome-associated cancer. The combination of a negative family history for Lynch syndrome and a body mass index greater than 30 was highly predictive of having no Lynch syndrome mutation, with a negative predictive value of 96%.

Recommendation for practice

Patients who have an hereditary cancer syndrome such as Lynch syndrome can begin cancer-prevention screening—and be engaged in that screening—when the syndrome is recognized early. Because women who have endometrial cancer that was diagnosed before they were 50 years old are at significant risk of a germline mutation, they should be offered genetic counseling and testing.