Genitourinary Cancer

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).¹

Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.

A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.

Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.

Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.

Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).

The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.

The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.²

The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.

Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.

New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.^3,4

In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).¹

Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.

A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.

Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.

Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.

Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).

The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.

The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.²

The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.

Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.

New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.^3,4

In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).¹

Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.

A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.

Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.

Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.

Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).

The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.

The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.²

The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.

Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.

New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.^3,4

MUNICH – Radiotherapy of the primary tumor can improve overall survival in men with untreated metastatic adenocarcinoma of the prostate, a finding that suggests a possible life-extending role of radiotherapy in other metastatic tumor types, investigators in the STAMPEDE trial reported.

Neil Osterweil/MDedge News

Among 2,061 men from the United Kingdom and Switzerland with previously untreated metastatic prostate cancer, there was no survival advantage to adding local radiation to standard drug therapy in the overall study population. But among men with low disease burden (local invasion of bone or lymphatics) radiation to the prostate plus standard of care was associated with a 32% improvement in overall survival compared with standard therapy alone, said Chris Parker, MD, from the Royal Marsden NHS Foundation Trust.

“Prostate radiotherapy is a simple treatment, it’s very well tolerated, and it’s widely available in any cancer center throughout the world,” Dr. Parker said in a briefing prior to his presentation in a presidential symposium at the European Society for Medical Oncology Congress.

The study was published online in the Lancet Oncology to coincide with the presentation.

Neil Osterweil/MDedge News

Men who first present with metastatic prostate cancer account for about 10% of prostate cancer patients in the Western world, but may comprise as much as 60% of the prostate cancer population in some parts of Asia, noted briefing moderator and discussant Ignacio Duran, MD, from the Hospital Universitario Marques de Valdecilla, in Santander, Spain.

Prior to STAMPEDE, “we had never considered treating the local tumor in the context of wider-spread disease, and this is what the group of STAMPEDE really answered today with this study,” he said. “I think there is a substantial group of prostate cancer patients who might benefit from that. This opens the door to apply a new treatment that may have an impact in the life of these patients.”

The overarching goal of the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study is to assess novel approaches for men with hormone-naive prostate cancer.

For this aspect of the randomized, phase 3 trial, 2,061 men with newly diagnosed M1 prostate cancer were enrolled and randomly assigned to either androgen deprivation with or without docetaxel or to the same standard of care plus radiotherapy. Radiation was delivered in one of two schedules: 55 Gy delivered in 20 fractions over 4 weeks or 36 Gy in 6 fractions delivered over 6 weeks, started within 8 weeks of randomization or the start of docetaxel.

As noted before, death from any cause, the primary endpoint, was not significantly different between the study arms. But in a subgroup analysis by metastatic burden, the rate of 3-year overall survival in patients with low burden was 81% in the radiotherapy group, compared with 73% in the standard-of-care arm. The hazard ratio was 0.68 (P = .007) favoring radiation.

In contrast, the 3-year overall survival rate in the high metastatic burden arm (patients with four or more metastases to bone with at least one outside the axial skeleton and/or visceral metastases) was 53% with radiation, versus 54% without.

In all, 5% of patients in the radiotherapy arm had grade 3 or 4 adverse events during therapy, and 4% had postradiation adverse events.

Radiation was associated with small increases in the risk for bladder and bowel events, but these were generally “modest” in nature and were outweighed by the survival benefit, Dr. Parker said.

He noted that men with regional nodal invasion but not metastases were not included in the trial. “However, if prostate radiotherapy improves survival for men with distant metastases, we can be very confident that it would improve survival for men with regional nodal disease. There aren’t any trials addressing that question, and currently many of these men receive drug treatment alone. So going forward, prostate radiotherapy should be the standard treatment for these men as well.”

The concept of primary tumor irradiation may work for patients with other malignancies who have low burden (oligometastatic) disease, he added.

“Based on the findings of STAMPEDE, radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment,” commented R. Jeffrey Karnes, MD, from the Mayo Clinic in Rochester, Minnesota, and his colleagues, in an editorial accompanying the article in the Lancet Oncology.

The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.

SOURCE: Parker C et al. ESMO 2018, Abstract LBA5_PR.

MUNICH – Radiotherapy of the primary tumor can improve overall survival in men with untreated metastatic adenocarcinoma of the prostate, a finding that suggests a possible life-extending role of radiotherapy in other metastatic tumor types, investigators in the STAMPEDE trial reported.

Neil Osterweil/MDedge News

Among 2,061 men from the United Kingdom and Switzerland with previously untreated metastatic prostate cancer, there was no survival advantage to adding local radiation to standard drug therapy in the overall study population. But among men with low disease burden (local invasion of bone or lymphatics) radiation to the prostate plus standard of care was associated with a 32% improvement in overall survival compared with standard therapy alone, said Chris Parker, MD, from the Royal Marsden NHS Foundation Trust.

“Prostate radiotherapy is a simple treatment, it’s very well tolerated, and it’s widely available in any cancer center throughout the world,” Dr. Parker said in a briefing prior to his presentation in a presidential symposium at the European Society for Medical Oncology Congress.

The study was published online in the Lancet Oncology to coincide with the presentation.

Neil Osterweil/MDedge News

Men who first present with metastatic prostate cancer account for about 10% of prostate cancer patients in the Western world, but may comprise as much as 60% of the prostate cancer population in some parts of Asia, noted briefing moderator and discussant Ignacio Duran, MD, from the Hospital Universitario Marques de Valdecilla, in Santander, Spain.

Prior to STAMPEDE, “we had never considered treating the local tumor in the context of wider-spread disease, and this is what the group of STAMPEDE really answered today with this study,” he said. “I think there is a substantial group of prostate cancer patients who might benefit from that. This opens the door to apply a new treatment that may have an impact in the life of these patients.”

The overarching goal of the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study is to assess novel approaches for men with hormone-naive prostate cancer.

For this aspect of the randomized, phase 3 trial, 2,061 men with newly diagnosed M1 prostate cancer were enrolled and randomly assigned to either androgen deprivation with or without docetaxel or to the same standard of care plus radiotherapy. Radiation was delivered in one of two schedules: 55 Gy delivered in 20 fractions over 4 weeks or 36 Gy in 6 fractions delivered over 6 weeks, started within 8 weeks of randomization or the start of docetaxel.

As noted before, death from any cause, the primary endpoint, was not significantly different between the study arms. But in a subgroup analysis by metastatic burden, the rate of 3-year overall survival in patients with low burden was 81% in the radiotherapy group, compared with 73% in the standard-of-care arm. The hazard ratio was 0.68 (P = .007) favoring radiation.

In contrast, the 3-year overall survival rate in the high metastatic burden arm (patients with four or more metastases to bone with at least one outside the axial skeleton and/or visceral metastases) was 53% with radiation, versus 54% without.

In all, 5% of patients in the radiotherapy arm had grade 3 or 4 adverse events during therapy, and 4% had postradiation adverse events.

Radiation was associated with small increases in the risk for bladder and bowel events, but these were generally “modest” in nature and were outweighed by the survival benefit, Dr. Parker said.

He noted that men with regional nodal invasion but not metastases were not included in the trial. “However, if prostate radiotherapy improves survival for men with distant metastases, we can be very confident that it would improve survival for men with regional nodal disease. There aren’t any trials addressing that question, and currently many of these men receive drug treatment alone. So going forward, prostate radiotherapy should be the standard treatment for these men as well.”

The concept of primary tumor irradiation may work for patients with other malignancies who have low burden (oligometastatic) disease, he added.

“Based on the findings of STAMPEDE, radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment,” commented R. Jeffrey Karnes, MD, from the Mayo Clinic in Rochester, Minnesota, and his colleagues, in an editorial accompanying the article in the Lancet Oncology.

The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.

SOURCE: Parker C et al. ESMO 2018, Abstract LBA5_PR.

MUNICH – Radiotherapy of the primary tumor can improve overall survival in men with untreated metastatic adenocarcinoma of the prostate, a finding that suggests a possible life-extending role of radiotherapy in other metastatic tumor types, investigators in the STAMPEDE trial reported.

Neil Osterweil/MDedge News

Among 2,061 men from the United Kingdom and Switzerland with previously untreated metastatic prostate cancer, there was no survival advantage to adding local radiation to standard drug therapy in the overall study population. But among men with low disease burden (local invasion of bone or lymphatics) radiation to the prostate plus standard of care was associated with a 32% improvement in overall survival compared with standard therapy alone, said Chris Parker, MD, from the Royal Marsden NHS Foundation Trust.

“Prostate radiotherapy is a simple treatment, it’s very well tolerated, and it’s widely available in any cancer center throughout the world,” Dr. Parker said in a briefing prior to his presentation in a presidential symposium at the European Society for Medical Oncology Congress.

The study was published online in the Lancet Oncology to coincide with the presentation.

Neil Osterweil/MDedge News

Men who first present with metastatic prostate cancer account for about 10% of prostate cancer patients in the Western world, but may comprise as much as 60% of the prostate cancer population in some parts of Asia, noted briefing moderator and discussant Ignacio Duran, MD, from the Hospital Universitario Marques de Valdecilla, in Santander, Spain.

Prior to STAMPEDE, “we had never considered treating the local tumor in the context of wider-spread disease, and this is what the group of STAMPEDE really answered today with this study,” he said. “I think there is a substantial group of prostate cancer patients who might benefit from that. This opens the door to apply a new treatment that may have an impact in the life of these patients.”

The overarching goal of the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study is to assess novel approaches for men with hormone-naive prostate cancer.

For this aspect of the randomized, phase 3 trial, 2,061 men with newly diagnosed M1 prostate cancer were enrolled and randomly assigned to either androgen deprivation with or without docetaxel or to the same standard of care plus radiotherapy. Radiation was delivered in one of two schedules: 55 Gy delivered in 20 fractions over 4 weeks or 36 Gy in 6 fractions delivered over 6 weeks, started within 8 weeks of randomization or the start of docetaxel.

As noted before, death from any cause, the primary endpoint, was not significantly different between the study arms. But in a subgroup analysis by metastatic burden, the rate of 3-year overall survival in patients with low burden was 81% in the radiotherapy group, compared with 73% in the standard-of-care arm. The hazard ratio was 0.68 (P = .007) favoring radiation.

In contrast, the 3-year overall survival rate in the high metastatic burden arm (patients with four or more metastases to bone with at least one outside the axial skeleton and/or visceral metastases) was 53% with radiation, versus 54% without.

In all, 5% of patients in the radiotherapy arm had grade 3 or 4 adverse events during therapy, and 4% had postradiation adverse events.

Radiation was associated with small increases in the risk for bladder and bowel events, but these were generally “modest” in nature and were outweighed by the survival benefit, Dr. Parker said.

He noted that men with regional nodal invasion but not metastases were not included in the trial. “However, if prostate radiotherapy improves survival for men with distant metastases, we can be very confident that it would improve survival for men with regional nodal disease. There aren’t any trials addressing that question, and currently many of these men receive drug treatment alone. So going forward, prostate radiotherapy should be the standard treatment for these men as well.”

The concept of primary tumor irradiation may work for patients with other malignancies who have low burden (oligometastatic) disease, he added.

“Based on the findings of STAMPEDE, radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment,” commented R. Jeffrey Karnes, MD, from the Mayo Clinic in Rochester, Minnesota, and his colleagues, in an editorial accompanying the article in the Lancet Oncology.

The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.

SOURCE: Parker C et al. ESMO 2018, Abstract LBA5_PR.

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

There was no difference in the incidence of adverse events in a group of patients being treated with pazopanib for metastatic renal cell carcinoma with comorbid renal dysfunction.

In a multicenter, retrospective study that included 229 patients with or without renal insufficiency being treated for metastatic renal cell carcinoma with pazopanib, no significant differences were found in the incidence of adverse events between groups. Similar results were demonstrated for both efficacy parameters, progression-free survival, and overall survival (P = .6), Cristina Masini, MD, of AUSL-IRCCS in Reggio Emilia, Italy, and colleagues reported in Clinical Genitourinary Cancer.

The researchers also determined that dose reductions occurred more often in patients with renal insufficiency, compared with those that were renal competent (52% vs. 36%; P = .04).

The majority of study participants received a starting dose of 800 mg daily of pazopanib, which was reduced to a minimum of 200 mg daily in 19% of participants from the renal impairment group, compared with less than 1% in the nonrenally impaired group.

“The similar efficacy and safety displayed by pazopanib in patients with poor renal function, compared with those with normal function may have a major relevance for therapy individualization in clinical practice,” the investigators concluded, adding that, because of the retrospective study design, further research is needed to fully establish any causal links between pazopanib and renal insufficiency.

The authors reported that editorial assistance was supported by Novartis. No other conflict of interests were reported
 

SOURCE: Masini C et al. Clin Genitourin Cancer. 2018 Oct 1. doi: 10.1016/j.clgc.2018.10.001.

There was no difference in the incidence of adverse events in a group of patients being treated with pazopanib for metastatic renal cell carcinoma with comorbid renal dysfunction.

In a multicenter, retrospective study that included 229 patients with or without renal insufficiency being treated for metastatic renal cell carcinoma with pazopanib, no significant differences were found in the incidence of adverse events between groups. Similar results were demonstrated for both efficacy parameters, progression-free survival, and overall survival (P = .6), Cristina Masini, MD, of AUSL-IRCCS in Reggio Emilia, Italy, and colleagues reported in Clinical Genitourinary Cancer.

The researchers also determined that dose reductions occurred more often in patients with renal insufficiency, compared with those that were renal competent (52% vs. 36%; P = .04).

The majority of study participants received a starting dose of 800 mg daily of pazopanib, which was reduced to a minimum of 200 mg daily in 19% of participants from the renal impairment group, compared with less than 1% in the nonrenally impaired group.

“The similar efficacy and safety displayed by pazopanib in patients with poor renal function, compared with those with normal function may have a major relevance for therapy individualization in clinical practice,” the investigators concluded, adding that, because of the retrospective study design, further research is needed to fully establish any causal links between pazopanib and renal insufficiency.

The authors reported that editorial assistance was supported by Novartis. No other conflict of interests were reported
 

SOURCE: Masini C et al. Clin Genitourin Cancer. 2018 Oct 1. doi: 10.1016/j.clgc.2018.10.001.

There was no difference in the incidence of adverse events in a group of patients being treated with pazopanib for metastatic renal cell carcinoma with comorbid renal dysfunction.

In a multicenter, retrospective study that included 229 patients with or without renal insufficiency being treated for metastatic renal cell carcinoma with pazopanib, no significant differences were found in the incidence of adverse events between groups. Similar results were demonstrated for both efficacy parameters, progression-free survival, and overall survival (P = .6), Cristina Masini, MD, of AUSL-IRCCS in Reggio Emilia, Italy, and colleagues reported in Clinical Genitourinary Cancer.

The researchers also determined that dose reductions occurred more often in patients with renal insufficiency, compared with those that were renal competent (52% vs. 36%; P = .04).

The majority of study participants received a starting dose of 800 mg daily of pazopanib, which was reduced to a minimum of 200 mg daily in 19% of participants from the renal impairment group, compared with less than 1% in the nonrenally impaired group.

“The similar efficacy and safety displayed by pazopanib in patients with poor renal function, compared with those with normal function may have a major relevance for therapy individualization in clinical practice,” the investigators concluded, adding that, because of the retrospective study design, further research is needed to fully establish any causal links between pazopanib and renal insufficiency.

The authors reported that editorial assistance was supported by Novartis. No other conflict of interests were reported
 

SOURCE: Masini C et al. Clin Genitourin Cancer. 2018 Oct 1. doi: 10.1016/j.clgc.2018.10.001.

Moderate hypofractionation is preferred over conventional fractionation in treatment of patients with localized prostate cancer who are candidates for external beam radiotherapy (EBRT), according to new a clinical practice guideline.

A meta-analysis of randomized clinical trials showed that moderate fractionation delivered the same efficacy as did conventional fractionation with a mild increase in gastrointestinal toxicity, reported lead author Scott C. Morgan, MD of OSF Medical Group in Bloomington, Illinois, and his colleagues. The drawback of toxicity is outweighed by distinct advantages in resource utilization and patient convenience, which make moderate hypofractionation the winning choice.

For many types of cancer, a shift toward fewer fractions of higher radiation is ongoing, driven largely by technological advances in radiation planning and delivery.

“Technical advances have permitted more precise and conformal delivery of escalated doses of radiation to the prostate, thereby improving the therapeutic ratio,” the authors wrote in the Journal of Clinical Oncology.

Fractionation is typically limited by adjacent tissue sensitivity, but prostate tumors are more sensitive to radiation than the rectum, allowing for higher doses of radiation without damaging healthy tissue. While conventional fractionation doses are between 180 and 200 cGy, moderate hypofractionation delivers doses of 240-340 cGy. Ultrahypofractionation is defined by doses equal to or greater than 500 cGy (the upper limit of the linear-quadratic model of cell survival).

The present guideline was developed through a 2-year, collaborative effort between the American Society of Radiation Oncology, the Society of Clinical Oncology, and the American Urological Association. Task force members included urologic surgeons and oncologists, medical physicists, and radiation oncologists from academic and nonacademic settings. A patient representative and radiation oncology resident also were involved. After completing a systematic literature review, the team developed recommendations with varying degrees of strength. Supporting evidence quality and level of consensus also were described.

Of note, the guideline calls for moderate hypofractionation for patients with localized prostate cancer regardless of urinary function, anatomy, comorbidity, or age, with or without radiation to the seminal vesicles. Along with this recommendation, clinicians should discuss with patients the small increased risk of acute gastrointestinal toxicity, compared with conventional fractionation and the limited follow-up time in most relevant clinical trials (often less than 5 years).

The guideline conveyed more skepticism regarding ultrahypofractionation because of a lack of supporting evidence and comparative trials. As such, the authors conditionally recommended ultrahypofractionation for low-risk and intermediate patients, the latter of whom should be encouraged to enter clinical trials.

“The conditional recommendations regarding ultrahypofractionation underscore the importance of shared decision making between clinicians and patients in this setting,” the authors wrote. “The decision to use ultrahypofractionated EBRT at this time should follow a detailed discussion of the existing uncertainties in the risk-benefit balance associated with this treatment approach and should be informed at all stages by the patient’s values and preferences.”

The authors reported financial affiliations with Amgen, GlaxoSmithKline, Bristol-Myers Squibb, and others.

SOURCE: Morgan et al. J Clin Oncol. 2018 Oct 11. doi: 10.1200/JCO.18.01097.

Moderate hypofractionation is preferred over conventional fractionation in treatment of patients with localized prostate cancer who are candidates for external beam radiotherapy (EBRT), according to new a clinical practice guideline.

A meta-analysis of randomized clinical trials showed that moderate fractionation delivered the same efficacy as did conventional fractionation with a mild increase in gastrointestinal toxicity, reported lead author Scott C. Morgan, MD of OSF Medical Group in Bloomington, Illinois, and his colleagues. The drawback of toxicity is outweighed by distinct advantages in resource utilization and patient convenience, which make moderate hypofractionation the winning choice.

For many types of cancer, a shift toward fewer fractions of higher radiation is ongoing, driven largely by technological advances in radiation planning and delivery.

“Technical advances have permitted more precise and conformal delivery of escalated doses of radiation to the prostate, thereby improving the therapeutic ratio,” the authors wrote in the Journal of Clinical Oncology.

Fractionation is typically limited by adjacent tissue sensitivity, but prostate tumors are more sensitive to radiation than the rectum, allowing for higher doses of radiation without damaging healthy tissue. While conventional fractionation doses are between 180 and 200 cGy, moderate hypofractionation delivers doses of 240-340 cGy. Ultrahypofractionation is defined by doses equal to or greater than 500 cGy (the upper limit of the linear-quadratic model of cell survival).

The present guideline was developed through a 2-year, collaborative effort between the American Society of Radiation Oncology, the Society of Clinical Oncology, and the American Urological Association. Task force members included urologic surgeons and oncologists, medical physicists, and radiation oncologists from academic and nonacademic settings. A patient representative and radiation oncology resident also were involved. After completing a systematic literature review, the team developed recommendations with varying degrees of strength. Supporting evidence quality and level of consensus also were described.

Of note, the guideline calls for moderate hypofractionation for patients with localized prostate cancer regardless of urinary function, anatomy, comorbidity, or age, with or without radiation to the seminal vesicles. Along with this recommendation, clinicians should discuss with patients the small increased risk of acute gastrointestinal toxicity, compared with conventional fractionation and the limited follow-up time in most relevant clinical trials (often less than 5 years).

The guideline conveyed more skepticism regarding ultrahypofractionation because of a lack of supporting evidence and comparative trials. As such, the authors conditionally recommended ultrahypofractionation for low-risk and intermediate patients, the latter of whom should be encouraged to enter clinical trials.

“The conditional recommendations regarding ultrahypofractionation underscore the importance of shared decision making between clinicians and patients in this setting,” the authors wrote. “The decision to use ultrahypofractionated EBRT at this time should follow a detailed discussion of the existing uncertainties in the risk-benefit balance associated with this treatment approach and should be informed at all stages by the patient’s values and preferences.”

The authors reported financial affiliations with Amgen, GlaxoSmithKline, Bristol-Myers Squibb, and others.

SOURCE: Morgan et al. J Clin Oncol. 2018 Oct 11. doi: 10.1200/JCO.18.01097.

Moderate hypofractionation is preferred over conventional fractionation in treatment of patients with localized prostate cancer who are candidates for external beam radiotherapy (EBRT), according to new a clinical practice guideline.

A meta-analysis of randomized clinical trials showed that moderate fractionation delivered the same efficacy as did conventional fractionation with a mild increase in gastrointestinal toxicity, reported lead author Scott C. Morgan, MD of OSF Medical Group in Bloomington, Illinois, and his colleagues. The drawback of toxicity is outweighed by distinct advantages in resource utilization and patient convenience, which make moderate hypofractionation the winning choice.

For many types of cancer, a shift toward fewer fractions of higher radiation is ongoing, driven largely by technological advances in radiation planning and delivery.

“Technical advances have permitted more precise and conformal delivery of escalated doses of radiation to the prostate, thereby improving the therapeutic ratio,” the authors wrote in the Journal of Clinical Oncology.

Fractionation is typically limited by adjacent tissue sensitivity, but prostate tumors are more sensitive to radiation than the rectum, allowing for higher doses of radiation without damaging healthy tissue. While conventional fractionation doses are between 180 and 200 cGy, moderate hypofractionation delivers doses of 240-340 cGy. Ultrahypofractionation is defined by doses equal to or greater than 500 cGy (the upper limit of the linear-quadratic model of cell survival).

The present guideline was developed through a 2-year, collaborative effort between the American Society of Radiation Oncology, the Society of Clinical Oncology, and the American Urological Association. Task force members included urologic surgeons and oncologists, medical physicists, and radiation oncologists from academic and nonacademic settings. A patient representative and radiation oncology resident also were involved. After completing a systematic literature review, the team developed recommendations with varying degrees of strength. Supporting evidence quality and level of consensus also were described.

Of note, the guideline calls for moderate hypofractionation for patients with localized prostate cancer regardless of urinary function, anatomy, comorbidity, or age, with or without radiation to the seminal vesicles. Along with this recommendation, clinicians should discuss with patients the small increased risk of acute gastrointestinal toxicity, compared with conventional fractionation and the limited follow-up time in most relevant clinical trials (often less than 5 years).

The guideline conveyed more skepticism regarding ultrahypofractionation because of a lack of supporting evidence and comparative trials. As such, the authors conditionally recommended ultrahypofractionation for low-risk and intermediate patients, the latter of whom should be encouraged to enter clinical trials.

“The conditional recommendations regarding ultrahypofractionation underscore the importance of shared decision making between clinicians and patients in this setting,” the authors wrote. “The decision to use ultrahypofractionated EBRT at this time should follow a detailed discussion of the existing uncertainties in the risk-benefit balance associated with this treatment approach and should be informed at all stages by the patient’s values and preferences.”

The authors reported financial affiliations with Amgen, GlaxoSmithKline, Bristol-Myers Squibb, and others.

SOURCE: Morgan et al. J Clin Oncol. 2018 Oct 11. doi: 10.1200/JCO.18.01097.

In contrast to other recent studies, androgen deprivation therapy (ADT) had no link to dementia in a observational cohort study of more than 45,000 men with prostate cancer who received definitive radiotherapy, investigators have reported.

No significant associations were found between ADT and Alzheimer’s disease or vascular dementia, or between shorter or longer courses of ADT and any dementia studied, according to Rishi Deka, PhD, of Veterans Affairs San Diego Health Care System, La Jolla, Calif., and coinvestigators.

“These results may mitigate concerns regarding the long-term risks of ADT on cognitive health in the treatment of prostate cancer,” Dr. Deka and colleagues wrote in JAMA Oncology.

Two other recent studies showed strong, statistically significant associations between ADT and dementia in prostate cancer. However, those studies combined patients with local and metastatic disease, receiving ADT in the upfront or recurrent settings, while the present study looked specifically at men with nonmetastatic prostate cancer who received radiotherapy.

“Different treatment modalities and disease stages are associated with substantial selection bias that may predispose results to false associations,” noted Dr. Deka and coauthors.

Their observational cohort study comprised 45,218 men diagnosed with nonmetastatic prostate cancer at the U.S. Department of Veterans Affairs who underwent radiotherapy with or without ADT. The investigators excluded men who had a diagnosis of dementia within 1 year of the prostate cancer diagnosis or who had prior diagnoses of dementia, stroke, or cognitive impairment.

A total of 1,497 patients were diagnosed with dementia over a median of 6.8 years of follow-up: 404 with Alzheimer disease, 335 with vascular dementia, and 758 with other types or unclassified dementias.

The investigators found no significant association between use of ADT and development of any dementia, the primary outcome of the analysis (subdistribution hazard ratio [SHR], 1.04; 95% confidence interval, 0.94-1.16; P = .43).

Likewise, there was no association between ADT and vascular dementia, specifically, with an SHR of 1.20 (95% CI, 0.97-1.50; P = .10) or Alzheimer’s disease, with an SHR of 1.11 (95% CI, 0.91-1.36; P = .29).

Duration of ADT longer than 1 year was not significantly associated with dementia, nor was duration shorter than 1 year, with SHRs, of 1.08 and 1.01 respectively, the analysis shows.

The SHRs in these and other analysis reported ranged from 1.00 to 1.21. That is substantially lower than hazard ratios of 1.66 to 2.32 in one previous study linking ADT to dementia, according to the investigators, suggesting that the results of the current analysis were not due to inadequate power to detect differences.

Nevertheless, the findings may not be generalizable to some other populations, they cautioned, since it was focused demographically on veterans, and was limited to radiotherapy-treated patients.

Dr. Deka and coauthors reported no conflict of interest. Their study was funded by grants from the University of California San Diego Center for Precision Radiation Medicine.

SOURCE: Deka R et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4423.

In contrast to other recent studies, androgen deprivation therapy (ADT) had no link to dementia in a observational cohort study of more than 45,000 men with prostate cancer who received definitive radiotherapy, investigators have reported.

No significant associations were found between ADT and Alzheimer’s disease or vascular dementia, or between shorter or longer courses of ADT and any dementia studied, according to Rishi Deka, PhD, of Veterans Affairs San Diego Health Care System, La Jolla, Calif., and coinvestigators.

“These results may mitigate concerns regarding the long-term risks of ADT on cognitive health in the treatment of prostate cancer,” Dr. Deka and colleagues wrote in JAMA Oncology.

Two other recent studies showed strong, statistically significant associations between ADT and dementia in prostate cancer. However, those studies combined patients with local and metastatic disease, receiving ADT in the upfront or recurrent settings, while the present study looked specifically at men with nonmetastatic prostate cancer who received radiotherapy.

“Different treatment modalities and disease stages are associated with substantial selection bias that may predispose results to false associations,” noted Dr. Deka and coauthors.

Their observational cohort study comprised 45,218 men diagnosed with nonmetastatic prostate cancer at the U.S. Department of Veterans Affairs who underwent radiotherapy with or without ADT. The investigators excluded men who had a diagnosis of dementia within 1 year of the prostate cancer diagnosis or who had prior diagnoses of dementia, stroke, or cognitive impairment.

A total of 1,497 patients were diagnosed with dementia over a median of 6.8 years of follow-up: 404 with Alzheimer disease, 335 with vascular dementia, and 758 with other types or unclassified dementias.

The investigators found no significant association between use of ADT and development of any dementia, the primary outcome of the analysis (subdistribution hazard ratio [SHR], 1.04; 95% confidence interval, 0.94-1.16; P = .43).

Likewise, there was no association between ADT and vascular dementia, specifically, with an SHR of 1.20 (95% CI, 0.97-1.50; P = .10) or Alzheimer’s disease, with an SHR of 1.11 (95% CI, 0.91-1.36; P = .29).

Duration of ADT longer than 1 year was not significantly associated with dementia, nor was duration shorter than 1 year, with SHRs, of 1.08 and 1.01 respectively, the analysis shows.

The SHRs in these and other analysis reported ranged from 1.00 to 1.21. That is substantially lower than hazard ratios of 1.66 to 2.32 in one previous study linking ADT to dementia, according to the investigators, suggesting that the results of the current analysis were not due to inadequate power to detect differences.

Nevertheless, the findings may not be generalizable to some other populations, they cautioned, since it was focused demographically on veterans, and was limited to radiotherapy-treated patients.

Dr. Deka and coauthors reported no conflict of interest. Their study was funded by grants from the University of California San Diego Center for Precision Radiation Medicine.

SOURCE: Deka R et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4423.

In contrast to other recent studies, androgen deprivation therapy (ADT) had no link to dementia in a observational cohort study of more than 45,000 men with prostate cancer who received definitive radiotherapy, investigators have reported.

No significant associations were found between ADT and Alzheimer’s disease or vascular dementia, or between shorter or longer courses of ADT and any dementia studied, according to Rishi Deka, PhD, of Veterans Affairs San Diego Health Care System, La Jolla, Calif., and coinvestigators.

“These results may mitigate concerns regarding the long-term risks of ADT on cognitive health in the treatment of prostate cancer,” Dr. Deka and colleagues wrote in JAMA Oncology.

Two other recent studies showed strong, statistically significant associations between ADT and dementia in prostate cancer. However, those studies combined patients with local and metastatic disease, receiving ADT in the upfront or recurrent settings, while the present study looked specifically at men with nonmetastatic prostate cancer who received radiotherapy.

“Different treatment modalities and disease stages are associated with substantial selection bias that may predispose results to false associations,” noted Dr. Deka and coauthors.

Their observational cohort study comprised 45,218 men diagnosed with nonmetastatic prostate cancer at the U.S. Department of Veterans Affairs who underwent radiotherapy with or without ADT. The investigators excluded men who had a diagnosis of dementia within 1 year of the prostate cancer diagnosis or who had prior diagnoses of dementia, stroke, or cognitive impairment.

A total of 1,497 patients were diagnosed with dementia over a median of 6.8 years of follow-up: 404 with Alzheimer disease, 335 with vascular dementia, and 758 with other types or unclassified dementias.

The investigators found no significant association between use of ADT and development of any dementia, the primary outcome of the analysis (subdistribution hazard ratio [SHR], 1.04; 95% confidence interval, 0.94-1.16; P = .43).

Likewise, there was no association between ADT and vascular dementia, specifically, with an SHR of 1.20 (95% CI, 0.97-1.50; P = .10) or Alzheimer’s disease, with an SHR of 1.11 (95% CI, 0.91-1.36; P = .29).

Duration of ADT longer than 1 year was not significantly associated with dementia, nor was duration shorter than 1 year, with SHRs, of 1.08 and 1.01 respectively, the analysis shows.

The SHRs in these and other analysis reported ranged from 1.00 to 1.21. That is substantially lower than hazard ratios of 1.66 to 2.32 in one previous study linking ADT to dementia, according to the investigators, suggesting that the results of the current analysis were not due to inadequate power to detect differences.

Nevertheless, the findings may not be generalizable to some other populations, they cautioned, since it was focused demographically on veterans, and was limited to radiotherapy-treated patients.

Dr. Deka and coauthors reported no conflict of interest. Their study was funded by grants from the University of California San Diego Center for Precision Radiation Medicine.

SOURCE: Deka R et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4423.

Renal cell carcinoma (RCC) incidence rates increased in recent years, but have stabilized, while mortality rates have dropped precipitously, according to an analysis of more than 20 years of U.S. cancer registry data.

The introduction of antiangiogenic agents is likely one key factor that led to the mortality decrease, said authors of the analysis of Surveillance, Epidemiology, and End Results data from 1992 to 2015.

Incidence trends are likely more complex and may reflect the interplay between increased detection, on one hand, and decreases in modifiable risk factors such as smoking on the other, the authors reported in Clinical Genitourinary Cancer.

The analysis, conducted by Anas M. Saad, a final-year medical student at Ain Shams University, Cairo; Thai H. Ho, MD, PhD, of Mayo Clinic Cancer Center, Phoenix; and coinvestigators, included a total of 104,584 patients with an RCC diagnosis, of whom nearly 64% were male and 80% were white. The majority of tumors were small and localized at diagnosis, and clear cell was the histologic subtype in 44%, according to the report.

Overall incidence of RCC was 11.3 per 100,000 person-years over the 1992-2015 study period, Dr. Saad and coauthors said in their report.

The incidence rate increased by about 2.4% per year, averaged over the course of the entire study period, though the plateau in rates began around 2008, according to the investigators. A figure in their report shows that the age-adjusted rate was just over 8 per 100,000 person-years in 1992; it climbed steadily until 2008, at which point it remained in the range of about 12-14 per 100,000 person-years for the next 7 years.

The uptick in incidence from 1992 to 2008 was concentrated mostly in localized and regional RCC, rather than distant disease, according to Dr. Saad and colleagues.

The overall incidence-based mortality rate for RCC was 5.3 per 100,000 person-years from 1992 to 2015, Dr. Saad and coauthors said.

Mortality rates increased from 1992 and peaked in 2001, at which point they started to drop at an ever accelerating pace. The annual percent decrease in that mortality rate was 1.5% between 2001 and 2008, 9.3% between 2008 and 2013, and 32.2% from 2013 to 2015, according to the report.

Incidence rate trends are probably affected by increases in incidental diagnoses and changes in RCC risk factor prevalence, investigators noted. For example, there has been a significant increase in use of advanced abdominal imaging, which has improved sensitivity in picking up renal masses, but cannot reliably distinguish between benign and malignant features, they said. On the other hand, smoking, which increases risk of RCC, has been trending downward for decades, which they said correlated with RCC trends.

Authors said RCC survival has been improved by antiangiogenic agents known as vascular endothelial growth factor inhibitors, and more recently immune checkpoint therapies, as clinical trials have shown.

“The decreasing mortality trend starting in 2007 and continuing until 2015 is associated with the introduction of such therapies for RCC treatment,” Dr. Saad and coauthors said in their report.

Support for the study came from the National Cancer Institute and the Department of Defense. Dr. Saad and coauthors declared that they had no conflicts of interest.

SOURCE: Saad AM et al. Clin Genitourin Cancer. 2018. doi: 10.1016/j.clgc.2018.10.002.

Renal cell carcinoma (RCC) incidence rates increased in recent years, but have stabilized, while mortality rates have dropped precipitously, according to an analysis of more than 20 years of U.S. cancer registry data.

The introduction of antiangiogenic agents is likely one key factor that led to the mortality decrease, said authors of the analysis of Surveillance, Epidemiology, and End Results data from 1992 to 2015.

Incidence trends are likely more complex and may reflect the interplay between increased detection, on one hand, and decreases in modifiable risk factors such as smoking on the other, the authors reported in Clinical Genitourinary Cancer.

The analysis, conducted by Anas M. Saad, a final-year medical student at Ain Shams University, Cairo; Thai H. Ho, MD, PhD, of Mayo Clinic Cancer Center, Phoenix; and coinvestigators, included a total of 104,584 patients with an RCC diagnosis, of whom nearly 64% were male and 80% were white. The majority of tumors were small and localized at diagnosis, and clear cell was the histologic subtype in 44%, according to the report.

Overall incidence of RCC was 11.3 per 100,000 person-years over the 1992-2015 study period, Dr. Saad and coauthors said in their report.

The incidence rate increased by about 2.4% per year, averaged over the course of the entire study period, though the plateau in rates began around 2008, according to the investigators. A figure in their report shows that the age-adjusted rate was just over 8 per 100,000 person-years in 1992; it climbed steadily until 2008, at which point it remained in the range of about 12-14 per 100,000 person-years for the next 7 years.

The uptick in incidence from 1992 to 2008 was concentrated mostly in localized and regional RCC, rather than distant disease, according to Dr. Saad and colleagues.

The overall incidence-based mortality rate for RCC was 5.3 per 100,000 person-years from 1992 to 2015, Dr. Saad and coauthors said.

Mortality rates increased from 1992 and peaked in 2001, at which point they started to drop at an ever accelerating pace. The annual percent decrease in that mortality rate was 1.5% between 2001 and 2008, 9.3% between 2008 and 2013, and 32.2% from 2013 to 2015, according to the report.

Incidence rate trends are probably affected by increases in incidental diagnoses and changes in RCC risk factor prevalence, investigators noted. For example, there has been a significant increase in use of advanced abdominal imaging, which has improved sensitivity in picking up renal masses, but cannot reliably distinguish between benign and malignant features, they said. On the other hand, smoking, which increases risk of RCC, has been trending downward for decades, which they said correlated with RCC trends.

Authors said RCC survival has been improved by antiangiogenic agents known as vascular endothelial growth factor inhibitors, and more recently immune checkpoint therapies, as clinical trials have shown.

“The decreasing mortality trend starting in 2007 and continuing until 2015 is associated with the introduction of such therapies for RCC treatment,” Dr. Saad and coauthors said in their report.

Support for the study came from the National Cancer Institute and the Department of Defense. Dr. Saad and coauthors declared that they had no conflicts of interest.

SOURCE: Saad AM et al. Clin Genitourin Cancer. 2018. doi: 10.1016/j.clgc.2018.10.002.

Renal cell carcinoma (RCC) incidence rates increased in recent years, but have stabilized, while mortality rates have dropped precipitously, according to an analysis of more than 20 years of U.S. cancer registry data.

The introduction of antiangiogenic agents is likely one key factor that led to the mortality decrease, said authors of the analysis of Surveillance, Epidemiology, and End Results data from 1992 to 2015.

Incidence trends are likely more complex and may reflect the interplay between increased detection, on one hand, and decreases in modifiable risk factors such as smoking on the other, the authors reported in Clinical Genitourinary Cancer.

The analysis, conducted by Anas M. Saad, a final-year medical student at Ain Shams University, Cairo; Thai H. Ho, MD, PhD, of Mayo Clinic Cancer Center, Phoenix; and coinvestigators, included a total of 104,584 patients with an RCC diagnosis, of whom nearly 64% were male and 80% were white. The majority of tumors were small and localized at diagnosis, and clear cell was the histologic subtype in 44%, according to the report.

Overall incidence of RCC was 11.3 per 100,000 person-years over the 1992-2015 study period, Dr. Saad and coauthors said in their report.

The incidence rate increased by about 2.4% per year, averaged over the course of the entire study period, though the plateau in rates began around 2008, according to the investigators. A figure in their report shows that the age-adjusted rate was just over 8 per 100,000 person-years in 1992; it climbed steadily until 2008, at which point it remained in the range of about 12-14 per 100,000 person-years for the next 7 years.

The uptick in incidence from 1992 to 2008 was concentrated mostly in localized and regional RCC, rather than distant disease, according to Dr. Saad and colleagues.

The overall incidence-based mortality rate for RCC was 5.3 per 100,000 person-years from 1992 to 2015, Dr. Saad and coauthors said.

Mortality rates increased from 1992 and peaked in 2001, at which point they started to drop at an ever accelerating pace. The annual percent decrease in that mortality rate was 1.5% between 2001 and 2008, 9.3% between 2008 and 2013, and 32.2% from 2013 to 2015, according to the report.

Incidence rate trends are probably affected by increases in incidental diagnoses and changes in RCC risk factor prevalence, investigators noted. For example, there has been a significant increase in use of advanced abdominal imaging, which has improved sensitivity in picking up renal masses, but cannot reliably distinguish between benign and malignant features, they said. On the other hand, smoking, which increases risk of RCC, has been trending downward for decades, which they said correlated with RCC trends.

Authors said RCC survival has been improved by antiangiogenic agents known as vascular endothelial growth factor inhibitors, and more recently immune checkpoint therapies, as clinical trials have shown.

“The decreasing mortality trend starting in 2007 and continuing until 2015 is associated with the introduction of such therapies for RCC treatment,” Dr. Saad and coauthors said in their report.

Support for the study came from the National Cancer Institute and the Department of Defense. Dr. Saad and coauthors declared that they had no conflicts of interest.

SOURCE: Saad AM et al. Clin Genitourin Cancer. 2018. doi: 10.1016/j.clgc.2018.10.002.

A comparison of the genomic landscapes of both primary and metastatic clear cell renal cell carcinoma (ccRCC) found no significant differences in gene expression or mutational burden between the disease states, suggesting that there is no single genetic driver of metastases, investigators reported.

An analysis of targeted next-generation sequencing of both primary tumors and metastases in two independent patient cohorts showed that only the gene encoding for the tumor suppressor TP53 was significantly more frequently mutated in metastases, compared with primary tumors, but this finding did not pass a false positive test (false discovery rate), noted Toni K. Choueiri, MD, from the Dana-Farber Cancer Institute in Boston, and his colleagues, in the British Journal of Cancer.

“No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumors. Mutation burden was not significantly different between the metastases and primary tumors or between metastatic sites,” they wrote.

Frequently mutated genes in ccRCC include VHL, the gene encoding for von Hippel–Lindau syndrome, as well as tumor suppressor genes such as PBRM1, SEDT2, BAP1 and KDM5C, but few mutations are clinically actionable, the investigators noted. “However, the value of genomic alterations will be determined by understanding the interactions between acquired genetic alterations, treatments received, heterogeneity, and the dynamics of mutations during evolution of disease.”

To see whether they could improve understanding of the genomic differences between primary and metastatic ccRCC and potentially develop personalized therapies, the investigators studied targeted next-generation sequencing data from two separate cohorts.

The first cohort included data on 349 ccRCC primary tumors and 229 unmatched cases of metastatic ccRCC from the Foundation Medicine database. The second, a validation cohort, included data on 177 ccRCC primary tumors and 80 metastases from patients treated at Dana-Farber. In each cohort, sequencing was performed on 275 genes and intronic regions in 30 genes for a total of 282 unique genes.

In cohort 1, which included tumor samples from 417 men and 169 women with a median age of 58 years, the frequency of mutations was similar in primary tumors and metastases. As noted before, mutations in TP53 were significantly more frequent in metastases than in primary tumors, detected in 14.85% versus 8.90% of samples, respectively (P = .031). This difference did not, however, pass the false discovery rate test (q = 0.21). Two other tumor suppressor genes, PBRM1 and KDM5C, were numerically but not significantly more frequent in metastases.

There were no differences in median tumor mutational burden between primary and metastatic samples and no difference in either mutations or mutational burden across different metastatic sites.

In cohort 2 there were no significantly different mutational frequencies between primary and metastatic samples for any gene and no differences in median tumor mutational burden.

An analysis comparing the frequency of gene mutations in primary tumors of patients in this cohort who went on to develop metastatic disease versus those of patients with only localized disease showed that, after a median follow-up of 21.9 months, there were no significant differences in either mutational frequency or tumor mutational burden.

“It is currently unknown if cohortwide genomic alterations in RCC metastases have a different genomic profile, including potential actionable mutations, compared to samples derived from the primary site. To our knowledge, our analysis is the largest genomic ccRCC study that compares cohortwide mutational differences between metastases and primary tumors,” the investigators wrote.

They acknowledged that because they did not match primary tumors with metastatic tumors in the same patients they were unable to evaluate how individual tumors evolve over time or how systemic therapies may alter the tumor genomic landscape.

Dr. Choueri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at the Dana-Farber Cancer Institute. Six of the study’s coauthors are employed by Foundation Medicine. The remaining authors declared no competing interests.

SOURCE: Choueiri TK et al. Br J Cancer. 2018 May;118(9):1238-42.

A comparison of the genomic landscapes of both primary and metastatic clear cell renal cell carcinoma (ccRCC) found no significant differences in gene expression or mutational burden between the disease states, suggesting that there is no single genetic driver of metastases, investigators reported.

An analysis of targeted next-generation sequencing of both primary tumors and metastases in two independent patient cohorts showed that only the gene encoding for the tumor suppressor TP53 was significantly more frequently mutated in metastases, compared with primary tumors, but this finding did not pass a false positive test (false discovery rate), noted Toni K. Choueiri, MD, from the Dana-Farber Cancer Institute in Boston, and his colleagues, in the British Journal of Cancer.

“No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumors. Mutation burden was not significantly different between the metastases and primary tumors or between metastatic sites,” they wrote.

Frequently mutated genes in ccRCC include VHL, the gene encoding for von Hippel–Lindau syndrome, as well as tumor suppressor genes such as PBRM1, SEDT2, BAP1 and KDM5C, but few mutations are clinically actionable, the investigators noted. “However, the value of genomic alterations will be determined by understanding the interactions between acquired genetic alterations, treatments received, heterogeneity, and the dynamics of mutations during evolution of disease.”

To see whether they could improve understanding of the genomic differences between primary and metastatic ccRCC and potentially develop personalized therapies, the investigators studied targeted next-generation sequencing data from two separate cohorts.

The first cohort included data on 349 ccRCC primary tumors and 229 unmatched cases of metastatic ccRCC from the Foundation Medicine database. The second, a validation cohort, included data on 177 ccRCC primary tumors and 80 metastases from patients treated at Dana-Farber. In each cohort, sequencing was performed on 275 genes and intronic regions in 30 genes for a total of 282 unique genes.

In cohort 1, which included tumor samples from 417 men and 169 women with a median age of 58 years, the frequency of mutations was similar in primary tumors and metastases. As noted before, mutations in TP53 were significantly more frequent in metastases than in primary tumors, detected in 14.85% versus 8.90% of samples, respectively (P = .031). This difference did not, however, pass the false discovery rate test (q = 0.21). Two other tumor suppressor genes, PBRM1 and KDM5C, were numerically but not significantly more frequent in metastases.

There were no differences in median tumor mutational burden between primary and metastatic samples and no difference in either mutations or mutational burden across different metastatic sites.

In cohort 2 there were no significantly different mutational frequencies between primary and metastatic samples for any gene and no differences in median tumor mutational burden.

An analysis comparing the frequency of gene mutations in primary tumors of patients in this cohort who went on to develop metastatic disease versus those of patients with only localized disease showed that, after a median follow-up of 21.9 months, there were no significant differences in either mutational frequency or tumor mutational burden.

“It is currently unknown if cohortwide genomic alterations in RCC metastases have a different genomic profile, including potential actionable mutations, compared to samples derived from the primary site. To our knowledge, our analysis is the largest genomic ccRCC study that compares cohortwide mutational differences between metastases and primary tumors,” the investigators wrote.

They acknowledged that because they did not match primary tumors with metastatic tumors in the same patients they were unable to evaluate how individual tumors evolve over time or how systemic therapies may alter the tumor genomic landscape.

Dr. Choueri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at the Dana-Farber Cancer Institute. Six of the study’s coauthors are employed by Foundation Medicine. The remaining authors declared no competing interests.

SOURCE: Choueiri TK et al. Br J Cancer. 2018 May;118(9):1238-42.

A comparison of the genomic landscapes of both primary and metastatic clear cell renal cell carcinoma (ccRCC) found no significant differences in gene expression or mutational burden between the disease states, suggesting that there is no single genetic driver of metastases, investigators reported.

An analysis of targeted next-generation sequencing of both primary tumors and metastases in two independent patient cohorts showed that only the gene encoding for the tumor suppressor TP53 was significantly more frequently mutated in metastases, compared with primary tumors, but this finding did not pass a false positive test (false discovery rate), noted Toni K. Choueiri, MD, from the Dana-Farber Cancer Institute in Boston, and his colleagues, in the British Journal of Cancer.

“No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumors. Mutation burden was not significantly different between the metastases and primary tumors or between metastatic sites,” they wrote.

Frequently mutated genes in ccRCC include VHL, the gene encoding for von Hippel–Lindau syndrome, as well as tumor suppressor genes such as PBRM1, SEDT2, BAP1 and KDM5C, but few mutations are clinically actionable, the investigators noted. “However, the value of genomic alterations will be determined by understanding the interactions between acquired genetic alterations, treatments received, heterogeneity, and the dynamics of mutations during evolution of disease.”

To see whether they could improve understanding of the genomic differences between primary and metastatic ccRCC and potentially develop personalized therapies, the investigators studied targeted next-generation sequencing data from two separate cohorts.

The first cohort included data on 349 ccRCC primary tumors and 229 unmatched cases of metastatic ccRCC from the Foundation Medicine database. The second, a validation cohort, included data on 177 ccRCC primary tumors and 80 metastases from patients treated at Dana-Farber. In each cohort, sequencing was performed on 275 genes and intronic regions in 30 genes for a total of 282 unique genes.

In cohort 1, which included tumor samples from 417 men and 169 women with a median age of 58 years, the frequency of mutations was similar in primary tumors and metastases. As noted before, mutations in TP53 were significantly more frequent in metastases than in primary tumors, detected in 14.85% versus 8.90% of samples, respectively (P = .031). This difference did not, however, pass the false discovery rate test (q = 0.21). Two other tumor suppressor genes, PBRM1 and KDM5C, were numerically but not significantly more frequent in metastases.

There were no differences in median tumor mutational burden between primary and metastatic samples and no difference in either mutations or mutational burden across different metastatic sites.

In cohort 2 there were no significantly different mutational frequencies between primary and metastatic samples for any gene and no differences in median tumor mutational burden.

An analysis comparing the frequency of gene mutations in primary tumors of patients in this cohort who went on to develop metastatic disease versus those of patients with only localized disease showed that, after a median follow-up of 21.9 months, there were no significant differences in either mutational frequency or tumor mutational burden.

“It is currently unknown if cohortwide genomic alterations in RCC metastases have a different genomic profile, including potential actionable mutations, compared to samples derived from the primary site. To our knowledge, our analysis is the largest genomic ccRCC study that compares cohortwide mutational differences between metastases and primary tumors,” the investigators wrote.

They acknowledged that because they did not match primary tumors with metastatic tumors in the same patients they were unable to evaluate how individual tumors evolve over time or how systemic therapies may alter the tumor genomic landscape.

Dr. Choueri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at the Dana-Farber Cancer Institute. Six of the study’s coauthors are employed by Foundation Medicine. The remaining authors declared no competing interests.

SOURCE: Choueiri TK et al. Br J Cancer. 2018 May;118(9):1238-42.

An updated analysis of interim results for JAVELIN Renal 101 will be presented at a Presidential Symposium during the annual congress of the European Society for Medical Oncology (ESMO 2018), to be held Oct. 19-23 in Munich.

The phase 3 trial compared avelumab (Bavencio) in combination with axitinib (Inlyta) to sunitinib monotherapy as first-line treatment, in patients with advanced renal cell carcinoma (RCC). Interim analysis results announced by the company in a September press release indicated the combination of immunotherapy and a tyrosine kinase inhibitor showed “a statistically significant improvement in progression-free survival by central review for patients treated with the combination whose tumors had programmed death ligand-1‒positive (PD-L1+) expression greater than 1% (primary objective), as well as in the entire study population regardless of PD-L1 tumor expression (secondary objective).”

An updated analysis of progression-free survival and overall response rates will be presented at ESMO 2018 by Robert J. Motzer, MD of Memorial Sloan Kettering Cancer Center, New York.

A phase 1b study (JAVELIN Renal 100), published in Lancet Oncology, found the safety profile of the combination to be similar to either drug alone.

For the phase 3 trial, more than 800 patients with advanced RCC were randomized to first-line treatment with the combination of avelumab (10 mg/kg IV every 2 weeks) plus axitinib (5 mg orally, twice daily) or monotherapy with sunitinib (50 mg orally once daily, 4 weeks on/2 weeks off). The overall survival results will be presented at the Presidential Symposium 2 on Oct. 21.

This article was updated on 10/15/18 to reflect the fact that interim results will be presented.






 

An updated analysis of interim results for JAVELIN Renal 101 will be presented at a Presidential Symposium during the annual congress of the European Society for Medical Oncology (ESMO 2018), to be held Oct. 19-23 in Munich.

The phase 3 trial compared avelumab (Bavencio) in combination with axitinib (Inlyta) to sunitinib monotherapy as first-line treatment, in patients with advanced renal cell carcinoma (RCC). Interim analysis results announced by the company in a September press release indicated the combination of immunotherapy and a tyrosine kinase inhibitor showed “a statistically significant improvement in progression-free survival by central review for patients treated with the combination whose tumors had programmed death ligand-1‒positive (PD-L1+) expression greater than 1% (primary objective), as well as in the entire study population regardless of PD-L1 tumor expression (secondary objective).”

An updated analysis of progression-free survival and overall response rates will be presented at ESMO 2018 by Robert J. Motzer, MD of Memorial Sloan Kettering Cancer Center, New York.

A phase 1b study (JAVELIN Renal 100), published in Lancet Oncology, found the safety profile of the combination to be similar to either drug alone.

For the phase 3 trial, more than 800 patients with advanced RCC were randomized to first-line treatment with the combination of avelumab (10 mg/kg IV every 2 weeks) plus axitinib (5 mg orally, twice daily) or monotherapy with sunitinib (50 mg orally once daily, 4 weeks on/2 weeks off). The overall survival results will be presented at the Presidential Symposium 2 on Oct. 21.

This article was updated on 10/15/18 to reflect the fact that interim results will be presented.






 

An updated analysis of interim results for JAVELIN Renal 101 will be presented at a Presidential Symposium during the annual congress of the European Society for Medical Oncology (ESMO 2018), to be held Oct. 19-23 in Munich.

The phase 3 trial compared avelumab (Bavencio) in combination with axitinib (Inlyta) to sunitinib monotherapy as first-line treatment, in patients with advanced renal cell carcinoma (RCC). Interim analysis results announced by the company in a September press release indicated the combination of immunotherapy and a tyrosine kinase inhibitor showed “a statistically significant improvement in progression-free survival by central review for patients treated with the combination whose tumors had programmed death ligand-1‒positive (PD-L1+) expression greater than 1% (primary objective), as well as in the entire study population regardless of PD-L1 tumor expression (secondary objective).”

An updated analysis of progression-free survival and overall response rates will be presented at ESMO 2018 by Robert J. Motzer, MD of Memorial Sloan Kettering Cancer Center, New York.

A phase 1b study (JAVELIN Renal 100), published in Lancet Oncology, found the safety profile of the combination to be similar to either drug alone.

For the phase 3 trial, more than 800 patients with advanced RCC were randomized to first-line treatment with the combination of avelumab (10 mg/kg IV every 2 weeks) plus axitinib (5 mg orally, twice daily) or monotherapy with sunitinib (50 mg orally once daily, 4 weeks on/2 weeks off). The overall survival results will be presented at the Presidential Symposium 2 on Oct. 21.

This article was updated on 10/15/18 to reflect the fact that interim results will be presented.