AVAHO

Lung cancer is the leading cause of cancer death in the United States.¹ The 2011 National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography (LDCT) screening provided a 20% relative reduction in lung cancer–specific mortality.² Based on these findings, the United States Preventive Services Task Force (USPSTF) published lung cancer screening guidelines in 2013 recommending an annual LDCT of the thorax in patients aged 55 to 80 years with a 30 pack-year smoking history and who currently smoke or quit within the past 15 years. 

In 2021, the USPSTF updated its recommendations by reducing the qualifications for annual screening to a 20 pack-year smoking history.³ The updated guidelines recognized the increased risk of lung cancer for Black individuals.^4,5 Evidence suggests the 2013 screening criteria was too conservative for this population.^6,7

Similarly, US Department of Veteran Affairs (VA) patients are a population at higher risk for lung cancer due to a male predominance, presence of comorbidities, exposure to carcinogenic agents, and possibly a higher prevalence of tobacco smoking.⁸ This study sought to examine the applicability of the USPSTF guidelines in a VA health care system with a predominantly Black population.

Methods

A retrospective chart review of adult patients who were diagnosed and treated with early-stage small cell or non–small cell lung cancer (stage I or II) was performed within the Southeast Louisiana Veterans Health Care System (SLVHCS) in New Orleans. The review used data from the VA Cancer Registry from January 1, 2005, through December 31, 2017. Patients were grouped by whether they met 2013 USPSTF screening criteria at time of diagnosis vs those that did not. Data collected included type and stage of lung cancer at time of diagnosis, context of diagnosis (incidental, screening, symptomatic), diagnostic method, smoking history, and presence of chronic obstructive pulmonary disease (COPD). Patients without a clear smoking history documented in the health record were excluded.

Statistical analyses were performed with GraphPad Prism 8.0. Student t test and Fischer exact test were performed for most of the statistical analyses, with differences between groups noted to be statistically significant at a P < .05.

Results

A total of 182 patient charts were reviewed and 13 patients were excluded for missing information related to the USPSTF screening criteria. Of the 169 patients included, 122 (72%) met USPSTF screening criteria while 47 (28%) patients did not. The reasons for not meeting screening criteria were 14 patients were too young at and 9 patients were too old at time of diagnosis, 7 had a < 20 pack-year smoking history, 7 patients had quit > 15 years previously, and 12 patients met multiple exclusion criteria. The study population was 96% male and there was an overall predominance of Black patients (58%) within the sample (Table).

There was a significantly higher proportion of Black patients in the group that did not meet screening criteria compared with the group that met screening criteria (68% vs 54%, P = .04). Cancer type and stage at diagnosis were similar in both patient populations. There was a statistically significant difference in COPD diagnosis between the groups, with a larger proportion of COPD patients in the met screening criteria group (74% vs 45%, P < .001). The mean smoking history was 61.4 pack-years in the met criteria group and 43.3 pack-years in the did not meet criteria group.  

Five additional patients in the group that did not meet the 2013 USPSTF screening criteria would have met criteria if the 2021 USPSTF guidelines were applied. All 5 were Black patients. Using the 2021 guidelines, Black patients would have made up 56% of the patients who met screening criteria and 54% of the patients who did not meet screening criteria at time of diagnosis.

Discussion

This study sought to determine the hypothetical effectiveness of national lung cancer screening guidelines in detecting early-stage lung cancer for a high-risk population. Patients diagnosed with early-stage lung cancer were selected as these patients have improved outcomes with treatment, and thus would theoretically benefit from early detection through screening. As expected, the study population had a majority of Black veterans (58%), with a higher proportion of Black patients in the did not meet screening criteria group compared with the met screening criteria group (68% vs 54%, P = .04). This difference highlights the concern that Black individuals were being underscreened with the 2013 USPSTF guidelines.⁷ This is not all surprising as the NLST, from which the initial screening guidelines were based, included a majority White population with only 4.4% of their population being Black.² The USPSTF also cites the NELSON trial as evidence to support annual lung cancer screening, a trial that was performed in the Netherlands with a very different population compared with that of southeast Louisiana.⁹

Given concern that the old criteria were underscreening certain populations, the updated 2021 USPSTF guidelines sought to expand the screening population. In this study, the implementation of these new guidelines resulted in more Black patients meeting screening criteria.

Racial and ethnic disparities in health care in the US are no secret, as Black individuals consistently have increased disease and death rates, higher rates of unemployment, and decreased access to preventive medical care compared to White individuals.¹⁰ Despite the updated USPSTF guidelines, additional modifications to the screening criteria could improve the ability to identify high-risk patients. A modified model using data from the Prostate, Lung, Colorectal, and Ovarian Screening Trial (PLCO) incorporating COPD history, race and ethnicity, and personal history of cancer increased the sensitivity for high-risk Black ever-smokers.¹¹ Additional models and analyses also support the utility of incorporating race and ethnicity in lung cancer screening criteria.^7,12 Using race and ethnicity to guide screening criteria for cancer is not unheard of; in 2017, the US Multi-Society Task Force recommended that Black individuals start colon cancer screening at age 45 years rather than the typical age of 50 years, before updating the guidelines again in 2021 to recommend that all adults start at age 45 years.^13,14

Limitations

This study had the inherent weakness of being a retrospective study at a single institution. Additionally, the 7th edition of the International Association for the Study of Lung Cancer was published in 2010, during the 2005 to 2017 time frame from which our data was collected, leading to possible inconsistencies in staging between patients before and after 2010.¹⁵ However, these changes in staging are unlikely to significantly impact the results for in this study, since the vast majority of the patients diagnosed with lung cancer stage I or II before 2010 would still be in the those 2 stages in the 2010 edition. Finally, specific to our patient population, it was often difficult to ascertain an accurate smoking history for each patient, especially in the early years of the data set, likely due to the disruption of care caused by Hurricane Katrina.

Conclusions

In this retrospective study performed at the SLVHCS in New Orleans, a significantly higher proportion of Black patients compared with White patients with early-stage lung cancer did not meet the 2013 USPSTF lung cancer screening guidelines at time of diagnosis, highlighting the concern that this population was being underscreened. These findings demonstrate the challenges and failures of applying national guidelines to a unique, high-risk population. An individualized, risk-based screening model incorporating race and ethnicity could be more effective at diagnosing early-stage lung cancer and requires more investigation. Centralized lung cancer screening programs within the VA system could also be beneficial for early detection and treatment, as well as provide insight into the increased risk within the veteran population.

Lung cancer is the leading cause of cancer death in the United States.¹ The 2011 National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography (LDCT) screening provided a 20% relative reduction in lung cancer–specific mortality.² Based on these findings, the United States Preventive Services Task Force (USPSTF) published lung cancer screening guidelines in 2013 recommending an annual LDCT of the thorax in patients aged 55 to 80 years with a 30 pack-year smoking history and who currently smoke or quit within the past 15 years. 

In 2021, the USPSTF updated its recommendations by reducing the qualifications for annual screening to a 20 pack-year smoking history.³ The updated guidelines recognized the increased risk of lung cancer for Black individuals.^4,5 Evidence suggests the 2013 screening criteria was too conservative for this population.^6,7

Similarly, US Department of Veteran Affairs (VA) patients are a population at higher risk for lung cancer due to a male predominance, presence of comorbidities, exposure to carcinogenic agents, and possibly a higher prevalence of tobacco smoking.⁸ This study sought to examine the applicability of the USPSTF guidelines in a VA health care system with a predominantly Black population.

Methods

A retrospective chart review of adult patients who were diagnosed and treated with early-stage small cell or non–small cell lung cancer (stage I or II) was performed within the Southeast Louisiana Veterans Health Care System (SLVHCS) in New Orleans. The review used data from the VA Cancer Registry from January 1, 2005, through December 31, 2017. Patients were grouped by whether they met 2013 USPSTF screening criteria at time of diagnosis vs those that did not. Data collected included type and stage of lung cancer at time of diagnosis, context of diagnosis (incidental, screening, symptomatic), diagnostic method, smoking history, and presence of chronic obstructive pulmonary disease (COPD). Patients without a clear smoking history documented in the health record were excluded.

Statistical analyses were performed with GraphPad Prism 8.0. Student t test and Fischer exact test were performed for most of the statistical analyses, with differences between groups noted to be statistically significant at a P < .05.

Results

A total of 182 patient charts were reviewed and 13 patients were excluded for missing information related to the USPSTF screening criteria. Of the 169 patients included, 122 (72%) met USPSTF screening criteria while 47 (28%) patients did not. The reasons for not meeting screening criteria were 14 patients were too young at and 9 patients were too old at time of diagnosis, 7 had a < 20 pack-year smoking history, 7 patients had quit > 15 years previously, and 12 patients met multiple exclusion criteria. The study population was 96% male and there was an overall predominance of Black patients (58%) within the sample (Table).

There was a significantly higher proportion of Black patients in the group that did not meet screening criteria compared with the group that met screening criteria (68% vs 54%, P = .04). Cancer type and stage at diagnosis were similar in both patient populations. There was a statistically significant difference in COPD diagnosis between the groups, with a larger proportion of COPD patients in the met screening criteria group (74% vs 45%, P < .001). The mean smoking history was 61.4 pack-years in the met criteria group and 43.3 pack-years in the did not meet criteria group.  

Five additional patients in the group that did not meet the 2013 USPSTF screening criteria would have met criteria if the 2021 USPSTF guidelines were applied. All 5 were Black patients. Using the 2021 guidelines, Black patients would have made up 56% of the patients who met screening criteria and 54% of the patients who did not meet screening criteria at time of diagnosis.

Discussion

This study sought to determine the hypothetical effectiveness of national lung cancer screening guidelines in detecting early-stage lung cancer for a high-risk population. Patients diagnosed with early-stage lung cancer were selected as these patients have improved outcomes with treatment, and thus would theoretically benefit from early detection through screening. As expected, the study population had a majority of Black veterans (58%), with a higher proportion of Black patients in the did not meet screening criteria group compared with the met screening criteria group (68% vs 54%, P = .04). This difference highlights the concern that Black individuals were being underscreened with the 2013 USPSTF guidelines.⁷ This is not all surprising as the NLST, from which the initial screening guidelines were based, included a majority White population with only 4.4% of their population being Black.² The USPSTF also cites the NELSON trial as evidence to support annual lung cancer screening, a trial that was performed in the Netherlands with a very different population compared with that of southeast Louisiana.⁹

Given concern that the old criteria were underscreening certain populations, the updated 2021 USPSTF guidelines sought to expand the screening population. In this study, the implementation of these new guidelines resulted in more Black patients meeting screening criteria.

Racial and ethnic disparities in health care in the US are no secret, as Black individuals consistently have increased disease and death rates, higher rates of unemployment, and decreased access to preventive medical care compared to White individuals.¹⁰ Despite the updated USPSTF guidelines, additional modifications to the screening criteria could improve the ability to identify high-risk patients. A modified model using data from the Prostate, Lung, Colorectal, and Ovarian Screening Trial (PLCO) incorporating COPD history, race and ethnicity, and personal history of cancer increased the sensitivity for high-risk Black ever-smokers.¹¹ Additional models and analyses also support the utility of incorporating race and ethnicity in lung cancer screening criteria.^7,12 Using race and ethnicity to guide screening criteria for cancer is not unheard of; in 2017, the US Multi-Society Task Force recommended that Black individuals start colon cancer screening at age 45 years rather than the typical age of 50 years, before updating the guidelines again in 2021 to recommend that all adults start at age 45 years.^13,14

Limitations

This study had the inherent weakness of being a retrospective study at a single institution. Additionally, the 7th edition of the International Association for the Study of Lung Cancer was published in 2010, during the 2005 to 2017 time frame from which our data was collected, leading to possible inconsistencies in staging between patients before and after 2010.¹⁵ However, these changes in staging are unlikely to significantly impact the results for in this study, since the vast majority of the patients diagnosed with lung cancer stage I or II before 2010 would still be in the those 2 stages in the 2010 edition. Finally, specific to our patient population, it was often difficult to ascertain an accurate smoking history for each patient, especially in the early years of the data set, likely due to the disruption of care caused by Hurricane Katrina.

Conclusions

In this retrospective study performed at the SLVHCS in New Orleans, a significantly higher proportion of Black patients compared with White patients with early-stage lung cancer did not meet the 2013 USPSTF lung cancer screening guidelines at time of diagnosis, highlighting the concern that this population was being underscreened. These findings demonstrate the challenges and failures of applying national guidelines to a unique, high-risk population. An individualized, risk-based screening model incorporating race and ethnicity could be more effective at diagnosing early-stage lung cancer and requires more investigation. Centralized lung cancer screening programs within the VA system could also be beneficial for early detection and treatment, as well as provide insight into the increased risk within the veteran population.

Lung cancer is the leading cause of cancer death in the United States.¹ The 2011 National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography (LDCT) screening provided a 20% relative reduction in lung cancer–specific mortality.² Based on these findings, the United States Preventive Services Task Force (USPSTF) published lung cancer screening guidelines in 2013 recommending an annual LDCT of the thorax in patients aged 55 to 80 years with a 30 pack-year smoking history and who currently smoke or quit within the past 15 years. 

In 2021, the USPSTF updated its recommendations by reducing the qualifications for annual screening to a 20 pack-year smoking history.³ The updated guidelines recognized the increased risk of lung cancer for Black individuals.^4,5 Evidence suggests the 2013 screening criteria was too conservative for this population.^6,7

Similarly, US Department of Veteran Affairs (VA) patients are a population at higher risk for lung cancer due to a male predominance, presence of comorbidities, exposure to carcinogenic agents, and possibly a higher prevalence of tobacco smoking.⁸ This study sought to examine the applicability of the USPSTF guidelines in a VA health care system with a predominantly Black population.

Methods

A retrospective chart review of adult patients who were diagnosed and treated with early-stage small cell or non–small cell lung cancer (stage I or II) was performed within the Southeast Louisiana Veterans Health Care System (SLVHCS) in New Orleans. The review used data from the VA Cancer Registry from January 1, 2005, through December 31, 2017. Patients were grouped by whether they met 2013 USPSTF screening criteria at time of diagnosis vs those that did not. Data collected included type and stage of lung cancer at time of diagnosis, context of diagnosis (incidental, screening, symptomatic), diagnostic method, smoking history, and presence of chronic obstructive pulmonary disease (COPD). Patients without a clear smoking history documented in the health record were excluded.

Statistical analyses were performed with GraphPad Prism 8.0. Student t test and Fischer exact test were performed for most of the statistical analyses, with differences between groups noted to be statistically significant at a P < .05.

Results

A total of 182 patient charts were reviewed and 13 patients were excluded for missing information related to the USPSTF screening criteria. Of the 169 patients included, 122 (72%) met USPSTF screening criteria while 47 (28%) patients did not. The reasons for not meeting screening criteria were 14 patients were too young at and 9 patients were too old at time of diagnosis, 7 had a < 20 pack-year smoking history, 7 patients had quit > 15 years previously, and 12 patients met multiple exclusion criteria. The study population was 96% male and there was an overall predominance of Black patients (58%) within the sample (Table).

There was a significantly higher proportion of Black patients in the group that did not meet screening criteria compared with the group that met screening criteria (68% vs 54%, P = .04). Cancer type and stage at diagnosis were similar in both patient populations. There was a statistically significant difference in COPD diagnosis between the groups, with a larger proportion of COPD patients in the met screening criteria group (74% vs 45%, P < .001). The mean smoking history was 61.4 pack-years in the met criteria group and 43.3 pack-years in the did not meet criteria group.  

Five additional patients in the group that did not meet the 2013 USPSTF screening criteria would have met criteria if the 2021 USPSTF guidelines were applied. All 5 were Black patients. Using the 2021 guidelines, Black patients would have made up 56% of the patients who met screening criteria and 54% of the patients who did not meet screening criteria at time of diagnosis.

Discussion

This study sought to determine the hypothetical effectiveness of national lung cancer screening guidelines in detecting early-stage lung cancer for a high-risk population. Patients diagnosed with early-stage lung cancer were selected as these patients have improved outcomes with treatment, and thus would theoretically benefit from early detection through screening. As expected, the study population had a majority of Black veterans (58%), with a higher proportion of Black patients in the did not meet screening criteria group compared with the met screening criteria group (68% vs 54%, P = .04). This difference highlights the concern that Black individuals were being underscreened with the 2013 USPSTF guidelines.⁷ This is not all surprising as the NLST, from which the initial screening guidelines were based, included a majority White population with only 4.4% of their population being Black.² The USPSTF also cites the NELSON trial as evidence to support annual lung cancer screening, a trial that was performed in the Netherlands with a very different population compared with that of southeast Louisiana.⁹

Given concern that the old criteria were underscreening certain populations, the updated 2021 USPSTF guidelines sought to expand the screening population. In this study, the implementation of these new guidelines resulted in more Black patients meeting screening criteria.

Racial and ethnic disparities in health care in the US are no secret, as Black individuals consistently have increased disease and death rates, higher rates of unemployment, and decreased access to preventive medical care compared to White individuals.¹⁰ Despite the updated USPSTF guidelines, additional modifications to the screening criteria could improve the ability to identify high-risk patients. A modified model using data from the Prostate, Lung, Colorectal, and Ovarian Screening Trial (PLCO) incorporating COPD history, race and ethnicity, and personal history of cancer increased the sensitivity for high-risk Black ever-smokers.¹¹ Additional models and analyses also support the utility of incorporating race and ethnicity in lung cancer screening criteria.^7,12 Using race and ethnicity to guide screening criteria for cancer is not unheard of; in 2017, the US Multi-Society Task Force recommended that Black individuals start colon cancer screening at age 45 years rather than the typical age of 50 years, before updating the guidelines again in 2021 to recommend that all adults start at age 45 years.^13,14

Limitations

This study had the inherent weakness of being a retrospective study at a single institution. Additionally, the 7th edition of the International Association for the Study of Lung Cancer was published in 2010, during the 2005 to 2017 time frame from which our data was collected, leading to possible inconsistencies in staging between patients before and after 2010.¹⁵ However, these changes in staging are unlikely to significantly impact the results for in this study, since the vast majority of the patients diagnosed with lung cancer stage I or II before 2010 would still be in the those 2 stages in the 2010 edition. Finally, specific to our patient population, it was often difficult to ascertain an accurate smoking history for each patient, especially in the early years of the data set, likely due to the disruption of care caused by Hurricane Katrina.

Conclusions

In this retrospective study performed at the SLVHCS in New Orleans, a significantly higher proportion of Black patients compared with White patients with early-stage lung cancer did not meet the 2013 USPSTF lung cancer screening guidelines at time of diagnosis, highlighting the concern that this population was being underscreened. These findings demonstrate the challenges and failures of applying national guidelines to a unique, high-risk population. An individualized, risk-based screening model incorporating race and ethnicity could be more effective at diagnosing early-stage lung cancer and requires more investigation. Centralized lung cancer screening programs within the VA system could also be beneficial for early detection and treatment, as well as provide insight into the increased risk within the veteran population.

Penile cancer is rare with a worldwide incidence of 0.8 cases per 100,000 men.¹ The most common type is squamous cell carcinoma (SCC) followed by soft tissue sarcoma (STS) and Kaposi sarcoma.² Leiomyosarcoma (LMS) is the second most common STS subtype at this location.³ Approximately 50 cases of penile LMS have been reported in the English literature, most as isolated case reports while Fetsch and colleagues reported 14 cases from a single institute.⁴ We present a case of penile LMS with a review of 31 cases. We also describe presentation, treatment options, and recurrence pattern of this rare malignancy.

Case Presentation

A patient aged 70 years presented to the urology clinic with 1-year history of a slowly enlarging penile mass associated with phimosis. He reported no pain, dysuria, or hesitancy. On examination a 2 × 2-cm smooth, mobile, nonulcerating mass was seen on the tip of his left glans without inguinal lymphadenopathy. He underwent circumcision and excision biopsy that revealed an encapsulated tan-white mass measuring 3 × 2.2 × 1.5 cm under the surface of the foreskin. Histology showed a spindle cell tumor with areas of increased cellularity, prominent atypia, and pleomorphism, focal necrosis, and scattered mitoses, including atypical forms. The tumor stained positive for smooth muscle actin and desmin. Ki-67 staining showed foci with a very high proliferation index (Figure). Resection margins were negative. Final Fédération Nationale des Centres de Lutte Contre Le Cancer score was grade 2 (differentiation, 1; mitotic, 3; necrosis, 1). Computed tomography of the chest, abdomen, and pelvis did not show evidence of metastasis. The tumor was classified as superficial, stage IIA (pT1cN0cM0). Local excision with negative margins was deemed adequate treatment.

Discussion

Penile LMS is rare and arises from smooth muscles, which in the penis can be from dartos fascia, erector pili in the skin covering the shaft, or from tunica media of the superficial vessels and cavernosa.⁵ It commonly presents as a nodule or ulcer that might be accompanied by paraphimosis, phimosis, erectile dysfunction, and lower urinary tract symptoms depending on the extent of local tissue involvement. In our review of 31 cases, the age at presentation ranged from 38 to 85 years, with 1 case report of LMS in a 6-year-old. The highest incidence was in the 6th decade. Tumor behavior can be indolent or aggressive. Most patients in our review had asymptomatic, slow-growing lesions for 6 to 24 months before presentation—including our patient—while others had an aggressive tumor with symptoms for a few weeks followed by rapid metastatic spread.^6,7

Histology and Staging

Diagnosis requires biopsy followed by histologic examination and immunohistochemistry of the lesion. Typically, LMS shows fascicles of spindle cells with varying degrees of nuclear atypia, pleomorphisms, and necrotic regions. Mitotic rate is variable and usually > 5 per high power field. Cells stain positive for smooth muscle actin, desmin, and h-caldesmon.⁸ TNM (tumor, nodes, metastasis) stage is determined by the American Joint Committee on Cancer guidelines for STS.

Pratt and colleagues were the first to categorize penile LMS as superficial or deep.⁹ The former includes all lesions superficial to tunica albuginea while the latter run deep to this layer. Anatomical distinction is an important factor in tumor behavior, treatment selection, and prognosis. In our review, we found 14 cases of superficial and 17 cases of deep LMS.

Treatment

There are no established guidelines on optimum treatment of penile LMS. However, we can extrapolate principles from current guidelines on penile cancer, cutaneous leiomyosarcoma, and limb sarcomas. At present, the first-line treatment for superficial penile LMS is wide local excision to achieve negative margins. Circumcision alone might be sufficient for tumors of the distal prepuce, as in our case.¹⁰ Radical resection generally is not required for these early-stage tumors. In our review, no patient in this category developed recurrence or metastasis regardless of initial surgery type (Table 1).^6,11,12

For deep lesions, partial—if functional penile stump and negative margins can be achieved—or total penectomy is required.¹⁰ In our review, more conservative approaches to deep tumors were associated with local recurrences.^7,13,14 Lymphatic spread is rare for LMS. Additionally, involvement of local lymph nodes usually coincides with distant spread. Inguinal lymph node dissection is not indicated if initial negative surgical margins are achieved.

For STS at other sites in the body, radiation therapy is recommended postoperatively for high-grade lesions, which can be extrapolated to penile LMS as well. The benefit of preoperative radiation therapy is less certain. In limb sarcomas, radiation is associated with better local control for large-sized tumors and is used for patients with initial unresectable tumors.¹⁵ Similar recommendation could be extended to penile LMS with local spread to inguinal lymph nodes, scrotum, or abdominal wall. In our review, postoperative radiation therapy was used in 3 patients with deep tumors.^16-18 Of these, short-term relapse occurred in 1 patient.

Metastatic Disease

LMS tends to metastasize hematogenously and lymphatic spread is uncommon. In our review, 7 patients developed metastasis. These patients had deep tumors at presentation with tumor size > 3 cm. Five of 7 patients had involvement of corpora cavernosa at presentation. The lung was the most common site of metastasis, followed by local extension to lower abdominal wall and scrotum. Of the 7 patients, 3 were treated with initial limited excision or partial penectomy and then experienced local recurrence or distant metastasis.^7,13,14,23 This supports the use of radical surgery in large, deep tumors. In an additional 4 cases, metastasis occurred despite initial treatment with total penectomy and use of adjuvant chemoradiation therapy.

In most cases penile LMS is a de novo tumor, however, on occasion it could be accompanied by another epithelial malignancy. Similarly, penile LMS might be a site of recurrence for a primary LMS at another site, as seen in 3 of the reviewed cases. In the first, a patient presented with a nodule on the glans suspicious for SCC, second with synchronous SCC and LMS, and a third case where a patient presented with penile LMS 9 years after being treated for similar tumor in the epididymis.^17,24,25

Prognosis

Penile LMS prognosis is difficult to ascertain because reported cases are rare. In our review, the longest documented disease-free survival was 3.5 years for a patient with superficial LMS treated with local excision.²⁶ In cases of distant metastasis, average survival was 4.6 months, while the longest survival since initial presentation and last documented local recurrence was 16 years.¹⁴ Five-year survival has not been reported.

Conclusions

LMS of the penis is a rare and potentially aggressive malignancy. It can be classified as superficial or deep based on tumor relation to the tunica albuginea. Deep tumors, those > 3 cm, high-grade lesions, and tumors with involvement of corpora cavernosa, tend to spread locally, metastasize to distant areas, and require more radical surgery with or without postoperative radiation therapy. In comparison, superficial lesions can be treated with local excision only. Both superficial and deep tumors require close follow-up.

Penile cancer is rare with a worldwide incidence of 0.8 cases per 100,000 men.¹ The most common type is squamous cell carcinoma (SCC) followed by soft tissue sarcoma (STS) and Kaposi sarcoma.² Leiomyosarcoma (LMS) is the second most common STS subtype at this location.³ Approximately 50 cases of penile LMS have been reported in the English literature, most as isolated case reports while Fetsch and colleagues reported 14 cases from a single institute.⁴ We present a case of penile LMS with a review of 31 cases. We also describe presentation, treatment options, and recurrence pattern of this rare malignancy.

Case Presentation

A patient aged 70 years presented to the urology clinic with 1-year history of a slowly enlarging penile mass associated with phimosis. He reported no pain, dysuria, or hesitancy. On examination a 2 × 2-cm smooth, mobile, nonulcerating mass was seen on the tip of his left glans without inguinal lymphadenopathy. He underwent circumcision and excision biopsy that revealed an encapsulated tan-white mass measuring 3 × 2.2 × 1.5 cm under the surface of the foreskin. Histology showed a spindle cell tumor with areas of increased cellularity, prominent atypia, and pleomorphism, focal necrosis, and scattered mitoses, including atypical forms. The tumor stained positive for smooth muscle actin and desmin. Ki-67 staining showed foci with a very high proliferation index (Figure). Resection margins were negative. Final Fédération Nationale des Centres de Lutte Contre Le Cancer score was grade 2 (differentiation, 1; mitotic, 3; necrosis, 1). Computed tomography of the chest, abdomen, and pelvis did not show evidence of metastasis. The tumor was classified as superficial, stage IIA (pT1cN0cM0). Local excision with negative margins was deemed adequate treatment.

Discussion

Penile LMS is rare and arises from smooth muscles, which in the penis can be from dartos fascia, erector pili in the skin covering the shaft, or from tunica media of the superficial vessels and cavernosa.⁵ It commonly presents as a nodule or ulcer that might be accompanied by paraphimosis, phimosis, erectile dysfunction, and lower urinary tract symptoms depending on the extent of local tissue involvement. In our review of 31 cases, the age at presentation ranged from 38 to 85 years, with 1 case report of LMS in a 6-year-old. The highest incidence was in the 6th decade. Tumor behavior can be indolent or aggressive. Most patients in our review had asymptomatic, slow-growing lesions for 6 to 24 months before presentation—including our patient—while others had an aggressive tumor with symptoms for a few weeks followed by rapid metastatic spread.^6,7

Histology and Staging

Diagnosis requires biopsy followed by histologic examination and immunohistochemistry of the lesion. Typically, LMS shows fascicles of spindle cells with varying degrees of nuclear atypia, pleomorphisms, and necrotic regions. Mitotic rate is variable and usually > 5 per high power field. Cells stain positive for smooth muscle actin, desmin, and h-caldesmon.⁸ TNM (tumor, nodes, metastasis) stage is determined by the American Joint Committee on Cancer guidelines for STS.

Pratt and colleagues were the first to categorize penile LMS as superficial or deep.⁹ The former includes all lesions superficial to tunica albuginea while the latter run deep to this layer. Anatomical distinction is an important factor in tumor behavior, treatment selection, and prognosis. In our review, we found 14 cases of superficial and 17 cases of deep LMS.

Treatment

There are no established guidelines on optimum treatment of penile LMS. However, we can extrapolate principles from current guidelines on penile cancer, cutaneous leiomyosarcoma, and limb sarcomas. At present, the first-line treatment for superficial penile LMS is wide local excision to achieve negative margins. Circumcision alone might be sufficient for tumors of the distal prepuce, as in our case.¹⁰ Radical resection generally is not required for these early-stage tumors. In our review, no patient in this category developed recurrence or metastasis regardless of initial surgery type (Table 1).^6,11,12

For deep lesions, partial—if functional penile stump and negative margins can be achieved—or total penectomy is required.¹⁰ In our review, more conservative approaches to deep tumors were associated with local recurrences.^7,13,14 Lymphatic spread is rare for LMS. Additionally, involvement of local lymph nodes usually coincides with distant spread. Inguinal lymph node dissection is not indicated if initial negative surgical margins are achieved.

For STS at other sites in the body, radiation therapy is recommended postoperatively for high-grade lesions, which can be extrapolated to penile LMS as well. The benefit of preoperative radiation therapy is less certain. In limb sarcomas, radiation is associated with better local control for large-sized tumors and is used for patients with initial unresectable tumors.¹⁵ Similar recommendation could be extended to penile LMS with local spread to inguinal lymph nodes, scrotum, or abdominal wall. In our review, postoperative radiation therapy was used in 3 patients with deep tumors.^16-18 Of these, short-term relapse occurred in 1 patient.

Metastatic Disease

LMS tends to metastasize hematogenously and lymphatic spread is uncommon. In our review, 7 patients developed metastasis. These patients had deep tumors at presentation with tumor size > 3 cm. Five of 7 patients had involvement of corpora cavernosa at presentation. The lung was the most common site of metastasis, followed by local extension to lower abdominal wall and scrotum. Of the 7 patients, 3 were treated with initial limited excision or partial penectomy and then experienced local recurrence or distant metastasis.^7,13,14,23 This supports the use of radical surgery in large, deep tumors. In an additional 4 cases, metastasis occurred despite initial treatment with total penectomy and use of adjuvant chemoradiation therapy.

In most cases penile LMS is a de novo tumor, however, on occasion it could be accompanied by another epithelial malignancy. Similarly, penile LMS might be a site of recurrence for a primary LMS at another site, as seen in 3 of the reviewed cases. In the first, a patient presented with a nodule on the glans suspicious for SCC, second with synchronous SCC and LMS, and a third case where a patient presented with penile LMS 9 years after being treated for similar tumor in the epididymis.^17,24,25

Prognosis

Penile LMS prognosis is difficult to ascertain because reported cases are rare. In our review, the longest documented disease-free survival was 3.5 years for a patient with superficial LMS treated with local excision.²⁶ In cases of distant metastasis, average survival was 4.6 months, while the longest survival since initial presentation and last documented local recurrence was 16 years.¹⁴ Five-year survival has not been reported.

Conclusions

LMS of the penis is a rare and potentially aggressive malignancy. It can be classified as superficial or deep based on tumor relation to the tunica albuginea. Deep tumors, those > 3 cm, high-grade lesions, and tumors with involvement of corpora cavernosa, tend to spread locally, metastasize to distant areas, and require more radical surgery with or without postoperative radiation therapy. In comparison, superficial lesions can be treated with local excision only. Both superficial and deep tumors require close follow-up.

Penile cancer is rare with a worldwide incidence of 0.8 cases per 100,000 men.¹ The most common type is squamous cell carcinoma (SCC) followed by soft tissue sarcoma (STS) and Kaposi sarcoma.² Leiomyosarcoma (LMS) is the second most common STS subtype at this location.³ Approximately 50 cases of penile LMS have been reported in the English literature, most as isolated case reports while Fetsch and colleagues reported 14 cases from a single institute.⁴ We present a case of penile LMS with a review of 31 cases. We also describe presentation, treatment options, and recurrence pattern of this rare malignancy.

Case Presentation

A patient aged 70 years presented to the urology clinic with 1-year history of a slowly enlarging penile mass associated with phimosis. He reported no pain, dysuria, or hesitancy. On examination a 2 × 2-cm smooth, mobile, nonulcerating mass was seen on the tip of his left glans without inguinal lymphadenopathy. He underwent circumcision and excision biopsy that revealed an encapsulated tan-white mass measuring 3 × 2.2 × 1.5 cm under the surface of the foreskin. Histology showed a spindle cell tumor with areas of increased cellularity, prominent atypia, and pleomorphism, focal necrosis, and scattered mitoses, including atypical forms. The tumor stained positive for smooth muscle actin and desmin. Ki-67 staining showed foci with a very high proliferation index (Figure). Resection margins were negative. Final Fédération Nationale des Centres de Lutte Contre Le Cancer score was grade 2 (differentiation, 1; mitotic, 3; necrosis, 1). Computed tomography of the chest, abdomen, and pelvis did not show evidence of metastasis. The tumor was classified as superficial, stage IIA (pT1cN0cM0). Local excision with negative margins was deemed adequate treatment.

Discussion

Penile LMS is rare and arises from smooth muscles, which in the penis can be from dartos fascia, erector pili in the skin covering the shaft, or from tunica media of the superficial vessels and cavernosa.⁵ It commonly presents as a nodule or ulcer that might be accompanied by paraphimosis, phimosis, erectile dysfunction, and lower urinary tract symptoms depending on the extent of local tissue involvement. In our review of 31 cases, the age at presentation ranged from 38 to 85 years, with 1 case report of LMS in a 6-year-old. The highest incidence was in the 6th decade. Tumor behavior can be indolent or aggressive. Most patients in our review had asymptomatic, slow-growing lesions for 6 to 24 months before presentation—including our patient—while others had an aggressive tumor with symptoms for a few weeks followed by rapid metastatic spread.^6,7

Histology and Staging

Diagnosis requires biopsy followed by histologic examination and immunohistochemistry of the lesion. Typically, LMS shows fascicles of spindle cells with varying degrees of nuclear atypia, pleomorphisms, and necrotic regions. Mitotic rate is variable and usually > 5 per high power field. Cells stain positive for smooth muscle actin, desmin, and h-caldesmon.⁸ TNM (tumor, nodes, metastasis) stage is determined by the American Joint Committee on Cancer guidelines for STS.

Pratt and colleagues were the first to categorize penile LMS as superficial or deep.⁹ The former includes all lesions superficial to tunica albuginea while the latter run deep to this layer. Anatomical distinction is an important factor in tumor behavior, treatment selection, and prognosis. In our review, we found 14 cases of superficial and 17 cases of deep LMS.

Treatment

There are no established guidelines on optimum treatment of penile LMS. However, we can extrapolate principles from current guidelines on penile cancer, cutaneous leiomyosarcoma, and limb sarcomas. At present, the first-line treatment for superficial penile LMS is wide local excision to achieve negative margins. Circumcision alone might be sufficient for tumors of the distal prepuce, as in our case.¹⁰ Radical resection generally is not required for these early-stage tumors. In our review, no patient in this category developed recurrence or metastasis regardless of initial surgery type (Table 1).^6,11,12

For deep lesions, partial—if functional penile stump and negative margins can be achieved—or total penectomy is required.¹⁰ In our review, more conservative approaches to deep tumors were associated with local recurrences.^7,13,14 Lymphatic spread is rare for LMS. Additionally, involvement of local lymph nodes usually coincides with distant spread. Inguinal lymph node dissection is not indicated if initial negative surgical margins are achieved.

For STS at other sites in the body, radiation therapy is recommended postoperatively for high-grade lesions, which can be extrapolated to penile LMS as well. The benefit of preoperative radiation therapy is less certain. In limb sarcomas, radiation is associated with better local control for large-sized tumors and is used for patients with initial unresectable tumors.¹⁵ Similar recommendation could be extended to penile LMS with local spread to inguinal lymph nodes, scrotum, or abdominal wall. In our review, postoperative radiation therapy was used in 3 patients with deep tumors.^16-18 Of these, short-term relapse occurred in 1 patient.

Metastatic Disease

LMS tends to metastasize hematogenously and lymphatic spread is uncommon. In our review, 7 patients developed metastasis. These patients had deep tumors at presentation with tumor size > 3 cm. Five of 7 patients had involvement of corpora cavernosa at presentation. The lung was the most common site of metastasis, followed by local extension to lower abdominal wall and scrotum. Of the 7 patients, 3 were treated with initial limited excision or partial penectomy and then experienced local recurrence or distant metastasis.^7,13,14,23 This supports the use of radical surgery in large, deep tumors. In an additional 4 cases, metastasis occurred despite initial treatment with total penectomy and use of adjuvant chemoradiation therapy.

In most cases penile LMS is a de novo tumor, however, on occasion it could be accompanied by another epithelial malignancy. Similarly, penile LMS might be a site of recurrence for a primary LMS at another site, as seen in 3 of the reviewed cases. In the first, a patient presented with a nodule on the glans suspicious for SCC, second with synchronous SCC and LMS, and a third case where a patient presented with penile LMS 9 years after being treated for similar tumor in the epididymis.^17,24,25

Prognosis

Penile LMS prognosis is difficult to ascertain because reported cases are rare. In our review, the longest documented disease-free survival was 3.5 years for a patient with superficial LMS treated with local excision.²⁶ In cases of distant metastasis, average survival was 4.6 months, while the longest survival since initial presentation and last documented local recurrence was 16 years.¹⁴ Five-year survival has not been reported.

Conclusions

LMS of the penis is a rare and potentially aggressive malignancy. It can be classified as superficial or deep based on tumor relation to the tunica albuginea. Deep tumors, those > 3 cm, high-grade lesions, and tumors with involvement of corpora cavernosa, tend to spread locally, metastasize to distant areas, and require more radical surgery with or without postoperative radiation therapy. In comparison, superficial lesions can be treated with local excision only. Both superficial and deep tumors require close follow-up.

Hepatocellular carcinoma (HCC) remains a major global health problem and is the third leading cause of cancer-related mortality worldwide.¹ Management of HCC is complex; as it largely occurs in the background of chronic liver disease, its management must simultaneously address challenges related to the patient’s tumor burden, as well as their underlying liver dysfunction and performance status. HCC is universally fatal without treatment, with a 5-year survival < 10%.² However, if detected early HCC is potentially curable, with treatments such as hepatic resection, ablation, and/or liver transplantation, which are associated with 5-year survival rates as high as 70%.² HCC-specific palliative treatments, including intra-arterial therapies (eg, trans-arterial chemoembolization, radioembolization) and systemic chemotherapy, have also been shown to prolong survival in patients with advanced HCC. Therefore, a key driver of patient survival is receipt of HCC-specific therapy.

There is rising incidence and mortality related to HCC in the US veteran population, largely attributed to acquisition of chronic hepatitis C virus (HCV) infection decades prior.³ There is also a high prevalence of psychosocial barriers in this population, such as low socioeconomic status, homelessness, alcohol and substance use disorders, and psychiatric disorders which can negatively influence receipt of medical treatment, including cancer care.^4,5 Given the complexity of managing HCC, as well as the plethora of potential treatment options available, it is widely accepted that a multidisciplinary team approach, such as the multidisciplinary tumor board (MDTB) provides optimal care to patients with HCC.^2,6 The aim of the present study was to identify in a population of veterans diagnosed with HCC the prevalence of psychosocial barriers to care and assess their impact and the role of an MDTB on receipt of HCC-specific care.

Methods

In June 2007, a joint institutional MDTB was established for patients with primary liver tumors receiving care at the William S. Middleton Memorial Veterans’ Hospital (WSMMVH) in Madison, Wisconsin. As we have described elsewhere, individual cases with their corresponding imaging studies were reviewed at a weekly conference attended by transplant hepatologists, medical oncologists, hepatobiliary and transplant surgeons, pathologists, diagnostic and interventional radiologists, and nurse coordinators.⁶ Potential therapies offered included surgical resection, liver transplantation (LT), thermal ablation, intra-arterial therapies (chemo and/or radioembolization), systemic chemotherapy, stereotactic radiation, and best supportive care. Decisions regarding the appropriate treatment modality were made based on patient factors, review of their cross-sectional imaging studies and/or histopathology, and context of their underlying liver dysfunction. The tumor board discussion was summarized in meeting minutes as well as tumor board encounters recorded in each patient’s health record. Although patients with benign tumors were presented at the MDTB, only patients with a diagnosis of HCC were included in this study.

A database analysis was conducted of all veteran patients with HCC managed through the WSMMVH MDTB, since its inception up to December 31, 2016, with follow-up until December 31, 2018. Data for analysis included demographics, laboratory parameters at time of diagnosis and treatment, imaging findings, histopathology and/or surgical pathology, treatment rendered, and follow-up information. The primary outcome measured in this study included receipt of any therapy and secondarily, patient survival.

Discrete variables were analyzed with χ² statistics or Fisher exact test and continuous variables with the student t test. Multivariable analyses were carried out with logistic regression. Variables with a P < .05 were considered statistically significant. Analyses were carried out using IBM SPSS v24.0.

As a quality-improvement initiative for the care and management of veterans with HCC, this study was determined to be exempt from review by the WSMMVH and University of Wisconsin School of Medicine and Public Health Institutional Review Board.

Results

From January 1, 2007, through December 31, 2016, 149 patients with HCC were managed through the MDTB. Baseline demographic data, Model for End-stage Liver Disease (MELD) score and Child-Turcotte-Pugh class, and baseline HCC characteristics of the cohort are shown in Tables 1 and 2.

There was a high prevalence of psychosocial barriers in our study cohort, including alcohol or substance use disorder, mental illness diagnosis, and low socioeconomic status (Table 3). The mean distance traveled to WSMMVH for HCC-specific care was 206 km. Fifty patients in the cohort utilized travel assistance and 33 patients accessed lodging assistance.

HCC Treatments

There was a high rate of receipt of treatment in our study cohort with 127 (85%) patients receiving at least one HCC-specific therapy. Care was individualized and coordinated through our institutional MDTB, with both curative and palliative treatment modalities utilized (Table 4).

Curative treatment, which includes LT, ablation, or resection, was offered to 78 (52%) patients who were within T2 stage. Of these 78 patients who were potential candidates for LT as a curative treatment for HCC, 31 were not deemed suitable transplant candidates. Psychosocial barriers precluded consideration for LT in 7 of the 31 patients due to active substance use, homelessness in 1 patient, and severe mental illness in 3 patients. Medical comorbidities, advanced patient age, and patient preference accounted for the remainder.

In a univariate analysis of the cohort of 149 patients, factors that decreased the likelihood of receipt of curative HCC therapy included T2 stage or higher at diagnosis and a diagnosis of depression, whereas provision for lodging was associated with increased likelihood of receiving HCC-specific care (Table 5). Other factors that influenced receipt of any treatment included patient’s MELD score, total bilirubin, and serum α-fetoprotein, a surrogate marker for tumor stage. In the multivariable analysis, predictors of receiving curative therapy included absence of substance use, within T2 stage of tumor, and Child-Turcotte-Pugh class A cirrhosis. The presence of psychosocial barriers apart from substance use did not predict a lower chance of receiving curative HCC therapy (including homelessness, distance traveled to center, mental health disorder, and low income).

Discussion

Increases in prevalence and mortality related to cirrhosis and HCC have been reported among the US veteran population.³ This is in large part attributable to the burden of chronic HCV infection in this population. As mirrored in the US population in general, we may be at a turning point regarding the gradual increase in prevalence in HCC.⁷ The prevalence of cirrhosis and viral-related HCC related to HCV infection will decline with availability of effective antiviral therapy. Alcoholic liver disease remains a main etiological factor for development of cirrhosis and HCC. Nonalcoholic fatty liver disease is becoming a more prevalent cause for development of cirrhosis, indication for liver transplantation, and development of HCC, and indeed may lead to HCC even in the absence of cirrhosis.⁸

HCC remains a challenging clinical problem.² As the vast majority of cases arise in the context of cirrhosis, management of HCC not only must address the cancer stage at diagnosis, but also the patient’s underlying liver dysfunction and performance status. Receipt of HCC-specific therapy is a key driver of patient outcome, with curative therapies available for those diagnosed with early-stage disease. We and others have shown that a multidisciplinary approach to coordinate, individualize, and optimize care for these complex patients can improve the rate of treatment utilization, reduce treatment delays, and improve patient survival.^6,9,10

Patient psychosocial barriers, such as low socioeconomic status, homelessness, alcohol and substance use, and psychiatric disorders, are more prevalent among the veteran population and have the potential to negatively influence successful health care delivery. One retrospective study of 100 veterans at a US Department of Veterans Affairs (VA) medical center treated for HCC from 2009 to 2014 showed a majority of the patients lived on a meager income, a high prevalence of homelessness, substance use history in 96% of their cohort, and psychiatric illness in 65% of patients.¹¹ Other studies have documented similar findings in the veteran population, with alcohol, substance use, as well as other uncontrolled comorbidities as barriers to providing care, such as antiviral therapy for chronic HCV infection.¹²

Herein, we present a cohort of veterans with HCC managed through our MDTB from 2007 to 2016, for whom chronic HCV infection and/or alcoholic liver disease were the main causes of cirrhosis. Our cohort had a high burden of alcohol and substance use disorders while other psychiatric illnesses were also common. Our cohort includes patients who were poor, and even some veterans who lacked a stable home. This profile of poverty and social deprivation among veterans is matched in national data.^13-15 Using a tumor board model of nurse navigation and multidisciplinary care, we were able to provide travel and lodging assistance to 50 (34%) and 33 (22%) patients, respectively, in order to facilitate their care.

Conclusions

Our study demonstrates a high burden of psychosocial challenges in veterans with HCC. These accounted for a significant barrier to receive HCC-specific care. Despite the presence of these patient barriers, high rates of HCC-specific treatment are attainable through individualization and coordination of patient care in the context of a MDTB model with nurse navigation. Provision of targeted social support to ameliorate these modifiable factors improves patient outcomes.

Hepatocellular carcinoma (HCC) remains a major global health problem and is the third leading cause of cancer-related mortality worldwide.¹ Management of HCC is complex; as it largely occurs in the background of chronic liver disease, its management must simultaneously address challenges related to the patient’s tumor burden, as well as their underlying liver dysfunction and performance status. HCC is universally fatal without treatment, with a 5-year survival < 10%.² However, if detected early HCC is potentially curable, with treatments such as hepatic resection, ablation, and/or liver transplantation, which are associated with 5-year survival rates as high as 70%.² HCC-specific palliative treatments, including intra-arterial therapies (eg, trans-arterial chemoembolization, radioembolization) and systemic chemotherapy, have also been shown to prolong survival in patients with advanced HCC. Therefore, a key driver of patient survival is receipt of HCC-specific therapy.

There is rising incidence and mortality related to HCC in the US veteran population, largely attributed to acquisition of chronic hepatitis C virus (HCV) infection decades prior.³ There is also a high prevalence of psychosocial barriers in this population, such as low socioeconomic status, homelessness, alcohol and substance use disorders, and psychiatric disorders which can negatively influence receipt of medical treatment, including cancer care.^4,5 Given the complexity of managing HCC, as well as the plethora of potential treatment options available, it is widely accepted that a multidisciplinary team approach, such as the multidisciplinary tumor board (MDTB) provides optimal care to patients with HCC.^2,6 The aim of the present study was to identify in a population of veterans diagnosed with HCC the prevalence of psychosocial barriers to care and assess their impact and the role of an MDTB on receipt of HCC-specific care.

Methods

In June 2007, a joint institutional MDTB was established for patients with primary liver tumors receiving care at the William S. Middleton Memorial Veterans’ Hospital (WSMMVH) in Madison, Wisconsin. As we have described elsewhere, individual cases with their corresponding imaging studies were reviewed at a weekly conference attended by transplant hepatologists, medical oncologists, hepatobiliary and transplant surgeons, pathologists, diagnostic and interventional radiologists, and nurse coordinators.⁶ Potential therapies offered included surgical resection, liver transplantation (LT), thermal ablation, intra-arterial therapies (chemo and/or radioembolization), systemic chemotherapy, stereotactic radiation, and best supportive care. Decisions regarding the appropriate treatment modality were made based on patient factors, review of their cross-sectional imaging studies and/or histopathology, and context of their underlying liver dysfunction. The tumor board discussion was summarized in meeting minutes as well as tumor board encounters recorded in each patient’s health record. Although patients with benign tumors were presented at the MDTB, only patients with a diagnosis of HCC were included in this study.

A database analysis was conducted of all veteran patients with HCC managed through the WSMMVH MDTB, since its inception up to December 31, 2016, with follow-up until December 31, 2018. Data for analysis included demographics, laboratory parameters at time of diagnosis and treatment, imaging findings, histopathology and/or surgical pathology, treatment rendered, and follow-up information. The primary outcome measured in this study included receipt of any therapy and secondarily, patient survival.

Discrete variables were analyzed with χ² statistics or Fisher exact test and continuous variables with the student t test. Multivariable analyses were carried out with logistic regression. Variables with a P < .05 were considered statistically significant. Analyses were carried out using IBM SPSS v24.0.

As a quality-improvement initiative for the care and management of veterans with HCC, this study was determined to be exempt from review by the WSMMVH and University of Wisconsin School of Medicine and Public Health Institutional Review Board.

Results

From January 1, 2007, through December 31, 2016, 149 patients with HCC were managed through the MDTB. Baseline demographic data, Model for End-stage Liver Disease (MELD) score and Child-Turcotte-Pugh class, and baseline HCC characteristics of the cohort are shown in Tables 1 and 2.

There was a high prevalence of psychosocial barriers in our study cohort, including alcohol or substance use disorder, mental illness diagnosis, and low socioeconomic status (Table 3). The mean distance traveled to WSMMVH for HCC-specific care was 206 km. Fifty patients in the cohort utilized travel assistance and 33 patients accessed lodging assistance.

HCC Treatments

There was a high rate of receipt of treatment in our study cohort with 127 (85%) patients receiving at least one HCC-specific therapy. Care was individualized and coordinated through our institutional MDTB, with both curative and palliative treatment modalities utilized (Table 4).

Curative treatment, which includes LT, ablation, or resection, was offered to 78 (52%) patients who were within T2 stage. Of these 78 patients who were potential candidates for LT as a curative treatment for HCC, 31 were not deemed suitable transplant candidates. Psychosocial barriers precluded consideration for LT in 7 of the 31 patients due to active substance use, homelessness in 1 patient, and severe mental illness in 3 patients. Medical comorbidities, advanced patient age, and patient preference accounted for the remainder.

In a univariate analysis of the cohort of 149 patients, factors that decreased the likelihood of receipt of curative HCC therapy included T2 stage or higher at diagnosis and a diagnosis of depression, whereas provision for lodging was associated with increased likelihood of receiving HCC-specific care (Table 5). Other factors that influenced receipt of any treatment included patient’s MELD score, total bilirubin, and serum α-fetoprotein, a surrogate marker for tumor stage. In the multivariable analysis, predictors of receiving curative therapy included absence of substance use, within T2 stage of tumor, and Child-Turcotte-Pugh class A cirrhosis. The presence of psychosocial barriers apart from substance use did not predict a lower chance of receiving curative HCC therapy (including homelessness, distance traveled to center, mental health disorder, and low income).

Discussion

Increases in prevalence and mortality related to cirrhosis and HCC have been reported among the US veteran population.³ This is in large part attributable to the burden of chronic HCV infection in this population. As mirrored in the US population in general, we may be at a turning point regarding the gradual increase in prevalence in HCC.⁷ The prevalence of cirrhosis and viral-related HCC related to HCV infection will decline with availability of effective antiviral therapy. Alcoholic liver disease remains a main etiological factor for development of cirrhosis and HCC. Nonalcoholic fatty liver disease is becoming a more prevalent cause for development of cirrhosis, indication for liver transplantation, and development of HCC, and indeed may lead to HCC even in the absence of cirrhosis.⁸

HCC remains a challenging clinical problem.² As the vast majority of cases arise in the context of cirrhosis, management of HCC not only must address the cancer stage at diagnosis, but also the patient’s underlying liver dysfunction and performance status. Receipt of HCC-specific therapy is a key driver of patient outcome, with curative therapies available for those diagnosed with early-stage disease. We and others have shown that a multidisciplinary approach to coordinate, individualize, and optimize care for these complex patients can improve the rate of treatment utilization, reduce treatment delays, and improve patient survival.^6,9,10

Patient psychosocial barriers, such as low socioeconomic status, homelessness, alcohol and substance use, and psychiatric disorders, are more prevalent among the veteran population and have the potential to negatively influence successful health care delivery. One retrospective study of 100 veterans at a US Department of Veterans Affairs (VA) medical center treated for HCC from 2009 to 2014 showed a majority of the patients lived on a meager income, a high prevalence of homelessness, substance use history in 96% of their cohort, and psychiatric illness in 65% of patients.¹¹ Other studies have documented similar findings in the veteran population, with alcohol, substance use, as well as other uncontrolled comorbidities as barriers to providing care, such as antiviral therapy for chronic HCV infection.¹²

Herein, we present a cohort of veterans with HCC managed through our MDTB from 2007 to 2016, for whom chronic HCV infection and/or alcoholic liver disease were the main causes of cirrhosis. Our cohort had a high burden of alcohol and substance use disorders while other psychiatric illnesses were also common. Our cohort includes patients who were poor, and even some veterans who lacked a stable home. This profile of poverty and social deprivation among veterans is matched in national data.^13-15 Using a tumor board model of nurse navigation and multidisciplinary care, we were able to provide travel and lodging assistance to 50 (34%) and 33 (22%) patients, respectively, in order to facilitate their care.

Conclusions

Our study demonstrates a high burden of psychosocial challenges in veterans with HCC. These accounted for a significant barrier to receive HCC-specific care. Despite the presence of these patient barriers, high rates of HCC-specific treatment are attainable through individualization and coordination of patient care in the context of a MDTB model with nurse navigation. Provision of targeted social support to ameliorate these modifiable factors improves patient outcomes.

Hepatocellular carcinoma (HCC) remains a major global health problem and is the third leading cause of cancer-related mortality worldwide.¹ Management of HCC is complex; as it largely occurs in the background of chronic liver disease, its management must simultaneously address challenges related to the patient’s tumor burden, as well as their underlying liver dysfunction and performance status. HCC is universally fatal without treatment, with a 5-year survival < 10%.² However, if detected early HCC is potentially curable, with treatments such as hepatic resection, ablation, and/or liver transplantation, which are associated with 5-year survival rates as high as 70%.² HCC-specific palliative treatments, including intra-arterial therapies (eg, trans-arterial chemoembolization, radioembolization) and systemic chemotherapy, have also been shown to prolong survival in patients with advanced HCC. Therefore, a key driver of patient survival is receipt of HCC-specific therapy.

There is rising incidence and mortality related to HCC in the US veteran population, largely attributed to acquisition of chronic hepatitis C virus (HCV) infection decades prior.³ There is also a high prevalence of psychosocial barriers in this population, such as low socioeconomic status, homelessness, alcohol and substance use disorders, and psychiatric disorders which can negatively influence receipt of medical treatment, including cancer care.^4,5 Given the complexity of managing HCC, as well as the plethora of potential treatment options available, it is widely accepted that a multidisciplinary team approach, such as the multidisciplinary tumor board (MDTB) provides optimal care to patients with HCC.^2,6 The aim of the present study was to identify in a population of veterans diagnosed with HCC the prevalence of psychosocial barriers to care and assess their impact and the role of an MDTB on receipt of HCC-specific care.

Methods

In June 2007, a joint institutional MDTB was established for patients with primary liver tumors receiving care at the William S. Middleton Memorial Veterans’ Hospital (WSMMVH) in Madison, Wisconsin. As we have described elsewhere, individual cases with their corresponding imaging studies were reviewed at a weekly conference attended by transplant hepatologists, medical oncologists, hepatobiliary and transplant surgeons, pathologists, diagnostic and interventional radiologists, and nurse coordinators.⁶ Potential therapies offered included surgical resection, liver transplantation (LT), thermal ablation, intra-arterial therapies (chemo and/or radioembolization), systemic chemotherapy, stereotactic radiation, and best supportive care. Decisions regarding the appropriate treatment modality were made based on patient factors, review of their cross-sectional imaging studies and/or histopathology, and context of their underlying liver dysfunction. The tumor board discussion was summarized in meeting minutes as well as tumor board encounters recorded in each patient’s health record. Although patients with benign tumors were presented at the MDTB, only patients with a diagnosis of HCC were included in this study.

A database analysis was conducted of all veteran patients with HCC managed through the WSMMVH MDTB, since its inception up to December 31, 2016, with follow-up until December 31, 2018. Data for analysis included demographics, laboratory parameters at time of diagnosis and treatment, imaging findings, histopathology and/or surgical pathology, treatment rendered, and follow-up information. The primary outcome measured in this study included receipt of any therapy and secondarily, patient survival.

Discrete variables were analyzed with χ² statistics or Fisher exact test and continuous variables with the student t test. Multivariable analyses were carried out with logistic regression. Variables with a P < .05 were considered statistically significant. Analyses were carried out using IBM SPSS v24.0.

As a quality-improvement initiative for the care and management of veterans with HCC, this study was determined to be exempt from review by the WSMMVH and University of Wisconsin School of Medicine and Public Health Institutional Review Board.

Results

From January 1, 2007, through December 31, 2016, 149 patients with HCC were managed through the MDTB. Baseline demographic data, Model for End-stage Liver Disease (MELD) score and Child-Turcotte-Pugh class, and baseline HCC characteristics of the cohort are shown in Tables 1 and 2.

There was a high prevalence of psychosocial barriers in our study cohort, including alcohol or substance use disorder, mental illness diagnosis, and low socioeconomic status (Table 3). The mean distance traveled to WSMMVH for HCC-specific care was 206 km. Fifty patients in the cohort utilized travel assistance and 33 patients accessed lodging assistance.

HCC Treatments

There was a high rate of receipt of treatment in our study cohort with 127 (85%) patients receiving at least one HCC-specific therapy. Care was individualized and coordinated through our institutional MDTB, with both curative and palliative treatment modalities utilized (Table 4).

Curative treatment, which includes LT, ablation, or resection, was offered to 78 (52%) patients who were within T2 stage. Of these 78 patients who were potential candidates for LT as a curative treatment for HCC, 31 were not deemed suitable transplant candidates. Psychosocial barriers precluded consideration for LT in 7 of the 31 patients due to active substance use, homelessness in 1 patient, and severe mental illness in 3 patients. Medical comorbidities, advanced patient age, and patient preference accounted for the remainder.

In a univariate analysis of the cohort of 149 patients, factors that decreased the likelihood of receipt of curative HCC therapy included T2 stage or higher at diagnosis and a diagnosis of depression, whereas provision for lodging was associated with increased likelihood of receiving HCC-specific care (Table 5). Other factors that influenced receipt of any treatment included patient’s MELD score, total bilirubin, and serum α-fetoprotein, a surrogate marker for tumor stage. In the multivariable analysis, predictors of receiving curative therapy included absence of substance use, within T2 stage of tumor, and Child-Turcotte-Pugh class A cirrhosis. The presence of psychosocial barriers apart from substance use did not predict a lower chance of receiving curative HCC therapy (including homelessness, distance traveled to center, mental health disorder, and low income).

Discussion

Increases in prevalence and mortality related to cirrhosis and HCC have been reported among the US veteran population.³ This is in large part attributable to the burden of chronic HCV infection in this population. As mirrored in the US population in general, we may be at a turning point regarding the gradual increase in prevalence in HCC.⁷ The prevalence of cirrhosis and viral-related HCC related to HCV infection will decline with availability of effective antiviral therapy. Alcoholic liver disease remains a main etiological factor for development of cirrhosis and HCC. Nonalcoholic fatty liver disease is becoming a more prevalent cause for development of cirrhosis, indication for liver transplantation, and development of HCC, and indeed may lead to HCC even in the absence of cirrhosis.⁸

HCC remains a challenging clinical problem.² As the vast majority of cases arise in the context of cirrhosis, management of HCC not only must address the cancer stage at diagnosis, but also the patient’s underlying liver dysfunction and performance status. Receipt of HCC-specific therapy is a key driver of patient outcome, with curative therapies available for those diagnosed with early-stage disease. We and others have shown that a multidisciplinary approach to coordinate, individualize, and optimize care for these complex patients can improve the rate of treatment utilization, reduce treatment delays, and improve patient survival.^6,9,10

Patient psychosocial barriers, such as low socioeconomic status, homelessness, alcohol and substance use, and psychiatric disorders, are more prevalent among the veteran population and have the potential to negatively influence successful health care delivery. One retrospective study of 100 veterans at a US Department of Veterans Affairs (VA) medical center treated for HCC from 2009 to 2014 showed a majority of the patients lived on a meager income, a high prevalence of homelessness, substance use history in 96% of their cohort, and psychiatric illness in 65% of patients.¹¹ Other studies have documented similar findings in the veteran population, with alcohol, substance use, as well as other uncontrolled comorbidities as barriers to providing care, such as antiviral therapy for chronic HCV infection.¹²

Herein, we present a cohort of veterans with HCC managed through our MDTB from 2007 to 2016, for whom chronic HCV infection and/or alcoholic liver disease were the main causes of cirrhosis. Our cohort had a high burden of alcohol and substance use disorders while other psychiatric illnesses were also common. Our cohort includes patients who were poor, and even some veterans who lacked a stable home. This profile of poverty and social deprivation among veterans is matched in national data.^13-15 Using a tumor board model of nurse navigation and multidisciplinary care, we were able to provide travel and lodging assistance to 50 (34%) and 33 (22%) patients, respectively, in order to facilitate their care.

Conclusions

Our study demonstrates a high burden of psychosocial challenges in veterans with HCC. These accounted for a significant barrier to receive HCC-specific care. Despite the presence of these patient barriers, high rates of HCC-specific treatment are attainable through individualization and coordination of patient care in the context of a MDTB model with nurse navigation. Provision of targeted social support to ameliorate these modifiable factors improves patient outcomes.

The observation that women with lung cancer seem to live longer than men can be explained by known prognostic factors, a new study suggests.

“In this first Australian prospective study of lung cancer survival comparing men and women, we found that men had a 43% greater risk of dying from their lung cancer than women,” comments lead author Xue Qin Yu, PhD, the Daffodil Centre, the University of Sydney, and colleagues.

“[However], when all prognostic factors were considered together, most of the survival differential disappeared,” they add.

“These results suggest that sex differences in lung cancer survival can be largely explained by known prognostic factors,” Dr. Yu and colleagues emphasize.

The study was published in the May issue of the Journal of Thoracic Oncology.
 

The ‘45 and up’ study

The findings come from the Sax Institute’s 45 and Up Study, an ongoing trial involving over 267,000 participants aged 45 years and older living in New South Wales, Australia. Patients were recruited to the study between 2006 and 2009. At the time of recruitment, patients were cancer free.

A total of 1,130 participants were diagnosed with having lung cancer during follow-up – 488 women and 642 men. Compared with men, women were, on average, younger at the time of diagnosis, had fewer comorbidities, and were more likely to be never-smokers or to have been exposed to passive smoke.

Women were also more likely to be diagnosed with adenocarcinoma than men and to receive surgery within 6 months of their diagnosis.

“Lung cancer survival was significantly higher for women,” the authors report, at a median of 1.28 years versus 0.77 years for men (P < .0001).

Within each subgroup of major prognostic factors – histologic subtype, cancer stage, cancer treatment, and smoking status – women again survived significantly longer than men.

Interestingly, the authors note that “women with adenocarcinoma had significantly better survival than men with adenocarcinoma independent of smoking status,” (P = .0009). This suggests that sex differences in tumor biology may play a role in explaining the sex survival differential between men and women, they commented. That said, never-smokers had a 16% lower risk for lung cancer death than ever-smokers after adjusting for age, the authors point out.

The authors also note that approximately half of the disparity in survival between the sexes could be explained by differences in the receipt of anticancer therapy within 6 months of the diagnosis. “This could partly be due to a lower proportion of men having surgery within 6 months than women,” investigators speculate, at 17% versus 25%, respectively.

Men were also older than women at the time of diagnosis, were less likely to be never-smokers, and had more comorbidities, all of which might also have prevented them from having surgery. Women with lung cancer may also respond better to chemotherapy than men, although the sex disparity in survival persisted even among patients who did not receive any treatment for their cancer within 6 months of their diagnosis, investigators point out.

Furthermore, “smoking history at baseline was identified as a significant contributing factor to the sex survival disparity, explaining approximately 28% of the overall disparity,” Dr. Yu and colleagues observe.

Only 8% of men diagnosed with lung cancer were never-smokers, compared with 23% of women. The authors note that never-smokers are more likely to receive aggressive or complete treatment and respond well to treatment.

Similarly, tumor-related factors together explained about one-quarter of the overall sex disparity in survival.
 

Screening guidelines

Commenting on the findings in an accompanying editorial, Claudia Poleri, MD, Hospital María Ferrer, Buenos Aires, says that this Australian study provides “valuable information.”

“The risk of dying from lung cancer was significantly higher for men than for women,” she writes. “Differences in treatment-related factors explained 50% of the sex survival differential, followed by lifestyle and tumor-related factors (28% and 26%, respectively).

“Nevertheless, these differences alone do not explain the higher survival in women,” she comments.

“Does it matter to analyze the differences by sex in lung cancer?” Dr. Poleri asks in the editorial, and then answers herself: “It matters.”

“It is necessary to implement screening programs and build artificial intelligence diagnostic algorithms considering the role of sex and gender equity to ensure that innovative technologies do not induce disparities in clinical care,” she writes.

“It is crucial to conduct education and health public programs that consider these differences, optimizing the use of available resources, [and] it is essential to improve the accuracy of research design and clinical trials,” she adds.

Dr. Yu and Dr. Poleri declared no relevant financial interests.

A version of this article first appeared on Medscape.com.

The observation that women with lung cancer seem to live longer than men can be explained by known prognostic factors, a new study suggests.

“In this first Australian prospective study of lung cancer survival comparing men and women, we found that men had a 43% greater risk of dying from their lung cancer than women,” comments lead author Xue Qin Yu, PhD, the Daffodil Centre, the University of Sydney, and colleagues.

“[However], when all prognostic factors were considered together, most of the survival differential disappeared,” they add.

“These results suggest that sex differences in lung cancer survival can be largely explained by known prognostic factors,” Dr. Yu and colleagues emphasize.

The study was published in the May issue of the Journal of Thoracic Oncology.
 

The ‘45 and up’ study

The findings come from the Sax Institute’s 45 and Up Study, an ongoing trial involving over 267,000 participants aged 45 years and older living in New South Wales, Australia. Patients were recruited to the study between 2006 and 2009. At the time of recruitment, patients were cancer free.

A total of 1,130 participants were diagnosed with having lung cancer during follow-up – 488 women and 642 men. Compared with men, women were, on average, younger at the time of diagnosis, had fewer comorbidities, and were more likely to be never-smokers or to have been exposed to passive smoke.

Women were also more likely to be diagnosed with adenocarcinoma than men and to receive surgery within 6 months of their diagnosis.

“Lung cancer survival was significantly higher for women,” the authors report, at a median of 1.28 years versus 0.77 years for men (P < .0001).

Within each subgroup of major prognostic factors – histologic subtype, cancer stage, cancer treatment, and smoking status – women again survived significantly longer than men.

Interestingly, the authors note that “women with adenocarcinoma had significantly better survival than men with adenocarcinoma independent of smoking status,” (P = .0009). This suggests that sex differences in tumor biology may play a role in explaining the sex survival differential between men and women, they commented. That said, never-smokers had a 16% lower risk for lung cancer death than ever-smokers after adjusting for age, the authors point out.

The authors also note that approximately half of the disparity in survival between the sexes could be explained by differences in the receipt of anticancer therapy within 6 months of the diagnosis. “This could partly be due to a lower proportion of men having surgery within 6 months than women,” investigators speculate, at 17% versus 25%, respectively.

Men were also older than women at the time of diagnosis, were less likely to be never-smokers, and had more comorbidities, all of which might also have prevented them from having surgery. Women with lung cancer may also respond better to chemotherapy than men, although the sex disparity in survival persisted even among patients who did not receive any treatment for their cancer within 6 months of their diagnosis, investigators point out.

Furthermore, “smoking history at baseline was identified as a significant contributing factor to the sex survival disparity, explaining approximately 28% of the overall disparity,” Dr. Yu and colleagues observe.

Only 8% of men diagnosed with lung cancer were never-smokers, compared with 23% of women. The authors note that never-smokers are more likely to receive aggressive or complete treatment and respond well to treatment.

Similarly, tumor-related factors together explained about one-quarter of the overall sex disparity in survival.
 

Screening guidelines

Commenting on the findings in an accompanying editorial, Claudia Poleri, MD, Hospital María Ferrer, Buenos Aires, says that this Australian study provides “valuable information.”

“The risk of dying from lung cancer was significantly higher for men than for women,” she writes. “Differences in treatment-related factors explained 50% of the sex survival differential, followed by lifestyle and tumor-related factors (28% and 26%, respectively).

“Nevertheless, these differences alone do not explain the higher survival in women,” she comments.

“Does it matter to analyze the differences by sex in lung cancer?” Dr. Poleri asks in the editorial, and then answers herself: “It matters.”

“It is necessary to implement screening programs and build artificial intelligence diagnostic algorithms considering the role of sex and gender equity to ensure that innovative technologies do not induce disparities in clinical care,” she writes.

“It is crucial to conduct education and health public programs that consider these differences, optimizing the use of available resources, [and] it is essential to improve the accuracy of research design and clinical trials,” she adds.

Dr. Yu and Dr. Poleri declared no relevant financial interests.

A version of this article first appeared on Medscape.com.

The observation that women with lung cancer seem to live longer than men can be explained by known prognostic factors, a new study suggests.

“In this first Australian prospective study of lung cancer survival comparing men and women, we found that men had a 43% greater risk of dying from their lung cancer than women,” comments lead author Xue Qin Yu, PhD, the Daffodil Centre, the University of Sydney, and colleagues.

“[However], when all prognostic factors were considered together, most of the survival differential disappeared,” they add.

“These results suggest that sex differences in lung cancer survival can be largely explained by known prognostic factors,” Dr. Yu and colleagues emphasize.

The study was published in the May issue of the Journal of Thoracic Oncology.
 

The ‘45 and up’ study

The findings come from the Sax Institute’s 45 and Up Study, an ongoing trial involving over 267,000 participants aged 45 years and older living in New South Wales, Australia. Patients were recruited to the study between 2006 and 2009. At the time of recruitment, patients were cancer free.

A total of 1,130 participants were diagnosed with having lung cancer during follow-up – 488 women and 642 men. Compared with men, women were, on average, younger at the time of diagnosis, had fewer comorbidities, and were more likely to be never-smokers or to have been exposed to passive smoke.

Women were also more likely to be diagnosed with adenocarcinoma than men and to receive surgery within 6 months of their diagnosis.

“Lung cancer survival was significantly higher for women,” the authors report, at a median of 1.28 years versus 0.77 years for men (P < .0001).

Within each subgroup of major prognostic factors – histologic subtype, cancer stage, cancer treatment, and smoking status – women again survived significantly longer than men.

Interestingly, the authors note that “women with adenocarcinoma had significantly better survival than men with adenocarcinoma independent of smoking status,” (P = .0009). This suggests that sex differences in tumor biology may play a role in explaining the sex survival differential between men and women, they commented. That said, never-smokers had a 16% lower risk for lung cancer death than ever-smokers after adjusting for age, the authors point out.

The authors also note that approximately half of the disparity in survival between the sexes could be explained by differences in the receipt of anticancer therapy within 6 months of the diagnosis. “This could partly be due to a lower proportion of men having surgery within 6 months than women,” investigators speculate, at 17% versus 25%, respectively.

Men were also older than women at the time of diagnosis, were less likely to be never-smokers, and had more comorbidities, all of which might also have prevented them from having surgery. Women with lung cancer may also respond better to chemotherapy than men, although the sex disparity in survival persisted even among patients who did not receive any treatment for their cancer within 6 months of their diagnosis, investigators point out.

Furthermore, “smoking history at baseline was identified as a significant contributing factor to the sex survival disparity, explaining approximately 28% of the overall disparity,” Dr. Yu and colleagues observe.

Only 8% of men diagnosed with lung cancer were never-smokers, compared with 23% of women. The authors note that never-smokers are more likely to receive aggressive or complete treatment and respond well to treatment.

Similarly, tumor-related factors together explained about one-quarter of the overall sex disparity in survival.
 

Screening guidelines

Commenting on the findings in an accompanying editorial, Claudia Poleri, MD, Hospital María Ferrer, Buenos Aires, says that this Australian study provides “valuable information.”

“The risk of dying from lung cancer was significantly higher for men than for women,” she writes. “Differences in treatment-related factors explained 50% of the sex survival differential, followed by lifestyle and tumor-related factors (28% and 26%, respectively).

“Nevertheless, these differences alone do not explain the higher survival in women,” she comments.

“Does it matter to analyze the differences by sex in lung cancer?” Dr. Poleri asks in the editorial, and then answers herself: “It matters.”

“It is necessary to implement screening programs and build artificial intelligence diagnostic algorithms considering the role of sex and gender equity to ensure that innovative technologies do not induce disparities in clinical care,” she writes.

“It is crucial to conduct education and health public programs that consider these differences, optimizing the use of available resources, [and] it is essential to improve the accuracy of research design and clinical trials,” she adds.

Dr. Yu and Dr. Poleri declared no relevant financial interests.

A version of this article first appeared on Medscape.com.

A relationship between consumption of dairy products and risk of various cancers has been intensively investigated in the past but yielded inconclusive or conflicting results. Now a large new study comparing Chinese dairy consumption with that in the United Kingdom, shows that increased dairy consumption was linked to higher risks of liver cancer and female breast cancer.

The study, by researchers from Oxford University’s department of population health, and Peking University and the Chinese Academy of Medical Sciences in Beijing, used data from the China Kadoorie Biobank Study, a long-term prospective study involving more than over 510,000 participants recruited from 10 geographically diverse areas across China, including both rural and urban regions. They compared this to data from the UK biobank.

Subjects were 59% female, 41% male, aged 30-79 years, and had no history of cancer at recruitment between 2004 and 2008. Food questionnaires were completed at the outset and participants followed for an average of 11 years, using national cancer and death registries and health insurance records to identify new cancer diagnoses, including both fatal and nonfatal events.

Participants were categorized into three groups according to how often they consumed dairy products (primarily milk):

• Regular consumers (at least once a week): 20.4% of the cohort.
• Monthly consumers: 11.1%.
• Nonconsumers who never or rarely consumed dairy products: 68.5%.

Average dairy consumption was 37.9 g/day overall and 80.8 g/day among regular consumers. This compares with an average consumption of around 300 g/day in participants in the UK Biobank cohort.

Over the course of the study, 29,277 new cancer cases were recorded, including 6,282 lung, 2,582 female breast, 3,577 stomach, 3,350 colorectal, and 3,191 liver cancer cases.

Analyses correlating cases with consumption took into account a range of other factors potentially affecting cancer risk, including age, sex, region, family history of cancer, socioeconomic status (education and income), lifestyle factors (alcohol intake, smoking, physical activity, soy consumption, and fresh fruit intake), body mass index, chronic hepatitis B virus infection, and female reproductive factors.

Higher dairy intakes linked with risk of liver and breast cancers

Results revealed that higher regular dairy intake was associated with significantly higher risks of liver cancer and female breast cancer, both common types of cancer in China. Analyses indicated that for each 50-g/day intake, the risks increased by 12% and 17%, respectively.

There was also an increase in total cancer diagnoses, and an increased risk of lymphoma, though this was not statistically significant after correction for confounders. No association was found between dairy products and colorectal cancer, prostate cancer, or any other site-specific cancer.

The research, published in BMC Medicine, is the first major study to investigate dairy consumption and cancer risk in Chinese adults. The results conflict with previous studies on Western populations, which have suggested that dairy products may be associated with a lower risk of colorectal cancer and a higher risk of prostate cancer but have found no clear link for breast or other types of cancer.

Lead researchers Maria Kakkoura, PhD, MSc, and associate professor Huaidong Du, MD, PhD, told this news organization that, although they don’t know the reason for the difference, “there is clear evidence that colorectal cancer has a different incidence pattern in China, compared with Western countries. Other risk factors, like adiposity, may have a stronger effect on the risk of colorectal cancer in Western countries than in China.” Notably, the mean body mass index in the study population was around 23 kg/m², they said – by contrast in the United Kingdom it is 27.6 kg/m2.

Effects not necessarily causal

Ian Givens, PhD, professor of food chain nutrition at the University of Reading (England), said the study was “potentially very important for Chinese people, if it can be confirmed that dairy products affect the risk of breast and/or liver cancer differently in Chinese subjects to those in Western Societies, especially as dairy consumption in China is much lower than in most Western diets.”

He added: “As always it needs to be kept in mind that this type of study can only establish associations with disease risk, not cause.”

Dr. Kakkoura, nutritional epidemiologist at Oxford (England) University’s department of population health, said: “This was the first major study to investigate the link between dairy products and cancer risk in a Chinese population. Further studies are needed to validate these current findings, establish if these associations are causal, and investigate the potential underlying mechanisms involved.”

The researchers said that, while the results do not prove causation, “there are several plausible biological mechanisms that may explain these associations.” They pointed to higher dairy consumption potentially increasing levels of insulinlike growth factor-I, known to promote cell proliferation and associated with higher risks of several types of cancer.

In addition, estrogen and progesterone present in cows’ milk may play a role in increasing breast cancer risk, whilst saturated and trans-fatty acids from dairy products may increase the risk of liver cancer. As many Chinese people are lactase deficient, dairy products may also be broken down into products that affect cancer risk.

No justification for dietary change

Confounding factors may also have influenced the results, commented Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow at Aston University, Birmingham, England. “Those in the study who consumed dairy were more likely to live in cities and have other health conditions, including cardiovascular disease and diabetes – although some of these factors were considered in the analysis, not all of these covariates were, which could influence the findings.

“In my view this study alone does not provide strong evidence that reducing dairy intake would reduce cancer risk.”

He added: “Although the paper suggests a 12% increased relative risk for female breast cancer, this does not equate to 12 more cases per 100 individuals – in absolute terms this would be more like 1 or 2 cases per 1,000 people.”

Similarly, Kevin McConway, PhD, emeritus professor of applied statistics at the Open University, Milton Keynes, England, said: “An issue is that there were many differences between the people that consumed different amounts of dairy products, apart from their difference in dairy consumption. For instance, of those who never or rarely consumed dairy products, fewer than a third lived in urban areas, but of regular dairy consumers (at least once a week), 83% lived in urban areas. Regular consumers were considerably more likely to be well educated than those who never or rarely consumed dairy products, and there were other differences too. 

“So if, as the researchers found, a greater proportion of the regular consumers than of the never or rare consumers had a cancer diagnosis, that could have been because of their different dairy consumption, or it could have been (in part or entirely) because of the different places they lived, or their different education levels, or any of the other factors on which the groups differed.

“One can never be sure that all the relevant factors have been adjusted for. That’s why the researchers rightly say that these results can’t establish whether the associations between dairy consumption and the risks of some cancers, that they found, are there because the dairy consumption differences change the cancer risks in a cause-and-effect way. They might, or they might not.”

He cautioned: “I don’t think anyone should decide to change their individual diet solely because of the results of this new study.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, London, told this news organization: “This early-stage study found an association between dairy consumption and the risks of certain cancers, but that doesn’t mean that they’re causing them or that people need to avoid dairy. Dairy products can be part of a healthy balanced diet and, in the U.K., the Food Standards Agency regulates them to make sure they’re safe. There’s good evidence that dairy reduces the risk of bowel cancer, but no clear evidence for other cancer types, and this is no different for people who are lactose intolerant.”

A version of this article first appeared on Medscape UK.

A relationship between consumption of dairy products and risk of various cancers has been intensively investigated in the past but yielded inconclusive or conflicting results. Now a large new study comparing Chinese dairy consumption with that in the United Kingdom, shows that increased dairy consumption was linked to higher risks of liver cancer and female breast cancer.

The study, by researchers from Oxford University’s department of population health, and Peking University and the Chinese Academy of Medical Sciences in Beijing, used data from the China Kadoorie Biobank Study, a long-term prospective study involving more than over 510,000 participants recruited from 10 geographically diverse areas across China, including both rural and urban regions. They compared this to data from the UK biobank.

Subjects were 59% female, 41% male, aged 30-79 years, and had no history of cancer at recruitment between 2004 and 2008. Food questionnaires were completed at the outset and participants followed for an average of 11 years, using national cancer and death registries and health insurance records to identify new cancer diagnoses, including both fatal and nonfatal events.

Participants were categorized into three groups according to how often they consumed dairy products (primarily milk):

• Regular consumers (at least once a week): 20.4% of the cohort.
• Monthly consumers: 11.1%.
• Nonconsumers who never or rarely consumed dairy products: 68.5%.

Average dairy consumption was 37.9 g/day overall and 80.8 g/day among regular consumers. This compares with an average consumption of around 300 g/day in participants in the UK Biobank cohort.

Over the course of the study, 29,277 new cancer cases were recorded, including 6,282 lung, 2,582 female breast, 3,577 stomach, 3,350 colorectal, and 3,191 liver cancer cases.

Analyses correlating cases with consumption took into account a range of other factors potentially affecting cancer risk, including age, sex, region, family history of cancer, socioeconomic status (education and income), lifestyle factors (alcohol intake, smoking, physical activity, soy consumption, and fresh fruit intake), body mass index, chronic hepatitis B virus infection, and female reproductive factors.

Higher dairy intakes linked with risk of liver and breast cancers

Results revealed that higher regular dairy intake was associated with significantly higher risks of liver cancer and female breast cancer, both common types of cancer in China. Analyses indicated that for each 50-g/day intake, the risks increased by 12% and 17%, respectively.

There was also an increase in total cancer diagnoses, and an increased risk of lymphoma, though this was not statistically significant after correction for confounders. No association was found between dairy products and colorectal cancer, prostate cancer, or any other site-specific cancer.

The research, published in BMC Medicine, is the first major study to investigate dairy consumption and cancer risk in Chinese adults. The results conflict with previous studies on Western populations, which have suggested that dairy products may be associated with a lower risk of colorectal cancer and a higher risk of prostate cancer but have found no clear link for breast or other types of cancer.

Lead researchers Maria Kakkoura, PhD, MSc, and associate professor Huaidong Du, MD, PhD, told this news organization that, although they don’t know the reason for the difference, “there is clear evidence that colorectal cancer has a different incidence pattern in China, compared with Western countries. Other risk factors, like adiposity, may have a stronger effect on the risk of colorectal cancer in Western countries than in China.” Notably, the mean body mass index in the study population was around 23 kg/m², they said – by contrast in the United Kingdom it is 27.6 kg/m2.

Effects not necessarily causal

Ian Givens, PhD, professor of food chain nutrition at the University of Reading (England), said the study was “potentially very important for Chinese people, if it can be confirmed that dairy products affect the risk of breast and/or liver cancer differently in Chinese subjects to those in Western Societies, especially as dairy consumption in China is much lower than in most Western diets.”

He added: “As always it needs to be kept in mind that this type of study can only establish associations with disease risk, not cause.”

Dr. Kakkoura, nutritional epidemiologist at Oxford (England) University’s department of population health, said: “This was the first major study to investigate the link between dairy products and cancer risk in a Chinese population. Further studies are needed to validate these current findings, establish if these associations are causal, and investigate the potential underlying mechanisms involved.”

The researchers said that, while the results do not prove causation, “there are several plausible biological mechanisms that may explain these associations.” They pointed to higher dairy consumption potentially increasing levels of insulinlike growth factor-I, known to promote cell proliferation and associated with higher risks of several types of cancer.

In addition, estrogen and progesterone present in cows’ milk may play a role in increasing breast cancer risk, whilst saturated and trans-fatty acids from dairy products may increase the risk of liver cancer. As many Chinese people are lactase deficient, dairy products may also be broken down into products that affect cancer risk.

No justification for dietary change

Confounding factors may also have influenced the results, commented Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow at Aston University, Birmingham, England. “Those in the study who consumed dairy were more likely to live in cities and have other health conditions, including cardiovascular disease and diabetes – although some of these factors were considered in the analysis, not all of these covariates were, which could influence the findings.

“In my view this study alone does not provide strong evidence that reducing dairy intake would reduce cancer risk.”

He added: “Although the paper suggests a 12% increased relative risk for female breast cancer, this does not equate to 12 more cases per 100 individuals – in absolute terms this would be more like 1 or 2 cases per 1,000 people.”

Similarly, Kevin McConway, PhD, emeritus professor of applied statistics at the Open University, Milton Keynes, England, said: “An issue is that there were many differences between the people that consumed different amounts of dairy products, apart from their difference in dairy consumption. For instance, of those who never or rarely consumed dairy products, fewer than a third lived in urban areas, but of regular dairy consumers (at least once a week), 83% lived in urban areas. Regular consumers were considerably more likely to be well educated than those who never or rarely consumed dairy products, and there were other differences too. 

“So if, as the researchers found, a greater proportion of the regular consumers than of the never or rare consumers had a cancer diagnosis, that could have been because of their different dairy consumption, or it could have been (in part or entirely) because of the different places they lived, or their different education levels, or any of the other factors on which the groups differed.

“One can never be sure that all the relevant factors have been adjusted for. That’s why the researchers rightly say that these results can’t establish whether the associations between dairy consumption and the risks of some cancers, that they found, are there because the dairy consumption differences change the cancer risks in a cause-and-effect way. They might, or they might not.”

He cautioned: “I don’t think anyone should decide to change their individual diet solely because of the results of this new study.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, London, told this news organization: “This early-stage study found an association between dairy consumption and the risks of certain cancers, but that doesn’t mean that they’re causing them or that people need to avoid dairy. Dairy products can be part of a healthy balanced diet and, in the U.K., the Food Standards Agency regulates them to make sure they’re safe. There’s good evidence that dairy reduces the risk of bowel cancer, but no clear evidence for other cancer types, and this is no different for people who are lactose intolerant.”

A version of this article first appeared on Medscape UK.

A relationship between consumption of dairy products and risk of various cancers has been intensively investigated in the past but yielded inconclusive or conflicting results. Now a large new study comparing Chinese dairy consumption with that in the United Kingdom, shows that increased dairy consumption was linked to higher risks of liver cancer and female breast cancer.

The study, by researchers from Oxford University’s department of population health, and Peking University and the Chinese Academy of Medical Sciences in Beijing, used data from the China Kadoorie Biobank Study, a long-term prospective study involving more than over 510,000 participants recruited from 10 geographically diverse areas across China, including both rural and urban regions. They compared this to data from the UK biobank.

Subjects were 59% female, 41% male, aged 30-79 years, and had no history of cancer at recruitment between 2004 and 2008. Food questionnaires were completed at the outset and participants followed for an average of 11 years, using national cancer and death registries and health insurance records to identify new cancer diagnoses, including both fatal and nonfatal events.

Participants were categorized into three groups according to how often they consumed dairy products (primarily milk):

• Regular consumers (at least once a week): 20.4% of the cohort.
• Monthly consumers: 11.1%.
• Nonconsumers who never or rarely consumed dairy products: 68.5%.

Average dairy consumption was 37.9 g/day overall and 80.8 g/day among regular consumers. This compares with an average consumption of around 300 g/day in participants in the UK Biobank cohort.

Over the course of the study, 29,277 new cancer cases were recorded, including 6,282 lung, 2,582 female breast, 3,577 stomach, 3,350 colorectal, and 3,191 liver cancer cases.

Analyses correlating cases with consumption took into account a range of other factors potentially affecting cancer risk, including age, sex, region, family history of cancer, socioeconomic status (education and income), lifestyle factors (alcohol intake, smoking, physical activity, soy consumption, and fresh fruit intake), body mass index, chronic hepatitis B virus infection, and female reproductive factors.

Higher dairy intakes linked with risk of liver and breast cancers

Results revealed that higher regular dairy intake was associated with significantly higher risks of liver cancer and female breast cancer, both common types of cancer in China. Analyses indicated that for each 50-g/day intake, the risks increased by 12% and 17%, respectively.

There was also an increase in total cancer diagnoses, and an increased risk of lymphoma, though this was not statistically significant after correction for confounders. No association was found between dairy products and colorectal cancer, prostate cancer, or any other site-specific cancer.

The research, published in BMC Medicine, is the first major study to investigate dairy consumption and cancer risk in Chinese adults. The results conflict with previous studies on Western populations, which have suggested that dairy products may be associated with a lower risk of colorectal cancer and a higher risk of prostate cancer but have found no clear link for breast or other types of cancer.

Lead researchers Maria Kakkoura, PhD, MSc, and associate professor Huaidong Du, MD, PhD, told this news organization that, although they don’t know the reason for the difference, “there is clear evidence that colorectal cancer has a different incidence pattern in China, compared with Western countries. Other risk factors, like adiposity, may have a stronger effect on the risk of colorectal cancer in Western countries than in China.” Notably, the mean body mass index in the study population was around 23 kg/m², they said – by contrast in the United Kingdom it is 27.6 kg/m2.

Effects not necessarily causal

Ian Givens, PhD, professor of food chain nutrition at the University of Reading (England), said the study was “potentially very important for Chinese people, if it can be confirmed that dairy products affect the risk of breast and/or liver cancer differently in Chinese subjects to those in Western Societies, especially as dairy consumption in China is much lower than in most Western diets.”

He added: “As always it needs to be kept in mind that this type of study can only establish associations with disease risk, not cause.”

Dr. Kakkoura, nutritional epidemiologist at Oxford (England) University’s department of population health, said: “This was the first major study to investigate the link between dairy products and cancer risk in a Chinese population. Further studies are needed to validate these current findings, establish if these associations are causal, and investigate the potential underlying mechanisms involved.”

The researchers said that, while the results do not prove causation, “there are several plausible biological mechanisms that may explain these associations.” They pointed to higher dairy consumption potentially increasing levels of insulinlike growth factor-I, known to promote cell proliferation and associated with higher risks of several types of cancer.

In addition, estrogen and progesterone present in cows’ milk may play a role in increasing breast cancer risk, whilst saturated and trans-fatty acids from dairy products may increase the risk of liver cancer. As many Chinese people are lactase deficient, dairy products may also be broken down into products that affect cancer risk.

No justification for dietary change

Confounding factors may also have influenced the results, commented Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow at Aston University, Birmingham, England. “Those in the study who consumed dairy were more likely to live in cities and have other health conditions, including cardiovascular disease and diabetes – although some of these factors were considered in the analysis, not all of these covariates were, which could influence the findings.

“In my view this study alone does not provide strong evidence that reducing dairy intake would reduce cancer risk.”

He added: “Although the paper suggests a 12% increased relative risk for female breast cancer, this does not equate to 12 more cases per 100 individuals – in absolute terms this would be more like 1 or 2 cases per 1,000 people.”

Similarly, Kevin McConway, PhD, emeritus professor of applied statistics at the Open University, Milton Keynes, England, said: “An issue is that there were many differences between the people that consumed different amounts of dairy products, apart from their difference in dairy consumption. For instance, of those who never or rarely consumed dairy products, fewer than a third lived in urban areas, but of regular dairy consumers (at least once a week), 83% lived in urban areas. Regular consumers were considerably more likely to be well educated than those who never or rarely consumed dairy products, and there were other differences too. 

“So if, as the researchers found, a greater proportion of the regular consumers than of the never or rare consumers had a cancer diagnosis, that could have been because of their different dairy consumption, or it could have been (in part or entirely) because of the different places they lived, or their different education levels, or any of the other factors on which the groups differed.

“One can never be sure that all the relevant factors have been adjusted for. That’s why the researchers rightly say that these results can’t establish whether the associations between dairy consumption and the risks of some cancers, that they found, are there because the dairy consumption differences change the cancer risks in a cause-and-effect way. They might, or they might not.”

He cautioned: “I don’t think anyone should decide to change their individual diet solely because of the results of this new study.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, London, told this news organization: “This early-stage study found an association between dairy consumption and the risks of certain cancers, but that doesn’t mean that they’re causing them or that people need to avoid dairy. Dairy products can be part of a healthy balanced diet and, in the U.K., the Food Standards Agency regulates them to make sure they’re safe. There’s good evidence that dairy reduces the risk of bowel cancer, but no clear evidence for other cancer types, and this is no different for people who are lactose intolerant.”

A version of this article first appeared on Medscape UK.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

Women with ductal carcinoma in situ (DCIS) breast cancer are generally uninformed about their diagnosis and are making uninformed treatment decisions, according to results of a study presented this month at ESMO Breast Cancer 2022, an annual meeting of the European Society for Medical Oncology.

The standard of care for women diagnosed with DCIS includes surgery with or without radiotherapy – even low-risk patients who are increasingly being steered toward active surveillance with annual mammograms. But few patients understand their diagnosis well enough to make informed decisions about treatment, according to a study led by Ellen Engelhardt, PhD, a postdoctoral fellow at The Netherlands Cancer Institute, Amsterdam.

“You’re not able to really have an informed preference until you understand the choices,” she said.

Dr. Engelhardt and colleagues surveyed 200 patients (mean age 59 years) from the LORD study, which is currently underway at The Netherlands Cancer Institute. The women were asked to complete a survey before treatment decisions were made. Their objective was to determine how knowledgeable patients were about DCIS. They found that only 34% of women answered four out of seven questions correctly: 19% of patients believed that DCIS could metastasize to organs other than the breast; 31% did not realize DCIS could progress to invasive breast cancer if left untreated; 79% thought DCIS could always be seen on mammograms; and, 93% said that progression could always be detected before it becomes “too extensive.” Knowledge of DCIS was found not to be associated with patient education level.

Susie X. Sun, MD, FACS, a breast surgeon at the University of Texas MD Anderson Cancer Center, Houston, said the findings clearly highlight a disconnect in communication between doctor and patient.

“I was surprised, because this clearly demonstrates there is a disconnect between what patients are being told by their providers and what is being perceived. It really shows us that we need to do a better job of making sure that our patients understand the information they’re given,” she said.

Dr. Sun, who was not involved in the study, said that DCIS needs to be explained well to patients. When they receive a diagnosis, often all they hear is, “I have breast cancer. It is really important for us to stress to patients how DCIS is different from invasive breast cancer,” she said.

The “Management of Low-risk (grade I and II) DCIS (LORD)” study is one of three studies comparing active surveillance to surgery (with or without radiotherapy).

A limitation of the study presented at ESMO Breast Cancer is that it remains unclear why patients answered questions incorrectly. Was information never communicated to them? Or, did they mishear or misunderstand the doctor? In future studies, Dr. Engelhardt and her colleagues plan to record and analyze audio tapes of consultations to determine where the communication disconnect lies.

Dr. Engelhardt did not disclose any conflicts associated with this work.

Women with ductal carcinoma in situ (DCIS) breast cancer are generally uninformed about their diagnosis and are making uninformed treatment decisions, according to results of a study presented this month at ESMO Breast Cancer 2022, an annual meeting of the European Society for Medical Oncology.

The standard of care for women diagnosed with DCIS includes surgery with or without radiotherapy – even low-risk patients who are increasingly being steered toward active surveillance with annual mammograms. But few patients understand their diagnosis well enough to make informed decisions about treatment, according to a study led by Ellen Engelhardt, PhD, a postdoctoral fellow at The Netherlands Cancer Institute, Amsterdam.

“You’re not able to really have an informed preference until you understand the choices,” she said.

Dr. Engelhardt and colleagues surveyed 200 patients (mean age 59 years) from the LORD study, which is currently underway at The Netherlands Cancer Institute. The women were asked to complete a survey before treatment decisions were made. Their objective was to determine how knowledgeable patients were about DCIS. They found that only 34% of women answered four out of seven questions correctly: 19% of patients believed that DCIS could metastasize to organs other than the breast; 31% did not realize DCIS could progress to invasive breast cancer if left untreated; 79% thought DCIS could always be seen on mammograms; and, 93% said that progression could always be detected before it becomes “too extensive.” Knowledge of DCIS was found not to be associated with patient education level.

Susie X. Sun, MD, FACS, a breast surgeon at the University of Texas MD Anderson Cancer Center, Houston, said the findings clearly highlight a disconnect in communication between doctor and patient.

“I was surprised, because this clearly demonstrates there is a disconnect between what patients are being told by their providers and what is being perceived. It really shows us that we need to do a better job of making sure that our patients understand the information they’re given,” she said.

Dr. Sun, who was not involved in the study, said that DCIS needs to be explained well to patients. When they receive a diagnosis, often all they hear is, “I have breast cancer. It is really important for us to stress to patients how DCIS is different from invasive breast cancer,” she said.

The “Management of Low-risk (grade I and II) DCIS (LORD)” study is one of three studies comparing active surveillance to surgery (with or without radiotherapy).

A limitation of the study presented at ESMO Breast Cancer is that it remains unclear why patients answered questions incorrectly. Was information never communicated to them? Or, did they mishear or misunderstand the doctor? In future studies, Dr. Engelhardt and her colleagues plan to record and analyze audio tapes of consultations to determine where the communication disconnect lies.

Dr. Engelhardt did not disclose any conflicts associated with this work.

Women with ductal carcinoma in situ (DCIS) breast cancer are generally uninformed about their diagnosis and are making uninformed treatment decisions, according to results of a study presented this month at ESMO Breast Cancer 2022, an annual meeting of the European Society for Medical Oncology.

The standard of care for women diagnosed with DCIS includes surgery with or without radiotherapy – even low-risk patients who are increasingly being steered toward active surveillance with annual mammograms. But few patients understand their diagnosis well enough to make informed decisions about treatment, according to a study led by Ellen Engelhardt, PhD, a postdoctoral fellow at The Netherlands Cancer Institute, Amsterdam.

“You’re not able to really have an informed preference until you understand the choices,” she said.

Dr. Engelhardt and colleagues surveyed 200 patients (mean age 59 years) from the LORD study, which is currently underway at The Netherlands Cancer Institute. The women were asked to complete a survey before treatment decisions were made. Their objective was to determine how knowledgeable patients were about DCIS. They found that only 34% of women answered four out of seven questions correctly: 19% of patients believed that DCIS could metastasize to organs other than the breast; 31% did not realize DCIS could progress to invasive breast cancer if left untreated; 79% thought DCIS could always be seen on mammograms; and, 93% said that progression could always be detected before it becomes “too extensive.” Knowledge of DCIS was found not to be associated with patient education level.

Susie X. Sun, MD, FACS, a breast surgeon at the University of Texas MD Anderson Cancer Center, Houston, said the findings clearly highlight a disconnect in communication between doctor and patient.

“I was surprised, because this clearly demonstrates there is a disconnect between what patients are being told by their providers and what is being perceived. It really shows us that we need to do a better job of making sure that our patients understand the information they’re given,” she said.

Dr. Sun, who was not involved in the study, said that DCIS needs to be explained well to patients. When they receive a diagnosis, often all they hear is, “I have breast cancer. It is really important for us to stress to patients how DCIS is different from invasive breast cancer,” she said.

The “Management of Low-risk (grade I and II) DCIS (LORD)” study is one of three studies comparing active surveillance to surgery (with or without radiotherapy).

A limitation of the study presented at ESMO Breast Cancer is that it remains unclear why patients answered questions incorrectly. Was information never communicated to them? Or, did they mishear or misunderstand the doctor? In future studies, Dr. Engelhardt and her colleagues plan to record and analyze audio tapes of consultations to determine where the communication disconnect lies.

Dr. Engelhardt did not disclose any conflicts associated with this work.

Nasopharyngeal carcinoma (NPC) differs from other head and neck (H&N) cancers in its epidemiology and treatment. Unlike other H&N cancers, NPC has a distinct geographical distribution with a much higher incidence in endemic areas, such as southern China, than in areas where it is relatively uncommon, such as the United States.¹ The etiology of NPC varies based on the geographical distribution, with Epstein-Barr virus (EBV) thought to be the primary etiologic agent in endemic areas. On the other hand, in North America 2 additional subsets of NPC have been identified: human papillomavirus (HPV)–positive/EBV-negative and HPV-negative/EBV-negative.^2,3 NPC arises from the epithelial lining of the nasopharynx, often in the fossa of Rosenmuller, and is the most seen tumor in the nasopharynx.⁴ NPC is less surgically accessible than other H&N cancers, and surgery to the nasopharynx poses more risks given the proximity of critical surrounding structures. NPC is radiosensitive, and therefore radiotherapy (RT), in combination with chemotherapy for locally advanced tumors, has become the mainstay of treatment for nonmetastatic NPC.⁴

NPC often presents with an asymptomatic neck mass or with symptoms of epistaxis, nasal obstruction, and otitis media.⁵ Advanced cases of NPC can present with direct extension into the skull base, paranasal sinuses, and orbit, as well as involvement of cranial nerves. Radiation planning for tumors of the nasopharynx is complicated by the need to deliver an adequate dose to the tumor while limiting dose and toxicity to nearby critical structures such as the brainstem, optic chiasm, eyes, spinal cord (SC), temporal lobes, and cochleae. Achieving an adequate dose to nasopharyngeal primary tumors is especially complicated for T4 tumors invading the skull base with intracranial extension, in direct contact with these critical structures (Table 1).

Case Presentation

A 34-year-old male patient with no previous medical history presented to the emergency department with worsening diplopia, nasal obstruction, facial pain, and neck stiffness. The patient reported a 3 pack-year smoking history with recent smoking cessation. His physical examination was notable for a right abducens nerve palsy and an ulcerated nasopharyngeal mass on endoscopy.

Computed tomography (CT) scan revealed a 7-cm mass in the nasopharynx, eroding through the skull base with destruction and replacement of the clivus by tumor. Also noted was erosion of the petrous apices, carotid canals, sella turcica, dens, and the bilateral occipital condyles. There was intracranial extension with replacement of portions of the cavernous sinuses as well as mass effect on the prepontine cistern. Additional brain imaging studies, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, were obtained for completion of the staging workup. The MRI correlated with the findings noted on CT and demonstrated involvement of Meckel cave, foramen ovale, foramen rotundum, Dorello canal, and the hypoglossal canals. No cervical lymphadenopathy or distant metastases were noted on imaging. Pathology from biopsy revealed poorly differentiated squamous cell carcinoma, EBV-negative, strongly p16-positive, HPV-16 positive, and P53-negative.

RT planning was complicated by the tumor’s contact with the brainstem and upper cervical SC, as well as proximity of the tumor to the optic apparatus. The patient underwent 2 replanning CT scans at 26 Gy and 44 Gy to evaluate for tumor shrinkage. These CT scans demonstrated shrinkage of the tumor away from critical neural structures, allowing the treatment volume to be reduced away from these structures in order to achieve required dose tolerances (brainstem < 54 Gy, optic nerves and chiasm < 50 Gy, SC < 45 Gy for this case). The replanning CT scan at 44 Gy, 5 weeks after treatment initiation, demonstrated that dramatic tumor shrinkage had occurred early in treatment, with separation of the remaining tumor from the area of the SC and brainstem with which it was initially in contact (Figure 1). This improvement allowed for shrinkage of the high-dose radiation field away from these critical neural structures.

Discussion

RT for NPC is complicated by the proximity of these tumors to critical surrounding neural structures. It is challenging to achieve the required dose constraints to surrounding neural tissues while delivering the usual 70-Gy dose to the gross tumor, especially when the tumor comes into direct contact with these structures.

This case provides an example of response-adapted RT using imaging during treatment to shrink the high-dose target as the tumor shrinks away from critical surrounding structures.⁷ This strategy permits delivery of the maximum dose to the tumor while minimizing radiation dose, and therefore risk of toxicity, to normal surrounding structures. While it is typical to deliver 70 Gy to the full extent of tumor involvement for H&N tumors, this was not possible in this case as the tumor was in contact with the brainstem and upper cervical SC. Delivering the full 70 Gy to these areas of tumor would have placed this patient at substantial risk of brainstem and/or SC toxicity. This report demonstrates that response-adapted RT with shrinking fields can allow for tumor control while avoiding toxicity to critical neural structures for cases of locally advanced NPC in which tumor is abutting these structures.

Bony regeneration of the skull base following RT has been reported in the literature, but in limited reviews. Early reports used plain radiography to follow changes. Unger and colleagues demonstrated the regeneration of bone using skull radiographs 4 to 6 months after completion of RT for NPC.⁸ More recent literature details the ability of bone to regenerate after RT based on CT findings. Fang and colleagues reported on 90 cases of NPC with skull base destruction, with 63% having bony regeneration on posttreatment CT.⁹ Most of the patients in Fang’s report had bony regeneration within 1 year of treatment, and in general, bony regeneration became more evident on imaging with longer follow-up. Of note, local control was significantly greater in patients with regeneration vs persistent destruction (77% vs 21%, P < .001). On multivariate analysis, complete tumor response was significantly associated with bony regeneration; other factors such as age, sex, radiation dose, and chemotherapy were not significantly associated with the likelihood of bony regeneration.

Our report details a nasopharyngeal tumor that destroyed the skull base with no intact bony barrier. In such cases, concern arises regarding craniospinal instability with tumor regression if there is not simultaneous bone regeneration. Tumor invasion of the skull base and C1-2 vertebral bodies and complications from treatment of such tumor extent can lead to symptoms of craniospinal instability, including pain, difficulty with neck range of motion, and loss of strength and sensation in the upper and lower extremities.¹⁰ A case report of a woman treated with chemoradiation for a plasmacytoma of the skull base detailed her posttreatment presentation with quadriparesis resulting from craniospinal instability after tumor regression.¹¹ Such instability is generally treated surgically, and during this woman’s surgery, there was an injury to the right vertebral artery, although this did not cause any additional neurologic deficits.

Conclusions

There is a paucity of literature on bony regeneration in patients with skull base destruction from advanced NPC, and in particular, the ability of skull base regeneration to occur during treatment simultaneous with tumor regression. Our patient had HPV-positive/EBV-negative NPC, but it is unclear how this subtype affected his prognosis. Factors such as tumor histology, radiosensitivity with rapid tumor regression, and young age may have all contributed to the rapidity of bone regeneration in our patient. This case report demonstrates that an impressive tumor response to chemoradiation with simultaneous bony regeneration is possible among patients presenting with tumor destruction of the skull base, precluding the need for neurosurgical intervention.

Nasopharyngeal carcinoma (NPC) differs from other head and neck (H&N) cancers in its epidemiology and treatment. Unlike other H&N cancers, NPC has a distinct geographical distribution with a much higher incidence in endemic areas, such as southern China, than in areas where it is relatively uncommon, such as the United States.¹ The etiology of NPC varies based on the geographical distribution, with Epstein-Barr virus (EBV) thought to be the primary etiologic agent in endemic areas. On the other hand, in North America 2 additional subsets of NPC have been identified: human papillomavirus (HPV)–positive/EBV-negative and HPV-negative/EBV-negative.^2,3 NPC arises from the epithelial lining of the nasopharynx, often in the fossa of Rosenmuller, and is the most seen tumor in the nasopharynx.⁴ NPC is less surgically accessible than other H&N cancers, and surgery to the nasopharynx poses more risks given the proximity of critical surrounding structures. NPC is radiosensitive, and therefore radiotherapy (RT), in combination with chemotherapy for locally advanced tumors, has become the mainstay of treatment for nonmetastatic NPC.⁴

NPC often presents with an asymptomatic neck mass or with symptoms of epistaxis, nasal obstruction, and otitis media.⁵ Advanced cases of NPC can present with direct extension into the skull base, paranasal sinuses, and orbit, as well as involvement of cranial nerves. Radiation planning for tumors of the nasopharynx is complicated by the need to deliver an adequate dose to the tumor while limiting dose and toxicity to nearby critical structures such as the brainstem, optic chiasm, eyes, spinal cord (SC), temporal lobes, and cochleae. Achieving an adequate dose to nasopharyngeal primary tumors is especially complicated for T4 tumors invading the skull base with intracranial extension, in direct contact with these critical structures (Table 1).

Case Presentation

A 34-year-old male patient with no previous medical history presented to the emergency department with worsening diplopia, nasal obstruction, facial pain, and neck stiffness. The patient reported a 3 pack-year smoking history with recent smoking cessation. His physical examination was notable for a right abducens nerve palsy and an ulcerated nasopharyngeal mass on endoscopy.

Computed tomography (CT) scan revealed a 7-cm mass in the nasopharynx, eroding through the skull base with destruction and replacement of the clivus by tumor. Also noted was erosion of the petrous apices, carotid canals, sella turcica, dens, and the bilateral occipital condyles. There was intracranial extension with replacement of portions of the cavernous sinuses as well as mass effect on the prepontine cistern. Additional brain imaging studies, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, were obtained for completion of the staging workup. The MRI correlated with the findings noted on CT and demonstrated involvement of Meckel cave, foramen ovale, foramen rotundum, Dorello canal, and the hypoglossal canals. No cervical lymphadenopathy or distant metastases were noted on imaging. Pathology from biopsy revealed poorly differentiated squamous cell carcinoma, EBV-negative, strongly p16-positive, HPV-16 positive, and P53-negative.

RT planning was complicated by the tumor’s contact with the brainstem and upper cervical SC, as well as proximity of the tumor to the optic apparatus. The patient underwent 2 replanning CT scans at 26 Gy and 44 Gy to evaluate for tumor shrinkage. These CT scans demonstrated shrinkage of the tumor away from critical neural structures, allowing the treatment volume to be reduced away from these structures in order to achieve required dose tolerances (brainstem < 54 Gy, optic nerves and chiasm < 50 Gy, SC < 45 Gy for this case). The replanning CT scan at 44 Gy, 5 weeks after treatment initiation, demonstrated that dramatic tumor shrinkage had occurred early in treatment, with separation of the remaining tumor from the area of the SC and brainstem with which it was initially in contact (Figure 1). This improvement allowed for shrinkage of the high-dose radiation field away from these critical neural structures.

Discussion

RT for NPC is complicated by the proximity of these tumors to critical surrounding neural structures. It is challenging to achieve the required dose constraints to surrounding neural tissues while delivering the usual 70-Gy dose to the gross tumor, especially when the tumor comes into direct contact with these structures.

This case provides an example of response-adapted RT using imaging during treatment to shrink the high-dose target as the tumor shrinks away from critical surrounding structures.⁷ This strategy permits delivery of the maximum dose to the tumor while minimizing radiation dose, and therefore risk of toxicity, to normal surrounding structures. While it is typical to deliver 70 Gy to the full extent of tumor involvement for H&N tumors, this was not possible in this case as the tumor was in contact with the brainstem and upper cervical SC. Delivering the full 70 Gy to these areas of tumor would have placed this patient at substantial risk of brainstem and/or SC toxicity. This report demonstrates that response-adapted RT with shrinking fields can allow for tumor control while avoiding toxicity to critical neural structures for cases of locally advanced NPC in which tumor is abutting these structures.

Bony regeneration of the skull base following RT has been reported in the literature, but in limited reviews. Early reports used plain radiography to follow changes. Unger and colleagues demonstrated the regeneration of bone using skull radiographs 4 to 6 months after completion of RT for NPC.⁸ More recent literature details the ability of bone to regenerate after RT based on CT findings. Fang and colleagues reported on 90 cases of NPC with skull base destruction, with 63% having bony regeneration on posttreatment CT.⁹ Most of the patients in Fang’s report had bony regeneration within 1 year of treatment, and in general, bony regeneration became more evident on imaging with longer follow-up. Of note, local control was significantly greater in patients with regeneration vs persistent destruction (77% vs 21%, P < .001). On multivariate analysis, complete tumor response was significantly associated with bony regeneration; other factors such as age, sex, radiation dose, and chemotherapy were not significantly associated with the likelihood of bony regeneration.

Our report details a nasopharyngeal tumor that destroyed the skull base with no intact bony barrier. In such cases, concern arises regarding craniospinal instability with tumor regression if there is not simultaneous bone regeneration. Tumor invasion of the skull base and C1-2 vertebral bodies and complications from treatment of such tumor extent can lead to symptoms of craniospinal instability, including pain, difficulty with neck range of motion, and loss of strength and sensation in the upper and lower extremities.¹⁰ A case report of a woman treated with chemoradiation for a plasmacytoma of the skull base detailed her posttreatment presentation with quadriparesis resulting from craniospinal instability after tumor regression.¹¹ Such instability is generally treated surgically, and during this woman’s surgery, there was an injury to the right vertebral artery, although this did not cause any additional neurologic deficits.

Conclusions

There is a paucity of literature on bony regeneration in patients with skull base destruction from advanced NPC, and in particular, the ability of skull base regeneration to occur during treatment simultaneous with tumor regression. Our patient had HPV-positive/EBV-negative NPC, but it is unclear how this subtype affected his prognosis. Factors such as tumor histology, radiosensitivity with rapid tumor regression, and young age may have all contributed to the rapidity of bone regeneration in our patient. This case report demonstrates that an impressive tumor response to chemoradiation with simultaneous bony regeneration is possible among patients presenting with tumor destruction of the skull base, precluding the need for neurosurgical intervention.

Nasopharyngeal carcinoma (NPC) differs from other head and neck (H&N) cancers in its epidemiology and treatment. Unlike other H&N cancers, NPC has a distinct geographical distribution with a much higher incidence in endemic areas, such as southern China, than in areas where it is relatively uncommon, such as the United States.¹ The etiology of NPC varies based on the geographical distribution, with Epstein-Barr virus (EBV) thought to be the primary etiologic agent in endemic areas. On the other hand, in North America 2 additional subsets of NPC have been identified: human papillomavirus (HPV)–positive/EBV-negative and HPV-negative/EBV-negative.^2,3 NPC arises from the epithelial lining of the nasopharynx, often in the fossa of Rosenmuller, and is the most seen tumor in the nasopharynx.⁴ NPC is less surgically accessible than other H&N cancers, and surgery to the nasopharynx poses more risks given the proximity of critical surrounding structures. NPC is radiosensitive, and therefore radiotherapy (RT), in combination with chemotherapy for locally advanced tumors, has become the mainstay of treatment for nonmetastatic NPC.⁴

NPC often presents with an asymptomatic neck mass or with symptoms of epistaxis, nasal obstruction, and otitis media.⁵ Advanced cases of NPC can present with direct extension into the skull base, paranasal sinuses, and orbit, as well as involvement of cranial nerves. Radiation planning for tumors of the nasopharynx is complicated by the need to deliver an adequate dose to the tumor while limiting dose and toxicity to nearby critical structures such as the brainstem, optic chiasm, eyes, spinal cord (SC), temporal lobes, and cochleae. Achieving an adequate dose to nasopharyngeal primary tumors is especially complicated for T4 tumors invading the skull base with intracranial extension, in direct contact with these critical structures (Table 1).

Case Presentation

A 34-year-old male patient with no previous medical history presented to the emergency department with worsening diplopia, nasal obstruction, facial pain, and neck stiffness. The patient reported a 3 pack-year smoking history with recent smoking cessation. His physical examination was notable for a right abducens nerve palsy and an ulcerated nasopharyngeal mass on endoscopy.

Computed tomography (CT) scan revealed a 7-cm mass in the nasopharynx, eroding through the skull base with destruction and replacement of the clivus by tumor. Also noted was erosion of the petrous apices, carotid canals, sella turcica, dens, and the bilateral occipital condyles. There was intracranial extension with replacement of portions of the cavernous sinuses as well as mass effect on the prepontine cistern. Additional brain imaging studies, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, were obtained for completion of the staging workup. The MRI correlated with the findings noted on CT and demonstrated involvement of Meckel cave, foramen ovale, foramen rotundum, Dorello canal, and the hypoglossal canals. No cervical lymphadenopathy or distant metastases were noted on imaging. Pathology from biopsy revealed poorly differentiated squamous cell carcinoma, EBV-negative, strongly p16-positive, HPV-16 positive, and P53-negative.

RT planning was complicated by the tumor’s contact with the brainstem and upper cervical SC, as well as proximity of the tumor to the optic apparatus. The patient underwent 2 replanning CT scans at 26 Gy and 44 Gy to evaluate for tumor shrinkage. These CT scans demonstrated shrinkage of the tumor away from critical neural structures, allowing the treatment volume to be reduced away from these structures in order to achieve required dose tolerances (brainstem < 54 Gy, optic nerves and chiasm < 50 Gy, SC < 45 Gy for this case). The replanning CT scan at 44 Gy, 5 weeks after treatment initiation, demonstrated that dramatic tumor shrinkage had occurred early in treatment, with separation of the remaining tumor from the area of the SC and brainstem with which it was initially in contact (Figure 1). This improvement allowed for shrinkage of the high-dose radiation field away from these critical neural structures.

Discussion

RT for NPC is complicated by the proximity of these tumors to critical surrounding neural structures. It is challenging to achieve the required dose constraints to surrounding neural tissues while delivering the usual 70-Gy dose to the gross tumor, especially when the tumor comes into direct contact with these structures.

This case provides an example of response-adapted RT using imaging during treatment to shrink the high-dose target as the tumor shrinks away from critical surrounding structures.⁷ This strategy permits delivery of the maximum dose to the tumor while minimizing radiation dose, and therefore risk of toxicity, to normal surrounding structures. While it is typical to deliver 70 Gy to the full extent of tumor involvement for H&N tumors, this was not possible in this case as the tumor was in contact with the brainstem and upper cervical SC. Delivering the full 70 Gy to these areas of tumor would have placed this patient at substantial risk of brainstem and/or SC toxicity. This report demonstrates that response-adapted RT with shrinking fields can allow for tumor control while avoiding toxicity to critical neural structures for cases of locally advanced NPC in which tumor is abutting these structures.

Bony regeneration of the skull base following RT has been reported in the literature, but in limited reviews. Early reports used plain radiography to follow changes. Unger and colleagues demonstrated the regeneration of bone using skull radiographs 4 to 6 months after completion of RT for NPC.⁸ More recent literature details the ability of bone to regenerate after RT based on CT findings. Fang and colleagues reported on 90 cases of NPC with skull base destruction, with 63% having bony regeneration on posttreatment CT.⁹ Most of the patients in Fang’s report had bony regeneration within 1 year of treatment, and in general, bony regeneration became more evident on imaging with longer follow-up. Of note, local control was significantly greater in patients with regeneration vs persistent destruction (77% vs 21%, P < .001). On multivariate analysis, complete tumor response was significantly associated with bony regeneration; other factors such as age, sex, radiation dose, and chemotherapy were not significantly associated with the likelihood of bony regeneration.

Our report details a nasopharyngeal tumor that destroyed the skull base with no intact bony barrier. In such cases, concern arises regarding craniospinal instability with tumor regression if there is not simultaneous bone regeneration. Tumor invasion of the skull base and C1-2 vertebral bodies and complications from treatment of such tumor extent can lead to symptoms of craniospinal instability, including pain, difficulty with neck range of motion, and loss of strength and sensation in the upper and lower extremities.¹⁰ A case report of a woman treated with chemoradiation for a plasmacytoma of the skull base detailed her posttreatment presentation with quadriparesis resulting from craniospinal instability after tumor regression.¹¹ Such instability is generally treated surgically, and during this woman’s surgery, there was an injury to the right vertebral artery, although this did not cause any additional neurologic deficits.

Conclusions

There is a paucity of literature on bony regeneration in patients with skull base destruction from advanced NPC, and in particular, the ability of skull base regeneration to occur during treatment simultaneous with tumor regression. Our patient had HPV-positive/EBV-negative NPC, but it is unclear how this subtype affected his prognosis. Factors such as tumor histology, radiosensitivity with rapid tumor regression, and young age may have all contributed to the rapidity of bone regeneration in our patient. This case report demonstrates that an impressive tumor response to chemoradiation with simultaneous bony regeneration is possible among patients presenting with tumor destruction of the skull base, precluding the need for neurosurgical intervention.

Early-onset colorectal cancer (CRC) affecting patients younger than 50 years has risen sharply since 1988 from 7.9 to 12.9 cases in 2015 per 100,000 people. The reason for the increase isn’t well understood.

The findings were highlighted in a recent review article published online in the New England Journal of Medicine. “It’s a national phenomenon and it’s also occurring in other parts of the developed world. We’re used to seeing mostly older people who have this diagnosis. Now we’re seeing a lot of younger people with this disease. It’s rather alarming,” said author Frank Sinicrope, MD, a medical oncologist with Mayo Clinic, Rochester, Minn.

The trend contrasts with a decline in later-onset CRC likely attributable to increases in screening. As a result of the two trends, but especially the increased number of early-onset cases, the median age of diagnosis dropped from 72 in the early 2000s to 66 today.

“Although patients with early-onset colorectal cancer are more likely to have a hereditary syndrome than those who have later-onset disease, most cases are sporadic, with no identifiable cause. Furthermore, somatic mutational profiling of early-onset colorectal cancers has not revealed previously unidentified or actionable alterations to inform our understanding of the pathogenesis of these cancers or to guide treatment,” he wrote in the review.

“Early-onset colorectal cancers are most commonly detected in the rectum, followed by the distal colon; more than 70% of early-onset colorectal cancers are in the left colon at presentation,” he wrote in the review. Younger patients tend to be unfamiliar with CRC symptoms, which are often mistaken for benign conditions.

“We’ve moved the screening age down to 45, but that still is not going to capture a lot of these patients,” Dr. Sinicrope said. He estimates that 25% of rectal cancers and 10%-12% of colon cancers diagnosed in the next 10 years will be early onset.

Although the direct cause of the increased incidence isn’t clear, Dr. Sinicrope suggested it may reflect changing dietary habits and rising obesity among adolescents. “The sugar-containing beverages, the processed sugar and a lot of red meat in the diet and refined grains … reflect changes in the diet over the last 50 years. We may now be seeing the end result of many of these dietary changes that have occurred,” he said, calling for a greater emphasis on plant-based diets, which promote a healthier gut microbiome that may reduce CRC risk. Western-style diets can change the gut microbiome leading to inflammation which increases the risk of CRC.

Most patients with early CRC present with advanced disease in the left colon. And, pathogenic germline variants are present in one in six patients – half of which are associated with Lynch syndrome which increases the risk for CRC.

Dr. Sinicrope highlighted the need for more risk-based intervention, which in turn requires a better knowledge of family history.

“We need to do better job to risk stratify, and that will help us figure out who’s best to target our screening efforts toward,” Dr. Sinicrope said. He pointed out guidelines from the U.S. Multi-Society Task Force on Colorectal Cancer and the American Cancer Society that can help physicians identify patients who might benefit from earlier screening. The American Cancer Society recommends that CRC screening be conducted at 45 years for average-risk individuals.

“The best screening test is the one that the patient will do,” Dr. Sinicrope said.

Early-onset colorectal cancer (CRC) affecting patients younger than 50 years has risen sharply since 1988 from 7.9 to 12.9 cases in 2015 per 100,000 people. The reason for the increase isn’t well understood.

The findings were highlighted in a recent review article published online in the New England Journal of Medicine. “It’s a national phenomenon and it’s also occurring in other parts of the developed world. We’re used to seeing mostly older people who have this diagnosis. Now we’re seeing a lot of younger people with this disease. It’s rather alarming,” said author Frank Sinicrope, MD, a medical oncologist with Mayo Clinic, Rochester, Minn.

The trend contrasts with a decline in later-onset CRC likely attributable to increases in screening. As a result of the two trends, but especially the increased number of early-onset cases, the median age of diagnosis dropped from 72 in the early 2000s to 66 today.

“Although patients with early-onset colorectal cancer are more likely to have a hereditary syndrome than those who have later-onset disease, most cases are sporadic, with no identifiable cause. Furthermore, somatic mutational profiling of early-onset colorectal cancers has not revealed previously unidentified or actionable alterations to inform our understanding of the pathogenesis of these cancers or to guide treatment,” he wrote in the review.

“Early-onset colorectal cancers are most commonly detected in the rectum, followed by the distal colon; more than 70% of early-onset colorectal cancers are in the left colon at presentation,” he wrote in the review. Younger patients tend to be unfamiliar with CRC symptoms, which are often mistaken for benign conditions.

“We’ve moved the screening age down to 45, but that still is not going to capture a lot of these patients,” Dr. Sinicrope said. He estimates that 25% of rectal cancers and 10%-12% of colon cancers diagnosed in the next 10 years will be early onset.

Although the direct cause of the increased incidence isn’t clear, Dr. Sinicrope suggested it may reflect changing dietary habits and rising obesity among adolescents. “The sugar-containing beverages, the processed sugar and a lot of red meat in the diet and refined grains … reflect changes in the diet over the last 50 years. We may now be seeing the end result of many of these dietary changes that have occurred,” he said, calling for a greater emphasis on plant-based diets, which promote a healthier gut microbiome that may reduce CRC risk. Western-style diets can change the gut microbiome leading to inflammation which increases the risk of CRC.

Most patients with early CRC present with advanced disease in the left colon. And, pathogenic germline variants are present in one in six patients – half of which are associated with Lynch syndrome which increases the risk for CRC.

Dr. Sinicrope highlighted the need for more risk-based intervention, which in turn requires a better knowledge of family history.

“We need to do better job to risk stratify, and that will help us figure out who’s best to target our screening efforts toward,” Dr. Sinicrope said. He pointed out guidelines from the U.S. Multi-Society Task Force on Colorectal Cancer and the American Cancer Society that can help physicians identify patients who might benefit from earlier screening. The American Cancer Society recommends that CRC screening be conducted at 45 years for average-risk individuals.

“The best screening test is the one that the patient will do,” Dr. Sinicrope said.

Early-onset colorectal cancer (CRC) affecting patients younger than 50 years has risen sharply since 1988 from 7.9 to 12.9 cases in 2015 per 100,000 people. The reason for the increase isn’t well understood.

The findings were highlighted in a recent review article published online in the New England Journal of Medicine. “It’s a national phenomenon and it’s also occurring in other parts of the developed world. We’re used to seeing mostly older people who have this diagnosis. Now we’re seeing a lot of younger people with this disease. It’s rather alarming,” said author Frank Sinicrope, MD, a medical oncologist with Mayo Clinic, Rochester, Minn.

The trend contrasts with a decline in later-onset CRC likely attributable to increases in screening. As a result of the two trends, but especially the increased number of early-onset cases, the median age of diagnosis dropped from 72 in the early 2000s to 66 today.

“Although patients with early-onset colorectal cancer are more likely to have a hereditary syndrome than those who have later-onset disease, most cases are sporadic, with no identifiable cause. Furthermore, somatic mutational profiling of early-onset colorectal cancers has not revealed previously unidentified or actionable alterations to inform our understanding of the pathogenesis of these cancers or to guide treatment,” he wrote in the review.

“Early-onset colorectal cancers are most commonly detected in the rectum, followed by the distal colon; more than 70% of early-onset colorectal cancers are in the left colon at presentation,” he wrote in the review. Younger patients tend to be unfamiliar with CRC symptoms, which are often mistaken for benign conditions.

“We’ve moved the screening age down to 45, but that still is not going to capture a lot of these patients,” Dr. Sinicrope said. He estimates that 25% of rectal cancers and 10%-12% of colon cancers diagnosed in the next 10 years will be early onset.

Although the direct cause of the increased incidence isn’t clear, Dr. Sinicrope suggested it may reflect changing dietary habits and rising obesity among adolescents. “The sugar-containing beverages, the processed sugar and a lot of red meat in the diet and refined grains … reflect changes in the diet over the last 50 years. We may now be seeing the end result of many of these dietary changes that have occurred,” he said, calling for a greater emphasis on plant-based diets, which promote a healthier gut microbiome that may reduce CRC risk. Western-style diets can change the gut microbiome leading to inflammation which increases the risk of CRC.

Most patients with early CRC present with advanced disease in the left colon. And, pathogenic germline variants are present in one in six patients – half of which are associated with Lynch syndrome which increases the risk for CRC.

Dr. Sinicrope highlighted the need for more risk-based intervention, which in turn requires a better knowledge of family history.

“We need to do better job to risk stratify, and that will help us figure out who’s best to target our screening efforts toward,” Dr. Sinicrope said. He pointed out guidelines from the U.S. Multi-Society Task Force on Colorectal Cancer and the American Cancer Society that can help physicians identify patients who might benefit from earlier screening. The American Cancer Society recommends that CRC screening be conducted at 45 years for average-risk individuals.

“The best screening test is the one that the patient will do,” Dr. Sinicrope said.

A qualitative analysis of 20 people with head and neck cancer (HNC) has led to recommendations for improvements in care.

HNC has a high burden of treatment-related adverse events, along with frequent trouble with speech, swallowing, facial disfigurement, and psychological distress.

Among cancer patients, “they have the highest rates of emergency department use and hospitalization during treatment. They also have the highest rates of psychological distress. We have some Ontario data that shows they’ve got the highest rates of suicide and self-harm. So I think this is a really special population that we need to support,” Christopher Noel, MD, PhD, said in an interview. Dr. Noel was the lead author of the study, which was published in JAMA Otolaryngology – Head & Neck Surgery.

These issues can strongly affect quality of life, and even patient outcomes. “Even a 1-day interruption in treatment has been shown to impact oncologic outcomes. This is a very big issue whether you’re a surgeon, a medical oncologist, or a radiation oncologist,” said Dr. Noel, who is a resident physician at the University of Toronto.

He advocates that physicians interview patients and review the results in a structured way and then act on it. “If we just rely on patient [provided] communication, we’re going to miss about 50% of patient symptoms,” he said.

The researchers aimed for the patient’s perspective on treatment. “What is the patient’s perception of going through head neck cancer and their treatment, and managing their symptoms at home? And where do they think that we could do better?” Dr. Noel asked.

The most pressing issue was that patients felt their emotional and informational needs often were not met. That challenge is even harder for patients who have trouble communicating, which in turn makes them more prone to isolation and loneliness. Many felt that they had to get the information on their own. “They wanted it to be a more effortless process,” said Dr. Noel.

He described one patient with oropharynx cancer who was able to talk to people about her grief over her diagnosis, but treatment led to her throat becoming swollen and she lost the ability to communicate. “She felt very isolated and lonely. She really highlighted the emotional and psychosocial barriers in cancer care. Her treatment inherently leaves her feeling very isolated and lonely, and she had such a hard time connecting with a psychotherapist,” Dr. Noel said.

Another common issue revolved around efforts to communicate about symptoms and adverse effects of treatment. Resources often aren’t available on evenings or weekends, and it can take time for a nurse to call them back. Patients wanted to see more modern approaches, such as use of email or apps.

The patients in the study recommended 11 health care improvements.

• 1. Nurse navigator teams should have hours extended to evenings and weekends.
• 2. Patient communication methods should be expanded, using methods like email or apps.
• 3. HNC resources should be more broadly disseminated.
• 4. Education and information approaches should be individualized to the patient.
• 5. All HNC patients should be offered psychological resources.
• 6. Mental health needs should be assessed repeatedly throughout treatment and extended care.
• 7. Physicians should recognize the added symptom burden often faced by patients who travel extensively for treatment.
• 8. Partners and caregivers should be included as part of the treatment team.
• 9. Share symptom data with patients, which can improve engagement.
• 10. Review symptom scores and act on them regularly.
• 11. A member of the care team should be identified to oversee symptom management.

Dr. Noel had no relevant financial disclosures.

A qualitative analysis of 20 people with head and neck cancer (HNC) has led to recommendations for improvements in care.

HNC has a high burden of treatment-related adverse events, along with frequent trouble with speech, swallowing, facial disfigurement, and psychological distress.

Among cancer patients, “they have the highest rates of emergency department use and hospitalization during treatment. They also have the highest rates of psychological distress. We have some Ontario data that shows they’ve got the highest rates of suicide and self-harm. So I think this is a really special population that we need to support,” Christopher Noel, MD, PhD, said in an interview. Dr. Noel was the lead author of the study, which was published in JAMA Otolaryngology – Head & Neck Surgery.

These issues can strongly affect quality of life, and even patient outcomes. “Even a 1-day interruption in treatment has been shown to impact oncologic outcomes. This is a very big issue whether you’re a surgeon, a medical oncologist, or a radiation oncologist,” said Dr. Noel, who is a resident physician at the University of Toronto.

He advocates that physicians interview patients and review the results in a structured way and then act on it. “If we just rely on patient [provided] communication, we’re going to miss about 50% of patient symptoms,” he said.

The researchers aimed for the patient’s perspective on treatment. “What is the patient’s perception of going through head neck cancer and their treatment, and managing their symptoms at home? And where do they think that we could do better?” Dr. Noel asked.

The most pressing issue was that patients felt their emotional and informational needs often were not met. That challenge is even harder for patients who have trouble communicating, which in turn makes them more prone to isolation and loneliness. Many felt that they had to get the information on their own. “They wanted it to be a more effortless process,” said Dr. Noel.

He described one patient with oropharynx cancer who was able to talk to people about her grief over her diagnosis, but treatment led to her throat becoming swollen and she lost the ability to communicate. “She felt very isolated and lonely. She really highlighted the emotional and psychosocial barriers in cancer care. Her treatment inherently leaves her feeling very isolated and lonely, and she had such a hard time connecting with a psychotherapist,” Dr. Noel said.

Another common issue revolved around efforts to communicate about symptoms and adverse effects of treatment. Resources often aren’t available on evenings or weekends, and it can take time for a nurse to call them back. Patients wanted to see more modern approaches, such as use of email or apps.

The patients in the study recommended 11 health care improvements.

• 1. Nurse navigator teams should have hours extended to evenings and weekends.
• 2. Patient communication methods should be expanded, using methods like email or apps.
• 3. HNC resources should be more broadly disseminated.
• 4. Education and information approaches should be individualized to the patient.
• 5. All HNC patients should be offered psychological resources.
• 6. Mental health needs should be assessed repeatedly throughout treatment and extended care.
• 7. Physicians should recognize the added symptom burden often faced by patients who travel extensively for treatment.
• 8. Partners and caregivers should be included as part of the treatment team.
• 9. Share symptom data with patients, which can improve engagement.
• 10. Review symptom scores and act on them regularly.
• 11. A member of the care team should be identified to oversee symptom management.

Dr. Noel had no relevant financial disclosures.

A qualitative analysis of 20 people with head and neck cancer (HNC) has led to recommendations for improvements in care.

HNC has a high burden of treatment-related adverse events, along with frequent trouble with speech, swallowing, facial disfigurement, and psychological distress.

Among cancer patients, “they have the highest rates of emergency department use and hospitalization during treatment. They also have the highest rates of psychological distress. We have some Ontario data that shows they’ve got the highest rates of suicide and self-harm. So I think this is a really special population that we need to support,” Christopher Noel, MD, PhD, said in an interview. Dr. Noel was the lead author of the study, which was published in JAMA Otolaryngology – Head & Neck Surgery.

These issues can strongly affect quality of life, and even patient outcomes. “Even a 1-day interruption in treatment has been shown to impact oncologic outcomes. This is a very big issue whether you’re a surgeon, a medical oncologist, or a radiation oncologist,” said Dr. Noel, who is a resident physician at the University of Toronto.

He advocates that physicians interview patients and review the results in a structured way and then act on it. “If we just rely on patient [provided] communication, we’re going to miss about 50% of patient symptoms,” he said.

The researchers aimed for the patient’s perspective on treatment. “What is the patient’s perception of going through head neck cancer and their treatment, and managing their symptoms at home? And where do they think that we could do better?” Dr. Noel asked.

The most pressing issue was that patients felt their emotional and informational needs often were not met. That challenge is even harder for patients who have trouble communicating, which in turn makes them more prone to isolation and loneliness. Many felt that they had to get the information on their own. “They wanted it to be a more effortless process,” said Dr. Noel.

He described one patient with oropharynx cancer who was able to talk to people about her grief over her diagnosis, but treatment led to her throat becoming swollen and she lost the ability to communicate. “She felt very isolated and lonely. She really highlighted the emotional and psychosocial barriers in cancer care. Her treatment inherently leaves her feeling very isolated and lonely, and she had such a hard time connecting with a psychotherapist,” Dr. Noel said.

Another common issue revolved around efforts to communicate about symptoms and adverse effects of treatment. Resources often aren’t available on evenings or weekends, and it can take time for a nurse to call them back. Patients wanted to see more modern approaches, such as use of email or apps.

The patients in the study recommended 11 health care improvements.

• 1. Nurse navigator teams should have hours extended to evenings and weekends.
• 2. Patient communication methods should be expanded, using methods like email or apps.
• 3. HNC resources should be more broadly disseminated.
• 4. Education and information approaches should be individualized to the patient.
• 5. All HNC patients should be offered psychological resources.
• 6. Mental health needs should be assessed repeatedly throughout treatment and extended care.
• 7. Physicians should recognize the added symptom burden often faced by patients who travel extensively for treatment.
• 8. Partners and caregivers should be included as part of the treatment team.
• 9. Share symptom data with patients, which can improve engagement.
• 10. Review symptom scores and act on them regularly.
• 11. A member of the care team should be identified to oversee symptom management.

Dr. Noel had no relevant financial disclosures.