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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 6  |  Page : 1303-1311

Efficacy, safety, and prognostic indicators of first-line sunitinib in patients with metastatic renal cell carcinoma: A single center experience


1 Department of Clinical Oncology, University Malaya Medical Centre, Kuala Lumpur, Malaysia
2 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

Date of Web Publication28-Nov-2018

Correspondence Address:
Teng Aik Ong
Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.189247

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 > Abstract 


Background: We assessed the efficacy and safety of sunitinib as the first-line treatment in metastatic renal cell carcinoma (mRCC) patients. The predictors of survival and efficacy in mRCC as identified from previous studies, including the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic RCC Database Consortium (IMDC) factors, were also evaluated.
Patients and Methods: Data from 56 patients with mRCC, treated with sunitinib at our institute (2006–2014), were analyzed retrospectively. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated using univariate and multivariate analyses performed by log-rank test and Cox regression.
Results: Fifty-one (91.1%) patients received starting dose of sunitinib of 50 mg/day in 4/2 schedule. The median PFS was 12.7 months (95% confidence interval [CI], 4.5–20.9 months) and the median OS was 16.9 months (95% CI, 3.8–29.9 months). The objective response rate was 27.5%. Dose interruption and reduction due to toxicities were required in 37.5% and 60.7% of patients, respectively. The most common Grades 3–4 toxicities were hand-foot syndrome (HFS) (23.2%), thrombocytopenia (16.1%), and hypertension (14.3%). The Eastern Cooperative Oncology Group performance status ≥2, hemoglobin < lower limit of normal, neutrophil > upper limit of normal (ULN), platelet > ULN, no prior nephrectomy, metastatic sites >:1, liver metastases, lymph node metastases, and development of HFS were independent prognostic factors.
Conclusions: Sunitinib treatment has acceptable efficacy and safety profile in Malaysian mRCC patients. The MSKCC and IMDC factors are relevant for predicting survival in our patient cohort while HFS is a promising prognostic predictor which warrants further investigation.

Keywords: Efficacy, metastatic, prognostic, Renal cell carcinoma, safety, sunitinib


How to cite this article:
Abd Ghafar NK, Alip A, Ong TA, Yap NY, Saad M. Efficacy, safety, and prognostic indicators of first-line sunitinib in patients with metastatic renal cell carcinoma: A single center experience. J Can Res Ther 2018;14:1303-11

How to cite this URL:
Abd Ghafar NK, Alip A, Ong TA, Yap NY, Saad M. Efficacy, safety, and prognostic indicators of first-line sunitinib in patients with metastatic renal cell carcinoma: A single center experience. J Can Res Ther [serial online] 2018 [cited 2020 Jun 3];14:1303-11. Available from: http://www.cancerjournal.net/text.asp?2018/14/6/1303/189247




 > Introduction Top


Renal cell carcinoma (RCC) has a metastatic rate of 20–30% at diagnosis and up to 40% develop recurrence after the initial treatment of a localized tumor.[1],[2] Previously, treatment for metastatic RCC (mRCC) mainly involved the use of immunotherapy with cytokine as the disease is relatively chemotherapy-resistant. However, given its modest response and associated toxicities, there was a need for better therapeutic agents. The discovery of the von Hippel–Lindau gene has resulted in better understanding of the pathogenesis of RCC. This led to a paradigm shift in the treatment of mRCC about a decade ago from the era of immunotherapy to the era of molecularly targeted therapy. Molecular agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways are now the standard of care in the treatment of mRCC. Recently, an immunotherapy agent targeting the immune checkpoint pathway called programmed cell death ligand-1 (PD-L1) inhibitor has been approved. The currently approved agents for the treatment of mRCC include VEGF-mediated agents: sunitinib, bevacizumab, pazopanib, axitinib, sorafenib, cabozantinib, and lenvatinib; mTOR inhibitors: temsirolimus and everolimus; and PD-L1 inhibitor: nivolumab.[3],[4],[5]

Sunitinib, a VEGF tyrosine kinase inhibitor (TKI), was among the first targeted therapy approved as first-line treatment for mRCC. Patients who received sunitinib were shown to have significant improvement in survival and response rate compared to interferon-α in a phase III, randomized study that was considered a landmark trial.[6] Sunitinib treatment, as similar to other targeted therapies, is associated with distinct tolerability profiles. Some of the sunitinib-induced adverse effects have been proposed as surrogate markers of its clinical activity to predict response to treatment. However, this hypothesis was never validated in the prospective trials. A number of surrogate markers have been investigated and among the more promising and well-studied are hypertension, hypothyroidism, hand-foot syndrome (HFS), and fatigue.[7],[8],[9] These adverse events may be a reaction to the drug's inhibition of target receptors such as VEGF receptors (VEGFRs) or tyrosine kinase receptors and confer a favorable outcome.[9]

Sunitinib remains to be one of the standards of care treatment in the first-line setting worldwide, including Malaysia. However, data on the efficacy and safety in Asian population, especially in Southeast Asian country like Malaysia, are lacking. A majority of landmark studies were conducted in the Western population, and reports from Asia were mainly from South Korea or Japan.[10],[11],[12],[13],[14],[15],[16] Therefore, it is of interest to confirm whether similar treatment is also effective for our patients, especially in the usual daily practice as compared to the results seen in the highly controlled environment of clinical studies. We retrospectively reviewed our cohort of patients who were treated with sunitinib to determine the efficacy of sunitinib treatment in terms of objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We also assessed the safety of sunitinib in the same patients and validated the predictors of survival and markers of efficacy in mRCC as identified from the previous studies.


 > Patients and Methods Top


This was a retrospective study of new mRCC patients who were treated at the Department of Clinical Oncology at our institute (January 2006 to November 2014). This study was approved by the Medical Ethics Committee. Patients included for the analysis were (1) 18 years of age or older, (2) had metastatic disease, and (3) received sunitinib as first-line targeted therapy (pretreatment with cytokine-based therapy was allowed). Those with brain metastases were also included in the study.

Medical records were reviewed for demographic and clinicopathological characteristics such as age, sex, race, histology, prior treatments, Eastern Cooperative Oncology Group (ECOG) performance status (PS), sites of metastasis, and baseline laboratory parameters (hemoglobin, corrected calcium, lactate dehydrogenase (LDH), neutrophil, and platelet levels). The patterns of sunitinib prescribing, including starting dose and dose modification, toxicity data, which were recorded at each visit as well as tumor response based on documented radiographic assessment by radiologists, were retrieved. Evaluation of tumor response was based on the Response Evaluation Criteria in Solid Tumors criteria. Mortality data were obtained from the National Registration Department of Malaysia.

Efficacy of sunitinib is defined by the ORR, PFS, and OS. ORR is the proportion of patients with either partial (PR) or complete response (CR) as their best overall response. PFS was determined from the date of initiation of sunitinib until the date of progressive disease (PD) on imaging or death of any cause. OS was defined from the date of initiation of sunitinib until the date of death of any cause. Those who were still alive or have not progressed at the end of the data cutoff analysis (December 31, 2014) were censored.

The relationship between baseline parameters and OS was assessed. Sunitinib-related toxicities (hypertension, hypothyroidism, HFS, and fatigue) were evaluated for their prognostic significance on OS and PFS. For hypothyroidism, fatigue, and HFS, survival outcomes for those who developed any grade toxicity were compared with those who did not have toxicity. For hypertension, survival outcomes for those with Grades 2–4 hypertension were compared with those who had Grade 1 and no hypertension.

Statistical analysis

Descriptive statistics were used for patient characteristics, toxicity data, and best tumor response. PFS and OS were estimated using the Kaplan–Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model to assess the relationship between OS and baseline parameters, as well as for relationship between OS/PFS and treatment-related toxicities. Patients were stratified into risk groups (favorable, intermediate and poor) based on the Memorial Sloan-Kettering Cancer Center (MSKCC) or the International Metastatic RCC Database Consortium (IMDC) models and assessed for survival using the log-rank test. P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 22.0 (IBM Corporation, USA).


 > Results Top


Patients and disease characteristics

Sixty-one patients (58 treatment-naïve and 3 cytokine-pretreated patients) who were treated with sunitinib as first-line targeted therapy were eligible for this analysis. Three patients had sunitinib at a different institution before presentation to our center and, therefore, were excluded from the study. Another two patients were excluded because their medical records could not be traced. The analysis was made based on 56 patients. Baseline characteristics are shown in [Table 1].
Table 1: Baseline patient characteristics

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Half of the patients in this study were initially diagnosed with localized disease and had radical nephrectomy. Approximately 43% of those who had metastatic disease at presentation underwent cytoreductive nephrectomy before sunitinib treatment. Five (8.9%) patients had metastasectomy before sunitinib treatment, and the median duration from the first metastasectomy to sunitinib initiation was 45.5 months (14.6–50.3 months). One patient had metastasectomy for solitary brain metastases before sunitinib which rendered him in complete remission; hence, this patient was excluded from survival analysis. The majority of patients did not have baseline LDH level before starting sunitinib; therefore, only 29 patients could be evaluated for MSKCC and IMDC risk stratification.

Dosing and schedule

Sunitinib was administered as conventional dose regimen of 50 mg/day (4 weeks of treatment, 2 weeks of treatment) in 51 patients (91.1%). Five (8.9%) patients received attenuated dose of sunitinib upfront; 4 patients were prescribed 37.5 mg/day (continuous) and one patient had 25 mg/day (sunitinib was prescribed as 50 mg/day but the patient took 25 mg/day).

Dose interruption was documented in 25 (44.6%) patients. The reasons for dose interruption were treatment-related toxicities (n = 21), disease-related complications (3), and comorbidity-related illness (1). Dose reduction was reported in 37 (66.1%) patients. The reasons for dose reduction were treatment-related toxicities (n = 34), disease-related complications (2), and worsening general health (1).

All patients received at least one dose of sunitinib. Fifty-two patients (92.9%) received more than one cycle of sunitinib. Of those four patients who did not complete one cycle of sunitinib, the reasons for discontinuing treatment were worsening general health (n = 2), death (1), and patient refusal (1). The median treatment duration for the study population was 8.2 months (0.2–90.9 months). Six patients (10.7%) were still on sunitinib at the time of analysis. Of the remaining 50 patients, reasons for treatment discontinuation were progression of disease (n = 23), deterioration of general health (10), toxicity (9), death (4), and loss to follow-up (4).

Efficacy and survival analysis

Responses to sunitinib were evaluable in forty patients. Eleven (27.5%) patients achieved PR and 19 (47.5%) had stable disease. Ten (25%) patients had PD. None of them achieved a CR. The ORR and disease control rate were 27.5% and 75.0%, respectively. Treatment response was not evaluable in 16 (28.6%) patients due to treatment discontinuation before imaging was done (n = 12), loss to follow-up (2), baseline imaging not available for comparison (1), and metastasectomy before sunitinib (1).

The median duration of follow-up was 13.7 months. The median PFS and OS for the overall population are shown in [Figure 1]. At the time of analysis, nine patients were still alive and were censored from OS and PFS analyses.
Figure 1: Kaplan–Meier estimate of progression-free survival and overall survival in overall study population. OS = Overall survival, PFS = Progression-free survival, CI = Confidence interval

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Safety analysis

[Table 2] summarizes the sunitinib-related toxicities observed in the study population. The most frequent nonhematological side effects reported were mucositis (67.9%), yellow discoloration of skin (62.5%), HFS (62.5%), fatigue (51.8%), and rashes (42.9%). The most common Grades 3–4 nonhematological toxicities were HFS (23.2%), hypertension (14.3%), and mucositis (8.9%). Raised aspartate aminotransferase was the most common (41.1%) hepatotoxicity reported. Around two-third (33.9%) of patients had raised creatinine level throughout the treatment period. Both sunitinib-related hypertension and hypothyroidism occurred in 30.4% and 21.4% of all patients, respectively. Neutropenia was the most frequent hematological toxicity reported (69.6%), followed by anemia (64.3%) and thrombocytopenia (51.8%). Thrombocytopenia (16.1%) was the most frequent Grades 3–4 hematological side effects reported.
Table 2: Sunitinib-related toxicities in overall population

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Sunitinib was discontinued due to intolerable toxicities in 9 (16.1%) patients, all of who had starting dose of 50 mg/day. The toxicity reasons for sunitinib discontinuation were raised creatinine (n = 2), reduced left ventricular ejection fraction (2), hepatotoxicity (2), thrombocytopenia (1), both neutropenia and thrombocytopenia (1), and mucositis (1). There was one sunitinib-related death due to hepatic failure.

Association of Baseline Parameters and Treatment-related toxicity with overall survival/progression-free survival

Various baseline parameters were investigated for association with OS [Table 3]. From univariate analysis, ECOG PS of 2 or more, low hemoglobin level, high neutrophil count, high platelet count, no prior nephrectomy, more than one metastatic site, presence of liver metastases, and lymph node metastases were all prognostic of poorer OS. Multivariate analysis revealed that all the parameters mentioned above were independently associated with poorer OS.
Table 3: Analysis of baseline factors associated with overall survival

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The stratification of patients using either MSKCC or IMDC models significantly affect survival as shown in [Figure 2].
Figure 2: Kaplan–Meier estimates of overall survival based on (a) Memorial Sloan Kettering Cancer Center Risk criteria and (b) International Metastatic Renal Cell Carcinoma Database Consortium risk criteria. OS = Overall survival, CI = Confidence interval, MSKCC = Memorial Sloan Kettering Cancer Center, IMDC = International Metastatic RCC Database Consortium

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Treatment-related toxicities were analyzed and those who experienced HFS had significant improvement in median OS and PFS [Table 4]. Multivariate analysis revealed that the development of HFS is an independent predictor of improved OS (hazard ratio [HR] 0.309, 95% confidence interval [CI] 0.165–0.580; P = 0.000) and PFS (HR 0.208, 95% CI 0.088–0.494; P = 0.000). However, there is no significant survival difference in higher Grades (2 or 3) compared to Grade 1 HFS. Improvement in median OS and PFS was also observed in patients with hypertension, hypothyroidism, and fatigue; however, the differences did not achieve statistical significance.
Table 4: Univariate analysis of overall survival and progression-free survival according to sunitinib-related toxicities

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 > Discussion Top


The use of sunitinib in the treatment of mRCC has been proven to be effective in the landmark Phase III trial.[6],[10] Asian patients who were treated with sunitinib in expanded access program (EAP) had comparable outcome to the non-Asian patients.[17] To the best of our knowledge, this is the first study to report the efficacy and safety profile of sunitinib treatment in Malaysian patients with mRCC.

[Table 5] provides a summary of the landmark Phase III trial, global EAP, EAP in Asian patients, and other Asian studies on sunitinib in mRCC. The ORR of sunitinib treatment in our cohort (27.5%) was lower than the previous Phase III trial (47%), but higher than the ORR reported in the Asian patients treated in EAP (18%) and the 2015 global EAP (16%). Our ORR is consistent with the Korean (27.6%), Japanese (27.3%), and Chinese (26.9%) retrospective studies.[13],[16],[18],[19] The median PFS and OS in the present study were 12.7 and 16.9 months, respectively. Our median PFS was comparable with the Phase III trial (11 months) but longer than many other Asian studies, including the Asian EAP (6.7–12.2 months). However, our median OS was shorter than the Phase III (26.4 months), global EAP (18.7), and all other Asian studies (18.3–33.2 months). The longer PFS observed in our study could be due to lack of prespecified imaging protocol for tumor assessments, unlike in clinical trial setting. The inconsistent interval of repeat imaging to assess tumor response may have resulted in longer PFS as those who progressed on treatment may have been detected later. However, we do not consider this as a limitation because this reflects the usual practice in nonclinical trial setting.
Table 5: Overview of global and Asian sunitinib studies

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We analyzed baseline parameters of clinical and laboratory variables and their association with OS [Table 3]. Only two of five risk factors in MSKCC (ECOG PS 2 or more and low hemoglobin) and three of six risk factors in IMDC (ECOG PS 2 or more and high neutrophil and platelet counts) were associated with poorer OS in our patients. Individually, the other risk factors in the models did not reach statistical significance level, but the MSKCC and IMDC stratification models as a whole significantly predicted survival outcome. No prior nephrectomy, which is a known poor prognostic factor in mRCC, and higher disease burden as reflected by a number of disease sites of more than one, were also shown to be independent prognostic factors in our population.[20] The presence of liver metastasis as a negative prognostic indicator for OS is of interest. In the MSKCC model, the presence of liver metastases was associated with poorer OS in both univariate and multivariate analyses.[21] However, due to marginal significance level (P = 0.02), it was not included in the final model.[21] Another study which evaluated the MSKCC model showed prognostic significance for liver metastases and number of metastatic site, and hence proposed for the inclusion into the model.[22] Lymph node metastasis was also an independent prognostic factor in this analysis. Other studies have reported the adverse effect of lymph node metastases on the survival of mRCC patients, suggesting for the evaluation of lymphadenectomy in improving the outcome of these patients.[23],[24]

The challenge with sunitinib treatment, like many other molecular-based targeted agents, is the associated toxicities. HFS was the most common toxicity that led to dose interruption and reduction in this cohort. We observed a much higher incidence of HFS (63%) than those reported in the Phase III trial (29%) and global EAP (27%). This finding is consistent with those reported in other Asian studies whereby at least 49% of their study population experienced all-grade HFS [Table 5]. Despite the high incidence, none of our patients discontinued treatment because of HFS.

The incidence of hypertension in our study (30%) was comparable with the Phase III trial (30%), global EAP (24%), and the EAP Asian patients (23%). The incidence of fatigue and hypothyroidism was also comparable to all other studies. In the EAP, Asian patients treated with sunitinib experienced a higher incidence of hematological toxicities than non-Asian patients.[17] Grades 3–4 anemia, neutropenia, and thrombocytopenia in Asian patients were 14%, 17%, and 26%, respectively, compared to 8%, 11%, and 14% in non-Asian patients.[17] Reasons for the higher toxicities are unknown as the elevated toxicity rates were not seen in Asian patients at non-Asian sites.[17] Our patients had comparable Grades 3–4 hematological toxicities (anemia 11%, neutropenia 13%, and thrombocytopenia 16%) with the non-Asian patients in EAP.[17]

Of the all adverse effects analyzed, only HFS was an independent predictor for improved OS and PFS in our study. Similarly, several other studies have found that the development of sunitinib-related HFS improved the survival outcome of mRCC patients.[7],[25],[26],[27] The exact mechanisms of TKIs leading to HFS are unclear but the inhibition at VEGF and platelet-derived growth factor pathways may cause dermal endothelial cell apoptosis.[9] HFS is a significant predictor of sunitinib efficacy in this cohort and is potentially a valuable prognostic factor, especially in Asian patients who show higher incidence. Sunitinib-related hypertension (≥Grade 2) and hypothyroidism also showed a trend toward improved survival, but failed to reach significance level. A limitation of our study is the smaller sample size compared to other studies as the prevalence of RCC is still relatively low in Malaysia, with an age-standardized incidence of 2.4/100,000 according to the latest National Cancer Registry.[1] Apart from sunitinib, treatments with other VEGF inhibitors have shown improvements in ORR, PFS, and OS in patients who developed hypertension in subgroup analyses in a number of recent Phase II and III trials.[28],[29],[30] Hypertension is thought to develop as a result of diminished angiogenesis caused by TKI, impairing the general microcirculation of the body and affecting blood pressure control.[9] Hypothyroidism was suggested as a predictor for response to sunitinib treatment in few studies.[31],[32] However, thyroid hormone replacement for those with hypothyroidism seemed to have cancelled the possible beneficial effect on survival.[33] The direct effect of these adverse events on survival is still not understood, but they occur as an indication of the inhibition of various TKI targets and could be predictive of the drug's efficacy. Malaysia is a multiracial country consisting of Malays, Chinese, and Indians, thus allowing for a comparison of sunitinib-related toxicities incidence among the different races. However, there seem to be no significant racial differences in sunitinib-related toxicities observed in our study population (results not shown).


 > Conclusions Top


Treatment with sunitinib has comparable efficacy in Malaysian mRCC patients as compared to the published data from other centers. Both MSKCC and IMDC prognostic models are valid and relevant for predicting survival in our cohort of patients. Even though some of the toxicities were found to be higher than the Western patients, treatment could be continued with appropriate dose modification, achieving acceptable outcomes. HFS showed promise as a prognostic factor and could be further investigated in a larger cohort.

Financial support and sponsorship

This study was partially supported by the University Malaya Research Grant RG524/13HTM.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

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



 

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