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ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 4  |  Page : 579-582
 

Patterns of care and outcomes for second-line targeted therapy in metastatic renal cell carcinomas: A registry based analysis


1 Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Radiology, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication21-Apr-2017

Correspondence Address:
K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_25_17

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 » Abstract 

AIM: Patterns of care for metastatic renal cell carcinomas (mRCC) have seen tremendous reform in the last decade. Here, we present our pattern of care in second-line targeted therapy for mRCC. METHODS: Patients with mRCC treated with second-line therapy were included from a prospective database. Demographics, risk stratification, and treatment details were noted. Event-free survival (EFS) and overall survival (OS) was calculated using Kaplan–Meier method. Log-rank test was used to identify factors affecting EFS and OS. Multivariate analysis was performed using cox regression. RESULTS: Nearly 21.7% (46/212) of patients received second-line targeted treatment. Heng score for risk stratification showed 21.7% of patients in low risk, 36.9% in intermediate, and 34.8% in high risk group. Everolimus followed by pazopanib were the most common second-line therapies used in 65.2% and 13% of patients, respectively. The estimated median EFS was 3.5 months (95% confidence interval [CI] 2.7–4.26 months) and estimated median OS from the start of second-line therapy was 6.2 months (95% CI 3.4–9.0 months) with a median follow-up of 4.3 months. On univariate log-rank analysis, EFS of more than 6 months with first-line therapy was associated with improvement in EFS with second-line therapy (9.5 vs. 2.0 months; hazard ratio (HR) 0.364; P = 0.002). There was no factor independently associated with EFS or OS on multivariate analysis. CONCLUSION: Patterns of care for second line targeted therapy tend to vary with setting. A longer EFS with first-line therapy predicts improved outcomes with second-line treatment.


Keywords: Indian Kidney Cancer Registry, metastatic renal cell carcinoma, second-line targeted therapy renal cell carcinoma


How to cite this article:
Zanwar S, Joshi A, Noronha V, Patil V, Sable N, Popat P, Menon S, Kothari R, Bhargava P, Kapoor A, Prabhash K. Patterns of care and outcomes for second-line targeted therapy in metastatic renal cell carcinomas: A registry based analysis. Indian J Cancer 2016;53:579-82

How to cite this URL:
Zanwar S, Joshi A, Noronha V, Patil V, Sable N, Popat P, Menon S, Kothari R, Bhargava P, Kapoor A, Prabhash K. Patterns of care and outcomes for second-line targeted therapy in metastatic renal cell carcinomas: A registry based analysis. Indian J Cancer [serial online] 2016 [cited 2019 Nov 13];53:579-82. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/579/204757



 » Introduction Top


Treatment of metastatic renal cell carcinoma (mRCC) has seen a tremendous reform in the past decade.[1] The impressive results of targeted therapy have not been restricted to the first line setting with multiple agents being added to the therapeutic armamentarium for second-line therapy and beyond.[2],[3],[4],[5],[6] Till recently, there were only two drugs approved by the United States Food and Drug Administration for use in the second-line setting. This has changed dramatically in the last 2–3 years.[7] The patient population seen in the clinic is often underrepresented in clinical trial setting undermining the applicability of their results in day-to-day clinical practice.[8] Because of various reasons drug used in routine clinical practice may vary from the approved label. Herein lies the importance to evaluate the pattern of treatment and evaluate outcomes of patients treated in the clinic. In this study, we present the results of pattern of use of drugs and also outcome of mRCC patients treated with second-line treatment in palliative setting.


 » Methods Top


Patient selection

Patients were included in this study from a prospective database maintained in the medical oncology department. All patients with histologically proven and receiving second-line therapy in palliative setting for RCC between January 2012 and August 2016 were selected for this study. Patients either had radiologic progression post first-line therapy or required stopping first-line therapy due to unacceptable toxicity. Tumors with all histologies were included in the study population. Patients' date of diagnosis, date of diagnosis for metastatic disease, demographic details, date of progression, date of change of treatment, and date of death were also collected. Data for risk stratification were also collected including performance status, time from diagnosis to systemic treatment, serum calcium and lactate dehydrogenase, hemoglobin, baseline platelets, and neutrophils.

Treatment details

Details of the systemic therapy including drug, dose schedule, dose modification, dose interruption were collected. Therapy administered in first line was also collected.

Efficacy

Response assessment was performed using computed tomography scans of the thorax, abdomen and pelvis with contrast enhancement unless contraindication due to deranged renal functions. Response scans were performed every 3–4 months or earlier in case of clinical suspicion of progression. Response was assessed using RECIST version 1.1 criteria.[9] Definitions of complete response (CR), partial response (PR), stable disease, and progressive disease were as per RECIST 1.1 criteria.[9] Objective response rate (ORR) was defined as CR plus PR. Radiologic response was assessed by experienced radiologists in the uro-oncology disease management group.

Statistical analysis

Demographic data are described in percentages. Event free survival (EFS) was calculated from start of second line therapy till progression, death, stoppage of therapy due to unacceptable toxicity or loss to follow up. Overall survival (OS) was calculated from the start of second line therapy till death or loss to follow-up. EFS and OS were estimated using Kaplan–Meier method. Data were censored for analysis with the last date as August 30, 2016. Univariate Log-rank test was applied for identifying factors affecting EFS and OS. Eastern Cooperative Oncology Group (ECOG) Performance status at the start of second-line therapy, Heng score at diagnosis with mRCC, EFS with first-line therapy and type of second-line therapy used (mTOR vs. multikinase inhibitors [MKI]) were analyzed using multivariate logistic regression for factors affecting EFS and OS. Statistical analysis was performed using SPSS version 20.0 software (IBM SPSS Statistics for Windows, Version 20.0, IBM Corporation, Armonk, NY, USA).

Ethical considerations

This study was approved by the Institutional Review Board attached to Tata Memorial Hospital, Mumbai (Kidney Cancer Registry; project number 79). Informed consent of all participants was obtained before enrollment on the study. The study was registered with Clinical Trials Registry of India (approval number CTRI/2012/11/003147).


 » Results Top


From January 2012 to August 2016, out of the 212 patients treated with first-line therapy, a total of 46 patients (21.7%) received second line targeted treatment. Sorafenib followed by sunitinib were the most common first line therapies used in 41.3% and 32.6% of patients, respectively. The median age of the cohort was 57 years (22–76 years). Majority of the patients (69.6%) had clear cell histology. Heng score for risk stratification showed patients to be predominantly in intermediate (36.9%) or high risk (34.8%) group with 21.7% of patients belonging to low risk group at presentation. Risk stratification data were incomplete in three patients. Performance status was 2 or less on the ECOG scale in 93.5% of the patients. Majority of the patients had undergone a curative intent nephrectomy (58.7%), either partial or radical, prior to presentation with metastatic disease and three patients had undergone cytoreductive nephrectomy on the diagnosis of metastatic disease. The demographic and baseline characteristics are shown in [Table 1].
Table 1: Baseline Characteristics

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Response assessment showed an ORR of 2.2% (95% confidence interval [CI] 0.3–11.3%). One patient had partial response and no patients had a CR. Stable disease was noted in more than one-third (36.9%) of the patients, whereas 21 patients (45.7%) had progressive disease at first response evaluation. Response evaluation data were not available for 7 (15.2%) patents. Everolimus (65.4%) followed by pazopanib (13%) were the most commonly used drugs in second line. Drugs used in second-line therapy are shown in [Table 2]. Four patients (8.7%) required stopping of therapy due to unacceptable toxicity; one patients had grade III mucositis with everolimus which recurred despite dose reduction, one had grade III proteinuria with sunitinib despite dose reduction and drug free interval, one patient developed cardiac decompensation with congestive heart failure on sorafenib and another patient treated with axitinib had grade III hyperbilirubinemia.
Table 2: Drugs used in second line RCC

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The estimated median EFS of the cohort was 3.5 months (95% CI 2.7–4.26 months) and estimated median OS from start of second line therapy was 6.2 months (95% CI 3.4–9.0 months) by Kaplan–Meier method with a median follow-up of 4.3 months. On univariate log-rank analysis, EFS of more than 6 months with first line therapy was the only factor associated with improvement in EFS with second line therapy (median EFS - 9.5 vs. 2.0 months; HR 0.364; P = 0.002) [Figure 1]. Among factors affecting OS, second line therapy with MKIs over mTOR inhibitors (P = 0.058) and EFS >6 months with first line therapy (P = 0.055) showed trend toward improvement in OS. The median survival in low risk group as per Heng criteria was 16 months as compared to median of 3.5 months in intermediate risk and 2.0 months in high risk patients. This difference however did not reach statistical significance (P = 0.08). The Memorial Sloan Kettering Cancer Centre criteria for risk stratification did not have an impact on EFS or OS for second line therapy. On multivariate analysis using Cox regression incorporating ECOG performance status, Heng score, EFS with first line therapy and type of second-line therapy (MKIs vs. mTOR inhibitors), there was no factor independently affecting EFS or OS.
Figure 1: Second line EFS comparison for patients with event free survival of >6 months versus ≤6 months with first-line therapy

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 » Discussion Top


Improvements in outcomes with first line treatment strategies means that more and more patients are being subjected to second line therapies and beyond. Indeed, as many as ten treatment options are recommended in the second line setting by the current National Comprehensive Cancer Network guidelines in patients pretreated with anti-angiogenic agents.[7] Many studies have shown improvement in progression free survival and now also in OS with nivolumab and cabozantinib.[4],[10],[11],[12],[13] Indeed, exposure to second line therapy has also been found to be independently associated with improvement OS in a recent report from clinical practice setting.[14]

Our study looked at the pattern of use of systemic therapy and outcomes of mRCC treated with second line targeted therapy. We were able to administer second-line therapy in approximately one-fifth of our patients who had received first line treatment. This figure is similar to that reported by the RECCORD registry where 15% of patients receiving second line therapy.[14] With the nonavailability of nivolumab or cabozantinib in the country and axitinib not being available for a fair duration of the study, majority of the second line therapy decisions were taken keeping in mind the cost and logistic constraints. MKIs used included sunitinib, sorafenib, pazopanib and axitinib and mTOR inhibitors used included everolimus. The treatment plan took into consideration the prior therapy, comorbidities and resource constraints of the patients. Nevertheless, all the patients received one of the many accepted standard second line treatment options. Everolimus was the most commonly used drug in second line. This is in line with majority of the registry data.[14],[15],[16] The median age, male predominance and clear cell histology predominance seen in our study were similar to previous reports.[8],[14] Risk stratification was done using the criteria elaborated by Heng et al.[17] Majority of our study population belonged to high or intermediate risk group as per Heng criteria. This is in contrast to majority of clinical trial data where high risk patients have traditionally been underrepresented and is in cohesion with other reports from nontrial clinical practice setting.[8],[18]

The ORR of 2.2% is somewhat similar to previous reports from everolimus data.[4],[11]

The median EFS in our study is similar to previous reports of progression free survival with second line therapy.[4],[11],[12] However, the OS from start of second-line therapy appears to be lower than as compared to the OS reported from start of second-line therapy by the IMDC database review.[18] One of the factors that could have led to lower OS could be a higher proportion of patients in high risk group. The nonavailability of nivolumab or cabozantinib would not seem to have affected this survival as the historical data for comparison is from the prenivolumab era. The low number of cytoreductive nephrectomies performed in our study population is likely a reflection of the fact that majority underwent nephrectomy as radical treatment before relapse.

Among factors affecting EFS with second line therapy, an EFS of more than 6 months with first-line therapy was significantly associated with improved survival. This might be an explained by selection of a good biology disease that continues to respond well to second line therapy as well. On multivariate analysis, there was however no factor individually affecting EFS. Among factors affecting OS, Heng criteria based risk stratification suggested a trend toward its utility as a prognostic tool in this setting. Indeed, these criteria have been validated in the targeted therapy era and have shown to predict prognostic even for outcomes with second line therapy.[19] Another factor which showed trend toward survival benefit on univariate analysis was the use of MKI such as sunitinib, pazopanib and sorafenib in second line over the mTOR inhibitors, everolimus and temsirolimus. This might be explained by the results of a randomized phase III study where sorafenib was found to be superior to temsirolimus in patients treated previously with sunitinib.[20] Majority of our patients had received MKI in the form of either sunitinib, sorafenib or pazopanib in first-line setting providing a similar clinical context as that evaluated in this study.[20] There was no factor independently associated with OS on multivariate analysis.

Toxicity analysis was excluded from the purview of this study as majority patients took the advised treatment at their primary care centers coming primarily for three monthly follow ups and response evaluation to us. The documentation of toxicities, especially grade I/II adverse events was at the best patchy. In our study, 8.7% of patients had to discontinue treatment due to unacceptable toxicity even in the face of a stable disease on treatment. This figure is similar to previous reports with various agents in second line setting.[11],[19]

This study is an earnest attempt to look into the outcomes of second line treatment in mRCC in a resource limited setting as ours. The small numbers and retrospective nature represent the most important constraints in interpretation of the findings of this study. Nevertheless, it does add assurity to the feasibility of this intervention with comparable PFS and toxicity related drug discontinuations as compared to existing clinical trial literature. It also gives an overview of the current practices and feasibility of these interventions in the “real world” setting given the disparity in the patient population enrolled in clinical trials. It would be interesting to have more data on toxicity and quality of life with different agents to better guide our treatment strategies in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Escudier B, Albiges L, Sonpavde G. Optimal management of metastatic renal cell carcinoma: Current status. Drugs 2013;73:427-38.  Back to cited text no. 1
    
2.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.  Back to cited text no. 2
    
3.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-34.  Back to cited text no. 3
    
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Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-56.  Back to cited text no. 4
    
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Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): Final analysis of overall survival. J Clin Oncol 2010;28:2144-50.  Back to cited text no. 5
    
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Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol 2010;28:1061-8.  Back to cited text no. 6
    
7.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer V.3.2016; 2016. Available from: http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. [Last accessed on 2016 Jan 09; 3:31:33 PM.]  Back to cited text no. 7
    
8.
Heng DY, Choueiri TK, Rini BI, Lee J, Yuasa T, Pal SK, et al. Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials. Ann Oncol 2014;25:149-54.  Back to cited text no. 8
    
9.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.  Back to cited text no. 9
    
10.
Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: Overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013;14:552-62.  Back to cited text no. 10
    
11.
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13.  Back to cited text no. 11
    
12.
Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814-23.  Back to cited text no. 12
    
13.
Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): Final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:917-27.  Back to cited text no. 13
    
14.
Wagstaff J, Jones R, Hawkins R, Porfiri E, Pickering L, Bahl A, et al. Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: Insights from the RECCORD registry. Ann Oncol 2016;27:159-65.  Back to cited text no. 14
    
15.
Jonasch E, Signorovitch JE, Lin PL, Liu Z, Culver K, Pal SK, et al. Treatment patterns in metastatic renal cell carcinoma: A retrospective review of medical records from US community oncology practices. Curr Med Res Opin 2014;30:2041-50.  Back to cited text no. 15
    
16.
De Groot S, Sleijfer S, Redekop WK, Oosterwijk E, Haanen JB, Kiemeney LA, et al. Variation in use of targeted therapies for metastatic renal cell carcinoma: Results from a Dutch population-based registry. BMC Cancer 2016;16:364.  Back to cited text no. 16
    
17.
Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. J Clin Oncol 2009;27:5794-9.  Back to cited text no. 17
    
18.
Ko JJ, Xie W, Kroeger N, Lee JL, Rini BI, Knox JJ, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: A population-based study. Lancet Oncol 2015;16:293-300.  Back to cited text no. 18
    
19.
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 2011;378:1931-9.  Back to cited text no. 19
    
20.
Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2014;32:760-7.  Back to cited text no. 20
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]

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