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 »  Abstract
 » Introduction
 » Methods
 » Results
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 » Conclusion
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 1  |  Page : 118-122
 

Sunitinib in metastatic renal cell carcinoma: Experience from single center study, efficacy and safety


Department of Medical and Paediatric Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India

Date of Web Publication28-Apr-2016

Correspondence Address:
K B Patel
Department of Medical and Paediatric Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat
India
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Source of Support: Department of Medical and Paediatric Oncology, Gujarat Cancer and Research Institute, Ahmedabad., Conflict of Interest: None


DOI: 10.4103/0019-509X.180844

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 » Abstract 

Background: The 5-year survival rate for metastatic renal cell carcinoma (RCC) is estimated to be <10%. RCC is highly resistant to chemotherapy. Targeted agents are now first choice of therapy for metastatic RCC such as sunitinib and sorafenib. Methods: This study is a retrospective analysis of 15 patients having metastatic RCC treated with sunitinib. Apart from three patients, all had clear cell histology. Thirteen patients received dosage of 50 mg/d (4 weeks on/2 weeks off cycles). In 14 patients sunitinib was used as 1st line. The primary end point was objective response rate. Secondary end points were progression free survival (PFS) and safety. Results: Until date of reporting, 3 out of 15 patients are currently on sunitinib. The most common Memorial Sloan = Kettering Cancer Centre poor prognostic factor was an interval of <1 year between diagnosis and starting of treatment (80%). The objective response rate was 13.66% (complete response [CR] + partial response [PR] = 0 + 2). Clinical benefit rate (CR + PR + stable disease) was 60% (n = 9). Median PFS in this study was 7.5 months, with a range of 2-22 month. Median overall survival (OS) of patients in this study was 12 months with a range of 3-24 month. An impact of the dose or/and number of cycles on response was seen in this study, with patients having average cycles >3 showing better response rates, PFS and OS. Major toxicities seen were fatigue ( n= 7), diarrhea (n = 3) and skin rash (n = 4) with majority patients experienced Grade 1-2 toxicities. While Grade 3-4 toxicities include fatigue (n = 1), mucositis (n = 1) and nausea (n = 1). Conclusions: These results confirm efficacy and safety profile of sunitinib in metastatic RCC, particularly as a first line. Sunitinib produced a 60% disease control rate for metastatic RCC in Indian patients, with acceptable rates of toxicity at a dose of 50 mg daily. Response rates were well matched to other studies confirming the efficacy of sunitinib.


Keywords: Efficacy, metastatic renal cell carcinoma, safety, sunitinib


How to cite this article:
Patel K B, Panchal H P, Karanwal A B, Parekh B B, Shah S, Prasad S. Sunitinib in metastatic renal cell carcinoma: Experience from single center study, efficacy and safety. Indian J Cancer 2016;53:118-22

How to cite this URL:
Patel K B, Panchal H P, Karanwal A B, Parekh B B, Shah S, Prasad S. Sunitinib in metastatic renal cell carcinoma: Experience from single center study, efficacy and safety. Indian J Cancer [serial online] 2016 [cited 2019 Aug 25];53:118-22. Available from: http://www.indianjcancer.com/text.asp?2016/53/1/118/180844



 » Introduction Top


Renal cancer accounts for almost 3% of adult malignancies globally with more than 21000 new cases and 100,000 deaths annually.[1] At 5 year survival for patients diagnosed with early-stage renal cell carcinoma (RCC) is as high as 66%.[2] However, for the 30% of patients with RCC who present with advanced or metastatic disease, 5 year survival is only 10%.[3],[4],[5]

In addition, local recurrence or distant metastasis develops in up to 40% of patients treated for localized tumors.[4],[6] There are several sub types of RCC, but over 80% of tumors contain clear-cell carcinoma. A better understanding of the genetic abnormalities associated with clear-cell RCC has helped to identify new targets for therapy. Studies have demonstrated that sporadic (non = hereditary) clear-cell RCC has similar genetics to von Hippel-Lindau syndrome (an inherited disorder that carries an increased risk for vascular tumors including RCC).[3] In both sporadic clear-cell RCC tumors and patients with the von Hippel-Lindau syndrome, genetic deletions, mutations, or chemical modifications result in non = functional or reduced levels of von Hippel-Lindau gene product.[3],[7] Loss of von Hippel-Lindau protein function leads to elevated levels of hypoxia inducible factor α and consequent over expression of vascular endothelial growth factor and platelet-derived growth factor.[7] These growth factors promote tumor angiogenesis, which likely contributes to the hypervascularity of RCC. Thus, inhibition of vascular endothelial growth factor and platelet-derived growth factor signaling pathways may, in part, reverse the physiologic consequences of losing von Hippel-Lindau protein function and inhibit tumor progression.[7],[8] Cytokine therapy with interferon=α (IFN=α) or interleukin = 2 (IL-2) produces a response in approximately 15% of patients, having advanced renal cancer [Table 1]. Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor that specifically inhibits vascular endothelial growth factor receptor (types 1-3) and platelet-derived growth factor receptor (α and β), as well as other tyrosine protein kinases.[8],[9],[10],[11] In an initial phase 2 study of sunitinib in cytokine-refractory metastatic RCC patients, an objective response rate of 40% was observed in 63 patients (95% confidence interval, 28-53%), which is unprecedented in this patient population.[12] Sunitinib was approved in 2006 as a treatment for kidney cancer in USA (January-2006) and in Europe (July-2006 as a second line therapy). Sunitinib was approved for first line treatment of metastatic RCC in Europe in January 2007. Sunitinib has since become a reference standard of care that is recommended in international treatment guidelines for the first-line treatment of favorable or intermediate-risk metastatic RCC.[13],[14] This study was carried out to confirm the antitumor efficacy of single-agent sunitinib in patients with metastatic clear-cell RCC at our institute in Indian patients.
Table 1: Historical experience with systemic therapy for metastatic renal cell carcinoma

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 » Methods Top


This study is a retrospective analysis of patients treated at our institute. Source of data was treatment records of patients. An inclusion criterion was metastatic RCC patients treated with sunitinib. A total of 15 (9 males) patients, treated in 2010 and 2011, were reviewed. The reported data applied until Jan 2012. Sunitinib has been used in these patients as a first line or second line after progression from other approved treatment. A total of 13 patients had received dosage of 50 mg/d (4/2 cycles) while 2 patients received 37.5 mg/d as the starting dose. In 14 patients sunitinib was used as 1st line therapy, while one had been previously treated with sirolimus. Average no of sunitinib cycles were 4. Sunitinib was self-administered orally once daily with an empty stomach. Dose reduction for toxicity was allowed (to 37.5 mg/d then 25 mg/d) depending on the type and severity of toxicity encountered. Sunitinib treatment had been continued until disease progression, unacceptable toxicity, or patient's will.

The primary objective was to determine the antitumor efficacy (response rate) of single agent sunitinib in patients with metastatic RCC. Secondary objectives include evaluations of duration of response, progression free survival (PFS), overall survival (OS) and safety.

Evaluations

Baseline evaluations included medical history and physical examination, tumor assessments (tumor imaging with computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest, abdomen and pelvis; and bone scan); assessment of Eastern Cooperative Oncology Group (ECOG) performance status; laboratory measurements (hematology, clinical chemistry, coagulation, urinalysis, calcium and lactate dehydrogenase). 2D-Echo or electrocardiogram was done to evaluate cardiac function.

Assessment of efficacy and safety

The primary study end point was overall objective response rate, defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). Clinical response (CR, PR, stable disease [SD] and progressive disease) was assessed according to response evaluation criteria in solid tumors [8] using CT/MRI scans and bone scans (if bone metastases were present at baseline) at baseline and at regular intervals.

Other assessments conducted through treatment included adverse events; ECOG performance status, hematology and biochemistry profiles and cardiac function. Adverse events are assessed by severity according to the common terminology criteria for adverse events.[15]


 » Results Top


All 15 patients (100%) had received at least 1 dose of sunitinib. The median age was 51 years (range 32-73). Sex distribution was not so significantly different [Table 2], [Figure 1]. Out of 15 patients of metastatic RCC, 13 had undergone debulking nephrectomy. The lungs were the most prevalent site of metastases (53%) and 8 (53%) patients had 2 or more disease sites[Figure 2]. Most of the patients (n = 14) had more than 1 poor risk factor. Most common Memorial Sloan = Kettering Cancer Centre poor prognostic factor was an interval of <1 year between diagnosis and starting of treatment (80%). Other poor prognostic factors were ≥2 metastatic sites (53%), anemia (47%) and Kauffman firm survey <70 (20%)[Figure 3]. Thirteen patients had clear cell histology. Other 3 were papillary, chromophobe and adenocarcinoma.
Table 2: Patient baseline characteristics

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Figure 1: Age and sex distribution

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Figure 2: Metastatic site distribution

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Figure 3: Memorial Sloan=Kettering Cancer Center prognosis factors

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Among all study populations 13.66% (n = 2) patients had got objective response (CR + PR). Clinical benefit rate (CR + PR + SD) was 60% (n = 9) [Table 3] and [Figure 4]. Median PFS in this study was 7.5 months [Figure 6], with a range of 2-22 month and median OS of patients in this study was 12 months with a range of 3-24 month. An important dose/cycles to response relationship was seen in this study with patients having average no cycles >3 showing better response rates, PFS and OS, which is significant [Table 5] and [Figure 7].
Table 3: Best response to sunitinib treatment

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Figure 4: Best response of sunitinib

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Figure 5: Side effect of sunitinib

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Figure 6: Progression free survival result of sunitib

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Table 4: Most commonly reported treatment-related adverse events and selected laboratory abnormalities by grade

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Table 5: Dose response relationship

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Figure 7: The dose response relationship

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Safety results

Diarrhoea (n = 5) and fatigue (n = 7) were the most commonly reported treatment related adverse events (all were Grade 1-2 except 1 patient having Grade 3 fatigue) [Table 4] and [Figure 5]. Diarrhea had been managed by oral hydration and oral anti-diarrheal agents (e.g. Loperamide) as needed. Other adverse events included stomatitis (n = 4), hand foot syndrome (n = 1) (characterized by painful lesions on the palms and soles) and hypertension (n = 1) [Table 4]. Selected laboratory abnormalities are also listed in [Table 4]. Neutropenia (n = 1) was reported, but there are no reports of associated fever or sepsis. No one had reported any thyroid dysfunction or cardiac abnormalities.

In patients who had progressed, everolimus has been given in 8 patients and 3 patients had received sorafenib as a second line treatment.


 » Discussion Top


Metastatic RCC is one of the most challenging malignancies to treat, showing nearly universal resistance to all cytotoxic chemotherapeutic agents and limited sensitivity to radiation therapy.[3] In the era before the advent of the targeted therapy, cytokine therapy with IFN=α or IL-2 produces a response in approximately 15% of patients and a multitude of new chemotherapy agents previously studied as second line therapy after cytokines, failed to show any evidence of clinical benefit.[16],[17] [Table 1] Patients with metastatic RCC who progress to cytokine therapy are generally managed by supportive care (including radiation therapy) or treatment in clinical trials of experimental agents. The median time to progression for patients treated in clinical trials with other experimental chemotherapy agents as second line therapy or receiving supportive care is estimated to be between 2 and 4 months.[18]

However this scenario has quite significantly changed since the advent and approval of sunitinib. In the last 6 years, a range of targeted agents have been licensed in Europe for the treatment of metastatic RCC. The vascular endothelial growth factor binding monoclonal antibody bevacizumab was approved in 2007 in combination with IFN=α; the mammalian target inhibitor of rapamycin inhibitor sirolimus and everolimus were approved in 2007 and 2009, respectively:[18] And pazopanib joined sunitinib and sorafinib in the class of multi targeted kinase inhibitors in 2010. In addition, a number of next generation vascular endothelial growth factor receptors-targeted tyrosine kinase inhibitors are currently in late stage clinical development, including axitinib, tivozanib and cediranib.

Clear-cell RCC was selected as a tumor type for initial clinical study with sunitinib, based on the inhibitory properties against vascular endothelial growth factor receptor and platelet derived growth factor receptor.[10] The high expression of pro-angiogenic growth factors to these receptors is a consequence of genetic abnormalities that characterise clear-cell RCC and are believed to contribute to RCC tumor growth and angiogenesis. Since the advent, quite a few trials have shown efficacy of sunitinib in metastatic RCC.

One of the largest studies was published by Motzer et al., in 2007 that showed superiority of sunitinib over IFN=α in a randomized phase 3 trial.[19] In that study objective response rate was 31% with median PFS was 11 months (primary end point).

Another study analyzed sunitinib in an unselected population of Korean patients. One hundred and thirty-two histological confirmed advanced RCC patients were enrolled. The PFS was 8.2 months and OS was 23.1 months. Nearly 7.6% of the patients discontinued due to adverse effects. The most common toxicity in this study was hematologic (anemia, thrombocytopenia and neutropenia).[20]

Another particularly important study to note is the one, done at Tata Memorial Hospital, India (Krishna et al.), recently.[21] In that study, patients who had received prior cytokine therapy, patients with performance status 2 or 3, impaired renal function, low hemoglobin and non-clear cell pathology were also included. Despite these factors, the overall clinical benefit rate (CR + PR + SD) was 76%, estimated median PFS and OS were 11.4 and 22.6 months respectively.

The results of our study confirm that sunitinib given once daily according to 4 weeks on/2 weeks off schedule have substantial antitumor effects against metastatic clear-cell RCC.

The sunitinib adverse event profile was acceptable as an orally administered outpatient therapy. Diarrhea and fatigue were the most commonly reported treatment related adverse events. Other commonly reported treatment related adverse events were stomatitis, hand foot syndrome and hypertension. In most instances, symptoms improved with dose modification. Cardiac toxicity is also one of the reported side effects in the literature with the use of sunitinib but overt cardiac failure was not seen in any of our study population. Grade 3-4 toxicities were also very few in our study and that are also related to mucositis only. The reason for a different toxicity profile needs to be further investigated. As discussed previously, our patients were an unselected group and had co morbidities, such as low hemoglobin, low albumin and impaired renal function. The metabolism of sunitinib and polymorphisms in the genetic profile of Indian patient is unknown.

In our study over all response rate is 60% which is almost equivalent to other previous studies. However, PFS and OS were 7.5 and 11 months respectively, which is considerably less than that seen in other studies. The reason for this might be a small sample size. Moreover side effect profile is similar to that seen in Tata hospital study, but different from other western studies. This difference needs to be investigated further, may be due to the genetic cause.


 » Conclusion Top


Sunitinib is one of several agents (including sorafenib and bevacizumab) that target the inhibition of proangiogenic growth factor activity and show activity in clinical trials against metastatic clear cell RCC. The data from this study confirm that the approach is a valid therapeutic strategy for clear cell RCC as studied earlier. Moreover, since systemic therapy options for RCC have been limited to cytokines, these therapies represent a new paradigm in the management of this notorious elusive malignancy. Although toxicity remains a concern, most of the adverse effects can be managed conservatively. Careful patient selection, tailoring the dose of therapy, adequate counseling and careful follow-up are essential for optimum therapy.


 » Acknowledgments Top


Dr. Shilin N. Shukla (MD, Hon director Gujarat Cancer and Research Institute Ahmedabad), Dr. Pankaj M. Shah (MD, Ex. Director Gujarat Cancer and Research Institute Ahmedabad), Dr Shailesh S. Talati (MD, Professor, Department of Medical and Paediatric Oncology GUJARAT Cancer and Research Institute Ahmedabad), Dr. Bharat J Parikh (MD, Ex Professor Department of medical and paediatric oncology Gujarat Cancer and Research Institute ahmedabad), Dr. Asha N. Anand (MD, DM Professor Department of Medical and Paediatric Oncology Gujarat Cancer and Research Institute Ahmedabad), Patients of Gujarat Cancer and Research Institute.

 
 » References Top

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Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, FIglin AR, et al. Activity of SU11248, a multi-targeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16-24.  Back to cited text no. 16
    
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Escudier B, Chevreau C, Lasset C, Douillard JY, Ravaud A, Fabbro M, et al. Cytokines in metastatic renal cell carcinoma: Is it useful to switch to interleukin=2 or interferon after failure of a first treatment? Groupe Français d'Immunothérape. J Clin Oncol 1999;17:2039-43.  Back to cited text no. 17
    
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Kondo K, Yao M, Yoshida M, Kishida T, Shuin T, Miura T, et al. Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: Relationship to clinicopathological parameters. Genes Chromosomes Cancer 2002;34:58-68.  Back to cited text no. 18
    
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Kim HS, Hong MH, Kim K, Shin SJ, Ahn JB, Jeung HC, et al. Sunitinib for Asian patients with advanced renal cell carcinoma: A comparable efficacy with different toxicity profiles. Oncology 2011;80:395-405.  Back to cited text no. 20
    
21.
Krishna VM, Noronha V, Prabhash K, Joshi A, Patil V, Bhosale B, et a l. Sunitinib in metastatic renal cell carcimoma: A single-center experience. Indian J Cancer 2013;50:268-73.  Back to cited text no. 21
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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