Genitourinary Cancer

The gut microbome may influence responses to immune checkpoint inhibitors, based on results from two studies, and one of the investigators is now gearing up for the next step - evaluating in a clinical trial whether altering the microflora will actually improve responses.

In the first study, investigators carried out a series of experiments using fecal microbiome samples from patients with metastatic melanoma embarking on therapy with a PD-1 (programmed cell death protein 1) inhibitor.

“In melanoma patients, there were differential signals in the gut microbiome of responders versus nonresponders, and I think the clincher was when we transplanted fecal samples from responders to nonresponders in germ-free mice, essentially reconstituting the microbiome and showing that it equally affected the systemic immunity and antitumor immunity when we implanted tumors, as well as response to checkpoint blockade,” lead author Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center in Houston, said in an interview.

Dr. Wargo and her colleagues first collected buccal and fecal microbiome samples from 112 patients with metastatic melanoma before they began therapy with a PD-1 inhibitor. After performing taxonomic profiling on all samples, they found that there was a clustering effect by response status in the gut microbiome, but not the oral microbiome, and because changes in the oral microbiome did not appear to be related to treatment response, they focused on the gut.

When Dr. Wargo and her colleagues studied the posttherapy microbiomes of 43 patients (30 responders and 13 nonresponders) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they found that the responders had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01). In addition, responders had a relative abundance of Ruminococcaceae, commonly occurring gut microbes that break down complex carbohydrates, the investigators reported (Science. 2017 Nov. 2. doi: 10.1126/science.aan4236).

They found that patients whose microbiomes were diverse in general, and in particular were enriched with Faecalibacterium and Clostridiales species, were more likely to respond to immunotherapy with a PD-1 inhibitor and have a longer duration of progression-free survival. In contrast, patients whose microbiomes were more enriched with Bacteroidales species were more likely to be nonresponders.

To get a better understanding of the mechanisms whereby gut bacteria may influence response to PD-1 inhibitors, they performed metagenomic analysis on samples from 14 responders and 11 nonresponders, and found that responders had micro-organisms predominantly associated with anabolic functions that may support host immunity, whereas nonresponders had microbiomes where catabolic functions were more common.

The investigators next performed immune profiling, and found that both systemic immunity and local immunity in the tumor microenvironment in responders were associated with the aforementioned favorable gut microbiome.

The researchers then transplanted feces from the human donors into germ-free mice and then injected tumor cells into the mice, and found that tumor growth was significantly reduced, and response to PD-1 inhibition was significantly enhanced, in mice who received feces from responders.

“An obvious next step is to run a clinical trial to test the hypothesis that by modulating the microbiome, you can actually enhance responses to therapy,” Dr. Wargo said. Details of the clinical trial are still being worked out, but will likely involve fecal transfers and other mechanisms for modulating the microbiome in hopes of improving responses to PD-1 inhibitors.

“It’s going to be a very biomarker-heavy trial,” she said. “We’re going to look, certainly, for changes in the microbiome, and will also do a lot of profiling in the blood, the tumor, and in the microbiome to see if there are changes that occur by modulating that microbiome. Then of course we’ll look for differences in response rates in patients as well.”
 

Bacteria also affect epithelial cancers

In a separate study, also published in Science, investigators led by Bertrand Routy, MD, of the Gustave Roussy Cancer Institute in Villejuif, France, reported that patients with non–small cell lung cancer and urothelial carcinoma who had previously used systemic antibiotics had reduced survival when treated with a PD-1 inhibitor, compared with patients who had never taken antibiotics (Science. 2017 Nov. 2 doi: 10.1126/science.aan3706).

Analysis of the gut microbiome in these patients showed that higher levels of Akkermansia muciniphila were associated with the best clinical outcomes, with the species detectable in the microbiome of 69% of patients who had partial responses to anti–PD-1 therapy, and in 58% of those with stable disease. In contrast, the bacterium was detectable in only 34% of patients who experienced disease progression.

As in the experiments by Dr. Wargo and her associates, when the French investigators first treated mice with antibiotics and then gave them oral supplements containing the bacteria, the supplements restored response to PD-1 blockade,

“We conclude from the study that the gut microbiome markedly influences the outcome of PD-1 blockade in mice and patients,” Dr. Routy and his associates wrote.

They acknowledged that the mechanism whereby a common organism such as Akkermansia muciniphila might have an immunomodulatory effect is still unknown,

“Irrespective of these remaining questions, our findings suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer[s] novel avenues for manipulating the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors],” they wrote.

The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his associates was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.

The gut microbome may influence responses to immune checkpoint inhibitors, based on results from two studies, and one of the investigators is now gearing up for the next step - evaluating in a clinical trial whether altering the microflora will actually improve responses.

In the first study, investigators carried out a series of experiments using fecal microbiome samples from patients with metastatic melanoma embarking on therapy with a PD-1 (programmed cell death protein 1) inhibitor.

“In melanoma patients, there were differential signals in the gut microbiome of responders versus nonresponders, and I think the clincher was when we transplanted fecal samples from responders to nonresponders in germ-free mice, essentially reconstituting the microbiome and showing that it equally affected the systemic immunity and antitumor immunity when we implanted tumors, as well as response to checkpoint blockade,” lead author Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center in Houston, said in an interview.

Dr. Wargo and her colleagues first collected buccal and fecal microbiome samples from 112 patients with metastatic melanoma before they began therapy with a PD-1 inhibitor. After performing taxonomic profiling on all samples, they found that there was a clustering effect by response status in the gut microbiome, but not the oral microbiome, and because changes in the oral microbiome did not appear to be related to treatment response, they focused on the gut.

When Dr. Wargo and her colleagues studied the posttherapy microbiomes of 43 patients (30 responders and 13 nonresponders) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they found that the responders had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01). In addition, responders had a relative abundance of Ruminococcaceae, commonly occurring gut microbes that break down complex carbohydrates, the investigators reported (Science. 2017 Nov. 2. doi: 10.1126/science.aan4236).

They found that patients whose microbiomes were diverse in general, and in particular were enriched with Faecalibacterium and Clostridiales species, were more likely to respond to immunotherapy with a PD-1 inhibitor and have a longer duration of progression-free survival. In contrast, patients whose microbiomes were more enriched with Bacteroidales species were more likely to be nonresponders.

To get a better understanding of the mechanisms whereby gut bacteria may influence response to PD-1 inhibitors, they performed metagenomic analysis on samples from 14 responders and 11 nonresponders, and found that responders had micro-organisms predominantly associated with anabolic functions that may support host immunity, whereas nonresponders had microbiomes where catabolic functions were more common.

The investigators next performed immune profiling, and found that both systemic immunity and local immunity in the tumor microenvironment in responders were associated with the aforementioned favorable gut microbiome.

The researchers then transplanted feces from the human donors into germ-free mice and then injected tumor cells into the mice, and found that tumor growth was significantly reduced, and response to PD-1 inhibition was significantly enhanced, in mice who received feces from responders.

“An obvious next step is to run a clinical trial to test the hypothesis that by modulating the microbiome, you can actually enhance responses to therapy,” Dr. Wargo said. Details of the clinical trial are still being worked out, but will likely involve fecal transfers and other mechanisms for modulating the microbiome in hopes of improving responses to PD-1 inhibitors.

“It’s going to be a very biomarker-heavy trial,” she said. “We’re going to look, certainly, for changes in the microbiome, and will also do a lot of profiling in the blood, the tumor, and in the microbiome to see if there are changes that occur by modulating that microbiome. Then of course we’ll look for differences in response rates in patients as well.”
 

Bacteria also affect epithelial cancers

In a separate study, also published in Science, investigators led by Bertrand Routy, MD, of the Gustave Roussy Cancer Institute in Villejuif, France, reported that patients with non–small cell lung cancer and urothelial carcinoma who had previously used systemic antibiotics had reduced survival when treated with a PD-1 inhibitor, compared with patients who had never taken antibiotics (Science. 2017 Nov. 2 doi: 10.1126/science.aan3706).

Analysis of the gut microbiome in these patients showed that higher levels of Akkermansia muciniphila were associated with the best clinical outcomes, with the species detectable in the microbiome of 69% of patients who had partial responses to anti–PD-1 therapy, and in 58% of those with stable disease. In contrast, the bacterium was detectable in only 34% of patients who experienced disease progression.

As in the experiments by Dr. Wargo and her associates, when the French investigators first treated mice with antibiotics and then gave them oral supplements containing the bacteria, the supplements restored response to PD-1 blockade,

“We conclude from the study that the gut microbiome markedly influences the outcome of PD-1 blockade in mice and patients,” Dr. Routy and his associates wrote.

They acknowledged that the mechanism whereby a common organism such as Akkermansia muciniphila might have an immunomodulatory effect is still unknown,

“Irrespective of these remaining questions, our findings suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer[s] novel avenues for manipulating the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors],” they wrote.

The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his associates was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.

The gut microbome may influence responses to immune checkpoint inhibitors, based on results from two studies, and one of the investigators is now gearing up for the next step - evaluating in a clinical trial whether altering the microflora will actually improve responses.

In the first study, investigators carried out a series of experiments using fecal microbiome samples from patients with metastatic melanoma embarking on therapy with a PD-1 (programmed cell death protein 1) inhibitor.

“In melanoma patients, there were differential signals in the gut microbiome of responders versus nonresponders, and I think the clincher was when we transplanted fecal samples from responders to nonresponders in germ-free mice, essentially reconstituting the microbiome and showing that it equally affected the systemic immunity and antitumor immunity when we implanted tumors, as well as response to checkpoint blockade,” lead author Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center in Houston, said in an interview.

Dr. Wargo and her colleagues first collected buccal and fecal microbiome samples from 112 patients with metastatic melanoma before they began therapy with a PD-1 inhibitor. After performing taxonomic profiling on all samples, they found that there was a clustering effect by response status in the gut microbiome, but not the oral microbiome, and because changes in the oral microbiome did not appear to be related to treatment response, they focused on the gut.

When Dr. Wargo and her colleagues studied the posttherapy microbiomes of 43 patients (30 responders and 13 nonresponders) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they found that the responders had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01). In addition, responders had a relative abundance of Ruminococcaceae, commonly occurring gut microbes that break down complex carbohydrates, the investigators reported (Science. 2017 Nov. 2. doi: 10.1126/science.aan4236).

They found that patients whose microbiomes were diverse in general, and in particular were enriched with Faecalibacterium and Clostridiales species, were more likely to respond to immunotherapy with a PD-1 inhibitor and have a longer duration of progression-free survival. In contrast, patients whose microbiomes were more enriched with Bacteroidales species were more likely to be nonresponders.

To get a better understanding of the mechanisms whereby gut bacteria may influence response to PD-1 inhibitors, they performed metagenomic analysis on samples from 14 responders and 11 nonresponders, and found that responders had micro-organisms predominantly associated with anabolic functions that may support host immunity, whereas nonresponders had microbiomes where catabolic functions were more common.

The investigators next performed immune profiling, and found that both systemic immunity and local immunity in the tumor microenvironment in responders were associated with the aforementioned favorable gut microbiome.

The researchers then transplanted feces from the human donors into germ-free mice and then injected tumor cells into the mice, and found that tumor growth was significantly reduced, and response to PD-1 inhibition was significantly enhanced, in mice who received feces from responders.

“An obvious next step is to run a clinical trial to test the hypothesis that by modulating the microbiome, you can actually enhance responses to therapy,” Dr. Wargo said. Details of the clinical trial are still being worked out, but will likely involve fecal transfers and other mechanisms for modulating the microbiome in hopes of improving responses to PD-1 inhibitors.

“It’s going to be a very biomarker-heavy trial,” she said. “We’re going to look, certainly, for changes in the microbiome, and will also do a lot of profiling in the blood, the tumor, and in the microbiome to see if there are changes that occur by modulating that microbiome. Then of course we’ll look for differences in response rates in patients as well.”
 

Bacteria also affect epithelial cancers

In a separate study, also published in Science, investigators led by Bertrand Routy, MD, of the Gustave Roussy Cancer Institute in Villejuif, France, reported that patients with non–small cell lung cancer and urothelial carcinoma who had previously used systemic antibiotics had reduced survival when treated with a PD-1 inhibitor, compared with patients who had never taken antibiotics (Science. 2017 Nov. 2 doi: 10.1126/science.aan3706).

Analysis of the gut microbiome in these patients showed that higher levels of Akkermansia muciniphila were associated with the best clinical outcomes, with the species detectable in the microbiome of 69% of patients who had partial responses to anti–PD-1 therapy, and in 58% of those with stable disease. In contrast, the bacterium was detectable in only 34% of patients who experienced disease progression.

As in the experiments by Dr. Wargo and her associates, when the French investigators first treated mice with antibiotics and then gave them oral supplements containing the bacteria, the supplements restored response to PD-1 blockade,

“We conclude from the study that the gut microbiome markedly influences the outcome of PD-1 blockade in mice and patients,” Dr. Routy and his associates wrote.

They acknowledged that the mechanism whereby a common organism such as Akkermansia muciniphila might have an immunomodulatory effect is still unknown,

“Irrespective of these remaining questions, our findings suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer[s] novel avenues for manipulating the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors],” they wrote.

The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his associates was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.

Perioperative blood transfusion (PBT) is associated with poorer outcomes among patients who underwent nephrectomy for renal cell carcinoma (RCC), according to a retrospective review of 1,159 patients.

Using multivariate analysis and controlling for potential confounders such as clinical and pathologic features, receipt of PBT was associated with significantly increased risk of tumor recurrence (HR = 2, P = .02, metastatic progression (HR = 2.5, P = .007), and death from RCC (HR = 2.5, P = .02).

Tomasz Gierygowski/Thinkstock

Perioperative blood transfusion (PBT) is associated with poorer outcomes among patients who underwent nephrectomy for renal cell carcinoma (RCC), according to a retrospective review of 1,159 patients.

Using multivariate analysis and controlling for potential confounders such as clinical and pathologic features, receipt of PBT was associated with significantly increased risk of tumor recurrence (HR = 2, P = .02, metastatic progression (HR = 2.5, P = .007), and death from RCC (HR = 2.5, P = .02).

Tomasz Gierygowski/Thinkstock

Perioperative blood transfusion (PBT) is associated with poorer outcomes among patients who underwent nephrectomy for renal cell carcinoma (RCC), according to a retrospective review of 1,159 patients.

Using multivariate analysis and controlling for potential confounders such as clinical and pathologic features, receipt of PBT was associated with significantly increased risk of tumor recurrence (HR = 2, P = .02, metastatic progression (HR = 2.5, P = .007), and death from RCC (HR = 2.5, P = .02).

Tomasz Gierygowski/Thinkstock

In patients with localized clear cell renal cell carcinoma (RCC), tumor levels of the oncogenic protein EZH2 (enhancer of zeste homolog 2) were predictive of risk of RCC-specific death, including in patients considered at low or intermediate risk by a standard prognostic model.

Among nearly 2,000 tumors from patients with RCC in three different cohorts, the risks of both all-cause mortality and RCC-specific death were approximately double for patients with tumors that had high expression of EZH2 compared with those whose tumors expressed only low levels, reported Thai Huu Ho, MD, PhD, from the Mayo Clinic in Phoenix, and colleagues.

Among patients deemed to be at low risk according to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score, high levels of EZH2 were associated with a sixfold increase in risk of death, the investigators wrote (J Clin Oncol. 2017 Oct 4. doi: 10.1200/JCO.2017.73.3238).

“With the increasing incidence of small RCC tumors detected by cross-sectional imaging, our study emphasizes the clinical utility of a biomarker that is compatible with a single FFPE [formalin-fixed, paraffin-embedded] slide that accurately predicts risk of RCC death beyond existing clinicopathologic models” they wrote.

EZH2 is a chromatin remodeler, a member of a family of proteins that are involved in epigenetic gene silencing. Although previous studies have explored potential associations between EZH2 expression and RCC outcomes, results have been conflicting, Dr. Ho and associates noted.

In hopes of getting a more definitive picture of the potential role of EZH2 as a prognostic biomarker for RCC, the investigators looked at the association between EZH2 expression and survival in tumors from 532 patients in the Cancer Genome Atlas (CGA) cohort, 122 patients from a University of Texas Southwestern Medical Center (Dallas) cohort, and from 1,338 patients in a Mayo Clinic cohort.

In a model adjusted for age and SSIGN score, patients in the CGA cohort whose tumors had high levels of EZH2 expression had a hazard ratio (HR) for worse overall survival of 1.54 (P less than .028) compared with patients with low expression. Respective HRs for overall survival in the UT Southwestern and Mayo Cohorts were 2.16 (P = .034) and 1.43 (P = .00026).

When the researchers looked at RCC-specific survival in patients in the Mayo cohort, they found that those with the highest levels of EZH2 expression had a twofold risk for death vs. those with the lowest levels (HR 1.97, P less than .001).

They also found that patients with a low-risk SSIGN score who had high levels of EZH2 protein expression had an HR for RCC-specific death of 6.14, and that patients with intermediate-risk SSIGN scores has an HR for RCC-related death of 2.12 (P less than .001 for both comparisons).

The investigators noted that EZH2 enzymatic activity in RCC could potentially be targeted by EZH2 inhibitors such as tazemetostat.

“Further studies are required to determine how to better incorporate molecular biomarkers with prognostic information into surveillance guidelines and adjuvant clinical trials,” they concluded.

The study was supported by the Mayo Clinic, Gerstner Family Career Development Award, National Cancer Institute, and Cancer Prevention Research Institute of Texas. Dr. Ho and seven coauthors reported no relationships to disclose. The remaining investigators reported relationships with various companies.

op@frontlinemedcom.com

In patients with localized clear cell renal cell carcinoma (RCC), tumor levels of the oncogenic protein EZH2 (enhancer of zeste homolog 2) were predictive of risk of RCC-specific death, including in patients considered at low or intermediate risk by a standard prognostic model.

Among nearly 2,000 tumors from patients with RCC in three different cohorts, the risks of both all-cause mortality and RCC-specific death were approximately double for patients with tumors that had high expression of EZH2 compared with those whose tumors expressed only low levels, reported Thai Huu Ho, MD, PhD, from the Mayo Clinic in Phoenix, and colleagues.

Among patients deemed to be at low risk according to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score, high levels of EZH2 were associated with a sixfold increase in risk of death, the investigators wrote (J Clin Oncol. 2017 Oct 4. doi: 10.1200/JCO.2017.73.3238).

“With the increasing incidence of small RCC tumors detected by cross-sectional imaging, our study emphasizes the clinical utility of a biomarker that is compatible with a single FFPE [formalin-fixed, paraffin-embedded] slide that accurately predicts risk of RCC death beyond existing clinicopathologic models” they wrote.

EZH2 is a chromatin remodeler, a member of a family of proteins that are involved in epigenetic gene silencing. Although previous studies have explored potential associations between EZH2 expression and RCC outcomes, results have been conflicting, Dr. Ho and associates noted.

In hopes of getting a more definitive picture of the potential role of EZH2 as a prognostic biomarker for RCC, the investigators looked at the association between EZH2 expression and survival in tumors from 532 patients in the Cancer Genome Atlas (CGA) cohort, 122 patients from a University of Texas Southwestern Medical Center (Dallas) cohort, and from 1,338 patients in a Mayo Clinic cohort.

In a model adjusted for age and SSIGN score, patients in the CGA cohort whose tumors had high levels of EZH2 expression had a hazard ratio (HR) for worse overall survival of 1.54 (P less than .028) compared with patients with low expression. Respective HRs for overall survival in the UT Southwestern and Mayo Cohorts were 2.16 (P = .034) and 1.43 (P = .00026).

When the researchers looked at RCC-specific survival in patients in the Mayo cohort, they found that those with the highest levels of EZH2 expression had a twofold risk for death vs. those with the lowest levels (HR 1.97, P less than .001).

They also found that patients with a low-risk SSIGN score who had high levels of EZH2 protein expression had an HR for RCC-specific death of 6.14, and that patients with intermediate-risk SSIGN scores has an HR for RCC-related death of 2.12 (P less than .001 for both comparisons).

The investigators noted that EZH2 enzymatic activity in RCC could potentially be targeted by EZH2 inhibitors such as tazemetostat.

“Further studies are required to determine how to better incorporate molecular biomarkers with prognostic information into surveillance guidelines and adjuvant clinical trials,” they concluded.

The study was supported by the Mayo Clinic, Gerstner Family Career Development Award, National Cancer Institute, and Cancer Prevention Research Institute of Texas. Dr. Ho and seven coauthors reported no relationships to disclose. The remaining investigators reported relationships with various companies.

op@frontlinemedcom.com

In patients with localized clear cell renal cell carcinoma (RCC), tumor levels of the oncogenic protein EZH2 (enhancer of zeste homolog 2) were predictive of risk of RCC-specific death, including in patients considered at low or intermediate risk by a standard prognostic model.

Among nearly 2,000 tumors from patients with RCC in three different cohorts, the risks of both all-cause mortality and RCC-specific death were approximately double for patients with tumors that had high expression of EZH2 compared with those whose tumors expressed only low levels, reported Thai Huu Ho, MD, PhD, from the Mayo Clinic in Phoenix, and colleagues.

Among patients deemed to be at low risk according to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score, high levels of EZH2 were associated with a sixfold increase in risk of death, the investigators wrote (J Clin Oncol. 2017 Oct 4. doi: 10.1200/JCO.2017.73.3238).

“With the increasing incidence of small RCC tumors detected by cross-sectional imaging, our study emphasizes the clinical utility of a biomarker that is compatible with a single FFPE [formalin-fixed, paraffin-embedded] slide that accurately predicts risk of RCC death beyond existing clinicopathologic models” they wrote.

EZH2 is a chromatin remodeler, a member of a family of proteins that are involved in epigenetic gene silencing. Although previous studies have explored potential associations between EZH2 expression and RCC outcomes, results have been conflicting, Dr. Ho and associates noted.

In hopes of getting a more definitive picture of the potential role of EZH2 as a prognostic biomarker for RCC, the investigators looked at the association between EZH2 expression and survival in tumors from 532 patients in the Cancer Genome Atlas (CGA) cohort, 122 patients from a University of Texas Southwestern Medical Center (Dallas) cohort, and from 1,338 patients in a Mayo Clinic cohort.

In a model adjusted for age and SSIGN score, patients in the CGA cohort whose tumors had high levels of EZH2 expression had a hazard ratio (HR) for worse overall survival of 1.54 (P less than .028) compared with patients with low expression. Respective HRs for overall survival in the UT Southwestern and Mayo Cohorts were 2.16 (P = .034) and 1.43 (P = .00026).

When the researchers looked at RCC-specific survival in patients in the Mayo cohort, they found that those with the highest levels of EZH2 expression had a twofold risk for death vs. those with the lowest levels (HR 1.97, P less than .001).

They also found that patients with a low-risk SSIGN score who had high levels of EZH2 protein expression had an HR for RCC-specific death of 6.14, and that patients with intermediate-risk SSIGN scores has an HR for RCC-related death of 2.12 (P less than .001 for both comparisons).

The investigators noted that EZH2 enzymatic activity in RCC could potentially be targeted by EZH2 inhibitors such as tazemetostat.

“Further studies are required to determine how to better incorporate molecular biomarkers with prognostic information into surveillance guidelines and adjuvant clinical trials,” they concluded.

The study was supported by the Mayo Clinic, Gerstner Family Career Development Award, National Cancer Institute, and Cancer Prevention Research Institute of Texas. Dr. Ho and seven coauthors reported no relationships to disclose. The remaining investigators reported relationships with various companies.

op@frontlinemedcom.com

In patients with castration-resistant prostate cancer (CRPC), a variant of the HSD3B1 gene predicts sensitivity to the CYP17A1 inhibitor ketoconazole, according to results of a single-center, observational study including 90 men treated between June 1998 and December 2012.

Median progression-free survival (PFS) increased along with the number of variant HSD3B1(1245C) alleles, wrote Nima Almassi, MD, of the Cleveland Clinic, and coauthors (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3159).

Specifically, median PFS was just 5.0 months for patients with no variant HSD3B1(1245C) alleles, 7.5 months for patients with one allele, and 12.3 months for those with two alleles (P = .03).

“These findings suggest that the variant allele … may be a predictive biomarker of tumor vulnerability to pharmacologic CYP17A1 inhibition with a nonsteroidal drug,” Dr. Almassi and colleagues wrote.

The HSD3B1(1245C) germline variant was already known in the prostate cancer research community as a marker of tumor resistance to androgen deprivation therapy (ADT) and more rapid disease onset. In a separate study published in the same issue (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3164) investigators provided additional evidence, showing that the genotype was associated with more rapid metastasis development in men with localized prostate cancer who received ADT for biochemical recurrence after radiation treatment.

In that observational study of 218 men treated between 1996 and 2003, median time to metastasis (TTM) decreased according to the number of inherited variant alleles, wrote Jason W. D. Hearn, MD, University of Michigan, Ann Arbor, and coauthors. Those with no variant HSD3B1(1245C) alleles had a TTM of 7.4 months, while those with one allele had a TTM of 5.8 months, and for those with two, TTM was only 4.4 months (P = .03).

However, investigators could not detect any such relationship between variant HSD3B1(1245C) alleles and time to progression (TTP) or overall survival (OS): “It is possible that the high rates of prior ADT exposure and frequent use of androgen receptor (AR) antagonists during salvage ADT modified the impact of genotype with respect to composite TTP and OS,” Dr. Hearn and colleagues wrote. “Nonetheless, the large impact on TTM is statistically and clinically significant.”

While the findings of Dr. Hearn and colleagues bolster existing knowledge that variant HSD3B1(1245C) alleles are associated with poorer outcomes in prostate cancer, the findings from Dr. Almassi and colleagues add new insights regarding the potential role of CYP17A1 inhibitors in patients with this genotype.

“As only a proportion of patients treated with potent CYP17A1 inhibitors or AR antagonists respond clinically, a predictive biomarker for the identification of patients who benefit would undoubtedly have clinical value,” Dr. Almassi and colleagues said.

The findings are somewhat limited, however, because they were focused on ketoconazole, a nonsteroidal CYP17A1 inhibitor that is no longer routinely used in clinic for prostate cancer.

Similar studies of the steroidal CYP17A1 inhibitor abiraterone acetate would be possible, however, “steroidal metabolites of [steroidal CYP17A1 inhibitors] make evaluation more complex,” Dr. Almassi and colleagues wrote.

In patients with castration-resistant prostate cancer (CRPC), a variant of the HSD3B1 gene predicts sensitivity to the CYP17A1 inhibitor ketoconazole, according to results of a single-center, observational study including 90 men treated between June 1998 and December 2012.

Median progression-free survival (PFS) increased along with the number of variant HSD3B1(1245C) alleles, wrote Nima Almassi, MD, of the Cleveland Clinic, and coauthors (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3159).

Specifically, median PFS was just 5.0 months for patients with no variant HSD3B1(1245C) alleles, 7.5 months for patients with one allele, and 12.3 months for those with two alleles (P = .03).

“These findings suggest that the variant allele … may be a predictive biomarker of tumor vulnerability to pharmacologic CYP17A1 inhibition with a nonsteroidal drug,” Dr. Almassi and colleagues wrote.

The HSD3B1(1245C) germline variant was already known in the prostate cancer research community as a marker of tumor resistance to androgen deprivation therapy (ADT) and more rapid disease onset. In a separate study published in the same issue (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3164) investigators provided additional evidence, showing that the genotype was associated with more rapid metastasis development in men with localized prostate cancer who received ADT for biochemical recurrence after radiation treatment.

In that observational study of 218 men treated between 1996 and 2003, median time to metastasis (TTM) decreased according to the number of inherited variant alleles, wrote Jason W. D. Hearn, MD, University of Michigan, Ann Arbor, and coauthors. Those with no variant HSD3B1(1245C) alleles had a TTM of 7.4 months, while those with one allele had a TTM of 5.8 months, and for those with two, TTM was only 4.4 months (P = .03).

However, investigators could not detect any such relationship between variant HSD3B1(1245C) alleles and time to progression (TTP) or overall survival (OS): “It is possible that the high rates of prior ADT exposure and frequent use of androgen receptor (AR) antagonists during salvage ADT modified the impact of genotype with respect to composite TTP and OS,” Dr. Hearn and colleagues wrote. “Nonetheless, the large impact on TTM is statistically and clinically significant.”

While the findings of Dr. Hearn and colleagues bolster existing knowledge that variant HSD3B1(1245C) alleles are associated with poorer outcomes in prostate cancer, the findings from Dr. Almassi and colleagues add new insights regarding the potential role of CYP17A1 inhibitors in patients with this genotype.

“As only a proportion of patients treated with potent CYP17A1 inhibitors or AR antagonists respond clinically, a predictive biomarker for the identification of patients who benefit would undoubtedly have clinical value,” Dr. Almassi and colleagues said.

The findings are somewhat limited, however, because they were focused on ketoconazole, a nonsteroidal CYP17A1 inhibitor that is no longer routinely used in clinic for prostate cancer.

Similar studies of the steroidal CYP17A1 inhibitor abiraterone acetate would be possible, however, “steroidal metabolites of [steroidal CYP17A1 inhibitors] make evaluation more complex,” Dr. Almassi and colleagues wrote.

In patients with castration-resistant prostate cancer (CRPC), a variant of the HSD3B1 gene predicts sensitivity to the CYP17A1 inhibitor ketoconazole, according to results of a single-center, observational study including 90 men treated between June 1998 and December 2012.

Median progression-free survival (PFS) increased along with the number of variant HSD3B1(1245C) alleles, wrote Nima Almassi, MD, of the Cleveland Clinic, and coauthors (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3159).

Specifically, median PFS was just 5.0 months for patients with no variant HSD3B1(1245C) alleles, 7.5 months for patients with one allele, and 12.3 months for those with two alleles (P = .03).

“These findings suggest that the variant allele … may be a predictive biomarker of tumor vulnerability to pharmacologic CYP17A1 inhibition with a nonsteroidal drug,” Dr. Almassi and colleagues wrote.

The HSD3B1(1245C) germline variant was already known in the prostate cancer research community as a marker of tumor resistance to androgen deprivation therapy (ADT) and more rapid disease onset. In a separate study published in the same issue (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3164) investigators provided additional evidence, showing that the genotype was associated with more rapid metastasis development in men with localized prostate cancer who received ADT for biochemical recurrence after radiation treatment.

In that observational study of 218 men treated between 1996 and 2003, median time to metastasis (TTM) decreased according to the number of inherited variant alleles, wrote Jason W. D. Hearn, MD, University of Michigan, Ann Arbor, and coauthors. Those with no variant HSD3B1(1245C) alleles had a TTM of 7.4 months, while those with one allele had a TTM of 5.8 months, and for those with two, TTM was only 4.4 months (P = .03).

However, investigators could not detect any such relationship between variant HSD3B1(1245C) alleles and time to progression (TTP) or overall survival (OS): “It is possible that the high rates of prior ADT exposure and frequent use of androgen receptor (AR) antagonists during salvage ADT modified the impact of genotype with respect to composite TTP and OS,” Dr. Hearn and colleagues wrote. “Nonetheless, the large impact on TTM is statistically and clinically significant.”

While the findings of Dr. Hearn and colleagues bolster existing knowledge that variant HSD3B1(1245C) alleles are associated with poorer outcomes in prostate cancer, the findings from Dr. Almassi and colleagues add new insights regarding the potential role of CYP17A1 inhibitors in patients with this genotype.

“As only a proportion of patients treated with potent CYP17A1 inhibitors or AR antagonists respond clinically, a predictive biomarker for the identification of patients who benefit would undoubtedly have clinical value,” Dr. Almassi and colleagues said.

The findings are somewhat limited, however, because they were focused on ketoconazole, a nonsteroidal CYP17A1 inhibitor that is no longer routinely used in clinic for prostate cancer.

Similar studies of the steroidal CYP17A1 inhibitor abiraterone acetate would be possible, however, “steroidal metabolites of [steroidal CYP17A1 inhibitors] make evaluation more complex,” Dr. Almassi and colleagues wrote.

Robot-assisted radical prostatectomy shows better early postoperative outcomes than does laparoscopic radical prostatectomy, but the differences between the two surgical approaches disappeared by the 6-month follow-up.

Dr. Hiroyuki Koike and his colleagues at Wakayama (Japan) Medical University Hospital conducted a study of two groups of patients treated for localized prostate cancer. One group of 229 patients underwent laparoscopic radical prostatectomy (LRP) between July 2007 and July 2013. The other group of 115 patients had robot-assisted radical prostatectomy (RARP) between December 2012 and August 2014 (J Robot Surg. 2017;11[3]:325-31).

Master Video/Shutterstock

“The RARP group showed significantly better scores in urinary summary and all urinary subscales at postoperative 3-month follow-up. However, these differences disappeared at postoperative 6 and 12-month follow-up,” the investigators wrote. For the urinary summary score, LRP significantly underperformed, compared with RARP, with scores of 63.3 vs. 75.8, respectively, after 3 months. In addition, the bowel function score was superior for RARP, compared with LRP, at 96.9 vs. 92.9, respectively. Sexual function results were similar, with RARP and LRP scores of 2.8 vs. 0.

The general measures of the PCS and MCS also favored RARP. At the 3-month follow-up, PCS (51.3 vs. 48.1) and MCS (50 vs. 47.8) scores were higher for RARP, compared with LRP.

“It is unclear why our superiority of urinary function in RARP was observed only in early period. However, we can speculate several reasons for better urinary function in RARP group. First, we were able to treat the apex area more delicately with RARP. Second, some of the new techniques which we employed after the introduction of RARP could influence the urinary continence recovery,” the investigators wrote.

The authors had no relevant financial disclosures.

ilacy@frontlinemedcom.com

Robot-assisted radical prostatectomy shows better early postoperative outcomes than does laparoscopic radical prostatectomy, but the differences between the two surgical approaches disappeared by the 6-month follow-up.

Dr. Hiroyuki Koike and his colleagues at Wakayama (Japan) Medical University Hospital conducted a study of two groups of patients treated for localized prostate cancer. One group of 229 patients underwent laparoscopic radical prostatectomy (LRP) between July 2007 and July 2013. The other group of 115 patients had robot-assisted radical prostatectomy (RARP) between December 2012 and August 2014 (J Robot Surg. 2017;11[3]:325-31).

Master Video/Shutterstock

“The RARP group showed significantly better scores in urinary summary and all urinary subscales at postoperative 3-month follow-up. However, these differences disappeared at postoperative 6 and 12-month follow-up,” the investigators wrote. For the urinary summary score, LRP significantly underperformed, compared with RARP, with scores of 63.3 vs. 75.8, respectively, after 3 months. In addition, the bowel function score was superior for RARP, compared with LRP, at 96.9 vs. 92.9, respectively. Sexual function results were similar, with RARP and LRP scores of 2.8 vs. 0.

The general measures of the PCS and MCS also favored RARP. At the 3-month follow-up, PCS (51.3 vs. 48.1) and MCS (50 vs. 47.8) scores were higher for RARP, compared with LRP.

“It is unclear why our superiority of urinary function in RARP was observed only in early period. However, we can speculate several reasons for better urinary function in RARP group. First, we were able to treat the apex area more delicately with RARP. Second, some of the new techniques which we employed after the introduction of RARP could influence the urinary continence recovery,” the investigators wrote.

The authors had no relevant financial disclosures.

ilacy@frontlinemedcom.com

Robot-assisted radical prostatectomy shows better early postoperative outcomes than does laparoscopic radical prostatectomy, but the differences between the two surgical approaches disappeared by the 6-month follow-up.

Dr. Hiroyuki Koike and his colleagues at Wakayama (Japan) Medical University Hospital conducted a study of two groups of patients treated for localized prostate cancer. One group of 229 patients underwent laparoscopic radical prostatectomy (LRP) between July 2007 and July 2013. The other group of 115 patients had robot-assisted radical prostatectomy (RARP) between December 2012 and August 2014 (J Robot Surg. 2017;11[3]:325-31).

Master Video/Shutterstock

“The RARP group showed significantly better scores in urinary summary and all urinary subscales at postoperative 3-month follow-up. However, these differences disappeared at postoperative 6 and 12-month follow-up,” the investigators wrote. For the urinary summary score, LRP significantly underperformed, compared with RARP, with scores of 63.3 vs. 75.8, respectively, after 3 months. In addition, the bowel function score was superior for RARP, compared with LRP, at 96.9 vs. 92.9, respectively. Sexual function results were similar, with RARP and LRP scores of 2.8 vs. 0.

The general measures of the PCS and MCS also favored RARP. At the 3-month follow-up, PCS (51.3 vs. 48.1) and MCS (50 vs. 47.8) scores were higher for RARP, compared with LRP.

“It is unclear why our superiority of urinary function in RARP was observed only in early period. However, we can speculate several reasons for better urinary function in RARP group. First, we were able to treat the apex area more delicately with RARP. Second, some of the new techniques which we employed after the introduction of RARP could influence the urinary continence recovery,” the investigators wrote.

The authors had no relevant financial disclosures.

ilacy@frontlinemedcom.com

MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.

Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).

“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.

But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”

He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”

He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.

In the RANGE trial, results of which were published in The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.

Patients were randomly assigned to receive intravenous docetaxel 75 mg/m² plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.

As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).

Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.

Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.

In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.

There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.

op@frontlinemedcom.com

MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.

Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).

“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.

But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”

He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”

He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.

In the RANGE trial, results of which were published in The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.

Patients were randomly assigned to receive intravenous docetaxel 75 mg/m² plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.

As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).

Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.

Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.

In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.

There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.

op@frontlinemedcom.com

MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.

Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).

“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.

But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”

He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”

He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.

In the RANGE trial, results of which were published in The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.

Patients were randomly assigned to receive intravenous docetaxel 75 mg/m² plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.

As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).

Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.

Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.

In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.

There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.

op@frontlinemedcom.com

Adjuvant pazopanib provided no disease-free survival benefit compared with placebo in the randomized phase 3 PROTECT trial of patients with locally advanced renal cell carcinoma at high risk for relapse after nephrectomy.

In the primary analysis for disease-free survival among 571 patients treated for 1 year with 600 mg of pazopanib and 564 who received placebo, no significant improvement was seen with pazopanib (hazard ratio, 0.86). In a follow-up analysis 12 months later, the hazard ratio was 0.94. Secondary analysis in 403 additional patients who were treated with 800 mg of pazopanib before the dose was lowered to 600 mg due to intolerance and toxicity attrition showed a benefit with pazopanib (HR, 0.69), but this group represented only a third of the study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues. The study results were published online in the Journal of Clinical Oncology.

sworcester@frontlinemedcom.com

Adjuvant pazopanib provided no disease-free survival benefit compared with placebo in the randomized phase 3 PROTECT trial of patients with locally advanced renal cell carcinoma at high risk for relapse after nephrectomy.

In the primary analysis for disease-free survival among 571 patients treated for 1 year with 600 mg of pazopanib and 564 who received placebo, no significant improvement was seen with pazopanib (hazard ratio, 0.86). In a follow-up analysis 12 months later, the hazard ratio was 0.94. Secondary analysis in 403 additional patients who were treated with 800 mg of pazopanib before the dose was lowered to 600 mg due to intolerance and toxicity attrition showed a benefit with pazopanib (HR, 0.69), but this group represented only a third of the study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues. The study results were published online in the Journal of Clinical Oncology.

sworcester@frontlinemedcom.com

Adjuvant pazopanib provided no disease-free survival benefit compared with placebo in the randomized phase 3 PROTECT trial of patients with locally advanced renal cell carcinoma at high risk for relapse after nephrectomy.

In the primary analysis for disease-free survival among 571 patients treated for 1 year with 600 mg of pazopanib and 564 who received placebo, no significant improvement was seen with pazopanib (hazard ratio, 0.86). In a follow-up analysis 12 months later, the hazard ratio was 0.94. Secondary analysis in 403 additional patients who were treated with 800 mg of pazopanib before the dose was lowered to 600 mg due to intolerance and toxicity attrition showed a benefit with pazopanib (HR, 0.69), but this group represented only a third of the study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues. The study results were published online in the Journal of Clinical Oncology.

sworcester@frontlinemedcom.com

As we head into vacation season and the dog days of summer, let’s reflect for a few minutes on some of the very important advances we heard about at this year’s annual meeting of the American Society of Clinical Oncology in Chicago. Nearly 40,000 individuals registered for the conference, an indication of both the interest and the excitement around the new agents and the emerging clinical trial data. Scientific sessions dedicated to the use of combination immunotherapy, the role of antibody drug conjugates, and targeting molecular aberrations with small molecules were among the most popular (p. e236).

As we head into vacation season and the dog days of summer, let’s reflect for a few minutes on some of the very important advances we heard about at this year’s annual meeting of the American Society of Clinical Oncology in Chicago. Nearly 40,000 individuals registered for the conference, an indication of both the interest and the excitement around the new agents and the emerging clinical trial data. Scientific sessions dedicated to the use of combination immunotherapy, the role of antibody drug conjugates, and targeting molecular aberrations with small molecules were among the most popular (p. e236).

As we head into vacation season and the dog days of summer, let’s reflect for a few minutes on some of the very important advances we heard about at this year’s annual meeting of the American Society of Clinical Oncology in Chicago. Nearly 40,000 individuals registered for the conference, an indication of both the interest and the excitement around the new agents and the emerging clinical trial data. Scientific sessions dedicated to the use of combination immunotherapy, the role of antibody drug conjugates, and targeting molecular aberrations with small molecules were among the most popular (p. e236).

Rates of opioid prescribing were about 1.2 times higher overall among cancer survivors up to 10 years after diagnosis, compared with matched controls, with more than threefold higher rates of opioid prescriptions for survivors of some cancers, according to a Canadian population-based cohort study.

Searching for the cause of these elevated rates reveals the complexity of the survivorship experience, and may also point the way to areas where there’s work to be done, according to physicians whose practices touch the lives of cancer survivors.

In a retrospective matched cohort study of participants in the Ontario Health Insurance Plan and the Ontario Drug Benefits Program, Rinku Sutradhar, PhD, of the University of Toronto, and her colleagues, identified patients aged 18-64 who had a cancer diagnosis at least 5 years previously. Patients were included only if they had not had a cancer recurrence or another malignancy. When compared 1:1 to age- and sex-matched controls, the 8,601 cancer survivors had a relative rate of opioid prescribing of 1.220 (95% confidence interval [CI], 1.209-1.232), the investigators reported (Cancer 2017 Aug 17. doi: 10.1002/cncr.30839).

Opioid prescribing rates varied according to the type of cancer the survivor had had, with a relative rate of 3.119 for noncolorectal gastrointestinal cancer survivors and a rate of 2.066 for lung cancer survivors. Individuals with nonprostate genitourinary cancers had a prescribing rate of 1.619. All of these differences were statistically significant.

Elevated prescribing rates were not seen in patients with brain, breast, colorectal, head and neck, or prostate cancers. The relative rate of prescribing for hematologic cancers was 1.383, a difference that approached, but did not quite reach, statistical significance (P = .0512).

When multivariable analysis was used to stratify individuals by length of time since cancer diagnosis, a significantly elevated relative rate of opioid prescribing persisted; for those 5-10 years from diagnosis, the relative rate was 1.190 (95% CI, 1.040-1.362, P = .011), while for those diagnosed at least 10 years ago, the relative rate was 1.244 (95% CI, 1.090-1.420; P = .00118).

Multivariable analysis was also used to control for income, rural residence, and comorbidities. However, the study could capture only opioids that were obtained with a prescription, and could not track whether medications were taken by the person for whom they were prescribed, Dr. Sutradhar and her colleagues said.

Cancer survivors may have a higher prevalence of chronic pain than the general population for reasons related both to their initial diagnosis and the sequelae of treatments such as surgery, chemotherapy, and radiation therapy, the investigators noted, adding, “it is also possible that a higher rate of opioid prescribing among survivors is due to a dependency that originated from opioid use earlier in the disease trajectory.”

Because of the potential for opioid use disorder and the many adverse effects that can be associated with long-term opioid use, they said, “primary care providers who treat cancer survivors should be encouraged to critically examine reasons for lingering opioid use among their patients.”

The oncologist’s perspective

Walter M. Stadler, MD, an oncologist who treats genitourinary and hematologic cancers, also wonders whether it’s pain or dependency that’s driving the increased prescribing rates in cancer survivors.

What can primary care offer?

Larissa Nekhlyudov, MD, is an internal medicine physician whose clinical practice straddles two domains. She sees patients, including some cancer survivors, as a primary care provider; she also provides care in a survivorship clinic to adult survivors of childhood cancers. There, she is able to focus more on survivorship care, developing a care plan and communicating with primary care providers about care elements her patients need.

Mental health implications of survivorship

Viewing the issue through the lens of mental health offers a slightly different perspective. Thomas B. Strouse, MD, is a psychiatrist who holds the Maddie Katz Chair in palliative care research and education at the University of California, Los Angeles. He said he laments the current “opioidophobia” that calls into question any long-term opioid prescribing.

Acknowledging that there’s certainly a serious nationwide problem with both prescription and nonprescription opioid abuse, Dr. Strouse said he still finds it unfortunate that the current situation has “reactivated for many people a certain set of reflexes that say that any chronic opioid use is always a bad thing. That’s simply not true,” he said.

“Whether opioids are the right treatment for all of those patients, of course, is an entirely fair question. But it’s unfortunate, or wrong, for everybody to approach this article and to say that we know that for all of these patients, chronic opioid therapy is not appropriate,” he added.

Chronic pain that lingers after cancer treatments affects “a very significant minority of cancer survivors,” he said. It’s also true that the meaning of pain can be different for cancer survivors, said Dr. Strouse. For a cancer survivor, “any new pain is cancer pain until proven otherwise,” he said.

Further, pivoting from the attentive, multidisciplinary, wraparound care often received during cancer treatment to the relatively unsupported survivorship experience can be a rough transition for some. Despite the grim reason for the connection, “frequently, it’s the best experience of patients’ lives from a human relations perspective. … We don’t think enough about the loss that the end of cancer treatment may mean for people who may have otherwise unsatisfactory relationships in their lives,” he said.

Dr. Strouse, who works extensively with cancer survivors, said that the elevated rate of opioid prescribing seen in this study “opens the door to a bigger discussion about the challenges in the relatively empty domain of survivorship.” After discharge from cancer care, patients are all too often left without a navigator to help them through the years when, though their treatment is complete, anxiety, financial and social strain, and pain may linger.

The study, he said, should be a call to physicians for “a more meaningful commitment to understanding the burdens of survivorship, and actually offering meaningful clinical services to those people in an integrated and appropriate way.” This might include determining a patient’s absolute minimum opioid requirement, with a goal of getting the patient off opioids, but also making sure the patient has knowledge of and access to alternative pharmacologic and nonpharmacologic treatments for pain. “That seems like a reasonable approach,” said Dr. Strouse.

None of the study’s authors or the physicians interviewed for commentary had relevant conflicts of interest.

koakes@frontlinemedcom.com

On Twitter @karioakes

Rates of opioid prescribing were about 1.2 times higher overall among cancer survivors up to 10 years after diagnosis, compared with matched controls, with more than threefold higher rates of opioid prescriptions for survivors of some cancers, according to a Canadian population-based cohort study.

Searching for the cause of these elevated rates reveals the complexity of the survivorship experience, and may also point the way to areas where there’s work to be done, according to physicians whose practices touch the lives of cancer survivors.

In a retrospective matched cohort study of participants in the Ontario Health Insurance Plan and the Ontario Drug Benefits Program, Rinku Sutradhar, PhD, of the University of Toronto, and her colleagues, identified patients aged 18-64 who had a cancer diagnosis at least 5 years previously. Patients were included only if they had not had a cancer recurrence or another malignancy. When compared 1:1 to age- and sex-matched controls, the 8,601 cancer survivors had a relative rate of opioid prescribing of 1.220 (95% confidence interval [CI], 1.209-1.232), the investigators reported (Cancer 2017 Aug 17. doi: 10.1002/cncr.30839).

Opioid prescribing rates varied according to the type of cancer the survivor had had, with a relative rate of 3.119 for noncolorectal gastrointestinal cancer survivors and a rate of 2.066 for lung cancer survivors. Individuals with nonprostate genitourinary cancers had a prescribing rate of 1.619. All of these differences were statistically significant.

Elevated prescribing rates were not seen in patients with brain, breast, colorectal, head and neck, or prostate cancers. The relative rate of prescribing for hematologic cancers was 1.383, a difference that approached, but did not quite reach, statistical significance (P = .0512).

When multivariable analysis was used to stratify individuals by length of time since cancer diagnosis, a significantly elevated relative rate of opioid prescribing persisted; for those 5-10 years from diagnosis, the relative rate was 1.190 (95% CI, 1.040-1.362, P = .011), while for those diagnosed at least 10 years ago, the relative rate was 1.244 (95% CI, 1.090-1.420; P = .00118).

Multivariable analysis was also used to control for income, rural residence, and comorbidities. However, the study could capture only opioids that were obtained with a prescription, and could not track whether medications were taken by the person for whom they were prescribed, Dr. Sutradhar and her colleagues said.

Cancer survivors may have a higher prevalence of chronic pain than the general population for reasons related both to their initial diagnosis and the sequelae of treatments such as surgery, chemotherapy, and radiation therapy, the investigators noted, adding, “it is also possible that a higher rate of opioid prescribing among survivors is due to a dependency that originated from opioid use earlier in the disease trajectory.”

Because of the potential for opioid use disorder and the many adverse effects that can be associated with long-term opioid use, they said, “primary care providers who treat cancer survivors should be encouraged to critically examine reasons for lingering opioid use among their patients.”

The oncologist’s perspective

Walter M. Stadler, MD, an oncologist who treats genitourinary and hematologic cancers, also wonders whether it’s pain or dependency that’s driving the increased prescribing rates in cancer survivors.

What can primary care offer?

Larissa Nekhlyudov, MD, is an internal medicine physician whose clinical practice straddles two domains. She sees patients, including some cancer survivors, as a primary care provider; she also provides care in a survivorship clinic to adult survivors of childhood cancers. There, she is able to focus more on survivorship care, developing a care plan and communicating with primary care providers about care elements her patients need.

Mental health implications of survivorship

Viewing the issue through the lens of mental health offers a slightly different perspective. Thomas B. Strouse, MD, is a psychiatrist who holds the Maddie Katz Chair in palliative care research and education at the University of California, Los Angeles. He said he laments the current “opioidophobia” that calls into question any long-term opioid prescribing.

Acknowledging that there’s certainly a serious nationwide problem with both prescription and nonprescription opioid abuse, Dr. Strouse said he still finds it unfortunate that the current situation has “reactivated for many people a certain set of reflexes that say that any chronic opioid use is always a bad thing. That’s simply not true,” he said.

“Whether opioids are the right treatment for all of those patients, of course, is an entirely fair question. But it’s unfortunate, or wrong, for everybody to approach this article and to say that we know that for all of these patients, chronic opioid therapy is not appropriate,” he added.

Chronic pain that lingers after cancer treatments affects “a very significant minority of cancer survivors,” he said. It’s also true that the meaning of pain can be different for cancer survivors, said Dr. Strouse. For a cancer survivor, “any new pain is cancer pain until proven otherwise,” he said.

Further, pivoting from the attentive, multidisciplinary, wraparound care often received during cancer treatment to the relatively unsupported survivorship experience can be a rough transition for some. Despite the grim reason for the connection, “frequently, it’s the best experience of patients’ lives from a human relations perspective. … We don’t think enough about the loss that the end of cancer treatment may mean for people who may have otherwise unsatisfactory relationships in their lives,” he said.

Dr. Strouse, who works extensively with cancer survivors, said that the elevated rate of opioid prescribing seen in this study “opens the door to a bigger discussion about the challenges in the relatively empty domain of survivorship.” After discharge from cancer care, patients are all too often left without a navigator to help them through the years when, though their treatment is complete, anxiety, financial and social strain, and pain may linger.

The study, he said, should be a call to physicians for “a more meaningful commitment to understanding the burdens of survivorship, and actually offering meaningful clinical services to those people in an integrated and appropriate way.” This might include determining a patient’s absolute minimum opioid requirement, with a goal of getting the patient off opioids, but also making sure the patient has knowledge of and access to alternative pharmacologic and nonpharmacologic treatments for pain. “That seems like a reasonable approach,” said Dr. Strouse.

None of the study’s authors or the physicians interviewed for commentary had relevant conflicts of interest.

koakes@frontlinemedcom.com

On Twitter @karioakes

Rates of opioid prescribing were about 1.2 times higher overall among cancer survivors up to 10 years after diagnosis, compared with matched controls, with more than threefold higher rates of opioid prescriptions for survivors of some cancers, according to a Canadian population-based cohort study.

Searching for the cause of these elevated rates reveals the complexity of the survivorship experience, and may also point the way to areas where there’s work to be done, according to physicians whose practices touch the lives of cancer survivors.

In a retrospective matched cohort study of participants in the Ontario Health Insurance Plan and the Ontario Drug Benefits Program, Rinku Sutradhar, PhD, of the University of Toronto, and her colleagues, identified patients aged 18-64 who had a cancer diagnosis at least 5 years previously. Patients were included only if they had not had a cancer recurrence or another malignancy. When compared 1:1 to age- and sex-matched controls, the 8,601 cancer survivors had a relative rate of opioid prescribing of 1.220 (95% confidence interval [CI], 1.209-1.232), the investigators reported (Cancer 2017 Aug 17. doi: 10.1002/cncr.30839).

Opioid prescribing rates varied according to the type of cancer the survivor had had, with a relative rate of 3.119 for noncolorectal gastrointestinal cancer survivors and a rate of 2.066 for lung cancer survivors. Individuals with nonprostate genitourinary cancers had a prescribing rate of 1.619. All of these differences were statistically significant.

Elevated prescribing rates were not seen in patients with brain, breast, colorectal, head and neck, or prostate cancers. The relative rate of prescribing for hematologic cancers was 1.383, a difference that approached, but did not quite reach, statistical significance (P = .0512).

When multivariable analysis was used to stratify individuals by length of time since cancer diagnosis, a significantly elevated relative rate of opioid prescribing persisted; for those 5-10 years from diagnosis, the relative rate was 1.190 (95% CI, 1.040-1.362, P = .011), while for those diagnosed at least 10 years ago, the relative rate was 1.244 (95% CI, 1.090-1.420; P = .00118).

Multivariable analysis was also used to control for income, rural residence, and comorbidities. However, the study could capture only opioids that were obtained with a prescription, and could not track whether medications were taken by the person for whom they were prescribed, Dr. Sutradhar and her colleagues said.

Cancer survivors may have a higher prevalence of chronic pain than the general population for reasons related both to their initial diagnosis and the sequelae of treatments such as surgery, chemotherapy, and radiation therapy, the investigators noted, adding, “it is also possible that a higher rate of opioid prescribing among survivors is due to a dependency that originated from opioid use earlier in the disease trajectory.”

Because of the potential for opioid use disorder and the many adverse effects that can be associated with long-term opioid use, they said, “primary care providers who treat cancer survivors should be encouraged to critically examine reasons for lingering opioid use among their patients.”

The oncologist’s perspective

Walter M. Stadler, MD, an oncologist who treats genitourinary and hematologic cancers, also wonders whether it’s pain or dependency that’s driving the increased prescribing rates in cancer survivors.

What can primary care offer?

Larissa Nekhlyudov, MD, is an internal medicine physician whose clinical practice straddles two domains. She sees patients, including some cancer survivors, as a primary care provider; she also provides care in a survivorship clinic to adult survivors of childhood cancers. There, she is able to focus more on survivorship care, developing a care plan and communicating with primary care providers about care elements her patients need.

Mental health implications of survivorship

Viewing the issue through the lens of mental health offers a slightly different perspective. Thomas B. Strouse, MD, is a psychiatrist who holds the Maddie Katz Chair in palliative care research and education at the University of California, Los Angeles. He said he laments the current “opioidophobia” that calls into question any long-term opioid prescribing.

Acknowledging that there’s certainly a serious nationwide problem with both prescription and nonprescription opioid abuse, Dr. Strouse said he still finds it unfortunate that the current situation has “reactivated for many people a certain set of reflexes that say that any chronic opioid use is always a bad thing. That’s simply not true,” he said.

“Whether opioids are the right treatment for all of those patients, of course, is an entirely fair question. But it’s unfortunate, or wrong, for everybody to approach this article and to say that we know that for all of these patients, chronic opioid therapy is not appropriate,” he added.

Chronic pain that lingers after cancer treatments affects “a very significant minority of cancer survivors,” he said. It’s also true that the meaning of pain can be different for cancer survivors, said Dr. Strouse. For a cancer survivor, “any new pain is cancer pain until proven otherwise,” he said.

Further, pivoting from the attentive, multidisciplinary, wraparound care often received during cancer treatment to the relatively unsupported survivorship experience can be a rough transition for some. Despite the grim reason for the connection, “frequently, it’s the best experience of patients’ lives from a human relations perspective. … We don’t think enough about the loss that the end of cancer treatment may mean for people who may have otherwise unsatisfactory relationships in their lives,” he said.

Dr. Strouse, who works extensively with cancer survivors, said that the elevated rate of opioid prescribing seen in this study “opens the door to a bigger discussion about the challenges in the relatively empty domain of survivorship.” After discharge from cancer care, patients are all too often left without a navigator to help them through the years when, though their treatment is complete, anxiety, financial and social strain, and pain may linger.

The study, he said, should be a call to physicians for “a more meaningful commitment to understanding the burdens of survivorship, and actually offering meaningful clinical services to those people in an integrated and appropriate way.” This might include determining a patient’s absolute minimum opioid requirement, with a goal of getting the patient off opioids, but also making sure the patient has knowledge of and access to alternative pharmacologic and nonpharmacologic treatments for pain. “That seems like a reasonable approach,” said Dr. Strouse.

None of the study’s authors or the physicians interviewed for commentary had relevant conflicts of interest.

koakes@frontlinemedcom.com

On Twitter @karioakes

The European Commission has approved tivozanib for the treatment of advanced renal cell carcinoma (RCC) in adult patients in the European Union, Norway, and Iceland.

Tivozanib (Fotivda) is a vascular endothelial growth factor receptor tyrosine kinase inhibitor, taken orally once daily. It is indicated for first-line treatment of patients, naive to both vascular endothelial growth factor receptors and mTOR pathway inhibitors, experiencing disease progression following one cytokine therapy treatment, according to the press release.

Its approval is based on superior progression-free survival (PFS) in TIVO-1, a phase 3 trial comparing the efficacy and tolerability of tivozanib (1.5 mg once daily) with that of sorafenib (400 mg twice daily). In the overall trial population of 517 patients with advanced RCC, PFS was 11.9 months for patients treated with tivozanib, compared with 9.1 months for those treated with sorafenib (hazard ratio, 0.797; 95% confidence interval, 0.639-0.993; P = .042).

Patients in the tivozanib arm also experienced fewer cases of diarrhea and hand-foot syndrome, and required fewer dose reductions because of adverse effects than did those taking sorafenib.

The approval follows a recommendation from the Committee for Medical Products for Human Use.

The Food and Drug Administration rejected the New Drug Application for tivozanib in 2013, based on TIVO-1 data. Aveo Oncology plans to reapply in the United States with data from TIVO-3, expected in early 2018, they said in the press release.

dwatson@frontlinemedcom.com

The European Commission has approved tivozanib for the treatment of advanced renal cell carcinoma (RCC) in adult patients in the European Union, Norway, and Iceland.

Tivozanib (Fotivda) is a vascular endothelial growth factor receptor tyrosine kinase inhibitor, taken orally once daily. It is indicated for first-line treatment of patients, naive to both vascular endothelial growth factor receptors and mTOR pathway inhibitors, experiencing disease progression following one cytokine therapy treatment, according to the press release.

Its approval is based on superior progression-free survival (PFS) in TIVO-1, a phase 3 trial comparing the efficacy and tolerability of tivozanib (1.5 mg once daily) with that of sorafenib (400 mg twice daily). In the overall trial population of 517 patients with advanced RCC, PFS was 11.9 months for patients treated with tivozanib, compared with 9.1 months for those treated with sorafenib (hazard ratio, 0.797; 95% confidence interval, 0.639-0.993; P = .042).

Patients in the tivozanib arm also experienced fewer cases of diarrhea and hand-foot syndrome, and required fewer dose reductions because of adverse effects than did those taking sorafenib.

The approval follows a recommendation from the Committee for Medical Products for Human Use.

The Food and Drug Administration rejected the New Drug Application for tivozanib in 2013, based on TIVO-1 data. Aveo Oncology plans to reapply in the United States with data from TIVO-3, expected in early 2018, they said in the press release.

dwatson@frontlinemedcom.com

The European Commission has approved tivozanib for the treatment of advanced renal cell carcinoma (RCC) in adult patients in the European Union, Norway, and Iceland.

Tivozanib (Fotivda) is a vascular endothelial growth factor receptor tyrosine kinase inhibitor, taken orally once daily. It is indicated for first-line treatment of patients, naive to both vascular endothelial growth factor receptors and mTOR pathway inhibitors, experiencing disease progression following one cytokine therapy treatment, according to the press release.

Its approval is based on superior progression-free survival (PFS) in TIVO-1, a phase 3 trial comparing the efficacy and tolerability of tivozanib (1.5 mg once daily) with that of sorafenib (400 mg twice daily). In the overall trial population of 517 patients with advanced RCC, PFS was 11.9 months for patients treated with tivozanib, compared with 9.1 months for those treated with sorafenib (hazard ratio, 0.797; 95% confidence interval, 0.639-0.993; P = .042).

Patients in the tivozanib arm also experienced fewer cases of diarrhea and hand-foot syndrome, and required fewer dose reductions because of adverse effects than did those taking sorafenib.

The approval follows a recommendation from the Committee for Medical Products for Human Use.

The Food and Drug Administration rejected the New Drug Application for tivozanib in 2013, based on TIVO-1 data. Aveo Oncology plans to reapply in the United States with data from TIVO-3, expected in early 2018, they said in the press release.

dwatson@frontlinemedcom.com