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Axial radiotherapy noninferior to cALND in early invasive breast cancer
AMSTERDAM – Axillary radiotherapy appears to be a safe and effective alternative to completion axillary lymph node dissection (cALND) for selected patients who have early invasive breast cancer with sentinel lymph node metastasis, a randomized phase III trial showed.
After a mean of just over 8 years of follow-up, there were no significant differences in breast cancer recurrence, overall survival (OS), disease-free survival (DFS), or breast cancer deaths between patients treated with cALND or axillary radiotherapy, reported Akos Savolt, MD, PhD, of the National Institute of Oncology in Budapest.
“This trial has changed our everyday practice about the optimal care of the axilla,” he said at an annual congress sponsored by the European Cancer Organisation.
An estimated 25%-50% of patients with positive sentinel lymph nodes will have disease that extends to other lymph nodes, and for these patients, cALND is the standard of care.
But patients for whom metastasis is limited to the sentinel lymph node are unlikely to benefit from more extensive dissections, and for these patients, the proven benefits of cALND must be weighed against the significant complications associated with the procedure, including lymphedema, arm pain, nerve injury, shoulder dysfunction, and paresthesias, Dr. Savolt noted.
The OTOASOR (Optimal Treatment of the Axilla – Surgery or Radiotherapy) trial was a single-center study designed to see whether axillary radiotherapy could be noninferior to cALND for preventing recurrence and breast cancer deaths.
From mid-2002 through mid-2009,the investigators enrolled women with primary invasive breast cancer (tumors 3 cm or smaller and no clinically detected lymph node metastases), and randomized them prior to surgery to receive either cALND or axillary radiotherapy at a dose of 50 Gy. Patients also received adjuvant therapy as per institutional guidelines.
A total of 474 patients were evaluable for follow-up: 244 assigned to cALND and 230 assigned to radiotherapy. In all, 94 patients assigned to cALND (38.5%) were found to have additional lymph node metastases.
At a mean follow-up of 97 months, 2% of women in the cALND group had experienced an axillary recurrence (the primary endpoint), compared with 1.7% in the axillary radiation arm.
Overall survival was also similar between the groups, at 77.9% vs. 84.8%, respectively, as was disease-free survival, at 72.1% and 77.4%; neither comparison yielded statistically significant results.
There were also no between-group differences in the percentage of patients alive with recurrence, breast cancer deaths (13.9% of patients in the cALND arm vs. 8.7 in the radiation arm), or deaths from other causes (8.2% vs. 6.5%, respectively).
In contrast, however, 15.3% of patients assigned to cALND reported lymphedema, paresthesia, swelling, arm pain, or shoulder mobility problems, compared with 4.7% treated with radiotherapy. There were no significant differences in quality of life as assessed by standard instruments, however.
The study was supported by the Hungarian National Institute of Oncology. Dr. Savolt and colleagues reported no competing interests.
AMSTERDAM – Axillary radiotherapy appears to be a safe and effective alternative to completion axillary lymph node dissection (cALND) for selected patients who have early invasive breast cancer with sentinel lymph node metastasis, a randomized phase III trial showed.
After a mean of just over 8 years of follow-up, there were no significant differences in breast cancer recurrence, overall survival (OS), disease-free survival (DFS), or breast cancer deaths between patients treated with cALND or axillary radiotherapy, reported Akos Savolt, MD, PhD, of the National Institute of Oncology in Budapest.
“This trial has changed our everyday practice about the optimal care of the axilla,” he said at an annual congress sponsored by the European Cancer Organisation.
An estimated 25%-50% of patients with positive sentinel lymph nodes will have disease that extends to other lymph nodes, and for these patients, cALND is the standard of care.
But patients for whom metastasis is limited to the sentinel lymph node are unlikely to benefit from more extensive dissections, and for these patients, the proven benefits of cALND must be weighed against the significant complications associated with the procedure, including lymphedema, arm pain, nerve injury, shoulder dysfunction, and paresthesias, Dr. Savolt noted.
The OTOASOR (Optimal Treatment of the Axilla – Surgery or Radiotherapy) trial was a single-center study designed to see whether axillary radiotherapy could be noninferior to cALND for preventing recurrence and breast cancer deaths.
From mid-2002 through mid-2009,the investigators enrolled women with primary invasive breast cancer (tumors 3 cm or smaller and no clinically detected lymph node metastases), and randomized them prior to surgery to receive either cALND or axillary radiotherapy at a dose of 50 Gy. Patients also received adjuvant therapy as per institutional guidelines.
A total of 474 patients were evaluable for follow-up: 244 assigned to cALND and 230 assigned to radiotherapy. In all, 94 patients assigned to cALND (38.5%) were found to have additional lymph node metastases.
At a mean follow-up of 97 months, 2% of women in the cALND group had experienced an axillary recurrence (the primary endpoint), compared with 1.7% in the axillary radiation arm.
Overall survival was also similar between the groups, at 77.9% vs. 84.8%, respectively, as was disease-free survival, at 72.1% and 77.4%; neither comparison yielded statistically significant results.
There were also no between-group differences in the percentage of patients alive with recurrence, breast cancer deaths (13.9% of patients in the cALND arm vs. 8.7 in the radiation arm), or deaths from other causes (8.2% vs. 6.5%, respectively).
In contrast, however, 15.3% of patients assigned to cALND reported lymphedema, paresthesia, swelling, arm pain, or shoulder mobility problems, compared with 4.7% treated with radiotherapy. There were no significant differences in quality of life as assessed by standard instruments, however.
The study was supported by the Hungarian National Institute of Oncology. Dr. Savolt and colleagues reported no competing interests.
AMSTERDAM – Axillary radiotherapy appears to be a safe and effective alternative to completion axillary lymph node dissection (cALND) for selected patients who have early invasive breast cancer with sentinel lymph node metastasis, a randomized phase III trial showed.
After a mean of just over 8 years of follow-up, there were no significant differences in breast cancer recurrence, overall survival (OS), disease-free survival (DFS), or breast cancer deaths between patients treated with cALND or axillary radiotherapy, reported Akos Savolt, MD, PhD, of the National Institute of Oncology in Budapest.
“This trial has changed our everyday practice about the optimal care of the axilla,” he said at an annual congress sponsored by the European Cancer Organisation.
An estimated 25%-50% of patients with positive sentinel lymph nodes will have disease that extends to other lymph nodes, and for these patients, cALND is the standard of care.
But patients for whom metastasis is limited to the sentinel lymph node are unlikely to benefit from more extensive dissections, and for these patients, the proven benefits of cALND must be weighed against the significant complications associated with the procedure, including lymphedema, arm pain, nerve injury, shoulder dysfunction, and paresthesias, Dr. Savolt noted.
The OTOASOR (Optimal Treatment of the Axilla – Surgery or Radiotherapy) trial was a single-center study designed to see whether axillary radiotherapy could be noninferior to cALND for preventing recurrence and breast cancer deaths.
From mid-2002 through mid-2009,the investigators enrolled women with primary invasive breast cancer (tumors 3 cm or smaller and no clinically detected lymph node metastases), and randomized them prior to surgery to receive either cALND or axillary radiotherapy at a dose of 50 Gy. Patients also received adjuvant therapy as per institutional guidelines.
A total of 474 patients were evaluable for follow-up: 244 assigned to cALND and 230 assigned to radiotherapy. In all, 94 patients assigned to cALND (38.5%) were found to have additional lymph node metastases.
At a mean follow-up of 97 months, 2% of women in the cALND group had experienced an axillary recurrence (the primary endpoint), compared with 1.7% in the axillary radiation arm.
Overall survival was also similar between the groups, at 77.9% vs. 84.8%, respectively, as was disease-free survival, at 72.1% and 77.4%; neither comparison yielded statistically significant results.
There were also no between-group differences in the percentage of patients alive with recurrence, breast cancer deaths (13.9% of patients in the cALND arm vs. 8.7 in the radiation arm), or deaths from other causes (8.2% vs. 6.5%, respectively).
In contrast, however, 15.3% of patients assigned to cALND reported lymphedema, paresthesia, swelling, arm pain, or shoulder mobility problems, compared with 4.7% treated with radiotherapy. There were no significant differences in quality of life as assessed by standard instruments, however.
The study was supported by the Hungarian National Institute of Oncology. Dr. Savolt and colleagues reported no competing interests.
Key clinical point: Women with early breast cancer with only sentinel lymph node involvement may be able to be spared morbidity from axillary dissection.
Major finding: Axillary radiotherapy was noninferior to completion axillary node dissection for recurrence, overall survival, and disease-free survival.
Data source: A randomized, single-center phase III trial in 474 women with early invasive breast cancer.
Disclosures: The study was supported by the Hungarian National Institute of Oncology. Dr. Savolt and colleagues reported no competing interests.
Breath test aims to sniff out GEJ cancers
AMSTERDAM – A test that samples exhaled breath and looks for the presence of just five volatile organic compounds shows promise as an inexpensive method for screening patients with suspected cancers of the gastroesophageal junction (GEJ), investigators from the United Kingdom reported.
In a multicenter clinical trial testing breath samples from patients with adenocarcinoma of the GEJ and matched controls, the test had an overall sensitivity of 80% and specificity of 81% for adenocarcinoma of the GEJ, said Sheraz R. Markar, MD, PhD, from Imperial College London.
If the test can be validated in larger studies, it could increase the number of patients screened and has the potential to save medical costs by reducing the number of unnecessary endoscopies and by catching GEJ cancers at earlier, potentially curable stages, he said.
The test uses selected ion flow tube mass spectrometry, or SIFT-MS to identify the olfactory signatures of specific chemical components among the millions of possible odors in a sample of air.
The investigators previously identified 13 volatile organic compounds (VOCs) associated with GEJ cancers and through additional analysis pared the number down to five: butyric acid, pentanoic acid, hexanoic acid, butanal, and decanal.
In tests of the five-VOC breath model, they found it had an area under the curve (AUC) of the receiver operating characteristic of 0.90, sensitivity of 84%, and a specificity of 88%.
They then sought to validate the model in a multicenter blinded study. They enrolled 163 treatment-naive patients diagnosed with nonmetastatic GEJ cancer (stages I-III), and 172 controls matched on a 1:1 basis.
Breath samples from all participants were collected in steel breath bags and sent to a central lab for SIFT-MS analysis. A statistician blinded to patient diagnosis then determined cancer risk based on previously determined odds ratios for each VOC.
The investigators used quality assurance measures to minimize the risk of errors, including sampling of the ambient air where the samples were collected, training of all researchers in uniform breath collection technique, and calibration to water.
They found that in this validation study, four of the five VOCs were significantly dysregulated in cases, compared with controls; pentanoic acid was the exception. The AUC was 0.85, with a sensitivity of 80% and specificity of 81%.
Looking at the association between VOCs and demographics of the patients as possible confounders, they saw that hexanoic acid levels could be affected by smoking history, and that butanal could be affected by smoking, white race, or history of using an ACE inhibitor.
Dr. Markar said that among the strengths of the study are that is was adequately powered, performed in multiple centers, and had quality assurance measures in place. In addition, the results compared well with results from the use of a cytosponge.
He acknowledged, however, that there were more late- than early-stage cancers among patients in the study, and that the 80% sensitivity level meant that one in five cancers would be missed.
Nonetheless, if the test is refined and can be further validated in an unenriched population, it could serve as an endoscopy triage test, he said.
He noted that we are just beginning to understand the importance of smell, the “most primitive” of the five senses, in relation to human health and joked that, just as many airports have drug-sniffing dogs, clinical practices could have patient-sniffing dogs that could be used to direct patients to the right specialist.
He was not involved in the study, but commented on it as part of a media briefing.
The study was supported by the UK National Institute for Health Research. The authors reported no competing interests.
AMSTERDAM – A test that samples exhaled breath and looks for the presence of just five volatile organic compounds shows promise as an inexpensive method for screening patients with suspected cancers of the gastroesophageal junction (GEJ), investigators from the United Kingdom reported.
In a multicenter clinical trial testing breath samples from patients with adenocarcinoma of the GEJ and matched controls, the test had an overall sensitivity of 80% and specificity of 81% for adenocarcinoma of the GEJ, said Sheraz R. Markar, MD, PhD, from Imperial College London.
If the test can be validated in larger studies, it could increase the number of patients screened and has the potential to save medical costs by reducing the number of unnecessary endoscopies and by catching GEJ cancers at earlier, potentially curable stages, he said.
The test uses selected ion flow tube mass spectrometry, or SIFT-MS to identify the olfactory signatures of specific chemical components among the millions of possible odors in a sample of air.
The investigators previously identified 13 volatile organic compounds (VOCs) associated with GEJ cancers and through additional analysis pared the number down to five: butyric acid, pentanoic acid, hexanoic acid, butanal, and decanal.
In tests of the five-VOC breath model, they found it had an area under the curve (AUC) of the receiver operating characteristic of 0.90, sensitivity of 84%, and a specificity of 88%.
They then sought to validate the model in a multicenter blinded study. They enrolled 163 treatment-naive patients diagnosed with nonmetastatic GEJ cancer (stages I-III), and 172 controls matched on a 1:1 basis.
Breath samples from all participants were collected in steel breath bags and sent to a central lab for SIFT-MS analysis. A statistician blinded to patient diagnosis then determined cancer risk based on previously determined odds ratios for each VOC.
The investigators used quality assurance measures to minimize the risk of errors, including sampling of the ambient air where the samples were collected, training of all researchers in uniform breath collection technique, and calibration to water.
They found that in this validation study, four of the five VOCs were significantly dysregulated in cases, compared with controls; pentanoic acid was the exception. The AUC was 0.85, with a sensitivity of 80% and specificity of 81%.
Looking at the association between VOCs and demographics of the patients as possible confounders, they saw that hexanoic acid levels could be affected by smoking history, and that butanal could be affected by smoking, white race, or history of using an ACE inhibitor.
Dr. Markar said that among the strengths of the study are that is was adequately powered, performed in multiple centers, and had quality assurance measures in place. In addition, the results compared well with results from the use of a cytosponge.
He acknowledged, however, that there were more late- than early-stage cancers among patients in the study, and that the 80% sensitivity level meant that one in five cancers would be missed.
Nonetheless, if the test is refined and can be further validated in an unenriched population, it could serve as an endoscopy triage test, he said.
He noted that we are just beginning to understand the importance of smell, the “most primitive” of the five senses, in relation to human health and joked that, just as many airports have drug-sniffing dogs, clinical practices could have patient-sniffing dogs that could be used to direct patients to the right specialist.
He was not involved in the study, but commented on it as part of a media briefing.
The study was supported by the UK National Institute for Health Research. The authors reported no competing interests.
AMSTERDAM – A test that samples exhaled breath and looks for the presence of just five volatile organic compounds shows promise as an inexpensive method for screening patients with suspected cancers of the gastroesophageal junction (GEJ), investigators from the United Kingdom reported.
In a multicenter clinical trial testing breath samples from patients with adenocarcinoma of the GEJ and matched controls, the test had an overall sensitivity of 80% and specificity of 81% for adenocarcinoma of the GEJ, said Sheraz R. Markar, MD, PhD, from Imperial College London.
If the test can be validated in larger studies, it could increase the number of patients screened and has the potential to save medical costs by reducing the number of unnecessary endoscopies and by catching GEJ cancers at earlier, potentially curable stages, he said.
The test uses selected ion flow tube mass spectrometry, or SIFT-MS to identify the olfactory signatures of specific chemical components among the millions of possible odors in a sample of air.
The investigators previously identified 13 volatile organic compounds (VOCs) associated with GEJ cancers and through additional analysis pared the number down to five: butyric acid, pentanoic acid, hexanoic acid, butanal, and decanal.
In tests of the five-VOC breath model, they found it had an area under the curve (AUC) of the receiver operating characteristic of 0.90, sensitivity of 84%, and a specificity of 88%.
They then sought to validate the model in a multicenter blinded study. They enrolled 163 treatment-naive patients diagnosed with nonmetastatic GEJ cancer (stages I-III), and 172 controls matched on a 1:1 basis.
Breath samples from all participants were collected in steel breath bags and sent to a central lab for SIFT-MS analysis. A statistician blinded to patient diagnosis then determined cancer risk based on previously determined odds ratios for each VOC.
The investigators used quality assurance measures to minimize the risk of errors, including sampling of the ambient air where the samples were collected, training of all researchers in uniform breath collection technique, and calibration to water.
They found that in this validation study, four of the five VOCs were significantly dysregulated in cases, compared with controls; pentanoic acid was the exception. The AUC was 0.85, with a sensitivity of 80% and specificity of 81%.
Looking at the association between VOCs and demographics of the patients as possible confounders, they saw that hexanoic acid levels could be affected by smoking history, and that butanal could be affected by smoking, white race, or history of using an ACE inhibitor.
Dr. Markar said that among the strengths of the study are that is was adequately powered, performed in multiple centers, and had quality assurance measures in place. In addition, the results compared well with results from the use of a cytosponge.
He acknowledged, however, that there were more late- than early-stage cancers among patients in the study, and that the 80% sensitivity level meant that one in five cancers would be missed.
Nonetheless, if the test is refined and can be further validated in an unenriched population, it could serve as an endoscopy triage test, he said.
He noted that we are just beginning to understand the importance of smell, the “most primitive” of the five senses, in relation to human health and joked that, just as many airports have drug-sniffing dogs, clinical practices could have patient-sniffing dogs that could be used to direct patients to the right specialist.
He was not involved in the study, but commented on it as part of a media briefing.
The study was supported by the UK National Institute for Health Research. The authors reported no competing interests.
Key clinical point: Breath analysis may be able detect early cancers of the gastroesophagel junction.
Major finding: A breath test had 80% sensitivity and 81% specificity for GEJ cancer.
Data source: Multicenter case-control study with 335 participants.
Disclosures: The study was supported by the UK National Institute for Health Research. The authors reported no competing interests.
Hand-foot syndrome less with S-1 than capecitabine in mCRC
AMSTERDAM – For patients with metastatic colorectal cancer, S-1 was comparable in efficacy to capecitabine (Xeloda), and was associated with a lower incidence of all grades of hand-foot syndrome, reported investigators.
Among 161 patients with untreated metastatic colorectal cancer, the investigator-assessed incidence of all grades of hand-foot syndrome was 73% for patients randomly assigned to capecitabine, compared with 45% for patients randomized to S-1 (P = .0005).
Patient-assessed symptoms also were lower with S-1 than with capecitabine, reported Robert Jan Kwakman, MD, of the Academic Medical Center in Amsterdam. 
“We conclude that treatment with S-1 is a useful alternative to capecitabine in the treatment of metastatic colorectal cancer,” he said at an annual congress sponsored by the European Cancer Organisation.
S-1 is an oral fluoropyrimidine consisting of tegafur, a prodrug of 5-fluorauracil (5-FU), combined with two 5-FU biochemical modulators. It is associated with a lower incidence of hand-foot syndrome than capecitabine, and has shown efficacy comparable to that of other fluoropyrimidines in Asian patients with gastrointestinal cancers, Dr. Kwakman noted.
Hand-foot syndrome can vary in severity from grade 1, marked by minimal skin changes or dermatitis without pain, to grade 3, characterized by severe skin changes with pain and significant limits to self care during activities of daily living.
In the randomized phase III SALTO trial (S1 Versus Capecitabine in the First Line Treatment of Metastatic Colorectal Cancer Patients), investigators in the Dutch Colorectal Cancer Group enrolled patients with untreated metastatic colorectal cancer with World Health Organization performance status 0-2 who were scheduled for treatment with fluoropyrimidine monotherapy. The patients were assigned to receive either capecitabine 1,250 mg/m2 for patients younger than 70, or 1,000 mg/m2 for those 70 and older, twice a day for days 1-14 of a 3-week cycle, or to S-1 30 mg/m2 twice daily on the same schedule.
In each arm, investigators could, at their discretion, also prescribe bevacizumab 7.5 mg/kg on day 1. In each arm, 59% of patients were scheduled to receive bevacizumab.
Patients were stratified by bevacizumab status, lactate dehydrogenase levels (normal vs. abnormal), performance status (0-1 vs. 2) and institution.
Patients were asked to keep diaries and record whether during the past 3 weeks they had experienced symptoms in their hands and/or feet such as tingling/numbness, pain, redness, swelling, and desquamation, and if so, whether the symptoms interfered with daily activities.
After a median follow-up of 16.1 months, investigators assessed hand-foot syndrome rates by grade were as follows:
• Grade 1: 21% for the capecitabine arm vs. 28% for the S-1 arm (not significant).
• Grade 2: 30% vs. 14% (P = .02).
• Grade 3: 21% vs. 4% (P = .003).
The incidence of patient-assessed hand-foot syndrome of all grades was 84% in the capecitabine arm and 58% in the S-1 arm (P = .004). Patient-reported grade 3 hand-foot syndrome occurred in 18% vs. 5%, respectively (P = .05).
The only other toxicity occurring more frequently among patients on S-1 was anorexia, which occurred in 29% of patients on capecitabine compared with 41% with S-1. Grade 3 or greater anorexia occurred in 3% vs. 13%, respectively (P = .03).
Significantly more dose reductions were required for patients on capecitabine (69% vs. 41%, P = .0008). The median relative dose intensity was higher for patients on S-1 (89% vs. 95%, P = .035).
Among all patients, median progression-free survival was 8.18 months with capecitabine vs. 8.39 months with S-1, a difference that was not significant. There was a trend toward better progression-free survival for patients in each arm who received bevacizumab (8.74 vs. 6.37 months without bevacizumab), but this difference was also not significant.
Overall survival rates at 12 months were 67% with capecitabine and 62% with S-1 (not significantly different), and respective rates at 18 months were 50% vs. 39%. The hazard ratio for mortality with S-1 was 1.28 (not significant).
The study was sponsored by the Dutch Colorectal Cancer Group, with research funds supplied by Nordic Pharma BV. Dr. Kwakman disclosed receiving an honorarium from the company.
AMSTERDAM – For patients with metastatic colorectal cancer, S-1 was comparable in efficacy to capecitabine (Xeloda), and was associated with a lower incidence of all grades of hand-foot syndrome, reported investigators.
Among 161 patients with untreated metastatic colorectal cancer, the investigator-assessed incidence of all grades of hand-foot syndrome was 73% for patients randomly assigned to capecitabine, compared with 45% for patients randomized to S-1 (P = .0005).
Patient-assessed symptoms also were lower with S-1 than with capecitabine, reported Robert Jan Kwakman, MD, of the Academic Medical Center in Amsterdam.
“We conclude that treatment with S-1 is a useful alternative to capecitabine in the treatment of metastatic colorectal cancer,” he said at an annual congress sponsored by the European Cancer Organisation.
S-1 is an oral fluoropyrimidine consisting of tegafur, a prodrug of 5-fluorauracil (5-FU), combined with two 5-FU biochemical modulators. It is associated with a lower incidence of hand-foot syndrome than capecitabine, and has shown efficacy comparable to that of other fluoropyrimidines in Asian patients with gastrointestinal cancers, Dr. Kwakman noted.
Hand-foot syndrome can vary in severity from grade 1, marked by minimal skin changes or dermatitis without pain, to grade 3, characterized by severe skin changes with pain and significant limits to self care during activities of daily living.
In the randomized phase III SALTO trial (S1 Versus Capecitabine in the First Line Treatment of Metastatic Colorectal Cancer Patients), investigators in the Dutch Colorectal Cancer Group enrolled patients with untreated metastatic colorectal cancer with World Health Organization performance status 0-2 who were scheduled for treatment with fluoropyrimidine monotherapy. The patients were assigned to receive either capecitabine 1,250 mg/m2 for patients younger than 70, or 1,000 mg/m2 for those 70 and older, twice a day for days 1-14 of a 3-week cycle, or to S-1 30 mg/m2 twice daily on the same schedule.
In each arm, investigators could, at their discretion, also prescribe bevacizumab 7.5 mg/kg on day 1. In each arm, 59% of patients were scheduled to receive bevacizumab.
Patients were stratified by bevacizumab status, lactate dehydrogenase levels (normal vs. abnormal), performance status (0-1 vs. 2) and institution.
Patients were asked to keep diaries and record whether during the past 3 weeks they had experienced symptoms in their hands and/or feet such as tingling/numbness, pain, redness, swelling, and desquamation, and if so, whether the symptoms interfered with daily activities.
After a median follow-up of 16.1 months, investigators assessed hand-foot syndrome rates by grade were as follows:
• Grade 1: 21% for the capecitabine arm vs. 28% for the S-1 arm (not significant).
• Grade 2: 30% vs. 14% (P = .02).
• Grade 3: 21% vs. 4% (P = .003).
The incidence of patient-assessed hand-foot syndrome of all grades was 84% in the capecitabine arm and 58% in the S-1 arm (P = .004). Patient-reported grade 3 hand-foot syndrome occurred in 18% vs. 5%, respectively (P = .05).
The only other toxicity occurring more frequently among patients on S-1 was anorexia, which occurred in 29% of patients on capecitabine compared with 41% with S-1. Grade 3 or greater anorexia occurred in 3% vs. 13%, respectively (P = .03).
Significantly more dose reductions were required for patients on capecitabine (69% vs. 41%, P = .0008). The median relative dose intensity was higher for patients on S-1 (89% vs. 95%, P = .035).
Among all patients, median progression-free survival was 8.18 months with capecitabine vs. 8.39 months with S-1, a difference that was not significant. There was a trend toward better progression-free survival for patients in each arm who received bevacizumab (8.74 vs. 6.37 months without bevacizumab), but this difference was also not significant.
Overall survival rates at 12 months were 67% with capecitabine and 62% with S-1 (not significantly different), and respective rates at 18 months were 50% vs. 39%. The hazard ratio for mortality with S-1 was 1.28 (not significant).
The study was sponsored by the Dutch Colorectal Cancer Group, with research funds supplied by Nordic Pharma BV. Dr. Kwakman disclosed receiving an honorarium from the company.
AMSTERDAM – For patients with metastatic colorectal cancer, S-1 was comparable in efficacy to capecitabine (Xeloda), and was associated with a lower incidence of all grades of hand-foot syndrome, reported investigators.
Among 161 patients with untreated metastatic colorectal cancer, the investigator-assessed incidence of all grades of hand-foot syndrome was 73% for patients randomly assigned to capecitabine, compared with 45% for patients randomized to S-1 (P = .0005).
Patient-assessed symptoms also were lower with S-1 than with capecitabine, reported Robert Jan Kwakman, MD, of the Academic Medical Center in Amsterdam.
“We conclude that treatment with S-1 is a useful alternative to capecitabine in the treatment of metastatic colorectal cancer,” he said at an annual congress sponsored by the European Cancer Organisation.
S-1 is an oral fluoropyrimidine consisting of tegafur, a prodrug of 5-fluorauracil (5-FU), combined with two 5-FU biochemical modulators. It is associated with a lower incidence of hand-foot syndrome than capecitabine, and has shown efficacy comparable to that of other fluoropyrimidines in Asian patients with gastrointestinal cancers, Dr. Kwakman noted.
Hand-foot syndrome can vary in severity from grade 1, marked by minimal skin changes or dermatitis without pain, to grade 3, characterized by severe skin changes with pain and significant limits to self care during activities of daily living.
In the randomized phase III SALTO trial (S1 Versus Capecitabine in the First Line Treatment of Metastatic Colorectal Cancer Patients), investigators in the Dutch Colorectal Cancer Group enrolled patients with untreated metastatic colorectal cancer with World Health Organization performance status 0-2 who were scheduled for treatment with fluoropyrimidine monotherapy. The patients were assigned to receive either capecitabine 1,250 mg/m2 for patients younger than 70, or 1,000 mg/m2 for those 70 and older, twice a day for days 1-14 of a 3-week cycle, or to S-1 30 mg/m2 twice daily on the same schedule.
In each arm, investigators could, at their discretion, also prescribe bevacizumab 7.5 mg/kg on day 1. In each arm, 59% of patients were scheduled to receive bevacizumab.
Patients were stratified by bevacizumab status, lactate dehydrogenase levels (normal vs. abnormal), performance status (0-1 vs. 2) and institution.
Patients were asked to keep diaries and record whether during the past 3 weeks they had experienced symptoms in their hands and/or feet such as tingling/numbness, pain, redness, swelling, and desquamation, and if so, whether the symptoms interfered with daily activities.
After a median follow-up of 16.1 months, investigators assessed hand-foot syndrome rates by grade were as follows:
• Grade 1: 21% for the capecitabine arm vs. 28% for the S-1 arm (not significant).
• Grade 2: 30% vs. 14% (P = .02).
• Grade 3: 21% vs. 4% (P = .003).
The incidence of patient-assessed hand-foot syndrome of all grades was 84% in the capecitabine arm and 58% in the S-1 arm (P = .004). Patient-reported grade 3 hand-foot syndrome occurred in 18% vs. 5%, respectively (P = .05).
The only other toxicity occurring more frequently among patients on S-1 was anorexia, which occurred in 29% of patients on capecitabine compared with 41% with S-1. Grade 3 or greater anorexia occurred in 3% vs. 13%, respectively (P = .03).
Significantly more dose reductions were required for patients on capecitabine (69% vs. 41%, P = .0008). The median relative dose intensity was higher for patients on S-1 (89% vs. 95%, P = .035).
Among all patients, median progression-free survival was 8.18 months with capecitabine vs. 8.39 months with S-1, a difference that was not significant. There was a trend toward better progression-free survival for patients in each arm who received bevacizumab (8.74 vs. 6.37 months without bevacizumab), but this difference was also not significant.
Overall survival rates at 12 months were 67% with capecitabine and 62% with S-1 (not significantly different), and respective rates at 18 months were 50% vs. 39%. The hazard ratio for mortality with S-1 was 1.28 (not significant).
The study was sponsored by the Dutch Colorectal Cancer Group, with research funds supplied by Nordic Pharma BV. Dr. Kwakman disclosed receiving an honorarium from the company.
AT ECCO2017
Key clinical point: S-1 was associated with a lower incidence of hand-foot syndrome than was capecitabine in patients with metastatic colorectal cancer.
Major finding: Hand-foot syndrome of any grade occurred in 73% of patients on capecitabine vs. 45% on S-1 (P = .0005).
Data source: Randomized phase III trial of 161 patients with previously untreated metastatic colorectal cancer.
Disclosures: The study was sponsored by the Dutch Colorectal Cancer Group, with research funds supplied by Nordic Pharma BV. Dr. Kwakman disclosed receiving an honorarium from the company.
Ruxolitinib beats best available care for hematocrit control in polycythemia
For patients with polycythemia vera without splenomegaly who had inadequate responses to hydroxyurea, targeted therapy with the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) offered better control of hematocrit and better improvement of symptoms than did the best available therapy, according to results of a multinational randomized phase IIIb trial.
Among 74 patients randomly assigned to receive ruxolitinib, 46 (62%) achieved hematocrit control, compared with 14 of 75 patients (19%) assigned to receive one of several different options lumped into the best available therapy category, noted investigators led by Francesco Passamonti, MD, of the University of Insubria in Varese, Italy.
“Ruxolitinib also led to an improved symptom burden and quality of life. Patients treated with ruxolitinib experienced improvements in all polycythemia vera–associated symptoms, including pruritus, whereas patients treated with best available therapy experienced worsening of most symptoms,” they wrote.
Unlike cytoreductive therapies such as hydroxyurea or pegylated interferon, ruxolitinib works by inhibition of JAK1 and JAK2 signaling. A majority of patients with polycythemia vera have an activating JAK2 mutation that leads to overactivation of the JAK-STAT signaling pathway, resulting in erythrocytosis, the hallmark symptom of polycythemia vera, and associated vascular complications.
“In some patients, conventional therapies can lose effectiveness over time. Although hydroxyurea is well tolerated in most patients, about 15%-20% of patients become resistant or intolerant, with hydroxyurea resistance affecting survival and increasing the risk of progression to myelofibrosis. Additionally, patients who are intolerant of hydroxyurea can have adverse side effects, such as drug-induced fever, mouth ulcers, leg ulcers, and skin malignancies, which necessitate discontinuation of first-line therapy,” the investigators noted.
RESPONSE trials
Ruxolitinib had previously been shown in the RESPONSE study to be superior to the best available therapy for controlling hematocrit and for improving splenomegaly and other symptoms in patients with polycythemia vera and disease-associated splenomegaly who had an inadequate response or unacceptable toxicities from treatment with hydroxyurea.
In the currently reported study, dubbed RESPONSE-2, patients 18 and older with polycythemia vera with no palpable splenomegaly who were intolerant of hydroxyurea or had disease that was resistant to it were randomized to receive either oral ruxolitinib 10 mg twice daily, or best available therapy at the investigators’ discretion. Best available therapy consisted of either hydroxyurea at the maximum tolerated dose, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment.
As noted, hematocrit control at week 28, the primary endpoint, was significantly higher among patients on ruxolitinib, with an odds ratio (OR) of 7.28 (P less than .0001).
Hematocrit levels among patients on ruxolitinib group decreased from a mean of 42.8% at baseline to 40.2% at week 28. In contrast, hematocrit in the best available therapy group increased from a mean of 42.7% to 44.9% at week 28.
Fewer patients on ruxolitinib required phlebotomy procedures during the 28 weeks of the study compared with patients on best available therapy, and of those patients who did undergo phlebotomy, fewer of those in the ruxolitinib group underwent more than two procedures. There were a total of 98 phlebotomies among best available care patients, vs. 19 among ruxolitinib patients.
Complete hematologic remissions, a secondary endpoint, occurred in 23% of patients on ruxolitinib, compared with 5% of those on best available care (OR 5.58, P = .0019).
The most frequent hematologic adverse events of any grade were anemia, which occurred in 10 patients on ruxolitinib (none grade 3 or greater) vs. two on best available therapy (one grade 3), and thrombocytopenia occurring in two (both grade 1 or 2) and six patients (three grade 1 or 2, two grade 3, and one grade 4) respectively.
Grade 3 or 4 nonhematologic adverse events included hypertension in five patients on ruxolitinib vs. three on best available care, and pruritus in none vs. two, respectively.
Two patients died; both were in the best available therapy group.
“Although the short follow-up of this study precludes any conclusions about vascular complications, an important finding is that patients treated with ruxolitinib in both RESPONSE and RESPONSE-2 had fewer thromboembolic events compared with those given best available therapy; there were two thromboembolic events with ruxolitinib (one in each study) versus nine with best available therapy across both studies (six in RESPONSE and three in RESPONSE-2). This finding could have been attributable to better control of hematocrit or white blood cell count with ruxolitinib, given that baseline risk factors were similar in both treatment groups,” the investigators wrote.
The findings from the two studies support the use of ruxolitinib as a standard of care for second-line therapy of patients with polycythemia vera following treatment with hydroxyurea, they contended.
Several coauthors disclosed ties to Novartis, which supported the study. Two are Novartis employees; one was previously employed by the company.
Ruxolitinib has now been assessed in two clinical trials in polycythemia vera without myelofibrosis. Francesco Passamonti and colleagues report the results of RESPONSE-2, a randomized, open-label, phase IIIb trial of ruxolitinib in patients with polycythemia vera without splenomegaly, who were intolerant of or unresponsive to hydroxyurea, versus the best available therapy (usually hydroxyurea), making this trial – like the previous RESPONSE trial, in which the effect of ruxolitinib was examined in hydroxyurea-intolerant or unresponsive patients with polycythemia vera with splenomegaly – a referendum on hydroxyurea. On the basis of their age, most RESPONSE-2 patients were defined as so-called high-risk patients, and were phlebotomy dependent.
Unsurprisingly, for the primary endpoint of patients achieving hematocrit control, ruxolitinib was superior to best available therapy (46 [62%] of 74 patients in the ruxolitinib group vs. 14 [19%] of 75 in the best available therapy group; odds ratio, 7.28 [95% CI 3.43–15.45]; P less than .0001), and also for the key secondary endpoint for patients achieving complete hematologic remission (23% vs .5%).
Symptom control, including pruritus, was superior in the ruxolitinib group, and adverse events were more common in the best available therapy group. The authors concluded that ruxolitinib “could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population”
However, I challenge this conclusion. First, the consensus that hydroxyurea is first-line therapy for polycythemia vera is not evidence based. Indeed, a trial using hydroxyurea in patients with polycythemia vera to achieve European LeukemiaNet criteria for complete hematologic remission did not result in better survival or less thrombosis compared with the expected survival of patients with similar disease characteristics.
Second, the primary endpoint of RESPONSE-2 was phlebotomy control but the appropriate control group (a phlebotomy-only group) was not included, nor was phlebotomy control or hematologic remission achieved with ruxolitinib in all patients. Ruxolitinib is an expensive drug, but phlebotomy is an inexpensive and immediately effective procedure, and it is unlikely that insurers would support the use of ruxolitinib in polycythemia vera for hematocrit control without proof of greater efficacy than phlebotomy therapy.
Third, no study of ruxolitinib in polycythemia vera has capitalized on the observation, based on both clinical and gene-expression data, that patients with polycythemia vera are not all alike; male and female patients differ clinically and in gene expression, and the disease is indolent in some patients and aggressive in others, who also differ in gene expression. Thus, it should not be presumed that all patients with polycythemia vera will require ruxolitinib therapy or that all patients who do receive this treatment will respond similarly. Finally, polycythemia vera is an hematopoietic stem-cell disorder and, so far, ruxolitinib does not seem to affect hematopoietic stem cell behavior. At present, pegylated interferon is the only drug that targets hematopoietic stem cells and produces hematologic and molecular remission, although not in all patients and, like ruxolitinib, we still do not know how best to use it. Thus, following the data recorded in the RESPONSE trials we now have access to two non-myelotoxic therapies (ruxolitinib and pegylated interferon) to treat a disease whose natural history is measured in decades but whose patients do not all have the same genetic background or require the same level of myelosuppression – a setting most appropriate for precision medicine.
Jerry L. Spivak, MD, is with Johns Hopkins University in Baltimore. His remarks were excerpted from an accompanying editorial.
Ruxolitinib has now been assessed in two clinical trials in polycythemia vera without myelofibrosis. Francesco Passamonti and colleagues report the results of RESPONSE-2, a randomized, open-label, phase IIIb trial of ruxolitinib in patients with polycythemia vera without splenomegaly, who were intolerant of or unresponsive to hydroxyurea, versus the best available therapy (usually hydroxyurea), making this trial – like the previous RESPONSE trial, in which the effect of ruxolitinib was examined in hydroxyurea-intolerant or unresponsive patients with polycythemia vera with splenomegaly – a referendum on hydroxyurea. On the basis of their age, most RESPONSE-2 patients were defined as so-called high-risk patients, and were phlebotomy dependent.
Unsurprisingly, for the primary endpoint of patients achieving hematocrit control, ruxolitinib was superior to best available therapy (46 [62%] of 74 patients in the ruxolitinib group vs. 14 [19%] of 75 in the best available therapy group; odds ratio, 7.28 [95% CI 3.43–15.45]; P less than .0001), and also for the key secondary endpoint for patients achieving complete hematologic remission (23% vs .5%).
Symptom control, including pruritus, was superior in the ruxolitinib group, and adverse events were more common in the best available therapy group. The authors concluded that ruxolitinib “could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population”
However, I challenge this conclusion. First, the consensus that hydroxyurea is first-line therapy for polycythemia vera is not evidence based. Indeed, a trial using hydroxyurea in patients with polycythemia vera to achieve European LeukemiaNet criteria for complete hematologic remission did not result in better survival or less thrombosis compared with the expected survival of patients with similar disease characteristics.
Second, the primary endpoint of RESPONSE-2 was phlebotomy control but the appropriate control group (a phlebotomy-only group) was not included, nor was phlebotomy control or hematologic remission achieved with ruxolitinib in all patients. Ruxolitinib is an expensive drug, but phlebotomy is an inexpensive and immediately effective procedure, and it is unlikely that insurers would support the use of ruxolitinib in polycythemia vera for hematocrit control without proof of greater efficacy than phlebotomy therapy.
Third, no study of ruxolitinib in polycythemia vera has capitalized on the observation, based on both clinical and gene-expression data, that patients with polycythemia vera are not all alike; male and female patients differ clinically and in gene expression, and the disease is indolent in some patients and aggressive in others, who also differ in gene expression. Thus, it should not be presumed that all patients with polycythemia vera will require ruxolitinib therapy or that all patients who do receive this treatment will respond similarly. Finally, polycythemia vera is an hematopoietic stem-cell disorder and, so far, ruxolitinib does not seem to affect hematopoietic stem cell behavior. At present, pegylated interferon is the only drug that targets hematopoietic stem cells and produces hematologic and molecular remission, although not in all patients and, like ruxolitinib, we still do not know how best to use it. Thus, following the data recorded in the RESPONSE trials we now have access to two non-myelotoxic therapies (ruxolitinib and pegylated interferon) to treat a disease whose natural history is measured in decades but whose patients do not all have the same genetic background or require the same level of myelosuppression – a setting most appropriate for precision medicine.
Jerry L. Spivak, MD, is with Johns Hopkins University in Baltimore. His remarks were excerpted from an accompanying editorial.
Ruxolitinib has now been assessed in two clinical trials in polycythemia vera without myelofibrosis. Francesco Passamonti and colleagues report the results of RESPONSE-2, a randomized, open-label, phase IIIb trial of ruxolitinib in patients with polycythemia vera without splenomegaly, who were intolerant of or unresponsive to hydroxyurea, versus the best available therapy (usually hydroxyurea), making this trial – like the previous RESPONSE trial, in which the effect of ruxolitinib was examined in hydroxyurea-intolerant or unresponsive patients with polycythemia vera with splenomegaly – a referendum on hydroxyurea. On the basis of their age, most RESPONSE-2 patients were defined as so-called high-risk patients, and were phlebotomy dependent.
Unsurprisingly, for the primary endpoint of patients achieving hematocrit control, ruxolitinib was superior to best available therapy (46 [62%] of 74 patients in the ruxolitinib group vs. 14 [19%] of 75 in the best available therapy group; odds ratio, 7.28 [95% CI 3.43–15.45]; P less than .0001), and also for the key secondary endpoint for patients achieving complete hematologic remission (23% vs .5%).
Symptom control, including pruritus, was superior in the ruxolitinib group, and adverse events were more common in the best available therapy group. The authors concluded that ruxolitinib “could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population”
However, I challenge this conclusion. First, the consensus that hydroxyurea is first-line therapy for polycythemia vera is not evidence based. Indeed, a trial using hydroxyurea in patients with polycythemia vera to achieve European LeukemiaNet criteria for complete hematologic remission did not result in better survival or less thrombosis compared with the expected survival of patients with similar disease characteristics.
Second, the primary endpoint of RESPONSE-2 was phlebotomy control but the appropriate control group (a phlebotomy-only group) was not included, nor was phlebotomy control or hematologic remission achieved with ruxolitinib in all patients. Ruxolitinib is an expensive drug, but phlebotomy is an inexpensive and immediately effective procedure, and it is unlikely that insurers would support the use of ruxolitinib in polycythemia vera for hematocrit control without proof of greater efficacy than phlebotomy therapy.
Third, no study of ruxolitinib in polycythemia vera has capitalized on the observation, based on both clinical and gene-expression data, that patients with polycythemia vera are not all alike; male and female patients differ clinically and in gene expression, and the disease is indolent in some patients and aggressive in others, who also differ in gene expression. Thus, it should not be presumed that all patients with polycythemia vera will require ruxolitinib therapy or that all patients who do receive this treatment will respond similarly. Finally, polycythemia vera is an hematopoietic stem-cell disorder and, so far, ruxolitinib does not seem to affect hematopoietic stem cell behavior. At present, pegylated interferon is the only drug that targets hematopoietic stem cells and produces hematologic and molecular remission, although not in all patients and, like ruxolitinib, we still do not know how best to use it. Thus, following the data recorded in the RESPONSE trials we now have access to two non-myelotoxic therapies (ruxolitinib and pegylated interferon) to treat a disease whose natural history is measured in decades but whose patients do not all have the same genetic background or require the same level of myelosuppression – a setting most appropriate for precision medicine.
Jerry L. Spivak, MD, is with Johns Hopkins University in Baltimore. His remarks were excerpted from an accompanying editorial.
For patients with polycythemia vera without splenomegaly who had inadequate responses to hydroxyurea, targeted therapy with the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) offered better control of hematocrit and better improvement of symptoms than did the best available therapy, according to results of a multinational randomized phase IIIb trial.
Among 74 patients randomly assigned to receive ruxolitinib, 46 (62%) achieved hematocrit control, compared with 14 of 75 patients (19%) assigned to receive one of several different options lumped into the best available therapy category, noted investigators led by Francesco Passamonti, MD, of the University of Insubria in Varese, Italy.
“Ruxolitinib also led to an improved symptom burden and quality of life. Patients treated with ruxolitinib experienced improvements in all polycythemia vera–associated symptoms, including pruritus, whereas patients treated with best available therapy experienced worsening of most symptoms,” they wrote.
Unlike cytoreductive therapies such as hydroxyurea or pegylated interferon, ruxolitinib works by inhibition of JAK1 and JAK2 signaling. A majority of patients with polycythemia vera have an activating JAK2 mutation that leads to overactivation of the JAK-STAT signaling pathway, resulting in erythrocytosis, the hallmark symptom of polycythemia vera, and associated vascular complications.
“In some patients, conventional therapies can lose effectiveness over time. Although hydroxyurea is well tolerated in most patients, about 15%-20% of patients become resistant or intolerant, with hydroxyurea resistance affecting survival and increasing the risk of progression to myelofibrosis. Additionally, patients who are intolerant of hydroxyurea can have adverse side effects, such as drug-induced fever, mouth ulcers, leg ulcers, and skin malignancies, which necessitate discontinuation of first-line therapy,” the investigators noted.
RESPONSE trials
Ruxolitinib had previously been shown in the RESPONSE study to be superior to the best available therapy for controlling hematocrit and for improving splenomegaly and other symptoms in patients with polycythemia vera and disease-associated splenomegaly who had an inadequate response or unacceptable toxicities from treatment with hydroxyurea.
In the currently reported study, dubbed RESPONSE-2, patients 18 and older with polycythemia vera with no palpable splenomegaly who were intolerant of hydroxyurea or had disease that was resistant to it were randomized to receive either oral ruxolitinib 10 mg twice daily, or best available therapy at the investigators’ discretion. Best available therapy consisted of either hydroxyurea at the maximum tolerated dose, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment.
As noted, hematocrit control at week 28, the primary endpoint, was significantly higher among patients on ruxolitinib, with an odds ratio (OR) of 7.28 (P less than .0001).
Hematocrit levels among patients on ruxolitinib group decreased from a mean of 42.8% at baseline to 40.2% at week 28. In contrast, hematocrit in the best available therapy group increased from a mean of 42.7% to 44.9% at week 28.
Fewer patients on ruxolitinib required phlebotomy procedures during the 28 weeks of the study compared with patients on best available therapy, and of those patients who did undergo phlebotomy, fewer of those in the ruxolitinib group underwent more than two procedures. There were a total of 98 phlebotomies among best available care patients, vs. 19 among ruxolitinib patients.
Complete hematologic remissions, a secondary endpoint, occurred in 23% of patients on ruxolitinib, compared with 5% of those on best available care (OR 5.58, P = .0019).
The most frequent hematologic adverse events of any grade were anemia, which occurred in 10 patients on ruxolitinib (none grade 3 or greater) vs. two on best available therapy (one grade 3), and thrombocytopenia occurring in two (both grade 1 or 2) and six patients (three grade 1 or 2, two grade 3, and one grade 4) respectively.
Grade 3 or 4 nonhematologic adverse events included hypertension in five patients on ruxolitinib vs. three on best available care, and pruritus in none vs. two, respectively.
Two patients died; both were in the best available therapy group.
“Although the short follow-up of this study precludes any conclusions about vascular complications, an important finding is that patients treated with ruxolitinib in both RESPONSE and RESPONSE-2 had fewer thromboembolic events compared with those given best available therapy; there were two thromboembolic events with ruxolitinib (one in each study) versus nine with best available therapy across both studies (six in RESPONSE and three in RESPONSE-2). This finding could have been attributable to better control of hematocrit or white blood cell count with ruxolitinib, given that baseline risk factors were similar in both treatment groups,” the investigators wrote.
The findings from the two studies support the use of ruxolitinib as a standard of care for second-line therapy of patients with polycythemia vera following treatment with hydroxyurea, they contended.
Several coauthors disclosed ties to Novartis, which supported the study. Two are Novartis employees; one was previously employed by the company.
For patients with polycythemia vera without splenomegaly who had inadequate responses to hydroxyurea, targeted therapy with the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) offered better control of hematocrit and better improvement of symptoms than did the best available therapy, according to results of a multinational randomized phase IIIb trial.
Among 74 patients randomly assigned to receive ruxolitinib, 46 (62%) achieved hematocrit control, compared with 14 of 75 patients (19%) assigned to receive one of several different options lumped into the best available therapy category, noted investigators led by Francesco Passamonti, MD, of the University of Insubria in Varese, Italy.
“Ruxolitinib also led to an improved symptom burden and quality of life. Patients treated with ruxolitinib experienced improvements in all polycythemia vera–associated symptoms, including pruritus, whereas patients treated with best available therapy experienced worsening of most symptoms,” they wrote.
Unlike cytoreductive therapies such as hydroxyurea or pegylated interferon, ruxolitinib works by inhibition of JAK1 and JAK2 signaling. A majority of patients with polycythemia vera have an activating JAK2 mutation that leads to overactivation of the JAK-STAT signaling pathway, resulting in erythrocytosis, the hallmark symptom of polycythemia vera, and associated vascular complications.
“In some patients, conventional therapies can lose effectiveness over time. Although hydroxyurea is well tolerated in most patients, about 15%-20% of patients become resistant or intolerant, with hydroxyurea resistance affecting survival and increasing the risk of progression to myelofibrosis. Additionally, patients who are intolerant of hydroxyurea can have adverse side effects, such as drug-induced fever, mouth ulcers, leg ulcers, and skin malignancies, which necessitate discontinuation of first-line therapy,” the investigators noted.
RESPONSE trials
Ruxolitinib had previously been shown in the RESPONSE study to be superior to the best available therapy for controlling hematocrit and for improving splenomegaly and other symptoms in patients with polycythemia vera and disease-associated splenomegaly who had an inadequate response or unacceptable toxicities from treatment with hydroxyurea.
In the currently reported study, dubbed RESPONSE-2, patients 18 and older with polycythemia vera with no palpable splenomegaly who were intolerant of hydroxyurea or had disease that was resistant to it were randomized to receive either oral ruxolitinib 10 mg twice daily, or best available therapy at the investigators’ discretion. Best available therapy consisted of either hydroxyurea at the maximum tolerated dose, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment.
As noted, hematocrit control at week 28, the primary endpoint, was significantly higher among patients on ruxolitinib, with an odds ratio (OR) of 7.28 (P less than .0001).
Hematocrit levels among patients on ruxolitinib group decreased from a mean of 42.8% at baseline to 40.2% at week 28. In contrast, hematocrit in the best available therapy group increased from a mean of 42.7% to 44.9% at week 28.
Fewer patients on ruxolitinib required phlebotomy procedures during the 28 weeks of the study compared with patients on best available therapy, and of those patients who did undergo phlebotomy, fewer of those in the ruxolitinib group underwent more than two procedures. There were a total of 98 phlebotomies among best available care patients, vs. 19 among ruxolitinib patients.
Complete hematologic remissions, a secondary endpoint, occurred in 23% of patients on ruxolitinib, compared with 5% of those on best available care (OR 5.58, P = .0019).
The most frequent hematologic adverse events of any grade were anemia, which occurred in 10 patients on ruxolitinib (none grade 3 or greater) vs. two on best available therapy (one grade 3), and thrombocytopenia occurring in two (both grade 1 or 2) and six patients (three grade 1 or 2, two grade 3, and one grade 4) respectively.
Grade 3 or 4 nonhematologic adverse events included hypertension in five patients on ruxolitinib vs. three on best available care, and pruritus in none vs. two, respectively.
Two patients died; both were in the best available therapy group.
“Although the short follow-up of this study precludes any conclusions about vascular complications, an important finding is that patients treated with ruxolitinib in both RESPONSE and RESPONSE-2 had fewer thromboembolic events compared with those given best available therapy; there were two thromboembolic events with ruxolitinib (one in each study) versus nine with best available therapy across both studies (six in RESPONSE and three in RESPONSE-2). This finding could have been attributable to better control of hematocrit or white blood cell count with ruxolitinib, given that baseline risk factors were similar in both treatment groups,” the investigators wrote.
The findings from the two studies support the use of ruxolitinib as a standard of care for second-line therapy of patients with polycythemia vera following treatment with hydroxyurea, they contended.
Several coauthors disclosed ties to Novartis, which supported the study. Two are Novartis employees; one was previously employed by the company.
FROM LANCET ONCOLOGY
Key clinical point: Ruxolitinib was superior to best available care for hematocrit control among patients with polycythemia vera without splenomegaly.
Major finding: In the ruxolitinib group, 62% had control of hematocrit at week 28, vs. 19% on best available care.
Data source: Randomized trial of 149 adults with polycythemia vera in the absence of palpable splenomegaly.
Disclosures: Several coauthors disclosed ties to Novartis, which supported the study. Two are Novartis employees; one was previously employed by the company.
Clonal hematopoiesis increases risk for therapy-related cancers
Small pre-leukemic clones left behind after treatment for non-myeloid malignancies appear to increase the risk for therapy-related myelodysplasia or leukemia, report investigators in two studies.
An analysis of peripheral blood samples taken from patients at the time of their primary cancer diagnosis and bone marrow samples taken at the time of a later therapy-related myeloid neoplasm diagnosis showed that 10 of 14 patients (71%) had clonal hematopoiesis before starting on cytotoxic chemotherapy. In contrast, clonal hematopoiesis was detected in pre-treatment samples of only 17 of 54 controls (31%), reported Koichi Takahashi, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
“Preleukemic clonal hematopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal hematopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms,” they wrote (Lancet Oncol 2017; 18: 100–11).
In a separate study, investigators from the Moffitt Cancer Center in Tampa, Florida, found in a nested case-control study that patients with therapy-related myeloid neoplasms were more likely than controls to have clonal hematopoiesis of indeterminate potential (CHIP), and that the CHIP was often present before exposure to chemotherapy.
“We recorded a significantly higher prevalence of CHIP in individuals who developed therapy-related myeloid neoplasms (cases) than in those who did not (controls); however, around 27% of individuals with CHIP did not develop therapy-related myeloid neoplasms, suggesting that this feature alone should not be used to determine a patient’s suitability for chemotherapy,” wrote Nancy K. Gillis, PharmD, and colleagues (Lancet Oncol 2017; 18:112-21).
Risk factors examined
Dr. Takahashi and colleagues noted that previous studies have identified several treatment-related risk factors as being associated with therapy-related myeloid dysplasia or leukemia, including the use of alkylating agents, topoisomerase II inhibitors, and high-dose chemotherapy with autologous stem-cell transplantation.
“By contrast, little is known about patient-specific risk factors. Older age was shown to increase the risk of therapy-related myeloid neoplasms. Several germline polymorphisms have also been associated with this risk, but none have been validated. As such, no predictive biomarkers exist for therapy-related myeloid neoplasms,” they wrote.
They performed a retrospective case-control study comparing patients treated for a primary cancer at their center from 1997 through 2015 who subsequently developed a myeloid neoplasm with controls treated during the same period. Controls were age-matched patients treated with combination chemotherapy for lymphoma who did not develop a therapy-related myeloid malignancy after at least 5 years of follow-up.
In addition, the investigators further explored the association between clonal hematopoiesis and therapy-related cancers in an external cohort of patients with lymphoma treated in a randomized trial at their center from 1999 through 2001. That trial compared the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with and without melatonin.
To detect clonal hematopoiesis in pre-treatment peripheral blood, the investigators used molecular barcode sequencing of 32 genes. They also used targeted gene sequencing on bone marrow samples from cases to investigate clonal evolution from clonal hematopoiesis to the development of therapy-related myeloid neoplasms.
As noted before, 10 of 14 cases had evidence of pre-treatment clonal hematopoiesis, compared with 17 of 54 controls. For both cases and controls, the cumulative incidence of therapy-related myeloid cancers after 5 years was significantly higher among those with baseline clonal hematopoiesis, at 30% vs. 7% for patients without it (P = .016).
Five of 74 patients in the external cohort (7%) went on to develop therapy-related myeloid neoplasms, and of this group, four (80%) had clonal hematopoiesis at baseline. In contrast, of the 69 patients who did not develop therapy-related cancers, 11 (16%) had baseline clonal hematopoiesis.
In a multivariate model using data from the external cohort, clonal hematopoiesis was significantly associated with risk for therapy-related myeloid neoplasms, with a hazard ratio of 13.7 (P = .013).
Elderly patient study
Dr. Gillis and her colleagues conducted a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not (controls).
The cases were identified from an internal biobank of 123,357 patients, and included all patients who were diagnosed with a primary cancer, treated with chemotherapy, and subsequently developed a therapy-related myeloid neoplasm. The patients had to be 70 or older at the time of either primary or therapy-related cancer diagnosis with peripheral blood or mononuclear samples collected before the diagnosis of the second cancer.
Controls were patients diagnosed with a primary malignancy at age 70 or older who had chemotherapy but did not develop therapy-related myeloid neoplasms. Every case was matched with at least four controls selected for sex, primary tumor type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow up.
They used sequential targeted and whole-exome sequencing to assess clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available.
They identified a total of 13 cases and 56 controls. Among all patients, CHIP was seen in 23 (33%). In contrast, previous studies have shown a prevalence of CHIP among older patients without cancer of about 10%, the authors note in their article.
The prevalence of CHIP was significantly higher among cases than among controls, occurring in 8 of 13 cases (62%) vs 15 of 56 controls (27%; P = .024). The odds ratio for therapy-related neoplasms with CHIP was 5.75 (P = .013).
The most commonly mutated genes were TET2 and TP53 among cases, and TET2 among controls.
“The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk,” the investigators write.
Dr. Takahashi’s study was supported by the Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The National Institutes of Health through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Dr. Gillis’ study was internally funded. Dr. Takahasi and colleagues reported no competing financial interests. Two of Dr. Gillis’ colleagues reported grants or fees from several drug companies.
The real importance of the work reported by Gillis and colleagues and Takahashi and colleagues will come when therapies exist that can effectively eradicate nascent clonal hematopoiesis, thereby preventing therapy-related myeloid neoplasm evolution in at-risk patients.
Although high-intensity treatments, such as anthracycline-based induction chemotherapy, can eradicate myeloid clones, their effectiveness in clearing TP53-mutant cells is limited, and it is difficult to imagine intense approaches having a favorable risk–benefit balance in patients whose clonal hematopoiesis might never become a problem. Existing lower-intensity therapies for myeloid neoplasms such as DNA hypomethylating agents are not curative and often do not result in the reduction of VAF [variant allele frequencies] even when hematopoietic improvement occurs during therapy, so such agents would not be expected to eliminate pre-therapy-related myeloid neoplasm clones (although this hypothesis might still be worth testing, given that the emergence of therapy-related myeloid neoplasm could at least be delayed – even if not entirely prevented – with azacitidine or decitabine).
More promising are strategies that change the bone marrow microenvironment or break the immune tolerance of abnormal clones, although the use of these approaches for myeloid neoplasia is still in the very early stages. Although no method yet exists to reliably eliminate the preleukemic clones that can give rise to therapy-related myeloid neoplasms, identification of higher risk patients could still affect monitoring practices, such as the frequency of clinical assessments. Molecular genetic panels are expensive at present but are becoming less so. Because VAF assessment by next-generation sequencing is quantitative and proportional to clone size, serial assessment could identify patients whose mutant clones are large and expanding and who therefore warrant closer monitoring or enrollment in so-called preventive hematology trials.
David P. Steensma, MD, is with the Dana-Farber Cancer Institute, Harvard Medical School, Boston. His remarks were excerpted from an accompanying editorial.
The real importance of the work reported by Gillis and colleagues and Takahashi and colleagues will come when therapies exist that can effectively eradicate nascent clonal hematopoiesis, thereby preventing therapy-related myeloid neoplasm evolution in at-risk patients.
Although high-intensity treatments, such as anthracycline-based induction chemotherapy, can eradicate myeloid clones, their effectiveness in clearing TP53-mutant cells is limited, and it is difficult to imagine intense approaches having a favorable risk–benefit balance in patients whose clonal hematopoiesis might never become a problem. Existing lower-intensity therapies for myeloid neoplasms such as DNA hypomethylating agents are not curative and often do not result in the reduction of VAF [variant allele frequencies] even when hematopoietic improvement occurs during therapy, so such agents would not be expected to eliminate pre-therapy-related myeloid neoplasm clones (although this hypothesis might still be worth testing, given that the emergence of therapy-related myeloid neoplasm could at least be delayed – even if not entirely prevented – with azacitidine or decitabine).
More promising are strategies that change the bone marrow microenvironment or break the immune tolerance of abnormal clones, although the use of these approaches for myeloid neoplasia is still in the very early stages. Although no method yet exists to reliably eliminate the preleukemic clones that can give rise to therapy-related myeloid neoplasms, identification of higher risk patients could still affect monitoring practices, such as the frequency of clinical assessments. Molecular genetic panels are expensive at present but are becoming less so. Because VAF assessment by next-generation sequencing is quantitative and proportional to clone size, serial assessment could identify patients whose mutant clones are large and expanding and who therefore warrant closer monitoring or enrollment in so-called preventive hematology trials.
David P. Steensma, MD, is with the Dana-Farber Cancer Institute, Harvard Medical School, Boston. His remarks were excerpted from an accompanying editorial.
The real importance of the work reported by Gillis and colleagues and Takahashi and colleagues will come when therapies exist that can effectively eradicate nascent clonal hematopoiesis, thereby preventing therapy-related myeloid neoplasm evolution in at-risk patients.
Although high-intensity treatments, such as anthracycline-based induction chemotherapy, can eradicate myeloid clones, their effectiveness in clearing TP53-mutant cells is limited, and it is difficult to imagine intense approaches having a favorable risk–benefit balance in patients whose clonal hematopoiesis might never become a problem. Existing lower-intensity therapies for myeloid neoplasms such as DNA hypomethylating agents are not curative and often do not result in the reduction of VAF [variant allele frequencies] even when hematopoietic improvement occurs during therapy, so such agents would not be expected to eliminate pre-therapy-related myeloid neoplasm clones (although this hypothesis might still be worth testing, given that the emergence of therapy-related myeloid neoplasm could at least be delayed – even if not entirely prevented – with azacitidine or decitabine).
More promising are strategies that change the bone marrow microenvironment or break the immune tolerance of abnormal clones, although the use of these approaches for myeloid neoplasia is still in the very early stages. Although no method yet exists to reliably eliminate the preleukemic clones that can give rise to therapy-related myeloid neoplasms, identification of higher risk patients could still affect monitoring practices, such as the frequency of clinical assessments. Molecular genetic panels are expensive at present but are becoming less so. Because VAF assessment by next-generation sequencing is quantitative and proportional to clone size, serial assessment could identify patients whose mutant clones are large and expanding and who therefore warrant closer monitoring or enrollment in so-called preventive hematology trials.
David P. Steensma, MD, is with the Dana-Farber Cancer Institute, Harvard Medical School, Boston. His remarks were excerpted from an accompanying editorial.
Small pre-leukemic clones left behind after treatment for non-myeloid malignancies appear to increase the risk for therapy-related myelodysplasia or leukemia, report investigators in two studies.
An analysis of peripheral blood samples taken from patients at the time of their primary cancer diagnosis and bone marrow samples taken at the time of a later therapy-related myeloid neoplasm diagnosis showed that 10 of 14 patients (71%) had clonal hematopoiesis before starting on cytotoxic chemotherapy. In contrast, clonal hematopoiesis was detected in pre-treatment samples of only 17 of 54 controls (31%), reported Koichi Takahashi, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
“Preleukemic clonal hematopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal hematopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms,” they wrote (Lancet Oncol 2017; 18: 100–11).
In a separate study, investigators from the Moffitt Cancer Center in Tampa, Florida, found in a nested case-control study that patients with therapy-related myeloid neoplasms were more likely than controls to have clonal hematopoiesis of indeterminate potential (CHIP), and that the CHIP was often present before exposure to chemotherapy.
“We recorded a significantly higher prevalence of CHIP in individuals who developed therapy-related myeloid neoplasms (cases) than in those who did not (controls); however, around 27% of individuals with CHIP did not develop therapy-related myeloid neoplasms, suggesting that this feature alone should not be used to determine a patient’s suitability for chemotherapy,” wrote Nancy K. Gillis, PharmD, and colleagues (Lancet Oncol 2017; 18:112-21).
Risk factors examined
Dr. Takahashi and colleagues noted that previous studies have identified several treatment-related risk factors as being associated with therapy-related myeloid dysplasia or leukemia, including the use of alkylating agents, topoisomerase II inhibitors, and high-dose chemotherapy with autologous stem-cell transplantation.
“By contrast, little is known about patient-specific risk factors. Older age was shown to increase the risk of therapy-related myeloid neoplasms. Several germline polymorphisms have also been associated with this risk, but none have been validated. As such, no predictive biomarkers exist for therapy-related myeloid neoplasms,” they wrote.
They performed a retrospective case-control study comparing patients treated for a primary cancer at their center from 1997 through 2015 who subsequently developed a myeloid neoplasm with controls treated during the same period. Controls were age-matched patients treated with combination chemotherapy for lymphoma who did not develop a therapy-related myeloid malignancy after at least 5 years of follow-up.
In addition, the investigators further explored the association between clonal hematopoiesis and therapy-related cancers in an external cohort of patients with lymphoma treated in a randomized trial at their center from 1999 through 2001. That trial compared the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with and without melatonin.
To detect clonal hematopoiesis in pre-treatment peripheral blood, the investigators used molecular barcode sequencing of 32 genes. They also used targeted gene sequencing on bone marrow samples from cases to investigate clonal evolution from clonal hematopoiesis to the development of therapy-related myeloid neoplasms.
As noted before, 10 of 14 cases had evidence of pre-treatment clonal hematopoiesis, compared with 17 of 54 controls. For both cases and controls, the cumulative incidence of therapy-related myeloid cancers after 5 years was significantly higher among those with baseline clonal hematopoiesis, at 30% vs. 7% for patients without it (P = .016).
Five of 74 patients in the external cohort (7%) went on to develop therapy-related myeloid neoplasms, and of this group, four (80%) had clonal hematopoiesis at baseline. In contrast, of the 69 patients who did not develop therapy-related cancers, 11 (16%) had baseline clonal hematopoiesis.
In a multivariate model using data from the external cohort, clonal hematopoiesis was significantly associated with risk for therapy-related myeloid neoplasms, with a hazard ratio of 13.7 (P = .013).
Elderly patient study
Dr. Gillis and her colleagues conducted a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not (controls).
The cases were identified from an internal biobank of 123,357 patients, and included all patients who were diagnosed with a primary cancer, treated with chemotherapy, and subsequently developed a therapy-related myeloid neoplasm. The patients had to be 70 or older at the time of either primary or therapy-related cancer diagnosis with peripheral blood or mononuclear samples collected before the diagnosis of the second cancer.
Controls were patients diagnosed with a primary malignancy at age 70 or older who had chemotherapy but did not develop therapy-related myeloid neoplasms. Every case was matched with at least four controls selected for sex, primary tumor type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow up.
They used sequential targeted and whole-exome sequencing to assess clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available.
They identified a total of 13 cases and 56 controls. Among all patients, CHIP was seen in 23 (33%). In contrast, previous studies have shown a prevalence of CHIP among older patients without cancer of about 10%, the authors note in their article.
The prevalence of CHIP was significantly higher among cases than among controls, occurring in 8 of 13 cases (62%) vs 15 of 56 controls (27%; P = .024). The odds ratio for therapy-related neoplasms with CHIP was 5.75 (P = .013).
The most commonly mutated genes were TET2 and TP53 among cases, and TET2 among controls.
“The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk,” the investigators write.
Dr. Takahashi’s study was supported by the Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The National Institutes of Health through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Dr. Gillis’ study was internally funded. Dr. Takahasi and colleagues reported no competing financial interests. Two of Dr. Gillis’ colleagues reported grants or fees from several drug companies.
Small pre-leukemic clones left behind after treatment for non-myeloid malignancies appear to increase the risk for therapy-related myelodysplasia or leukemia, report investigators in two studies.
An analysis of peripheral blood samples taken from patients at the time of their primary cancer diagnosis and bone marrow samples taken at the time of a later therapy-related myeloid neoplasm diagnosis showed that 10 of 14 patients (71%) had clonal hematopoiesis before starting on cytotoxic chemotherapy. In contrast, clonal hematopoiesis was detected in pre-treatment samples of only 17 of 54 controls (31%), reported Koichi Takahashi, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
“Preleukemic clonal hematopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal hematopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms,” they wrote (Lancet Oncol 2017; 18: 100–11).
In a separate study, investigators from the Moffitt Cancer Center in Tampa, Florida, found in a nested case-control study that patients with therapy-related myeloid neoplasms were more likely than controls to have clonal hematopoiesis of indeterminate potential (CHIP), and that the CHIP was often present before exposure to chemotherapy.
“We recorded a significantly higher prevalence of CHIP in individuals who developed therapy-related myeloid neoplasms (cases) than in those who did not (controls); however, around 27% of individuals with CHIP did not develop therapy-related myeloid neoplasms, suggesting that this feature alone should not be used to determine a patient’s suitability for chemotherapy,” wrote Nancy K. Gillis, PharmD, and colleagues (Lancet Oncol 2017; 18:112-21).
Risk factors examined
Dr. Takahashi and colleagues noted that previous studies have identified several treatment-related risk factors as being associated with therapy-related myeloid dysplasia or leukemia, including the use of alkylating agents, topoisomerase II inhibitors, and high-dose chemotherapy with autologous stem-cell transplantation.
“By contrast, little is known about patient-specific risk factors. Older age was shown to increase the risk of therapy-related myeloid neoplasms. Several germline polymorphisms have also been associated with this risk, but none have been validated. As such, no predictive biomarkers exist for therapy-related myeloid neoplasms,” they wrote.
They performed a retrospective case-control study comparing patients treated for a primary cancer at their center from 1997 through 2015 who subsequently developed a myeloid neoplasm with controls treated during the same period. Controls were age-matched patients treated with combination chemotherapy for lymphoma who did not develop a therapy-related myeloid malignancy after at least 5 years of follow-up.
In addition, the investigators further explored the association between clonal hematopoiesis and therapy-related cancers in an external cohort of patients with lymphoma treated in a randomized trial at their center from 1999 through 2001. That trial compared the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with and without melatonin.
To detect clonal hematopoiesis in pre-treatment peripheral blood, the investigators used molecular barcode sequencing of 32 genes. They also used targeted gene sequencing on bone marrow samples from cases to investigate clonal evolution from clonal hematopoiesis to the development of therapy-related myeloid neoplasms.
As noted before, 10 of 14 cases had evidence of pre-treatment clonal hematopoiesis, compared with 17 of 54 controls. For both cases and controls, the cumulative incidence of therapy-related myeloid cancers after 5 years was significantly higher among those with baseline clonal hematopoiesis, at 30% vs. 7% for patients without it (P = .016).
Five of 74 patients in the external cohort (7%) went on to develop therapy-related myeloid neoplasms, and of this group, four (80%) had clonal hematopoiesis at baseline. In contrast, of the 69 patients who did not develop therapy-related cancers, 11 (16%) had baseline clonal hematopoiesis.
In a multivariate model using data from the external cohort, clonal hematopoiesis was significantly associated with risk for therapy-related myeloid neoplasms, with a hazard ratio of 13.7 (P = .013).
Elderly patient study
Dr. Gillis and her colleagues conducted a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not (controls).
The cases were identified from an internal biobank of 123,357 patients, and included all patients who were diagnosed with a primary cancer, treated with chemotherapy, and subsequently developed a therapy-related myeloid neoplasm. The patients had to be 70 or older at the time of either primary or therapy-related cancer diagnosis with peripheral blood or mononuclear samples collected before the diagnosis of the second cancer.
Controls were patients diagnosed with a primary malignancy at age 70 or older who had chemotherapy but did not develop therapy-related myeloid neoplasms. Every case was matched with at least four controls selected for sex, primary tumor type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow up.
They used sequential targeted and whole-exome sequencing to assess clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available.
They identified a total of 13 cases and 56 controls. Among all patients, CHIP was seen in 23 (33%). In contrast, previous studies have shown a prevalence of CHIP among older patients without cancer of about 10%, the authors note in their article.
The prevalence of CHIP was significantly higher among cases than among controls, occurring in 8 of 13 cases (62%) vs 15 of 56 controls (27%; P = .024). The odds ratio for therapy-related neoplasms with CHIP was 5.75 (P = .013).
The most commonly mutated genes were TET2 and TP53 among cases, and TET2 among controls.
“The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk,” the investigators write.
Dr. Takahashi’s study was supported by the Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The National Institutes of Health through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Dr. Gillis’ study was internally funded. Dr. Takahasi and colleagues reported no competing financial interests. Two of Dr. Gillis’ colleagues reported grants or fees from several drug companies.
FROM LANCET ONCOLOGY
Key clinical point: Pre-therapy clonal hematopoiesis is associated with increased risk for therapy-related myeloid neoplasms.
Major finding: In two studies, the incidence of therapy-related myeloid neoplasms was higher among patients with clonal hematopoiesis at baseline.
Data source: Retrospective case-control studies.
Disclosures: Dr. Takahashi’s study was supported by the Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The National Institutes of Health through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Dr. Gillis’ study was internally funded. Dr. Takahasi and colleagues reported no competing financial interests. Two of Dr. Gillis’ colleagues reported grants or fees from several drug companies.
ASCO offers practice guidance on small renal masses
All patients with small renal masses detected on imaging should be considered for renal tumor biopsy when there is a likelihood that the results may affect management of the patient, says a new clinical oncology practice guideline from the American Society of Clinical Oncology.
The guideline defines small renal masses as incidentally image-detected, contrast-enhancing renal tumors 4 cm in diameter or less that are usually consistent with stage T1a renal cell carcinoma (RCC). Approximately one-fourth of all small renal masses turn out to be benign lesions such as oncocytoma or metanephric adenoma, and another 25% may be indolent tumors that can be managed more conservatively, the guidelines note.
Not too long ago, nearly all patients with small renal masses would have undergone radical nephrectomy for lesions of any size. Today, however, partial nephrectomy and percutaneous thermal ablation are safe and less debilitating surgical options for many patients, the authors point out. The purpose of the guideline, therefore, is to help clinicians manage patients with clinically localized small renal masses with evidence-based clinical recommendations.
Recommendations summarized
The guideline, developed with consensus from a multidisciplinary panel, includes six evidence-based recommendations, all based on intermediate quality sources, with recommendation strengths running from moderate to strong. In summary, the guideline recommends:
- All patients with a small renal mass should be considered for renal tumor biopsy “when the results may alter management.”
- For patients with significant comorbidities and a limited life expectancy, active surveillance should be one of the initial management options. Absolute indications for active surveillance include if the patient is at high risk for anesthesia and intervention or has a life expectancy of less than 5 years. Active surveillance is a relative indication for those patients with significant risk of end-stage renal disease if treated, small renal masses less than 1 cm, or a life expectancy of less than 10 years.
- For all patients for whom an intervention is indicated and who have a tumor amenable to limited resection, partial nephrectomy should be the standard treatment offered.
- Percutaneous thermal ablation can be considered as an option for patients whose tumors can be completely ablated. A biopsy should be performed either prior to or at the time of ablation.
- Radical nephrectomy for small renal masses should be reserved only for patients whose tumors are significantly complex to allow for successful partial nephrectomy or for whom or where partial nephrectomy “may result in unacceptable morbidity even when performed at centers with expertise. Referral to a surgeon and a center with experience in partial nephrectomy should be considered.”
- If the patient has chronic kidney disease (CKD), defined as an estimated glomerular filtration rate less than 45 mL/min per 1.73 m2, or develops progressive CKD after treatment, he or she should be considered for referral to a nephrologist, especially if the CKD is associated with proteinuria.
The guideline also offers advice for clinicians on communicating with patients and coordinating all aspects of care in a complex care environment.
“To begin, remember that today’s empowered patient will expect a greater role in his or her care. This means taking steps to ensure the patient is well educated and informed. Clinicians should take the time to orient the patient to his or her care but also make available recommended sources for information, including both print materials and online information,” the guideline authors advise.
They also recommend that clinicians share the details of pathology reports and test results with patients, families, and caregivers using terminology they can understand, including a thorough explanation of cancer staging, tumor types, and clinical options. Patients should also be informed, if appropriate, about the availability of clinical trials.
The guideline is sponsored by ASCO, Dr. Finelli and multiple coauthors disclosed relationships with various drug and/or device companies.
All patients with small renal masses detected on imaging should be considered for renal tumor biopsy when there is a likelihood that the results may affect management of the patient, says a new clinical oncology practice guideline from the American Society of Clinical Oncology.
The guideline defines small renal masses as incidentally image-detected, contrast-enhancing renal tumors 4 cm in diameter or less that are usually consistent with stage T1a renal cell carcinoma (RCC). Approximately one-fourth of all small renal masses turn out to be benign lesions such as oncocytoma or metanephric adenoma, and another 25% may be indolent tumors that can be managed more conservatively, the guidelines note.
Not too long ago, nearly all patients with small renal masses would have undergone radical nephrectomy for lesions of any size. Today, however, partial nephrectomy and percutaneous thermal ablation are safe and less debilitating surgical options for many patients, the authors point out. The purpose of the guideline, therefore, is to help clinicians manage patients with clinically localized small renal masses with evidence-based clinical recommendations.
Recommendations summarized
The guideline, developed with consensus from a multidisciplinary panel, includes six evidence-based recommendations, all based on intermediate quality sources, with recommendation strengths running from moderate to strong. In summary, the guideline recommends:
- All patients with a small renal mass should be considered for renal tumor biopsy “when the results may alter management.”
- For patients with significant comorbidities and a limited life expectancy, active surveillance should be one of the initial management options. Absolute indications for active surveillance include if the patient is at high risk for anesthesia and intervention or has a life expectancy of less than 5 years. Active surveillance is a relative indication for those patients with significant risk of end-stage renal disease if treated, small renal masses less than 1 cm, or a life expectancy of less than 10 years.
- For all patients for whom an intervention is indicated and who have a tumor amenable to limited resection, partial nephrectomy should be the standard treatment offered.
- Percutaneous thermal ablation can be considered as an option for patients whose tumors can be completely ablated. A biopsy should be performed either prior to or at the time of ablation.
- Radical nephrectomy for small renal masses should be reserved only for patients whose tumors are significantly complex to allow for successful partial nephrectomy or for whom or where partial nephrectomy “may result in unacceptable morbidity even when performed at centers with expertise. Referral to a surgeon and a center with experience in partial nephrectomy should be considered.”
- If the patient has chronic kidney disease (CKD), defined as an estimated glomerular filtration rate less than 45 mL/min per 1.73 m2, or develops progressive CKD after treatment, he or she should be considered for referral to a nephrologist, especially if the CKD is associated with proteinuria.
The guideline also offers advice for clinicians on communicating with patients and coordinating all aspects of care in a complex care environment.
“To begin, remember that today’s empowered patient will expect a greater role in his or her care. This means taking steps to ensure the patient is well educated and informed. Clinicians should take the time to orient the patient to his or her care but also make available recommended sources for information, including both print materials and online information,” the guideline authors advise.
They also recommend that clinicians share the details of pathology reports and test results with patients, families, and caregivers using terminology they can understand, including a thorough explanation of cancer staging, tumor types, and clinical options. Patients should also be informed, if appropriate, about the availability of clinical trials.
The guideline is sponsored by ASCO, Dr. Finelli and multiple coauthors disclosed relationships with various drug and/or device companies.
All patients with small renal masses detected on imaging should be considered for renal tumor biopsy when there is a likelihood that the results may affect management of the patient, says a new clinical oncology practice guideline from the American Society of Clinical Oncology.
The guideline defines small renal masses as incidentally image-detected, contrast-enhancing renal tumors 4 cm in diameter or less that are usually consistent with stage T1a renal cell carcinoma (RCC). Approximately one-fourth of all small renal masses turn out to be benign lesions such as oncocytoma or metanephric adenoma, and another 25% may be indolent tumors that can be managed more conservatively, the guidelines note.
Not too long ago, nearly all patients with small renal masses would have undergone radical nephrectomy for lesions of any size. Today, however, partial nephrectomy and percutaneous thermal ablation are safe and less debilitating surgical options for many patients, the authors point out. The purpose of the guideline, therefore, is to help clinicians manage patients with clinically localized small renal masses with evidence-based clinical recommendations.
Recommendations summarized
The guideline, developed with consensus from a multidisciplinary panel, includes six evidence-based recommendations, all based on intermediate quality sources, with recommendation strengths running from moderate to strong. In summary, the guideline recommends:
- All patients with a small renal mass should be considered for renal tumor biopsy “when the results may alter management.”
- For patients with significant comorbidities and a limited life expectancy, active surveillance should be one of the initial management options. Absolute indications for active surveillance include if the patient is at high risk for anesthesia and intervention or has a life expectancy of less than 5 years. Active surveillance is a relative indication for those patients with significant risk of end-stage renal disease if treated, small renal masses less than 1 cm, or a life expectancy of less than 10 years.
- For all patients for whom an intervention is indicated and who have a tumor amenable to limited resection, partial nephrectomy should be the standard treatment offered.
- Percutaneous thermal ablation can be considered as an option for patients whose tumors can be completely ablated. A biopsy should be performed either prior to or at the time of ablation.
- Radical nephrectomy for small renal masses should be reserved only for patients whose tumors are significantly complex to allow for successful partial nephrectomy or for whom or where partial nephrectomy “may result in unacceptable morbidity even when performed at centers with expertise. Referral to a surgeon and a center with experience in partial nephrectomy should be considered.”
- If the patient has chronic kidney disease (CKD), defined as an estimated glomerular filtration rate less than 45 mL/min per 1.73 m2, or develops progressive CKD after treatment, he or she should be considered for referral to a nephrologist, especially if the CKD is associated with proteinuria.
The guideline also offers advice for clinicians on communicating with patients and coordinating all aspects of care in a complex care environment.
“To begin, remember that today’s empowered patient will expect a greater role in his or her care. This means taking steps to ensure the patient is well educated and informed. Clinicians should take the time to orient the patient to his or her care but also make available recommended sources for information, including both print materials and online information,” the guideline authors advise.
They also recommend that clinicians share the details of pathology reports and test results with patients, families, and caregivers using terminology they can understand, including a thorough explanation of cancer staging, tumor types, and clinical options. Patients should also be informed, if appropriate, about the availability of clinical trials.
The guideline is sponsored by ASCO, Dr. Finelli and multiple coauthors disclosed relationships with various drug and/or device companies.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: The guideline recommends renal tumor biopsy for most patients with incidentally detected renal masses 4 cm or smaller.
Major finding: Approximately 25% of patients with incidental small renal masses will have benign lesions.
Data source: Evidence-based clinical guideline developed by a multidisciplinary panel.
Disclosures: The guideline is sponsored by ASCO, Dr. Finelli and multiple coauthors disclosed relationships with various drug and/or device companies.
Ibrutinib continues to wow in CLL/SLL
SAN DIEGO – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.
Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study, the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.
The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.
“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.
In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.
In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.
After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.
Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).
An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).
In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).
Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.
In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.
Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).
Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2, comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.
At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.
“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.
Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.
SAN DIEGO – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.
Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study, the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.
The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.
“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.
In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.
In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.
After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.
Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).
An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).
In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).
Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.
In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.
Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).
Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2, comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.
At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.
“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.
Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.
SAN DIEGO – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.
Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study, the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.
The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.
“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.
In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.
In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.
After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.
Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).
An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).
In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).
Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.
In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.
Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).
Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2, comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.
At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.
“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.
Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.
AT ASH 2016
Key clinical point: Long-term follow-up of two studies shows a progression-free and overall survival advantage with ibrutinib in chronic lymphocytic leukemia/small lymphocytic leukemia.
Major finding: 5-year PFS and OS rates were 92% for treatment-naive patients with CLL/SLL treated with ibrutinib.
Data source: Phase Ib/II study and randomized phase III study of ibrutinib for treatment-naive and relapsed/refractory CLL/SLL.
Disclosures: Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company; Dr. O’Brien disclosed honoraria and research funding from the company.
Gastric cancer yields to growth hormone antagonist in lab
It sounds counterintuitive, but targeting a neuropeptide hormone produced in the hypothalamus may be an effective strategy for treating gastric cancer, the second most common cause of cancer deaths worldwide, investigators from China and the United States contend.
Growth hormone–releasing hormone (GHRH) and its receptor (GHRH-R) are found primarily in the anterior pituitary gland, but are also present in gastric cancers, other solid tumors, and lymphomas. Increased levels of GHRH-R in tumor samples from patients with gastric cancer are associated with poor outcomes, noted Andrew V. Schally, PhD, MD, DSc, of the University of Miami, and his colleagues at the Shantou (China) University Medical College.
Furthermore, an experimental peptide drug labeled MIA-602 that targets GHRH-R inhibited the growth of gastric cancer cell lines and human tumor xenografts in mice, the investigators reported in the journal PNAS.
“The GHRH receptor is both a biomarker that can confirm prognosis and a therapeutic target,” Dr. Schally said in a statement.
Elevated GHRH-R expression in tumors
GHRH-R antagonists such as MIA-602 work through downregulation of the p21-activated kinase 1 (PAK1)–mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor–kappaB (NF-kappaB) inflammatory pathway. This pathway is involved in the interplay between inflammatory processes and intracellular signaling thought to be the cause of gastric cancer tumorigenesis and progression, the investigators explained.
They first looked for GHRH-R expression in gastric cancer samples from 106 patients, using immunohistochemistry staining of primary tumors and adjacent normal tissues. They found that gastric cancer tissues “exhibited robust expression of GHRH-R, compared with normal tissues.”
In 50 samples, GHRH-R was determined to be overexpressed, and this overexpression was significantly associated with both greater tumor size (P = .031) and high pathologic tumor stage (P = .001). Increasing expression of GHRH-R was also significantly associated with worse overall survival (P less than .001).
They confirmed these findings in samples from a multinational cohort of patients, which again showed that the highest levels of GHRH-R expression were associated with poor overall survival (P less than .001).
The authors also looked at messenger RNA expression and gene copy number in 65 gastric cancer samples and 19 adjacent normal tissue samples, and found that GHRH-R mRNA was significantly higher in tumor tissues than normal control tissues (P less than .001).
MAI-602 in vitro and in vivo
To see whether MAI-602 could inhibit the growth of gastric cancer cells, the investigators tried it at various doses in three human gastric cancer cell lines, and found that it inhibited cells in a dose-dependent fashion, compared with vehicle used as a control (P less than .001).
In addition, the experimental agent “exhibited remarkable inhibitory effects on tumor growth in vivo” in mice with human tumor xenografts (P less than .001).
Finally, they showed that the cancer suppression effects of MAI-602 work through inhibition of STAT3/NF-kappaB inflammatory signaling. In vitro and in vivo, MAI-602 decreased the expression of both GHRH and GHRH-R, whereas as a GHRH-R agonist increased levels of both the hormone and its receptor. They also demonstrated that PAK1 appears to be a critical mediator of STAT3/NF-kappaB activity, and that MAI-602 works primarily by blocking PAK1-mediated inflammatory signaling.
“MIA-602 remarkably inhibits the growth of human in vitro and in vivo through the suppression of PAK1–STAT3/NF-kappaB signaling. Our study strongly highlights the therapeutic potential of GHRH-R antagonists in the treatment of gastric cancer patients. Knowledge gained in our study will shed light on how to select the appropriate patients for personalized cancer therapy using GHRH-R antagonists,” Dr. Schally and his coauthors wrote.
The study was supported by the Li Ka Shing Foundation, Chinese foundation, and government grants to individual researchers, as well as support from the the Medical Research Service of the U.S. Department of Veterans Affairs, South Florida Veterans Affairs Foundation for Research and Education, and the University of Miami.
It sounds counterintuitive, but targeting a neuropeptide hormone produced in the hypothalamus may be an effective strategy for treating gastric cancer, the second most common cause of cancer deaths worldwide, investigators from China and the United States contend.
Growth hormone–releasing hormone (GHRH) and its receptor (GHRH-R) are found primarily in the anterior pituitary gland, but are also present in gastric cancers, other solid tumors, and lymphomas. Increased levels of GHRH-R in tumor samples from patients with gastric cancer are associated with poor outcomes, noted Andrew V. Schally, PhD, MD, DSc, of the University of Miami, and his colleagues at the Shantou (China) University Medical College.
Furthermore, an experimental peptide drug labeled MIA-602 that targets GHRH-R inhibited the growth of gastric cancer cell lines and human tumor xenografts in mice, the investigators reported in the journal PNAS.
“The GHRH receptor is both a biomarker that can confirm prognosis and a therapeutic target,” Dr. Schally said in a statement.
Elevated GHRH-R expression in tumors
GHRH-R antagonists such as MIA-602 work through downregulation of the p21-activated kinase 1 (PAK1)–mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor–kappaB (NF-kappaB) inflammatory pathway. This pathway is involved in the interplay between inflammatory processes and intracellular signaling thought to be the cause of gastric cancer tumorigenesis and progression, the investigators explained.
They first looked for GHRH-R expression in gastric cancer samples from 106 patients, using immunohistochemistry staining of primary tumors and adjacent normal tissues. They found that gastric cancer tissues “exhibited robust expression of GHRH-R, compared with normal tissues.”
In 50 samples, GHRH-R was determined to be overexpressed, and this overexpression was significantly associated with both greater tumor size (P = .031) and high pathologic tumor stage (P = .001). Increasing expression of GHRH-R was also significantly associated with worse overall survival (P less than .001).
They confirmed these findings in samples from a multinational cohort of patients, which again showed that the highest levels of GHRH-R expression were associated with poor overall survival (P less than .001).
The authors also looked at messenger RNA expression and gene copy number in 65 gastric cancer samples and 19 adjacent normal tissue samples, and found that GHRH-R mRNA was significantly higher in tumor tissues than normal control tissues (P less than .001).
MAI-602 in vitro and in vivo
To see whether MAI-602 could inhibit the growth of gastric cancer cells, the investigators tried it at various doses in three human gastric cancer cell lines, and found that it inhibited cells in a dose-dependent fashion, compared with vehicle used as a control (P less than .001).
In addition, the experimental agent “exhibited remarkable inhibitory effects on tumor growth in vivo” in mice with human tumor xenografts (P less than .001).
Finally, they showed that the cancer suppression effects of MAI-602 work through inhibition of STAT3/NF-kappaB inflammatory signaling. In vitro and in vivo, MAI-602 decreased the expression of both GHRH and GHRH-R, whereas as a GHRH-R agonist increased levels of both the hormone and its receptor. They also demonstrated that PAK1 appears to be a critical mediator of STAT3/NF-kappaB activity, and that MAI-602 works primarily by blocking PAK1-mediated inflammatory signaling.
“MIA-602 remarkably inhibits the growth of human in vitro and in vivo through the suppression of PAK1–STAT3/NF-kappaB signaling. Our study strongly highlights the therapeutic potential of GHRH-R antagonists in the treatment of gastric cancer patients. Knowledge gained in our study will shed light on how to select the appropriate patients for personalized cancer therapy using GHRH-R antagonists,” Dr. Schally and his coauthors wrote.
The study was supported by the Li Ka Shing Foundation, Chinese foundation, and government grants to individual researchers, as well as support from the the Medical Research Service of the U.S. Department of Veterans Affairs, South Florida Veterans Affairs Foundation for Research and Education, and the University of Miami.
It sounds counterintuitive, but targeting a neuropeptide hormone produced in the hypothalamus may be an effective strategy for treating gastric cancer, the second most common cause of cancer deaths worldwide, investigators from China and the United States contend.
Growth hormone–releasing hormone (GHRH) and its receptor (GHRH-R) are found primarily in the anterior pituitary gland, but are also present in gastric cancers, other solid tumors, and lymphomas. Increased levels of GHRH-R in tumor samples from patients with gastric cancer are associated with poor outcomes, noted Andrew V. Schally, PhD, MD, DSc, of the University of Miami, and his colleagues at the Shantou (China) University Medical College.
Furthermore, an experimental peptide drug labeled MIA-602 that targets GHRH-R inhibited the growth of gastric cancer cell lines and human tumor xenografts in mice, the investigators reported in the journal PNAS.
“The GHRH receptor is both a biomarker that can confirm prognosis and a therapeutic target,” Dr. Schally said in a statement.
Elevated GHRH-R expression in tumors
GHRH-R antagonists such as MIA-602 work through downregulation of the p21-activated kinase 1 (PAK1)–mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor–kappaB (NF-kappaB) inflammatory pathway. This pathway is involved in the interplay between inflammatory processes and intracellular signaling thought to be the cause of gastric cancer tumorigenesis and progression, the investigators explained.
They first looked for GHRH-R expression in gastric cancer samples from 106 patients, using immunohistochemistry staining of primary tumors and adjacent normal tissues. They found that gastric cancer tissues “exhibited robust expression of GHRH-R, compared with normal tissues.”
In 50 samples, GHRH-R was determined to be overexpressed, and this overexpression was significantly associated with both greater tumor size (P = .031) and high pathologic tumor stage (P = .001). Increasing expression of GHRH-R was also significantly associated with worse overall survival (P less than .001).
They confirmed these findings in samples from a multinational cohort of patients, which again showed that the highest levels of GHRH-R expression were associated with poor overall survival (P less than .001).
The authors also looked at messenger RNA expression and gene copy number in 65 gastric cancer samples and 19 adjacent normal tissue samples, and found that GHRH-R mRNA was significantly higher in tumor tissues than normal control tissues (P less than .001).
MAI-602 in vitro and in vivo
To see whether MAI-602 could inhibit the growth of gastric cancer cells, the investigators tried it at various doses in three human gastric cancer cell lines, and found that it inhibited cells in a dose-dependent fashion, compared with vehicle used as a control (P less than .001).
In addition, the experimental agent “exhibited remarkable inhibitory effects on tumor growth in vivo” in mice with human tumor xenografts (P less than .001).
Finally, they showed that the cancer suppression effects of MAI-602 work through inhibition of STAT3/NF-kappaB inflammatory signaling. In vitro and in vivo, MAI-602 decreased the expression of both GHRH and GHRH-R, whereas as a GHRH-R agonist increased levels of both the hormone and its receptor. They also demonstrated that PAK1 appears to be a critical mediator of STAT3/NF-kappaB activity, and that MAI-602 works primarily by blocking PAK1-mediated inflammatory signaling.
“MIA-602 remarkably inhibits the growth of human in vitro and in vivo through the suppression of PAK1–STAT3/NF-kappaB signaling. Our study strongly highlights the therapeutic potential of GHRH-R antagonists in the treatment of gastric cancer patients. Knowledge gained in our study will shed light on how to select the appropriate patients for personalized cancer therapy using GHRH-R antagonists,” Dr. Schally and his coauthors wrote.
The study was supported by the Li Ka Shing Foundation, Chinese foundation, and government grants to individual researchers, as well as support from the the Medical Research Service of the U.S. Department of Veterans Affairs, South Florida Veterans Affairs Foundation for Research and Education, and the University of Miami.
FROM PNAS
Key clinical point:
Major finding: The experimental GHRH-R antagonist MAI-602 inhibited gastric cancer growth in cell lines and human tumor xenograft models.
Data source: Proof of concept experiments showing the relationship between GHRH-R and gastric cancer, and elucidation of a method for targeting GHRH-R with an investigational peptide compound.
Disclosures: The study was supported by the Li Ka Shing Foundation, Chinese foundation, and government grants to individual researchers, as well as support from the the Medical Research Service of the U.S. Department of Veterans Affairs, South Florida Veterans Affairs Foundation for Research and Education, and the University of Miami.
Diagnostic laparoscopy identifies ovarian cancers amenable to PCS
For women with suspected advanced epithelial ovarian cancer, diagnostic laparoscopy can help to distinguish between patients who could benefit from primary cytoreductive surgery (PCS) and those who might have better outcomes with neoadjuvant chemotherapy and interval cytoreductive surgery, according to investigators in the Netherlands.
In a randomized controlled trial exploring whether initial diagnostic laparoscopy could spare some patients from undergoing futile PCS, the investigators found that only 10% of patients assigned to diagnostic laparoscopy prior to PCS underwent a subsequent futile laparotomy, defined as residual disease greater than 1 cm following surgery. In contrast, 39% of women assigned to primary PCS had disease that might have been better treated by chemotherapy and interval surgery,
“In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to [less than] 1 cm of residual disease seems feasible, to proceed with PCS,” wrote Marrije R. Buist, MD of Academic Medical Center, Amsterdam, and colleagues.
Among women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC to IV epithelial ovarian cancer, survival depends largely on the ability of surgery to either completely remove disease, or to leave at best less than 1 cm of residual disease. However, aggressive surgery in patients with more extensive disease is associated with significant morbidities, the authors noted.
“If at PCS, extensive disease is present, surgery could be ceased, and neoadjuvant chemotherapy with interval surgery could be a good alternative treatment. Therefore, the identification of patients with extensive disease who are likely to have [more than] 1 cm of residual tumor after PCS, defined as a futile laparotomy, is important,” they wrote.
To test this idea, the investigators, from eight cancer centers in the Netherlands, enrolled 201 patients with suspected FIGO stage IIB ovarian cancer or higher, and randomly assigned them to undergo either initial diagnostic laparoscopy or PCS.
They found that 10 of the 102 patients (10%) assigned to diagnostic laparoscopy went on to undergo PCS that revealed residual disease greater than 1 cm, compared with 39 of the 99 patients (39%) assigned to PCS. This difference translated into a relative risk for futile laparotomy of 0.25 for diagnostic laparoscopy compared with PCS (P less than .001).
Only 3 (3%) patients in the diagnostic laparoscopy group went on to have both PCS and interval surgery, compared with 28 (28%) patients initially assigned to PCS (P less than .001).
The Dutch Organization for Health Research and Development supported the study. All but one coauthor reported having no potential conflicts of interest.
For women with suspected advanced epithelial ovarian cancer, diagnostic laparoscopy can help to distinguish between patients who could benefit from primary cytoreductive surgery (PCS) and those who might have better outcomes with neoadjuvant chemotherapy and interval cytoreductive surgery, according to investigators in the Netherlands.
In a randomized controlled trial exploring whether initial diagnostic laparoscopy could spare some patients from undergoing futile PCS, the investigators found that only 10% of patients assigned to diagnostic laparoscopy prior to PCS underwent a subsequent futile laparotomy, defined as residual disease greater than 1 cm following surgery. In contrast, 39% of women assigned to primary PCS had disease that might have been better treated by chemotherapy and interval surgery,
“In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to [less than] 1 cm of residual disease seems feasible, to proceed with PCS,” wrote Marrije R. Buist, MD of Academic Medical Center, Amsterdam, and colleagues.
Among women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC to IV epithelial ovarian cancer, survival depends largely on the ability of surgery to either completely remove disease, or to leave at best less than 1 cm of residual disease. However, aggressive surgery in patients with more extensive disease is associated with significant morbidities, the authors noted.
“If at PCS, extensive disease is present, surgery could be ceased, and neoadjuvant chemotherapy with interval surgery could be a good alternative treatment. Therefore, the identification of patients with extensive disease who are likely to have [more than] 1 cm of residual tumor after PCS, defined as a futile laparotomy, is important,” they wrote.
To test this idea, the investigators, from eight cancer centers in the Netherlands, enrolled 201 patients with suspected FIGO stage IIB ovarian cancer or higher, and randomly assigned them to undergo either initial diagnostic laparoscopy or PCS.
They found that 10 of the 102 patients (10%) assigned to diagnostic laparoscopy went on to undergo PCS that revealed residual disease greater than 1 cm, compared with 39 of the 99 patients (39%) assigned to PCS. This difference translated into a relative risk for futile laparotomy of 0.25 for diagnostic laparoscopy compared with PCS (P less than .001).
Only 3 (3%) patients in the diagnostic laparoscopy group went on to have both PCS and interval surgery, compared with 28 (28%) patients initially assigned to PCS (P less than .001).
The Dutch Organization for Health Research and Development supported the study. All but one coauthor reported having no potential conflicts of interest.
For women with suspected advanced epithelial ovarian cancer, diagnostic laparoscopy can help to distinguish between patients who could benefit from primary cytoreductive surgery (PCS) and those who might have better outcomes with neoadjuvant chemotherapy and interval cytoreductive surgery, according to investigators in the Netherlands.
In a randomized controlled trial exploring whether initial diagnostic laparoscopy could spare some patients from undergoing futile PCS, the investigators found that only 10% of patients assigned to diagnostic laparoscopy prior to PCS underwent a subsequent futile laparotomy, defined as residual disease greater than 1 cm following surgery. In contrast, 39% of women assigned to primary PCS had disease that might have been better treated by chemotherapy and interval surgery,
“In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to [less than] 1 cm of residual disease seems feasible, to proceed with PCS,” wrote Marrije R. Buist, MD of Academic Medical Center, Amsterdam, and colleagues.
Among women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC to IV epithelial ovarian cancer, survival depends largely on the ability of surgery to either completely remove disease, or to leave at best less than 1 cm of residual disease. However, aggressive surgery in patients with more extensive disease is associated with significant morbidities, the authors noted.
“If at PCS, extensive disease is present, surgery could be ceased, and neoadjuvant chemotherapy with interval surgery could be a good alternative treatment. Therefore, the identification of patients with extensive disease who are likely to have [more than] 1 cm of residual tumor after PCS, defined as a futile laparotomy, is important,” they wrote.
To test this idea, the investigators, from eight cancer centers in the Netherlands, enrolled 201 patients with suspected FIGO stage IIB ovarian cancer or higher, and randomly assigned them to undergo either initial diagnostic laparoscopy or PCS.
They found that 10 of the 102 patients (10%) assigned to diagnostic laparoscopy went on to undergo PCS that revealed residual disease greater than 1 cm, compared with 39 of the 99 patients (39%) assigned to PCS. This difference translated into a relative risk for futile laparotomy of 0.25 for diagnostic laparoscopy compared with PCS (P less than .001).
Only 3 (3%) patients in the diagnostic laparoscopy group went on to have both PCS and interval surgery, compared with 28 (28%) patients initially assigned to PCS (P less than .001).
The Dutch Organization for Health Research and Development supported the study. All but one coauthor reported having no potential conflicts of interest.
Key clinical point: Diagnostic laparoscopy can help to identify patients with advanced ovarian cancer who can best benefit from primary surgery or chemotherapy.
Major finding: Ten percent of women assigned to diagnostic laparoscopy underwent futile laparotomy, vs. 39% assigned to primary cytoreductive surgery.
Data source: Randomized controlled trial of 201 women with suspected FIGO stage IIB or greater disease.
Disclosures The Dutch Organization for Health Research and Development supported the study. All but one coauthor reported having no potential conflicts of interest.
In NSCLC, delayed chemo yields survival benefit comparable to early chemo
Patients with non–small-cell lung cancer (NSCLC) for whom adjuvant chemotherapy must be delayed for as long as 18 weeks have mortality outcomes that are no worse than those of patients who start chemotherapy soon after surgery, and those who undergo delayed chemotherapy have a significantly lower risk for death than patients who have no chemotherapy at all, investigators report.
A retrospective review of data on 12,473 patients with previously untreated NSCLC showed that there were no significant differences in 5-year overall survival (OS) estimates among patients who started multi-agent chemotherapy at 18-38 days postoperatively, from 39 to 56 days after surgery (the reference interval), or from 57 to 127 days after surgery, reported Daniel J. Boffa, MD, of Yale University, New Haven, Conn., and his colleagues.
In addition, when they used propensity score matching to pair patients who received chemotherapy with patients who did not undergo chemotherapy, they found that even late chemotherapy was associated with a significantly lower risk for death.
“Clinicians should still consider chemotherapy in appropriately selected patients that are healthy enough to tolerate it, up to 4 months after NSCLC resection. Further study is warranted to confirm these findings,” the investigators concluded (JAMA Oncol. 2017 Jan. 5 doi: 10.1001/jamaoncol.2016.5829).
In the retrospective review of records from the National Cancer Database, the investigators limited the study to patients for whom chemotherapy is typically prescribed: those with lymph node metastases, tumors 4 cm or larger, and/or local extension of disease. They looked at the association between the time to initiation of adjuvant chemotherapy and survival using Cox modeling with restricted cubic splines, a validated statistical method for evaluating links between survival and independent variables.
Dr. Boffa and his associates found that the unadjusted Kaplan-Meier 5-year OS estimates did not differ between the groups, at 53% for the early chemotherapy group (hazard ratio [HR] vs. the reference group, 1.009, P = .79), 55% for the reference group, and 53% for the later chemotherapy group (HR 1.037, P = .27).
Comparing adjuvant chemotherapy timing on the efficacy of surgery alone in patients matched by tumor stage and other features, the researchers found that chemotherapy started during any of the three intervals was associated with an approximately 34% reduction in risk of death compared with no chemotherapy (HR for the respective time intervals 0.672, 0.645, and 0.664; P less than .001 for each comparison).
The study helps to clarify for clinicians the benefits of adjuvant chemotherapy in select patients with NSCLC in a real-world setting, Howard (Jack) West, MD, of the Swedish Cancer Institute, Seattle, said in an accompanying editorial (JAMA Oncol. 2017 Jan. 5 doi: 10.1001/jamaoncol.2016.5798).
“While retrospective data cannot define the benefit of delayed adjuvant chemotherapy with the clarity of a prospective randomized trial, we must remember that in the land of the blind, the one-eyed man is king; these limited data inject an evidence-based answer for a very common clinical question for which we have been forced by necessity to rely only on our best judgments,” he wrote.
The study was internally supported. The authors and Dr. West reported no conflict of interest disclosures.
Patients with non–small-cell lung cancer (NSCLC) for whom adjuvant chemotherapy must be delayed for as long as 18 weeks have mortality outcomes that are no worse than those of patients who start chemotherapy soon after surgery, and those who undergo delayed chemotherapy have a significantly lower risk for death than patients who have no chemotherapy at all, investigators report.
A retrospective review of data on 12,473 patients with previously untreated NSCLC showed that there were no significant differences in 5-year overall survival (OS) estimates among patients who started multi-agent chemotherapy at 18-38 days postoperatively, from 39 to 56 days after surgery (the reference interval), or from 57 to 127 days after surgery, reported Daniel J. Boffa, MD, of Yale University, New Haven, Conn., and his colleagues.
In addition, when they used propensity score matching to pair patients who received chemotherapy with patients who did not undergo chemotherapy, they found that even late chemotherapy was associated with a significantly lower risk for death.
“Clinicians should still consider chemotherapy in appropriately selected patients that are healthy enough to tolerate it, up to 4 months after NSCLC resection. Further study is warranted to confirm these findings,” the investigators concluded (JAMA Oncol. 2017 Jan. 5 doi: 10.1001/jamaoncol.2016.5829).
In the retrospective review of records from the National Cancer Database, the investigators limited the study to patients for whom chemotherapy is typically prescribed: those with lymph node metastases, tumors 4 cm or larger, and/or local extension of disease. They looked at the association between the time to initiation of adjuvant chemotherapy and survival using Cox modeling with restricted cubic splines, a validated statistical method for evaluating links between survival and independent variables.
Dr. Boffa and his associates found that the unadjusted Kaplan-Meier 5-year OS estimates did not differ between the groups, at 53% for the early chemotherapy group (hazard ratio [HR] vs. the reference group, 1.009, P = .79), 55% for the reference group, and 53% for the later chemotherapy group (HR 1.037, P = .27).
Comparing adjuvant chemotherapy timing on the efficacy of surgery alone in patients matched by tumor stage and other features, the researchers found that chemotherapy started during any of the three intervals was associated with an approximately 34% reduction in risk of death compared with no chemotherapy (HR for the respective time intervals 0.672, 0.645, and 0.664; P less than .001 for each comparison).
The study helps to clarify for clinicians the benefits of adjuvant chemotherapy in select patients with NSCLC in a real-world setting, Howard (Jack) West, MD, of the Swedish Cancer Institute, Seattle, said in an accompanying editorial (JAMA Oncol. 2017 Jan. 5 doi: 10.1001/jamaoncol.2016.5798).
“While retrospective data cannot define the benefit of delayed adjuvant chemotherapy with the clarity of a prospective randomized trial, we must remember that in the land of the blind, the one-eyed man is king; these limited data inject an evidence-based answer for a very common clinical question for which we have been forced by necessity to rely only on our best judgments,” he wrote.
The study was internally supported. The authors and Dr. West reported no conflict of interest disclosures.
Patients with non–small-cell lung cancer (NSCLC) for whom adjuvant chemotherapy must be delayed for as long as 18 weeks have mortality outcomes that are no worse than those of patients who start chemotherapy soon after surgery, and those who undergo delayed chemotherapy have a significantly lower risk for death than patients who have no chemotherapy at all, investigators report.
A retrospective review of data on 12,473 patients with previously untreated NSCLC showed that there were no significant differences in 5-year overall survival (OS) estimates among patients who started multi-agent chemotherapy at 18-38 days postoperatively, from 39 to 56 days after surgery (the reference interval), or from 57 to 127 days after surgery, reported Daniel J. Boffa, MD, of Yale University, New Haven, Conn., and his colleagues.
In addition, when they used propensity score matching to pair patients who received chemotherapy with patients who did not undergo chemotherapy, they found that even late chemotherapy was associated with a significantly lower risk for death.
“Clinicians should still consider chemotherapy in appropriately selected patients that are healthy enough to tolerate it, up to 4 months after NSCLC resection. Further study is warranted to confirm these findings,” the investigators concluded (JAMA Oncol. 2017 Jan. 5 doi: 10.1001/jamaoncol.2016.5829).
In the retrospective review of records from the National Cancer Database, the investigators limited the study to patients for whom chemotherapy is typically prescribed: those with lymph node metastases, tumors 4 cm or larger, and/or local extension of disease. They looked at the association between the time to initiation of adjuvant chemotherapy and survival using Cox modeling with restricted cubic splines, a validated statistical method for evaluating links between survival and independent variables.
Dr. Boffa and his associates found that the unadjusted Kaplan-Meier 5-year OS estimates did not differ between the groups, at 53% for the early chemotherapy group (hazard ratio [HR] vs. the reference group, 1.009, P = .79), 55% for the reference group, and 53% for the later chemotherapy group (HR 1.037, P = .27).
Comparing adjuvant chemotherapy timing on the efficacy of surgery alone in patients matched by tumor stage and other features, the researchers found that chemotherapy started during any of the three intervals was associated with an approximately 34% reduction in risk of death compared with no chemotherapy (HR for the respective time intervals 0.672, 0.645, and 0.664; P less than .001 for each comparison).
The study helps to clarify for clinicians the benefits of adjuvant chemotherapy in select patients with NSCLC in a real-world setting, Howard (Jack) West, MD, of the Swedish Cancer Institute, Seattle, said in an accompanying editorial (JAMA Oncol. 2017 Jan. 5 doi: 10.1001/jamaoncol.2016.5798).
“While retrospective data cannot define the benefit of delayed adjuvant chemotherapy with the clarity of a prospective randomized trial, we must remember that in the land of the blind, the one-eyed man is king; these limited data inject an evidence-based answer for a very common clinical question for which we have been forced by necessity to rely only on our best judgments,” he wrote.
The study was internally supported. The authors and Dr. West reported no conflict of interest disclosures.
FROM JAMA ONCOLOGY
Key clinical point: Chemotherapy delayed for up to 18 weeks after surgery offers survival benefits comparable to those of earlier chemotherapy in non–small-cell lung cancer.
Major finding: There were no statistical differences in 5-year survival of patients with NSCLC started on chemotherapy either 18-38, 39-56, or 57-127 days after surgery.
Data source: Retrospective observational study of 12,473 patients with untreated NSCLC in the National Cancer Database.
Disclosures: The study was internally supported. The authors and Dr. West reported no conflict of interest disclosures.