Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial

Background

Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy.

Objective

To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1.

Design, setting, and participants

The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416).

Intervention

Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity.

Measurements

Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety.

Results and limitations

In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation.

Conclusions

Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.     

Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear‐cell renal cell carcinoma receiving vascular endothelial growth factor‐targeted therapy

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

OBJECTIVE

To investigate the utility of tumour carbonic anhydrase IX (CAIX) expression and histological features for predicting the outcome in patients with metastatic clear‐cell renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)‐targeted therapy.

PATIENTS AND METHODS

We identified 118 patients with mRCC initiating first‐line VEGF‐targeted therapy, including 94 with clinical and histological data, and available tissue. The primary endpoint was to detect an interaction between sorafenib vs sunitinib treatment and CAIX status on tumour shrinkage. Other treatment outcomes were also assessed.

RESULTS

There was heterogeneity in tumour responsiveness to sunitinib or sorafenib according to CAIX status; the mean shrinkage was –17% vs –25% for sunitinib‐treated patients with high vs low tumour CAIX expression, compared to –13% vs +9% for sorafenib‐treated patients (P interaction, 0.05). A higher tumour clear‐cell component was independently associated with greater tumour shrinkage (P= 0.02), response (P= 0.02) and treatment duration (P= 0.02).

CONCLUSIONS

Although CAIX expression had no prognostic value in patients with clear‐cell mRCC treated with VEGF‐targeted therapy, it might be a predictive biomarker for response to sorafenib treatment. Patients with a higher clear‐cell component in their tumours are likely to have a superior clinical benefit from VEGF‐targeted therapy.     

Sunitinib in Advanced Renal Cell Carcinoma: Clinical Evidence

ContextThe development of targeted agents has improved the outlook for patients with metastatic renal cell carcinoma (mRCC). Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activities. In mRCC, sunitinib has demonstrated efficacy for the treatment of cytokine-refractory and previously untreated mRCC.ObjectiveThis article reviews the available efficacy data from sunitinib clinical studies, including data that led to the approval of sunitinib for mRCC.Evidence acquisitionThe efficacy data from sunitinib phase 2 and 3 trials as well as the expanded-access study were examined.Evidence synthesisIn a pivotal phase 3 trial in treatment-naïve mRCC patients, sunitinib was found to provide significantly superior efficacy compared with interferon-α (IFN-α; assessed as progression-free survival [PFS] and objective response). The median PFS was 11.0 mo (95% confidence interval [CI]: 10.7–13.4) in patients treated with sunitinib and 5.1 mo in IFN-α–treated patients (95% CI: 3.9–5.6; p < 0.000001). Sunitinib also demonstrated antitumor activity in two phase 2 trials of patients with cytokine-refractory mRCC. The expanded-access study provided access to sunitinib for patients ineligible for participation in the registrational studies and provides a useful insight into the profile of sunitinib in a heterogeneous mRCC population, including subgroups such as older patients (≥65 yr), patients with brain metastases, patients with poor performance status (PS ≥2), and patients with non–clear-cell histology.ConclusionsSunitinib is considered a reference standard of care for the first-line treatment of patients with mRCC, which is reflected in the current treatment guidelines. Sunitinib is now approved multinationally for the first- and second-line treatment of advanced renal cell carcinoma and/or mRCC.     

Feasibility and effects of high-dose hypofractionated radiation therapy and simultaneous multi-kinase inhibition with sunitinib in progressive metastatic renal cell cancer

ObjectivesRadiotherapy (RT) is considered oncologically ineffective in metastatic renal cell cancer (mRCC). Inhibition of angiogenetic pathway may lead to radiosensitization in mRCC. The aim of this study was to evaluate the efficacy of the simultaneous combination of RT with systemic treatment of bulky (mRCC) using sunitinib.Methods and materialsWe included 22 patients with progressive mRCC between 04/2007 and 08/2008 at the University Hospital Munich Großhadern. All patients underwent high-dose hypofractionated RT while they were simultaneously treated systemically with sunitinib 50 mg.ResultsMedian age was 63.0 years (range 26.7–84.4). Median dose of radiation was 40 Gy (range 25–50) in a median of 8 fractions (range 5–30). Treatment sites were brain, retroperitoneal and mediastinal lymph nodes, spinal cord, bones, liver, and kidney. Median follow-up was 14.3 months. After 3 months, 2 patients had complete remission (CR), 9 patients showed partial remission (PR) as measured by response evaluation criteria in solid tumors (RECIST) criteria, 2 patients had minor response (MR), and 8 patients had stable disease (SD). Only 1 patient did not respond to therapy. Toxicity was very low with only 1 grade 4 hypertension. Skin toxicities were manageable with no grade 3 event during the combination period.ConclusionsThe combination of RT with simultaneous systemic treatment using sunitinib is effective in patients with progressive mRCC. With high dose RT, complete response seems to be possible. Further evaluation should be based upon combination of RT with systemic therapy, rather than sequential RT regiments.     

Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cell carcinoma: a retrospective outcome analysis

Background

To date, few data are available about the sequential use of the tyrosine kinase inhibitors (TKI) sorafenib and sunitinib in metastatic renal cell carcinoma (mRCC).

Objective

To investigate the effectiveness of the use of sunitinib after progression under sorafenib in mRCC.

Design, setting, and participants

A retrospective analysis of 30 patients with progressive mRCC, treated with sorafenib between May 2005 and February 2008. When radiologic progression was diagnosed, treatment was switched to sunitinib and continued until a further tumour progression occurred.

Measurements

Radiologic evaluation of the treatment results was performed every 3 mo according to the criteria for Response Evaluation Criteria in Solid Tumors (RECIST). Adverse effects and therapeutic abnormalities (eg, dose reduction) were documented during regular visits.

Results and limitations

Of the patients, 50% benefited from the secondary use of sunitinib. In detail, a radiologically confirmed new disease stabilisation or partial response was observed in seven and eight patients, respectively. Median progression-free survival was 8.7 mo and 10.3 mo under sorafenib and sunitinib, respectively. Overall, the median time from the initialisation of the first TKI until progression under therapy with the second TKI was 17.3 mo.To our knowledge, this is the second largest study reporting results of sequential therapy from sorafenib followed by sunitinib. However, the number of patients is still not extensive enough to settle this important question conclusively.

Conclusions

This study supports the hypothesis that sequential TKI therapy with the sorafenib followed by sunitinib has clinical validity in some patients with advanced renal cell carcinoma when progressive disease occurs under the initial TKI therapy.     

Prognostic effect of preoperative serum albumin to globulin ratio in patients treated with cytoreductive nephrectomy for metastatic renal cell carcinoma

BackgroundAccurate identification of ideal candidates for cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is an unmet need. We tested the association between preoperative value of systemic albumin to globulin ratio (AGR) and overall survival (OS) as well as cancer-specific survival (CSS) in mRCC patients treated with CN.MethodsmRCC patients treated with CN were included. The overall population was therefore divided into two AGR groups using cut-off of 1.43 (low, <1.43 vs. high, ≥1.43). Univariable and multivariable Cox regression analyses tested the association between AGR and OS as well as CSS. The discrimination of the model was evaluated with the Harrel’s concordance index (C-index). The clinical value of the AGR was evaluated with decision curve analysis (DCA).ResultsAmong 613 mRCC patients, 159 (26%) patients had an AGR <1.43. Median follow-up was 31 (IQR: 16–58) months. On univariable analysis, low preoperative serum AGR was significantly associated with both OS (HR: 1.55, 95% CI: 1.26–1.89, P<0.001) and CSS (HR: 1.55, 95% CI: 1.27–1.90, P<0.001). On multivariable analysis, AGR <1.43 was associated with worse OS (HR: 1.51, 95% CI: 1.23–1.85, P<0.001) and CSS (HR: 1.52, 95% CI: 1.24–1.86, P<0.001). The addition of AGR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index=0.640 vs. C-index=0.629). On DCA, the inclusion of AGR marginally improved the net benefit of the prognostic model. Low AGR remained independently associated with OS and CSS in the IMDC intermediate risk group (HR: 1.52, 95% CI: 1.16–1.99, P=0.002).ConclusionsIn our study, low AGR before CN was associated with worse OS and CSS, particularly in intermediate risk patients.     

Liver and Pancreatic Resection in the Elderly

Background: Liver resection, or pancreaticoduodenectomy, has traditionally been thought to have a high morbidity and. mortality rate among the elderly. Recent improvements in surgical and anesthetic techniques, an increasing number of elderly patients, and an increasing need to justify use of limited health care resources prompted an assessment of recent surgical outcomes.Methods: Five hundred seventy-seven liver resections (July 1985–July 1994) performed for metastatic colorectal cancer and 488 pancreatic resections (October 1983–July 1994) performed for pancreatic malignancies were identified in departmental data bases. Outcomes of patients younger than age 70 years were compared with those of patients age 70 years or older.Results: Liver resection for 128 patients age 70 years or older resulted in a 4% perioperative. mortality rate and a 42% complication rate. Median hospital stay was 13 days, and 8% of the patients required admission to the intensive care unit (ICU). Median survival was 40 months, and the 5-year survival rate was 35%. No difference were found between results for the elderly and those for younger patients who had undergone liver resection, except for a minimally shorter hospital stay fortheyoungerpatients (median, 12 days vs. 13 days p=0.003). Pancreatic resection for 138 elderly patients resulted in a mortality rate of 6% and a complication rate of 45%. Median stay was 20 days, and 19% of the patients required ICU admission, results identical to those for the younger cohort. Long-term survival was poorer for the elderly patients, with a 5-year survival rate of 21% compared with 29% for the younger cohort (p=0.03).Conclusions: Major liver or pancreatic resections can be performed for the elderly with acceptable morbidity and mortality rates and possible long-term survival. Chronologic age alone is not a contraindication to liver or pancreatic resection for malignancy.     

Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma

Background

Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined.

Objective

To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective.

Design, setting, and participants

One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib–everolimus or temsirolimus–sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment.

Measurements

PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS).

Results and limitations

Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3–6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6–10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data.

Conclusions

Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.     

Tumor Growth Rate Provides Useful Information to Evaluate Sorafenib and Everolimus Treatment in Metastatic Renal Cell Carcinoma Patients: An Integrated Analysis of the TARGET and RECORD Phase 3 Trial Data

BackgroundResponse Evaluation Criteria in Solid Tumors (RECIST) criteria may not be sufficient to evaluate the response of targeted therapies in metastatic renal cell carcinoma (mRCC). The tumor growth rate (TGR) incorporates the time between evaluations and may be adequate.ObjectiveTo determine how TGR is modified along the treatment sequence and is associated with outcome in mRCC patients.Design, setting, and participantsMedical records from all patients prospectively treated at Gustave Roussy (IGR) in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) (sorafenib vs placebo, n = 84) and the RECORD (everolimus vs placebo, n = 43) phase 3 trials were analyzed. TGR was computed across clinically relevant periods: BEFORE treatment introduction (wash-out), UNDER (first cycle), at PROGRESSION (last cycle) and AFTER treatment discontinuation (washout). The association between TGR and outcome (overall survival [OS] and progression-free survival [PFS]) was computed in the entire TARGET cohort (n = 903).InterventionSorafenib, everolimus, or placebo.Outcome measurements and statistical analysisTGR, RECIST, OS, and PFS rates.Results and limitationsAlthough nearly all the patients (IGR) were classified as stable disease (RECIST) after the first cycle, the great majority of the patients exhibited a decrease in TGR UNDER compared with BEFORE (sorafenib: p < 0.00001; everolimus: p < 0.00001). In sorafenib-treated but not in everolimus-treated patients (IGR), TGR at PROGRESSION (last cycle) was still lower than TGR BEFORE (washout) (p = 0.012), while TGR AFTER progression (washout) was higher than TGR at PROGRESSION (last cycle) (p = 0.0012). Higher TGR (first cycle) was associated with worse PFS (hazard ratio [HR]: 3.61; 95% confidence interval [CI], 2.45–5.34) and worse OS (HR: 4.69; 95% CI, 1.54–14.39), independently from the Motzer score and from the treatment arm in the entire TARGET cohort.ConclusionsComputing TGR in mRCC patients is simple and provides clinically useful information for mRCC patients: (1) TGR is independently associated with prognosis (PFS, OS), (2) TGR allows for a subtle and quantitative characterization of drug activity at the first evaluation, and (3) TGR reveals clear drug-specific profiles at progression.     

Dynamic contrast-enhanced CT-derived blood flow measurements enable early prediction of long term outcome in metastatic renal cell cancer patients on antiangiogenic treatment

PurposeTo evaluate the role of dynamic contrast-enhanced CT (DCE-CT) as an independent non-invasive biomarker in predicting long term outcome in patients with metastatic renal cell carcinoma (mRCC) on antiangiogenic treatment.Material and methodsEighty two mRCC patients were prospectively enrolled from 09/2011 to 04/2015, out of which 71 were included in the final data analysis; the population was observed until 12/2020 to obtain complete overall survival data.DCE-CT imaging was performed at baseline and 10 to 12 weeks after start of treatment with targeted therapy. DCE-CT included a dynamic acquisition after injection of 50 ml of nonionic contrast agent at 6 ml/s using a 4D spiral mode (10 cm z-axis coverage, acquisition time 43 sec, 100 kVp (abdomen), 80 kVp (chest), 80–100 mAs) on a dual source scanner (Definition FLASH, Siemens). Blood flow (BF) was calculated for target tumor volumes using a deconvolution model. Progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier statistics (SPSS version 24).ResultsPatients were treated with either sunitinib, pazopanib, sorafenib, tivozanib, axitinib, or cabozantinib. A cut-off value of 50% blood flow reduction at follow-up allowed for identification of patients with favorable long-term outcome: Median OS in n = 42 patients with an average blood flow reduction of >50% (mean, 79%) was 34 (range, 14–54) months, while n = 21 patients with an average reduction of less than 50% (mean, 28%) showed a median OS of 12 (range, 6–18) months, and n = 8 patients with an increase in blood flow survived for a median of 7 (range, 3–11) months.ConclusionBlood flow in metastases measured with DCE-CT at first follow-up is a strong predictor of overall survival in mRCC patients on antiangiogenic treatment.     

Continued Progress in the Treatment of Advanced Renal Cell Carcinoma: An Update on the Role of Sunitinib

ContextRenal cell carcinoma (RCC) constitutes approximately 2–3% of all cancers worldwide. Approximately a third of patients diagnosed with RCC present with metastatic disease (mRCC) and in about a third of patients with localized disease, RCC recurs following treatment. Metastatic renal cell carcinoma (mRCC) is associated with poor survival rates, and until recently, cytokines were the only treatment options for mRCC.ObjectiveThe rationale for the use of targeted agents in mRCC is reviewed, and the key challenges to optimizing treatment are discussed.Evidence acquisitionClinical data on the safety and efficacy of targeted agents in mRCC, practical therapy management, and patient stratification strategies are reviewed.Evidence synthesisThe development of targeted agents, including sunitinib, sorafenib, temsirolimus, and bevacizumab (given with interferon-α [IFN-α]) has dramatically changed the outlook for patients with mRCC and improved survival rates. Sunitinib has demonstrated clinical efficacy for mRCC in phase 2 and phase 3 trials and in an expanded-access study. Sunitinib is now a reference standard of care for the first-line treatment of patients with mRCC.As with the other targeted agents, sunitinib treatment is associated with a particular profile of adverse events (AE). Management of AEs is critical, as tolerability can affect adherence to therapy and limit clinical benefit. The development of practical strategies to support the optimal use of targeted agents is essential.In addition, prognostic factors such as tumor histology affect treatment outcome. Patient stratification into risk groups based on prognostic factors allows optimal treatment selection. A treatment algorithm, based on patient stratification and the available clinical data for the targeted agents, may facilitate the optimal choice of treatment for patients with mRCC.ConclusionsThis supplement reviews the clinical data from sunitinib studies in mRCC as well as practical therapy-management strategies and presents a treatment algorithm for mRCC. Finally, experience from the clinic is presented.     

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial

BackgroundThe use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.ObjectiveTo evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.Design, setting, and participantsIMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.InterventionPatients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.Outcome measurements and statistical analysisThe secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.Results and limitationsFifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.ConclusionsThe atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.Patient summaryPatients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.     

Carbonic anhydrase IX as a potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma patients receiving sorafenib or placebo: Analysis from the treatment approaches in renal cancer global evaluation trial (TARGET)

ObjectiveRetrospective data analyses have suggested that carbonic anhydrase IX (CAIX) may have a predictive role in patients with metastatic clear cell renal cell carcinoma (ccRCC) receiving high dose interleukin-2 or sorafenib. We examined the predictive value of CAIX in estimating treatment outcome in patients receiving sorafenib vs. placebo as part of the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study.Materials and methodsParaffin embedded tumor tissues were collected from 133 patients from the TARGET study (n = 903). The percentage of CAIX-positive cells was assessed by a single pathologist. The impact of CAIX expression on progression-free survival (PFS, primary endpoint) and tumor shrinkage (TS, secondary endpoint) was analyzed.ResultsClinical characteristics were similarly distributed between patients with low vs. high CAIX staining, as well as patients with available CAIX data vs. not. Median PFS for patients with high CAIX vs. low CAIX expression was 5.5 and 5.4 months, respectively, on the sorafenib arm (P = 0.97), and 1.5 and 1.7 months on the placebo arm (P = 0.76). Median TS for patients with high CAIX status was ?14.9% vs. ?12.6% in patients with low CAIX status (P = 0.63) on the sorafenib arm, and +1.3% (high CAIX) vs. +4.8% (low CAIX) in patients on the placebo arm (P = 0.60).ConclusionsDespite suggestive retrospective evidence, data from the TARGET study did not find CAIX expression status to be either predictive of clinical benefit for treatment with sorafenib or of prognostic value in patients with metastatic ccRCC following cytokine therapy.     

Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: A registry-based analysis

ObjectivesThe aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs).Patients and methodsA national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs.ResultsMedian progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013.ConclusionPFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.     

Toxicities of targeted therapy and their management in kidney cancer

Context

The therapeutic scenario for metastatic renal cell carcinoma (mRCC) has been evolving rapidly, with sunitinib, sorafenib, bevacizumab, everolimus, pazopanib, and temsirolimus being successfully tested and approved in a short period of time. Oncologists must be familiar with the management of toxicity that these biologic agents cause, as such toxicity is different from that of conventional chemotherapeutic agents.

Objective

To describe toxic effects associated with targeted therapy of mRCC and their proper management on the basis of currently available evidence.

Evidence acquisition

We conducted a systematic analysis of the literature on 15th October 2010 by performing a search of Medical Subject Headings (MeSH) on PubMed using the words sorafenib, sunitinib, bevacizumab, everolimus, pazopanib, or temsirolimus combined with the MeSH term kidney neoplasms. Consideration for inclusion was given to articles providing data concerning (1) incidence and grading and (2) management of targeted therapy–related toxic effects. A separate search was conducted on PubMed to retrieve meta-analyses using each drug name and the word meta-analysis.

Evidence synthesis

Hypertension, fatigue, bone marrow toxicity, skin toxicity, and gastrointestinal side-effects are common with the six targeted agents. Everolimus and temsirolimus are associated with immunosuppression, metabolic alterations, and interstitial pneumonitis, while sunitinib is associated with hypothyroidism. Recommendations for treating these conditions usually follow those for the general population because of the lack of experimental data in this setting (eg, for management of sunitinib-induced hypertension).

Conclusions

The treating oncologist should try to manage side-effects associated with targeted therapy using supportive and pharmacologic interventions. Severe toxicity requires external specialist consultation and treatment suspension and/or dose reduction. Experimental data about the management of targeted therapy–related toxicity in mRCC is lacking and required in this setting.     

Sunitinib dosing schedule 2/1 improves tolerability,efficacy, and health-related quality of life in Chinese patients with metastatic renal cell carcinoma

PurposeTo assess the efficacy and tolerability of sunitinib dosing schedule of 2 weeks on and 1 week off (schedule 2/1) vs. the traditional schedule of 4 weeks on and 2 week off (schedule 4/2) and its influence on health-related quality of life (HRQoL) in Chinese patients with metastatic renal cell carcinoma (mRCC).Materials and methodsA retrospective analysis of 108 patients with mRCC who were treated with sunitinib regimens (50 mg daily) between January 2009 and July 2013 was undertaken. Overall, 3 groups of patients were studied according to the dosing schedule they received: schedule 4/2 (n = 50), transitional schedule 2/1 (T2/1; patients switched from schedule 4/2 to 2/1; n = 26), and initial schedule 2/1 (I2/1; n = 32). The tumor response, progression-free survival (PFS) time, adverse events, and HRQoL were assessed and compared among the groups.ResultsThe incidences of diarrhea, fatigue, hand-foot syndrome, and neutropenia induced by the treatment of sunitinib were all significantly less common with schedule I2/1 and T2/1 than with schedule 4/2 (P<0.05). Although there was no statistically significant difference in the tumor response among the 3 groups, the median PFS time was significantly longer with schedule I2/1 than with schedules T2/1 and 4/2 (11.2 vs. 9.4 and 9.5 mo, respectively, P = 0.030), and HRQoL (as determined by 19-item Functional Assessment of Cancer Therapy Kidney Symptom Index scores) was better.ConclusionsTreatment with sunitinib 50 mg daily using a 2/1 dosing schedule can provide better tolerability and a longer PFS with better HRQoL in Chinese patients with mRCC than the traditional schedule 4/2.     

Cisplatin-based combination chemotherapy in septuagenarians with metastatic urothelial cancer

PurposeCisplatin-based chemotherapy is standard first-line treatment for metastatic urothelial carcinoma. However, cisplatin is frequently avoided in elderly patients due to concerns regarding toxicities. We analyzed the efficacy, and tolerability, of cisplatin-based chemotherapy in elderly patients.MethodsIndividual patient data were pooled from 8 phase II and III trials evaluating cisplatin-based first-line chemotherapy in patients with metastatic urothelial carcinoma. Adverse events, treatment delivery, response proportions, and survival outcomes were compared between patients aged<70 vs.≥70 years.ResultsOf the 543 patients included, 162 patients (30%) were≥70 years old. The majority (93%) of elderly patients were aged 70 to 79 years. There was no significant difference in the proportions of patients experiencing Grade 3 to 4 renal failure, febrile neutropenia, or treatment-related death between younger and older patient cohorts. The median survival of the patients≥70 years was 12.1 months compared to 12.8 months for patients<70 years (P = 0.91). There was no significant difference in survival between age groups when controlling for baseline performance status or the presence of visceral metastases or both.ConclusionsFit septuagenarians, with adequate renal function, tolerate cisplatin-based chemotherapy similarly to their younger counterparts and achieve comparable clinical outcomes.     

Contemporary trends in high-dose interleukin-2 use for metastatic renal cell carcinoma in the United States

BackgroundTargeted therapies (TTs) have revolutionized metastatic renal cell carcinoma (mRCC) treatment in the past decade, largely replacing immunotherapy including high-dose interleukin-2 (HD IL-2) therapy. We evaluated trends in HD IL-2 use for mRCC in the TT era.MethodsOur cohort comprised a weighted estimate of all patients undergoing HD IL-2 treatment for mRCC from 2004 to 2012 using the Premier Hospital Database. We assessed temporal trends in HD IL-2 use including patient, disease, and hospital characteristics stratified by era (pre-TT uptake: 2004–2006, uptake: 2007–2009, and post-TT uptake: 2010–2012) and fitted multivariable regression models to identify predictors of treatment toxicity and tolerability.ResultsAn estimated 2,351 patients received HD IL-2 therapy for mRCC in the United States from 2004 to 2012. The use decreased from 2004 to 2008. HD IL-2 therapy became increasingly centralized in teaching hospitals (24% of treatments in 2004 and 89.5% in 2012). Most patients who received HD IL-2 therapy were men, white, younger than 60 years, had lung metastases, and were otherwise healthy. Vasopressors, intensive care unit admission, and hemodialysis were necessary in 53.4%, 33.0%, and 7.1%, respectively. Factors associated with toxicities in multivariable analyses included being unmarried, male sex, and multiple metastatic sites. African Americans and patients with single-site metastases were less likely to receive multiple treatment cycles.ConclusionsHD IL-2 therapy is used infrequently for mRCC in the United States, and its application has diminished with the uptake of TT. Patients are being increasingly treated in teaching hospitals, suggesting a centralization of care and possible barriers to access. A recent slight increase in HD IL-2 therapy use likely reflects recognition of the inability of TT to effect a complete response.     

Economic evaluation of new targeted therapies for the first-line treatment of patients with metastatic renal cell carcinoma

Study Type – Therapy (economic) Level of Evidence 2b What’s known on the subject? and What does the study add? Cost‐effectiveness of new targeted molecular therapies in patients with mRCC have been examined compared to interferon‐α. This study compares cost‐effectiveness of three new targeted therapies in mRCC head‐to‐head based on indirect comparison of clinical efficacy. The study shows that sunitinib is a cost‐effective therapy in first line treatment for patients with mRCC in the USA and Sweden compared to sorafenib and bevacizumab+interferon‐α.

OBJECTIVE

? To assess the economic value of targeted therapies as first‐line metastatic renal cell carcinoma (mRCC) treatment in the US and Sweden by indirect comparison of survival data.

METHODS

? A Markov model simulated disease progression, adverse events and survival with sunitinib vs sorafenib in the US and bevacizumab plus interferon‐α (IFN‐α) in both countries. ? Results, in life‐years (LYs), progression‐free LYs (PFLYs), quality‐adjusted LYs (QALYs) gained and treatment costs (2008 USD) were obtained through deterministic and probabilistic analyses over the patient’s lifetime.

RESULTS

? Sunitinib was more effective and less costly than sorafenib (gains of 0.52 PFLYs, 0.16 LYs and 0.17 QALYs and savings/patient of $13 576 in the US) and bevacizumab plus IFN‐α (gains of 0.19 PFLYs, 0.23 LYs and 0.16 QALYs in both countries and savings/patient of $67 798 and $47 264 in the US and Sweden, respectively). ? Results were most influenced by hazard ratios for progression‐free and overall survival and treatment costs, making results generalizable across other countries if relative costs were to fall within the ranges of those in the US and Sweden.

CONCLUSION

? The present analyses suggest that first‐line mRCC treatment with sunitinib is a cost‐effective alternative to sorafenib and bevacizumab plus IFN‐α.