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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 4  |  Page : 626-630
 

First-line tyrosine kinase inhibitors in metastatic renal cell carcinoma: A regional cancer center experience


Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Web Publication30-Jul-2018

Correspondence Address:
Dr. Tamojit Chaudhuri
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_380_17

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 » Abstract 


BACKGROUND: Renal cell carcinoma (RCC) is highly resistant to systemic chemotherapy, and historically a poor prognosis for metastatic disease has been reported, with a 5-year survival rate of <10%. Significant advances have been made in the last decade since the introduction of different tyrosine kinase inhibitors (TKIs) such as sunitinib, pazopanib, and sorafenib. Unfortunately, even though the TKIs have been used for a long time, there are very few published data regarding the experience of TKI therapy in metastatic RCC (mRCC) from India. MATERIALS AND METHODS: This is a single institutional review of mRCC patients treated between January 2012 and July 2017. Patients who received at least 1 month of first-line TKIs were included for analysis of response rates, toxicity, survival outcomes, and prognostic factors. RESULTS: Of the 40 mRCC patients, 31 (77.5%) were males. Median age at diagnosis was 58 years (range: 38–80 years). The most common site of metastasis was lungs (n = 24) followed by bone (n = 19) and liver (n = 7). Three patients had favorable risk disease, whereas 25 had intermediate risk and 12 had poor risk disease according to the MSKCC risk criteria. First-line TKI therapy used was sunitinib in 24, pazopanib in 11, and sorafenib in 5 patients. Toxicities of TKIs were Grade 1 or 2 in 13 patients and Grade 3 or 4 in 9 patients; the most common being fatigue, followed by hand-foot syndrome, skin rash, mucositis, and hypertension. Overall, 29 patients (72.5%) had disease control (complete responses in 1, partial responses in 10, and stable disease in 18 patients), whereas 11 had progression of disease at initial evaluation. At a median follow-up of 16 months (range: 2–38 months), median progression-free survival (PFS) was 10.8 months and median overall survival was 19.1 months. CONCLUSIONS: Sunitinib and pazopanib are viable first-line options for mRCC and showed a comparable PFS in Indian patients. Careful patient selection, tailoring of TKI doses, and careful toxicity management are essential for optimum therapy.


Keywords: Metastatic renal cell carcinoma, pazopanib, sorafenib, sunitinib


How to cite this article:
Rudresha A H, Chaudhuri T, Lakshmaiah K C, Babu GK, Lokanatha D, Jacob LA, Suresh Babu M C, Lokesh K N, Rajeev L K. First-line tyrosine kinase inhibitors in metastatic renal cell carcinoma: A regional cancer center experience. Indian J Cancer 2017;54:626-30

How to cite this URL:
Rudresha A H, Chaudhuri T, Lakshmaiah K C, Babu GK, Lokanatha D, Jacob LA, Suresh Babu M C, Lokesh K N, Rajeev L K. First-line tyrosine kinase inhibitors in metastatic renal cell carcinoma: A regional cancer center experience. Indian J Cancer [serial online] 2017 [cited 2020 Sep 29];54:626-30. Available from: http://www.indianjcancer.com/text.asp?2017/54/4/626/237894





 » Introduction Top


According to the GLOBOCAN estimates, 338,000 new cases of kidney cancer were diagnosed in 2012 worldwide accounting for 2.2% of all adult cancers.[1] In India, 9658 new cases of kidney cancer were diagnosed in 2012, with an age-standardized incidence rate of 1%.[1] Renal cell carcinoma (RCC) is the most common form of kidney cancer (90% of cases).[2] It is nearly twice as common in men as in women, with a median age at diagnosis of 64 years.[2] Clear cell tumors are the most common pathological subtype of RCC (80% of cases); other less common subtypes include papillary, chromophobe, and collecting duct tumors.[2],[3],[4] Smoking, obesity, and hypertension are well-known risk factors for RCC.[5] It primarily metastasizes to the lung, bone, liver, lymph nodes, adrenal gland, and brain.[5] Although the 5-year overall survival (OS) of early-stage RCC is as high as 66%, metastatic or advanced stage disease is only 8%–10%.[6],[7] Moreover, local recurrence or distant metastasis develops in up to 30%–40% of patients treated for localized stage disease.[8],[9] Metastatic RCC (mRCC) responds very poorly to conventional chemotherapy. Cytokine therapy is associated with modest response rates of 15%–20% but at the cost of significant toxicities.[10] Therefore, until recently, there was a dearth of effective systemic therapies for metastatic disease.

The last two decades have seen a better understanding of the genetic abnormalities underlying clear cell RCC, and advances in molecular biology have led to the development of new targeted agents. Studies have showed that, in both sporadic clear cell RCC and patients with von Hippel–Lindau (VHL) syndrome, genetic mutations result in decreased functioning of VHL gene product, which leads to elevated levels of hypoxia-inducible factor-α, and consequently, overexpression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor.[11] Thus, any drug targeting these molecular pathways may, in part, reverse the physiologic consequences of losing VHL protein function, and consequently inhibit tumor angiogenesis, tumor growth, and metastasis in mRCC patients. The proof of this concept was provided by an initial Phase II study of sunitinib, an oral multitarget tyrosine kinase inhibitor (TKI), in cytokine refractory mRCC patients.[12] An objective response rate of 40% was found in 63 patients, which was unprecedented in this patient population. Since then, multiple randomized trials have established the benefit of sunitinib and other multitarget TKIs (e.g., pazopanib, sorafenib) in mRCC.

Unfortunately, even though the TKIs have been used for a long time, there are very few published data of the experience of the first-line TKI therapy in mRCC from India. The aim of this retrospective study was to review the clinical data of patients with mRCC treated at our institute and to evaluate the survival outcomes and toxicity profile of various TKI therapies in the first-line setting in this patient population.


 » Materials and Methods Top


Patient selection, evaluation, and treatment

All consecutive cases diagnosed with mRCC and received at least 1 month of first-line TKI therapy between January 2012 and July 2017 at the Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India were investigated retrospectively. All patients underwent a detailed baseline evaluation including full medical history, physical examination, complete blood count, serum biochemical analysis, viral markers, electrocardiography, two-dimensional echocardiography, bone scan, and contrast-enhanced computed tomography (CECT) of the thorax, abdomen, and pelvis.

Patients were offered any one of the following first-line TKI therapy: sunitinib (50 mg orally once a day in 4 weeks on/2 weeks off cycle or 2 weeks on/1 week off cycle), pazopanib (orally at a once-daily dose of 800 mg), or sorafenib (orally at a twice-daily dose of 400 mg). Dose reductions for sunitinib (to 37.5 mg and then to 25 mg), pazopanib (to 600 mg and then to 400 mg), and sorafenib (to 400 mg once daily and then to 400 mg every other day) were determined according to the standard guidelines depending on the severity of adverse events. Patients were treated until documented disease progression, unacceptable toxicity, or withdrawal of consent. Response evaluation CECT scans were performed at every 3-month interval during TKI therapy and at any time, if clinically indicated. Response to TKI was classified according to Response Evaluation Criteria in Solid Tumors, version 1.1, based on clinicoradiological evaluation. The adverse events were classified based on the National Cancer Institute of Canada Common Terminology Criteria for Adverse Events, version 4.0.

Statistical analysis

Duration of progression-free survival (PFS) was defined by the time from the treatment initiation until the documented disease progression, and OS was calculated from the date of diagnosis until death. Median PFS and OS were taken as the primary end points for this retrospective analysis, and the secondary end points were response rates and toxicity profile. All statistical analyses were performed using SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).


 » Results Top


Patient characteristics

A total of forty cases of mRCC were retrospectively reviewed. Median age at diagnosis was 58 years and majority were males (n = 31, 77.5%). Thirty-eight (95%) patients had clear cell histology and 2 patients had papillary carcinoma. At presentation, median hemoglobin and serum calcium were 10.4% gm (range, 7.1–13.4) and 9.8 mg/dL (range, 8.0–11.8), respectively; whereas the median serum lactate dehydrogenase and creatinine were 224 U/L (range, 160–870) and 1.1 mg/dL (range, 0.7–2.2), respectively. Other baseline demographic and clinical characteristics are summarized in [Table 1].
Table 1: Baseline patient characteristics (n=40)

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Tyrosine kinase inhibitor therapy characteristics

Patients were treated with first-line sunitinib (n = 24), pazopanib (n = 11), or sorafenib (n = 5). Seventeen patients in the sunitinib arm (n = 24) were started on a 4-week on/2-week off schedule, and of them, 7 patients (41%) had dose interruptions or delays, requiring dose reductions due to Grade 3-4 toxicity. The other seven patients in the sunitinib arm received sunitinib in a 2-week on/1-week off schedule, and none of them required any dose modification. Out of the 11 patients in the pazopanib arm, 2 (18%) required dose reductions due to hepatotoxicity. None of the patients in the sorafenib arm (n = 5) required any dose modification.

Efficacy and survival

The response rates with various TKIs are summarized in [Table 2]. Overall, 29 patients (72.5%) had disease control (complete responses in 1, partial responses in 10, and stable disease in 18 patients), whereas 11 had progression of disease at initial evaluation. At the time of last follow-up, 7 patients in the sunitinib arm, 4 patients in the pazopanib arm, and 1 patient in the sorafenib arm were still on TKIs. At a median follow-up of 16 months (range: 2–38 months), median PFS was 10.8 months and median OS was 19.1 months, for the whole cohort (n = 40). The median PFS and OS were 11.8 months (95% confidence interval [CI]: 8.9–14.6) and 20.8 months (95% CI: 18.2–22.7) with sunitinib; 11.2 months (95% CI: 8.0–16.7) and 20.1 months (95% CI: 17.0–22.4) with pazopanib; and 5.3 months (95% CI: 3.1–7.4) and 11.0 months (95% CI: 9.8–14.3) with sorafenib [Figure 1] and [Figure 2]. The differences in median PFS and OS between the sunitinib arm and the pazopanib arm were not statistically significant (log-rank P > 0.05). However, the median PFS and OS of the sorafenib arm were statistically inferior than those of the other two TKIs (log-rank P < 0.01).
Table 2: Response rates with various tyrosine kinase inhibitors (n=40)

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Figure 1: Kaplan–Meier estimates of progression-free survival (in months) of the metastatic renal cell carcinoma patients treated with the 1st line sunitinib, pazopanib, and sorafenib

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Figure 2: Kaplan–Meier estimates of overall survival (in months) of the metastatic renal cell carcinoma patients treated with the 1st line sunitinib, pazopanib, and sorafenib

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Toxicity profile

Toxicities were Grade 1 or 2 in 13 patients (32.5%) and Grade 3 or 4 in 9 patients (22.5%). Fatigue, hand-foot syndrome, skin rash, mucositis, and thyroid dysfunction were more common in the sunitinib arm, whereas hepatotoxicity in the form of elevation of liver enzymes was more common with pazopanib. The overall toxicity profile of TKI therapy is summarized in [Table 3].
Table 3: Toxicity profile of tyrosine kinase inhibitors (n=40)

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 » Discussion Top


In the past decade, treatment options for mRCC have expanded dramatically with better understanding of the tumor biology and underlying molecular mechanisms responsible for tumor angiogenesis and metastases. Cytokines (e.g., interferon-alfa and interleukin-2) have been largely replaced by targeted agents, having favorable toxicity profiles and associated with higher response rates, longer PFS, or both. These agents, including anti-angiogenic drugs (e.g., TKIs), mTOR inhibitors, and immune checkpoint inhibitors, have improved the clinical outcomes of this difficult-to-treat metastatic cancer, which is otherwise universally resistant to conventional chemotherapeutic agents. Currently, at least ten agents (sunitinib, pazopanib, sorafenib, axitinib, cabozantinib, lenvatinib, bevacizumab, temsirolimus, everolimus, and nivolumab) have been approved by the Food and Drug Administration for the treatment of mRCC, with several more agents in the late stage of clinical development. Sunitinib and pazopanib are oral multi-targeted TKIs against the VEGF receptors 1, 2, and 3, platelet-derived growth factor receptors, and other tyrosine kinases. As per the current clinical practice, both are commonly being used as the first-line treatment in mRCC patients.

In a landmark randomized Phase III study published in 2007, Motzer et al. showed the superiority of sunitinib over interferon-alfa as a first line therapy in mRCC patients.[13] The objective response rate was 31%, and the median PFS (primary end point) was 11 months, with sunitinib. The major toxicities in the sunitinib arm were diarrhea, mucositis, and hand-foot syndrome. A total of 38% of the patients had a dose interruption and 32% had dose reduction due to toxicity. In an updated report of this study, the OS with sunitinib was 26.4 months.[14] On the other hand, pazopanib has been associated with higher objective response rates (30% vs. 3%, respectively) and longer PFS (9.2 months vs. 4.2 months, respectively) than placebo, in randomized Phase III trial setting.[15],[16] In a seminal Phase III trial of sunitinib versus pazopanib as the first-line treatment, pazopanib was noninferior to sunitinib with respect to PFS and OS.[17],[18] However, at the same time, these drugs have different toxicity profiles; pazopanib was associated with a higher incidence of hepatic toxicity, whereas sunitinib was associated with a higher incidence of fatigue, hand-foot syndrome, and thrombocytopenia.[17],[18] The sunitinib-related toxic effects had a greater impact on day-to-day activities, as reflected by patient-assessed health-related quality of life, which favored pazopanib over sunitinib.[19]

To our knowledge, till date, there are very few published reports of the experience of TKI therapy in Indian patients with mRCC. In 2013, Krishna et al. reported the outcomes of first-line sunitinib in 59 patients with mRCC who were treated at Tata Memorial Hospital, Mumbai.[20] In that study, patients who received prior cytokine therapy (n = 7), patients with performance status 2 or 3 (n = 9), impaired renal function, low hemoglobin, and nonclear cell pathology (n = 3) were also included. Lungs and bones were the most common sites of metastases. The patients received a median number of 4 cycles (range, 1–18), with 23 requiring dose modification and 12 discontinuing therapy due to toxicity (e.g., hand-foot syndrome, fatigue, mucositis, skin rash, and vomiting). The clinical benefit rate was 65% (n = 38), whereas 14 patients had disease progression or death at initial evaluation. The median PFS was 11.4 months and the median OS was 22.6 months.

Another particularly important study to note is the one done at the Gujarat Cancer and Research Institute, Gujarat, and reported in 2016.[21] In that retrospective analysis, Patel et al. reported their experience of the first-line sunitinib therapy in 15 patients with mRCC of clear cell histology.[21] The objective response rate with sunitinib was 13.66%, and clinical benefit rate was 60% (n = 9). Median PFS was 7.5 months (range, 2–22 months), and median OS was 12 months (range, 3–24 months). An impact of the dose and/or number of cycles on response was seen in that 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 of patients experiencing Grade 1-2 toxicities.

Finally, there have been several studies of the first-line sunitinib therapy in mRCC from other Asian countries that have shown similar PFS and OS with different toxicity profiles.[22],[23] The current study also showed comparable results.


 » Conclusions Top


In the current study, we retrospectively investigated the demographic and clinical features of mRCC cases together with an analysis of survival outcomes and toxicity profiles of different first-line TKIs in this patient population. Sunitinib and pazopanib are viable first-line options for mRCC and showed a comparable PFS and OS with different toxicity profiles in Indian patients. Although toxicity of sunitinib, particularly with a 4-week on/2-week off schedule, remains a concern, most adverse effects can be managed conservatively with careful dose modification. Clearly, larger prospective studies from other Indian centers are required for obtaining a better picture of mRCC and outcomes of various first-line TKI therapies in Indian patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Leibovich BC, Lohse CM, Crispen PL, Boorjian SA, Thompson RH, Blute ML, et al. Histological subtype is an independent predictor of outcome for patients with renal cell carcinoma. J Urol 2010;183:1309-15.  Back to cited text no. 2
    
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Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: Renal, penile, and testicular tumours. Eur Urol 2016;70:93-105.  Back to cited text no. 4
    
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Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol 2010;7:245-57.  Back to cited text no. 5
    
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Amato RJ. Renal cell carcinoma: Review of novel single-agent therapeutics and combination regimens. Ann Oncol 2005;16:7-15.  Back to cited text no. 7
    
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Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003;30:843-52.  Back to cited text no. 8
    
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Lam JS, Leppert JT, Belldegrun AS, Figlin RA. Novel approaches in the therapy of metastatic renal cell carcinoma. World J Urol 2005;23:202-12.  Back to cited text no. 9
    
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Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe français d'immunothérapie. N Engl J Med 1998;338:1272-8.  Back to cited text no. 10
    
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Kondo K, Kaelin WG Jr. The von Hippel-Lindau tumor suppressor gene. Exp Cell Res 2001;264:117-25.  Back to cited text no. 11
    
12.
Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25-35.  Back to cited text no. 12
    
13.
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. 13
    
14.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-90.  Back to cited text no. 14
    
15.
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. 15
    
16.
Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: Final overall survival results and safety update. Eur J Cancer 2013;49:1287-96.  Back to cited text no. 16
    
17.
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-31.  Back to cited text no. 17
    
18.
Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 2014;370:1769-70.  Back to cited text no. 18
    
19.
Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. J Clin Oncol 2014;32:1412-8.  Back to cited text no. 19
    
20.
Krishna VM, Noronha V, Prabhash K, Joshi A, Patil V, Bhosale B, et al. Sunitinib in metastatic renal cell carcinoma: A single-center experience. Indian J Cancer 2013;50:268-73.  Back to cited text no. 20
[PUBMED]  [Full text]  
21.
Patel KB, Panchal HP, Karanwal AB, Parekh BB, Shah S, Prasad S, et al. Sunitinib in metastatic renal cell carcinoma: Experience from single center study, efficacy and safety. Indian J Cancer 2016;53:118-22.  Back to cited text no. 21
[PUBMED]  [Full text]  
22.
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. 22
    
23.
Li XS, Wu X, Zhao PJ, Huang LH, Song Y, Gong K, et al. Efficacy and safety of sunitinib in the treatment of metastatic renal cell carcinoma. Chin Med J (Engl) 2011;124:2920-4.  Back to cited text no. 23
    


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