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Year : 2016  |  Volume : 53  |  Issue : 4  |  Page : 575--578

Initial experience with first-line pazopanib in the treatment of metastatic renal cell carcinoma: A single institution data

A Joshi1, V Agarwala1, A Ramaswamy1, V Noronha1, VM Patil1, S Menon2, P Popat3, N Sable3, K Prabhash1,  
1 Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
2 Department of Pathology, Tata Memorial Centre, Mumbai, Maharashtra, India
3 Department of Radiodiagnosis, Tata Memorial Centre, Mumbai, Maharashtra, India

Correspondence Address:
K Prabhash
Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra
India

Abstract

INTRODUCTION: Pazopanib is one of the recently introduced first-line therapeutic options in the treatment of metastatic renal cell carcinoma (mRCC). There is no published literature from India on the use of pazopanib in mRCC. MATERIALS AND METHODS: We report the efficacy and toxicity analysis of first-line pazopanib therapy administered for patients with mRCC at our institute. It is a retrospective analysis of a prospectively maintained continuous data. RESULTS: Between March 2013 and December 2015, 28 patients have been treated with pazopanib. The median age was 56.5 years with 23 males and five females. Sixty-eight percent patients had clear-cell histology. The most common site of metastasis was lung (75%), followed by bone (36%), liver (25%), and brain (14%) with 43% having more than one metastatic site. Partial response, stable disease, and progression were observed in 3 (11%), 10 (36%), and 4 (14%) cases, respectively, and the response was not evaluable in 11 patients. The median follow-up duration was 11.8 months, and progression-free survival was 5.9 months. Most of the toxicities were Grade I–II except in three patients who experienced Grade III hand-foot syndrome (HFS) and one patient who had Grade III anemia. Common side effects were hypertension, HFS, fatigue, transaminitis, hyperglycemia, dyslipidemia, and proteinuria which were quite manageable. No patient required treatment discontinuation due to toxicity. CONCLUSION: Based on this initial experience at our center, pazopanib seems a feasible first-line treatment for mRCC due to its well-tolerable toxicity profile. However, larger data are required to confirm its efficacy in Indian patients.



How to cite this article:
Joshi A, Agarwala V, Ramaswamy A, Noronha V, Patil V, Menon S, Popat P, Sable N, Prabhash K. Initial experience with first-line pazopanib in the treatment of metastatic renal cell carcinoma: A single institution data.Indian J Cancer 2016;53:575-578


How to cite this URL:
Joshi A, Agarwala V, Ramaswamy A, Noronha V, Patil V, Menon S, Popat P, Sable N, Prabhash K. Initial experience with first-line pazopanib in the treatment of metastatic renal cell carcinoma: A single institution data. Indian J Cancer [serial online] 2016 [cited 2020 Jul 10 ];53:575-578
Available from: http://www.indianjcancer.com/text.asp?2016/53/4/575/204769


Full Text

 Introduction



The prognosis of advanced or metastatic renal cell carcinoma (mRCC) is dismal with a 5-year relative survival rate of 12.1% as per the SEER database for the period 2006-2012.[1] Over the past few years, the prognosis and treatment of mRCC have greatly improved due to a better understanding of the molecular biology of RCC and introduction of several molecular targeted therapies. Pazopanib, a recent introduction in this list, has been in clinical practice for the last 3–4 years. It inhibits vascular endothelial growth factor-1, 2, and 3, c-kit, and platelet-derived growth factor receptor-α and β, which are involved in tumor cell angiogenesis and proliferation.[2] The therapeutic efficacy of pazopanib was first demonstrated in the VEG105192 study which demonstrated its prolonged progression-free survival (PFS) compared to placebo in both treatment-naïve and cytokine-pretreated patients of mRCC.[3] The open-label, phase-III, randomized COMPARZ study proved the noninferiority of pazopanib in comparison to sunitinib in terms of PFS (8.4 months vs. 9.5 months) as the first-line treatment.[4] Overall survival (OS) was also found similar in both arms in an updated report (28.3 months vs. 29.1 months).[5] The toxicity profile of the two agents reported in the study was different with significantly more myelotoxicity, fatigue, hand-foot syndrome (HFS), and mucositis with sunitinib and more transaminitis with pazopanib. Another innovative crossover study, the PISCES trial, showed a significant patient preference for pazopanib over sunitinib with health-related quality of life (QoL) and safety profile as key influencing factors.[6]

A “real world” population data outside the ideal clinical trial setting are important to confirm the therapeutic benefits of any new drug in a representative patient population. Hence, we report our initial experience with pazopanib at a tertiary care referral center in India. To the best of our knowledge, this is the first such report from India.

 Materials and Methods



This is a retrospective analysis of the 28 consecutive patients of mRCC who were treated with the first-line pazopanib at the Tata Memorial Hospital, Mumbai, between March 2013 and December 2015, in routine clinical practice. We excluded patients who had received any prior therapy, including other tyrosine kinase inhibitors (TKIs) or cytokine therapy. Data were obtained from the hospital electronic medical records and case files. Patients were analyzed with respect to the demographic profile, prior nephrectomy status, performance status, number and sites of metastases, and Motzer's and Heng's risk groups. The efficacy analysis included the best overall response to therapy and median PFS and tolerance assessment included toxicity profile and need for dose modification.

Written informed consent was obtained from each patient before starting treatment. Supportive care included monthly zoledronic acid for bone metastasis and palliative radiotherapy, if required. They were followed up in the outpatient department as per routine clinical practice. Patients were started on pazopanib at a dose of 800 mg once daily. Dose modification was done depending on the toxicity. Response to treatment was based on clinical assessment and radiology as per the Response Evaluation Criteria in Solid Tumors 1.1 criteria. Response evaluation was done after every 2–3 months of pazopanib with computed tomography or positron emission tomography scan or as and when required as per clinician's advice. Treatment was continued with pazopanib until disease progression or unacceptable toxicity, according to the clinician's judgement. PFS was calculated as the time between the start of therapy and the date of progression, change of treatment due to any reason or death from any cause. Toxicity was assessed according to CTCAE version 4.03. Statistical measures were calculated using software IBM SPSS Statistics 20.0.

 Results



At the time of analysis, a total of 28 patients received pazopanib. The mean duration of treatment was 14 months (range 1–33), and the median duration of follow-up was 11.8 months. The baseline demographic and clinical characteristics, tumor features including metastasis number and location, and risk group stratification as per Heng's and Motzer's model are listed in [Table 1].{Table 1}

The efficacy analysis is documented in [Table 2]. The best overall response rate could not be evaluated for 11 patients and nine patients were lost to follow-up. At the time of analysis, nine out of 28 patients were alive – three patients continuing pazopanib, three on the 2nd line everolimus, and three on palliative care only. Fifteen patients had documented progression on pazopanib, of which eight patients received 2nd line treatment – six received everolimus, and one patient received sorafenib and sunitinib each. Fifteen patients were dead and four were lost to follow-up. There were no patients with complete response. Only three patients (11%) had a partial response (PR) as their best overall response while ten patients (36%) had stable disease (SD). Four patients (14%) failed pazopanib therapy with primary progression. The overall estimated median PFS in our study was 5.9 months.{Table 2}

Tolerance to pazopanib was good with very few Grade III–IV toxicities. Only six patients (21%) needed dose modifications and no patient required discontinuation due to an adverse event. The toxicity profile in our study is illustrated in [Table 3]. The most common Grade III event was HFS occurring in three patients (10.7%), which recovered after withholding pazopanib for 1–2 weeks and conservative management. Pazopanib could be successfully resumed in those patients after dose reduction without further Grade III event.{Table 3}

 Discussion



Pazopanib is one of the standards of care in advanced renal cell cancer. There are limited data available from the use of this drug outside of the clinical trial, especially from the Indian subcontinent. A number of retrospective observational studies on the outcome of pazopanib in mRCC have been published from Europe in the last few years. A multicenter study from Spain reported the outcome of pazopanib as the first-line treatment in 81 patients of mRCC with significant differences in median time to treatment failure (10 months vs. 6 months) and 1-year OS (74% vs. 55%) for Memorial Sloan-Kettering Cancer Center good/intermediate (n = 60) and poor risk (n = 21) subsets, respectively, and expected safety profile.[7] Two small studies from Italy with 15 and nine patients each on pazopanib in mRCC, reported a median PFS of 10.5 months and 9.9 months, respectively.[8],[9] In both studies, adverse events reported were mostly mild or moderate with most frequent being diarrhea, fatigue, hypertension, and nausea. Another retrospective multicenter study from Hungary reported the outcome of 24 patients on pazopanib in mRCC with an objective response of 38% and median PFS of 12.4 months.[10] The median OS was not reached.

To the best of our knowledge, the present study is the first one from India reporting outcomes of pazopanib in Indian mRCC patients. In contrast to the clinical trials, our study included unselected cohort of patients, including those with nonclear cell histology (29%), performance status 2 or 3 (32%), and poor- or high-risk group patients (14% as per Heng's model and 21% as per Motzer's model). Despite these, the overall clinical benefit rate (PR + SD) of pazopanib treatment was 76% among all evaluable patients for response assessment (17 out of 28). The median PFS was 5.9 months which is less as compared to other studies. This may be due to less number of patients and our unselected cohort. We need larger studies to evaluate the PFS and OS of the first-line pazopanib in Indian mRCC patients.

The toxicity profile reported in our study is different from the pivotal trials as illustrated in [Table 3] which suggests better tolerance and safety of pazopanib in our patients. Only 21% patients required dose reduction in our study compared to 44% patients in COMPARZ study. No patient discontinued pazopanib due to toxicity in our cohort compared to 24% patients in COMPARZ study. The most significant and distressing toxicity of pazopanib in our study population was HFS which was the cause for dose reduction in most patients with three patients having Grade III toxicity requiring temporary discontinuation. The rates of HFS, proteinuria, and hypothyroidism in our study are similar to that in the COMPARZ study while all other toxicities are much less encountered. We did serial echocardiography of patients on approximately 6 monthly basis on follow-up and one patient had > 10% decline in ejection fraction. Pazopanib was continued at a reduced dose. Dyslipidemia was found in 21% patients with most having increased triglycerides and low-density lipoprotein after starting pazopanib although it did not require any intervention. Dyslipidemia as an adverse effect has not been reported in other studies. No patient showed significant hematological toxicity except one who had Grade III anemia and required blood transfusion and iron supplementation. Thirty-five percent patients had Grade I–II hypertension and 18% had Grade I–II proteinuria which was managed with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Most of the toxicities were mild to moderate and manageable.

There are significant study constraints with small cohort size, four patients lost to follow-up and 11 patients without any response assessment. This is due to logistical reasons as most of our patients are not from Mumbai and belong to different distant parts of the country. Lack of QoL data and compliance data is another shortcoming.

 Conclusion



The optimal sequencing and combination of different targeted therapies in mRCC to maximize their clinical efficacy are not clear. With the present data, pazopanib seems to be an option for the first-line treatment. Our findings suggest that pazopanib is associated with a safer and manageable toxicity profile in Indian patients to that observed in the pivotal prospective studies. However, we need larger studies to confirm its efficacy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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