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Ribociclib/letrozole combo a ‘game changer’ in advanced breast cancer
COPENHAGEN – Progression-free survival for postmenopausal women with hormone receptor–positive advanced breast cancer was significantly improved when the cyclin-dependent kinase inhibitor ribociclib was added to standard therapy with the aromatase inhibitor letrozole, interim analysis from a phase III randomized trial shows.
After 18 months of follow-up, the risk of progression-free survival (PFS) among patients assigned to receive letrozole (Femara) and ribociclib was 44% lower than for patients assigned to receive letrozole and placebo, reported Gabriel N. Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center, Houston, on behalf of coinvestigators in the MONALEESA-2 trial.
“We concluded that patients who received ribociclib with letrozole had a statistically significant and a clinically meaningful increase in progress-free survival compared to letrozole plus placebo, or letrozole alone,” he said at the European Society for Medical Oncology Congress.
“Is this a game changer? I think it probably is,” said invited discussant Stephen R.D. Johnston, MD, PhD, professor of breast cancer medicine and consultant oncologist at Royal Marsden Hospital in London.
Results of the first interim analysis of MONALEESA-2 (Mammary Oncology Assessment of LEE011’s Efficacy and Safety) were published simultaneously in the New England Journal of Medicine.
CDK 4 and 6 are frequently overexpressed in hormone receptor–positive breast cancer, and are key mediators of endocrine resistance, Dr. Hortobagyi explained.
Ribociclib is an oral small-molecule inhibitor of the pathway that includes CDK4/6 and the retinoblastoma protein, and has been shown to have efficacy in previously untreated HR-positive advanced breast cancer, and in patients with progressive disease on other therapies.
The MONALEESA-2 study is a phase III, double-blind, placebo-controlled trial of 668 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had not received prior therapy for advanced disease. Patients were stratified by the presence or absence of liver and/or lung metastases, and then assigned to receive letrozole 2.5 mg/day plus either ribociclib 600 mg/day for 3 weeks followed by 1 week off, or placebo on the same schedule.
At a preplanned interim analysis, after 243 events (disease progression or death) had occurred, the investigators found that the trial met its primary endpoint of locally assessed PFS, with a hazard ratio for ribociclib of 0.556 (P = .0000329 for superiority).
At the time of the analysis, median PFS had not been reached in the combination arm, compared with 14.7 months for the letrozole/placebo arm.
At 18 months’ follow-up (median 15.3 months), the PFS rate for ribociclib and letrozole was 63%, compared with 42.2% in the placebo group.
Respective response rates for patients with measurable disease at baseline were 52.7% vs. 37.1% (P less than .001).
Grade 3 or 4 adverse events occurring in more than 10% of patients included neutropenia in nearly two-thirds (59.3%) of the women who received ribociclib vs. 0.9% of those who received placebo, and leukopenia in 21% vs. 0.6%, respectively. In all, 7.5% of patients in the ribociclib group discontinued therapy because of adverse events, compared with 2.1% in the placebo group.
The challenge, Dr. Johnston said, will be to figure out how to integrate the findings from this trial and similar results with the CDK4/6 inhibitor palbociclib and letrozole seen in the PALOMA-2 trial into clinical practice.
Clinicians will be faced with deciding how to select various patient groups – endocrine sensitive, endocrine resistant, and treatment-naive – for targeted combinations or perhaps, for some patients, an aromatase inhibitor alone.
It also remains to be seen whether the CDK4/6 inhibitor/AI combination will be cost effective or affordable in many countries, and the pattern of resistance to CDK 4/6 inhibition is sill unknown, Dr. Johnston said.
The study was funded by Novartis. Dr. Hortobagyi disclosed grants and personal fees from the company during the conduct of the study, and personal fees from Eli Lilly and Pfizer outside the submitted work. Dr. Johnston disclosed consulting and/or research funding with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Eli Lilly, Roche/Genentech and Puma
COPENHAGEN – Progression-free survival for postmenopausal women with hormone receptor–positive advanced breast cancer was significantly improved when the cyclin-dependent kinase inhibitor ribociclib was added to standard therapy with the aromatase inhibitor letrozole, interim analysis from a phase III randomized trial shows.
After 18 months of follow-up, the risk of progression-free survival (PFS) among patients assigned to receive letrozole (Femara) and ribociclib was 44% lower than for patients assigned to receive letrozole and placebo, reported Gabriel N. Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center, Houston, on behalf of coinvestigators in the MONALEESA-2 trial.
“We concluded that patients who received ribociclib with letrozole had a statistically significant and a clinically meaningful increase in progress-free survival compared to letrozole plus placebo, or letrozole alone,” he said at the European Society for Medical Oncology Congress.
“Is this a game changer? I think it probably is,” said invited discussant Stephen R.D. Johnston, MD, PhD, professor of breast cancer medicine and consultant oncologist at Royal Marsden Hospital in London.
Results of the first interim analysis of MONALEESA-2 (Mammary Oncology Assessment of LEE011’s Efficacy and Safety) were published simultaneously in the New England Journal of Medicine.
CDK 4 and 6 are frequently overexpressed in hormone receptor–positive breast cancer, and are key mediators of endocrine resistance, Dr. Hortobagyi explained.
Ribociclib is an oral small-molecule inhibitor of the pathway that includes CDK4/6 and the retinoblastoma protein, and has been shown to have efficacy in previously untreated HR-positive advanced breast cancer, and in patients with progressive disease on other therapies.
The MONALEESA-2 study is a phase III, double-blind, placebo-controlled trial of 668 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had not received prior therapy for advanced disease. Patients were stratified by the presence or absence of liver and/or lung metastases, and then assigned to receive letrozole 2.5 mg/day plus either ribociclib 600 mg/day for 3 weeks followed by 1 week off, or placebo on the same schedule.
At a preplanned interim analysis, after 243 events (disease progression or death) had occurred, the investigators found that the trial met its primary endpoint of locally assessed PFS, with a hazard ratio for ribociclib of 0.556 (P = .0000329 for superiority).
At the time of the analysis, median PFS had not been reached in the combination arm, compared with 14.7 months for the letrozole/placebo arm.
At 18 months’ follow-up (median 15.3 months), the PFS rate for ribociclib and letrozole was 63%, compared with 42.2% in the placebo group.
Respective response rates for patients with measurable disease at baseline were 52.7% vs. 37.1% (P less than .001).
Grade 3 or 4 adverse events occurring in more than 10% of patients included neutropenia in nearly two-thirds (59.3%) of the women who received ribociclib vs. 0.9% of those who received placebo, and leukopenia in 21% vs. 0.6%, respectively. In all, 7.5% of patients in the ribociclib group discontinued therapy because of adverse events, compared with 2.1% in the placebo group.
The challenge, Dr. Johnston said, will be to figure out how to integrate the findings from this trial and similar results with the CDK4/6 inhibitor palbociclib and letrozole seen in the PALOMA-2 trial into clinical practice.
Clinicians will be faced with deciding how to select various patient groups – endocrine sensitive, endocrine resistant, and treatment-naive – for targeted combinations or perhaps, for some patients, an aromatase inhibitor alone.
It also remains to be seen whether the CDK4/6 inhibitor/AI combination will be cost effective or affordable in many countries, and the pattern of resistance to CDK 4/6 inhibition is sill unknown, Dr. Johnston said.
The study was funded by Novartis. Dr. Hortobagyi disclosed grants and personal fees from the company during the conduct of the study, and personal fees from Eli Lilly and Pfizer outside the submitted work. Dr. Johnston disclosed consulting and/or research funding with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Eli Lilly, Roche/Genentech and Puma
COPENHAGEN – Progression-free survival for postmenopausal women with hormone receptor–positive advanced breast cancer was significantly improved when the cyclin-dependent kinase inhibitor ribociclib was added to standard therapy with the aromatase inhibitor letrozole, interim analysis from a phase III randomized trial shows.
After 18 months of follow-up, the risk of progression-free survival (PFS) among patients assigned to receive letrozole (Femara) and ribociclib was 44% lower than for patients assigned to receive letrozole and placebo, reported Gabriel N. Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center, Houston, on behalf of coinvestigators in the MONALEESA-2 trial.
“We concluded that patients who received ribociclib with letrozole had a statistically significant and a clinically meaningful increase in progress-free survival compared to letrozole plus placebo, or letrozole alone,” he said at the European Society for Medical Oncology Congress.
“Is this a game changer? I think it probably is,” said invited discussant Stephen R.D. Johnston, MD, PhD, professor of breast cancer medicine and consultant oncologist at Royal Marsden Hospital in London.
Results of the first interim analysis of MONALEESA-2 (Mammary Oncology Assessment of LEE011’s Efficacy and Safety) were published simultaneously in the New England Journal of Medicine.
CDK 4 and 6 are frequently overexpressed in hormone receptor–positive breast cancer, and are key mediators of endocrine resistance, Dr. Hortobagyi explained.
Ribociclib is an oral small-molecule inhibitor of the pathway that includes CDK4/6 and the retinoblastoma protein, and has been shown to have efficacy in previously untreated HR-positive advanced breast cancer, and in patients with progressive disease on other therapies.
The MONALEESA-2 study is a phase III, double-blind, placebo-controlled trial of 668 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had not received prior therapy for advanced disease. Patients were stratified by the presence or absence of liver and/or lung metastases, and then assigned to receive letrozole 2.5 mg/day plus either ribociclib 600 mg/day for 3 weeks followed by 1 week off, or placebo on the same schedule.
At a preplanned interim analysis, after 243 events (disease progression or death) had occurred, the investigators found that the trial met its primary endpoint of locally assessed PFS, with a hazard ratio for ribociclib of 0.556 (P = .0000329 for superiority).
At the time of the analysis, median PFS had not been reached in the combination arm, compared with 14.7 months for the letrozole/placebo arm.
At 18 months’ follow-up (median 15.3 months), the PFS rate for ribociclib and letrozole was 63%, compared with 42.2% in the placebo group.
Respective response rates for patients with measurable disease at baseline were 52.7% vs. 37.1% (P less than .001).
Grade 3 or 4 adverse events occurring in more than 10% of patients included neutropenia in nearly two-thirds (59.3%) of the women who received ribociclib vs. 0.9% of those who received placebo, and leukopenia in 21% vs. 0.6%, respectively. In all, 7.5% of patients in the ribociclib group discontinued therapy because of adverse events, compared with 2.1% in the placebo group.
The challenge, Dr. Johnston said, will be to figure out how to integrate the findings from this trial and similar results with the CDK4/6 inhibitor palbociclib and letrozole seen in the PALOMA-2 trial into clinical practice.
Clinicians will be faced with deciding how to select various patient groups – endocrine sensitive, endocrine resistant, and treatment-naive – for targeted combinations or perhaps, for some patients, an aromatase inhibitor alone.
It also remains to be seen whether the CDK4/6 inhibitor/AI combination will be cost effective or affordable in many countries, and the pattern of resistance to CDK 4/6 inhibition is sill unknown, Dr. Johnston said.
The study was funded by Novartis. Dr. Hortobagyi disclosed grants and personal fees from the company during the conduct of the study, and personal fees from Eli Lilly and Pfizer outside the submitted work. Dr. Johnston disclosed consulting and/or research funding with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Eli Lilly, Roche/Genentech and Puma
Key clinical point: Adding the CDK 4/6 inhibitor ribociclib to an aromatase inhibitor significantly improved PFS in postmenopausal women with HR+/HER2- advanced breast cancer.
Major finding: The hazard ratio for progression with the combination of ribociclib and letrozole was 0.556 compared with letrozole/placebo.
Data source: Randomized phase III, placebo controlled trial in 668 postmenopausal women with untreated HR-positive/HER2- advanced breast cancer.
Disclosures: The study was funded by Novartis. Dr. Hortobagyi disclosed grants and personal fees from the company during the conduct of the study, and personal fees from Eli Lilly and Pfizer outside the submitted work. Dr. Johnston disclosed consulting and/or research funding with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Eli Lilly, Roche/Genentech and Puma.
Partial-breast irradiation alternative to mastectomy following recurrence
BOSTON – In women with in-breast failures following breast-conserving surgery and whole-breast irradiation, partial-breast irradiation with 3D conformal radiation appears to be an effective and safe alternative to mastectomy, results of a phase II trial indicate.
At a median follow-up of 3.6 years, there were only two ipsilateral breast recurrences, and four mastectomies required among 58 women treated with partial-breast irradiation after a second lumpectomy, reported Douglas W. Arthur, MD, chair of radiation oncology at Virginia Commonwealth University in Richmond.
“I think this information adds to the growing data supporting this treatment approach as an alternative to mastectomy for those who continue to want to preserve the breast,” he said at a late-breaking abstracts session at the annual meeting of the American Society of Radiation Oncology.
The NRG/RTOG 1014 study is a prospective phase II trial designed to evaluate skin, breast, and chest wall events occurring within 1 year of re-irradiation. One-year toxicity results from the trial were reported at the 2015 ASTRO annual meeting.
Dr. Arthur presented 3-year efficacy results from the trial. The investigators enrolled women with in-breast recurrences more than 1 year after whole-breast irradiation (WBI), with tumors that were smaller than 3 cm, unifocal, and resected with negative margins. Axillary involvement was limited to pathologic NO or N1 without extracapsular extension.
Partial-breast irradiation was targeted to the surgical cavity with a safety margin of plus 1.5 cm for the clinical target volume, and an additional 1-cm expansion. The prescribed dose was 45 Gy in 1.5-Gy fractions delivered via 3D conformal radiotherapy in 30 treatments.
Of 65 patients accrued, 58 completed treatment and were evaluable for efficacy. The median age was 67.5 years. In all, 23 patients had ductal carcinoma in situ, and 35 had invasive cancers. All patients were node negative.
A total of four patients (6.9%) reported late grade 3 toxicities, which included breast infection, fibrous deep connective tissue, skin induration, and breast atrophy, pain, and volume loss. There were no grade 4 toxicities, and no treatment-related deaths.
Two patients had in-breast recurrences, which translated into a year estimate of 3.7%. Four patients underwent mastectomies, for a 3-year estimated mastectomy failure rate of 5.2%. Two of the mastectomies were for the in-breast recurrences, one for a nonhealing wound, and one occurred in a patient who developed cancer in the contralateral breast and opted for a bilateral mastectomy.
BOSTON – In women with in-breast failures following breast-conserving surgery and whole-breast irradiation, partial-breast irradiation with 3D conformal radiation appears to be an effective and safe alternative to mastectomy, results of a phase II trial indicate.
At a median follow-up of 3.6 years, there were only two ipsilateral breast recurrences, and four mastectomies required among 58 women treated with partial-breast irradiation after a second lumpectomy, reported Douglas W. Arthur, MD, chair of radiation oncology at Virginia Commonwealth University in Richmond.
“I think this information adds to the growing data supporting this treatment approach as an alternative to mastectomy for those who continue to want to preserve the breast,” he said at a late-breaking abstracts session at the annual meeting of the American Society of Radiation Oncology.
The NRG/RTOG 1014 study is a prospective phase II trial designed to evaluate skin, breast, and chest wall events occurring within 1 year of re-irradiation. One-year toxicity results from the trial were reported at the 2015 ASTRO annual meeting.
Dr. Arthur presented 3-year efficacy results from the trial. The investigators enrolled women with in-breast recurrences more than 1 year after whole-breast irradiation (WBI), with tumors that were smaller than 3 cm, unifocal, and resected with negative margins. Axillary involvement was limited to pathologic NO or N1 without extracapsular extension.
Partial-breast irradiation was targeted to the surgical cavity with a safety margin of plus 1.5 cm for the clinical target volume, and an additional 1-cm expansion. The prescribed dose was 45 Gy in 1.5-Gy fractions delivered via 3D conformal radiotherapy in 30 treatments.
Of 65 patients accrued, 58 completed treatment and were evaluable for efficacy. The median age was 67.5 years. In all, 23 patients had ductal carcinoma in situ, and 35 had invasive cancers. All patients were node negative.
A total of four patients (6.9%) reported late grade 3 toxicities, which included breast infection, fibrous deep connective tissue, skin induration, and breast atrophy, pain, and volume loss. There were no grade 4 toxicities, and no treatment-related deaths.
Two patients had in-breast recurrences, which translated into a year estimate of 3.7%. Four patients underwent mastectomies, for a 3-year estimated mastectomy failure rate of 5.2%. Two of the mastectomies were for the in-breast recurrences, one for a nonhealing wound, and one occurred in a patient who developed cancer in the contralateral breast and opted for a bilateral mastectomy.
BOSTON – In women with in-breast failures following breast-conserving surgery and whole-breast irradiation, partial-breast irradiation with 3D conformal radiation appears to be an effective and safe alternative to mastectomy, results of a phase II trial indicate.
At a median follow-up of 3.6 years, there were only two ipsilateral breast recurrences, and four mastectomies required among 58 women treated with partial-breast irradiation after a second lumpectomy, reported Douglas W. Arthur, MD, chair of radiation oncology at Virginia Commonwealth University in Richmond.
“I think this information adds to the growing data supporting this treatment approach as an alternative to mastectomy for those who continue to want to preserve the breast,” he said at a late-breaking abstracts session at the annual meeting of the American Society of Radiation Oncology.
The NRG/RTOG 1014 study is a prospective phase II trial designed to evaluate skin, breast, and chest wall events occurring within 1 year of re-irradiation. One-year toxicity results from the trial were reported at the 2015 ASTRO annual meeting.
Dr. Arthur presented 3-year efficacy results from the trial. The investigators enrolled women with in-breast recurrences more than 1 year after whole-breast irradiation (WBI), with tumors that were smaller than 3 cm, unifocal, and resected with negative margins. Axillary involvement was limited to pathologic NO or N1 without extracapsular extension.
Partial-breast irradiation was targeted to the surgical cavity with a safety margin of plus 1.5 cm for the clinical target volume, and an additional 1-cm expansion. The prescribed dose was 45 Gy in 1.5-Gy fractions delivered via 3D conformal radiotherapy in 30 treatments.
Of 65 patients accrued, 58 completed treatment and were evaluable for efficacy. The median age was 67.5 years. In all, 23 patients had ductal carcinoma in situ, and 35 had invasive cancers. All patients were node negative.
A total of four patients (6.9%) reported late grade 3 toxicities, which included breast infection, fibrous deep connective tissue, skin induration, and breast atrophy, pain, and volume loss. There were no grade 4 toxicities, and no treatment-related deaths.
Two patients had in-breast recurrences, which translated into a year estimate of 3.7%. Four patients underwent mastectomies, for a 3-year estimated mastectomy failure rate of 5.2%. Two of the mastectomies were for the in-breast recurrences, one for a nonhealing wound, and one occurred in a patient who developed cancer in the contralateral breast and opted for a bilateral mastectomy.
AT ASTRO 2016
Key clinical point: Re-irradiation following second lumpectomy after in-breast cancer recurrences appears to be a safe and effective alternative to mastectomy.
Major finding: The 3-year estimated in-breast recurrence rate was 3.7%.
Data source: Phase II nonrandomized study in 58 women with in-breast failures following breast-conserving surgery and whole-breast irradiation.
Disclosures: The study was supported by the National Cancer Institute. Dr. Arthur reported formerly serving on the medical advisory board of Impedimed,
Glimmer of promise for nivolumab in neoadjuvant NSCLC therapy
COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.
Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.
To see whether immunotherapy could be safe and practical in the neoadjuvant setting, the investigators enrolled 18 patients with untreated, resectable disease and performed pretreatment tumor biopsies. Patients then received doses of nivolumab 3 mg/kg delivered at 4 weeks and 2 weeks prior to scheduled surgery. Following surgery, patients received adjuvant chemotherapy at the investigator’s discretion.
Treatment related adverse events included one grade 3 to 4 toxicity and one event leading to discontinuation. There were no adverse events requiring delay of surgery.
The investigators also conducted an exploratory analysis of response to treatment among 17 who had sufficient follow-up data for evaluation of the primary endpoints of safety and feasibility.
As noted, 12 patients had a measurable tumor response, and 7 had a major pathologic response. Of this latter group, three had no radiographic evidence of response, but tumor specimens from all 7 showed evidence of “substantial” T-cell infiltration, indicating an enhanced immune response, Dr. Forde said.
In all, 9 of the 17 patients had tumor regression of more than 50%, and 7 patients had pathologic downstaging from their pretreatment clinical stage.
Four of the seven tumors with the major pathologic response were tested with a programmed death–1 ligand immunohistochemical assay, and three were positive for the ligand.
The investigators also isolated both unique and shared T-cell clones from peripheral blood, and detected new infiltration of T-cell clones that were not seen in the tumor specimens taken prior to nivolumab therapy.
Based on these early results, the investigators plan to expand the study, with one cohort planned to receive a third presurgical dose of nivolumab, and a second cohort scheduled to receive both nivolumab and ipilimumab (Yervoy).
It remains to be seen, he said, whether patients should also receive maintenance therapy, and whether combined checkpoint inhibitors might be more effective.
However, Pieter Postmus, chair of thoracic oncology at the University of Liverpool (England), who was not involved in the study, said that he is reserving judgment on efficacy until further data are available.
“There is a potential for bias when comparing a small biopsy, which might not represent the whole tumor, with the resected tumor,” he said in a statement. “This is not a validated way to measure response to a treatment. It describes a biological effect but whether that has any clinical impact on survival is unproven.”
“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumor cells in tumor biopsies taken before and 4 to 8 weeks after immunotherapy,” he added. “If in this way regression – as defined in the preoperative study – correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies.”
COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.
Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.
To see whether immunotherapy could be safe and practical in the neoadjuvant setting, the investigators enrolled 18 patients with untreated, resectable disease and performed pretreatment tumor biopsies. Patients then received doses of nivolumab 3 mg/kg delivered at 4 weeks and 2 weeks prior to scheduled surgery. Following surgery, patients received adjuvant chemotherapy at the investigator’s discretion.
Treatment related adverse events included one grade 3 to 4 toxicity and one event leading to discontinuation. There were no adverse events requiring delay of surgery.
The investigators also conducted an exploratory analysis of response to treatment among 17 who had sufficient follow-up data for evaluation of the primary endpoints of safety and feasibility.
As noted, 12 patients had a measurable tumor response, and 7 had a major pathologic response. Of this latter group, three had no radiographic evidence of response, but tumor specimens from all 7 showed evidence of “substantial” T-cell infiltration, indicating an enhanced immune response, Dr. Forde said.
In all, 9 of the 17 patients had tumor regression of more than 50%, and 7 patients had pathologic downstaging from their pretreatment clinical stage.
Four of the seven tumors with the major pathologic response were tested with a programmed death–1 ligand immunohistochemical assay, and three were positive for the ligand.
The investigators also isolated both unique and shared T-cell clones from peripheral blood, and detected new infiltration of T-cell clones that were not seen in the tumor specimens taken prior to nivolumab therapy.
Based on these early results, the investigators plan to expand the study, with one cohort planned to receive a third presurgical dose of nivolumab, and a second cohort scheduled to receive both nivolumab and ipilimumab (Yervoy).
It remains to be seen, he said, whether patients should also receive maintenance therapy, and whether combined checkpoint inhibitors might be more effective.
However, Pieter Postmus, chair of thoracic oncology at the University of Liverpool (England), who was not involved in the study, said that he is reserving judgment on efficacy until further data are available.
“There is a potential for bias when comparing a small biopsy, which might not represent the whole tumor, with the resected tumor,” he said in a statement. “This is not a validated way to measure response to a treatment. It describes a biological effect but whether that has any clinical impact on survival is unproven.”
“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumor cells in tumor biopsies taken before and 4 to 8 weeks after immunotherapy,” he added. “If in this way regression – as defined in the preoperative study – correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies.”
COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.
Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.
To see whether immunotherapy could be safe and practical in the neoadjuvant setting, the investigators enrolled 18 patients with untreated, resectable disease and performed pretreatment tumor biopsies. Patients then received doses of nivolumab 3 mg/kg delivered at 4 weeks and 2 weeks prior to scheduled surgery. Following surgery, patients received adjuvant chemotherapy at the investigator’s discretion.
Treatment related adverse events included one grade 3 to 4 toxicity and one event leading to discontinuation. There were no adverse events requiring delay of surgery.
The investigators also conducted an exploratory analysis of response to treatment among 17 who had sufficient follow-up data for evaluation of the primary endpoints of safety and feasibility.
As noted, 12 patients had a measurable tumor response, and 7 had a major pathologic response. Of this latter group, three had no radiographic evidence of response, but tumor specimens from all 7 showed evidence of “substantial” T-cell infiltration, indicating an enhanced immune response, Dr. Forde said.
In all, 9 of the 17 patients had tumor regression of more than 50%, and 7 patients had pathologic downstaging from their pretreatment clinical stage.
Four of the seven tumors with the major pathologic response were tested with a programmed death–1 ligand immunohistochemical assay, and three were positive for the ligand.
The investigators also isolated both unique and shared T-cell clones from peripheral blood, and detected new infiltration of T-cell clones that were not seen in the tumor specimens taken prior to nivolumab therapy.
Based on these early results, the investigators plan to expand the study, with one cohort planned to receive a third presurgical dose of nivolumab, and a second cohort scheduled to receive both nivolumab and ipilimumab (Yervoy).
It remains to be seen, he said, whether patients should also receive maintenance therapy, and whether combined checkpoint inhibitors might be more effective.
However, Pieter Postmus, chair of thoracic oncology at the University of Liverpool (England), who was not involved in the study, said that he is reserving judgment on efficacy until further data are available.
“There is a potential for bias when comparing a small biopsy, which might not represent the whole tumor, with the resected tumor,” he said in a statement. “This is not a validated way to measure response to a treatment. It describes a biological effect but whether that has any clinical impact on survival is unproven.”
“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumor cells in tumor biopsies taken before and 4 to 8 weeks after immunotherapy,” he added. “If in this way regression – as defined in the preoperative study – correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies.”
AT ESMO 2016
Key clinical point: Checkpoint inhibitors have shown good efficacy for treatment of advanced NSCLC, but use in the neoadjuvant setting is still investigational.
Major finding: Seven of 17 patients had a major pathologic response (less than 10% viable tumor remaining).
Data source: Safety and feasibility study in 18 patients with stage I-IIIA non–small cell lung cancer.
Disclosures: The study was supported by the American Association for Cancer Research, the Cancer Research Institute, LUNGevity, and Stand Up to Cancer. Bristol-Myers Squibb donated nivolumab and provided funding for PD-L1 testing. Dr. Forde disclosed institution research grants from Bristol-Myers Squibb, Kyowa, Novartis, and uncompensated consulting for AstraZeneca and Celgene. Dr. Baas disclosed grants and research support from Bristol-Myers Squibb. Dr. Postmus had no disclosures.
In favorable intermediate-risk prostate cancer, brachytherapy alone suffices
BOSTON – In a finding hailed as “paradigm changing,” men with favorable intermediate-risk prostate cancer may have good disease control with brachytherapy alone, with fewer late-term toxicities than with brachytherapy combined with external-beam radiation, investigators reported.
After 5 years of follow-up, there were no significant differences in rates of freedom from disease progression among patients assigned to receive combined external-beam radiation (EBRT) and transperineal interstitial permanent brachytherapy (PB) or PB alone in selected patients with intermediate-risk prostatic carcinoma.
“I think you’re underselling your results – I’m pretty excited about these results,” Colleen Lawton, MD, professor and vice chair of radiation oncology at the Medical College of Wisconsin in Milwaukee, told Dr. Prestidge at the annual meeting of the American Society of Radiation Oncology.
The results show that, “for the intermediate-risk group, not the worst of intermediate [risk] but the vast majority, they don’t need the toxicity of that external beam, and they don’t need the cost of it,” she said at a briefing following his presentation of the data in a plenary session.
Dr. Lawton said that, when the NRG Oncology/RTOG 0232study was initiated (the first patients were enrolled in 2003), “there were factions that believed you could not treat intermediate-risk prostate cancer – which isn’t the best, isn’t the worse, but is somewhere in the middle – with anything but the combination, and this shows that’s not true.”
The trial was designed to test the hypothesis that patients with intermediate-risk prostate cancer treated with combined EBRT and PB would have a 10% improvement in freedom from progression (FFP), compared with men treated with PB alone.
A total of 579 patients with histologically confirmed prostate cancer, stages T1c-2b and Zubrod performance score 0 or 1 were enrolled. The patients also had Gleason score 2-6 and prostate-specific antigen (PSA) from 10 to less than 20 ng/mL; Gleason score and PSA less than 10 ng/mL; or prostate volume less than 60 cc.
In addition, androgen deprivation therapy (ADT) was not allowed on the study, and patients could not have distant metastases or radiographically suspicious nodes at the time of enrollment.
Patients were stratified by stage, Gleason score, PSA and history of ADT, and then randomized to the combined therapy, consisting of 45 Gy in a partial pelvis dose delivered in 1.8 Gy fractions for 5 weeks, followed 2-4 weeks later with brachytherapy using either a radioactive iodine (I-125) source prescribed as a 110-Gy boost dose, or palladium 103 in a 100 Gy boost dose; or brachytherapy alone (145-Gy dose with I-I25, 125-Gy dose with palladium 103). EBRT was delivered by either intensity-modulated radiation (43%) or 3D conformal radiation.
Five years after randomization, there were a total of 66 cases of treatment failure (measured as either biochemical failure according to ASTRO criteria, local progression, distant metastases, or death from any cause), 34 occurring in men treated with the combination, and 32 in men treated with brachytherapy alone. Biochemical failures accounted for 68% of events among patients on the combined modalities and 53% of those on brachytherapy alone. There were 9 deaths in the combined arm and 14 deaths in the brachytherapy-only arm, but none were prostate cancer related, Dr. Prestidge said.
In multivariate analysis adjusted for treatment type, age, race, prior hormonal therapy, Gleason/PSA, and tumor stage, the only significant predictor of FFP was Gleason 7/PSA less than 10 ng/mL, which was associated with better outcomes, compared with Gleason score less than 7/PSA 10-20 ng/mL (odds ratio, 0.5; P = .046).
There was no difference in 5-year overall survival between the groups.
As noted before, there were no significant differences in acute toxicities, but there were significantly more late grade 2 or greater toxicities among patients who underwent EBRT and PB (53% vs. 37%; P less than .0001), and more late grade 3 or greater toxicities (12% vs. 7%; P = .039).
Michael J Zelefsky, MD, professor of radiation oncology and chief of the brachytherapy service at Memorial Sloan Kettering Cancer Center in New York, the invited discussant, said that the study suggests that “combining EBRT with brachytherapy for favorable intermediate-risk disease may constitute unnecessary overkill.”
He asserted, however, that favorable intermediate-risk disease behaves clinically more like low-risk disease, whereas unfavorable intermediate-risk disease is closer to high-risk disease in its clinical behavior.
It is plausible that, for patients with unfavorable intermediate-risk disease, added dose intensification associated with combined modality therapy could result in improved FFP and local tumor control, he said.
The study was funded by the National Cancer Institute. Dr. Prestidge disclosed consulting for Varian, Elekta, and IsoRay. Dr. Zelefsky disclosed receiving honoraria from Bebig Brachytherapy, Augmenix, and as editor-in-chief of Brachytherapy. Dr. Lawton reported no relevant disclosures.
BOSTON – In a finding hailed as “paradigm changing,” men with favorable intermediate-risk prostate cancer may have good disease control with brachytherapy alone, with fewer late-term toxicities than with brachytherapy combined with external-beam radiation, investigators reported.
After 5 years of follow-up, there were no significant differences in rates of freedom from disease progression among patients assigned to receive combined external-beam radiation (EBRT) and transperineal interstitial permanent brachytherapy (PB) or PB alone in selected patients with intermediate-risk prostatic carcinoma.
“I think you’re underselling your results – I’m pretty excited about these results,” Colleen Lawton, MD, professor and vice chair of radiation oncology at the Medical College of Wisconsin in Milwaukee, told Dr. Prestidge at the annual meeting of the American Society of Radiation Oncology.
The results show that, “for the intermediate-risk group, not the worst of intermediate [risk] but the vast majority, they don’t need the toxicity of that external beam, and they don’t need the cost of it,” she said at a briefing following his presentation of the data in a plenary session.
Dr. Lawton said that, when the NRG Oncology/RTOG 0232study was initiated (the first patients were enrolled in 2003), “there were factions that believed you could not treat intermediate-risk prostate cancer – which isn’t the best, isn’t the worse, but is somewhere in the middle – with anything but the combination, and this shows that’s not true.”
The trial was designed to test the hypothesis that patients with intermediate-risk prostate cancer treated with combined EBRT and PB would have a 10% improvement in freedom from progression (FFP), compared with men treated with PB alone.
A total of 579 patients with histologically confirmed prostate cancer, stages T1c-2b and Zubrod performance score 0 or 1 were enrolled. The patients also had Gleason score 2-6 and prostate-specific antigen (PSA) from 10 to less than 20 ng/mL; Gleason score and PSA less than 10 ng/mL; or prostate volume less than 60 cc.
In addition, androgen deprivation therapy (ADT) was not allowed on the study, and patients could not have distant metastases or radiographically suspicious nodes at the time of enrollment.
Patients were stratified by stage, Gleason score, PSA and history of ADT, and then randomized to the combined therapy, consisting of 45 Gy in a partial pelvis dose delivered in 1.8 Gy fractions for 5 weeks, followed 2-4 weeks later with brachytherapy using either a radioactive iodine (I-125) source prescribed as a 110-Gy boost dose, or palladium 103 in a 100 Gy boost dose; or brachytherapy alone (145-Gy dose with I-I25, 125-Gy dose with palladium 103). EBRT was delivered by either intensity-modulated radiation (43%) or 3D conformal radiation.
Five years after randomization, there were a total of 66 cases of treatment failure (measured as either biochemical failure according to ASTRO criteria, local progression, distant metastases, or death from any cause), 34 occurring in men treated with the combination, and 32 in men treated with brachytherapy alone. Biochemical failures accounted for 68% of events among patients on the combined modalities and 53% of those on brachytherapy alone. There were 9 deaths in the combined arm and 14 deaths in the brachytherapy-only arm, but none were prostate cancer related, Dr. Prestidge said.
In multivariate analysis adjusted for treatment type, age, race, prior hormonal therapy, Gleason/PSA, and tumor stage, the only significant predictor of FFP was Gleason 7/PSA less than 10 ng/mL, which was associated with better outcomes, compared with Gleason score less than 7/PSA 10-20 ng/mL (odds ratio, 0.5; P = .046).
There was no difference in 5-year overall survival between the groups.
As noted before, there were no significant differences in acute toxicities, but there were significantly more late grade 2 or greater toxicities among patients who underwent EBRT and PB (53% vs. 37%; P less than .0001), and more late grade 3 or greater toxicities (12% vs. 7%; P = .039).
Michael J Zelefsky, MD, professor of radiation oncology and chief of the brachytherapy service at Memorial Sloan Kettering Cancer Center in New York, the invited discussant, said that the study suggests that “combining EBRT with brachytherapy for favorable intermediate-risk disease may constitute unnecessary overkill.”
He asserted, however, that favorable intermediate-risk disease behaves clinically more like low-risk disease, whereas unfavorable intermediate-risk disease is closer to high-risk disease in its clinical behavior.
It is plausible that, for patients with unfavorable intermediate-risk disease, added dose intensification associated with combined modality therapy could result in improved FFP and local tumor control, he said.
The study was funded by the National Cancer Institute. Dr. Prestidge disclosed consulting for Varian, Elekta, and IsoRay. Dr. Zelefsky disclosed receiving honoraria from Bebig Brachytherapy, Augmenix, and as editor-in-chief of Brachytherapy. Dr. Lawton reported no relevant disclosures.
BOSTON – In a finding hailed as “paradigm changing,” men with favorable intermediate-risk prostate cancer may have good disease control with brachytherapy alone, with fewer late-term toxicities than with brachytherapy combined with external-beam radiation, investigators reported.
After 5 years of follow-up, there were no significant differences in rates of freedom from disease progression among patients assigned to receive combined external-beam radiation (EBRT) and transperineal interstitial permanent brachytherapy (PB) or PB alone in selected patients with intermediate-risk prostatic carcinoma.
“I think you’re underselling your results – I’m pretty excited about these results,” Colleen Lawton, MD, professor and vice chair of radiation oncology at the Medical College of Wisconsin in Milwaukee, told Dr. Prestidge at the annual meeting of the American Society of Radiation Oncology.
The results show that, “for the intermediate-risk group, not the worst of intermediate [risk] but the vast majority, they don’t need the toxicity of that external beam, and they don’t need the cost of it,” she said at a briefing following his presentation of the data in a plenary session.
Dr. Lawton said that, when the NRG Oncology/RTOG 0232study was initiated (the first patients were enrolled in 2003), “there were factions that believed you could not treat intermediate-risk prostate cancer – which isn’t the best, isn’t the worse, but is somewhere in the middle – with anything but the combination, and this shows that’s not true.”
The trial was designed to test the hypothesis that patients with intermediate-risk prostate cancer treated with combined EBRT and PB would have a 10% improvement in freedom from progression (FFP), compared with men treated with PB alone.
A total of 579 patients with histologically confirmed prostate cancer, stages T1c-2b and Zubrod performance score 0 or 1 were enrolled. The patients also had Gleason score 2-6 and prostate-specific antigen (PSA) from 10 to less than 20 ng/mL; Gleason score and PSA less than 10 ng/mL; or prostate volume less than 60 cc.
In addition, androgen deprivation therapy (ADT) was not allowed on the study, and patients could not have distant metastases or radiographically suspicious nodes at the time of enrollment.
Patients were stratified by stage, Gleason score, PSA and history of ADT, and then randomized to the combined therapy, consisting of 45 Gy in a partial pelvis dose delivered in 1.8 Gy fractions for 5 weeks, followed 2-4 weeks later with brachytherapy using either a radioactive iodine (I-125) source prescribed as a 110-Gy boost dose, or palladium 103 in a 100 Gy boost dose; or brachytherapy alone (145-Gy dose with I-I25, 125-Gy dose with palladium 103). EBRT was delivered by either intensity-modulated radiation (43%) or 3D conformal radiation.
Five years after randomization, there were a total of 66 cases of treatment failure (measured as either biochemical failure according to ASTRO criteria, local progression, distant metastases, or death from any cause), 34 occurring in men treated with the combination, and 32 in men treated with brachytherapy alone. Biochemical failures accounted for 68% of events among patients on the combined modalities and 53% of those on brachytherapy alone. There were 9 deaths in the combined arm and 14 deaths in the brachytherapy-only arm, but none were prostate cancer related, Dr. Prestidge said.
In multivariate analysis adjusted for treatment type, age, race, prior hormonal therapy, Gleason/PSA, and tumor stage, the only significant predictor of FFP was Gleason 7/PSA less than 10 ng/mL, which was associated with better outcomes, compared with Gleason score less than 7/PSA 10-20 ng/mL (odds ratio, 0.5; P = .046).
There was no difference in 5-year overall survival between the groups.
As noted before, there were no significant differences in acute toxicities, but there were significantly more late grade 2 or greater toxicities among patients who underwent EBRT and PB (53% vs. 37%; P less than .0001), and more late grade 3 or greater toxicities (12% vs. 7%; P = .039).
Michael J Zelefsky, MD, professor of radiation oncology and chief of the brachytherapy service at Memorial Sloan Kettering Cancer Center in New York, the invited discussant, said that the study suggests that “combining EBRT with brachytherapy for favorable intermediate-risk disease may constitute unnecessary overkill.”
He asserted, however, that favorable intermediate-risk disease behaves clinically more like low-risk disease, whereas unfavorable intermediate-risk disease is closer to high-risk disease in its clinical behavior.
It is plausible that, for patients with unfavorable intermediate-risk disease, added dose intensification associated with combined modality therapy could result in improved FFP and local tumor control, he said.
The study was funded by the National Cancer Institute. Dr. Prestidge disclosed consulting for Varian, Elekta, and IsoRay. Dr. Zelefsky disclosed receiving honoraria from Bebig Brachytherapy, Augmenix, and as editor-in-chief of Brachytherapy. Dr. Lawton reported no relevant disclosures.
AT ASTRO 2016
Key clinical point: It may be clinically unnecessary to add external-beam radiation to brachytherapy in men with favorable intermediate-risk prostate cancer.
Major finding: Outcomes were comparable for men with favorable intermediate-risk prostate cancer treated with external-beam radiation plus brachytherapy or brachytherapy alone.
Data source: Randomized, controlled trial in 579 men with intermediate-risk prostate cancer.
Disclosures: The study was funded by the National Cancer Institute. Dr. Prestidge disclosed consulting for Varian, Elekta, and IsoRay. Dr. Zelefsky disclosed receiving honoraria from Bebig Brachytherapy, Augmenix, and as editor-in-chief of Brachytherapy. Dr. Lawton reported no relevant disclosures.
Extended half-life clotting factors are safe, effective, and pricey
ORLANDO – Early experience with extended half-life clotting factor concentrates suggests these products are generally safe and effective, at least in the short term, according to hemophilia experts.
“In adolescent and adult patients, the extended half-life clotting factor concentrates demonstrate efficacy and safety in a variety of clinical settings, including prophylaxis, treatment of bleeds, and perisurgical hemostasis,” said Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre in Johannesburg, South Africa.
Barriers to prophylaxis include “the need to inject the clotting factor concentrate at least two or three times a week, poor venous access, and, of course, poor adherence and compliance from our patients. Essentially, the extended half-life products were developed to mitigate these limitations,” he said.
Dr. Mahlangu and Guy Young, MD, a pediatric hematologist at Children’s Hospital Los Angeles, discussed results from published clinical trials of EHL products in children and adults.
The X factor
Extended half-life products currently available or in development include those created through fusion technology, including factor VIII products for treatment of hemophilia A, factor IX for treating hemophilia B, and factor VII products for treating factor VII deficiency (Alexander’s Disease).
More recent products created through pegylation technology include recombinant FVIII products.
Factor IX EHL CFCs
The three recombinant factor IX (rFIX) products that have completed phase III clinical trials are: nonacog beta pegol (N9-GP), rFIXFc (Alprolix), and rFIX-FP (Idelvion). The latter two are approved by the U.S. Food and Drug Administration; the former is waiting European and U.S. approval.
In clinical trials in adolescents and adults, these agents were associated with low median annualized bleeding rates, as follows:
• rFIXFc: 3.0 for a 50 IU/kg dose given every 7 days, and 1.4 for a 100 IU/kg dose given every 10 days
• rFIX-FP: 0.0 for a 40 IU/kg dose given every 7 days, and 1.08 for a 75 IU/kg dose given every 14 days
• Nonacog beta pegol: 2.93 for a 10 IU/kg dose and 1.0 for a 40 IU/kg dose, each given every 7 days.
All of these agents effectively treated bleeding episodes after one or two doses, Dr. Mahlangu said. The respective overall hemostatic efficacy rates were 97.2%, 96.7%, and 97.1%.
Safety analyses from published studies showed that no patients exposed to any of these agents developed inhibiting antibodies, although three patients treated with rFIXFc and nonacog beta pegol each developed noninhibitory antibodies.
There were no deaths from thromboembolic episodes and no drug-related serious adverse events.
Data are more limited for children treated with rFIX products, Dr. Young noted. In studies thus far, no children developed inhibitors, although this population had been heavily pretreated, he noted. Median annualized bleeding rates ranged from 1 to 3 and did not differ significantly between the products.
Factor VIII EHL CFCs
Four factor VIII EHL products are available or in development: rFVIIIFc (Eloctate); antihemophilic factor, pegylated (Adynovate); turoctocog alfa pegol (N8-GP); and BAY 94-9027. The former two agents are approved in the United States.
In adults and adolescents, these products have half-lives comparatively shorter than those seen with Factor IX products, the researchers noted.
Annualized bleeding rates for patients on prophylaxis with these agents were less than 4 bleeds per year, ranging from 1.3 to 3.6. In all, 96% of bleeds that did occur could be resolved with one or two injections of the extended half-life rFVIII products.
All patients had at least 50 exposures to these products, and none have developed inhibitors to date.
Only one study has been published to date of factor VIII products in children, comparing a standard half-life product with rFVIIIFc, Dr. Young said.
In this study, the patients were treated with a twice weekly, split-dose regimen. No patients developed inhibitors, and the mean annualized bleeding rate was a low 1.96.
Dr. Mahlangu disclosed research grants from Bayer, Biogen, CSL Behring, Novo Nordisk, and Roche, and speakers bureau participation for Amgen, Biotest, Biogen, CSL Behring, Novo Nordisk, and Sobi. Dr. Young disclosed honoraria and consulting fees from Baxalta, Bayer, Biogen, CSL Behring, and Novo Nordisk. Ellis J. Neufeld, MD, PhD, the invited discussant of the presentation, disclosed institutional grants from Baxalta, Novo Nordisk, and Octapharma, consulting/advising for those companies and for CSL Behring, Genentech, Hema Biologics, and Pfizer.
Improvements in half-life are incremental with the factor VIII products, but ground breaking with the factor IX products, allowing treatment intervals to be substantially prolonged. Pivotal trials of the several longer-acting products have been positive and generally convincing.
However, the pricing of these extended half-life products seems to reflect the so called “value proposition,” a concept from Big Pharma that puts a premium on convenience or novelty when determining the marketing price for a new drug. But the price may not always be commensurate with the clinical benefits patients derive from these newer agents.
How trials translate into treatment recommendations is complicated, and as Dr. Young and Dr. Mahlangu both made very clear, you need to consider that factor VIII and factor IX prolongation is entirely separate, even when the same technology is used, because the consequences are very different.
Ellis J. Neufeld, MD, PhD, is the associate chief of hematology/oncology at Boston Children’s Hospital, and was the invited discussant of the presentation.
Improvements in half-life are incremental with the factor VIII products, but ground breaking with the factor IX products, allowing treatment intervals to be substantially prolonged. Pivotal trials of the several longer-acting products have been positive and generally convincing.
However, the pricing of these extended half-life products seems to reflect the so called “value proposition,” a concept from Big Pharma that puts a premium on convenience or novelty when determining the marketing price for a new drug. But the price may not always be commensurate with the clinical benefits patients derive from these newer agents.
How trials translate into treatment recommendations is complicated, and as Dr. Young and Dr. Mahlangu both made very clear, you need to consider that factor VIII and factor IX prolongation is entirely separate, even when the same technology is used, because the consequences are very different.
Ellis J. Neufeld, MD, PhD, is the associate chief of hematology/oncology at Boston Children’s Hospital, and was the invited discussant of the presentation.
Improvements in half-life are incremental with the factor VIII products, but ground breaking with the factor IX products, allowing treatment intervals to be substantially prolonged. Pivotal trials of the several longer-acting products have been positive and generally convincing.
However, the pricing of these extended half-life products seems to reflect the so called “value proposition,” a concept from Big Pharma that puts a premium on convenience or novelty when determining the marketing price for a new drug. But the price may not always be commensurate with the clinical benefits patients derive from these newer agents.
How trials translate into treatment recommendations is complicated, and as Dr. Young and Dr. Mahlangu both made very clear, you need to consider that factor VIII and factor IX prolongation is entirely separate, even when the same technology is used, because the consequences are very different.
Ellis J. Neufeld, MD, PhD, is the associate chief of hematology/oncology at Boston Children’s Hospital, and was the invited discussant of the presentation.
ORLANDO – Early experience with extended half-life clotting factor concentrates suggests these products are generally safe and effective, at least in the short term, according to hemophilia experts.
“In adolescent and adult patients, the extended half-life clotting factor concentrates demonstrate efficacy and safety in a variety of clinical settings, including prophylaxis, treatment of bleeds, and perisurgical hemostasis,” said Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre in Johannesburg, South Africa.
Barriers to prophylaxis include “the need to inject the clotting factor concentrate at least two or three times a week, poor venous access, and, of course, poor adherence and compliance from our patients. Essentially, the extended half-life products were developed to mitigate these limitations,” he said.
Dr. Mahlangu and Guy Young, MD, a pediatric hematologist at Children’s Hospital Los Angeles, discussed results from published clinical trials of EHL products in children and adults.
The X factor
Extended half-life products currently available or in development include those created through fusion technology, including factor VIII products for treatment of hemophilia A, factor IX for treating hemophilia B, and factor VII products for treating factor VII deficiency (Alexander’s Disease).
More recent products created through pegylation technology include recombinant FVIII products.
Factor IX EHL CFCs
The three recombinant factor IX (rFIX) products that have completed phase III clinical trials are: nonacog beta pegol (N9-GP), rFIXFc (Alprolix), and rFIX-FP (Idelvion). The latter two are approved by the U.S. Food and Drug Administration; the former is waiting European and U.S. approval.
In clinical trials in adolescents and adults, these agents were associated with low median annualized bleeding rates, as follows:
• rFIXFc: 3.0 for a 50 IU/kg dose given every 7 days, and 1.4 for a 100 IU/kg dose given every 10 days
• rFIX-FP: 0.0 for a 40 IU/kg dose given every 7 days, and 1.08 for a 75 IU/kg dose given every 14 days
• Nonacog beta pegol: 2.93 for a 10 IU/kg dose and 1.0 for a 40 IU/kg dose, each given every 7 days.
All of these agents effectively treated bleeding episodes after one or two doses, Dr. Mahlangu said. The respective overall hemostatic efficacy rates were 97.2%, 96.7%, and 97.1%.
Safety analyses from published studies showed that no patients exposed to any of these agents developed inhibiting antibodies, although three patients treated with rFIXFc and nonacog beta pegol each developed noninhibitory antibodies.
There were no deaths from thromboembolic episodes and no drug-related serious adverse events.
Data are more limited for children treated with rFIX products, Dr. Young noted. In studies thus far, no children developed inhibitors, although this population had been heavily pretreated, he noted. Median annualized bleeding rates ranged from 1 to 3 and did not differ significantly between the products.
Factor VIII EHL CFCs
Four factor VIII EHL products are available or in development: rFVIIIFc (Eloctate); antihemophilic factor, pegylated (Adynovate); turoctocog alfa pegol (N8-GP); and BAY 94-9027. The former two agents are approved in the United States.
In adults and adolescents, these products have half-lives comparatively shorter than those seen with Factor IX products, the researchers noted.
Annualized bleeding rates for patients on prophylaxis with these agents were less than 4 bleeds per year, ranging from 1.3 to 3.6. In all, 96% of bleeds that did occur could be resolved with one or two injections of the extended half-life rFVIII products.
All patients had at least 50 exposures to these products, and none have developed inhibitors to date.
Only one study has been published to date of factor VIII products in children, comparing a standard half-life product with rFVIIIFc, Dr. Young said.
In this study, the patients were treated with a twice weekly, split-dose regimen. No patients developed inhibitors, and the mean annualized bleeding rate was a low 1.96.
Dr. Mahlangu disclosed research grants from Bayer, Biogen, CSL Behring, Novo Nordisk, and Roche, and speakers bureau participation for Amgen, Biotest, Biogen, CSL Behring, Novo Nordisk, and Sobi. Dr. Young disclosed honoraria and consulting fees from Baxalta, Bayer, Biogen, CSL Behring, and Novo Nordisk. Ellis J. Neufeld, MD, PhD, the invited discussant of the presentation, disclosed institutional grants from Baxalta, Novo Nordisk, and Octapharma, consulting/advising for those companies and for CSL Behring, Genentech, Hema Biologics, and Pfizer.
ORLANDO – Early experience with extended half-life clotting factor concentrates suggests these products are generally safe and effective, at least in the short term, according to hemophilia experts.
“In adolescent and adult patients, the extended half-life clotting factor concentrates demonstrate efficacy and safety in a variety of clinical settings, including prophylaxis, treatment of bleeds, and perisurgical hemostasis,” said Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre in Johannesburg, South Africa.
Barriers to prophylaxis include “the need to inject the clotting factor concentrate at least two or three times a week, poor venous access, and, of course, poor adherence and compliance from our patients. Essentially, the extended half-life products were developed to mitigate these limitations,” he said.
Dr. Mahlangu and Guy Young, MD, a pediatric hematologist at Children’s Hospital Los Angeles, discussed results from published clinical trials of EHL products in children and adults.
The X factor
Extended half-life products currently available or in development include those created through fusion technology, including factor VIII products for treatment of hemophilia A, factor IX for treating hemophilia B, and factor VII products for treating factor VII deficiency (Alexander’s Disease).
More recent products created through pegylation technology include recombinant FVIII products.
Factor IX EHL CFCs
The three recombinant factor IX (rFIX) products that have completed phase III clinical trials are: nonacog beta pegol (N9-GP), rFIXFc (Alprolix), and rFIX-FP (Idelvion). The latter two are approved by the U.S. Food and Drug Administration; the former is waiting European and U.S. approval.
In clinical trials in adolescents and adults, these agents were associated with low median annualized bleeding rates, as follows:
• rFIXFc: 3.0 for a 50 IU/kg dose given every 7 days, and 1.4 for a 100 IU/kg dose given every 10 days
• rFIX-FP: 0.0 for a 40 IU/kg dose given every 7 days, and 1.08 for a 75 IU/kg dose given every 14 days
• Nonacog beta pegol: 2.93 for a 10 IU/kg dose and 1.0 for a 40 IU/kg dose, each given every 7 days.
All of these agents effectively treated bleeding episodes after one or two doses, Dr. Mahlangu said. The respective overall hemostatic efficacy rates were 97.2%, 96.7%, and 97.1%.
Safety analyses from published studies showed that no patients exposed to any of these agents developed inhibiting antibodies, although three patients treated with rFIXFc and nonacog beta pegol each developed noninhibitory antibodies.
There were no deaths from thromboembolic episodes and no drug-related serious adverse events.
Data are more limited for children treated with rFIX products, Dr. Young noted. In studies thus far, no children developed inhibitors, although this population had been heavily pretreated, he noted. Median annualized bleeding rates ranged from 1 to 3 and did not differ significantly between the products.
Factor VIII EHL CFCs
Four factor VIII EHL products are available or in development: rFVIIIFc (Eloctate); antihemophilic factor, pegylated (Adynovate); turoctocog alfa pegol (N8-GP); and BAY 94-9027. The former two agents are approved in the United States.
In adults and adolescents, these products have half-lives comparatively shorter than those seen with Factor IX products, the researchers noted.
Annualized bleeding rates for patients on prophylaxis with these agents were less than 4 bleeds per year, ranging from 1.3 to 3.6. In all, 96% of bleeds that did occur could be resolved with one or two injections of the extended half-life rFVIII products.
All patients had at least 50 exposures to these products, and none have developed inhibitors to date.
Only one study has been published to date of factor VIII products in children, comparing a standard half-life product with rFVIIIFc, Dr. Young said.
In this study, the patients were treated with a twice weekly, split-dose regimen. No patients developed inhibitors, and the mean annualized bleeding rate was a low 1.96.
Dr. Mahlangu disclosed research grants from Bayer, Biogen, CSL Behring, Novo Nordisk, and Roche, and speakers bureau participation for Amgen, Biotest, Biogen, CSL Behring, Novo Nordisk, and Sobi. Dr. Young disclosed honoraria and consulting fees from Baxalta, Bayer, Biogen, CSL Behring, and Novo Nordisk. Ellis J. Neufeld, MD, PhD, the invited discussant of the presentation, disclosed institutional grants from Baxalta, Novo Nordisk, and Octapharma, consulting/advising for those companies and for CSL Behring, Genentech, Hema Biologics, and Pfizer.
AT WFH 2016 WORLD CONGRESS
Limit primary site radiation, but not craniospinal dose in medulloblastoma
BOSTON – For children with average-risk medulloblastoma, it is safe to limit the radiation boost to the posterior fossa, but reducing doses to the craniospinal axis results in worse outcomes among younger children, and is not advisable, according to results from the largest trial conducted in this population.
There were no significant differences in either 5-year event-free survival (EFS) or overall survival (OS) between children who received an involved field radiation therapy boost (boost to the tumor bed only) or a standard volume boost (to the whole posterior fossa) in a phase III randomized trial, reported lead author Jeff M. Michalski, MD, MBA, FASTRO, professor of radiation oncology at Washington University, St. Louis.
“We conclude that the survival rates and event-free survival rates following reduced boost volumes were comparable to standard radiation treatment volumes for the primary tumor site. This is the first trial to state definitively that there is no survival difference between these two approaches,” he said at a briefing following his presentation of the data in an oral abstract session at the annual meeting of the American Society for Radiation Oncology.
“However, the reduced craniospinal axis irradiation was associated with a higher event rate and worse survival. We believe that physicians can adopt smaller boost volumes to the posterior fossa in children with average-risk medulloblastoma, average risk being no evidence of spread at the time of diagnosis and near-complete or complete resection. But for all children, the standard of 23.4 Gy remains necessary to retain high-level tumor control,” he added.
Aggressive malignancy
Medulloblastoma, an aggressive tumor with the propensity to spread from the lower brain to the upper brain and spine, is the most common brain malignancy in children. The current standard of care for children with average-risk disease is surgical resection followed by systemic chemotherapy followed by irradiation to both the posterior fossa and to the craniospinal axis.
“Unfortunately, this strategy has significant negative consequences for the patients’ neurocognitive abilities, endocrine function, and hearing,” Dr. Michalski said.
The Children’s Oncology Group ACNS0331 trial was designed to determine whether reducing the volume of the boost from the whole posterior to the tumor bed only would compromise EFS and OS, and whether reducing the dose to the craniospinal axis from the current 23.4 Gy to 18 Gy in children aged 3-7 years would compromise survival measures.
The trial had two randomizations, both at the time of study enrollment. In the first, children from the ages of 3 to 7 years were randomly assigned to either low-dose craniospinal irradiation (18 Gy, 116 children) or to the standard dose (23.4 Gy, 110 children). All children aged 8 and older were assigned to receive the standard dose.
For the second randomization, all children were randomly allocated to either involved field RT boost or to standard volume boost to the whole posterior fossa.
Following radiation, all children were assigned to nine cycles of maintenance chemotherapy.
At a median follow-up of 6.6 years, 5-year EFS estimates for the primary site irradiation endpoint were 82.2% for 227 patients who received the involved-field radiation, compared with 80.8% for 237 patients who received whole posterior fossa irradiation.
Respective 5-year OS estimates were 84.1% and 85.2%. The upper limit of the hazard ratio confidence interval (CI) for the involved field therapy was lower than the prespecified limit, indicating that involved-field radiation was noninferior.
For the endpoint of low- vs. standard-dose craniospinal irradiation, the 5-year EFS estimates were 72.1% and 82.6%, respectively. The upper limit of the hazard ratio CI exceeded the prespecified limit, indicating that EFS was worse with the low-dose strategy.
Similarly, respective 5-year OS estimates were 78.1% and 85.9%, with the upper limit of the CI also higher than the prespecified upper limit.
When the investigators looked at the patterns of failure among the children in the two randomizations, they saw that there was no significant difference in the rate of isolated local failure between the involved-field or whole posterior fossa groups, or between the low-dose or high-dose craniospinal irradiation groups.
The finding that radiation volume to the primary site can be reduced is likely to be practice changing, said Geraldine Jacobson, MD, MPH, professor and chair of radiation oncology at West Virginia University, Morgantown. Dr. Jacobson moderated the briefing.
However, the worse survival with the low-dose craniospinal radiation “leaves the COG investigators with the challenge to explore other avenues for reducing toxicity of craniospinal irradiation,” she said.
BOSTON – For children with average-risk medulloblastoma, it is safe to limit the radiation boost to the posterior fossa, but reducing doses to the craniospinal axis results in worse outcomes among younger children, and is not advisable, according to results from the largest trial conducted in this population.
There were no significant differences in either 5-year event-free survival (EFS) or overall survival (OS) between children who received an involved field radiation therapy boost (boost to the tumor bed only) or a standard volume boost (to the whole posterior fossa) in a phase III randomized trial, reported lead author Jeff M. Michalski, MD, MBA, FASTRO, professor of radiation oncology at Washington University, St. Louis.
“We conclude that the survival rates and event-free survival rates following reduced boost volumes were comparable to standard radiation treatment volumes for the primary tumor site. This is the first trial to state definitively that there is no survival difference between these two approaches,” he said at a briefing following his presentation of the data in an oral abstract session at the annual meeting of the American Society for Radiation Oncology.
“However, the reduced craniospinal axis irradiation was associated with a higher event rate and worse survival. We believe that physicians can adopt smaller boost volumes to the posterior fossa in children with average-risk medulloblastoma, average risk being no evidence of spread at the time of diagnosis and near-complete or complete resection. But for all children, the standard of 23.4 Gy remains necessary to retain high-level tumor control,” he added.
Aggressive malignancy
Medulloblastoma, an aggressive tumor with the propensity to spread from the lower brain to the upper brain and spine, is the most common brain malignancy in children. The current standard of care for children with average-risk disease is surgical resection followed by systemic chemotherapy followed by irradiation to both the posterior fossa and to the craniospinal axis.
“Unfortunately, this strategy has significant negative consequences for the patients’ neurocognitive abilities, endocrine function, and hearing,” Dr. Michalski said.
The Children’s Oncology Group ACNS0331 trial was designed to determine whether reducing the volume of the boost from the whole posterior to the tumor bed only would compromise EFS and OS, and whether reducing the dose to the craniospinal axis from the current 23.4 Gy to 18 Gy in children aged 3-7 years would compromise survival measures.
The trial had two randomizations, both at the time of study enrollment. In the first, children from the ages of 3 to 7 years were randomly assigned to either low-dose craniospinal irradiation (18 Gy, 116 children) or to the standard dose (23.4 Gy, 110 children). All children aged 8 and older were assigned to receive the standard dose.
For the second randomization, all children were randomly allocated to either involved field RT boost or to standard volume boost to the whole posterior fossa.
Following radiation, all children were assigned to nine cycles of maintenance chemotherapy.
At a median follow-up of 6.6 years, 5-year EFS estimates for the primary site irradiation endpoint were 82.2% for 227 patients who received the involved-field radiation, compared with 80.8% for 237 patients who received whole posterior fossa irradiation.
Respective 5-year OS estimates were 84.1% and 85.2%. The upper limit of the hazard ratio confidence interval (CI) for the involved field therapy was lower than the prespecified limit, indicating that involved-field radiation was noninferior.
For the endpoint of low- vs. standard-dose craniospinal irradiation, the 5-year EFS estimates were 72.1% and 82.6%, respectively. The upper limit of the hazard ratio CI exceeded the prespecified limit, indicating that EFS was worse with the low-dose strategy.
Similarly, respective 5-year OS estimates were 78.1% and 85.9%, with the upper limit of the CI also higher than the prespecified upper limit.
When the investigators looked at the patterns of failure among the children in the two randomizations, they saw that there was no significant difference in the rate of isolated local failure between the involved-field or whole posterior fossa groups, or between the low-dose or high-dose craniospinal irradiation groups.
The finding that radiation volume to the primary site can be reduced is likely to be practice changing, said Geraldine Jacobson, MD, MPH, professor and chair of radiation oncology at West Virginia University, Morgantown. Dr. Jacobson moderated the briefing.
However, the worse survival with the low-dose craniospinal radiation “leaves the COG investigators with the challenge to explore other avenues for reducing toxicity of craniospinal irradiation,” she said.
BOSTON – For children with average-risk medulloblastoma, it is safe to limit the radiation boost to the posterior fossa, but reducing doses to the craniospinal axis results in worse outcomes among younger children, and is not advisable, according to results from the largest trial conducted in this population.
There were no significant differences in either 5-year event-free survival (EFS) or overall survival (OS) between children who received an involved field radiation therapy boost (boost to the tumor bed only) or a standard volume boost (to the whole posterior fossa) in a phase III randomized trial, reported lead author Jeff M. Michalski, MD, MBA, FASTRO, professor of radiation oncology at Washington University, St. Louis.
“We conclude that the survival rates and event-free survival rates following reduced boost volumes were comparable to standard radiation treatment volumes for the primary tumor site. This is the first trial to state definitively that there is no survival difference between these two approaches,” he said at a briefing following his presentation of the data in an oral abstract session at the annual meeting of the American Society for Radiation Oncology.
“However, the reduced craniospinal axis irradiation was associated with a higher event rate and worse survival. We believe that physicians can adopt smaller boost volumes to the posterior fossa in children with average-risk medulloblastoma, average risk being no evidence of spread at the time of diagnosis and near-complete or complete resection. But for all children, the standard of 23.4 Gy remains necessary to retain high-level tumor control,” he added.
Aggressive malignancy
Medulloblastoma, an aggressive tumor with the propensity to spread from the lower brain to the upper brain and spine, is the most common brain malignancy in children. The current standard of care for children with average-risk disease is surgical resection followed by systemic chemotherapy followed by irradiation to both the posterior fossa and to the craniospinal axis.
“Unfortunately, this strategy has significant negative consequences for the patients’ neurocognitive abilities, endocrine function, and hearing,” Dr. Michalski said.
The Children’s Oncology Group ACNS0331 trial was designed to determine whether reducing the volume of the boost from the whole posterior to the tumor bed only would compromise EFS and OS, and whether reducing the dose to the craniospinal axis from the current 23.4 Gy to 18 Gy in children aged 3-7 years would compromise survival measures.
The trial had two randomizations, both at the time of study enrollment. In the first, children from the ages of 3 to 7 years were randomly assigned to either low-dose craniospinal irradiation (18 Gy, 116 children) or to the standard dose (23.4 Gy, 110 children). All children aged 8 and older were assigned to receive the standard dose.
For the second randomization, all children were randomly allocated to either involved field RT boost or to standard volume boost to the whole posterior fossa.
Following radiation, all children were assigned to nine cycles of maintenance chemotherapy.
At a median follow-up of 6.6 years, 5-year EFS estimates for the primary site irradiation endpoint were 82.2% for 227 patients who received the involved-field radiation, compared with 80.8% for 237 patients who received whole posterior fossa irradiation.
Respective 5-year OS estimates were 84.1% and 85.2%. The upper limit of the hazard ratio confidence interval (CI) for the involved field therapy was lower than the prespecified limit, indicating that involved-field radiation was noninferior.
For the endpoint of low- vs. standard-dose craniospinal irradiation, the 5-year EFS estimates were 72.1% and 82.6%, respectively. The upper limit of the hazard ratio CI exceeded the prespecified limit, indicating that EFS was worse with the low-dose strategy.
Similarly, respective 5-year OS estimates were 78.1% and 85.9%, with the upper limit of the CI also higher than the prespecified upper limit.
When the investigators looked at the patterns of failure among the children in the two randomizations, they saw that there was no significant difference in the rate of isolated local failure between the involved-field or whole posterior fossa groups, or between the low-dose or high-dose craniospinal irradiation groups.
The finding that radiation volume to the primary site can be reduced is likely to be practice changing, said Geraldine Jacobson, MD, MPH, professor and chair of radiation oncology at West Virginia University, Morgantown. Dr. Jacobson moderated the briefing.
However, the worse survival with the low-dose craniospinal radiation “leaves the COG investigators with the challenge to explore other avenues for reducing toxicity of craniospinal irradiation,” she said.
Key clinical point: Primary site irradiation in children with medulloblastoma can be limited to the tumor bed rather than the whole posterior fossa.
Major finding: There were no differences in EFS or OS when radiation was limited to the tumor bed, but reduced dose to the craniospinal axis was associated with worse survival.
Data source: Randomized phase III trial of 690 children with average-risk medulloblastoma.
Disclosures: The National Cancer Institute funded the study. Dr. Michalski and Dr. Jacobson reported no relevant conflicts of interest.
Boost dose pays off long term after surgery, WBRT for DCIS
BOSTON – Adding a boost dose after surgery and whole-breast radiation therapy (WBRT) for ductal carcinoma in situ offers a small but significant reduction in long-term risk of same-breast recurrence, according to results of a multicenter study.
An analysis of pooled data from 10 institutions showed that after 15 years of follow-up, 91.6% of women who had been treated with breast-conserving surgery, WBRT, and a boost dose remained free of ipsilateral breast tumor recurrence (IBTR), compared with 88% of women who received WBRT alone, reported Meena Savur Moran, MD, director of the breast cancer radiotherapy program at Smilow Cancer Hospital, Yale New Haven, Connecticut.
The absolute differences between the groups – 3% at 10 years, and 4% at 15 years – “don’t seem like a lot, but it is clinically important for patients, because what we’ve learned from the invasive cancer data is that this small, incremental decrease results in about a 40% less mastectomy rate for salvage mastectomies for recurrences,” she said.
It is common practice in many centers to give a radiation boost to the tumor bed of 8-16 Gy in 4-8 additional fractions following breast-conserving surgery and WBRT. This has been shown in invasive cancers to be associated with a statistically significant decrease in risk for IBTR in all age groups of about 4% at 20 years.
Yet because DCIS generally has an excellent prognosis with very few recurrences after whole-breast irradiation, it has been harder to determine whether radiation boosting would offer similar benefit to that seen in invasive cancers,
In an attempt to answer this question, investigators from 10 centers collaborated to create a DCIS database of patients treated with WBRT either with or without boost, and then analyzed the results.
The final cohort included 4,131 patients, far exceeding the minimum sample size the statisticians calculated would be needed to detect a benefit.
The median age of patients at the time of therapy was 56.1 years, median follow-up was 9 years, and the median boost dose was 14 Gy. In all, 4% of patients had positive tumor margins after surgery.
Rates of IBTR-free survival with boost vs. no boost were 97.1% vs. 96.3% at 5 years, 94.1% vs. 92.5% at 10 years, and, as noted before, 91.6% vs. 88% at 15 years (P = .0389).
In both univariate and in multivariate analysis controlling for tumor grade, comedo carcinoma, tamoxifen use, margin status, and age, IBTR was significantly associated with lower risk for recurrence.
The investigators also conducted a boost/no boost analysis stratified by margin status using both the National Surgical Adjuvant Breast and Bowel Project (NSABP) definition of negative margins as no ink on tumor, and the joint Society of Surgical Oncology, ASTRO, and American Society of Clinical Oncology guideline definition as less than 2 mm, and in each case found that among patients with negative margins, boosting offered a significant recurrence-free advantage.
Finally, they found that boosting offered a significant advantage both for patients 50 and older (P = .0073) and those 49 and younger (P = .0166).
“For DCIS, most of who treat breast cancer have used a boost, but we really extrapolated from the treatment from invasive breast cancer. Evidence for this practice until now in specific for DCIS has been lacking,” said Geraldine Jacobson, MD, MPH, professor and chair of radiation oncology at West Virginia University, Morgantown. Dr. Jacobson moderated the briefing.
She noted that the large sample size and long follow-up of the study was necessary for the treatment benefit to emerge.
BOSTON – Adding a boost dose after surgery and whole-breast radiation therapy (WBRT) for ductal carcinoma in situ offers a small but significant reduction in long-term risk of same-breast recurrence, according to results of a multicenter study.
An analysis of pooled data from 10 institutions showed that after 15 years of follow-up, 91.6% of women who had been treated with breast-conserving surgery, WBRT, and a boost dose remained free of ipsilateral breast tumor recurrence (IBTR), compared with 88% of women who received WBRT alone, reported Meena Savur Moran, MD, director of the breast cancer radiotherapy program at Smilow Cancer Hospital, Yale New Haven, Connecticut.
The absolute differences between the groups – 3% at 10 years, and 4% at 15 years – “don’t seem like a lot, but it is clinically important for patients, because what we’ve learned from the invasive cancer data is that this small, incremental decrease results in about a 40% less mastectomy rate for salvage mastectomies for recurrences,” she said.
It is common practice in many centers to give a radiation boost to the tumor bed of 8-16 Gy in 4-8 additional fractions following breast-conserving surgery and WBRT. This has been shown in invasive cancers to be associated with a statistically significant decrease in risk for IBTR in all age groups of about 4% at 20 years.
Yet because DCIS generally has an excellent prognosis with very few recurrences after whole-breast irradiation, it has been harder to determine whether radiation boosting would offer similar benefit to that seen in invasive cancers,
In an attempt to answer this question, investigators from 10 centers collaborated to create a DCIS database of patients treated with WBRT either with or without boost, and then analyzed the results.
The final cohort included 4,131 patients, far exceeding the minimum sample size the statisticians calculated would be needed to detect a benefit.
The median age of patients at the time of therapy was 56.1 years, median follow-up was 9 years, and the median boost dose was 14 Gy. In all, 4% of patients had positive tumor margins after surgery.
Rates of IBTR-free survival with boost vs. no boost were 97.1% vs. 96.3% at 5 years, 94.1% vs. 92.5% at 10 years, and, as noted before, 91.6% vs. 88% at 15 years (P = .0389).
In both univariate and in multivariate analysis controlling for tumor grade, comedo carcinoma, tamoxifen use, margin status, and age, IBTR was significantly associated with lower risk for recurrence.
The investigators also conducted a boost/no boost analysis stratified by margin status using both the National Surgical Adjuvant Breast and Bowel Project (NSABP) definition of negative margins as no ink on tumor, and the joint Society of Surgical Oncology, ASTRO, and American Society of Clinical Oncology guideline definition as less than 2 mm, and in each case found that among patients with negative margins, boosting offered a significant recurrence-free advantage.
Finally, they found that boosting offered a significant advantage both for patients 50 and older (P = .0073) and those 49 and younger (P = .0166).
“For DCIS, most of who treat breast cancer have used a boost, but we really extrapolated from the treatment from invasive breast cancer. Evidence for this practice until now in specific for DCIS has been lacking,” said Geraldine Jacobson, MD, MPH, professor and chair of radiation oncology at West Virginia University, Morgantown. Dr. Jacobson moderated the briefing.
She noted that the large sample size and long follow-up of the study was necessary for the treatment benefit to emerge.
BOSTON – Adding a boost dose after surgery and whole-breast radiation therapy (WBRT) for ductal carcinoma in situ offers a small but significant reduction in long-term risk of same-breast recurrence, according to results of a multicenter study.
An analysis of pooled data from 10 institutions showed that after 15 years of follow-up, 91.6% of women who had been treated with breast-conserving surgery, WBRT, and a boost dose remained free of ipsilateral breast tumor recurrence (IBTR), compared with 88% of women who received WBRT alone, reported Meena Savur Moran, MD, director of the breast cancer radiotherapy program at Smilow Cancer Hospital, Yale New Haven, Connecticut.
The absolute differences between the groups – 3% at 10 years, and 4% at 15 years – “don’t seem like a lot, but it is clinically important for patients, because what we’ve learned from the invasive cancer data is that this small, incremental decrease results in about a 40% less mastectomy rate for salvage mastectomies for recurrences,” she said.
It is common practice in many centers to give a radiation boost to the tumor bed of 8-16 Gy in 4-8 additional fractions following breast-conserving surgery and WBRT. This has been shown in invasive cancers to be associated with a statistically significant decrease in risk for IBTR in all age groups of about 4% at 20 years.
Yet because DCIS generally has an excellent prognosis with very few recurrences after whole-breast irradiation, it has been harder to determine whether radiation boosting would offer similar benefit to that seen in invasive cancers,
In an attempt to answer this question, investigators from 10 centers collaborated to create a DCIS database of patients treated with WBRT either with or without boost, and then analyzed the results.
The final cohort included 4,131 patients, far exceeding the minimum sample size the statisticians calculated would be needed to detect a benefit.
The median age of patients at the time of therapy was 56.1 years, median follow-up was 9 years, and the median boost dose was 14 Gy. In all, 4% of patients had positive tumor margins after surgery.
Rates of IBTR-free survival with boost vs. no boost were 97.1% vs. 96.3% at 5 years, 94.1% vs. 92.5% at 10 years, and, as noted before, 91.6% vs. 88% at 15 years (P = .0389).
In both univariate and in multivariate analysis controlling for tumor grade, comedo carcinoma, tamoxifen use, margin status, and age, IBTR was significantly associated with lower risk for recurrence.
The investigators also conducted a boost/no boost analysis stratified by margin status using both the National Surgical Adjuvant Breast and Bowel Project (NSABP) definition of negative margins as no ink on tumor, and the joint Society of Surgical Oncology, ASTRO, and American Society of Clinical Oncology guideline definition as less than 2 mm, and in each case found that among patients with negative margins, boosting offered a significant recurrence-free advantage.
Finally, they found that boosting offered a significant advantage both for patients 50 and older (P = .0073) and those 49 and younger (P = .0166).
“For DCIS, most of who treat breast cancer have used a boost, but we really extrapolated from the treatment from invasive breast cancer. Evidence for this practice until now in specific for DCIS has been lacking,” said Geraldine Jacobson, MD, MPH, professor and chair of radiation oncology at West Virginia University, Morgantown. Dr. Jacobson moderated the briefing.
She noted that the large sample size and long follow-up of the study was necessary for the treatment benefit to emerge.
AT THE ASTRO ANNUAL MEETING 2016
Key clinical point: This study shows a significant benefit for adding a boost radiation dose following breast-conserving surgery and whole-breast radiation for ductal carcinoma in situ (DCIS).
Major finding: After 15 years of follow-up, 91.6% of women who had received a boost dose were free of ipsilateral breast recurrence, compared with 88% of women who did not have a boost.
Data source: Analysis of pooled data on 4,131 patients with DCIS treated at 10 academic medical centers.
Disclosures: The study was supported by participating institutions. Dr. Moran and Dr. Jacobson reported no conflicts of interest.
Database review supports chemoradiation for high-risk sarcomas
BOSTON – Neoadjuvant chemotherapy and radiation appear to offer long-term benefits in patients with high-risk soft tissue sarcomas of the extremities.
The key word is “appear,” however, because the idea is drawn more from inference than from evidence, and not all sarcoma specialists are convinced that neoadjuvant chemotherapy and radiation add anything more than toxicity.
In studies presented at the annual meeting of the American Society of Radiation Oncology, including a retrospective case series and a national database review, investigators found evidence supporting the use of combined modality therapy with radiation and chemotherapy in patients with soft tissue sarcomas of the extremities.
“Large high-grade extremity soft-tissue sarcomas are at high risk of failure and death compared to our typical high-risk patients who present with one [risk] factor,” said Omar Mahmoud, MD, PhD, from the Rutgers Cancer Institute of New Jersey, New Brunswick.
He and his colleagues combed through the National Cancer Database to identify 3,840 otherwise healthy patients with grade 3 or 4 soft-tissue sarcomas (STS) of the extremities of various histologies larger than 8 cm, who underwent surgical resections during 2004-2013.
They looked at overall survival in patients who received no neoadjuvant or adjuvant therapy and those who received either neoadjuvant or adjuvant chemotherapy and/or radiation therapy. They used propensity score matching to adjust for imbalances of covariates across treatment subgroups.
They found that chemotherapy was associated with significantly better 5-year overall survival, at 57%, compared with 45% with no chemotherapy (P less than .001)
In multivariate analysis, age older than 50 years, positive tumor margins, larger tumors, and tumors located in the trunk or pelvis were associated with worse prognosis, whereas receipt of chemotherapy and radiotherapy were associated independently with better prognosis.
Out to 100 months (8.3 years) of follow-up, overall survival was significantly higher for patients who received combined modality adjunctive therapies, compared with either single modality therapy (chemotherapy or radiotherapy alone) or no therapy (P less than .001).
Using propensity score matching to compare patients who received combined vs. single-modality therapy, the investigators found that combined therapies were associated with significantly better overall survival, with a hazard ratio of 0.72 (95% confidence interval, 0.62-0.84).
There was no difference in survival according to the timing of therapy, whether preoperative, postoperative, or concurrent), however.
Finally, looking at survival among all subgroups, they saw that combined therapies remained significantly better than single-modality therapies (P less than .001).
Drop the ‘D’ in MAID?
In a separate study, Neilayan Sen, MD, and colleagues from Rush University Medical Center in Chicago reported that a modified protocol involving neoadjuvant chemotherapy interdigitated with radiation followed by surgery and adjuvant chemotherapy was associated with good disease control and survival and lower toxicity in patients with large STS of the extremities or abdominal wall.
The original protocol, dubbed MAID (mesna, doxorubicin, ifosfamide, dacarbazine), was shown in the RTOG 9514 trial to be associated with higher rates of disease-free, distant disease-free, and overall survival than older regimens, but at the price of high short-term toxicities. Among 64 evaluable patients, 97% had grade 3 or higher toxicities, including three deaths, two of which were from myelodysplasia.
To see whether they could match the efficacy of MAID while reducing toxicity, the Rush team modified the MAID protocol by dropping the dacarbazine. For the radiation component, they used either 3-D conformal radiation therapy or intensity-modulated radiation therapy, set the maximum dose penetration (Dmax) at 112% or less, and used reduced volumes while maintaining the dose and fractions (44 Gy delivered in 22 fractions, 11 each between chemotherapy cycles 1-2 and 2-3). Patients then underwent surgery, followed by three additional cycles of chemotherapy.
In a retrospective analysis of 26 patients treated with the modified protocol, there were no toxicity-related amputations, and no amputations were required for tumor management. Two patients had in-field fractures.
At a median follow-up of 39 months, 25 of the 26 patients were still alive and there were no cases of treatment-related malignancies or myelodysplasia.
The 3-year actuarial results with MAI also compared favorably with those of RTOG 9514, with locoregional recurrence-free survival rates of 87.2% with the modified protocol vs. 82.4% for the original MAID protocol, distant metastasis-free survival of 67.9% vs. 64.%, respectively, disease-free survival of 67.9% vs. 56.6%, and overall survival of 93.3% vs. 75.1%.
“The omission of dacarbazine does not compromise any disease-control endpoints. With the integration of 3-D techniques as well as intensity modulation and smaller fields than were used in [RTOG] 9514, there’s a significantly reduced grade 4 and 5 toxicity rate. We think that the integration of image guidance with reduced target volume parameters further,” Dr. Sen said.
Better Agents Needed
Elizabeth H Baldini, MD, MPH, from the Dana-Farber/Brigham & Women’s Cancer Center, Boston, the invited discussant, agreed that there is a need for better systemic therapy to reduce the risk of distant recurrence in patients with high-risk localized sarcomas.
“But the bottom line is that the benefit of chemotherapy with the agents we have today is uncertain,” she said.
Assessment of systemic chemotherapy in sarcoma is hampered by the rarity of the tumors, with more than 50 different histologic subtypes, and wide tumor heterogeneity, and although the studies reported here appear to show benefit for chemotherapy, they appear to overlap with those for surgery and radiation alone, she said.
Session comoderator Yen-Lin Evelyn Chen, MD, a radiation oncologist at Massachusetts General Hospital Cancer Center, Boston, said in an interview that studies presented during the session show that, “chemotherapy in experienced hands can be delivered safely.”
Dr. Chen added, however, that the local control rates reported by Dr. Sen and colleagues were a little lower than she would have expected in the modern era, suggesting that either the radiation modification or elimination of dacarbazine may have played a role.
BOSTON – Neoadjuvant chemotherapy and radiation appear to offer long-term benefits in patients with high-risk soft tissue sarcomas of the extremities.
The key word is “appear,” however, because the idea is drawn more from inference than from evidence, and not all sarcoma specialists are convinced that neoadjuvant chemotherapy and radiation add anything more than toxicity.
In studies presented at the annual meeting of the American Society of Radiation Oncology, including a retrospective case series and a national database review, investigators found evidence supporting the use of combined modality therapy with radiation and chemotherapy in patients with soft tissue sarcomas of the extremities.
“Large high-grade extremity soft-tissue sarcomas are at high risk of failure and death compared to our typical high-risk patients who present with one [risk] factor,” said Omar Mahmoud, MD, PhD, from the Rutgers Cancer Institute of New Jersey, New Brunswick.
He and his colleagues combed through the National Cancer Database to identify 3,840 otherwise healthy patients with grade 3 or 4 soft-tissue sarcomas (STS) of the extremities of various histologies larger than 8 cm, who underwent surgical resections during 2004-2013.
They looked at overall survival in patients who received no neoadjuvant or adjuvant therapy and those who received either neoadjuvant or adjuvant chemotherapy and/or radiation therapy. They used propensity score matching to adjust for imbalances of covariates across treatment subgroups.
They found that chemotherapy was associated with significantly better 5-year overall survival, at 57%, compared with 45% with no chemotherapy (P less than .001)
In multivariate analysis, age older than 50 years, positive tumor margins, larger tumors, and tumors located in the trunk or pelvis were associated with worse prognosis, whereas receipt of chemotherapy and radiotherapy were associated independently with better prognosis.
Out to 100 months (8.3 years) of follow-up, overall survival was significantly higher for patients who received combined modality adjunctive therapies, compared with either single modality therapy (chemotherapy or radiotherapy alone) or no therapy (P less than .001).
Using propensity score matching to compare patients who received combined vs. single-modality therapy, the investigators found that combined therapies were associated with significantly better overall survival, with a hazard ratio of 0.72 (95% confidence interval, 0.62-0.84).
There was no difference in survival according to the timing of therapy, whether preoperative, postoperative, or concurrent), however.
Finally, looking at survival among all subgroups, they saw that combined therapies remained significantly better than single-modality therapies (P less than .001).
Drop the ‘D’ in MAID?
In a separate study, Neilayan Sen, MD, and colleagues from Rush University Medical Center in Chicago reported that a modified protocol involving neoadjuvant chemotherapy interdigitated with radiation followed by surgery and adjuvant chemotherapy was associated with good disease control and survival and lower toxicity in patients with large STS of the extremities or abdominal wall.
The original protocol, dubbed MAID (mesna, doxorubicin, ifosfamide, dacarbazine), was shown in the RTOG 9514 trial to be associated with higher rates of disease-free, distant disease-free, and overall survival than older regimens, but at the price of high short-term toxicities. Among 64 evaluable patients, 97% had grade 3 or higher toxicities, including three deaths, two of which were from myelodysplasia.
To see whether they could match the efficacy of MAID while reducing toxicity, the Rush team modified the MAID protocol by dropping the dacarbazine. For the radiation component, they used either 3-D conformal radiation therapy or intensity-modulated radiation therapy, set the maximum dose penetration (Dmax) at 112% or less, and used reduced volumes while maintaining the dose and fractions (44 Gy delivered in 22 fractions, 11 each between chemotherapy cycles 1-2 and 2-3). Patients then underwent surgery, followed by three additional cycles of chemotherapy.
In a retrospective analysis of 26 patients treated with the modified protocol, there were no toxicity-related amputations, and no amputations were required for tumor management. Two patients had in-field fractures.
At a median follow-up of 39 months, 25 of the 26 patients were still alive and there were no cases of treatment-related malignancies or myelodysplasia.
The 3-year actuarial results with MAI also compared favorably with those of RTOG 9514, with locoregional recurrence-free survival rates of 87.2% with the modified protocol vs. 82.4% for the original MAID protocol, distant metastasis-free survival of 67.9% vs. 64.%, respectively, disease-free survival of 67.9% vs. 56.6%, and overall survival of 93.3% vs. 75.1%.
“The omission of dacarbazine does not compromise any disease-control endpoints. With the integration of 3-D techniques as well as intensity modulation and smaller fields than were used in [RTOG] 9514, there’s a significantly reduced grade 4 and 5 toxicity rate. We think that the integration of image guidance with reduced target volume parameters further,” Dr. Sen said.
Better Agents Needed
Elizabeth H Baldini, MD, MPH, from the Dana-Farber/Brigham & Women’s Cancer Center, Boston, the invited discussant, agreed that there is a need for better systemic therapy to reduce the risk of distant recurrence in patients with high-risk localized sarcomas.
“But the bottom line is that the benefit of chemotherapy with the agents we have today is uncertain,” she said.
Assessment of systemic chemotherapy in sarcoma is hampered by the rarity of the tumors, with more than 50 different histologic subtypes, and wide tumor heterogeneity, and although the studies reported here appear to show benefit for chemotherapy, they appear to overlap with those for surgery and radiation alone, she said.
Session comoderator Yen-Lin Evelyn Chen, MD, a radiation oncologist at Massachusetts General Hospital Cancer Center, Boston, said in an interview that studies presented during the session show that, “chemotherapy in experienced hands can be delivered safely.”
Dr. Chen added, however, that the local control rates reported by Dr. Sen and colleagues were a little lower than she would have expected in the modern era, suggesting that either the radiation modification or elimination of dacarbazine may have played a role.
BOSTON – Neoadjuvant chemotherapy and radiation appear to offer long-term benefits in patients with high-risk soft tissue sarcomas of the extremities.
The key word is “appear,” however, because the idea is drawn more from inference than from evidence, and not all sarcoma specialists are convinced that neoadjuvant chemotherapy and radiation add anything more than toxicity.
In studies presented at the annual meeting of the American Society of Radiation Oncology, including a retrospective case series and a national database review, investigators found evidence supporting the use of combined modality therapy with radiation and chemotherapy in patients with soft tissue sarcomas of the extremities.
“Large high-grade extremity soft-tissue sarcomas are at high risk of failure and death compared to our typical high-risk patients who present with one [risk] factor,” said Omar Mahmoud, MD, PhD, from the Rutgers Cancer Institute of New Jersey, New Brunswick.
He and his colleagues combed through the National Cancer Database to identify 3,840 otherwise healthy patients with grade 3 or 4 soft-tissue sarcomas (STS) of the extremities of various histologies larger than 8 cm, who underwent surgical resections during 2004-2013.
They looked at overall survival in patients who received no neoadjuvant or adjuvant therapy and those who received either neoadjuvant or adjuvant chemotherapy and/or radiation therapy. They used propensity score matching to adjust for imbalances of covariates across treatment subgroups.
They found that chemotherapy was associated with significantly better 5-year overall survival, at 57%, compared with 45% with no chemotherapy (P less than .001)
In multivariate analysis, age older than 50 years, positive tumor margins, larger tumors, and tumors located in the trunk or pelvis were associated with worse prognosis, whereas receipt of chemotherapy and radiotherapy were associated independently with better prognosis.
Out to 100 months (8.3 years) of follow-up, overall survival was significantly higher for patients who received combined modality adjunctive therapies, compared with either single modality therapy (chemotherapy or radiotherapy alone) or no therapy (P less than .001).
Using propensity score matching to compare patients who received combined vs. single-modality therapy, the investigators found that combined therapies were associated with significantly better overall survival, with a hazard ratio of 0.72 (95% confidence interval, 0.62-0.84).
There was no difference in survival according to the timing of therapy, whether preoperative, postoperative, or concurrent), however.
Finally, looking at survival among all subgroups, they saw that combined therapies remained significantly better than single-modality therapies (P less than .001).
Drop the ‘D’ in MAID?
In a separate study, Neilayan Sen, MD, and colleagues from Rush University Medical Center in Chicago reported that a modified protocol involving neoadjuvant chemotherapy interdigitated with radiation followed by surgery and adjuvant chemotherapy was associated with good disease control and survival and lower toxicity in patients with large STS of the extremities or abdominal wall.
The original protocol, dubbed MAID (mesna, doxorubicin, ifosfamide, dacarbazine), was shown in the RTOG 9514 trial to be associated with higher rates of disease-free, distant disease-free, and overall survival than older regimens, but at the price of high short-term toxicities. Among 64 evaluable patients, 97% had grade 3 or higher toxicities, including three deaths, two of which were from myelodysplasia.
To see whether they could match the efficacy of MAID while reducing toxicity, the Rush team modified the MAID protocol by dropping the dacarbazine. For the radiation component, they used either 3-D conformal radiation therapy or intensity-modulated radiation therapy, set the maximum dose penetration (Dmax) at 112% or less, and used reduced volumes while maintaining the dose and fractions (44 Gy delivered in 22 fractions, 11 each between chemotherapy cycles 1-2 and 2-3). Patients then underwent surgery, followed by three additional cycles of chemotherapy.
In a retrospective analysis of 26 patients treated with the modified protocol, there were no toxicity-related amputations, and no amputations were required for tumor management. Two patients had in-field fractures.
At a median follow-up of 39 months, 25 of the 26 patients were still alive and there were no cases of treatment-related malignancies or myelodysplasia.
The 3-year actuarial results with MAI also compared favorably with those of RTOG 9514, with locoregional recurrence-free survival rates of 87.2% with the modified protocol vs. 82.4% for the original MAID protocol, distant metastasis-free survival of 67.9% vs. 64.%, respectively, disease-free survival of 67.9% vs. 56.6%, and overall survival of 93.3% vs. 75.1%.
“The omission of dacarbazine does not compromise any disease-control endpoints. With the integration of 3-D techniques as well as intensity modulation and smaller fields than were used in [RTOG] 9514, there’s a significantly reduced grade 4 and 5 toxicity rate. We think that the integration of image guidance with reduced target volume parameters further,” Dr. Sen said.
Better Agents Needed
Elizabeth H Baldini, MD, MPH, from the Dana-Farber/Brigham & Women’s Cancer Center, Boston, the invited discussant, agreed that there is a need for better systemic therapy to reduce the risk of distant recurrence in patients with high-risk localized sarcomas.
“But the bottom line is that the benefit of chemotherapy with the agents we have today is uncertain,” she said.
Assessment of systemic chemotherapy in sarcoma is hampered by the rarity of the tumors, with more than 50 different histologic subtypes, and wide tumor heterogeneity, and although the studies reported here appear to show benefit for chemotherapy, they appear to overlap with those for surgery and radiation alone, she said.
Session comoderator Yen-Lin Evelyn Chen, MD, a radiation oncologist at Massachusetts General Hospital Cancer Center, Boston, said in an interview that studies presented during the session show that, “chemotherapy in experienced hands can be delivered safely.”
Dr. Chen added, however, that the local control rates reported by Dr. Sen and colleagues were a little lower than she would have expected in the modern era, suggesting that either the radiation modification or elimination of dacarbazine may have played a role.
Key clinical point: Sarcoma specialists do not agree on whether neoadjuvant or adjuvant chemotherapy adds benefit in patients with high-risk soft-tissue sarcomas.
Major finding: In a cancer database, chemotherapy was associated with 57% 5-year overall survival, compared with 45% with no chemotherapy (P less than .001)
Data source: A National Cancer Database review of 3,840 patients with grade 3 or 4 soft-tissue sarcomas and a retrospective case series of 26 patients with large STS of the extremities or abdominal wall.
Disclosures: The studies were internally supported. The authors, Dr. Baldini and Dr. Chen, reported no relevant disclosures. Dr. Chen is the reporter’s personal radiation oncologist.
NSCLC survival comparable with accelerated and conventional RT
BOSTON – Patients with stage II or III non–small-cell lung cancer with comorbidities that make them poor candidates for surgery or chemotherapy may still benefit from accelerated hypofractionated radiation, an interim analysis of a randomized trial suggests.
Among 48 patients followed for a median of 24 months, there were no statistical differences in either overall survival (OS) or progression-free survival between patients with stage II or III NSCLC and poor performance status treated with either conventional radiation delivered over 6 weeks, or image-guided radiation therapy (IGRT) delivered over 3 weeks, reported Puneeth Iyengar, MD, PhD, of the University of Texas Southwestern in Dallas.
“There is limited grade 3-5 toxicity, and as importantly, and more important to patients, is that the treatment time is cut in half and may be acceptable to the patient as well as to the treating physician,” he added.
The investigators are hopeful that the study, when completed, will “change the paradigm of how we treat these patients who can’t receive the standard-of-care treatment.”
The UT Southwestern investigators had previously shown in a phase I dose-escalation study that treating patients with 60 Gy delivered in 15 fractions instead of the conventional 30 fractions did not increase treatment-related toxicity,
In the current study, they explored the question of whether accelerated hypofractionated radiation therapy could improve survival in a difficult-to-treat population.
They have enrolled to date 60 patients with stage II or III NSCLC and Zubrod performance status of 2 or greater.
In arm A, 28 patients were assigned to receive conventional radiation at total doses of 60 to 66 Gy delivered in 30-33 fractions of 2 Gy each, In arm B, 32 patients were assigned to receive a total dose of 60 Gy delivered in 15 fractions of 4 Gy each.
The median age was 68 in both arms. The male-to-female ratio was equal in arm A, but 4:1 in arm B, The distribution of tumor types was equally weighted in each arm, with squamous cell carcinomas accounting for 53% of lesions, and adenocarcinomas accounting for the remainder.
Among all 60 patients, 53 presented with stage III disease, and 7 with stage II.
Of the 60 patients, 48 had follow-up sufficient for interim evaluation, and of this group, 27 (56%) were alive at last follow-up.
Median OS on Kaplan-Meier analysis was 11.5 months, with no statistical differences between the groups (per-group rates were not shown), Median PFS was 14 months, also with no statistical differences.
There were three deaths from hypoxia possibly related to radiation, two in the conventional fractionation arm, and one in the IGRT, accelerated fractionation arm. There were 10 grade 3 radiation-associated toxicities in arm A, and 6 in Arm B. There were no grade 4 toxicities in either group.
George Rodrigues, MD, of London (Ontario) Health Sciences Center, who moderated the briefing, said that in addition to patients with poor performance status, there are some patients who simply do not want to undergo chemotherapy, and for these patients the efficacy, low side effects, and convenience of accelerated fractionation radiation therapy may prove to be a good treatment option.
BOSTON – Patients with stage II or III non–small-cell lung cancer with comorbidities that make them poor candidates for surgery or chemotherapy may still benefit from accelerated hypofractionated radiation, an interim analysis of a randomized trial suggests.
Among 48 patients followed for a median of 24 months, there were no statistical differences in either overall survival (OS) or progression-free survival between patients with stage II or III NSCLC and poor performance status treated with either conventional radiation delivered over 6 weeks, or image-guided radiation therapy (IGRT) delivered over 3 weeks, reported Puneeth Iyengar, MD, PhD, of the University of Texas Southwestern in Dallas.
“There is limited grade 3-5 toxicity, and as importantly, and more important to patients, is that the treatment time is cut in half and may be acceptable to the patient as well as to the treating physician,” he added.
The investigators are hopeful that the study, when completed, will “change the paradigm of how we treat these patients who can’t receive the standard-of-care treatment.”
The UT Southwestern investigators had previously shown in a phase I dose-escalation study that treating patients with 60 Gy delivered in 15 fractions instead of the conventional 30 fractions did not increase treatment-related toxicity,
In the current study, they explored the question of whether accelerated hypofractionated radiation therapy could improve survival in a difficult-to-treat population.
They have enrolled to date 60 patients with stage II or III NSCLC and Zubrod performance status of 2 or greater.
In arm A, 28 patients were assigned to receive conventional radiation at total doses of 60 to 66 Gy delivered in 30-33 fractions of 2 Gy each, In arm B, 32 patients were assigned to receive a total dose of 60 Gy delivered in 15 fractions of 4 Gy each.
The median age was 68 in both arms. The male-to-female ratio was equal in arm A, but 4:1 in arm B, The distribution of tumor types was equally weighted in each arm, with squamous cell carcinomas accounting for 53% of lesions, and adenocarcinomas accounting for the remainder.
Among all 60 patients, 53 presented with stage III disease, and 7 with stage II.
Of the 60 patients, 48 had follow-up sufficient for interim evaluation, and of this group, 27 (56%) were alive at last follow-up.
Median OS on Kaplan-Meier analysis was 11.5 months, with no statistical differences between the groups (per-group rates were not shown), Median PFS was 14 months, also with no statistical differences.
There were three deaths from hypoxia possibly related to radiation, two in the conventional fractionation arm, and one in the IGRT, accelerated fractionation arm. There were 10 grade 3 radiation-associated toxicities in arm A, and 6 in Arm B. There were no grade 4 toxicities in either group.
George Rodrigues, MD, of London (Ontario) Health Sciences Center, who moderated the briefing, said that in addition to patients with poor performance status, there are some patients who simply do not want to undergo chemotherapy, and for these patients the efficacy, low side effects, and convenience of accelerated fractionation radiation therapy may prove to be a good treatment option.
BOSTON – Patients with stage II or III non–small-cell lung cancer with comorbidities that make them poor candidates for surgery or chemotherapy may still benefit from accelerated hypofractionated radiation, an interim analysis of a randomized trial suggests.
Among 48 patients followed for a median of 24 months, there were no statistical differences in either overall survival (OS) or progression-free survival between patients with stage II or III NSCLC and poor performance status treated with either conventional radiation delivered over 6 weeks, or image-guided radiation therapy (IGRT) delivered over 3 weeks, reported Puneeth Iyengar, MD, PhD, of the University of Texas Southwestern in Dallas.
“There is limited grade 3-5 toxicity, and as importantly, and more important to patients, is that the treatment time is cut in half and may be acceptable to the patient as well as to the treating physician,” he added.
The investigators are hopeful that the study, when completed, will “change the paradigm of how we treat these patients who can’t receive the standard-of-care treatment.”
The UT Southwestern investigators had previously shown in a phase I dose-escalation study that treating patients with 60 Gy delivered in 15 fractions instead of the conventional 30 fractions did not increase treatment-related toxicity,
In the current study, they explored the question of whether accelerated hypofractionated radiation therapy could improve survival in a difficult-to-treat population.
They have enrolled to date 60 patients with stage II or III NSCLC and Zubrod performance status of 2 or greater.
In arm A, 28 patients were assigned to receive conventional radiation at total doses of 60 to 66 Gy delivered in 30-33 fractions of 2 Gy each, In arm B, 32 patients were assigned to receive a total dose of 60 Gy delivered in 15 fractions of 4 Gy each.
The median age was 68 in both arms. The male-to-female ratio was equal in arm A, but 4:1 in arm B, The distribution of tumor types was equally weighted in each arm, with squamous cell carcinomas accounting for 53% of lesions, and adenocarcinomas accounting for the remainder.
Among all 60 patients, 53 presented with stage III disease, and 7 with stage II.
Of the 60 patients, 48 had follow-up sufficient for interim evaluation, and of this group, 27 (56%) were alive at last follow-up.
Median OS on Kaplan-Meier analysis was 11.5 months, with no statistical differences between the groups (per-group rates were not shown), Median PFS was 14 months, also with no statistical differences.
There were three deaths from hypoxia possibly related to radiation, two in the conventional fractionation arm, and one in the IGRT, accelerated fractionation arm. There were 10 grade 3 radiation-associated toxicities in arm A, and 6 in Arm B. There were no grade 4 toxicities in either group.
George Rodrigues, MD, of London (Ontario) Health Sciences Center, who moderated the briefing, said that in addition to patients with poor performance status, there are some patients who simply do not want to undergo chemotherapy, and for these patients the efficacy, low side effects, and convenience of accelerated fractionation radiation therapy may prove to be a good treatment option.
Key clinical point: Accelerated hypofractionated radiation therapy offers survival and safety comparable to that of conventional radiation in non–small-cell lung cancer in half the time.
Major finding: There were no differences in overall or progression-free survival among patients with NSCLC treated with either accelerated or conventional fractionation radiation.
Data source: Interim analysis of randomized phase III trial in 48 of 60 evaluable patients with stage II or III NSCLC and poor performance status.
Disclosures: UT Southwestern Medical Center, Dallas, sponsored the trial. Dr. Iyengar and Dr. Rodrigues reported having no conflicts of interest.
Hypofractionated RT safe, convenient in low-risk prostate cancer
BOSTON – Shortening the radiation dosing schedule by 3 weeks in men with early-stage, low-risk prostate cancer does not appear to result in worse outcomes or diminished quality of life, according to investigators in the NRG Oncology/RTOG 0415 trial.
Efficacy results from the trial, reported at the annual meeting of the American Society for Radiation Oncology, showed that a radiation schedule of 70 Gy in 28 fractions delivered over 5.6 weeks was not inferior to 73.8 Gy delivered in 41 fractions over 8.2 weeks in terms of disease-free, progression-free, or overall survival.
“The International Atomic Energy [Agency] in its prostate cancer guidelines still lists hypofractionated radiation therapy as investigational, but I think we are at the stage where there is a ton of evidence, and this is really no leap of faith anymore that this can become the standard of care,” said Deborah W. Bruner, PhD, of Emory University and the Winship Cancer Institute in Atlanta.
In the treatment of patients with low-risk prostate cancer who opt for therapy over active surveillance, it is essential that “we treat them with the absolute minimum amount of treatment, with minimum side effects, and with minimum cost,” she said at a plenary session.
As reported by the investigators in 2015, there were small but significant increases in clinician-reported adverse gastrointestinal and genitourinary adverse events in the hypofractionation arm compared with the conventional fractionation arm in the trial, prompting the researchers to see whether patients were actually experiencing what clinicians thought they were seeing.
The investigators examined health-related quality of life and symptoms using the Expanded Prostate Index Composite (EPIC instrument).
They used a 50-item patient-reported outcomes questionnaire using a scale of 0 (no problem) to 4 (big problem), with responses transferred to a 0-100 scale. The questionnaire asked about symptoms in four domains: bowel, urinary, sexual, and hormonal. Patients filled out the questionnaire at baseline and at 6 and 12 months of follow-up.
At 1 year, there were no changes from baseline in hormonal scores in either study arm, but sexual function scores declined by approximately 15 points among patients treated with conventional fractionation and by 11 points among patients treated with hypofractionation (between-group difference nonsignificant).
There was a small decline in urinary scores in both arms, but this difference was not significant.
Patients treated with hypofractionation had a statistically larger decline in bowel scores compared with patients treated with conventional fractionation, a 1.8-point difference, but this difference did not translate into a clinically significant difference; that is, patients themselves could not detect a significant decline in bowel function, Dr. Bruner said.
The invited discussant, Ronald Chen, MD, MPH, director of the comparative effectiveness research program at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, agreed that a difference of only 1.8 points on a 0-100 scale, while technically significant, is clinically meaningless.
“So now we have the complete story and a better understanding of perhaps the value of hypofractionation versus standard fractionation from the patient’s perspective,” he said.
He also emphasized that “quality of life is a central component of any value framework in cancer care, and we must hear the patient’s voice. For clinical trials to truly inform patient decision making and allow patients to assess the value of their treatment options, quality of life must be studied.”
BOSTON – Shortening the radiation dosing schedule by 3 weeks in men with early-stage, low-risk prostate cancer does not appear to result in worse outcomes or diminished quality of life, according to investigators in the NRG Oncology/RTOG 0415 trial.
Efficacy results from the trial, reported at the annual meeting of the American Society for Radiation Oncology, showed that a radiation schedule of 70 Gy in 28 fractions delivered over 5.6 weeks was not inferior to 73.8 Gy delivered in 41 fractions over 8.2 weeks in terms of disease-free, progression-free, or overall survival.
“The International Atomic Energy [Agency] in its prostate cancer guidelines still lists hypofractionated radiation therapy as investigational, but I think we are at the stage where there is a ton of evidence, and this is really no leap of faith anymore that this can become the standard of care,” said Deborah W. Bruner, PhD, of Emory University and the Winship Cancer Institute in Atlanta.
In the treatment of patients with low-risk prostate cancer who opt for therapy over active surveillance, it is essential that “we treat them with the absolute minimum amount of treatment, with minimum side effects, and with minimum cost,” she said at a plenary session.
As reported by the investigators in 2015, there were small but significant increases in clinician-reported adverse gastrointestinal and genitourinary adverse events in the hypofractionation arm compared with the conventional fractionation arm in the trial, prompting the researchers to see whether patients were actually experiencing what clinicians thought they were seeing.
The investigators examined health-related quality of life and symptoms using the Expanded Prostate Index Composite (EPIC instrument).
They used a 50-item patient-reported outcomes questionnaire using a scale of 0 (no problem) to 4 (big problem), with responses transferred to a 0-100 scale. The questionnaire asked about symptoms in four domains: bowel, urinary, sexual, and hormonal. Patients filled out the questionnaire at baseline and at 6 and 12 months of follow-up.
At 1 year, there were no changes from baseline in hormonal scores in either study arm, but sexual function scores declined by approximately 15 points among patients treated with conventional fractionation and by 11 points among patients treated with hypofractionation (between-group difference nonsignificant).
There was a small decline in urinary scores in both arms, but this difference was not significant.
Patients treated with hypofractionation had a statistically larger decline in bowel scores compared with patients treated with conventional fractionation, a 1.8-point difference, but this difference did not translate into a clinically significant difference; that is, patients themselves could not detect a significant decline in bowel function, Dr. Bruner said.
The invited discussant, Ronald Chen, MD, MPH, director of the comparative effectiveness research program at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, agreed that a difference of only 1.8 points on a 0-100 scale, while technically significant, is clinically meaningless.
“So now we have the complete story and a better understanding of perhaps the value of hypofractionation versus standard fractionation from the patient’s perspective,” he said.
He also emphasized that “quality of life is a central component of any value framework in cancer care, and we must hear the patient’s voice. For clinical trials to truly inform patient decision making and allow patients to assess the value of their treatment options, quality of life must be studied.”
BOSTON – Shortening the radiation dosing schedule by 3 weeks in men with early-stage, low-risk prostate cancer does not appear to result in worse outcomes or diminished quality of life, according to investigators in the NRG Oncology/RTOG 0415 trial.
Efficacy results from the trial, reported at the annual meeting of the American Society for Radiation Oncology, showed that a radiation schedule of 70 Gy in 28 fractions delivered over 5.6 weeks was not inferior to 73.8 Gy delivered in 41 fractions over 8.2 weeks in terms of disease-free, progression-free, or overall survival.
“The International Atomic Energy [Agency] in its prostate cancer guidelines still lists hypofractionated radiation therapy as investigational, but I think we are at the stage where there is a ton of evidence, and this is really no leap of faith anymore that this can become the standard of care,” said Deborah W. Bruner, PhD, of Emory University and the Winship Cancer Institute in Atlanta.
In the treatment of patients with low-risk prostate cancer who opt for therapy over active surveillance, it is essential that “we treat them with the absolute minimum amount of treatment, with minimum side effects, and with minimum cost,” she said at a plenary session.
As reported by the investigators in 2015, there were small but significant increases in clinician-reported adverse gastrointestinal and genitourinary adverse events in the hypofractionation arm compared with the conventional fractionation arm in the trial, prompting the researchers to see whether patients were actually experiencing what clinicians thought they were seeing.
The investigators examined health-related quality of life and symptoms using the Expanded Prostate Index Composite (EPIC instrument).
They used a 50-item patient-reported outcomes questionnaire using a scale of 0 (no problem) to 4 (big problem), with responses transferred to a 0-100 scale. The questionnaire asked about symptoms in four domains: bowel, urinary, sexual, and hormonal. Patients filled out the questionnaire at baseline and at 6 and 12 months of follow-up.
At 1 year, there were no changes from baseline in hormonal scores in either study arm, but sexual function scores declined by approximately 15 points among patients treated with conventional fractionation and by 11 points among patients treated with hypofractionation (between-group difference nonsignificant).
There was a small decline in urinary scores in both arms, but this difference was not significant.
Patients treated with hypofractionation had a statistically larger decline in bowel scores compared with patients treated with conventional fractionation, a 1.8-point difference, but this difference did not translate into a clinically significant difference; that is, patients themselves could not detect a significant decline in bowel function, Dr. Bruner said.
The invited discussant, Ronald Chen, MD, MPH, director of the comparative effectiveness research program at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, agreed that a difference of only 1.8 points on a 0-100 scale, while technically significant, is clinically meaningless.
“So now we have the complete story and a better understanding of perhaps the value of hypofractionation versus standard fractionation from the patient’s perspective,” he said.
He also emphasized that “quality of life is a central component of any value framework in cancer care, and we must hear the patient’s voice. For clinical trials to truly inform patient decision making and allow patients to assess the value of their treatment options, quality of life must be studied.”
Key clinical point: There were no clinically significant differences in survival or patient-reported outcomes between hypofractionated or conventional radiation schedules for patients with low-risk prostate cancer.
Major finding: There was statistically but not clinically significant difference of 1.8 out of 100 patients on a quality-of-life scale.
Data source: Analysis of patient-reported QoL in the NRG//RTOG 0415 trial.
Disclosures: The National Cancer Institute supported the study. Dr. Bruner and Dr. Chen reported having no conflicts of interest.