|Year : 2013 | Volume
| Issue : 3 | Page : 268-273
Sunitinib in metastatic renal cell carcimoma: A single-center experience
VM Krishna1, V Noronha1, K Prabhash1, A Joshi1, V Patil1, B Bhosale1, T Ravi1, H Menon1, S Gupta1, SD Banavali1, G Bakshi2, HB Tangaonkar2
1 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
2 Department of Urologic Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
|Date of Web Publication||23-Sep-2013|
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Introduction: Historically, metastatic renal cell carcinoma (RCC) has had poor prognosis; the outcomes have improved with the introduction of tyrosine-kinase inhibitors, such as sunitinib. There is no reported literature from India on the use of sunitinib in metastatic RCC. We present an analysis of sunitinib at our institute over 4 years. Materials and Methods: An unselected population of patients with metastatic or relapsed metastatic RCC receiving sunitinib was analyzed with respect to patient characteristics, response, toxicity, and outcomes. Results: Fifty-nine patients (51 males, 8 females) with a median age of 55 years were included in the study. Lungs and bones were the most common site of metastases. The patients received a median number of 4 cycles, with 23 patients requiring dose-modification and 12 discontinuing therapy due to toxicity. Overall, 38 patients (65%) had CR, PR, or standard deviation while 14 had progression or death at initial evaluation. The median progression-free survival (PFS) was 11.4 months and overall survival was 22.6 months. Hand-foot syndrome, fatigue, mucositis, skin rash, and vomiting were seen more often among our patients, whereas hypertension was not as common compared with previously published reports. Conclusion: Sunitinib is a viable option for the treatment of metastatic RCC and shows a comparable PFS in Indian patients. 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 is essential for optimum therapy.
Keywords: Metastatic, renal cell cancer, sunitinib, targeted therapies, tyrosine kinase inhibitors
|How to cite this article:|
Krishna V M, Noronha V, Prabhash K, Joshi A, Patil V, Bhosale B, Ravi T, Menon H, Gupta S, Banavali S D, Bakshi G, Tangaonkar H B. Sunitinib in metastatic renal cell carcimoma: A single-center experience. Indian J Cancer 2013;50:268-73
|How to cite this URL:|
Krishna V M, Noronha V, Prabhash K, Joshi A, Patil V, Bhosale B, Ravi T, Menon H, Gupta S, Banavali S D, Bakshi G, Tangaonkar H B. Sunitinib in metastatic renal cell carcimoma: A single-center experience. Indian J Cancer [serial online] 2013 [cited 2019 Jun 26];50:268-73. Available from: http://www.indianjcancer.com/text.asp?2013/50/3/268/118725
| » Introduction|| |
Renal cell carcinoma (RCC) presents with metastasis in around 30% of the cases; up to 25% of patients who undergo localized resection can relapse with metastases. , Metastatic RCC has poor response to conventional chemotherapy. Cytokine therapy with interferon-alfa or interleukins is associated with modest response rates of less than 20% and significant toxicities. ,
The prognosis and treatment of RCC has undergone a sea change in recent times due to an improved understanding of the underlying molecular pathways in RCC. In clear-cell carcinoma, the most common type of RCC, Von-Hippel-Landau (VHL) gene is found to be deleted, mutated, or altered in up to 80% of the patients.  The normal function of the product of this tumor-suppressor gene is the regulation of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and other hypoxia-inducible factors (HIF).  Consequently, inactivation of the VHL gene causes persistent stimulation of the HIF-alpha, which then leads to activation of HIF and consequently, tumor angiogenesis, tumor growth, and metastasis. Logically, any drug targeting these pathways ought to be beneficial in mRCC. The proof of concept was provided by phase II trials of sunitinib, an orally administered multiple tyrosine kinase inhibitor, including VEGF-R types 1-3, PDGF-R-alpha, and PDGF-R-beta. , Since then, multiple randomized trials have established the benefit of sunitinib with respect to increased response rates, increased progression-free and overall survival (OS) with acceptable quality of life when used as the first-line therapy of mRCC. The experience with sunitinib has been mainly reported in western populations and a few studies in Asian patients. We present our experience with sunitinib at a tertiary care referral care 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 an unselected group of Indian patients, who received sunitinib for metastatic RCC at Tata Memorial Hospital between January, 2007 and October, 2011. The patients were given sunitinib as the first therapy or at relapse after initial treatment. We included patients who had received any prior therapy, including other TKIs or cytokine therapy. The patients were analyzed with respect to the demographic profile, sites of metastases, starting dose of sunitinib, response, toxicity profile, PFS, and OS. The presence of comorbidites, especially hypertension and performance status were noted. Patients were started on sunitinib at a dose of 50 mg once a day for 4 weeks and then a gap of 2 weeks with dose modification depending on the toxicity. Response to treatment was based on clinical progression and on radiology. Since the imaging was done at different centers by different radiologists, a central review and RECIST (response Evaluation Criteria in Solid Tumors) criteria could not be applied to all the patients. Response was classified as complete response, partial response, stable disease, or progressive disease, based on radiologist's opinion and clinical status. Clinical progression and cancer-related deaths were considered as progression. Response evaluation was done after 2-4 cycles of sunitinib. Progression-free survival (PFS) was calculated as the time between start of therapy and the date of progression or death from any cause. OS was calculated as the time between start of therapy and the date of death due to any cause. Toxicity profile was calculated according to the common terminology criteria for adverse effects (CTCAE) version 4.0. Statistics were calculated using SPSS. Survival was calculated using Kaplan-Meir method.
| » Results|| |
There were 62 patients planned for therapy. Three patients did not follow-up after initial visit. There were 59 patients who had documented progression, death, or received sunitinib for at least 2 cycles. The patient profile is shown in [Table 1]. Most of the patients were male (86.4%) with a median age of 56 years (range, 32-77 years; 17 patients of age 60 years and above). Twenty-eight patients had localized disease at presentation and underwent surgery upfront. One patient was inoperable and hence was started on sunitinib. Although adjuvant therapy not considered as a standard practice, a few patients had received adjuvant interferon off-protocol. Of the 5 patients who received adjuvant therapy, 2 progressed while on treatment after 12 months and 7 months. Three other patients progressed after 7, 36, and 78 months of starting therapy. The remaining 22 patients who were nonmetastatic at presentation had a relapse after a median period of 20 months (range, 3-120 months).
Thirty-one patients (52.5% of the patients) had metastatic disease at presentation. Twenty of these patients underwent cytoreductive nephrectomy before starting sunitinib. Among the total patient set, 51 patients received sunitinib as the first line of therapy, 3 as the second line, 2 as the third line, and 3 as the fourth line. The agents used prior to sunitinib were interferon-alpha (5 patients), bevacizumab, and thalidomide (3 cases each); high-dose interleukin-2 (2 patients); everolimus, sorafenib, vinblastine, and gemcitabine (1 case each). Pathology was reviewed in our institute in 55 patients; 52 had conventional clear cell carcinoma while transitional cell carcinoma, papillary cell carcinoma, and sarcomatoid carcinoma were diagnosed in 1 case each.
Overall, the most common site of metastasis was the lung (59.3%). The skeletal system was the next common site, followed by lymph nodes and liver involvement. Most of the patients had performance status of ECOG 0 or 1 (50 patients, 85%); 6 patients (10%) had performance status 2 at baseline. The median creatinine in our patients was 1.2 mg/dL (range, 0.8-2.6; 8 patients ≥1.5), whereas the median hemoglobin at baseline was 11.6 gram% (range, 7.8-15.2; 18 patients below 11 g%). The median albumin was 3.8 g/dL (range, 2.2-5.0; 12 patients below 3.5 g/dL).
The starting dose of sunitinib is detailed in [Table 2]. All the patients were started at a dose of 50 mg once a day for 4 weeks and then 2 weeks rest except for 2 patients who received 37.5 and 25 mg in view of impaired performance status. Of these patients, 23 had dose interruptions or delays and 23 (39%) required dose modification due to toxicity. Three patients did not tolerate the new dose and required further reduction in dose.
The response rate is documented in [Table 3]. None of the patients achieved complete remission after 2-4 cycles of sunitinib. Two patients expired due to progression during the first cycle while 4 patients discontinued therapy due to toxicity and 3 did not do any imaging after initial presentation and were lost to follow-up. Of the remaining 50 patients, 11 (22%) had partial response and 27 (54%) had stable disease. The overall clinical benefit rate [(CR + PR + standard deviation (SD)] was 76%. Twelve had progression at initial evaluation. On follow-up, there were 10 deaths while 7 more patients discontinued therapy due to toxicity. One patient discontinued therapy after 15 cycles due to unwillingness for further therapy. At the time of writing, 14 were on therapy with sunitinib. With a median follow-up of 8 months (range, 1.4-36.5 months), the overall estimated median PFS in our study was 11.4 months. The estimated median OS was 22.6 months [Figure 1].
The toxicity profile is documented in [Table 4]. As this is a retrospective analysis, the documentation of toxicity is based on clinical follow-up notes and may not be complete. While all the grade 3-4 toxicities have been recorded, the same is not true for grade 1-2. Overall, 11 patients (18.6%) discontinued therapy at some point due to toxicity. The cause of discontinuation was a combination of factors, including extensive mucositis (5/11), recurrent hyponatremia (2/11), debilitating hand-foot syndrome (8/11), fatigue (6/11), and extensive upper limb DVT, recurrent hematuria, and persistent thrombocytopenia (despite dose reduction) in 1 patient each.
The most common grade 3 and 4 adverse effects were fatigue occurring in 53% patients followed by hand-foot syndrome in 51% and skin rash in 39%. Mucositis was seen in 29% of the patients. Other side effects seen (all grades) were yellow skin discoloration, fever, diarrhea, fluid retention, anorexia, vomiting, and hematuria. Uncommon toxicities noted during the course of treatment included inflammatory plexopathy, scrotal ulcers, and deep vein thrombosis, which occurred in 1 patient each. One patient who was treated for leprosy in the past had a flare-up of leprosy and required dermatologic consultation and antileprotic treatment.
Hematologic toxicity in the form of grade 3 and 4 anemia, thrombocytopenia, and neutropenia occurred in 3, 10, and 4 patients, respectively. Two patients had grade 3 febrile neutropenia. An 18.6% (11 patients) required admission for treatment-related complications and for supportive care. A total of 14 patients (23.7%) had thyroid function abnormalities, 12 having raised thyroid stimulating hormone, and 2 having increased T3 and T4. Eight required treatment; 6 were on thyroid supplements, while 2 required antithyroid medication. Eighteen patients were hypertensive at the time of starting sunitinib. A further 13 patients developed hypertension during the treatment. All these patients except one were well controlled with medications alone and did not require any dose-modification of sunitinib for hypertension. Renal dysfunction and rising serum creatinine was observed in 6 patients.
In the patients who had progression (23 patients) or unacceptable toxicity (11 patients), second-line treatment was started in 12 patients [Table 3]. Four patients received the mTOR inhibitor everolimus. Of these, 3 did not follow-up for evaluation, the fourth patient progressed after 4 months of treatment. Seven patients were treated with another TKI sorafenib. Three patients had progression after 2, 3, and 10 months, whereas 1 patient has stable disease after 7 months. The other 3 patients are lost to follow-up. One patient was started on high-dose interleukin-2 but progressed after 6 weeks of treatment.
| » Discussion|| |
The treatment of metastatic RCC has been revolutionized over the past decade with increased understanding of the tumor biology and recognizing the importance of the VHL gene and the receptor tyrosine kinases in tumor metastases. Presently, at least 6 agents (sunitinib, sorafenib, bevacizumab, pazopanib, temsirolimus, and everolimus) have been approved by the Federal Drug Agency with several more in the pipeline.  All these drugs have increased the PFS compared with standard therapy and placebo in metastatic RCC and can be used upfront as well as in the relapsed setting. Sunitinib and temsirolimus have been associated with OS benefit. Although no direct comparison has been done, an indirect meta-analysis of 6 trials showed superiority of sunitinib over sorafenib and bevacizumab-interferon alpha.  In the same analysis, temsirolimus was shown to have benefit in poor-prognosis patients.
Motzer et al. published the seminal paper in 2007 that established the superiority of sunitinib over interferon-alfa in a randomized phase 3 trial.  Seven hundred and fifty previously untreated patients were randomized between sunitinib and interferon with the primary end point being PFS. The objective response rate was 31% for sunitinib. With a median duration of treatment of 6 months, the median PFS in this study was 11 months. The major toxicities in the sunitinib group were nausea, diarrhea, mucositis, and hand-foot syndrome. A total of 38% of the patients had a dose interruption and 32% had dose reduction in this study. Significantly, only 8% discontinued therapy due to toxicity. In the updated results published later, the OS with sunitinib was 26.4 months. 
The results of sunitinib used under an expanded access program were published later and included 4371 patients.  This was an unselected population and included patients with poor performance status (ECOG PS 2 or higher), non-clear cell histology, and age more than 65 years and brain metastases. The most common adverse effects were diarrhea and fatigue, with discontinuation due to adverse effects in 8% of the patients. The objective response rate (ORR) was 17%, median PFS was 10·9 months, and OS was 18·4 months.
Another study analyzed sunitinib in unselected population of Korean patients. One hundred and thirty-two histologically confirmed advanced RCC patients were enrolled.  The PFS was 8.2 months and OS rate was 23.1 months. A 7.6% of the patients discontinued due to adverse effects. The most common toxicity in this study was hematologic (anemia, thrombocytopenia, and neutropenia). The authors concluded that their patients had comparable treatment outcomes despite different toxicity profile. Similar results were reported in a group of Chinese patients.  The PFS in this study was 15 months and the most common adverse effects were hand-foot syndrome (77.8%), thrombocytopenia (75.0%), hypertension (61.1%), and diarrhea (46.0%).
To the best of our knowledge, the present study is the first one from India. We have studied an unselected population with metastatic RCC. Unlike the clinical trials, our patient cohort included patients who had received prior cytokine therapy, patients with performance status 2 or 3 (15%), impaired renal function (21 patients with creatinine greater than 1.3 mg/dL), low hemoglobin (18 patients with hemoglobin 11g% or less) and non-clear cell pathology (3 patients). Despite these factors, the overall clinical benefit rate (CR + PR + SD), estimated PFS and OS in our study are similar to the published literature. The patients who had progression or toxicity either did not start second-line therapy or could not continue therapy in 50% of the cases. The cost of therapy, toxicity, limited benefit, and logistical reasons (our patients are from across the country and not native to Mumbai) could be the reasons for inadequate follow-up.
The toxicity profile as highlighted in [Table 4] is different from the large studies reported in the western population. Our patients appear to have significantly greater incidence of fatigue, hand-foot syndrome, skin rash, and mucositis. The landmark study by Motzer et al. reported grade 3 and 4 mucositis at only 2%, whereas our study in an unselected population showed an incidence of more than 25%. The incidence of hypothyroidism appears to be similar and is manageable. Previous studies have shown that developing hypertension can act as a predictor of better response to sunitinib.  Significantly, in our study, the incidence of new-onset hypertension is lower than previously reported. All the patients save one had blood pressure adequately controlled with medication.
Cardiotoxicity is an important adverse effect with sunitinib and has been highlighted in various studies. , However, in our study, although we did not assess serial cardiac function by echocardiography, none of the patients developed overt cardiac failure.
Grade 3 and 4 hyponatremia was a significant complication noted in our patients with around 10% patients requiring inpatient admission and sodium supplementation. The patients had received treatment at their local hospital and further investigations for the cause of hyponatremia were not done. This side effect has not been highlighted in previous studies and should always be sought for in patients.
The reason for a different toxicity profile needs to be further investigated. As discussed previously, our patients were an unselected group and had comorbidities, 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. A study published recently from Spain assessed RECIST response, PFS, OS, and toxicity of sunitinib with 16 key polymorphisms in 9 genes and showed that polymorphisms in VEGFR3 and CYP3A5*1 were associated with lower responses and poorer tolerability.  Similar studies are warranted in Indian patients.
There have been several studies in Asian patients that have shown similar PFS of around 10 months with different toxicity profiles. ,, Our study too shows similar results with a different toxicity profile. Finally, second-line therapy with newer TKIs is well established in RCC. Newer molecules are being evaluated in this setting. One recent study showed superiority of axitinib over sorafenib in the second-line setting.  Our study did not have adequate number of patients for a definite conclusion; however, at least 2 patients had PFS of 7 months with sorafenib after progressing on sunitinib.
To conclude, sunitinib is a viable option for the treatment of metastatic RCC and shows a comparable response rate and survival in Indian patients. 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.
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[Table 1], [Table 2], [Table 3], [Table 4]
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