Renal Cell Carcinoma

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

The link between obesity and renal cell carcinoma (RCC) appears to be complex and may provide insight into differing etiologies for various histologic subtypes of this cancer, according to a nested case-control study and subsequent meta-analysis.

Investigators led by Catherine L. Callahan, PhD, a postdoctoral fellow with the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Md., first analyzed data from the Kaiser Permanente Northern California health care network. They matched 685 patients with RCC (421 clear cell, 65 papillary, 24 chromophobe, 35 other, and 140 not otherwise specified) with 4,266 unaffected control patients on age, sex, race/ethnicity, duration of network membership, and medical center of diagnosis.

Compared with normal-weight counterparts (body mass index less than 25 kg/m²), obese patients (body mass index of at least 30 kg/m²), had a significantly elevated risk of clear cell RCC (odds ratio, 1.5) and a nonsignificantly elevated risk of chromophobe RCC (2.5), but a similar risk of papillary RCC (1.0), according to results reported in Cancer Epidemiology. Associations weakened when cases were restricted to stage II or higher RCC, suggesting potential bias from incidental diagnoses related to abdominal imaging. Patients who were overweight (body mass index of 25 to 29.9 kg/m²) did not have significantly elevated risks of any subtype of RCC.

The investigators next conducted a meta-analysis, including this new study and three others. Results showed a significant link between obesity and clear cell RCC (summary relative risk, 1.8) and chromophobe RCC (2.2), but not papillary RCC (1.2). Here, however, patients who were overweight also had elevated risks of clear cell RCC (1.3) and chromophobe RCC (1.9).

“Our results provide support for the hypothesis that histologic subtypes of RCC represent distinct etiologic pathways, and that obesity is more strongly associated with risk of clear cell RCC. Additional research to elucidate the underlying biology of specific subtypes of RCC is warranted,” wrote Dr. Callahan and her coinvestigators. “More generally, our findings underscore the importance of accounting for histologic subtype in investigations of RCC etiology.”

The investigators disclosed that they had no conflicts of interest. The research was supported by the Intramural Research Program of the NIH and the National Cancer Institute.

SOURCE: Callahan CL et al. Cancer Epidemiol. 2018 Jul 18, doi: 10.1016/j.canep.2018.07.002.

The link between obesity and renal cell carcinoma (RCC) appears to be complex and may provide insight into differing etiologies for various histologic subtypes of this cancer, according to a nested case-control study and subsequent meta-analysis.

Investigators led by Catherine L. Callahan, PhD, a postdoctoral fellow with the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Md., first analyzed data from the Kaiser Permanente Northern California health care network. They matched 685 patients with RCC (421 clear cell, 65 papillary, 24 chromophobe, 35 other, and 140 not otherwise specified) with 4,266 unaffected control patients on age, sex, race/ethnicity, duration of network membership, and medical center of diagnosis.

Compared with normal-weight counterparts (body mass index less than 25 kg/m²), obese patients (body mass index of at least 30 kg/m²), had a significantly elevated risk of clear cell RCC (odds ratio, 1.5) and a nonsignificantly elevated risk of chromophobe RCC (2.5), but a similar risk of papillary RCC (1.0), according to results reported in Cancer Epidemiology. Associations weakened when cases were restricted to stage II or higher RCC, suggesting potential bias from incidental diagnoses related to abdominal imaging. Patients who were overweight (body mass index of 25 to 29.9 kg/m²) did not have significantly elevated risks of any subtype of RCC.

The investigators next conducted a meta-analysis, including this new study and three others. Results showed a significant link between obesity and clear cell RCC (summary relative risk, 1.8) and chromophobe RCC (2.2), but not papillary RCC (1.2). Here, however, patients who were overweight also had elevated risks of clear cell RCC (1.3) and chromophobe RCC (1.9).

“Our results provide support for the hypothesis that histologic subtypes of RCC represent distinct etiologic pathways, and that obesity is more strongly associated with risk of clear cell RCC. Additional research to elucidate the underlying biology of specific subtypes of RCC is warranted,” wrote Dr. Callahan and her coinvestigators. “More generally, our findings underscore the importance of accounting for histologic subtype in investigations of RCC etiology.”

The investigators disclosed that they had no conflicts of interest. The research was supported by the Intramural Research Program of the NIH and the National Cancer Institute.

SOURCE: Callahan CL et al. Cancer Epidemiol. 2018 Jul 18, doi: 10.1016/j.canep.2018.07.002.

The link between obesity and renal cell carcinoma (RCC) appears to be complex and may provide insight into differing etiologies for various histologic subtypes of this cancer, according to a nested case-control study and subsequent meta-analysis.

Investigators led by Catherine L. Callahan, PhD, a postdoctoral fellow with the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Md., first analyzed data from the Kaiser Permanente Northern California health care network. They matched 685 patients with RCC (421 clear cell, 65 papillary, 24 chromophobe, 35 other, and 140 not otherwise specified) with 4,266 unaffected control patients on age, sex, race/ethnicity, duration of network membership, and medical center of diagnosis.

Compared with normal-weight counterparts (body mass index less than 25 kg/m²), obese patients (body mass index of at least 30 kg/m²), had a significantly elevated risk of clear cell RCC (odds ratio, 1.5) and a nonsignificantly elevated risk of chromophobe RCC (2.5), but a similar risk of papillary RCC (1.0), according to results reported in Cancer Epidemiology. Associations weakened when cases were restricted to stage II or higher RCC, suggesting potential bias from incidental diagnoses related to abdominal imaging. Patients who were overweight (body mass index of 25 to 29.9 kg/m²) did not have significantly elevated risks of any subtype of RCC.

The investigators next conducted a meta-analysis, including this new study and three others. Results showed a significant link between obesity and clear cell RCC (summary relative risk, 1.8) and chromophobe RCC (2.2), but not papillary RCC (1.2). Here, however, patients who were overweight also had elevated risks of clear cell RCC (1.3) and chromophobe RCC (1.9).

“Our results provide support for the hypothesis that histologic subtypes of RCC represent distinct etiologic pathways, and that obesity is more strongly associated with risk of clear cell RCC. Additional research to elucidate the underlying biology of specific subtypes of RCC is warranted,” wrote Dr. Callahan and her coinvestigators. “More generally, our findings underscore the importance of accounting for histologic subtype in investigations of RCC etiology.”

The investigators disclosed that they had no conflicts of interest. The research was supported by the Intramural Research Program of the NIH and the National Cancer Institute.

SOURCE: Callahan CL et al. Cancer Epidemiol. 2018 Jul 18, doi: 10.1016/j.canep.2018.07.002.

Credit improvements in therapy rather than diagnosis at an earlier stage for improved survival of renal cell carcinoma in recent years, investigators say.

A review of records on nearly 263,000 patients diagnosed with renal cell carcinoma (RCC ) from 2004 through 2015 showed that better 5-year overall survival (OS) in later years was likely attributable to better treatments rather than an uptick in detection of cancers at an earlier stage, a trend known as “stage migration,” reported Hiten D. Patel, MD, of the Brady Urological Institute at Johns Hopkins Medicine in Baltimore, and his colleagues.

“While survival has improved over time when considering all RCC patients, the primary benefit was observed in advanced RCC (stage III–IV), with 5-year survival increasing from 9.8% in 2004 to 13.2% in 2010 for patients with distant metastatic disease. The results indicate that stage migration no longer contributes to improvements in survival for RCC, and additional gains reflect improvements in advanced treatment options,” they wrote in European Urology Oncology.

Dr. Patel and colleagues noted that the incidence of RCC has been on the rise worldwide for nearly 3 decades because of both environmental risk factors and improvements in medical imaging that have resulted in an increase in incidental cancers.

“Data from the National Cancer Database (NCDB) indicated an increase in the proportion of patients presenting with cT1 RCC from 40% before 1993 to 60% through 2004. However, it is unknown if clinical stage migration has continued into recent years, which has implications for patient outcomes,” they wrote.

To try to answer this question, they sifted through data on 262,597 patients diagnosed with RCC from 2004 through 2015 at more than 1,500 facilities covered by the U.S. National Cancer Database.

They found that, up to 2007, there were statistically significant trends toward more frequent diagnosis of clinical stage I disease (70% of cases) and less frequent diagnoses of stage III (8%) and stage IV (11%; P less than .001 for all comparisons). From 2008 through 2015, however, the respective rates stabilized.

They also noticed a trend throughout the study period for decreased size of localized tumors at diagnosis, with a mean decrease of 0.22 cm for stage I lesions, and 1.24 cm for stage II tumors.

When they looked at 5-year overall survival by Kaplan-Meier analysis, they saw that it improved from 67.9% in 2004 to 72.3% in 2010. As noted before, most of the benefit was attributable to gains in survival among patients with stage III or IV disease.

In multivariable Cox proportional hazard models, diagnosis in recent years was a statistically significant predictor of improved survival, even after adjustment for stage distribution. In addition, receipt of systemic therapy was associated with improved survival, with a hazard ratio of 0.811 (P less than .001).

The authors acknowledged that a limitation of the findings is the reliance on the NCDB, which includes data on most cancer diagnoses in the United States, but is not a population-based sample.

No study funding source was reported. Dr. Patel and coauthors reported having no conflicts of interest to disclose.

SOURCE: Patel HD et al. Eur Urol Oncol. 2018 Sep 25. doi: 10.1016/j.euo.2018.08.023.
 

Credit improvements in therapy rather than diagnosis at an earlier stage for improved survival of renal cell carcinoma in recent years, investigators say.

A review of records on nearly 263,000 patients diagnosed with renal cell carcinoma (RCC ) from 2004 through 2015 showed that better 5-year overall survival (OS) in later years was likely attributable to better treatments rather than an uptick in detection of cancers at an earlier stage, a trend known as “stage migration,” reported Hiten D. Patel, MD, of the Brady Urological Institute at Johns Hopkins Medicine in Baltimore, and his colleagues.

“While survival has improved over time when considering all RCC patients, the primary benefit was observed in advanced RCC (stage III–IV), with 5-year survival increasing from 9.8% in 2004 to 13.2% in 2010 for patients with distant metastatic disease. The results indicate that stage migration no longer contributes to improvements in survival for RCC, and additional gains reflect improvements in advanced treatment options,” they wrote in European Urology Oncology.

Dr. Patel and colleagues noted that the incidence of RCC has been on the rise worldwide for nearly 3 decades because of both environmental risk factors and improvements in medical imaging that have resulted in an increase in incidental cancers.

“Data from the National Cancer Database (NCDB) indicated an increase in the proportion of patients presenting with cT1 RCC from 40% before 1993 to 60% through 2004. However, it is unknown if clinical stage migration has continued into recent years, which has implications for patient outcomes,” they wrote.

To try to answer this question, they sifted through data on 262,597 patients diagnosed with RCC from 2004 through 2015 at more than 1,500 facilities covered by the U.S. National Cancer Database.

They found that, up to 2007, there were statistically significant trends toward more frequent diagnosis of clinical stage I disease (70% of cases) and less frequent diagnoses of stage III (8%) and stage IV (11%; P less than .001 for all comparisons). From 2008 through 2015, however, the respective rates stabilized.

They also noticed a trend throughout the study period for decreased size of localized tumors at diagnosis, with a mean decrease of 0.22 cm for stage I lesions, and 1.24 cm for stage II tumors.

When they looked at 5-year overall survival by Kaplan-Meier analysis, they saw that it improved from 67.9% in 2004 to 72.3% in 2010. As noted before, most of the benefit was attributable to gains in survival among patients with stage III or IV disease.

In multivariable Cox proportional hazard models, diagnosis in recent years was a statistically significant predictor of improved survival, even after adjustment for stage distribution. In addition, receipt of systemic therapy was associated with improved survival, with a hazard ratio of 0.811 (P less than .001).

The authors acknowledged that a limitation of the findings is the reliance on the NCDB, which includes data on most cancer diagnoses in the United States, but is not a population-based sample.

No study funding source was reported. Dr. Patel and coauthors reported having no conflicts of interest to disclose.

SOURCE: Patel HD et al. Eur Urol Oncol. 2018 Sep 25. doi: 10.1016/j.euo.2018.08.023.
 

Credit improvements in therapy rather than diagnosis at an earlier stage for improved survival of renal cell carcinoma in recent years, investigators say.

A review of records on nearly 263,000 patients diagnosed with renal cell carcinoma (RCC ) from 2004 through 2015 showed that better 5-year overall survival (OS) in later years was likely attributable to better treatments rather than an uptick in detection of cancers at an earlier stage, a trend known as “stage migration,” reported Hiten D. Patel, MD, of the Brady Urological Institute at Johns Hopkins Medicine in Baltimore, and his colleagues.

“While survival has improved over time when considering all RCC patients, the primary benefit was observed in advanced RCC (stage III–IV), with 5-year survival increasing from 9.8% in 2004 to 13.2% in 2010 for patients with distant metastatic disease. The results indicate that stage migration no longer contributes to improvements in survival for RCC, and additional gains reflect improvements in advanced treatment options,” they wrote in European Urology Oncology.

Dr. Patel and colleagues noted that the incidence of RCC has been on the rise worldwide for nearly 3 decades because of both environmental risk factors and improvements in medical imaging that have resulted in an increase in incidental cancers.

“Data from the National Cancer Database (NCDB) indicated an increase in the proportion of patients presenting with cT1 RCC from 40% before 1993 to 60% through 2004. However, it is unknown if clinical stage migration has continued into recent years, which has implications for patient outcomes,” they wrote.

To try to answer this question, they sifted through data on 262,597 patients diagnosed with RCC from 2004 through 2015 at more than 1,500 facilities covered by the U.S. National Cancer Database.

They found that, up to 2007, there were statistically significant trends toward more frequent diagnosis of clinical stage I disease (70% of cases) and less frequent diagnoses of stage III (8%) and stage IV (11%; P less than .001 for all comparisons). From 2008 through 2015, however, the respective rates stabilized.

They also noticed a trend throughout the study period for decreased size of localized tumors at diagnosis, with a mean decrease of 0.22 cm for stage I lesions, and 1.24 cm for stage II tumors.

When they looked at 5-year overall survival by Kaplan-Meier analysis, they saw that it improved from 67.9% in 2004 to 72.3% in 2010. As noted before, most of the benefit was attributable to gains in survival among patients with stage III or IV disease.

In multivariable Cox proportional hazard models, diagnosis in recent years was a statistically significant predictor of improved survival, even after adjustment for stage distribution. In addition, receipt of systemic therapy was associated with improved survival, with a hazard ratio of 0.811 (P less than .001).

The authors acknowledged that a limitation of the findings is the reliance on the NCDB, which includes data on most cancer diagnoses in the United States, but is not a population-based sample.

No study funding source was reported. Dr. Patel and coauthors reported having no conflicts of interest to disclose.

SOURCE: Patel HD et al. Eur Urol Oncol. 2018 Sep 25. doi: 10.1016/j.euo.2018.08.023.
 

The oral, multitargeted tyrosine kinase inhibitor pazopanib (Votrient) is active and safe in patients with renal cell carcinoma and other neoplasms caused by von Hippel-Lindau disease, a phase 2 trial has found.

Eric Jonasch, MD, and his coinvestigators at the University of Texas MD Anderson Cancer Center, Houston, conducted the single-arm trial among 31 adult patients with clinical manifestations of von Hippel-Lindau disease, an autosomal dominant disorder that currently has no approved treatment.

All patients were treated with open-label pazopanib (800 mg daily with dose reductions permitted) for 24 weeks, with an option to continue thereafter. Pazopanib derives its antiangiogenic and antineoplastic activity from its selective inhibition of vascular endothelial growth factor receptors (VEGFR)–1, –2, and –3; c-KIT; and platelet-derived growth factor receptor (PDGFR). It is currently approved by the FDA for treatment of advanced renal cell carcinoma and advanced soft-tissue sarcoma.

The trial was stopped before attaining planned enrollment because accrual slowed and it met a prespecified toxicity stopping threshold, according to results reported in Lancet Oncology.

At a median follow-up of 12 months, 42% of patients overall had an objective response to pazopanib. By site, response was seen in 52% of 59 renal cell carcinomas, 53% of 17 pancreatic lesions (mainly serous cystadenomas), and 4% of 49 CNS hemangioblastomas; the median reduction in tumor size was 40.5%, 30.5%, and 13%, respectively.

Slightly more than half of patients, 52%, opted to stay on pazopanib after 24 weeks, with the longest duration being 60 months at data cutoff.

Some 13% of patients withdrew from the study because of grade 3 or 4 transaminitis, and 10% stopped treatment because of general intolerance related to multiple grade 1 and 2 toxicities. There were three treatment-related serious adverse events: one case of appendicitis, one case of gastritis, and one case of fatal CNS bleeding after a fall.

“Pazopanib was associated with encouraging preliminary activity in von Hippel-Lindau disease, with a side effect profile consistent with that seen in previous trials,” the investigators concluded. “Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients.”

Dr. Jonasch disclosed that he receives research support and honoraria from Novartis. The study was funded by Novartis and by a National Institutes of Health National Cancer Institute core grant.

SOURCE: Jonasch E et al. Lancet Oncol. 2018 Sep 17. doi: 10.1016/S1470-2045(18)30487-X,

The oral, multitargeted tyrosine kinase inhibitor pazopanib (Votrient) is active and safe in patients with renal cell carcinoma and other neoplasms caused by von Hippel-Lindau disease, a phase 2 trial has found.

Eric Jonasch, MD, and his coinvestigators at the University of Texas MD Anderson Cancer Center, Houston, conducted the single-arm trial among 31 adult patients with clinical manifestations of von Hippel-Lindau disease, an autosomal dominant disorder that currently has no approved treatment.

All patients were treated with open-label pazopanib (800 mg daily with dose reductions permitted) for 24 weeks, with an option to continue thereafter. Pazopanib derives its antiangiogenic and antineoplastic activity from its selective inhibition of vascular endothelial growth factor receptors (VEGFR)–1, –2, and –3; c-KIT; and platelet-derived growth factor receptor (PDGFR). It is currently approved by the FDA for treatment of advanced renal cell carcinoma and advanced soft-tissue sarcoma.

The trial was stopped before attaining planned enrollment because accrual slowed and it met a prespecified toxicity stopping threshold, according to results reported in Lancet Oncology.

At a median follow-up of 12 months, 42% of patients overall had an objective response to pazopanib. By site, response was seen in 52% of 59 renal cell carcinomas, 53% of 17 pancreatic lesions (mainly serous cystadenomas), and 4% of 49 CNS hemangioblastomas; the median reduction in tumor size was 40.5%, 30.5%, and 13%, respectively.

Slightly more than half of patients, 52%, opted to stay on pazopanib after 24 weeks, with the longest duration being 60 months at data cutoff.

Some 13% of patients withdrew from the study because of grade 3 or 4 transaminitis, and 10% stopped treatment because of general intolerance related to multiple grade 1 and 2 toxicities. There were three treatment-related serious adverse events: one case of appendicitis, one case of gastritis, and one case of fatal CNS bleeding after a fall.

“Pazopanib was associated with encouraging preliminary activity in von Hippel-Lindau disease, with a side effect profile consistent with that seen in previous trials,” the investigators concluded. “Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients.”

Dr. Jonasch disclosed that he receives research support and honoraria from Novartis. The study was funded by Novartis and by a National Institutes of Health National Cancer Institute core grant.

SOURCE: Jonasch E et al. Lancet Oncol. 2018 Sep 17. doi: 10.1016/S1470-2045(18)30487-X,

The oral, multitargeted tyrosine kinase inhibitor pazopanib (Votrient) is active and safe in patients with renal cell carcinoma and other neoplasms caused by von Hippel-Lindau disease, a phase 2 trial has found.

Eric Jonasch, MD, and his coinvestigators at the University of Texas MD Anderson Cancer Center, Houston, conducted the single-arm trial among 31 adult patients with clinical manifestations of von Hippel-Lindau disease, an autosomal dominant disorder that currently has no approved treatment.

All patients were treated with open-label pazopanib (800 mg daily with dose reductions permitted) for 24 weeks, with an option to continue thereafter. Pazopanib derives its antiangiogenic and antineoplastic activity from its selective inhibition of vascular endothelial growth factor receptors (VEGFR)–1, –2, and –3; c-KIT; and platelet-derived growth factor receptor (PDGFR). It is currently approved by the FDA for treatment of advanced renal cell carcinoma and advanced soft-tissue sarcoma.

The trial was stopped before attaining planned enrollment because accrual slowed and it met a prespecified toxicity stopping threshold, according to results reported in Lancet Oncology.

At a median follow-up of 12 months, 42% of patients overall had an objective response to pazopanib. By site, response was seen in 52% of 59 renal cell carcinomas, 53% of 17 pancreatic lesions (mainly serous cystadenomas), and 4% of 49 CNS hemangioblastomas; the median reduction in tumor size was 40.5%, 30.5%, and 13%, respectively.

Slightly more than half of patients, 52%, opted to stay on pazopanib after 24 weeks, with the longest duration being 60 months at data cutoff.

Some 13% of patients withdrew from the study because of grade 3 or 4 transaminitis, and 10% stopped treatment because of general intolerance related to multiple grade 1 and 2 toxicities. There were three treatment-related serious adverse events: one case of appendicitis, one case of gastritis, and one case of fatal CNS bleeding after a fall.

“Pazopanib was associated with encouraging preliminary activity in von Hippel-Lindau disease, with a side effect profile consistent with that seen in previous trials,” the investigators concluded. “Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients.”

Dr. Jonasch disclosed that he receives research support and honoraria from Novartis. The study was funded by Novartis and by a National Institutes of Health National Cancer Institute core grant.

SOURCE: Jonasch E et al. Lancet Oncol. 2018 Sep 17. doi: 10.1016/S1470-2045(18)30487-X,

Radiofrequency ablation (RFA) of small renal tumors is safe and effective, and is associated with high rates of disease-free survival, according to a study that followed patients for up to 10 years.

In 106 patients who had a total of 112 tumors and who were followed for a median 79 months, 10 recurrences were seen, after an initial procedural success rate of 97%.

Over a 6-year period, Kaplan-Meier disease-free survival (DFS) was 89%, and cancer-specific survival (CSS) was 96%. In the subgroup followed for 10 years, DFS was 82%, CSS was 94%, and overall survival (OS) was 49%.

Tumors were, on average, small (mean 2.5 cm), but for patients whose tumors were larger than 3 cm, the DFS rate fell to 68%. Patients were included in the study if they had a solitary renal mass; those who had metastatic renal cell carcinoma (RCC) or a hereditary kidney cancer syndrome were excluded.

Brett Johnson, MD, and his collaborators from the University of Texas Southwestern, Dallas, noted that an additional 29 patients received RFA but also had partial nephrectomy; these patients were excluded. “Healthier patients with larger tumors may have been advised to undergo partial nephrectomy, thereby selecting for more comorbid patients for RFA,” they noted in discussing their findings. The report was published in The Journal of Urology

Within these parameters, Dr. Johnson and his colleagues conducted a retrospective review of clinic patients whose renal tumors were successfully treated with RFA between the years 2000 and 2007. Patients were followed with yearly imaging, and were considered to have a recurrence if contrast enhancement was seen within the ablation zone at any point after a negative imaging study.

Of the 10 recurrences that were seen, eight were local and two were local and metastatic. An additional patient developed metastatic RCC without evidence of local recurrence; all patients with metastases died of their disease, said Dr. Johnson and his coauthors.

For patients whose tumors recurred, the mean initial tumor size was 3.2 cm, compared with 2.4 cm in those whose tumors didn’t recur (P = .005). Looking at the tumor size data another way, tumor size “was an independent risk factor for cancer recurrence,” with an odds ratio of 3.01 (P = .025), wrote Dr. Johnson and his collaborators.

They noted that it was not routine practice for biopsies to be performed during the initial study period; the seven patients with recurrences who had biopsy data all had clear cell RCC. Median time to local recurrence was 26 months, with no recurrences seen after 5 years.

At the time of the initial procedure, patients were a mean 63.1 years old. The relatively low OS in the subgroup with 10 years of follow-up was likely related to advancing age.

In the subgroup analysis of patients for whom 10-year data were available, the investigators used only data from patients whose initial tumors were biopsied when calculating CSS and metastasis-free survival; these rates were both 94% for those analyzed.

“Age, gender, and time of follow-up had no statistically significant effect on disease-free recurrence” in a univariate analysis, said Dr. Johnson and his colleagues.

“Nephron sparing surgery is the gold standard for treatment of small renal masses,” and the study bolsters the safety and durable efficacy of RFA by using actual survival data rather than actuarial disease survival, said the investigators.

The current study is unique in having such a long duration of follow-up and a subgroup of individuals with 10 years of annual imaging data. In addition, experienced urologists at a single site all used a uniform technique to perform thermal ablation on solitary tumors, noted Dr. Johnson and his coauthors. Successful ablations were followed only by surveillance, in keeping with current American Urological Association recommendations.

However, the study’s retrospective, nonrandomized nature introduces the possibility of selection bias, and variations in follow-up protocols may be a source of ascertainment bias, they said.

The authors reported no conflicts of interest and no outside sources of funding.

SOURCE: Johnson B et al. J Urol. 2018. doi:10.1016/j.juro.2018.08.045.

Radiofrequency ablation (RFA) of small renal tumors is safe and effective, and is associated with high rates of disease-free survival, according to a study that followed patients for up to 10 years.

In 106 patients who had a total of 112 tumors and who were followed for a median 79 months, 10 recurrences were seen, after an initial procedural success rate of 97%.

Over a 6-year period, Kaplan-Meier disease-free survival (DFS) was 89%, and cancer-specific survival (CSS) was 96%. In the subgroup followed for 10 years, DFS was 82%, CSS was 94%, and overall survival (OS) was 49%.

Tumors were, on average, small (mean 2.5 cm), but for patients whose tumors were larger than 3 cm, the DFS rate fell to 68%. Patients were included in the study if they had a solitary renal mass; those who had metastatic renal cell carcinoma (RCC) or a hereditary kidney cancer syndrome were excluded.

Brett Johnson, MD, and his collaborators from the University of Texas Southwestern, Dallas, noted that an additional 29 patients received RFA but also had partial nephrectomy; these patients were excluded. “Healthier patients with larger tumors may have been advised to undergo partial nephrectomy, thereby selecting for more comorbid patients for RFA,” they noted in discussing their findings. The report was published in The Journal of Urology

Within these parameters, Dr. Johnson and his colleagues conducted a retrospective review of clinic patients whose renal tumors were successfully treated with RFA between the years 2000 and 2007. Patients were followed with yearly imaging, and were considered to have a recurrence if contrast enhancement was seen within the ablation zone at any point after a negative imaging study.

Of the 10 recurrences that were seen, eight were local and two were local and metastatic. An additional patient developed metastatic RCC without evidence of local recurrence; all patients with metastases died of their disease, said Dr. Johnson and his coauthors.

For patients whose tumors recurred, the mean initial tumor size was 3.2 cm, compared with 2.4 cm in those whose tumors didn’t recur (P = .005). Looking at the tumor size data another way, tumor size “was an independent risk factor for cancer recurrence,” with an odds ratio of 3.01 (P = .025), wrote Dr. Johnson and his collaborators.

They noted that it was not routine practice for biopsies to be performed during the initial study period; the seven patients with recurrences who had biopsy data all had clear cell RCC. Median time to local recurrence was 26 months, with no recurrences seen after 5 years.

At the time of the initial procedure, patients were a mean 63.1 years old. The relatively low OS in the subgroup with 10 years of follow-up was likely related to advancing age.

In the subgroup analysis of patients for whom 10-year data were available, the investigators used only data from patients whose initial tumors were biopsied when calculating CSS and metastasis-free survival; these rates were both 94% for those analyzed.

“Age, gender, and time of follow-up had no statistically significant effect on disease-free recurrence” in a univariate analysis, said Dr. Johnson and his colleagues.

“Nephron sparing surgery is the gold standard for treatment of small renal masses,” and the study bolsters the safety and durable efficacy of RFA by using actual survival data rather than actuarial disease survival, said the investigators.

The current study is unique in having such a long duration of follow-up and a subgroup of individuals with 10 years of annual imaging data. In addition, experienced urologists at a single site all used a uniform technique to perform thermal ablation on solitary tumors, noted Dr. Johnson and his coauthors. Successful ablations were followed only by surveillance, in keeping with current American Urological Association recommendations.

However, the study’s retrospective, nonrandomized nature introduces the possibility of selection bias, and variations in follow-up protocols may be a source of ascertainment bias, they said.

The authors reported no conflicts of interest and no outside sources of funding.

SOURCE: Johnson B et al. J Urol. 2018. doi:10.1016/j.juro.2018.08.045.

Radiofrequency ablation (RFA) of small renal tumors is safe and effective, and is associated with high rates of disease-free survival, according to a study that followed patients for up to 10 years.

In 106 patients who had a total of 112 tumors and who were followed for a median 79 months, 10 recurrences were seen, after an initial procedural success rate of 97%.

Over a 6-year period, Kaplan-Meier disease-free survival (DFS) was 89%, and cancer-specific survival (CSS) was 96%. In the subgroup followed for 10 years, DFS was 82%, CSS was 94%, and overall survival (OS) was 49%.

Tumors were, on average, small (mean 2.5 cm), but for patients whose tumors were larger than 3 cm, the DFS rate fell to 68%. Patients were included in the study if they had a solitary renal mass; those who had metastatic renal cell carcinoma (RCC) or a hereditary kidney cancer syndrome were excluded.

Brett Johnson, MD, and his collaborators from the University of Texas Southwestern, Dallas, noted that an additional 29 patients received RFA but also had partial nephrectomy; these patients were excluded. “Healthier patients with larger tumors may have been advised to undergo partial nephrectomy, thereby selecting for more comorbid patients for RFA,” they noted in discussing their findings. The report was published in The Journal of Urology

Within these parameters, Dr. Johnson and his colleagues conducted a retrospective review of clinic patients whose renal tumors were successfully treated with RFA between the years 2000 and 2007. Patients were followed with yearly imaging, and were considered to have a recurrence if contrast enhancement was seen within the ablation zone at any point after a negative imaging study.

Of the 10 recurrences that were seen, eight were local and two were local and metastatic. An additional patient developed metastatic RCC without evidence of local recurrence; all patients with metastases died of their disease, said Dr. Johnson and his coauthors.

For patients whose tumors recurred, the mean initial tumor size was 3.2 cm, compared with 2.4 cm in those whose tumors didn’t recur (P = .005). Looking at the tumor size data another way, tumor size “was an independent risk factor for cancer recurrence,” with an odds ratio of 3.01 (P = .025), wrote Dr. Johnson and his collaborators.

They noted that it was not routine practice for biopsies to be performed during the initial study period; the seven patients with recurrences who had biopsy data all had clear cell RCC. Median time to local recurrence was 26 months, with no recurrences seen after 5 years.

At the time of the initial procedure, patients were a mean 63.1 years old. The relatively low OS in the subgroup with 10 years of follow-up was likely related to advancing age.

In the subgroup analysis of patients for whom 10-year data were available, the investigators used only data from patients whose initial tumors were biopsied when calculating CSS and metastasis-free survival; these rates were both 94% for those analyzed.

“Age, gender, and time of follow-up had no statistically significant effect on disease-free recurrence” in a univariate analysis, said Dr. Johnson and his colleagues.

“Nephron sparing surgery is the gold standard for treatment of small renal masses,” and the study bolsters the safety and durable efficacy of RFA by using actual survival data rather than actuarial disease survival, said the investigators.

The current study is unique in having such a long duration of follow-up and a subgroup of individuals with 10 years of annual imaging data. In addition, experienced urologists at a single site all used a uniform technique to perform thermal ablation on solitary tumors, noted Dr. Johnson and his coauthors. Successful ablations were followed only by surveillance, in keeping with current American Urological Association recommendations.

However, the study’s retrospective, nonrandomized nature introduces the possibility of selection bias, and variations in follow-up protocols may be a source of ascertainment bias, they said.

The authors reported no conflicts of interest and no outside sources of funding.

SOURCE: Johnson B et al. J Urol. 2018. doi:10.1016/j.juro.2018.08.045.

SAN FRANCISCO – Partial nephrectomy for localized renal cell carcinomas (RCCs) is on the rise, but the procedure is still less commonly performed than radical nephrectomy and more commonly performed at high-volume surgical centers.

About half of localized renal tumors are excised through partial nephrectomy, based on results from a new analysis of The National Cancer Database. The study also indicated that patient mortality rates were lower at high volume centers, those in the top 10 percentile of treatment volume, said David Cahn, DO, who presented the results at the annual meeting of the American Urological Association.

The study looked at surgeries among 142,000 patients with pT1a-T2b RCCs (no involvement of lymph nodes or metastases) who underwent procedures during 2004-2014.

Overall, 41% of patients had partial nephrectomies, 58% had radical nephrectomies, and 1% received ablative therapy. The frequency of partial nephrectomies rose markedly over the course of the study, increasing from 24% of cases in 2004 to 53% in 2014. The vast majority of partial nephrectomies, 81%, were performed for pT1a tumors; 24% of pT1b tumors also were excised using partial nephrectomy.

Compared with the reference point of T1a tumors, T1b tumors (odds ratio, 0.22; P less than .0001), T2a (OR, 0.06; P less than .0001), and T2b tumors (OR, 0.03; P less than .0001) were progressively less likely to be treated with partial nephrectomy. A multivariate analysis showed that patients at a high volume center were significantly more likely to undergo partial nephrectomy (OR, 1.89; P less than .0001). Overall mortality was lower at high volume centers (hazard ratio, 0.92; P = .012).

SOURCE: AUA Annual Meeting, Abstract PD07-04.

SAN FRANCISCO – Partial nephrectomy for localized renal cell carcinomas (RCCs) is on the rise, but the procedure is still less commonly performed than radical nephrectomy and more commonly performed at high-volume surgical centers.

About half of localized renal tumors are excised through partial nephrectomy, based on results from a new analysis of The National Cancer Database. The study also indicated that patient mortality rates were lower at high volume centers, those in the top 10 percentile of treatment volume, said David Cahn, DO, who presented the results at the annual meeting of the American Urological Association.

The study looked at surgeries among 142,000 patients with pT1a-T2b RCCs (no involvement of lymph nodes or metastases) who underwent procedures during 2004-2014.

Overall, 41% of patients had partial nephrectomies, 58% had radical nephrectomies, and 1% received ablative therapy. The frequency of partial nephrectomies rose markedly over the course of the study, increasing from 24% of cases in 2004 to 53% in 2014. The vast majority of partial nephrectomies, 81%, were performed for pT1a tumors; 24% of pT1b tumors also were excised using partial nephrectomy.

Compared with the reference point of T1a tumors, T1b tumors (odds ratio, 0.22; P less than .0001), T2a (OR, 0.06; P less than .0001), and T2b tumors (OR, 0.03; P less than .0001) were progressively less likely to be treated with partial nephrectomy. A multivariate analysis showed that patients at a high volume center were significantly more likely to undergo partial nephrectomy (OR, 1.89; P less than .0001). Overall mortality was lower at high volume centers (hazard ratio, 0.92; P = .012).

SOURCE: AUA Annual Meeting, Abstract PD07-04.

SAN FRANCISCO – Partial nephrectomy for localized renal cell carcinomas (RCCs) is on the rise, but the procedure is still less commonly performed than radical nephrectomy and more commonly performed at high-volume surgical centers.

About half of localized renal tumors are excised through partial nephrectomy, based on results from a new analysis of The National Cancer Database. The study also indicated that patient mortality rates were lower at high volume centers, those in the top 10 percentile of treatment volume, said David Cahn, DO, who presented the results at the annual meeting of the American Urological Association.

The study looked at surgeries among 142,000 patients with pT1a-T2b RCCs (no involvement of lymph nodes or metastases) who underwent procedures during 2004-2014.

Overall, 41% of patients had partial nephrectomies, 58% had radical nephrectomies, and 1% received ablative therapy. The frequency of partial nephrectomies rose markedly over the course of the study, increasing from 24% of cases in 2004 to 53% in 2014. The vast majority of partial nephrectomies, 81%, were performed for pT1a tumors; 24% of pT1b tumors also were excised using partial nephrectomy.

Compared with the reference point of T1a tumors, T1b tumors (odds ratio, 0.22; P less than .0001), T2a (OR, 0.06; P less than .0001), and T2b tumors (OR, 0.03; P less than .0001) were progressively less likely to be treated with partial nephrectomy. A multivariate analysis showed that patients at a high volume center were significantly more likely to undergo partial nephrectomy (OR, 1.89; P less than .0001). Overall mortality was lower at high volume centers (hazard ratio, 0.92; P = .012).

SOURCE: AUA Annual Meeting, Abstract PD07-04.

In patients with renal cell carcinoma, high levels of the inflammation marker C-reactive protein may signal the presence of an immunosuppressive tumor microenvironment, a feature associated with poor prognosis, investigators contend.

Among 111 patients with renal cell carcinoma (RCC) treated with either partial or radical nephrectomy, those with high C-reactive protein (CRP) levels had significantly worse cancer-specific survival (CSS) compared with patients with normal CRP levels, and CRP levels were significantly higher among patients whose tumors showed strong infiltration of immune-suppressor cells, reported Takayuki Nakayama, MD, of Tokyo Medical and Dental Graduate University in Japan, and his colleagues.

“We have found that CRP level is positively associated with the infiltration of Treg and M2 macrophage[s] in patients with RCC, indicating that CRP reflects an immunosuppressive microenvironment. However, further studies are required to confirm these findings and provide a better understanding of the association between host systemic inflammation and the immunosuppressive microenvironment,” they wrote in Clinical Genitourinary Cancer.

The investigators had previously proposed CRP as a biomarker for urologic malignancies, including RCC. The current study was designed to look at the association between CRP and the tumor microenvironment, and to determine whether serum CRP levels correlate with prognosis.

To do this, they performed immunohistochemistry studies of immune cells, including immunosuppressive M2 macrophages (CD4, CD8, and CD163 cells) and Foxp4 regulatory T cells (Tregs) on resected renal tissues from 111 patients with RCC treated in their center.

They found that 33 of the 111 patients (30%) had high CRP levels, defined as 0.5 mg/L or greater. These patients had a 5-year CSS rate of 51%, compared with 91% for patients with CRP levels below the 0.5 mg/L cutoff (P less than .001).

They also found that tumors with strong infiltration of M2 macrophages had significantly worse disease and poorer prognoses. For example, patients with strong infiltration of CD163-positive cells had higher tumor and nodal stages, as well as higher rates of distant metastases and higher Fuhrman nuclear grade (respective P values less than .001, = .003, less than .001, and = .008).

CRP levels were significantly higher among patients with strong infiltration of CD8-positive cells (P = .041), Foxp3-positive cells (P = .001), or CD163-positive (P = .035). These patients also had significantly worse CSS compared with patients with weak tumor infiltration of the respective cells (P = .040, P = .026, and P less than .001, respectively).

Independent prognostic factors for CSS in multivariate analysis included strong CD163-positive cell infiltration (P =.001), pathologic stage T3 (P = .036), lymph-node involvement (P = .007), distant metastasis (P less than .001), and Fuhrman nuclear grade 4 (P = .003).

The authors acknowledged that the study was limited by its retrospective design, small sample size, and limited analysis of components of the tumor microenvironment.

The study was supported by the Japan Society for the Promotion of Science. The authors reported having no conflicts of interest to disclose.

SOURCE: Nakayama T et al. Clin Genitourin Cancer. 2018 Aug 11. doi: 10.1016/j.clgc.2018.07.027.

In patients with renal cell carcinoma, high levels of the inflammation marker C-reactive protein may signal the presence of an immunosuppressive tumor microenvironment, a feature associated with poor prognosis, investigators contend.

Among 111 patients with renal cell carcinoma (RCC) treated with either partial or radical nephrectomy, those with high C-reactive protein (CRP) levels had significantly worse cancer-specific survival (CSS) compared with patients with normal CRP levels, and CRP levels were significantly higher among patients whose tumors showed strong infiltration of immune-suppressor cells, reported Takayuki Nakayama, MD, of Tokyo Medical and Dental Graduate University in Japan, and his colleagues.

“We have found that CRP level is positively associated with the infiltration of Treg and M2 macrophage[s] in patients with RCC, indicating that CRP reflects an immunosuppressive microenvironment. However, further studies are required to confirm these findings and provide a better understanding of the association between host systemic inflammation and the immunosuppressive microenvironment,” they wrote in Clinical Genitourinary Cancer.

The investigators had previously proposed CRP as a biomarker for urologic malignancies, including RCC. The current study was designed to look at the association between CRP and the tumor microenvironment, and to determine whether serum CRP levels correlate with prognosis.

To do this, they performed immunohistochemistry studies of immune cells, including immunosuppressive M2 macrophages (CD4, CD8, and CD163 cells) and Foxp4 regulatory T cells (Tregs) on resected renal tissues from 111 patients with RCC treated in their center.

They found that 33 of the 111 patients (30%) had high CRP levels, defined as 0.5 mg/L or greater. These patients had a 5-year CSS rate of 51%, compared with 91% for patients with CRP levels below the 0.5 mg/L cutoff (P less than .001).

They also found that tumors with strong infiltration of M2 macrophages had significantly worse disease and poorer prognoses. For example, patients with strong infiltration of CD163-positive cells had higher tumor and nodal stages, as well as higher rates of distant metastases and higher Fuhrman nuclear grade (respective P values less than .001, = .003, less than .001, and = .008).

CRP levels were significantly higher among patients with strong infiltration of CD8-positive cells (P = .041), Foxp3-positive cells (P = .001), or CD163-positive (P = .035). These patients also had significantly worse CSS compared with patients with weak tumor infiltration of the respective cells (P = .040, P = .026, and P less than .001, respectively).

Independent prognostic factors for CSS in multivariate analysis included strong CD163-positive cell infiltration (P =.001), pathologic stage T3 (P = .036), lymph-node involvement (P = .007), distant metastasis (P less than .001), and Fuhrman nuclear grade 4 (P = .003).

The authors acknowledged that the study was limited by its retrospective design, small sample size, and limited analysis of components of the tumor microenvironment.

The study was supported by the Japan Society for the Promotion of Science. The authors reported having no conflicts of interest to disclose.

SOURCE: Nakayama T et al. Clin Genitourin Cancer. 2018 Aug 11. doi: 10.1016/j.clgc.2018.07.027.

In patients with renal cell carcinoma, high levels of the inflammation marker C-reactive protein may signal the presence of an immunosuppressive tumor microenvironment, a feature associated with poor prognosis, investigators contend.

Among 111 patients with renal cell carcinoma (RCC) treated with either partial or radical nephrectomy, those with high C-reactive protein (CRP) levels had significantly worse cancer-specific survival (CSS) compared with patients with normal CRP levels, and CRP levels were significantly higher among patients whose tumors showed strong infiltration of immune-suppressor cells, reported Takayuki Nakayama, MD, of Tokyo Medical and Dental Graduate University in Japan, and his colleagues.

“We have found that CRP level is positively associated with the infiltration of Treg and M2 macrophage[s] in patients with RCC, indicating that CRP reflects an immunosuppressive microenvironment. However, further studies are required to confirm these findings and provide a better understanding of the association between host systemic inflammation and the immunosuppressive microenvironment,” they wrote in Clinical Genitourinary Cancer.

The investigators had previously proposed CRP as a biomarker for urologic malignancies, including RCC. The current study was designed to look at the association between CRP and the tumor microenvironment, and to determine whether serum CRP levels correlate with prognosis.

To do this, they performed immunohistochemistry studies of immune cells, including immunosuppressive M2 macrophages (CD4, CD8, and CD163 cells) and Foxp4 regulatory T cells (Tregs) on resected renal tissues from 111 patients with RCC treated in their center.

They found that 33 of the 111 patients (30%) had high CRP levels, defined as 0.5 mg/L or greater. These patients had a 5-year CSS rate of 51%, compared with 91% for patients with CRP levels below the 0.5 mg/L cutoff (P less than .001).

They also found that tumors with strong infiltration of M2 macrophages had significantly worse disease and poorer prognoses. For example, patients with strong infiltration of CD163-positive cells had higher tumor and nodal stages, as well as higher rates of distant metastases and higher Fuhrman nuclear grade (respective P values less than .001, = .003, less than .001, and = .008).

CRP levels were significantly higher among patients with strong infiltration of CD8-positive cells (P = .041), Foxp3-positive cells (P = .001), or CD163-positive (P = .035). These patients also had significantly worse CSS compared with patients with weak tumor infiltration of the respective cells (P = .040, P = .026, and P less than .001, respectively).

Independent prognostic factors for CSS in multivariate analysis included strong CD163-positive cell infiltration (P =.001), pathologic stage T3 (P = .036), lymph-node involvement (P = .007), distant metastasis (P less than .001), and Fuhrman nuclear grade 4 (P = .003).

The authors acknowledged that the study was limited by its retrospective design, small sample size, and limited analysis of components of the tumor microenvironment.

The study was supported by the Japan Society for the Promotion of Science. The authors reported having no conflicts of interest to disclose.

SOURCE: Nakayama T et al. Clin Genitourin Cancer. 2018 Aug 11. doi: 10.1016/j.clgc.2018.07.027.

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with oligometastatic renal cell carcinoma (RCC), according to investigators.

Patients with clear cell RCC who had previously received systemic therapy were more likely to achieve local control, reported Ciro Franzese, MD of Humanitas Clinical and Research Center in Milan, and his coauthors.

These findings contribute to a shifting landscape in RCC; modern techniques are opening doors once closed by disappointing historical results. Several recent SBRT studies have demonstrated local control rates of approximately 90%, compared with conventional RT rates of 20%.

“While the outcomes from conventional RT were quite poor, with SBRT, different biological mechanisms occur due to the use of higher doses per fraction,” the authors wrote in The Journal of Urology.

The present retrospective study involved 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006. Patients previously underwent primary tumor excision, had no greater than three distant extracranial metastases, and were not surgical candidates. Study endpoints included median overall survival (OS), progression-free survival (PFS), and in-field local control (LC). Stratified analysis was also performed in patients with clear cell RCC.

Just over 90% of patients achieved LC at 18 months. Slightly less than half (46.2%) were progression-free at 1 year, and this number dropped to one-third (35%) by 18 months. Median OS was just over 2 years (28 months). Although all patients (100%) were alive at 2 years, this rate dropped to 83% by the 5-year mark.

In patients with clear cell RCC, those treated with systemic therapy prior to SBRT were more likely to achieve LC compared with patients who did not receive systemic therapy (HR 0.15; P = .032).

Overall, SBRT was well tolerated. No grade 3 or higher adverse events occurred. The most common adverse events were pain, fatigue, nausea, and vomiting.

The authors concluded that SBRT is a safe and effective option for patients with oligometastatic RCC. They called for future research to address “the radiobiology of RCC” in order to “understand the role of SBRT and, particularly, its possible interaction with medical therapies.”

The authors reported no conflicts of interest.

SOURCE: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with oligometastatic renal cell carcinoma (RCC), according to investigators.

Patients with clear cell RCC who had previously received systemic therapy were more likely to achieve local control, reported Ciro Franzese, MD of Humanitas Clinical and Research Center in Milan, and his coauthors.

These findings contribute to a shifting landscape in RCC; modern techniques are opening doors once closed by disappointing historical results. Several recent SBRT studies have demonstrated local control rates of approximately 90%, compared with conventional RT rates of 20%.

“While the outcomes from conventional RT were quite poor, with SBRT, different biological mechanisms occur due to the use of higher doses per fraction,” the authors wrote in The Journal of Urology.

The present retrospective study involved 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006. Patients previously underwent primary tumor excision, had no greater than three distant extracranial metastases, and were not surgical candidates. Study endpoints included median overall survival (OS), progression-free survival (PFS), and in-field local control (LC). Stratified analysis was also performed in patients with clear cell RCC.

Just over 90% of patients achieved LC at 18 months. Slightly less than half (46.2%) were progression-free at 1 year, and this number dropped to one-third (35%) by 18 months. Median OS was just over 2 years (28 months). Although all patients (100%) were alive at 2 years, this rate dropped to 83% by the 5-year mark.

In patients with clear cell RCC, those treated with systemic therapy prior to SBRT were more likely to achieve LC compared with patients who did not receive systemic therapy (HR 0.15; P = .032).

Overall, SBRT was well tolerated. No grade 3 or higher adverse events occurred. The most common adverse events were pain, fatigue, nausea, and vomiting.

The authors concluded that SBRT is a safe and effective option for patients with oligometastatic RCC. They called for future research to address “the radiobiology of RCC” in order to “understand the role of SBRT and, particularly, its possible interaction with medical therapies.”

The authors reported no conflicts of interest.

SOURCE: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with oligometastatic renal cell carcinoma (RCC), according to investigators.

Patients with clear cell RCC who had previously received systemic therapy were more likely to achieve local control, reported Ciro Franzese, MD of Humanitas Clinical and Research Center in Milan, and his coauthors.

These findings contribute to a shifting landscape in RCC; modern techniques are opening doors once closed by disappointing historical results. Several recent SBRT studies have demonstrated local control rates of approximately 90%, compared with conventional RT rates of 20%.

“While the outcomes from conventional RT were quite poor, with SBRT, different biological mechanisms occur due to the use of higher doses per fraction,” the authors wrote in The Journal of Urology.

The present retrospective study involved 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006. Patients previously underwent primary tumor excision, had no greater than three distant extracranial metastases, and were not surgical candidates. Study endpoints included median overall survival (OS), progression-free survival (PFS), and in-field local control (LC). Stratified analysis was also performed in patients with clear cell RCC.

Just over 90% of patients achieved LC at 18 months. Slightly less than half (46.2%) were progression-free at 1 year, and this number dropped to one-third (35%) by 18 months. Median OS was just over 2 years (28 months). Although all patients (100%) were alive at 2 years, this rate dropped to 83% by the 5-year mark.

In patients with clear cell RCC, those treated with systemic therapy prior to SBRT were more likely to achieve LC compared with patients who did not receive systemic therapy (HR 0.15; P = .032).

Overall, SBRT was well tolerated. No grade 3 or higher adverse events occurred. The most common adverse events were pain, fatigue, nausea, and vomiting.

The authors concluded that SBRT is a safe and effective option for patients with oligometastatic RCC. They called for future research to address “the radiobiology of RCC” in order to “understand the role of SBRT and, particularly, its possible interaction with medical therapies.”

The authors reported no conflicts of interest.

SOURCE: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.

The use of tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib to treat metastatic clear cell renal cell carcinoma (RCC) is feasible and effective in Brazil, even though limitations of the public health system mean not all patients have access to these or other therapies, researchers wrote.

In a retrospective analysis of 222 patients with advanced clear cell RCC who were treated with either sunitinib (n = 109) or pazopanib (n = 113), overall survival was 15.2 months with sunitinib and 14.2 months with pazopanib, investigators reported in the Journal of Global Oncology.

Overall survival rates, based on Memorial Sloan Kettering Cancer Center risk categories, were 32.9 months for patients with low risk disease, 15.9 months for intermediate risk patients, and 8.1 months for patient with poor risk – which constituted 29% of the patient population.

Pedro I. Velho, MD, of Johns Hopkins University, Baltimore, and his coauthors noted that these survival rates were lower than those seen in phase 3 trials in the same population.

They suggested this could be caused by the fact that the patients in this real-world study had worse baseline prognoses than those seen in previous clinical trials.

However, they also pointed out that, in the Brazilian public health system, there was no standard systemic treatment option outside clinical trials for patients who have progressed on a TKI as a first-line treatment. Only around half the patients in this study (101) would have been eligible for participation in a clinical trial.

“In our opinion, it is crucial to extend the access to these TKIs for the Brazilian population and also patients in other countries with limited access to targeted therapies,” the authors wrote.

However, the 14 patients who were eligible for treatment with nivolumab under a compassionate use program showed a significantly better overall survival rate, compared with patients who did not have access to a second-line therapy (36.7 months vs. 13.6 months; P less than .001).

“Also, it is imperative to provide systemic sequential treatment options for this population as an attempt to improve survival and offer the best outcomes for patients with metastatic RCC.”

The median duration of treatment with sunitinib was 6.4 months, and with pazopanib, it was 6.7 months. Adverse events were responsible for discontinuation of treatment in 28.4% of patients on sunitinib and 22.1% of patients on pazopanib, with fatigue, diarrhea, nausea and vomiting as the most common toxicities in both groups.

Six authors declared honoraria, funding, expenses or consultancies with the pharmaceutical industry. Two authors had no conflicts of interest to declare.

SOURCE: Velho PI et al. J Glob Oncol. 2018 Sep 10. doi: 10.1200/JGO.18.00073.

The use of tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib to treat metastatic clear cell renal cell carcinoma (RCC) is feasible and effective in Brazil, even though limitations of the public health system mean not all patients have access to these or other therapies, researchers wrote.

In a retrospective analysis of 222 patients with advanced clear cell RCC who were treated with either sunitinib (n = 109) or pazopanib (n = 113), overall survival was 15.2 months with sunitinib and 14.2 months with pazopanib, investigators reported in the Journal of Global Oncology.

Overall survival rates, based on Memorial Sloan Kettering Cancer Center risk categories, were 32.9 months for patients with low risk disease, 15.9 months for intermediate risk patients, and 8.1 months for patient with poor risk – which constituted 29% of the patient population.

Pedro I. Velho, MD, of Johns Hopkins University, Baltimore, and his coauthors noted that these survival rates were lower than those seen in phase 3 trials in the same population.

They suggested this could be caused by the fact that the patients in this real-world study had worse baseline prognoses than those seen in previous clinical trials.

However, they also pointed out that, in the Brazilian public health system, there was no standard systemic treatment option outside clinical trials for patients who have progressed on a TKI as a first-line treatment. Only around half the patients in this study (101) would have been eligible for participation in a clinical trial.

“In our opinion, it is crucial to extend the access to these TKIs for the Brazilian population and also patients in other countries with limited access to targeted therapies,” the authors wrote.

However, the 14 patients who were eligible for treatment with nivolumab under a compassionate use program showed a significantly better overall survival rate, compared with patients who did not have access to a second-line therapy (36.7 months vs. 13.6 months; P less than .001).

“Also, it is imperative to provide systemic sequential treatment options for this population as an attempt to improve survival and offer the best outcomes for patients with metastatic RCC.”

The median duration of treatment with sunitinib was 6.4 months, and with pazopanib, it was 6.7 months. Adverse events were responsible for discontinuation of treatment in 28.4% of patients on sunitinib and 22.1% of patients on pazopanib, with fatigue, diarrhea, nausea and vomiting as the most common toxicities in both groups.

Six authors declared honoraria, funding, expenses or consultancies with the pharmaceutical industry. Two authors had no conflicts of interest to declare.

SOURCE: Velho PI et al. J Glob Oncol. 2018 Sep 10. doi: 10.1200/JGO.18.00073.

The use of tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib to treat metastatic clear cell renal cell carcinoma (RCC) is feasible and effective in Brazil, even though limitations of the public health system mean not all patients have access to these or other therapies, researchers wrote.

In a retrospective analysis of 222 patients with advanced clear cell RCC who were treated with either sunitinib (n = 109) or pazopanib (n = 113), overall survival was 15.2 months with sunitinib and 14.2 months with pazopanib, investigators reported in the Journal of Global Oncology.

Overall survival rates, based on Memorial Sloan Kettering Cancer Center risk categories, were 32.9 months for patients with low risk disease, 15.9 months for intermediate risk patients, and 8.1 months for patient with poor risk – which constituted 29% of the patient population.

Pedro I. Velho, MD, of Johns Hopkins University, Baltimore, and his coauthors noted that these survival rates were lower than those seen in phase 3 trials in the same population.

They suggested this could be caused by the fact that the patients in this real-world study had worse baseline prognoses than those seen in previous clinical trials.

However, they also pointed out that, in the Brazilian public health system, there was no standard systemic treatment option outside clinical trials for patients who have progressed on a TKI as a first-line treatment. Only around half the patients in this study (101) would have been eligible for participation in a clinical trial.

“In our opinion, it is crucial to extend the access to these TKIs for the Brazilian population and also patients in other countries with limited access to targeted therapies,” the authors wrote.

However, the 14 patients who were eligible for treatment with nivolumab under a compassionate use program showed a significantly better overall survival rate, compared with patients who did not have access to a second-line therapy (36.7 months vs. 13.6 months; P less than .001).

“Also, it is imperative to provide systemic sequential treatment options for this population as an attempt to improve survival and offer the best outcomes for patients with metastatic RCC.”

The median duration of treatment with sunitinib was 6.4 months, and with pazopanib, it was 6.7 months. Adverse events were responsible for discontinuation of treatment in 28.4% of patients on sunitinib and 22.1% of patients on pazopanib, with fatigue, diarrhea, nausea and vomiting as the most common toxicities in both groups.

Six authors declared honoraria, funding, expenses or consultancies with the pharmaceutical industry. Two authors had no conflicts of interest to declare.

SOURCE: Velho PI et al. J Glob Oncol. 2018 Sep 10. doi: 10.1200/JGO.18.00073.

The combination of a targeted antiangiogenic agent and denosumab (Xgeva) appears to significantly increase the risk for osteonecrosis of the jaw in patients with metastatic renal cell carcinoma (mRCC), French investigators cautioned.

Among 41 patients with RCC metastatic to bone treated with an antiangiogenic agent and denosumab, 7 (17%) developed osteonecrosis of the jaw (ONJ). All seven received the combination in the first line, reported Aline Guillot, MD, from the Institut de cancérologie Lucien Neuwirth in Saint-Priest-en-Jarez, France, and her colleagues.

“The incidence of ONJ was high in this real-life population of patients with mRCC treated with antiangiogenic therapies combined with denosumab. This toxicity signal should warn physicians about this combination in the mRCC population,” they wrote in Clinical Genitourinary Cancer.

Previous studies have shown that the combination of another bone-targeted therapy – zoledronic acid – with antiangiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib (Sutent) is associated with increased risk for ONJ. In addition, ONJ with the combination of denosumab and antiangiogenic therapies “has been noticed but never estimated,” the authors noted.

To evaluate the incidence of hypocalcemia and ONJ in patients with RCC metastatic to bone treated with denosumab and a TKI or mammalian target of rapamycin inhibitor, the investigators gathered data retrospectively from 10 French centers.

They identified 25 men and 16 women with a median age of 62 years (range, 54-68 years). Of this group, 40 received denosumab in the first line in combination with either sunitinib (31 patients), pazopanib (6), everolimus (Afinitor and generics; 2), and temsirolimus (Torisel and generics; 1). The median duration of first-line therapy was 12 months.

Denosumab was given in the second line with axitinib (Inlyta) to nine patients, with everolimus to nine, and with sunitinib to three patients. The median duration of second-line therapy was 3 months.

Skeletal-related events occurred in 41% of patients prior to receiving denosumab and in 61% (25 patients) after denosumab. The events included clinical fracture, bone pain requiring radiation, and spinal compression.

Of the seven patients who developed ONJ, six received denosumab and sunitinib in the first line and one received denosumab plus temsirolimus, with a median duration of treatment of 11.8 months. Three of these patients also received denosumab in the second line with either axitinib, everolimus, or sunitinib, with a median duration of 9.8 months. Data on second-line therapy for the remaining four patients with ONJ were not available.

The investigators noted that the 17% incidence of ONJ was higher than the 10% rate seen in a study of patients with mRCC treated with a TKI and a bisphosphonate (Acta Clin Belg. 2018 Apr;73(2):100-9), and the 1.8% incidence seen in an analysis of three phase 3 trials in cancer patients with bone metastases (Ann Oncol. 2012 May;23(5):1341-7).

Although the etiology of ONJ is unknown, patient education and oral hygiene may reduce the risk in patients treated with denosumab and a TKI.

“The benefit of denosumab in this setting in regard [to] toxicity needs to be demonstrated in a prospective trial,” they wrote.

No conflicts of interest or disclosures were reported.

SOURCE: Guillot A et al. Clin Genitourin Cancer. 2018 Sep 6. doi: 10.1016/j.clgc.2018.08.006.

The combination of a targeted antiangiogenic agent and denosumab (Xgeva) appears to significantly increase the risk for osteonecrosis of the jaw in patients with metastatic renal cell carcinoma (mRCC), French investigators cautioned.

Among 41 patients with RCC metastatic to bone treated with an antiangiogenic agent and denosumab, 7 (17%) developed osteonecrosis of the jaw (ONJ). All seven received the combination in the first line, reported Aline Guillot, MD, from the Institut de cancérologie Lucien Neuwirth in Saint-Priest-en-Jarez, France, and her colleagues.

“The incidence of ONJ was high in this real-life population of patients with mRCC treated with antiangiogenic therapies combined with denosumab. This toxicity signal should warn physicians about this combination in the mRCC population,” they wrote in Clinical Genitourinary Cancer.

Previous studies have shown that the combination of another bone-targeted therapy – zoledronic acid – with antiangiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib (Sutent) is associated with increased risk for ONJ. In addition, ONJ with the combination of denosumab and antiangiogenic therapies “has been noticed but never estimated,” the authors noted.

To evaluate the incidence of hypocalcemia and ONJ in patients with RCC metastatic to bone treated with denosumab and a TKI or mammalian target of rapamycin inhibitor, the investigators gathered data retrospectively from 10 French centers.

They identified 25 men and 16 women with a median age of 62 years (range, 54-68 years). Of this group, 40 received denosumab in the first line in combination with either sunitinib (31 patients), pazopanib (6), everolimus (Afinitor and generics; 2), and temsirolimus (Torisel and generics; 1). The median duration of first-line therapy was 12 months.

Denosumab was given in the second line with axitinib (Inlyta) to nine patients, with everolimus to nine, and with sunitinib to three patients. The median duration of second-line therapy was 3 months.

Skeletal-related events occurred in 41% of patients prior to receiving denosumab and in 61% (25 patients) after denosumab. The events included clinical fracture, bone pain requiring radiation, and spinal compression.

Of the seven patients who developed ONJ, six received denosumab and sunitinib in the first line and one received denosumab plus temsirolimus, with a median duration of treatment of 11.8 months. Three of these patients also received denosumab in the second line with either axitinib, everolimus, or sunitinib, with a median duration of 9.8 months. Data on second-line therapy for the remaining four patients with ONJ were not available.

The investigators noted that the 17% incidence of ONJ was higher than the 10% rate seen in a study of patients with mRCC treated with a TKI and a bisphosphonate (Acta Clin Belg. 2018 Apr;73(2):100-9), and the 1.8% incidence seen in an analysis of three phase 3 trials in cancer patients with bone metastases (Ann Oncol. 2012 May;23(5):1341-7).

Although the etiology of ONJ is unknown, patient education and oral hygiene may reduce the risk in patients treated with denosumab and a TKI.

“The benefit of denosumab in this setting in regard [to] toxicity needs to be demonstrated in a prospective trial,” they wrote.

No conflicts of interest or disclosures were reported.

SOURCE: Guillot A et al. Clin Genitourin Cancer. 2018 Sep 6. doi: 10.1016/j.clgc.2018.08.006.

The combination of a targeted antiangiogenic agent and denosumab (Xgeva) appears to significantly increase the risk for osteonecrosis of the jaw in patients with metastatic renal cell carcinoma (mRCC), French investigators cautioned.

Among 41 patients with RCC metastatic to bone treated with an antiangiogenic agent and denosumab, 7 (17%) developed osteonecrosis of the jaw (ONJ). All seven received the combination in the first line, reported Aline Guillot, MD, from the Institut de cancérologie Lucien Neuwirth in Saint-Priest-en-Jarez, France, and her colleagues.

“The incidence of ONJ was high in this real-life population of patients with mRCC treated with antiangiogenic therapies combined with denosumab. This toxicity signal should warn physicians about this combination in the mRCC population,” they wrote in Clinical Genitourinary Cancer.

Previous studies have shown that the combination of another bone-targeted therapy – zoledronic acid – with antiangiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib (Sutent) is associated with increased risk for ONJ. In addition, ONJ with the combination of denosumab and antiangiogenic therapies “has been noticed but never estimated,” the authors noted.

To evaluate the incidence of hypocalcemia and ONJ in patients with RCC metastatic to bone treated with denosumab and a TKI or mammalian target of rapamycin inhibitor, the investigators gathered data retrospectively from 10 French centers.

They identified 25 men and 16 women with a median age of 62 years (range, 54-68 years). Of this group, 40 received denosumab in the first line in combination with either sunitinib (31 patients), pazopanib (6), everolimus (Afinitor and generics; 2), and temsirolimus (Torisel and generics; 1). The median duration of first-line therapy was 12 months.

Denosumab was given in the second line with axitinib (Inlyta) to nine patients, with everolimus to nine, and with sunitinib to three patients. The median duration of second-line therapy was 3 months.

Skeletal-related events occurred in 41% of patients prior to receiving denosumab and in 61% (25 patients) after denosumab. The events included clinical fracture, bone pain requiring radiation, and spinal compression.

Of the seven patients who developed ONJ, six received denosumab and sunitinib in the first line and one received denosumab plus temsirolimus, with a median duration of treatment of 11.8 months. Three of these patients also received denosumab in the second line with either axitinib, everolimus, or sunitinib, with a median duration of 9.8 months. Data on second-line therapy for the remaining four patients with ONJ were not available.

The investigators noted that the 17% incidence of ONJ was higher than the 10% rate seen in a study of patients with mRCC treated with a TKI and a bisphosphonate (Acta Clin Belg. 2018 Apr;73(2):100-9), and the 1.8% incidence seen in an analysis of three phase 3 trials in cancer patients with bone metastases (Ann Oncol. 2012 May;23(5):1341-7).

Although the etiology of ONJ is unknown, patient education and oral hygiene may reduce the risk in patients treated with denosumab and a TKI.

“The benefit of denosumab in this setting in regard [to] toxicity needs to be demonstrated in a prospective trial,” they wrote.

No conflicts of interest or disclosures were reported.

SOURCE: Guillot A et al. Clin Genitourin Cancer. 2018 Sep 6. doi: 10.1016/j.clgc.2018.08.006.