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TP53 status signals neoadjuvant cetuximab benefit in rectal cancer
AMSTERDAM – TP53 mutational status was a strong, independent predictor of cetuximab benefit in high-risk, locally advanced rectal cancer in the phase II EXPERT-C trial.
For TP53 wildtype patients, adding cetuximab (Erbitux) to neoadjuvant chemoradiotherapy resulted in a significant 24.3% improvement in 5-year progression-free survival from 65% to 89.3% (hazard ratio, 0.23; P = .02) and a 25.2% increase in overall survival from 67.5% to 92.7% (HR, 0.16; P = .02).
In contrast, TP53-mutant patients experienced no benefit with neoadjuvant cetuximab in either progression-free (60.9% vs. 52.3%; HR, 1.21; P = .59) or overall survival (67.1% vs. 67.3%; HR, 0.97; P = .94), Dr. Francesco Sclafani reported at the multidisciplinary European cancer congresses.
In a multivariable analysis, a statistically significant interaction was found between TP53 status and cetuximab effect for progression-free and overall survival, even after investigators adjusted for prognostic variables and KRAS status.
"TP53 mutational status was not prognostic, but emerged as an independent predictive factor for cetuximab benefit," he said. "The benefit from cetuximab in TP53 wildtype patients was independent of RAS and did not appear to be related to its radiosensitizing effect."
TP53 is a tumor-suppressor gene located in chromosome 17p, and mutations in this gene occur in about half of colorectal cancers. Functional p53 may predict response to radiotherapy, and preclinical evidence suggests p53 also has a role in modulating response to anti–epidermal growth factor therapies.
Neoadjuvant chemoradiotherapy (CRT) or short-course radiotherapy followed by total mesorectal excision (TME) is a standard treatment for locally advanced rectal cancer. Alternative multimodality strategies have in most cases failed to demonstrate a significant advantage over standard CRT, and there is a lack of validated prognostic or predictive biomarkers to guide optimal treatment selection. Thus, TP53 status could prove useful, if the current results are validated, said Dr. Sclafani of the Royal Marsden NHS Foundation Trust, London.
EXPERT-C compared neoadjuvant capecitabine (Xeloda) plus oxaliplatin (Eloxatin) and preoperative radiotherapy, with or without cetuximab, followed by TME in patients with high-risk rectal cancer. As previously reported, the addition of cetuximab did not improve the primary endpoint of complete response, but improved radiologic response and overall survival in patients with wildtype KRAS/BRAF status (J. Clin. Oncol. 2012;30:1620-7).
For the biomarker analysis, TP53 status was analyzed in 144 patients (47 patients with biopsy only, 42 with surgical specimens only, and 55 with paired specimens). Of these, 75 patients (52%) had a TP53 mutation. Median follow-up was 65 months.
The EXPERT-C marker study is an interesting, hypothesis-generating study, but is a retrospective analysis without an adequate sample size for validation of biomarkers and had a relatively high degree of discordance between the initial biopsy before neoadjuvant treatment and the biopsy in surgery, said Dr. Eric Van Cutsem of the University Hospitals Leuven (Belgium), who was invited to discuss the results.
"It’s clearly not practice changing, but it may be the basis for further translational studies," he said.
Dr. Sclafani reported having no relevant financial disclosures.
AMSTERDAM – TP53 mutational status was a strong, independent predictor of cetuximab benefit in high-risk, locally advanced rectal cancer in the phase II EXPERT-C trial.
For TP53 wildtype patients, adding cetuximab (Erbitux) to neoadjuvant chemoradiotherapy resulted in a significant 24.3% improvement in 5-year progression-free survival from 65% to 89.3% (hazard ratio, 0.23; P = .02) and a 25.2% increase in overall survival from 67.5% to 92.7% (HR, 0.16; P = .02).
In contrast, TP53-mutant patients experienced no benefit with neoadjuvant cetuximab in either progression-free (60.9% vs. 52.3%; HR, 1.21; P = .59) or overall survival (67.1% vs. 67.3%; HR, 0.97; P = .94), Dr. Francesco Sclafani reported at the multidisciplinary European cancer congresses.
In a multivariable analysis, a statistically significant interaction was found between TP53 status and cetuximab effect for progression-free and overall survival, even after investigators adjusted for prognostic variables and KRAS status.
"TP53 mutational status was not prognostic, but emerged as an independent predictive factor for cetuximab benefit," he said. "The benefit from cetuximab in TP53 wildtype patients was independent of RAS and did not appear to be related to its radiosensitizing effect."
TP53 is a tumor-suppressor gene located in chromosome 17p, and mutations in this gene occur in about half of colorectal cancers. Functional p53 may predict response to radiotherapy, and preclinical evidence suggests p53 also has a role in modulating response to anti–epidermal growth factor therapies.
Neoadjuvant chemoradiotherapy (CRT) or short-course radiotherapy followed by total mesorectal excision (TME) is a standard treatment for locally advanced rectal cancer. Alternative multimodality strategies have in most cases failed to demonstrate a significant advantage over standard CRT, and there is a lack of validated prognostic or predictive biomarkers to guide optimal treatment selection. Thus, TP53 status could prove useful, if the current results are validated, said Dr. Sclafani of the Royal Marsden NHS Foundation Trust, London.
EXPERT-C compared neoadjuvant capecitabine (Xeloda) plus oxaliplatin (Eloxatin) and preoperative radiotherapy, with or without cetuximab, followed by TME in patients with high-risk rectal cancer. As previously reported, the addition of cetuximab did not improve the primary endpoint of complete response, but improved radiologic response and overall survival in patients with wildtype KRAS/BRAF status (J. Clin. Oncol. 2012;30:1620-7).
For the biomarker analysis, TP53 status was analyzed in 144 patients (47 patients with biopsy only, 42 with surgical specimens only, and 55 with paired specimens). Of these, 75 patients (52%) had a TP53 mutation. Median follow-up was 65 months.
The EXPERT-C marker study is an interesting, hypothesis-generating study, but is a retrospective analysis without an adequate sample size for validation of biomarkers and had a relatively high degree of discordance between the initial biopsy before neoadjuvant treatment and the biopsy in surgery, said Dr. Eric Van Cutsem of the University Hospitals Leuven (Belgium), who was invited to discuss the results.
"It’s clearly not practice changing, but it may be the basis for further translational studies," he said.
Dr. Sclafani reported having no relevant financial disclosures.
AMSTERDAM – TP53 mutational status was a strong, independent predictor of cetuximab benefit in high-risk, locally advanced rectal cancer in the phase II EXPERT-C trial.
For TP53 wildtype patients, adding cetuximab (Erbitux) to neoadjuvant chemoradiotherapy resulted in a significant 24.3% improvement in 5-year progression-free survival from 65% to 89.3% (hazard ratio, 0.23; P = .02) and a 25.2% increase in overall survival from 67.5% to 92.7% (HR, 0.16; P = .02).
In contrast, TP53-mutant patients experienced no benefit with neoadjuvant cetuximab in either progression-free (60.9% vs. 52.3%; HR, 1.21; P = .59) or overall survival (67.1% vs. 67.3%; HR, 0.97; P = .94), Dr. Francesco Sclafani reported at the multidisciplinary European cancer congresses.
In a multivariable analysis, a statistically significant interaction was found between TP53 status and cetuximab effect for progression-free and overall survival, even after investigators adjusted for prognostic variables and KRAS status.
"TP53 mutational status was not prognostic, but emerged as an independent predictive factor for cetuximab benefit," he said. "The benefit from cetuximab in TP53 wildtype patients was independent of RAS and did not appear to be related to its radiosensitizing effect."
TP53 is a tumor-suppressor gene located in chromosome 17p, and mutations in this gene occur in about half of colorectal cancers. Functional p53 may predict response to radiotherapy, and preclinical evidence suggests p53 also has a role in modulating response to anti–epidermal growth factor therapies.
Neoadjuvant chemoradiotherapy (CRT) or short-course radiotherapy followed by total mesorectal excision (TME) is a standard treatment for locally advanced rectal cancer. Alternative multimodality strategies have in most cases failed to demonstrate a significant advantage over standard CRT, and there is a lack of validated prognostic or predictive biomarkers to guide optimal treatment selection. Thus, TP53 status could prove useful, if the current results are validated, said Dr. Sclafani of the Royal Marsden NHS Foundation Trust, London.
EXPERT-C compared neoadjuvant capecitabine (Xeloda) plus oxaliplatin (Eloxatin) and preoperative radiotherapy, with or without cetuximab, followed by TME in patients with high-risk rectal cancer. As previously reported, the addition of cetuximab did not improve the primary endpoint of complete response, but improved radiologic response and overall survival in patients with wildtype KRAS/BRAF status (J. Clin. Oncol. 2012;30:1620-7).
For the biomarker analysis, TP53 status was analyzed in 144 patients (47 patients with biopsy only, 42 with surgical specimens only, and 55 with paired specimens). Of these, 75 patients (52%) had a TP53 mutation. Median follow-up was 65 months.
The EXPERT-C marker study is an interesting, hypothesis-generating study, but is a retrospective analysis without an adequate sample size for validation of biomarkers and had a relatively high degree of discordance between the initial biopsy before neoadjuvant treatment and the biopsy in surgery, said Dr. Eric Van Cutsem of the University Hospitals Leuven (Belgium), who was invited to discuss the results.
"It’s clearly not practice changing, but it may be the basis for further translational studies," he said.
Dr. Sclafani reported having no relevant financial disclosures.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: In TP53 wildtype patients, neoadjuvant cetuximab improved 5-year progression-free survival by 24.3% (hazard ratio, 0.23; P = .02) and overall survival by 25.2% (HR, 0.16; P = .02).
Data source: A retrospective biomarkers analysis of 144 rectal cancer samples from the phase II EXPERT-C study.
Disclosures: Dr. Sclafani reported having no relevant financial disclosures.
HLA class I plays role in aspirin’s benefit in colon ca
AMSTERDAM – Low-dose aspirin was associated with a survival benefit only in colon cancer patients whose tumors expressed human leukocyte antigen class I in an analysis of 999 colon cancers.
"HLA class I might serve as a predictive biomarker to help identify patients who could benefit from aspirin therapy after diagnosis," Dr. Marlies Reimers reported at the multidisciplinary European cancer congresses.
Several studies, including most recently the Women’s Health Study, have reported that regular low-dose aspirin use can help lower the risk of colorectal cancer, particularly hereditary cases, and reduce polyp formation. Aspirin use after diagnosis has also been associated with better survival. The current findings may explain aspirin’s role in this second pathway, Dr. Reimers said.
In an attempt to elucidate the biologic mechanisms behind aspirin’s benefit, the investigators used tissue microarrays to evaluate the expression of HLA class I and cyclooxygenase (COX)-2 in 999 colon cancers and extracted DNA from 663 tumors to study PIK3CA mutations. The patients were registered with the Eindhoven Cancer Registry between 1998 and 2007, and their aspirin use was obtained from a community pharmacy database.
COX-2 is expressed by about 70% of all colon cancers and is related to tumor genesis, as are PIK3CA mutations. HLA class I is produced by the HLA gene family, which is involved in the immune response.
The investigators hypothesized that aspirin’s role in improved survival could be explained by the interaction of platelets with HLA-positive tumor cells circulating in the bloodstream. Platelets are thought to shield tumor cells in the blood so they can’t be recognized by the immune system, promoting their metastatic potential.
Because aspirin attacks platelet formation, "the protective shield will be lost and the tumor cells could be eliminated by the innate immune system," said Dr. Reimers, who is a PhD student in the department of surgery, Leiden (the Netherlands) University Medical Center.
During the 4-year follow-up, aspirin use after diagnosis was associated with a significantly better overall survival (hazard ratio, 0.64; P = .001).
In patients whose tumors expressed HLA class I, aspirin use cut the risk of death in half, Dr. Reimers said at a press briefing.
No protective effect of aspirin was seen in patients whose tumors did not express HLA class I, expressed COX-2, or contained PIK3CA mutations. A possible explanation for finding no association between COX-2 and PIK3CA with survival could be that pharmacologic data on aspirin indicate that systemic concentrations of aspirin, reached with low-dose aspirin, are inadequate to permanently acetylate COX-2, but are optimal for platelet inhibition, she said in an interview.
Dr. Reimers cautioned reporters that the results are not sufficient to suggest that all colorectal cancer patients should begin taking aspirin and that additional evidence from larger trials is needed to support their findings. Two phase III trials are currently underway: the ASCOLT study of aspirin use in Asian patients with Dukes’ C or high-risk Dukes’ B colorectal cancer and the Add Aspirin trial in the United Kingdom.
Dr. Peter Naredi, president of the European Society of Surgical Oncology, commented in a statement that the results are interesting and that ongoing placebo-controlled randomized trials evaluating the effect of aspirin in colorectal cancer can hopefully strengthen the evidence that aspirin is useful in patients with HLA class I expression."
Dr. Reimers reported having no relevant financial disclosures.
AMSTERDAM – Low-dose aspirin was associated with a survival benefit only in colon cancer patients whose tumors expressed human leukocyte antigen class I in an analysis of 999 colon cancers.
"HLA class I might serve as a predictive biomarker to help identify patients who could benefit from aspirin therapy after diagnosis," Dr. Marlies Reimers reported at the multidisciplinary European cancer congresses.
Several studies, including most recently the Women’s Health Study, have reported that regular low-dose aspirin use can help lower the risk of colorectal cancer, particularly hereditary cases, and reduce polyp formation. Aspirin use after diagnosis has also been associated with better survival. The current findings may explain aspirin’s role in this second pathway, Dr. Reimers said.
In an attempt to elucidate the biologic mechanisms behind aspirin’s benefit, the investigators used tissue microarrays to evaluate the expression of HLA class I and cyclooxygenase (COX)-2 in 999 colon cancers and extracted DNA from 663 tumors to study PIK3CA mutations. The patients were registered with the Eindhoven Cancer Registry between 1998 and 2007, and their aspirin use was obtained from a community pharmacy database.
COX-2 is expressed by about 70% of all colon cancers and is related to tumor genesis, as are PIK3CA mutations. HLA class I is produced by the HLA gene family, which is involved in the immune response.
The investigators hypothesized that aspirin’s role in improved survival could be explained by the interaction of platelets with HLA-positive tumor cells circulating in the bloodstream. Platelets are thought to shield tumor cells in the blood so they can’t be recognized by the immune system, promoting their metastatic potential.
Because aspirin attacks platelet formation, "the protective shield will be lost and the tumor cells could be eliminated by the innate immune system," said Dr. Reimers, who is a PhD student in the department of surgery, Leiden (the Netherlands) University Medical Center.
During the 4-year follow-up, aspirin use after diagnosis was associated with a significantly better overall survival (hazard ratio, 0.64; P = .001).
In patients whose tumors expressed HLA class I, aspirin use cut the risk of death in half, Dr. Reimers said at a press briefing.
No protective effect of aspirin was seen in patients whose tumors did not express HLA class I, expressed COX-2, or contained PIK3CA mutations. A possible explanation for finding no association between COX-2 and PIK3CA with survival could be that pharmacologic data on aspirin indicate that systemic concentrations of aspirin, reached with low-dose aspirin, are inadequate to permanently acetylate COX-2, but are optimal for platelet inhibition, she said in an interview.
Dr. Reimers cautioned reporters that the results are not sufficient to suggest that all colorectal cancer patients should begin taking aspirin and that additional evidence from larger trials is needed to support their findings. Two phase III trials are currently underway: the ASCOLT study of aspirin use in Asian patients with Dukes’ C or high-risk Dukes’ B colorectal cancer and the Add Aspirin trial in the United Kingdom.
Dr. Peter Naredi, president of the European Society of Surgical Oncology, commented in a statement that the results are interesting and that ongoing placebo-controlled randomized trials evaluating the effect of aspirin in colorectal cancer can hopefully strengthen the evidence that aspirin is useful in patients with HLA class I expression."
Dr. Reimers reported having no relevant financial disclosures.
AMSTERDAM – Low-dose aspirin was associated with a survival benefit only in colon cancer patients whose tumors expressed human leukocyte antigen class I in an analysis of 999 colon cancers.
"HLA class I might serve as a predictive biomarker to help identify patients who could benefit from aspirin therapy after diagnosis," Dr. Marlies Reimers reported at the multidisciplinary European cancer congresses.
Several studies, including most recently the Women’s Health Study, have reported that regular low-dose aspirin use can help lower the risk of colorectal cancer, particularly hereditary cases, and reduce polyp formation. Aspirin use after diagnosis has also been associated with better survival. The current findings may explain aspirin’s role in this second pathway, Dr. Reimers said.
In an attempt to elucidate the biologic mechanisms behind aspirin’s benefit, the investigators used tissue microarrays to evaluate the expression of HLA class I and cyclooxygenase (COX)-2 in 999 colon cancers and extracted DNA from 663 tumors to study PIK3CA mutations. The patients were registered with the Eindhoven Cancer Registry between 1998 and 2007, and their aspirin use was obtained from a community pharmacy database.
COX-2 is expressed by about 70% of all colon cancers and is related to tumor genesis, as are PIK3CA mutations. HLA class I is produced by the HLA gene family, which is involved in the immune response.
The investigators hypothesized that aspirin’s role in improved survival could be explained by the interaction of platelets with HLA-positive tumor cells circulating in the bloodstream. Platelets are thought to shield tumor cells in the blood so they can’t be recognized by the immune system, promoting their metastatic potential.
Because aspirin attacks platelet formation, "the protective shield will be lost and the tumor cells could be eliminated by the innate immune system," said Dr. Reimers, who is a PhD student in the department of surgery, Leiden (the Netherlands) University Medical Center.
During the 4-year follow-up, aspirin use after diagnosis was associated with a significantly better overall survival (hazard ratio, 0.64; P = .001).
In patients whose tumors expressed HLA class I, aspirin use cut the risk of death in half, Dr. Reimers said at a press briefing.
No protective effect of aspirin was seen in patients whose tumors did not express HLA class I, expressed COX-2, or contained PIK3CA mutations. A possible explanation for finding no association between COX-2 and PIK3CA with survival could be that pharmacologic data on aspirin indicate that systemic concentrations of aspirin, reached with low-dose aspirin, are inadequate to permanently acetylate COX-2, but are optimal for platelet inhibition, she said in an interview.
Dr. Reimers cautioned reporters that the results are not sufficient to suggest that all colorectal cancer patients should begin taking aspirin and that additional evidence from larger trials is needed to support their findings. Two phase III trials are currently underway: the ASCOLT study of aspirin use in Asian patients with Dukes’ C or high-risk Dukes’ B colorectal cancer and the Add Aspirin trial in the United Kingdom.
Dr. Peter Naredi, president of the European Society of Surgical Oncology, commented in a statement that the results are interesting and that ongoing placebo-controlled randomized trials evaluating the effect of aspirin in colorectal cancer can hopefully strengthen the evidence that aspirin is useful in patients with HLA class I expression."
Dr. Reimers reported having no relevant financial disclosures.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: Low-dose aspirin cut the risk of death in half in colon cancer patients with tumors expressing HLA class I.
Data source: Microarray analysis of 999 colon cancers.
Disclosures: Dr. Reimers reported having no relevant financial disclosures.
Molecular profile finds treatment targets in unknown primary site cancers
AMSTERDAM – Molecular profiling of cancers with an unknown primary site identified a targetable alteration in 77% of more than 1,400 cases.
Moreover, in a high proportion of cases, profiling directed clinicians to drugs not traditionally considered for cancers of unknown primary site (CUP), Dr. Zoran Gatalica said at the multidisciplinary European cancer congresses.
The study involved 1,459 CUPs, or about 3% of what is expected in the general population, and more than 50,000 patients from 30 countries. This makes it the largest group of patients to date to have their tumor biomarker profiles characterized, said Dr. Gatalica, executive medical director of Caris Life Sciences, Phoenix, Ariz.
A multiplatform approach was used that included mutational analysis by Sanger sequencing, next-generation sequencing, and polymerase chain reaction (PCR) testing; gene copy number by fluorescent or chromogenic in situ hybridization; O6-methylguanine DNA methyltransferase methylation by PCR; and protein expression analysis by immunohistochemistry.
Contrary to expectations, CUP was more prevalent in women (55%, or 822/1,459), and age offered no protection, with patients as young as 11 years and as old as 92 (average, 61 years), Dr. Gatalica said.
The most common site affected by cancer was the liver (24%), followed by other (30%) and lymph nodes (16%).
Not surprisingly, adenocarcinoma was the most common histology (45.3%), but there were also several differences in biomarkers based on histologic subtype, he said. For example, 7% of carcinomas had androgen receptor expression versus 3.3% of undifferentiated and neuroendocrine tumors.
The top "performers" were alterations in TP53 (33%), KRAS (17.5%), PIK3CA (7.4%), APC (3.6%), BRAF (3%), and epidermal growth factor receptor (EGFR) (1.1%), Dr. Gatalica said.
Dr. Gatalica also presented a few illustrative cases including a patient with liver metastases who had significant tumor reduction after being put on irinotecan (Camptostar)/5-fluorouracil on the basis of molecular profiling showing DNA topoisomerase 1 overexpression and thymidylate synthase underexpression.
A second case involved a 64-year-old woman with extensive bone disease who had a near-complete response after being directed to the EGFR-kinase inhibitor erlotinib (Tarceva) because profiling showed she carried an EGFR mutation.
Invited discussant Dr. Lajos Pusztai, codirector of the Yale Cancer Center genetics and genomics program, New Haven, Conn., described the cases as "inspiring" and said the results represent "a treasure trove of data."
Several questions remain, however, including the distribution of anomalies, how the authors defined "targetable," and whether treatment recommendations were actually followed.
"So you give a molecularly targeted treatment recommendation, but how often do physicians follow that?" he asked. "That would be a good way of gauging the test in practicality. What is the benefit rate?"
Audience members also questioned the cost of the test. An unidentified Caris spokesperson rose from the overflow crowd to say the full panel costs about €4,900 Euros (about $6,650 US), but that efforts are underway to bring the price down.
Dr. Gatalica said that in rare instances, molecular profiling "may actually improve the diagnosis of the primary site."
A recent study from the Sarah Cannon Research Institute showed that molecular profiling, using only a 92-gene reverse transcriptase PCR assay, allowed clinicians to predict the site of origin and direct site-specific therapy in 289 CUP patients, resulting in a 3-month gain in overall survival from the historic median of 9 months to 12.5 months (J. Clin. Oncol. 2013;31:217-23).
While molecular profiling represents a "conceptual leap" in the approach to CUP by emphasizing the biology of the tumor and not the primary site, "the problem is we don’t have enough good drugs," Dr. Pusztai observed.
Dr. Gatalica reported ownership and stock options in Caris Life Sciences, which sponsored the study and provided the molecular panel. Dr. Pusztai reported no relevant financial conflicts of interest.
AMSTERDAM – Molecular profiling of cancers with an unknown primary site identified a targetable alteration in 77% of more than 1,400 cases.
Moreover, in a high proportion of cases, profiling directed clinicians to drugs not traditionally considered for cancers of unknown primary site (CUP), Dr. Zoran Gatalica said at the multidisciplinary European cancer congresses.
The study involved 1,459 CUPs, or about 3% of what is expected in the general population, and more than 50,000 patients from 30 countries. This makes it the largest group of patients to date to have their tumor biomarker profiles characterized, said Dr. Gatalica, executive medical director of Caris Life Sciences, Phoenix, Ariz.
A multiplatform approach was used that included mutational analysis by Sanger sequencing, next-generation sequencing, and polymerase chain reaction (PCR) testing; gene copy number by fluorescent or chromogenic in situ hybridization; O6-methylguanine DNA methyltransferase methylation by PCR; and protein expression analysis by immunohistochemistry.
Contrary to expectations, CUP was more prevalent in women (55%, or 822/1,459), and age offered no protection, with patients as young as 11 years and as old as 92 (average, 61 years), Dr. Gatalica said.
The most common site affected by cancer was the liver (24%), followed by other (30%) and lymph nodes (16%).
Not surprisingly, adenocarcinoma was the most common histology (45.3%), but there were also several differences in biomarkers based on histologic subtype, he said. For example, 7% of carcinomas had androgen receptor expression versus 3.3% of undifferentiated and neuroendocrine tumors.
The top "performers" were alterations in TP53 (33%), KRAS (17.5%), PIK3CA (7.4%), APC (3.6%), BRAF (3%), and epidermal growth factor receptor (EGFR) (1.1%), Dr. Gatalica said.
Dr. Gatalica also presented a few illustrative cases including a patient with liver metastases who had significant tumor reduction after being put on irinotecan (Camptostar)/5-fluorouracil on the basis of molecular profiling showing DNA topoisomerase 1 overexpression and thymidylate synthase underexpression.
A second case involved a 64-year-old woman with extensive bone disease who had a near-complete response after being directed to the EGFR-kinase inhibitor erlotinib (Tarceva) because profiling showed she carried an EGFR mutation.
Invited discussant Dr. Lajos Pusztai, codirector of the Yale Cancer Center genetics and genomics program, New Haven, Conn., described the cases as "inspiring" and said the results represent "a treasure trove of data."
Several questions remain, however, including the distribution of anomalies, how the authors defined "targetable," and whether treatment recommendations were actually followed.
"So you give a molecularly targeted treatment recommendation, but how often do physicians follow that?" he asked. "That would be a good way of gauging the test in practicality. What is the benefit rate?"
Audience members also questioned the cost of the test. An unidentified Caris spokesperson rose from the overflow crowd to say the full panel costs about €4,900 Euros (about $6,650 US), but that efforts are underway to bring the price down.
Dr. Gatalica said that in rare instances, molecular profiling "may actually improve the diagnosis of the primary site."
A recent study from the Sarah Cannon Research Institute showed that molecular profiling, using only a 92-gene reverse transcriptase PCR assay, allowed clinicians to predict the site of origin and direct site-specific therapy in 289 CUP patients, resulting in a 3-month gain in overall survival from the historic median of 9 months to 12.5 months (J. Clin. Oncol. 2013;31:217-23).
While molecular profiling represents a "conceptual leap" in the approach to CUP by emphasizing the biology of the tumor and not the primary site, "the problem is we don’t have enough good drugs," Dr. Pusztai observed.
Dr. Gatalica reported ownership and stock options in Caris Life Sciences, which sponsored the study and provided the molecular panel. Dr. Pusztai reported no relevant financial conflicts of interest.
AMSTERDAM – Molecular profiling of cancers with an unknown primary site identified a targetable alteration in 77% of more than 1,400 cases.
Moreover, in a high proportion of cases, profiling directed clinicians to drugs not traditionally considered for cancers of unknown primary site (CUP), Dr. Zoran Gatalica said at the multidisciplinary European cancer congresses.
The study involved 1,459 CUPs, or about 3% of what is expected in the general population, and more than 50,000 patients from 30 countries. This makes it the largest group of patients to date to have their tumor biomarker profiles characterized, said Dr. Gatalica, executive medical director of Caris Life Sciences, Phoenix, Ariz.
A multiplatform approach was used that included mutational analysis by Sanger sequencing, next-generation sequencing, and polymerase chain reaction (PCR) testing; gene copy number by fluorescent or chromogenic in situ hybridization; O6-methylguanine DNA methyltransferase methylation by PCR; and protein expression analysis by immunohistochemistry.
Contrary to expectations, CUP was more prevalent in women (55%, or 822/1,459), and age offered no protection, with patients as young as 11 years and as old as 92 (average, 61 years), Dr. Gatalica said.
The most common site affected by cancer was the liver (24%), followed by other (30%) and lymph nodes (16%).
Not surprisingly, adenocarcinoma was the most common histology (45.3%), but there were also several differences in biomarkers based on histologic subtype, he said. For example, 7% of carcinomas had androgen receptor expression versus 3.3% of undifferentiated and neuroendocrine tumors.
The top "performers" were alterations in TP53 (33%), KRAS (17.5%), PIK3CA (7.4%), APC (3.6%), BRAF (3%), and epidermal growth factor receptor (EGFR) (1.1%), Dr. Gatalica said.
Dr. Gatalica also presented a few illustrative cases including a patient with liver metastases who had significant tumor reduction after being put on irinotecan (Camptostar)/5-fluorouracil on the basis of molecular profiling showing DNA topoisomerase 1 overexpression and thymidylate synthase underexpression.
A second case involved a 64-year-old woman with extensive bone disease who had a near-complete response after being directed to the EGFR-kinase inhibitor erlotinib (Tarceva) because profiling showed she carried an EGFR mutation.
Invited discussant Dr. Lajos Pusztai, codirector of the Yale Cancer Center genetics and genomics program, New Haven, Conn., described the cases as "inspiring" and said the results represent "a treasure trove of data."
Several questions remain, however, including the distribution of anomalies, how the authors defined "targetable," and whether treatment recommendations were actually followed.
"So you give a molecularly targeted treatment recommendation, but how often do physicians follow that?" he asked. "That would be a good way of gauging the test in practicality. What is the benefit rate?"
Audience members also questioned the cost of the test. An unidentified Caris spokesperson rose from the overflow crowd to say the full panel costs about €4,900 Euros (about $6,650 US), but that efforts are underway to bring the price down.
Dr. Gatalica said that in rare instances, molecular profiling "may actually improve the diagnosis of the primary site."
A recent study from the Sarah Cannon Research Institute showed that molecular profiling, using only a 92-gene reverse transcriptase PCR assay, allowed clinicians to predict the site of origin and direct site-specific therapy in 289 CUP patients, resulting in a 3-month gain in overall survival from the historic median of 9 months to 12.5 months (J. Clin. Oncol. 2013;31:217-23).
While molecular profiling represents a "conceptual leap" in the approach to CUP by emphasizing the biology of the tumor and not the primary site, "the problem is we don’t have enough good drugs," Dr. Pusztai observed.
Dr. Gatalica reported ownership and stock options in Caris Life Sciences, which sponsored the study and provided the molecular panel. Dr. Pusztai reported no relevant financial conflicts of interest.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: Targetable alterations were identified in 77% of cases.
Data source: A retrospective molecular analysis of 1,459 patients with cancers of unknown primary site.
Disclosures: Dr. Gatalica reported ownership and stock options in Caris Life Sciences, which sponsored the study and provided the molecular panel. Dr. Pusztai reported no relevant financial conflicts of interest.
Low-grade toxicities take a toll on older cancer patients
AMSTERDAM – Low-grade toxicity resulted in modification of chemotherapy regimens for nearly one in five older cancer patients and discontinuation of treatment in one in ten, judging from findings from a recent study.
"This is a quite clinically meaningful finding in a large, but understudied patient group," Dr. Tania Kalsi said at the multidisciplinary European cancer congresses.
More than half of cancer diagnoses occur in patients older than 65 years, and this heterogeneous group is growing in size with the aging world population.
Dr. Kalsi reported on a subsample of 108 patients treated with chemotherapy who were part of a prospective, cohort of 516 patients, aged 65 years and older, receiving any cancer treatment at the chemotherapy day unit in a tertiary referral hospital in London. All patients completed the Comprehensive Geriatric Assessment screening questionnaire to evaluate their comorbidities, functional status, and quality of life.
Their mean age was 72 years (range 65-86), 51% were male, and 59.3% were receiving chemotherapy with a palliative intent. Cancers were colorectal in 33, gynecologic in 18, upper gastrointestinal in 16, lung in 15, and other in 26. On average, 4.2 cycles of chemotherapy were delivered.
Of the 108 patients studied, 66 (55.5%) required modification of their chemotherapy regimen due to toxicity, and 21 of them (19.4%) had toxicity of grade 2 or lower, said Dr. Kalsi, a geriatric oncology research fellow at Guy’s and St. Thomas’ NHS Foundation Trust, London.
The mean number of grade 2 toxicities resulting in treatment modification was 2.19; seven patients who needed treatment modification had only one grade 2 toxicity.
Dose modifications were most commonly triggered by fatigue and hematologic toxicity (eight patients each), gastrointestinal (six patients), and infections (five patients), she said.
In univariate analysis, no significant association was seen between low- vs. high-grade toxicity treatment modifications and performance status (P = .730), treatment intent (P = .978), and patient age (less than 75 years vs. at least 75 years; P = .47).
"This is really one of the first studies to look at the impact of low-grade toxicity in older people"
Low-grade toxicity, however, triggered treatment modifications significantly more often in patients with multiple comorbidities (four or more) vs. fewer comorbidities (24.4% vs. 58%; P = .011), Dr. Kalsi said.
Although the series involved few patients, this finding is particularly interesting, said Dr. Riccardo Audisio of the University of Liverpool, U.K., who featured the study (Ab. 1555) in a highlights session at the meeting.
Overall, 23 patients (21.2%) stopped chemotherapy early due to toxicity, and nine (8.3%) of these patients had no toxicity above grade 2.
An average of 1.78 grade 2 toxicities prompted treatment discontinuation and 3 patients had only one grade 2 toxicity. The same culprits of fatigue (5 patients) and hematological toxicity (4 patients) caused early discontinuation, Dr. Kalsi said.
Univariate analysis found no significant association between low- vs. high-grade toxicity treatment discontinuation and performance status (P = 1.00), treatment intent (P = .657), patient age (P = .417), or comorbidities (P = .657), although the small sample size may have influenced the analyses, she said.
"This is really one of the first studies to look at the impact of low-grade toxicity in older people" and "highlights some key questions around clinical decision making" Dr. Kalsi said. Future research will need to tease out whether low-grade toxicity truly has a greater clinical impact on older people or whether there are differences in the clinical interaction between doctors and older patients. For example, is there a lower threshold for modifying/discontinuing treatment in older people; do older people report their symptoms differently than younger patients; and would additional support from a geriatrician liaison improve treatment tolerance; she asked.
Dr. Kalsi reported no relevant conflicts of interest.
AMSTERDAM – Low-grade toxicity resulted in modification of chemotherapy regimens for nearly one in five older cancer patients and discontinuation of treatment in one in ten, judging from findings from a recent study.
"This is a quite clinically meaningful finding in a large, but understudied patient group," Dr. Tania Kalsi said at the multidisciplinary European cancer congresses.
More than half of cancer diagnoses occur in patients older than 65 years, and this heterogeneous group is growing in size with the aging world population.
Dr. Kalsi reported on a subsample of 108 patients treated with chemotherapy who were part of a prospective, cohort of 516 patients, aged 65 years and older, receiving any cancer treatment at the chemotherapy day unit in a tertiary referral hospital in London. All patients completed the Comprehensive Geriatric Assessment screening questionnaire to evaluate their comorbidities, functional status, and quality of life.
Their mean age was 72 years (range 65-86), 51% were male, and 59.3% were receiving chemotherapy with a palliative intent. Cancers were colorectal in 33, gynecologic in 18, upper gastrointestinal in 16, lung in 15, and other in 26. On average, 4.2 cycles of chemotherapy were delivered.
Of the 108 patients studied, 66 (55.5%) required modification of their chemotherapy regimen due to toxicity, and 21 of them (19.4%) had toxicity of grade 2 or lower, said Dr. Kalsi, a geriatric oncology research fellow at Guy’s and St. Thomas’ NHS Foundation Trust, London.
The mean number of grade 2 toxicities resulting in treatment modification was 2.19; seven patients who needed treatment modification had only one grade 2 toxicity.
Dose modifications were most commonly triggered by fatigue and hematologic toxicity (eight patients each), gastrointestinal (six patients), and infections (five patients), she said.
In univariate analysis, no significant association was seen between low- vs. high-grade toxicity treatment modifications and performance status (P = .730), treatment intent (P = .978), and patient age (less than 75 years vs. at least 75 years; P = .47).
"This is really one of the first studies to look at the impact of low-grade toxicity in older people"
Low-grade toxicity, however, triggered treatment modifications significantly more often in patients with multiple comorbidities (four or more) vs. fewer comorbidities (24.4% vs. 58%; P = .011), Dr. Kalsi said.
Although the series involved few patients, this finding is particularly interesting, said Dr. Riccardo Audisio of the University of Liverpool, U.K., who featured the study (Ab. 1555) in a highlights session at the meeting.
Overall, 23 patients (21.2%) stopped chemotherapy early due to toxicity, and nine (8.3%) of these patients had no toxicity above grade 2.
An average of 1.78 grade 2 toxicities prompted treatment discontinuation and 3 patients had only one grade 2 toxicity. The same culprits of fatigue (5 patients) and hematological toxicity (4 patients) caused early discontinuation, Dr. Kalsi said.
Univariate analysis found no significant association between low- vs. high-grade toxicity treatment discontinuation and performance status (P = 1.00), treatment intent (P = .657), patient age (P = .417), or comorbidities (P = .657), although the small sample size may have influenced the analyses, she said.
"This is really one of the first studies to look at the impact of low-grade toxicity in older people" and "highlights some key questions around clinical decision making" Dr. Kalsi said. Future research will need to tease out whether low-grade toxicity truly has a greater clinical impact on older people or whether there are differences in the clinical interaction between doctors and older patients. For example, is there a lower threshold for modifying/discontinuing treatment in older people; do older people report their symptoms differently than younger patients; and would additional support from a geriatrician liaison improve treatment tolerance; she asked.
Dr. Kalsi reported no relevant conflicts of interest.
AMSTERDAM – Low-grade toxicity resulted in modification of chemotherapy regimens for nearly one in five older cancer patients and discontinuation of treatment in one in ten, judging from findings from a recent study.
"This is a quite clinically meaningful finding in a large, but understudied patient group," Dr. Tania Kalsi said at the multidisciplinary European cancer congresses.
More than half of cancer diagnoses occur in patients older than 65 years, and this heterogeneous group is growing in size with the aging world population.
Dr. Kalsi reported on a subsample of 108 patients treated with chemotherapy who were part of a prospective, cohort of 516 patients, aged 65 years and older, receiving any cancer treatment at the chemotherapy day unit in a tertiary referral hospital in London. All patients completed the Comprehensive Geriatric Assessment screening questionnaire to evaluate their comorbidities, functional status, and quality of life.
Their mean age was 72 years (range 65-86), 51% were male, and 59.3% were receiving chemotherapy with a palliative intent. Cancers were colorectal in 33, gynecologic in 18, upper gastrointestinal in 16, lung in 15, and other in 26. On average, 4.2 cycles of chemotherapy were delivered.
Of the 108 patients studied, 66 (55.5%) required modification of their chemotherapy regimen due to toxicity, and 21 of them (19.4%) had toxicity of grade 2 or lower, said Dr. Kalsi, a geriatric oncology research fellow at Guy’s and St. Thomas’ NHS Foundation Trust, London.
The mean number of grade 2 toxicities resulting in treatment modification was 2.19; seven patients who needed treatment modification had only one grade 2 toxicity.
Dose modifications were most commonly triggered by fatigue and hematologic toxicity (eight patients each), gastrointestinal (six patients), and infections (five patients), she said.
In univariate analysis, no significant association was seen between low- vs. high-grade toxicity treatment modifications and performance status (P = .730), treatment intent (P = .978), and patient age (less than 75 years vs. at least 75 years; P = .47).
"This is really one of the first studies to look at the impact of low-grade toxicity in older people"
Low-grade toxicity, however, triggered treatment modifications significantly more often in patients with multiple comorbidities (four or more) vs. fewer comorbidities (24.4% vs. 58%; P = .011), Dr. Kalsi said.
Although the series involved few patients, this finding is particularly interesting, said Dr. Riccardo Audisio of the University of Liverpool, U.K., who featured the study (Ab. 1555) in a highlights session at the meeting.
Overall, 23 patients (21.2%) stopped chemotherapy early due to toxicity, and nine (8.3%) of these patients had no toxicity above grade 2.
An average of 1.78 grade 2 toxicities prompted treatment discontinuation and 3 patients had only one grade 2 toxicity. The same culprits of fatigue (5 patients) and hematological toxicity (4 patients) caused early discontinuation, Dr. Kalsi said.
Univariate analysis found no significant association between low- vs. high-grade toxicity treatment discontinuation and performance status (P = 1.00), treatment intent (P = .657), patient age (P = .417), or comorbidities (P = .657), although the small sample size may have influenced the analyses, she said.
"This is really one of the first studies to look at the impact of low-grade toxicity in older people" and "highlights some key questions around clinical decision making" Dr. Kalsi said. Future research will need to tease out whether low-grade toxicity truly has a greater clinical impact on older people or whether there are differences in the clinical interaction between doctors and older patients. For example, is there a lower threshold for modifying/discontinuing treatment in older people; do older people report their symptoms differently than younger patients; and would additional support from a geriatrician liaison improve treatment tolerance; she asked.
Dr. Kalsi reported no relevant conflicts of interest.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: Low-grade toxicity resulted in chemotherapy modifications in 19.4% and treatment discontinuation in 8.3% of older cancer patients.
Data source: A subsample of 108 cancer patients, aged 65 years and older.
Disclosures: Dr. Kalsi reported no relevant conflicts of interest.
Internal mammary chain radiation ups breast cancer survival
AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.
At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).
Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.
With irradiation, "we might be able to stop metastasis at their source," he said.
Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.
The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.
More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).
Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.
Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.
After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.
A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.
Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.
Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).
He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.
"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.
The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.
AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.
At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).
Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.
With irradiation, "we might be able to stop metastasis at their source," he said.
Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.
The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.
More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).
Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.
Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.
After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.
A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.
Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.
Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).
He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.
"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.
The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.
AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.
At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).
Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.
With irradiation, "we might be able to stop metastasis at their source," he said.
Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.
The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.
More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).
Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.
Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.
After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.
A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.
Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.
Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).
He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.
"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.
The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: Ten-year overall survival was 82.3% with internal mammary and medial supraclavicular radiation therapy vs. 80.7% without IM-MS radiation (P = .056).
Data source: A prospective, phase III study of 4,004 women with stage I, II, and III breast cancer.
Disclosures: The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.
Alectinib active in ALK-positive, crizotinib-refractory NSCLC
AMSTERDAM – The investigational second-generation ALK inhibitor alectinib produced objective responses in 54.5% of patients with ALK-positive non–small cell lung cancer refractory to crizotinib in a phase I dose-finding study.
Alectinib had consistent clinical activity in patients with symptomatic brain metastases, including two cases of leptomeningeal carcinomatosis. One of those patients, a 29-year-old woman with a 7-year history of anaplastic lymphoma kinase (ALK)–positive lung cancer, cleared malignant brain cells within 4 weeks after starting oral alectinib, Dr. Sai-Hong Ou said at the multidisciplinary European cancer congresses.
Alectinib, which is being developed by study sponsor Roche/Chugai Pharmaceutical, has already demonstrated an objective response rate of 93.5% in crizotinib (Xalkori)-naive ALK-positive non–small cell lung cancer. Among those patients, a previously untreated 2.5-cm brain lesion decreased in size by 47% in about 3 weeks and the patient continues to have a confirmed response to alectinib, he said.
Based on the new data, alectinib was granted a breakthrough therapy designation by the Food and Drug Administration to expedite its development and review.
Crizotinib is the only approved ALK-inhibitor for use in ALK-rearranged non–small cell lung cancer; it is available for use in any line therapy in the United States and as second-line therapy only in Europe.
A total of 47 patients were enrolled in the phase I study and treated with twice-daily alectinib at doses ranging from 300 mg to 900 mg. All patients had adenocarcinoma histology, an ECOG performance status of 0-2, and no prior exposure to other ALK inhibitors.
Two dose-limiting toxicities occurred at the 900-mg dose – a grade 3 headache and grade 3 neutropenia requiring dose interruption for 7 days. No patient had to be dose reduced at 600 mg twice daily, which was identified as the recommended phase II dose.
Overall, there were very few grade 3/4 treatment-emergent adverse events, said Dr. Ou of the Chao Family Comprehensive Cancer Center at the University of California Irvine Medical Center, Orange. Most were increased gamma-glutamyl transpeptidase, neutrophil decrease, and hypophosphatemia.
The most common toxicities were fatigue (30%), myalgia and peripheral edema (17%), elevated creatine phosphokinase (15%), and photosensitivity (13%).
Among the 21 patients with brain metastases at baseline, 13 had partial responses to alectinib at varying doses, 6 had stable disease, 1 had progressive disease, and 1 had a pending evaluation.
Dr. Ou said that a new 150-mg capsule has been formulated to reduce the number of capsules needed each day and that a phase II study (Accalia G2L) of alectinib is underway in crizotinib-resistant ALK-positive non–small cell lung cancer. A phase III head-to-head comparison between alectinib and crizotinib is also planned, with the protocol to be completed by January 2014, he said.
Roche/Chugai Pharmaceuticals sponsored the trial. Dr. Ou reported consulting for Chugai, Genentech, and Pfizer and serving on speakers bureaus for Boehringer Ingelheim, Genentech, and Pfizer.
The responses in patients with brain metastases, particularly in patients with leptomeningeal carcinomatosis, are good news as these patients can be challenging to manage. Also, the benefit on brain metastases could be directly linked to alectinib, since four patients had no prior brain radiation therapy. Two patients had brain radiation within a month of enrollment, and 15 had radiation more than 4 weeks prior to enrollment.
Crizotinib and the investigational second-generation tyrosine kinase inhibitor AP26113 are also active in brain metastases, however.
Alectinib is entering a crowded field that targets a niche area of lung cancer that represents less than 5% of all lung cancers. The drug’s favorable safety profile will be key versus the other competitors, but really what we need is biology to guide treatment.
Dr. Benjamin Besse of the Institut Gustave Roussy in Villejuif, France, was the invited discussant of the study. He reported no conflicts of interest.
The responses in patients with brain metastases, particularly in patients with leptomeningeal carcinomatosis, are good news as these patients can be challenging to manage. Also, the benefit on brain metastases could be directly linked to alectinib, since four patients had no prior brain radiation therapy. Two patients had brain radiation within a month of enrollment, and 15 had radiation more than 4 weeks prior to enrollment.
Crizotinib and the investigational second-generation tyrosine kinase inhibitor AP26113 are also active in brain metastases, however.
Alectinib is entering a crowded field that targets a niche area of lung cancer that represents less than 5% of all lung cancers. The drug’s favorable safety profile will be key versus the other competitors, but really what we need is biology to guide treatment.
Dr. Benjamin Besse of the Institut Gustave Roussy in Villejuif, France, was the invited discussant of the study. He reported no conflicts of interest.
The responses in patients with brain metastases, particularly in patients with leptomeningeal carcinomatosis, are good news as these patients can be challenging to manage. Also, the benefit on brain metastases could be directly linked to alectinib, since four patients had no prior brain radiation therapy. Two patients had brain radiation within a month of enrollment, and 15 had radiation more than 4 weeks prior to enrollment.
Crizotinib and the investigational second-generation tyrosine kinase inhibitor AP26113 are also active in brain metastases, however.
Alectinib is entering a crowded field that targets a niche area of lung cancer that represents less than 5% of all lung cancers. The drug’s favorable safety profile will be key versus the other competitors, but really what we need is biology to guide treatment.
Dr. Benjamin Besse of the Institut Gustave Roussy in Villejuif, France, was the invited discussant of the study. He reported no conflicts of interest.
AMSTERDAM – The investigational second-generation ALK inhibitor alectinib produced objective responses in 54.5% of patients with ALK-positive non–small cell lung cancer refractory to crizotinib in a phase I dose-finding study.
Alectinib had consistent clinical activity in patients with symptomatic brain metastases, including two cases of leptomeningeal carcinomatosis. One of those patients, a 29-year-old woman with a 7-year history of anaplastic lymphoma kinase (ALK)–positive lung cancer, cleared malignant brain cells within 4 weeks after starting oral alectinib, Dr. Sai-Hong Ou said at the multidisciplinary European cancer congresses.
Alectinib, which is being developed by study sponsor Roche/Chugai Pharmaceutical, has already demonstrated an objective response rate of 93.5% in crizotinib (Xalkori)-naive ALK-positive non–small cell lung cancer. Among those patients, a previously untreated 2.5-cm brain lesion decreased in size by 47% in about 3 weeks and the patient continues to have a confirmed response to alectinib, he said.
Based on the new data, alectinib was granted a breakthrough therapy designation by the Food and Drug Administration to expedite its development and review.
Crizotinib is the only approved ALK-inhibitor for use in ALK-rearranged non–small cell lung cancer; it is available for use in any line therapy in the United States and as second-line therapy only in Europe.
A total of 47 patients were enrolled in the phase I study and treated with twice-daily alectinib at doses ranging from 300 mg to 900 mg. All patients had adenocarcinoma histology, an ECOG performance status of 0-2, and no prior exposure to other ALK inhibitors.
Two dose-limiting toxicities occurred at the 900-mg dose – a grade 3 headache and grade 3 neutropenia requiring dose interruption for 7 days. No patient had to be dose reduced at 600 mg twice daily, which was identified as the recommended phase II dose.
Overall, there were very few grade 3/4 treatment-emergent adverse events, said Dr. Ou of the Chao Family Comprehensive Cancer Center at the University of California Irvine Medical Center, Orange. Most were increased gamma-glutamyl transpeptidase, neutrophil decrease, and hypophosphatemia.
The most common toxicities were fatigue (30%), myalgia and peripheral edema (17%), elevated creatine phosphokinase (15%), and photosensitivity (13%).
Among the 21 patients with brain metastases at baseline, 13 had partial responses to alectinib at varying doses, 6 had stable disease, 1 had progressive disease, and 1 had a pending evaluation.
Dr. Ou said that a new 150-mg capsule has been formulated to reduce the number of capsules needed each day and that a phase II study (Accalia G2L) of alectinib is underway in crizotinib-resistant ALK-positive non–small cell lung cancer. A phase III head-to-head comparison between alectinib and crizotinib is also planned, with the protocol to be completed by January 2014, he said.
Roche/Chugai Pharmaceuticals sponsored the trial. Dr. Ou reported consulting for Chugai, Genentech, and Pfizer and serving on speakers bureaus for Boehringer Ingelheim, Genentech, and Pfizer.
AMSTERDAM – The investigational second-generation ALK inhibitor alectinib produced objective responses in 54.5% of patients with ALK-positive non–small cell lung cancer refractory to crizotinib in a phase I dose-finding study.
Alectinib had consistent clinical activity in patients with symptomatic brain metastases, including two cases of leptomeningeal carcinomatosis. One of those patients, a 29-year-old woman with a 7-year history of anaplastic lymphoma kinase (ALK)–positive lung cancer, cleared malignant brain cells within 4 weeks after starting oral alectinib, Dr. Sai-Hong Ou said at the multidisciplinary European cancer congresses.
Alectinib, which is being developed by study sponsor Roche/Chugai Pharmaceutical, has already demonstrated an objective response rate of 93.5% in crizotinib (Xalkori)-naive ALK-positive non–small cell lung cancer. Among those patients, a previously untreated 2.5-cm brain lesion decreased in size by 47% in about 3 weeks and the patient continues to have a confirmed response to alectinib, he said.
Based on the new data, alectinib was granted a breakthrough therapy designation by the Food and Drug Administration to expedite its development and review.
Crizotinib is the only approved ALK-inhibitor for use in ALK-rearranged non–small cell lung cancer; it is available for use in any line therapy in the United States and as second-line therapy only in Europe.
A total of 47 patients were enrolled in the phase I study and treated with twice-daily alectinib at doses ranging from 300 mg to 900 mg. All patients had adenocarcinoma histology, an ECOG performance status of 0-2, and no prior exposure to other ALK inhibitors.
Two dose-limiting toxicities occurred at the 900-mg dose – a grade 3 headache and grade 3 neutropenia requiring dose interruption for 7 days. No patient had to be dose reduced at 600 mg twice daily, which was identified as the recommended phase II dose.
Overall, there were very few grade 3/4 treatment-emergent adverse events, said Dr. Ou of the Chao Family Comprehensive Cancer Center at the University of California Irvine Medical Center, Orange. Most were increased gamma-glutamyl transpeptidase, neutrophil decrease, and hypophosphatemia.
The most common toxicities were fatigue (30%), myalgia and peripheral edema (17%), elevated creatine phosphokinase (15%), and photosensitivity (13%).
Among the 21 patients with brain metastases at baseline, 13 had partial responses to alectinib at varying doses, 6 had stable disease, 1 had progressive disease, and 1 had a pending evaluation.
Dr. Ou said that a new 150-mg capsule has been formulated to reduce the number of capsules needed each day and that a phase II study (Accalia G2L) of alectinib is underway in crizotinib-resistant ALK-positive non–small cell lung cancer. A phase III head-to-head comparison between alectinib and crizotinib is also planned, with the protocol to be completed by January 2014, he said.
Roche/Chugai Pharmaceuticals sponsored the trial. Dr. Ou reported consulting for Chugai, Genentech, and Pfizer and serving on speakers bureaus for Boehringer Ingelheim, Genentech, and Pfizer.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: Among the 21 patients with brain metastases at baseline, 13 had partial responses to alectinib at varying doses, 6 had stable disease, 1 had progressive disease, and 1 had a pending evaluation.
Data source: Dose-finding phase I study of 47 patients with crizotinib-refractory ALK-positive non–small cell lung cancer.
Disclosures: Roche/Chugai Pharmaceuticals sponsored the trial. Dr. Ou reported consulting for Chugai, Genentech, and Pfizer and serving on speakers bureaus for Boehringer Ingelheim, Genentech, and Pfizer.
T-DM1 tops physician’s choice in advanced HER2-positive breast cancer
AMSTERDAM – Ado-trastuzumab emtansine nearly doubled the time to disease progression for women with heavily pretreated, HER2-positive metastatic breast cancer compared with physician’s choice of treatment in the open-label, phase III TH3RESA trial.
Median progression-free survival was 6.2 months with ado-trastuzumab emtansine (Kadcyla), previously known as T-DM1, and 3.3 months with a treatment of physician’s choice (hazard ratio 0.528; P less than .0001).
Physician’s choice included chemotherapy and trastuzumab (Herceptin) (68.5%), lapatinib and trastuzumab (10.3%), chemotherapy and lapatinib (2.7%), and hormonal therapy and trastuzumab (1.6%).
An interim overall survival analysis also favored T-DM1 (median not reached vs. 14.9 months; HR 0.552; P = .0034), with the final analysis expected in 2015, Dr. Hans Wildiers said in a presidential session at the multidisciplinary European cancer congresses.
The data reaffirm results from the phase III EMILIA trial, demonstrating a consistent benefit with T-DM1 in previously treated human epidermal growth factor receptor 2–positive (HER2-positive) advanced breast cancer.
"In my opinion, combining EMELIA and TH3RESA, T-DM1 should become the standard of care," he added.
As previously reported, EMILIA showed a 5-month gain in overall survival with T-DM1 over capecitabine (Xeloda) plus lapatinib (Tykerb) in relapsed, metastatic breast cancer.
This led to the approval of T-DM1 in February 2013 in the United States for the treatment of HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. T-DM1 is expected to gain European Union approval by the end of the year, according to Genentech, which markets the drug.
Notably, a total of 80.4% of patients in that arm received a regimen containing trastuzumab.* Median progression-free survival (PFS) in this subgroup was significantly extended by 3 months with T-DM1 compared with physician’s choice (3.2 vs. 6.2; HR 0.558; P less than .001), said Dr. Wildiers of University Hospitals Leuven, Belgium.
Commenting on the results, invited discussant Dr. Clifford Hudis, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York, said he is optimistic T-DM1 will deliver an overall survival advantage because prior research has shown that a small incremental improvement in PFS, measured in weeks, can lead to an improvement in months in overall survival simply by reintroducing trastuzumab (J. Clin. Oncol. 2012;30:2585-92).
"A definitive and clinically meaningful overall survival may just be what some markets need to bless this approach, but cost will be an issue," he said. "Arguably, we’re more willing to tolerate the higher cost when overall survival is improved, but even without it, I would see the toxicity advantage as worth a lot."
Patients treated with T-DM1 were less likely than were those given their physician’s choice to reduce dosage (9.4% vs. 19.6%) or stop treatment due to an adverse event (6.7% vs. 11%), Dr. Wildiers said. Grade 3 or higher adverse events were also lower with T-DM1 (32.3% vs. 43.5%).
Significantly more women also responded to T-DM1 than to their physician’s choice (31.3% vs. 8.6%; P less than .001). Further, analyses showed "a clear and consistent effect" that T-DM1 was better across all subgroups, he said.
When pressed by the audience on how T-DM1 should be used in clinical practice, Dr. Wildiers said T-DM1 should likely be reserved for the second-line setting until results are known from the ongoing MARIANNE trial. The phase III trial is evaluating T-DM1 with pertuzumab (Perjeta) versus trastuzumab plus a taxane in women with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer.
Dr. Wildiers reported serving on an advisory board for Roche. His coauthors disclosed ties with several firms, including employment with Genentech, which markets ado-trastuzumab emtansine.
*CORRECTION, 10/10/13: A previous version of this story did not clearly describe the patients who received trastuzumab in the physician's choice arm of TH3RESA.
AMSTERDAM – Ado-trastuzumab emtansine nearly doubled the time to disease progression for women with heavily pretreated, HER2-positive metastatic breast cancer compared with physician’s choice of treatment in the open-label, phase III TH3RESA trial.
Median progression-free survival was 6.2 months with ado-trastuzumab emtansine (Kadcyla), previously known as T-DM1, and 3.3 months with a treatment of physician’s choice (hazard ratio 0.528; P less than .0001).
Physician’s choice included chemotherapy and trastuzumab (Herceptin) (68.5%), lapatinib and trastuzumab (10.3%), chemotherapy and lapatinib (2.7%), and hormonal therapy and trastuzumab (1.6%).
An interim overall survival analysis also favored T-DM1 (median not reached vs. 14.9 months; HR 0.552; P = .0034), with the final analysis expected in 2015, Dr. Hans Wildiers said in a presidential session at the multidisciplinary European cancer congresses.
The data reaffirm results from the phase III EMILIA trial, demonstrating a consistent benefit with T-DM1 in previously treated human epidermal growth factor receptor 2–positive (HER2-positive) advanced breast cancer.
"In my opinion, combining EMELIA and TH3RESA, T-DM1 should become the standard of care," he added.
As previously reported, EMILIA showed a 5-month gain in overall survival with T-DM1 over capecitabine (Xeloda) plus lapatinib (Tykerb) in relapsed, metastatic breast cancer.
This led to the approval of T-DM1 in February 2013 in the United States for the treatment of HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. T-DM1 is expected to gain European Union approval by the end of the year, according to Genentech, which markets the drug.
Notably, a total of 80.4% of patients in that arm received a regimen containing trastuzumab.* Median progression-free survival (PFS) in this subgroup was significantly extended by 3 months with T-DM1 compared with physician’s choice (3.2 vs. 6.2; HR 0.558; P less than .001), said Dr. Wildiers of University Hospitals Leuven, Belgium.
Commenting on the results, invited discussant Dr. Clifford Hudis, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York, said he is optimistic T-DM1 will deliver an overall survival advantage because prior research has shown that a small incremental improvement in PFS, measured in weeks, can lead to an improvement in months in overall survival simply by reintroducing trastuzumab (J. Clin. Oncol. 2012;30:2585-92).
"A definitive and clinically meaningful overall survival may just be what some markets need to bless this approach, but cost will be an issue," he said. "Arguably, we’re more willing to tolerate the higher cost when overall survival is improved, but even without it, I would see the toxicity advantage as worth a lot."
Patients treated with T-DM1 were less likely than were those given their physician’s choice to reduce dosage (9.4% vs. 19.6%) or stop treatment due to an adverse event (6.7% vs. 11%), Dr. Wildiers said. Grade 3 or higher adverse events were also lower with T-DM1 (32.3% vs. 43.5%).
Significantly more women also responded to T-DM1 than to their physician’s choice (31.3% vs. 8.6%; P less than .001). Further, analyses showed "a clear and consistent effect" that T-DM1 was better across all subgroups, he said.
When pressed by the audience on how T-DM1 should be used in clinical practice, Dr. Wildiers said T-DM1 should likely be reserved for the second-line setting until results are known from the ongoing MARIANNE trial. The phase III trial is evaluating T-DM1 with pertuzumab (Perjeta) versus trastuzumab plus a taxane in women with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer.
Dr. Wildiers reported serving on an advisory board for Roche. His coauthors disclosed ties with several firms, including employment with Genentech, which markets ado-trastuzumab emtansine.
*CORRECTION, 10/10/13: A previous version of this story did not clearly describe the patients who received trastuzumab in the physician's choice arm of TH3RESA.
AMSTERDAM – Ado-trastuzumab emtansine nearly doubled the time to disease progression for women with heavily pretreated, HER2-positive metastatic breast cancer compared with physician’s choice of treatment in the open-label, phase III TH3RESA trial.
Median progression-free survival was 6.2 months with ado-trastuzumab emtansine (Kadcyla), previously known as T-DM1, and 3.3 months with a treatment of physician’s choice (hazard ratio 0.528; P less than .0001).
Physician’s choice included chemotherapy and trastuzumab (Herceptin) (68.5%), lapatinib and trastuzumab (10.3%), chemotherapy and lapatinib (2.7%), and hormonal therapy and trastuzumab (1.6%).
An interim overall survival analysis also favored T-DM1 (median not reached vs. 14.9 months; HR 0.552; P = .0034), with the final analysis expected in 2015, Dr. Hans Wildiers said in a presidential session at the multidisciplinary European cancer congresses.
The data reaffirm results from the phase III EMILIA trial, demonstrating a consistent benefit with T-DM1 in previously treated human epidermal growth factor receptor 2–positive (HER2-positive) advanced breast cancer.
"In my opinion, combining EMELIA and TH3RESA, T-DM1 should become the standard of care," he added.
As previously reported, EMILIA showed a 5-month gain in overall survival with T-DM1 over capecitabine (Xeloda) plus lapatinib (Tykerb) in relapsed, metastatic breast cancer.
This led to the approval of T-DM1 in February 2013 in the United States for the treatment of HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. T-DM1 is expected to gain European Union approval by the end of the year, according to Genentech, which markets the drug.
Notably, a total of 80.4% of patients in that arm received a regimen containing trastuzumab.* Median progression-free survival (PFS) in this subgroup was significantly extended by 3 months with T-DM1 compared with physician’s choice (3.2 vs. 6.2; HR 0.558; P less than .001), said Dr. Wildiers of University Hospitals Leuven, Belgium.
Commenting on the results, invited discussant Dr. Clifford Hudis, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York, said he is optimistic T-DM1 will deliver an overall survival advantage because prior research has shown that a small incremental improvement in PFS, measured in weeks, can lead to an improvement in months in overall survival simply by reintroducing trastuzumab (J. Clin. Oncol. 2012;30:2585-92).
"A definitive and clinically meaningful overall survival may just be what some markets need to bless this approach, but cost will be an issue," he said. "Arguably, we’re more willing to tolerate the higher cost when overall survival is improved, but even without it, I would see the toxicity advantage as worth a lot."
Patients treated with T-DM1 were less likely than were those given their physician’s choice to reduce dosage (9.4% vs. 19.6%) or stop treatment due to an adverse event (6.7% vs. 11%), Dr. Wildiers said. Grade 3 or higher adverse events were also lower with T-DM1 (32.3% vs. 43.5%).
Significantly more women also responded to T-DM1 than to their physician’s choice (31.3% vs. 8.6%; P less than .001). Further, analyses showed "a clear and consistent effect" that T-DM1 was better across all subgroups, he said.
When pressed by the audience on how T-DM1 should be used in clinical practice, Dr. Wildiers said T-DM1 should likely be reserved for the second-line setting until results are known from the ongoing MARIANNE trial. The phase III trial is evaluating T-DM1 with pertuzumab (Perjeta) versus trastuzumab plus a taxane in women with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer.
Dr. Wildiers reported serving on an advisory board for Roche. His coauthors disclosed ties with several firms, including employment with Genentech, which markets ado-trastuzumab emtansine.
*CORRECTION, 10/10/13: A previous version of this story did not clearly describe the patients who received trastuzumab in the physician's choice arm of TH3RESA.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: Median progression-free survival was 6.2 months with T-DM1 vs. 3.3 months with physician’s choice of treatment (P less than .0001).
Data source: An open-label, phase III study of 602 women with HER2-positive metastatic breast cancer.
Disclosures: Dr. Wildiers reported serving on an advisory board for Roche. His coauthors disclosed ties with several firms, including employment with Genentech, which markets ado-trastuzumab emtansine.
ICON6 ovarian cancer results may resurrect cediranib
AMSTERDAM – Cediranib plus chemotherapy followed by cediranib maintenance treatment stalled recurrence and death by roughly 3 months in women with platinum-sensitive, relapsed ovarian cancer in the ICON6 study.
"This is the first trial to demonstrate a significant improvement in the progression-free and overall survival with an oral VEGF tyrosine kinase inhibitor in ovarian cancer, and these results suggest that cediranib has a clinically meaningful role in the treatment of recurrent ovarian cancer," Professor Jonathan Ledermann said at the multidisciplinary European cancer congresses.
The phase III results may provide women with another treatment option and bring cediranib (Recentin) back to life. AstraZeneca ceased development of the small molecule vascular endothelial growth factor (VEGF) inhibitor in September 2011 following disappointing results in first-line metastatic colorectal cancer, as well as non-small cell lung cancer
The three-arm, double-blinded ICON6 Gynecologic Cancer Intergroup Trial enrolled 456 women with epithelial ovarian, fallopian tube, or serous primary peritoneal cancer relapsing more than 6 months after first-line chemotherapy.
Patients were randomly assigned to platinum-based chemotherapy plus placebo and placebo maintenance therapy (chemotherapy-only arm) or cediranib 20 mg/day during chemotherapy followed by placebo (concurrent arm), or cediranib 20 mg/day during chemotherapy followed by maintenance cediranib (maintenance arm).
Treatment continued for 18 months or until disease progression, but could be used longer for patients continuing to benefit. Chemotherapy was up to six cycles of carboplatin (Paraplatin)/paclitaxel (Taxol), carboplatin/gemcitabine (Gemzar), or single-agent platinum therapy.
Median progression-free survival (PFS) was 8.7 months in the chemotherapy arm and 11.1 months in the cediranib maintenance arm (hazard ratio, 0.57; P = .00001).
However, because a test for nonproportionality was positive (P = .024), a restricted means analysis was done, resulting in a 3.1 month difference favoring cediranib (9.4 months vs. 12.5 months), said Prof. Ledermann, with University College London (UCL) Cancer Institute, Cancer Research UK, and UCL Cancer Trials Centre, London.
As a secondary endpoint, an analysis was performed on the concurrent arm showing a trend in favor of cediranib, with a PFS of 10.1 months and 11.4 months using restricted means analysis.
"There is strong evidence that cediranib has an effect by itself on progression-free survival both during and after chemotherapy," Prof. Ledermann said.
Median overall survival reached 20.3 months in the chemotherapy arm and 26.3 months in the cediranib maintenance arm (HR, 0.70; P = .042). Overall survival fell to 17.6 months and 20.3 months, respectively, in a restricted means analysis, following a positive test for nonproportionality (P = .0042). No overall survival data were presented for the concurrent arm.
"These are important results for women with recurrence ovarian cancer," Prof. Cornelis van de Velde, European Cancer Organization president, commented in a statement. "Once the disease has recurred, there are few treatment options available that make a significant difference to its progression and to overall survival. The ICON6 trial shows that cediranib does make a difference and it is to be hoped that it can be made available to women as soon as is practicable."
Laura Woodin, U.S. science media director for AstraZeneca, said in an interview that the company welcomes the commitment of the ICON6 investigators and the study sponsor, Britain’s Medical Research Council, and that "We look forward to assessing the positive results from the ICON6 study in more detail, to determine the future potential for cediranib in ovarian cancer."
Invited discussant Prof. Ignace Vergote, head of gynecological oncology at University Hospitals Leuven, Belgium, questioned why overall survival was so low in ICON6, compared with a median of 35.5 months reported with the addition of the VEGF-inhibitor bevacizumab to platinum-based chemotherapy in recurrent ovarian cancer in the phase III OCEANS trial. The cediranib dose was reduced from 30 mg/day to 20 mg/day after part one of ICON6, but it is unclear whether a higher dose in the maintenance phase would be more effective because 30-45 mg are used in most trials of cediranib monotherapy. Also unknown is whether there was less treatment in ICON6 after progression than there was in OCEANS.
The 15-month difference in overall survival between the two trials, however, might explain why overall survival was significant in ICON6 and not in the OCEANS study, Prof. Vergote said.
Finally, cediranib was associated with more treatment discontinuation, diarrhea, and fatigue, but less hypertension than bevacizumab at the dose used in the study, he observed.
Prof. Ledermann said hypertension (P = .004), diarrhea (P less than .001), and nausea (P = .008) were all significantly worse when cediranib was given during chemotherapy, but when it came to the maintenance phase, "hypertension was really quite manageable by this stage and the only side effect that was significantly worse with cediranib was diarrhea [P less than .001]."
Prof. Ledermann and his coauthors reported no relevant disclosures. AstraZeneca provided the study drug. Britain’s Medical Research Council sponsored the trial.
AMSTERDAM – Cediranib plus chemotherapy followed by cediranib maintenance treatment stalled recurrence and death by roughly 3 months in women with platinum-sensitive, relapsed ovarian cancer in the ICON6 study.
"This is the first trial to demonstrate a significant improvement in the progression-free and overall survival with an oral VEGF tyrosine kinase inhibitor in ovarian cancer, and these results suggest that cediranib has a clinically meaningful role in the treatment of recurrent ovarian cancer," Professor Jonathan Ledermann said at the multidisciplinary European cancer congresses.
The phase III results may provide women with another treatment option and bring cediranib (Recentin) back to life. AstraZeneca ceased development of the small molecule vascular endothelial growth factor (VEGF) inhibitor in September 2011 following disappointing results in first-line metastatic colorectal cancer, as well as non-small cell lung cancer
The three-arm, double-blinded ICON6 Gynecologic Cancer Intergroup Trial enrolled 456 women with epithelial ovarian, fallopian tube, or serous primary peritoneal cancer relapsing more than 6 months after first-line chemotherapy.
Patients were randomly assigned to platinum-based chemotherapy plus placebo and placebo maintenance therapy (chemotherapy-only arm) or cediranib 20 mg/day during chemotherapy followed by placebo (concurrent arm), or cediranib 20 mg/day during chemotherapy followed by maintenance cediranib (maintenance arm).
Treatment continued for 18 months or until disease progression, but could be used longer for patients continuing to benefit. Chemotherapy was up to six cycles of carboplatin (Paraplatin)/paclitaxel (Taxol), carboplatin/gemcitabine (Gemzar), or single-agent platinum therapy.
Median progression-free survival (PFS) was 8.7 months in the chemotherapy arm and 11.1 months in the cediranib maintenance arm (hazard ratio, 0.57; P = .00001).
However, because a test for nonproportionality was positive (P = .024), a restricted means analysis was done, resulting in a 3.1 month difference favoring cediranib (9.4 months vs. 12.5 months), said Prof. Ledermann, with University College London (UCL) Cancer Institute, Cancer Research UK, and UCL Cancer Trials Centre, London.
As a secondary endpoint, an analysis was performed on the concurrent arm showing a trend in favor of cediranib, with a PFS of 10.1 months and 11.4 months using restricted means analysis.
"There is strong evidence that cediranib has an effect by itself on progression-free survival both during and after chemotherapy," Prof. Ledermann said.
Median overall survival reached 20.3 months in the chemotherapy arm and 26.3 months in the cediranib maintenance arm (HR, 0.70; P = .042). Overall survival fell to 17.6 months and 20.3 months, respectively, in a restricted means analysis, following a positive test for nonproportionality (P = .0042). No overall survival data were presented for the concurrent arm.
"These are important results for women with recurrence ovarian cancer," Prof. Cornelis van de Velde, European Cancer Organization president, commented in a statement. "Once the disease has recurred, there are few treatment options available that make a significant difference to its progression and to overall survival. The ICON6 trial shows that cediranib does make a difference and it is to be hoped that it can be made available to women as soon as is practicable."
Laura Woodin, U.S. science media director for AstraZeneca, said in an interview that the company welcomes the commitment of the ICON6 investigators and the study sponsor, Britain’s Medical Research Council, and that "We look forward to assessing the positive results from the ICON6 study in more detail, to determine the future potential for cediranib in ovarian cancer."
Invited discussant Prof. Ignace Vergote, head of gynecological oncology at University Hospitals Leuven, Belgium, questioned why overall survival was so low in ICON6, compared with a median of 35.5 months reported with the addition of the VEGF-inhibitor bevacizumab to platinum-based chemotherapy in recurrent ovarian cancer in the phase III OCEANS trial. The cediranib dose was reduced from 30 mg/day to 20 mg/day after part one of ICON6, but it is unclear whether a higher dose in the maintenance phase would be more effective because 30-45 mg are used in most trials of cediranib monotherapy. Also unknown is whether there was less treatment in ICON6 after progression than there was in OCEANS.
The 15-month difference in overall survival between the two trials, however, might explain why overall survival was significant in ICON6 and not in the OCEANS study, Prof. Vergote said.
Finally, cediranib was associated with more treatment discontinuation, diarrhea, and fatigue, but less hypertension than bevacizumab at the dose used in the study, he observed.
Prof. Ledermann said hypertension (P = .004), diarrhea (P less than .001), and nausea (P = .008) were all significantly worse when cediranib was given during chemotherapy, but when it came to the maintenance phase, "hypertension was really quite manageable by this stage and the only side effect that was significantly worse with cediranib was diarrhea [P less than .001]."
Prof. Ledermann and his coauthors reported no relevant disclosures. AstraZeneca provided the study drug. Britain’s Medical Research Council sponsored the trial.
AMSTERDAM – Cediranib plus chemotherapy followed by cediranib maintenance treatment stalled recurrence and death by roughly 3 months in women with platinum-sensitive, relapsed ovarian cancer in the ICON6 study.
"This is the first trial to demonstrate a significant improvement in the progression-free and overall survival with an oral VEGF tyrosine kinase inhibitor in ovarian cancer, and these results suggest that cediranib has a clinically meaningful role in the treatment of recurrent ovarian cancer," Professor Jonathan Ledermann said at the multidisciplinary European cancer congresses.
The phase III results may provide women with another treatment option and bring cediranib (Recentin) back to life. AstraZeneca ceased development of the small molecule vascular endothelial growth factor (VEGF) inhibitor in September 2011 following disappointing results in first-line metastatic colorectal cancer, as well as non-small cell lung cancer
The three-arm, double-blinded ICON6 Gynecologic Cancer Intergroup Trial enrolled 456 women with epithelial ovarian, fallopian tube, or serous primary peritoneal cancer relapsing more than 6 months after first-line chemotherapy.
Patients were randomly assigned to platinum-based chemotherapy plus placebo and placebo maintenance therapy (chemotherapy-only arm) or cediranib 20 mg/day during chemotherapy followed by placebo (concurrent arm), or cediranib 20 mg/day during chemotherapy followed by maintenance cediranib (maintenance arm).
Treatment continued for 18 months or until disease progression, but could be used longer for patients continuing to benefit. Chemotherapy was up to six cycles of carboplatin (Paraplatin)/paclitaxel (Taxol), carboplatin/gemcitabine (Gemzar), or single-agent platinum therapy.
Median progression-free survival (PFS) was 8.7 months in the chemotherapy arm and 11.1 months in the cediranib maintenance arm (hazard ratio, 0.57; P = .00001).
However, because a test for nonproportionality was positive (P = .024), a restricted means analysis was done, resulting in a 3.1 month difference favoring cediranib (9.4 months vs. 12.5 months), said Prof. Ledermann, with University College London (UCL) Cancer Institute, Cancer Research UK, and UCL Cancer Trials Centre, London.
As a secondary endpoint, an analysis was performed on the concurrent arm showing a trend in favor of cediranib, with a PFS of 10.1 months and 11.4 months using restricted means analysis.
"There is strong evidence that cediranib has an effect by itself on progression-free survival both during and after chemotherapy," Prof. Ledermann said.
Median overall survival reached 20.3 months in the chemotherapy arm and 26.3 months in the cediranib maintenance arm (HR, 0.70; P = .042). Overall survival fell to 17.6 months and 20.3 months, respectively, in a restricted means analysis, following a positive test for nonproportionality (P = .0042). No overall survival data were presented for the concurrent arm.
"These are important results for women with recurrence ovarian cancer," Prof. Cornelis van de Velde, European Cancer Organization president, commented in a statement. "Once the disease has recurred, there are few treatment options available that make a significant difference to its progression and to overall survival. The ICON6 trial shows that cediranib does make a difference and it is to be hoped that it can be made available to women as soon as is practicable."
Laura Woodin, U.S. science media director for AstraZeneca, said in an interview that the company welcomes the commitment of the ICON6 investigators and the study sponsor, Britain’s Medical Research Council, and that "We look forward to assessing the positive results from the ICON6 study in more detail, to determine the future potential for cediranib in ovarian cancer."
Invited discussant Prof. Ignace Vergote, head of gynecological oncology at University Hospitals Leuven, Belgium, questioned why overall survival was so low in ICON6, compared with a median of 35.5 months reported with the addition of the VEGF-inhibitor bevacizumab to platinum-based chemotherapy in recurrent ovarian cancer in the phase III OCEANS trial. The cediranib dose was reduced from 30 mg/day to 20 mg/day after part one of ICON6, but it is unclear whether a higher dose in the maintenance phase would be more effective because 30-45 mg are used in most trials of cediranib monotherapy. Also unknown is whether there was less treatment in ICON6 after progression than there was in OCEANS.
The 15-month difference in overall survival between the two trials, however, might explain why overall survival was significant in ICON6 and not in the OCEANS study, Prof. Vergote said.
Finally, cediranib was associated with more treatment discontinuation, diarrhea, and fatigue, but less hypertension than bevacizumab at the dose used in the study, he observed.
Prof. Ledermann said hypertension (P = .004), diarrhea (P less than .001), and nausea (P = .008) were all significantly worse when cediranib was given during chemotherapy, but when it came to the maintenance phase, "hypertension was really quite manageable by this stage and the only side effect that was significantly worse with cediranib was diarrhea [P less than .001]."
Prof. Ledermann and his coauthors reported no relevant disclosures. AstraZeneca provided the study drug. Britain’s Medical Research Council sponsored the trial.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: Median progression-free survival was 8.7 months platinum-based chemotherapy plus placebo maintenance and 11.1 months with cediranib during chemotherapy plus cediranib maintenance (hazard ratio 0.57; P = .00001).
Data source: A phase III, prospective study in 456 women with platinum-sensitive, relapsed ovarian, fallopian tube, or peritoneal cancer.
Disclosures: Prof. Ledermann, his coauthors, and Prof. Vergote reported no relevant disclosures. AstraZeneca provided the study drug. Britain’s Medical Research Council sponsored the trial.
TRINOVA-1 signals new direction in ovarian cancer
AMSTERDAM – Adding the investigational peptibody trebananib to weekly paclitaxel prolongs the time to disease progression or death in women with recurrent, advanced ovarian cancer, the phase III TRINOVA-1 trial has shown.
The primary endpoint of median progression-free survival was 7.2 months with paclitaxel plus trebananib and 5.4 months with paclitaxel (Abraxane) alone (hazard ratio, 0.66; P less than .001).
The beneficial effect of trebananib was seen across all prespecified subgroups including prior antiangiogenesis therapy, prior lines of therapy, platinum-free interval, bulky disease, ethnicity, and age, Dr. Bradley Monk said at the European Cancer Congress 2013.
Overall survival data are not expected to mature until 2014; however, an interim analysis with 50% of deaths indicates a nonsignificant trend in favor of the trebananib arm (19.0 months vs. 17.3 months; HR 0.86; P = .19), he said.
The results are intriguing because trebananib targets the angiopoietin axis, a new antiangiogenesis strategy in ovarian cancer that is not directed at the vascular endothelial growth factor (VEGF) receptor.
Instead, the recombinant peptide-Fc fusion protein, or peptibody, binds angiopoietin-1 and -2 with the Tie2 receptor, a signaling pathway that mediates vascular remodeling, explained Dr. Monk, a gynecologic oncologist at the University of Arizona Cancer Center, St. Joseph’s Hospital and Medical Center, Tucson, Ariz. Ang-1 and Ang-2 are associated with poor outcome in ovarian cancer.
Trebananib, formerly known as AMG 386, has shown single-agent activity in relapsed ovarian cancer in a phase I trial and prolonged progression-free survival in recurrent ovarian cancer in combination with paclitaxel in a randomized, phase II study.
The agent is also being studied in two ongoing phase III trials in combination with pegylated liposomal doxorubicin in recurrent ovarian cancer (TRINOVA-2) and in combination with first-line paclitaxel (Taxol) and carboplatin (Paraplatin) in newly diagnosed ovarian cancer (TRINOVA-3).
TRINOVA-1 enrolled 919 women with recurrent, partially platinum-sensitive or platinum-resistant epithelial ovarian cancer (91%), primary peritoneal cancer, or fallopian tube cancer. Patients were randomized 1:1 to weekly paclitaxel 80 mg/m2 plus placebo or weekly intravenous trebananib 15 mg/kg, which was 50% higher than the trebananib dose in the phase II study because of a signal that increased exposure increased efficacy, Dr. Monk said.
The women could have received up to three prior cytotoxic regimens; prior treatment with the VEGF-targeted monoclonal antibody bevacizumab (Avastin) was allowed. About half of the patients in each arm had a platinum-free interval of less than 6 months.
Adding trebananib to paclitaxel significantly improved the objective response rate from 29.8% with paclitaxel alone to 38.4% (P = .007), Dr. Monk said. Of the 435 trebananib patients, 17 (4%) had complete responses, 150 had partial responses (35%), and 159 had stable disease (37%), he reported at the multidisciplinary European cancer congresses.
Adverse event–related treatment discontinuations were higher with trebananib than with paclitaxel alone (17% vs. 6%).
The major toxicity seen with trebananib was edema, experienced at any grade by 57% of patients versus 26% of controls, with grade 3 or higher edema seen in only 5% vs. 1%, he said. There was no significant increase in the other adverse events generally seen with paclitaxel, such as grade 3 nausea (2% vs. 1%), alopecia (0% vs. less than 1%), and diarrhea (2% vs. 3%).
Further, trebananib did not increase the constellation of adverse events typically seen with anti-VEGF inhibition. Though there were some numeric differences between the control and trebananib arms in hypertension (4% vs. 6%) and GI perforation (less than 1% vs. 1%), "I think you get the sense that there really is not the signal of anti-VEGF–associated adverse events with trebananib that you’re accustomed to," Dr. Monk said.
There was no difference in patient-reported quality of life, "neither a detriment nor an improvement," on three different instruments, he said.
Invited discussant Dr. Antonio Casado, with San Carlos University Hospital, Madrid, said patients with prior bevacizumab appear to derive a similar benefit from trebananib, but the numbers were too small, at just 72 patients, to draw conclusions.
He went on to say that patients who relapse on bevacizumab will be increasingly seen in everyday clinical practice, making the identification of mechanisms to overcome resistance essential. Preclinical observations raise the possibility that Ang-1/Tie-2 activation may function to support tumor vasculature in the specific context of VEGF blockade, suggesting that sequential use of bevacizumab and trebananib could be a potential strategy to overcome resistance.
Dr. Monk reported that his institution has received research funding from Amgen, which sponsored the trial.
AMSTERDAM – Adding the investigational peptibody trebananib to weekly paclitaxel prolongs the time to disease progression or death in women with recurrent, advanced ovarian cancer, the phase III TRINOVA-1 trial has shown.
The primary endpoint of median progression-free survival was 7.2 months with paclitaxel plus trebananib and 5.4 months with paclitaxel (Abraxane) alone (hazard ratio, 0.66; P less than .001).
The beneficial effect of trebananib was seen across all prespecified subgroups including prior antiangiogenesis therapy, prior lines of therapy, platinum-free interval, bulky disease, ethnicity, and age, Dr. Bradley Monk said at the European Cancer Congress 2013.
Overall survival data are not expected to mature until 2014; however, an interim analysis with 50% of deaths indicates a nonsignificant trend in favor of the trebananib arm (19.0 months vs. 17.3 months; HR 0.86; P = .19), he said.
The results are intriguing because trebananib targets the angiopoietin axis, a new antiangiogenesis strategy in ovarian cancer that is not directed at the vascular endothelial growth factor (VEGF) receptor.
Instead, the recombinant peptide-Fc fusion protein, or peptibody, binds angiopoietin-1 and -2 with the Tie2 receptor, a signaling pathway that mediates vascular remodeling, explained Dr. Monk, a gynecologic oncologist at the University of Arizona Cancer Center, St. Joseph’s Hospital and Medical Center, Tucson, Ariz. Ang-1 and Ang-2 are associated with poor outcome in ovarian cancer.
Trebananib, formerly known as AMG 386, has shown single-agent activity in relapsed ovarian cancer in a phase I trial and prolonged progression-free survival in recurrent ovarian cancer in combination with paclitaxel in a randomized, phase II study.
The agent is also being studied in two ongoing phase III trials in combination with pegylated liposomal doxorubicin in recurrent ovarian cancer (TRINOVA-2) and in combination with first-line paclitaxel (Taxol) and carboplatin (Paraplatin) in newly diagnosed ovarian cancer (TRINOVA-3).
TRINOVA-1 enrolled 919 women with recurrent, partially platinum-sensitive or platinum-resistant epithelial ovarian cancer (91%), primary peritoneal cancer, or fallopian tube cancer. Patients were randomized 1:1 to weekly paclitaxel 80 mg/m2 plus placebo or weekly intravenous trebananib 15 mg/kg, which was 50% higher than the trebananib dose in the phase II study because of a signal that increased exposure increased efficacy, Dr. Monk said.
The women could have received up to three prior cytotoxic regimens; prior treatment with the VEGF-targeted monoclonal antibody bevacizumab (Avastin) was allowed. About half of the patients in each arm had a platinum-free interval of less than 6 months.
Adding trebananib to paclitaxel significantly improved the objective response rate from 29.8% with paclitaxel alone to 38.4% (P = .007), Dr. Monk said. Of the 435 trebananib patients, 17 (4%) had complete responses, 150 had partial responses (35%), and 159 had stable disease (37%), he reported at the multidisciplinary European cancer congresses.
Adverse event–related treatment discontinuations were higher with trebananib than with paclitaxel alone (17% vs. 6%).
The major toxicity seen with trebananib was edema, experienced at any grade by 57% of patients versus 26% of controls, with grade 3 or higher edema seen in only 5% vs. 1%, he said. There was no significant increase in the other adverse events generally seen with paclitaxel, such as grade 3 nausea (2% vs. 1%), alopecia (0% vs. less than 1%), and diarrhea (2% vs. 3%).
Further, trebananib did not increase the constellation of adverse events typically seen with anti-VEGF inhibition. Though there were some numeric differences between the control and trebananib arms in hypertension (4% vs. 6%) and GI perforation (less than 1% vs. 1%), "I think you get the sense that there really is not the signal of anti-VEGF–associated adverse events with trebananib that you’re accustomed to," Dr. Monk said.
There was no difference in patient-reported quality of life, "neither a detriment nor an improvement," on three different instruments, he said.
Invited discussant Dr. Antonio Casado, with San Carlos University Hospital, Madrid, said patients with prior bevacizumab appear to derive a similar benefit from trebananib, but the numbers were too small, at just 72 patients, to draw conclusions.
He went on to say that patients who relapse on bevacizumab will be increasingly seen in everyday clinical practice, making the identification of mechanisms to overcome resistance essential. Preclinical observations raise the possibility that Ang-1/Tie-2 activation may function to support tumor vasculature in the specific context of VEGF blockade, suggesting that sequential use of bevacizumab and trebananib could be a potential strategy to overcome resistance.
Dr. Monk reported that his institution has received research funding from Amgen, which sponsored the trial.
AMSTERDAM – Adding the investigational peptibody trebananib to weekly paclitaxel prolongs the time to disease progression or death in women with recurrent, advanced ovarian cancer, the phase III TRINOVA-1 trial has shown.
The primary endpoint of median progression-free survival was 7.2 months with paclitaxel plus trebananib and 5.4 months with paclitaxel (Abraxane) alone (hazard ratio, 0.66; P less than .001).
The beneficial effect of trebananib was seen across all prespecified subgroups including prior antiangiogenesis therapy, prior lines of therapy, platinum-free interval, bulky disease, ethnicity, and age, Dr. Bradley Monk said at the European Cancer Congress 2013.
Overall survival data are not expected to mature until 2014; however, an interim analysis with 50% of deaths indicates a nonsignificant trend in favor of the trebananib arm (19.0 months vs. 17.3 months; HR 0.86; P = .19), he said.
The results are intriguing because trebananib targets the angiopoietin axis, a new antiangiogenesis strategy in ovarian cancer that is not directed at the vascular endothelial growth factor (VEGF) receptor.
Instead, the recombinant peptide-Fc fusion protein, or peptibody, binds angiopoietin-1 and -2 with the Tie2 receptor, a signaling pathway that mediates vascular remodeling, explained Dr. Monk, a gynecologic oncologist at the University of Arizona Cancer Center, St. Joseph’s Hospital and Medical Center, Tucson, Ariz. Ang-1 and Ang-2 are associated with poor outcome in ovarian cancer.
Trebananib, formerly known as AMG 386, has shown single-agent activity in relapsed ovarian cancer in a phase I trial and prolonged progression-free survival in recurrent ovarian cancer in combination with paclitaxel in a randomized, phase II study.
The agent is also being studied in two ongoing phase III trials in combination with pegylated liposomal doxorubicin in recurrent ovarian cancer (TRINOVA-2) and in combination with first-line paclitaxel (Taxol) and carboplatin (Paraplatin) in newly diagnosed ovarian cancer (TRINOVA-3).
TRINOVA-1 enrolled 919 women with recurrent, partially platinum-sensitive or platinum-resistant epithelial ovarian cancer (91%), primary peritoneal cancer, or fallopian tube cancer. Patients were randomized 1:1 to weekly paclitaxel 80 mg/m2 plus placebo or weekly intravenous trebananib 15 mg/kg, which was 50% higher than the trebananib dose in the phase II study because of a signal that increased exposure increased efficacy, Dr. Monk said.
The women could have received up to three prior cytotoxic regimens; prior treatment with the VEGF-targeted monoclonal antibody bevacizumab (Avastin) was allowed. About half of the patients in each arm had a platinum-free interval of less than 6 months.
Adding trebananib to paclitaxel significantly improved the objective response rate from 29.8% with paclitaxel alone to 38.4% (P = .007), Dr. Monk said. Of the 435 trebananib patients, 17 (4%) had complete responses, 150 had partial responses (35%), and 159 had stable disease (37%), he reported at the multidisciplinary European cancer congresses.
Adverse event–related treatment discontinuations were higher with trebananib than with paclitaxel alone (17% vs. 6%).
The major toxicity seen with trebananib was edema, experienced at any grade by 57% of patients versus 26% of controls, with grade 3 or higher edema seen in only 5% vs. 1%, he said. There was no significant increase in the other adverse events generally seen with paclitaxel, such as grade 3 nausea (2% vs. 1%), alopecia (0% vs. less than 1%), and diarrhea (2% vs. 3%).
Further, trebananib did not increase the constellation of adverse events typically seen with anti-VEGF inhibition. Though there were some numeric differences between the control and trebananib arms in hypertension (4% vs. 6%) and GI perforation (less than 1% vs. 1%), "I think you get the sense that there really is not the signal of anti-VEGF–associated adverse events with trebananib that you’re accustomed to," Dr. Monk said.
There was no difference in patient-reported quality of life, "neither a detriment nor an improvement," on three different instruments, he said.
Invited discussant Dr. Antonio Casado, with San Carlos University Hospital, Madrid, said patients with prior bevacizumab appear to derive a similar benefit from trebananib, but the numbers were too small, at just 72 patients, to draw conclusions.
He went on to say that patients who relapse on bevacizumab will be increasingly seen in everyday clinical practice, making the identification of mechanisms to overcome resistance essential. Preclinical observations raise the possibility that Ang-1/Tie-2 activation may function to support tumor vasculature in the specific context of VEGF blockade, suggesting that sequential use of bevacizumab and trebananib could be a potential strategy to overcome resistance.
Dr. Monk reported that his institution has received research funding from Amgen, which sponsored the trial.
AT THE EUROPEAN CANCER CONGRESS 2013
Major finding: Progression-free survival was 7.2 months with paclitaxel plus trebananib vs. 5.4 months with paclitaxel alone (HR, 0.66; P less than .001).
Data source: A double-blind, prospective phase III study in 919 women with recurrent, advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer.
Disclosures: Dr. Monk reported that his institution has received research funding from Amgen, which sponsored the trial.
Safely doing less can be the best patient-safety move
NEW ORLEANS – How did dehydration, an order for a peripherally inserted central catheter line, and the bright lights of the ward add up to a full-thickness burn on an infant?
The simple answer is a flashlight.
The more telling response is that the PICC line wasn’t needed in the first place – much less the 20 minutes spent trying to isolate a vein with a flashlight. The infant rebounded with intravenous fluids and by simply advancing feeding volumes, Dr. Alan R. Schroeder said at the Pediatric Hospital Medicine 2013 meeting.
"When we think about patient safety and errors, we spend an awful lot of time talking about how could we better optimize the PICC line process, but we don’t spend as much time on whether this PICC line was even necessary," he said at the meeting, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Indeed, physicians are quite good at responding when asked to do more. A recent study of ambulatory health care utilization shows that six of nine quality indicators of underuse improved between 1999 and 2009, whereas only two of eleven overuse indicators got better (JAMA Intern. Med. 2013;173:142-8).
Still, the unnecessary care movement is picking up steam in recent years, insists Dr. Schroeder of the department of pediatrics, Santa Clara Valley Medical Center, San Jose, Calif.
Three medical meetings, including the Preventing Overdiagnosis Conference, were organized this year specifically on medical overutilization, with at least one article devoted each month to the topic in JAMA Internal Medicine.
The Image Wisely initiative has garnered 18,621 pledges to lower the amount of radiation used, while the Choosing Wisely campaign, challenging medical societies to identify five things physicians and patients should question, is bearing fruit.
The pediatric committee of the Society of Hospital Medicine was the first pediatric subspecialty group to respond to the challenge, with a panel of experts, including Schroeder, recently publishing the top five recommendations for pediatric hospital medicine (J. Hosp. Med. 2013 [doi:10.1002/jhm.2064]).
" ‘Less is more’ is almost becoming a trend," Dr. Schroeder said.
Widely publicized public health mistakes in adult medicine, like near-universal prostate-specific antigen testing in men and hormone therapy for menopausal women, coupled with a financially stressed health care system, have helped move the needle. But several barriers to safely doing less still remain, he observed.
Time pressures, malpractice concerns, and pressure from families and colleagues all push physicians to increase healthcare utilization. The case of 12-year-old Rory Staunton, who died last year from potentially preventable septic shock after being released from the emergency department, has prompted new measures nationwide to spot sepsis earlier and a slew of stories in the New York Times and other publications.
The response was quite different, however, when two other adolescents, Jenny Olenick and Ben Ellis, died during or within hours of routine wisdom teeth extraction, a procedure that has been suggested as unnecessary 60% of the time, Dr. Schroeder said.
"They were killed by health care," he said. "This is a commission error, yet this has had scant media coverage. This is the type of case that should really, really upset you."
He went on to say that the omission/commission philosophy has its roots in medical education school.
"A lot of you are doing noble jobs trying to change that, but traditionally we are taught from day one not to miss a diagnosis," he said. "You have to generate these very, very broad differential diagnoses. We don’t want to be the guy that misses a diagnosis on day one and someone else comes in and makes a diagnosis on day two."
Money as motive
Another powerful barrier to safely doing less is the financial motive. Some of the best work in this area was the 2009 watershed essay by surgeon Atul Gawande showing that the strong entrepreneurial spirit in McAllen, Texas, doubled Medicare spending, compared with nearby El Paso, without improving outcomes, Dr. Schroeder observed. Recent research also refuted the widely endorsed belief that PSA screening improves outcomes by picking up more cancers than diagnosing based on symptoms. It was a hard-fought battle with high financial stakes, with some 30 million men undergoing PSA testing each year at a cost of $3 billion.
"There’s not a billboard outside my hospital saying ‘Come see Dr. Schroeder because today he will do less for you,’ " he said. "I wish there were one, but it’s not going to bring patients in or help the hospital’s bottom line."
Dr. Schroeder called for financing reform to disconnect reimbursement from utilization by compensating physicians for how they do their job, not what they do. There was also a pitch for comparative-effectiveness research to confirm that existing therapies are of benefit and if not, should not be reimbursed. As role models, he cited an unfunded, randomized controlled study presented at the meeting on nebulized hypertonic saline, and a voluntary quality improvement collaborative of pediatric hospitalists that cut bronchodilator use by 46% among inpatients with bronchiolitis (J. Hosp. Med. 2013;8:25-30). Not surprising, one of the top five new recommendations for pediatric hospital medicine is: "Do not use bronchodilators in children with bronchiolitis."
Talk about ‘less’
Dr. Schroeder urged the audience of some 1,000 pediatric hospitalists to introduce "safely doing less" into the patient-safety dialogue. Clinicians should always remind their patients and trainees of unanticipated harms. Instead of saying, "It’s a straightforward procedure," try saying, "There isn’t a procedure out there that can’t make someone worse or cause harm."
When there’s an adverse event at your institution, he advised clinicians not to just focus on the details of the incident, but also on the necessity of the interventions that led up to the incident. This strategy was conspicuous in its absence during the recent meningitis outbreak from contaminated steroid injections for back and neuropathic pain, that prompted 749 cases of fungal infection, 63 deaths, and a massive, multistate investigation.
"Everyone wanted to know how this could have happened; where was the regulation behind the compounding pharmacy, which is a worthy question," he said. "But it took weeks before it came out that these epidural steroid injections aren’t evidence based, although they sure make a lot of money."
Finally, he suggested the audience redefine the term "conservative" care from its current definition of test and treat to watch and wait.
During a discussion immediately following the lecture, however, attendee and pediatric hospitalist Lynn Campbell, who is with Dell Children’s Medical Center of Central Texas, in Austin, pointed out that, unlike primary care providers or ED physicians, hospitalists come into the game midstream and thus don’t have the same trust level established with families when trying to take away unnecessary tests or therapies.
Dr. Schroeder said many families don’t want more therapies, like antibiotics, and just want to take their child home, but added, "There are no easy answers."
Dr. Schroeder reported having no financial disclosures.
NEW ORLEANS – How did dehydration, an order for a peripherally inserted central catheter line, and the bright lights of the ward add up to a full-thickness burn on an infant?
The simple answer is a flashlight.
The more telling response is that the PICC line wasn’t needed in the first place – much less the 20 minutes spent trying to isolate a vein with a flashlight. The infant rebounded with intravenous fluids and by simply advancing feeding volumes, Dr. Alan R. Schroeder said at the Pediatric Hospital Medicine 2013 meeting.
"When we think about patient safety and errors, we spend an awful lot of time talking about how could we better optimize the PICC line process, but we don’t spend as much time on whether this PICC line was even necessary," he said at the meeting, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Indeed, physicians are quite good at responding when asked to do more. A recent study of ambulatory health care utilization shows that six of nine quality indicators of underuse improved between 1999 and 2009, whereas only two of eleven overuse indicators got better (JAMA Intern. Med. 2013;173:142-8).
Still, the unnecessary care movement is picking up steam in recent years, insists Dr. Schroeder of the department of pediatrics, Santa Clara Valley Medical Center, San Jose, Calif.
Three medical meetings, including the Preventing Overdiagnosis Conference, were organized this year specifically on medical overutilization, with at least one article devoted each month to the topic in JAMA Internal Medicine.
The Image Wisely initiative has garnered 18,621 pledges to lower the amount of radiation used, while the Choosing Wisely campaign, challenging medical societies to identify five things physicians and patients should question, is bearing fruit.
The pediatric committee of the Society of Hospital Medicine was the first pediatric subspecialty group to respond to the challenge, with a panel of experts, including Schroeder, recently publishing the top five recommendations for pediatric hospital medicine (J. Hosp. Med. 2013 [doi:10.1002/jhm.2064]).
" ‘Less is more’ is almost becoming a trend," Dr. Schroeder said.
Widely publicized public health mistakes in adult medicine, like near-universal prostate-specific antigen testing in men and hormone therapy for menopausal women, coupled with a financially stressed health care system, have helped move the needle. But several barriers to safely doing less still remain, he observed.
Time pressures, malpractice concerns, and pressure from families and colleagues all push physicians to increase healthcare utilization. The case of 12-year-old Rory Staunton, who died last year from potentially preventable septic shock after being released from the emergency department, has prompted new measures nationwide to spot sepsis earlier and a slew of stories in the New York Times and other publications.
The response was quite different, however, when two other adolescents, Jenny Olenick and Ben Ellis, died during or within hours of routine wisdom teeth extraction, a procedure that has been suggested as unnecessary 60% of the time, Dr. Schroeder said.
"They were killed by health care," he said. "This is a commission error, yet this has had scant media coverage. This is the type of case that should really, really upset you."
He went on to say that the omission/commission philosophy has its roots in medical education school.
"A lot of you are doing noble jobs trying to change that, but traditionally we are taught from day one not to miss a diagnosis," he said. "You have to generate these very, very broad differential diagnoses. We don’t want to be the guy that misses a diagnosis on day one and someone else comes in and makes a diagnosis on day two."
Money as motive
Another powerful barrier to safely doing less is the financial motive. Some of the best work in this area was the 2009 watershed essay by surgeon Atul Gawande showing that the strong entrepreneurial spirit in McAllen, Texas, doubled Medicare spending, compared with nearby El Paso, without improving outcomes, Dr. Schroeder observed. Recent research also refuted the widely endorsed belief that PSA screening improves outcomes by picking up more cancers than diagnosing based on symptoms. It was a hard-fought battle with high financial stakes, with some 30 million men undergoing PSA testing each year at a cost of $3 billion.
"There’s not a billboard outside my hospital saying ‘Come see Dr. Schroeder because today he will do less for you,’ " he said. "I wish there were one, but it’s not going to bring patients in or help the hospital’s bottom line."
Dr. Schroeder called for financing reform to disconnect reimbursement from utilization by compensating physicians for how they do their job, not what they do. There was also a pitch for comparative-effectiveness research to confirm that existing therapies are of benefit and if not, should not be reimbursed. As role models, he cited an unfunded, randomized controlled study presented at the meeting on nebulized hypertonic saline, and a voluntary quality improvement collaborative of pediatric hospitalists that cut bronchodilator use by 46% among inpatients with bronchiolitis (J. Hosp. Med. 2013;8:25-30). Not surprising, one of the top five new recommendations for pediatric hospital medicine is: "Do not use bronchodilators in children with bronchiolitis."
Talk about ‘less’
Dr. Schroeder urged the audience of some 1,000 pediatric hospitalists to introduce "safely doing less" into the patient-safety dialogue. Clinicians should always remind their patients and trainees of unanticipated harms. Instead of saying, "It’s a straightforward procedure," try saying, "There isn’t a procedure out there that can’t make someone worse or cause harm."
When there’s an adverse event at your institution, he advised clinicians not to just focus on the details of the incident, but also on the necessity of the interventions that led up to the incident. This strategy was conspicuous in its absence during the recent meningitis outbreak from contaminated steroid injections for back and neuropathic pain, that prompted 749 cases of fungal infection, 63 deaths, and a massive, multistate investigation.
"Everyone wanted to know how this could have happened; where was the regulation behind the compounding pharmacy, which is a worthy question," he said. "But it took weeks before it came out that these epidural steroid injections aren’t evidence based, although they sure make a lot of money."
Finally, he suggested the audience redefine the term "conservative" care from its current definition of test and treat to watch and wait.
During a discussion immediately following the lecture, however, attendee and pediatric hospitalist Lynn Campbell, who is with Dell Children’s Medical Center of Central Texas, in Austin, pointed out that, unlike primary care providers or ED physicians, hospitalists come into the game midstream and thus don’t have the same trust level established with families when trying to take away unnecessary tests or therapies.
Dr. Schroeder said many families don’t want more therapies, like antibiotics, and just want to take their child home, but added, "There are no easy answers."
Dr. Schroeder reported having no financial disclosures.
NEW ORLEANS – How did dehydration, an order for a peripherally inserted central catheter line, and the bright lights of the ward add up to a full-thickness burn on an infant?
The simple answer is a flashlight.
The more telling response is that the PICC line wasn’t needed in the first place – much less the 20 minutes spent trying to isolate a vein with a flashlight. The infant rebounded with intravenous fluids and by simply advancing feeding volumes, Dr. Alan R. Schroeder said at the Pediatric Hospital Medicine 2013 meeting.
"When we think about patient safety and errors, we spend an awful lot of time talking about how could we better optimize the PICC line process, but we don’t spend as much time on whether this PICC line was even necessary," he said at the meeting, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Indeed, physicians are quite good at responding when asked to do more. A recent study of ambulatory health care utilization shows that six of nine quality indicators of underuse improved between 1999 and 2009, whereas only two of eleven overuse indicators got better (JAMA Intern. Med. 2013;173:142-8).
Still, the unnecessary care movement is picking up steam in recent years, insists Dr. Schroeder of the department of pediatrics, Santa Clara Valley Medical Center, San Jose, Calif.
Three medical meetings, including the Preventing Overdiagnosis Conference, were organized this year specifically on medical overutilization, with at least one article devoted each month to the topic in JAMA Internal Medicine.
The Image Wisely initiative has garnered 18,621 pledges to lower the amount of radiation used, while the Choosing Wisely campaign, challenging medical societies to identify five things physicians and patients should question, is bearing fruit.
The pediatric committee of the Society of Hospital Medicine was the first pediatric subspecialty group to respond to the challenge, with a panel of experts, including Schroeder, recently publishing the top five recommendations for pediatric hospital medicine (J. Hosp. Med. 2013 [doi:10.1002/jhm.2064]).
" ‘Less is more’ is almost becoming a trend," Dr. Schroeder said.
Widely publicized public health mistakes in adult medicine, like near-universal prostate-specific antigen testing in men and hormone therapy for menopausal women, coupled with a financially stressed health care system, have helped move the needle. But several barriers to safely doing less still remain, he observed.
Time pressures, malpractice concerns, and pressure from families and colleagues all push physicians to increase healthcare utilization. The case of 12-year-old Rory Staunton, who died last year from potentially preventable septic shock after being released from the emergency department, has prompted new measures nationwide to spot sepsis earlier and a slew of stories in the New York Times and other publications.
The response was quite different, however, when two other adolescents, Jenny Olenick and Ben Ellis, died during or within hours of routine wisdom teeth extraction, a procedure that has been suggested as unnecessary 60% of the time, Dr. Schroeder said.
"They were killed by health care," he said. "This is a commission error, yet this has had scant media coverage. This is the type of case that should really, really upset you."
He went on to say that the omission/commission philosophy has its roots in medical education school.
"A lot of you are doing noble jobs trying to change that, but traditionally we are taught from day one not to miss a diagnosis," he said. "You have to generate these very, very broad differential diagnoses. We don’t want to be the guy that misses a diagnosis on day one and someone else comes in and makes a diagnosis on day two."
Money as motive
Another powerful barrier to safely doing less is the financial motive. Some of the best work in this area was the 2009 watershed essay by surgeon Atul Gawande showing that the strong entrepreneurial spirit in McAllen, Texas, doubled Medicare spending, compared with nearby El Paso, without improving outcomes, Dr. Schroeder observed. Recent research also refuted the widely endorsed belief that PSA screening improves outcomes by picking up more cancers than diagnosing based on symptoms. It was a hard-fought battle with high financial stakes, with some 30 million men undergoing PSA testing each year at a cost of $3 billion.
"There’s not a billboard outside my hospital saying ‘Come see Dr. Schroeder because today he will do less for you,’ " he said. "I wish there were one, but it’s not going to bring patients in or help the hospital’s bottom line."
Dr. Schroeder called for financing reform to disconnect reimbursement from utilization by compensating physicians for how they do their job, not what they do. There was also a pitch for comparative-effectiveness research to confirm that existing therapies are of benefit and if not, should not be reimbursed. As role models, he cited an unfunded, randomized controlled study presented at the meeting on nebulized hypertonic saline, and a voluntary quality improvement collaborative of pediatric hospitalists that cut bronchodilator use by 46% among inpatients with bronchiolitis (J. Hosp. Med. 2013;8:25-30). Not surprising, one of the top five new recommendations for pediatric hospital medicine is: "Do not use bronchodilators in children with bronchiolitis."
Talk about ‘less’
Dr. Schroeder urged the audience of some 1,000 pediatric hospitalists to introduce "safely doing less" into the patient-safety dialogue. Clinicians should always remind their patients and trainees of unanticipated harms. Instead of saying, "It’s a straightforward procedure," try saying, "There isn’t a procedure out there that can’t make someone worse or cause harm."
When there’s an adverse event at your institution, he advised clinicians not to just focus on the details of the incident, but also on the necessity of the interventions that led up to the incident. This strategy was conspicuous in its absence during the recent meningitis outbreak from contaminated steroid injections for back and neuropathic pain, that prompted 749 cases of fungal infection, 63 deaths, and a massive, multistate investigation.
"Everyone wanted to know how this could have happened; where was the regulation behind the compounding pharmacy, which is a worthy question," he said. "But it took weeks before it came out that these epidural steroid injections aren’t evidence based, although they sure make a lot of money."
Finally, he suggested the audience redefine the term "conservative" care from its current definition of test and treat to watch and wait.
During a discussion immediately following the lecture, however, attendee and pediatric hospitalist Lynn Campbell, who is with Dell Children’s Medical Center of Central Texas, in Austin, pointed out that, unlike primary care providers or ED physicians, hospitalists come into the game midstream and thus don’t have the same trust level established with families when trying to take away unnecessary tests or therapies.
Dr. Schroeder said many families don’t want more therapies, like antibiotics, and just want to take their child home, but added, "There are no easy answers."
Dr. Schroeder reported having no financial disclosures.
EXPERT ANALYSIS FROM PEDIATRIC HOSPITAL MEDICINE 2013
