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Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx
Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): A systematic review of the literature Omar Abdel-Rahman a,∗ , Mona Fouad b b
a Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt Medical Microbiology and Immunology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Received 5 June 2014; received in revised form 2 September 2014; accepted 12 January 2015
Contents 1.
2. 3.
4.
5. 6.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Relevant molecular profiling of non clear cell RCC subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Published clinical data for different therapeutics in non clear cell RCC (Table 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Objective of the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodology for selecting and analyzing the data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Selection of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Prospective clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Retrospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Studies and patients characteristics (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Progression free survival and overall survival (PFS and OS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Tumor response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Toxicities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Source of funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Background: The randomized phase III trial of sunitinib versus interferon Alfa provided level-A evidence for the use of sunitinib in advanced clear cell renal cell carcinoma (RCC). This systematic literature review aims at the evaluation of the level of evidence for the use of sunitinib monotherapy for advanced non clear cell RCC in terms of efficacy and toxicity parameters.
∗
Corresponding author. Tel.: +20 1008541806; fax: +20 33028656. E-mail address: [email protected] (O. Abdel-Rahman).
http://dx.doi.org/10.1016/j.critrevonc.2015.01.006 1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Abdel-Rahman O, Fouad M. Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): A systematic review of the literature. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.006
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Methods: Eligible studies were identified using MEDLINE, Google scholar, ASCO, ESMO and the Cochrane databases. Searches were last updated on 1 June 2014. Eligible studies reported survival and/or response data for patients with non clear cell RCC receiving sunitinib monotherapy. Results: four hundred and five results were obtained from the searches in MEDLINE (n = 319 studies) and other databases (n = 86). Twelve studies (involving 980 patients) were considered eligible and were included in the final analysis: six phase II clinical trials, one expanded access prospective trial and five retrospective analyses. Median PFS was reported in 11 studies ranging from 1.6 to 8.9 months. Median OS was reported in 9 studies ranging from 12 months to 22 months. The disease control rate (DCR) was reported in 10 studies, and it ranged from 35% to 91%. The overall response rate (ORR) was reported in 10 studies and it ranged from 0% to 36%. Frequently reported Grade 3/4 toxicities were gastrointestinal toxicities, mucocutaneous toxicities and hematologic toxicities. Conclusion: There is insufficient evidence (level C) to recommend sunitinib monotherapy in advanced non clear cell RCC and the available data suggests it appears less efficacious than that in advanced clear cell RCC. Further prospective and randomized studies are needed to explore alternative therapies in this setting. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Sunitinib, Non clear RCC; Papillary RCC; Chromophobe RCC
1. Introduction Renal cell carcinoma (RCC) accounts for 3% of all adult cancers, representing the seventh most common cancer in men and the ninth most common cancer in women [1]. Worldwide, there are ∼209,000 new cases per year; additionally, the incidence of all stages of RCC has increased over the past 2 decades, contributing to a steadily increasing mortality rate per unit population [2]. RCC is a heterogeneous disease with multiple pathological subtypes, the most frequent being conventional clear cell, papillary type 1, papillary type 2 and chromophobe: other, rarer histotype have been described in an evolving refinement of the histoathological classification of kidney cancers [3]. According to a recent report from the California cancer registry (including 38,251 RCC cases), 19,149 (50%) were of clear cell type; 14,619 (38.2%) were “unclassified” while 4483 (11.7%) were of non clear cell type. Histology distribution for non clear cell RCC was (n, %): papillary—2863 (63.9%); Chromophobe—1507 (33.6%); and other including medullary and collecting duct—113 (2.5%) [42]. This pathological sub-typing has many molecular, etiological and therapeutic consequences [4]. Different patho-genetic pathways for each of these different subtypes have been suggested for some of these different subtypes with consequent rationalization of targeted therapeutic strategies for some subtypes [5]. For example, the hypoxia inducible pathway and mTOR pathway have been linked to clear cell and papillary type II subtypes with consequent evaluation of VEGF-targeted and mTOR-targeted therapeutics in this setting [6,7]. While the MAP kinase pathway has been linked to chromophobe and papillary type I subtypes with consequent evaluation of RAF-targeted therapeutics in this setting [8]. At initial diagnosis, surgical resection is considered a potentially curative modality for localized RCC, however not all patients have resectable disease. On the other hand, the spectrum of available treatments for advanced RCC is diverse and rapidly developing, including for clear cell RCC: sunitinib, pazopanib, bevaizumab/interferon combination, high
dose interleukin therapy in addition to axitinib, sorafenib and temsitolimus and Everolimus in later lines of treatment [9–15]. However, the situation is less clear for non clear cell RCC because of the lack of prospective controlled phase III studies dedicated to non clear cell RCC. While many systemic treatment options are available, none can be considered the ultimate gold standard in this subset of RCC.
1.1. Relevant molecular profiling of non clear cell RCC subtypes A number of molecular studies have shed the light in the past decade on the distinctive molecular profiling of different subtypes of non clear cell RCC with consequent important implications for a refined personalized treatment selection. Klatte and coworkers have evaluated the cytogenetic and molecular tumor profiling for type 1 and type 2 papillary RCC (pRCC). They found that Type 2 pRCC is associated with more aggressive clinic-pathologic features and worse outcome and molecularly, Type 2 showed greater expression of vascular endothelial growth factor receptor (VEGF)-R2 in the tumor epithelium, and of VEGF-R3 in both tumor epithelium and endothelium [23]. In another Swedish study, the differential vascular endothelial growth factor (VEGF), VEGF-receptor 1 and -2 mRNA expression profiles between clear cell and papillary renal cell carcinoma were evaluated. In this study, it was shown that Among the RCC types, clear cell RCC (cRCC) had higher VEGF levels than papillary RCC (pRCC). In cRCC, VEGF-R2 levels were higher in stage I–II than in more advanced stages. In pRCC, VEGF and VEGF-R2 levels were higher in stage III than in stage I–II tumors [24]. However, we have to acknowledge that for some histotypes a pathogenic correlation to a specific genetic alteration has been proposed: clear cell and VHL, papillary type I and Met, papillary type II and FH, chromophobe and BHD. Beyond these correlations, and not necessarily as a
Please cite this article in press as: Abdel-Rahman O, Fouad M. Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): A systematic review of the literature. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.006
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consequence of them, the activation of several growth and pro-angiogenic pathways have been demonstrated. 1.2. Published clinical data for different therapeutics in non clear cell RCC (Table 1) Table 1 A number of different agents including cytotoxic chemotherapy and molecularly targeted agents have been studied in advanced non clear cell RCC; most notably included suntinib and sorafenib, which have been studied in a number of phase II studies with initially encouraging results [16–18]. Additionally, mTOR inhibitors Everolimus and temsirolimus have been evaluated in a number of phase II results with encouraging results [12,19]. Moreover, a number of cytotoxic chemotherapy regimens (including capecitabine monotherapy and carboplatin/paclitaxel) have been evaluated; and while capecitabine data was encouraging, paclitaxel/carboplatin data was disappointing [20,21]. And more recently, the dual MET/FGFR inhibitor foretinib has been evaluated in pRCC and has shown considerable activity particularly in those with germline MET mutation [25]. Moreover, across the globe, a number of cooperative groups are conducting clinical studies on multiple newer targeted agents for RCC (including non clear cell subtype) in multiple phases of development; the results of these studies are expected within the next 5 years. These studies span a wide spectrum of targeted therapeutics (including newer monoclonal antibodies as well as newer VEGFR tyrosine kinase inhibitors like pazopanib) [22].
3
data-bases: the Cochrane library, Google scholar and PubMed/Medline to identify all potentially relevant publications; the date of the last search was the first of June 2014. Meeting abstracts including ASCO and ESMO were also reviewed. Articles with the following text words or Medical Subject Headings (MeSH) in their titles, abstracts or keyword lists were examined:”renal cell carcinoma” OR “non clear cell renal cell carcinoma” OR “papillary renal cell carcinoma” OR “chromophobe renal cell carcinoma “AND “sunitinib” OR “target therapy” OR “tyrosine kinase inhibitor”. Detailed search strategy for Pubmed was as follows: “renal cell carcinoma”[All Fields] OR “non clear cell renal cell carcinoma”[All Fields] OR “papillary renal cell carcinoma”[All Fields] OR “chromophobe renal cell carcinoma” [All Fields] AND “sunitinib” [All Fields] OR “target therapy” [All Fields] OR “tyrosine kinase inhibitor”[All Fields] AND Clinical Trial [ptyp]. Reference lists of primary original studies and review articles were also checked manually for further related articles (cross-references). 3.2. Selection criteria Inclusion criteria: (1) Studies that described sunitinib monotherapy for the treatment of advanced non clear cell RCC. (2) Tumor response outcome measures and toxicities were reported. (3) Age more than 18 years. Exclusion criteria:
2. Objective of the systematic review
(1) Non English language records were also excluded.
In this systematic review, we will provide an overview of the clinical experience (efficacy and toxicity) related to the use of sunitinib for non clear cell RCC.
3.3. Data extraction
3. Methodology for selecting and analyzing the data 3.1. Search strategy A comprehensive systematic search for English speaking literature was conducted in the following electronic
Data were extracted by two independent reviewers. All eligible articles underwent initially full text review for relevancy and reporting of outcomes of interest. The following information/data were extracted from the studies where available: histo-pathological subtype, Eastern Cooperative Oncology Group (ECOG) Performance Status, treatment regimen and schedule, Memorial Sloan Kettering Cancer Center (MSKCC) prognostic class (favorable, intermediate or poor), complete response (CR) rate, partial response (PR)
Table 1 Published data for systemic agents (other than sunitinib) in the treatment of non clear cell RCC. Progression free survival (PFS)
Grade 3–4 toxicities
Everolimus 10 mg 10.2 daily Capectabine 26 (1250 mg/m) twice daily for 14 days
5.2 Months
Carboplatin and paclitaxel
N/R*
Anemia (10.2%), hyperglycemia (8.2%), and infection (6.1%) Diarrhea (2%), esophageal mucosal inflammation (2%), hand-foot syndrome (4%), thrombocytopenia (9.8%), and neutropenia (8%) Leukopenia and neutropenia, nausea, vomiting, neuropathy, fatigue, seizure
Study
Phase
Number
Agent used
Koh et al. [19]
II
49 Patients
Tsimafeyeu et al. [20] II
51 Patients
Bylow et al. [21]
17 Patients
*
II
Objective response rate (ORR) (%)
7
10.1 Months
N/R: not reported.
Please cite this article in press as: Abdel-Rahman O, Fouad M. Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): A systematic review of the literature. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.006
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Idenficaon
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Records idenfied through MEDLINE database searching (n = 319 )
Addional records idenfied through other sources (n = 86 )
Screening
Records aer duplicates removed (n = 286)
Eligibility
Records excluded (n = 264) Records screened (n = 286)
Full-text arcles excluded, (n = 10) • 6 review arcles • 4 editorials
Included
Arcles assessed for eligibility (n = 22)
Studies included in qualitave synthesis (n = 12)
Fig. 1. PRISMA flowchart for the study selection procedure.
rate, stable disease (SD) rate, disease control rate (DCR: CR + PR + SD), progression-free survival (PFS), overall survival (OS), and the incidence of toxicities.
3.4. Outcome measures The outcome measures of interest were PFS (progression free survival), OS (overall survival), tumor response, and toxicities. Tumor response (CR, PR, and SD) was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Toxicities were categorized using National Cancer Institute criteria. The main outcome measures are summarized using descriptive statistics. This systematic review adheres to the guidelines provided by the Preferred Reporting Items for Systematic Reviews and MetaAnalyses report (PRISMA Statement) [26].
4. Results 4.1. Selection of studies Fig. 1 summarizes the PRISMA flow diagram for selection of eligible studies; 405 results were obtained from the searches in MEDLINE (n = 319 studies) and other databases (n = 86). Of these 119 were duplicates and 264 did not meet the inclusion criteria and were therefore excluded (either the treatment was not sunitinib monotherapy or the study was for disease categories other than non clear cell RCC). Of the 22 studies which appeared to be eligible after the initial screening, a full text search was performed. Ten studies were removed after the full text search; thus, twelve studies were included in the final analysis: six phase II clinical trials [16,17,27,28,35,37], one expanded access prospective trial [30] and five retrospective analyses (Tables 2–4)
Please cite this article in press as: Abdel-Rahman O, Fouad M. Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): A systematic review of the literature. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.006
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Phase
Number
Histo-pathological subtype
ECOG PS score
MSKCC score
Dose
Prior treatment (if applicable)
Phase II
57
0 = 20 (35%) 1 = 32 (56%) 2 = 25 (9%)
Favorable: 16% Intermediate: 63% Poor: 21%
Sunitinib 50 mg daily on a 4-week on, 2-week off schedule
Previous nephrectomy: 70% Previous systemic therapy (chemo/immunotherapy): 14%
Lee et al. [16]
Phase II
31
0 = 15 1 = 16
Favorable: 29% Intermediate: 45% Poor: 26%
Patients were treated with 50 mg/day oral sunitinib for 4 weeks, followed by 2 weeks of rest
Prior nephrectomy: 77% Previous immunotherapy: 23% Previous chemotherapy: 13%
Molina et al. [17]
Phase II
23
0 = 78% 1 = 22%
Favorable: 52% Intermediate: 44% Poor: 4%
50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest (4/2)
Previous nephrectomy: 78% previous immunotherapy: 4% previous chemotherapy/targeted therapy: 13%
Tannir et al. [28]
Randomized phase II
33
N/R*
Favorable: 12% intermediate: 88%
Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off)
Previous nephrectomy: 77%
Ravaud et al. [27]
Phase II
28
[Papillary (27), chromophobe (5), unclassified (8), collecting duct or medullary carcinoma (6), sarcomatoid (7), others (4)] Histological type Papillary type 2: 17 (55%) Papillary NOS: 5 (16%) Chromophobe: 3 (10%) Xp11.2 translocation: 1 (3%) Unclassified: 5 (16%) Papillary = 8 Chromophobe = 2 Collecting duct = 4 Medullary = 1 Unclassified = 5 HLRCC-related = 3 Papillary = 40% Chromophobe = 16% Sarcomatoid = 19% Unclassified = 13% Translocation = 10% Papillary type I = 5 patients Papillary type II = 23 patients
0 = 56% 1 = 44%
Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off)
Previous nephrectomy: 89%
Plimack et al. [35]
Phase II
23
Expanded access trial
588 (13%) non-clear-cell RCC
Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off) Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off)
Previous nephrectomy: 65%
Gore et al. [30]
Favorable: 16% Intermediate: 56% pts Poor: 14% Undetermined: 14% Intermediate risk: 14 (61%) Poor risk: 3 (13%) Favorable: 36% Intermediate: 44% Poor: 9% Missing: 11%
50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest (4/2) Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off) Oral sunitinib 50 mg/day in repeated 6 weekly cycles (4 weeks on and 2 weeks off)
Previous systemic therapy: 62%
Papillary type I = 2 papillary type II = 10 pRCC type not specified = 13 N/R
N/R
0 = 24 (45%) 1 = 26 (49%) 2 = 3 (6%) N/R
N/R
PS was 0 in 14 (56%) pts 1 in 11 (44%) pts
Favorable: 5 Intermediate: 14 Poor: 4 Undetermined: 4 HENG risk groups: Favorable: 11%, Intermediate: 56% Poor: 33%. N/R
0 = 42% 1 = 43% 2 = 12% 3 = 3%
ii. Retrospective studies Choueiri et al. [18] Retrospective study
53
Papillary = 41 (77%) Chromophobe = 12 (23%)
Yildiz et al. [29]
Retrospective
63
Paglino et al. [31]
Retrospective
21
Papillary RCC = 46 pts (88%) Chromophobe = 10 pts. Unclassified = 7 pts N/R
Lee et al. [32]
Retrospective
74
Papillary = 100%
N/R
Casuscelli et al. [33]
Retrospective
16
Papillary type II = 100%
N/R
*
N/R
Previous nephrectomy: 89% Previous antiangiogenic therapy: 5% Previous immunotherapy: 68%
Previous nephrectomy: 89% Previous immunotherapy: 61.9% Previous chemotherapy: 3.5% N/R
Oral sunitinib 50 mg/day in repeated 6 weekly cycles (4 weeks on and 2 weeks off)
Previous nephrectomy: 78%
Oral sunitinib 50 mg/day in repeated 6 weekly cycles (4 weeks on and 2 weeks off)
N/R
N/R: not reported.
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Study i. Prospective studies Tannir et al. [37]
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Table 2 baseline characteristics of included trials.
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Disease control rate (DCR)
Objective response rate (ORR)
Median (PFS)
Median (OS)
ORR and PFS
58%
5%
16.8 months (95% CI: 10.7, 26.3).
Lee et al. [16]
ORR
91%
36%
For the entire group: 2.7 months [95% CI: 1.4, 5.4]. For patients with papillary histology: 1.6 months (95% CI: 1.4, 5.4). For patients with chromophobe histology: 12.7 months (95% CI: 8.5, NA) With a median follow up duration of 18.7 months (95% CI 13.7–23.7 months), the median PFS was 6.4 months (95% CI 4.2–8.6 months) and the 1-year PFS rate was 40%
Molina et al. [17]
ORR
69%
4%
Tannir et al. [28]
ORR and PFS
N/R
ORR in first line was 12% (2 pts had chromophobe, 1 pt had papillary type 1 and 1 pt had 99% sarcomatoid)
Ravaud et al. [27] Plimack et al. [35]
ORR ORR and PFS
60% 35%
4% 0%
Gore et al. [30]
ORR and PFS
86%
11%
Progression-free survival: 7.8 (95% CI 6.3–8.3) months
ii. Retrospective studies Choueiri et al. [18] ORR and PFS
78%
10%
Yildiz et al. [29]
ORR and PFS
63.5%
11.1%
Paglino et al. [31]
ORR and PFS
52.4%
14.3%
Lee et al. [32]
ORR and PFS
70%
N/R
Progression-free survival for entire study: 8.6 months Sunitinib-treated PRCC patients had a PFS of 11.9 months Median PFS was 7.6 months (95% CI, 5.5–9.7 months) and 1-year PFS rate was 33.7% The median progression-free survival was 4.1 months Median PFS = 5 months Factors associated with PFS were sunitinib-induced HTN (HR 0.31, P = 0.002), pre-treatment NLR > 3 (HR 5.3, P = 0.001), and active smoking (HR 2.5, P = 0.01)
Casuscelli et al. [33]
PFS
N/R
N/R
• DCR = (CR + PR = SD). • ORR = (CR + PR).
The median progression-free survival was 5.5 months (95% CI, 2.5–7.1) in all 23 patients, and 5.6 months for the 8 papillary patients (95% CI, 1.4–7.1). Median PFS in first line was 6.1 mos (95% CI: 4.7, 10.8) Median PFS in second line was 1.8 mos (95% CI: 1.5, NA) N/R Median PFS was 1.6 months (95% CI, 1.3–12)
Median PFS = 8.9 months
The median OS times of the poor and intermediate risk groups were 7.7 months (95% CI 7.3–8.1 months) and 25.6 months (95% CI 4.5–46.9 months), respectively. Median OS had not been reached in the favorable risk group. N.B. Patients with prior nephrectomy had a tendency of better OS (HR 0.37, 95% CI 0.1–1.4, P = 0.19), but it did not meet statistical significance. Prior exposure to cytokines did not affect PFS or OS N/R
Median OS with first line was not reached
N/R Median OS of 10.8 months (95% CI, 6.2-NE) Fewer disease sites, better performance status, prior nephrectomy, and normal baseline albumin and LDH levels correlated with longer OS. Overall survival: 13.4 (95% CI 10.7–14.9)
Overall survival time (for the entire study): 19.6 months
Median OS was 22.0 months (95% CI, 13.4–30.6 months) and 1-year OS rate was 64.7% Median overall survival was 14.6 months Median OS = 12 months Factors associated with OS were sunitinib-induced hypothyroidism (HR 0.4, P = 0.024), past nephrectomy (HR 0.41, P = 0.02), pre-treatment NLR > 3 (HR 2.25, P = 0.036), and active smoking (HR 2.3, P = 0.027) Median OS = 15 months
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Primary endpoint
i. Prospective studies Tannir et al. [37]
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Please cite this article in press as: Abdel-Rahman O, Fouad M. Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): A systematic review of the literature. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.006
Table 3 Summary of efficacy measures.
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Hypertension
Thromboembolism
Proteinuria
Anemia and leukopenia
thrombocytopenia
Fatigue
Hepatotoxicty/ hypothyroidism
GI toxicity
Mucocutaneous
Bleeding
Lee et al. [16]
23 (74%)
N/R
12 (39%)
Anemia = 23 (77%) Neutropenia = 28 (93%) Leucopenia = 26 (87%)
27 (90%)
21 (67%)
Elevated ALT = 16(54%) Elevated AST = 23(77%) Hyperbilirubinemia = 8 (27%)
Stomatitis = 27 (88%) Alopecia = 6 (19%) HFSR = 23 (65%) Rash = 3 (10%)
17 (55%)
Molina et al. [17]
6 (26%)
2 (9%)
N/R
19 (83%)
11 (48%)
Elevated ALT = 17 (74%) Elevated AST = 16 (70%) Elevated AP = 14 (61%)
Mucositis = 9 (39%) Skin (HFSR + other) = 11 (48%)
N/R
Gore et al. [30]
22%
N/R
N/R
Anemia = 21(91%) Neutropenia = 10 (43%) Leucopenia = 16 (70%) Lymphopenia = 5 (22%) Anemia = 15% Neutropenia 15%
Anorexia = 18 (58%) Nausea = 14 (45%) Vomiting = 11 (35%) Constipation = 11 (36%) Diarrhea = 13 (42%) Epigastric pain = 14 (45%) Vomiting = 7 (30%) Diarrhea = 6 (26%)
22%
37%
N/R
Epistaxis = 13%
Lee et al. [32]
43%
N/R
N/R
N/R
N/R
N/R
Hypothyroidism: 30%
Mucosal inflammation = 28% Stomatitis = 27% Rash = 15% HFSN = 24% N/R
Diarrhea = 44% Anorexia = 26% Nausea = 34% Vomiting = 25% Constipation = 13% N/R
N/R
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Table 4 Summary of all-grade toxicities.
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[18,29,31–33]. No phase III clinical trials and only one Meta analysis published in abstract form about systemic therapy-in general-in non clear cell RCC were found [34]. 4.1.1. Prospective clinical trials Only six phase II clinical trials involving sunitinib in non clear cell RCC met the inclusion criteria. They are summarized in Tables 2–4. • Four phase II studies involving sunitinib treatment for all subtypes of non clear cell RCC (Papillary, chromophobe, translocation and unclassified). These four studies included fifty seven [37], thirty one [16], twenty three [17], and thirty three [28] patients. • Two phase II studies involving sunitinib treatment for papillary RCC only. These two studies included twenty eight [27] and twenty three [35] patients. • One expanded access program including 588 patients with non clear cell RCC [30]. 4.1.2. Retrospective studies • Three retrospective studies involving sunitinib treatment for all subtypes of non clear cell RCC. These three studies included fifty three [18], sixty three [29] and twenty one [31] patients. • Two retrospective studies involving sunitinib treatment for papillary RCC only. These two studies included seventy four [32] and sixteen patients [33]. 4.2. Studies and patients characteristics (Table 2) All the studies included advanced disease that was not amenable to local resection. All 9 trials reported ECOG Performance Status. The vast majority (90% to 100%) of patients had ECOG scores of 0 or 1, and no more than 10% of patients had a score equal to or greater than greater than 2. MSKCC scoring system was evaluated in the majority of studies and the majority of patients lie either in the favorable or intermediate group. The dose schedule used by sunitinib in almost all studies was: Sunitinib 50 mg daily on a 4-week on, 2week off schedule. The majority of included patients had prior nehrectomy (range 68–89%). A considerable proportion of included patients had received prior systemic therapy (immune/chemo/targeted therapy), ranging from (15–65%). Median PFS was reported in 8 out of the 9 studies and there was inter- trial variability in median PFS (Table 3). Median reported PFS ranged from 8.2 to 16.5 months. 4.3. Progression free survival and overall survival (PFS and OS) Median PFS was reported in eleven out of the twelve studies and there was inter- trial variability in median PFS (Table 3). Median reported PFS ranged from 1.6 to 8.9 months. One study reported that sunitinib-induced HTN was associated with better PFS [32]. Some studies reported
differential PFS outcomes according to histology (papillary vs. chromophobe) [37], while the rest of the studies do not show such a difference. Median OS was reported in nine studies and it ranged from 12 months to 22 months, was not reported in two studies and it was not reached in one study (Table 3). Fewer disease sites, better performance status, prior nephrectomy was reported to correlate with better overall all survival [16,35]; while the use of prior cytokine therapy was not related to better survival [16]. 4.4. Tumor response Response assessment was done by RECIST (Response Evaluation in Solid Tumors) in all studies. The DCR (Disease Control Rate defined as complete response + partial response + stable disease) was reported in ten studies, and it ranged from 35% to 91%. The ORR (objective response rate defined as complete response + partial response) was reported in ten studies and it ranged from 0% to 36%. Stable disease was the major response subtype in most of the studies. 4.5. Toxicities All-grade toxicities (grades 1–4) were reported in four trials, while high-grade toxicities were reported in five trials (Tables 4–5). The more common all grade toxicities included hypertension, mucocutaneous toxicities, gastrointestinal, hepatic and hematologic toxicities. The most common grade 3 or 4 toxicities were gastrointestinal toxicities, mucocutaneous toxicities and hematologic toxicities. Treatment-related toxicities have resulted in treatment interruption and/or discontinuation in a number of studies (Table 6). Noted toxicity-related reasons for treatment discontinuation included hepatotoxicity, hypertension/cardiac toxicities and hematologic toxicities; however, detailed reasons for patient withdrawal were not available in all studies.
5. Discussion According to FDA approval data, a number of agents have been approved for advanced RCC: this includes sunitinib, pazopanib, bevacizumab/interferon, high dose interleukin (in selected patients), temsirolimus (in poor risk patients), in addition to a number of other agents in second and third lines of treatment including Everolimus, sorafenib and axitinib. Additionally, many other agents are in the developmental pipeline with multiple Phase II and III trials and results are eagerly awaited. However the available phase III studiesupon which FDA approval has been based-included mainly clear cell RCC and for non clear cell RCC, we do not have similar level of evidence or diversity of armamentarium for the choice of proper systemic treatment.
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Hypertension
Thromboembolism
Proteinuria
Hematologic Toxicities
Mucocutaneous
Fatigue
Hepatotoxicity
GI toxicity
Tannir et al. [37]
16
1
N/R
Anemia = 5 Neutropenia = 12 Leucopenia = 3
Mucositis = 6 HFSR = 1 Rash = 1
16
Hypoalbuminemia =1 Hyperlipidemia = 1
Lee et al. [16]
1 (3%)
N/R
4 (13%)
Anemia = 2 (7%) Leucopenia = 2(7%) Neutropenia = 10 (33%) Thrombocytopenia = 8(27%)
Stomatitis = 2(7%) Alopecia = 0% HFSR = 9 (29%) Rash = 0%
1 (3%)
AST elevation = 1(3%) ALT elevation = 2(7%) Hyperbilirubinemia = 0%
Molina et al. [17]
1 (4%)
2 (9%)
N/R
Mucositis = 1(4%) Other = 3 (13%)
0%
AST elevation = 0% ALT elevation = 2(9%) AP elevation = 0%
Plimack et al. [35]
Hypertension (3 pts) 5%
N/R
N/R
Mucositis (3 pts)
N/R
N/R
N/R
N/R
N/R
Anemia = 4(17%) Leucopenia = 1(4%) Lymphopenia = 2(4%) Neutropenia = 2(9%) Thrombocytopenia = 1(4%) Neutropenia (3 pts) and thrombocytopenia (2 pts) Anemia = 4% Neutropenia = 6% Thrombocytopenia = 8%
Diarrhea = 3 Nausea = 3 Anorexia = 2 Vomiting = 2 Dysphagia = 1 Anorexia = 1 (3%) Nausea = 0% Vomiting = 0% Constipation = 0% Diarrhea = 0% Epigastric Pain = 2 (7%) Diarrhea = 6 (26%) Vomiting = 0%
Mucosal inflammation = 3% Stomatitis = 3% HFSR = 6% Rash = 1%
8%
Epistaxis = 1%
Diarrhea = 5% Anorexia = 2% Nausea = 2% Vomiting = 3% Constipation =
ARTICLE IN PRESS
Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx
Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): A systematic review of the literature Omar Abdel-Rahman a,∗ , Mona Fouad b b
a Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt Medical Microbiology and Immunology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Received 5 June 2014; received in revised form 2 September 2014; accepted 12 January 2015
Contents 1.
2. 3.
4.
5. 6.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Relevant molecular profiling of non clear cell RCC subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Published clinical data for different therapeutics in non clear cell RCC (Table 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Objective of the systematic review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodology for selecting and analyzing the data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Selection of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Prospective clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Retrospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Studies and patients characteristics (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Progression free survival and overall survival (PFS and OS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Tumor response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Toxicities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Source of funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
Abstract Background: The randomized phase III trial of sunitinib versus interferon Alfa provided level-A evidence for the use of sunitinib in advanced clear cell renal cell carcinoma (RCC). This systematic literature review aims at the evaluation of the level of evidence for the use of sunitinib monotherapy for advanced non clear cell RCC in terms of efficacy and toxicity parameters.
∗
Corresponding author. Tel.: +20 1008541806; fax: +20 33028656. E-mail address: [email protected] (O. Abdel-Rahman).
http://dx.doi.org/10.1016/j.critrevonc.2015.01.006 1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.
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Methods: Eligible studies were identified using MEDLINE, Google scholar, ASCO, ESMO and the Cochrane databases. Searches were last updated on 1 June 2014. Eligible studies reported survival and/or response data for patients with non clear cell RCC receiving sunitinib monotherapy. Results: four hundred and five results were obtained from the searches in MEDLINE (n = 319 studies) and other databases (n = 86). Twelve studies (involving 980 patients) were considered eligible and were included in the final analysis: six phase II clinical trials, one expanded access prospective trial and five retrospective analyses. Median PFS was reported in 11 studies ranging from 1.6 to 8.9 months. Median OS was reported in 9 studies ranging from 12 months to 22 months. The disease control rate (DCR) was reported in 10 studies, and it ranged from 35% to 91%. The overall response rate (ORR) was reported in 10 studies and it ranged from 0% to 36%. Frequently reported Grade 3/4 toxicities were gastrointestinal toxicities, mucocutaneous toxicities and hematologic toxicities. Conclusion: There is insufficient evidence (level C) to recommend sunitinib monotherapy in advanced non clear cell RCC and the available data suggests it appears less efficacious than that in advanced clear cell RCC. Further prospective and randomized studies are needed to explore alternative therapies in this setting. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Sunitinib, Non clear RCC; Papillary RCC; Chromophobe RCC
1. Introduction Renal cell carcinoma (RCC) accounts for 3% of all adult cancers, representing the seventh most common cancer in men and the ninth most common cancer in women [1]. Worldwide, there are ∼209,000 new cases per year; additionally, the incidence of all stages of RCC has increased over the past 2 decades, contributing to a steadily increasing mortality rate per unit population [2]. RCC is a heterogeneous disease with multiple pathological subtypes, the most frequent being conventional clear cell, papillary type 1, papillary type 2 and chromophobe: other, rarer histotype have been described in an evolving refinement of the histoathological classification of kidney cancers [3]. According to a recent report from the California cancer registry (including 38,251 RCC cases), 19,149 (50%) were of clear cell type; 14,619 (38.2%) were “unclassified” while 4483 (11.7%) were of non clear cell type. Histology distribution for non clear cell RCC was (n, %): papillary—2863 (63.9%); Chromophobe—1507 (33.6%); and other including medullary and collecting duct—113 (2.5%) [42]. This pathological sub-typing has many molecular, etiological and therapeutic consequences [4]. Different patho-genetic pathways for each of these different subtypes have been suggested for some of these different subtypes with consequent rationalization of targeted therapeutic strategies for some subtypes [5]. For example, the hypoxia inducible pathway and mTOR pathway have been linked to clear cell and papillary type II subtypes with consequent evaluation of VEGF-targeted and mTOR-targeted therapeutics in this setting [6,7]. While the MAP kinase pathway has been linked to chromophobe and papillary type I subtypes with consequent evaluation of RAF-targeted therapeutics in this setting [8]. At initial diagnosis, surgical resection is considered a potentially curative modality for localized RCC, however not all patients have resectable disease. On the other hand, the spectrum of available treatments for advanced RCC is diverse and rapidly developing, including for clear cell RCC: sunitinib, pazopanib, bevaizumab/interferon combination, high
dose interleukin therapy in addition to axitinib, sorafenib and temsitolimus and Everolimus in later lines of treatment [9–15]. However, the situation is less clear for non clear cell RCC because of the lack of prospective controlled phase III studies dedicated to non clear cell RCC. While many systemic treatment options are available, none can be considered the ultimate gold standard in this subset of RCC.
1.1. Relevant molecular profiling of non clear cell RCC subtypes A number of molecular studies have shed the light in the past decade on the distinctive molecular profiling of different subtypes of non clear cell RCC with consequent important implications for a refined personalized treatment selection. Klatte and coworkers have evaluated the cytogenetic and molecular tumor profiling for type 1 and type 2 papillary RCC (pRCC). They found that Type 2 pRCC is associated with more aggressive clinic-pathologic features and worse outcome and molecularly, Type 2 showed greater expression of vascular endothelial growth factor receptor (VEGF)-R2 in the tumor epithelium, and of VEGF-R3 in both tumor epithelium and endothelium [23]. In another Swedish study, the differential vascular endothelial growth factor (VEGF), VEGF-receptor 1 and -2 mRNA expression profiles between clear cell and papillary renal cell carcinoma were evaluated. In this study, it was shown that Among the RCC types, clear cell RCC (cRCC) had higher VEGF levels than papillary RCC (pRCC). In cRCC, VEGF-R2 levels were higher in stage I–II than in more advanced stages. In pRCC, VEGF and VEGF-R2 levels were higher in stage III than in stage I–II tumors [24]. However, we have to acknowledge that for some histotypes a pathogenic correlation to a specific genetic alteration has been proposed: clear cell and VHL, papillary type I and Met, papillary type II and FH, chromophobe and BHD. Beyond these correlations, and not necessarily as a
Please cite this article in press as: Abdel-Rahman O, Fouad M. Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): A systematic review of the literature. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.006
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consequence of them, the activation of several growth and pro-angiogenic pathways have been demonstrated. 1.2. Published clinical data for different therapeutics in non clear cell RCC (Table 1) Table 1 A number of different agents including cytotoxic chemotherapy and molecularly targeted agents have been studied in advanced non clear cell RCC; most notably included suntinib and sorafenib, which have been studied in a number of phase II studies with initially encouraging results [16–18]. Additionally, mTOR inhibitors Everolimus and temsirolimus have been evaluated in a number of phase II results with encouraging results [12,19]. Moreover, a number of cytotoxic chemotherapy regimens (including capecitabine monotherapy and carboplatin/paclitaxel) have been evaluated; and while capecitabine data was encouraging, paclitaxel/carboplatin data was disappointing [20,21]. And more recently, the dual MET/FGFR inhibitor foretinib has been evaluated in pRCC and has shown considerable activity particularly in those with germline MET mutation [25]. Moreover, across the globe, a number of cooperative groups are conducting clinical studies on multiple newer targeted agents for RCC (including non clear cell subtype) in multiple phases of development; the results of these studies are expected within the next 5 years. These studies span a wide spectrum of targeted therapeutics (including newer monoclonal antibodies as well as newer VEGFR tyrosine kinase inhibitors like pazopanib) [22].
3
data-bases: the Cochrane library, Google scholar and PubMed/Medline to identify all potentially relevant publications; the date of the last search was the first of June 2014. Meeting abstracts including ASCO and ESMO were also reviewed. Articles with the following text words or Medical Subject Headings (MeSH) in their titles, abstracts or keyword lists were examined:”renal cell carcinoma” OR “non clear cell renal cell carcinoma” OR “papillary renal cell carcinoma” OR “chromophobe renal cell carcinoma “AND “sunitinib” OR “target therapy” OR “tyrosine kinase inhibitor”. Detailed search strategy for Pubmed was as follows: “renal cell carcinoma”[All Fields] OR “non clear cell renal cell carcinoma”[All Fields] OR “papillary renal cell carcinoma”[All Fields] OR “chromophobe renal cell carcinoma” [All Fields] AND “sunitinib” [All Fields] OR “target therapy” [All Fields] OR “tyrosine kinase inhibitor”[All Fields] AND Clinical Trial [ptyp]. Reference lists of primary original studies and review articles were also checked manually for further related articles (cross-references). 3.2. Selection criteria Inclusion criteria: (1) Studies that described sunitinib monotherapy for the treatment of advanced non clear cell RCC. (2) Tumor response outcome measures and toxicities were reported. (3) Age more than 18 years. Exclusion criteria:
2. Objective of the systematic review
(1) Non English language records were also excluded.
In this systematic review, we will provide an overview of the clinical experience (efficacy and toxicity) related to the use of sunitinib for non clear cell RCC.
3.3. Data extraction
3. Methodology for selecting and analyzing the data 3.1. Search strategy A comprehensive systematic search for English speaking literature was conducted in the following electronic
Data were extracted by two independent reviewers. All eligible articles underwent initially full text review for relevancy and reporting of outcomes of interest. The following information/data were extracted from the studies where available: histo-pathological subtype, Eastern Cooperative Oncology Group (ECOG) Performance Status, treatment regimen and schedule, Memorial Sloan Kettering Cancer Center (MSKCC) prognostic class (favorable, intermediate or poor), complete response (CR) rate, partial response (PR)
Table 1 Published data for systemic agents (other than sunitinib) in the treatment of non clear cell RCC. Progression free survival (PFS)
Grade 3–4 toxicities
Everolimus 10 mg 10.2 daily Capectabine 26 (1250 mg/m) twice daily for 14 days
5.2 Months
Carboplatin and paclitaxel
N/R*
Anemia (10.2%), hyperglycemia (8.2%), and infection (6.1%) Diarrhea (2%), esophageal mucosal inflammation (2%), hand-foot syndrome (4%), thrombocytopenia (9.8%), and neutropenia (8%) Leukopenia and neutropenia, nausea, vomiting, neuropathy, fatigue, seizure
Study
Phase
Number
Agent used
Koh et al. [19]
II
49 Patients
Tsimafeyeu et al. [20] II
51 Patients
Bylow et al. [21]
17 Patients
*
II
Objective response rate (ORR) (%)
7
10.1 Months
N/R: not reported.
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Idenficaon
O. Abdel-Rahman, M. Fouad / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx
Records idenfied through MEDLINE database searching (n = 319 )
Addional records idenfied through other sources (n = 86 )
Screening
Records aer duplicates removed (n = 286)
Eligibility
Records excluded (n = 264) Records screened (n = 286)
Full-text arcles excluded, (n = 10) • 6 review arcles • 4 editorials
Included
Arcles assessed for eligibility (n = 22)
Studies included in qualitave synthesis (n = 12)
Fig. 1. PRISMA flowchart for the study selection procedure.
rate, stable disease (SD) rate, disease control rate (DCR: CR + PR + SD), progression-free survival (PFS), overall survival (OS), and the incidence of toxicities.
3.4. Outcome measures The outcome measures of interest were PFS (progression free survival), OS (overall survival), tumor response, and toxicities. Tumor response (CR, PR, and SD) was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Toxicities were categorized using National Cancer Institute criteria. The main outcome measures are summarized using descriptive statistics. This systematic review adheres to the guidelines provided by the Preferred Reporting Items for Systematic Reviews and MetaAnalyses report (PRISMA Statement) [26].
4. Results 4.1. Selection of studies Fig. 1 summarizes the PRISMA flow diagram for selection of eligible studies; 405 results were obtained from the searches in MEDLINE (n = 319 studies) and other databases (n = 86). Of these 119 were duplicates and 264 did not meet the inclusion criteria and were therefore excluded (either the treatment was not sunitinib monotherapy or the study was for disease categories other than non clear cell RCC). Of the 22 studies which appeared to be eligible after the initial screening, a full text search was performed. Ten studies were removed after the full text search; thus, twelve studies were included in the final analysis: six phase II clinical trials [16,17,27,28,35,37], one expanded access prospective trial [30] and five retrospective analyses (Tables 2–4)
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Phase
Number
Histo-pathological subtype
ECOG PS score
MSKCC score
Dose
Prior treatment (if applicable)
Phase II
57
0 = 20 (35%) 1 = 32 (56%) 2 = 25 (9%)
Favorable: 16% Intermediate: 63% Poor: 21%
Sunitinib 50 mg daily on a 4-week on, 2-week off schedule
Previous nephrectomy: 70% Previous systemic therapy (chemo/immunotherapy): 14%
Lee et al. [16]
Phase II
31
0 = 15 1 = 16
Favorable: 29% Intermediate: 45% Poor: 26%
Patients were treated with 50 mg/day oral sunitinib for 4 weeks, followed by 2 weeks of rest
Prior nephrectomy: 77% Previous immunotherapy: 23% Previous chemotherapy: 13%
Molina et al. [17]
Phase II
23
0 = 78% 1 = 22%
Favorable: 52% Intermediate: 44% Poor: 4%
50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest (4/2)
Previous nephrectomy: 78% previous immunotherapy: 4% previous chemotherapy/targeted therapy: 13%
Tannir et al. [28]
Randomized phase II
33
N/R*
Favorable: 12% intermediate: 88%
Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off)
Previous nephrectomy: 77%
Ravaud et al. [27]
Phase II
28
[Papillary (27), chromophobe (5), unclassified (8), collecting duct or medullary carcinoma (6), sarcomatoid (7), others (4)] Histological type Papillary type 2: 17 (55%) Papillary NOS: 5 (16%) Chromophobe: 3 (10%) Xp11.2 translocation: 1 (3%) Unclassified: 5 (16%) Papillary = 8 Chromophobe = 2 Collecting duct = 4 Medullary = 1 Unclassified = 5 HLRCC-related = 3 Papillary = 40% Chromophobe = 16% Sarcomatoid = 19% Unclassified = 13% Translocation = 10% Papillary type I = 5 patients Papillary type II = 23 patients
0 = 56% 1 = 44%
Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off)
Previous nephrectomy: 89%
Plimack et al. [35]
Phase II
23
Expanded access trial
588 (13%) non-clear-cell RCC
Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off) Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off)
Previous nephrectomy: 65%
Gore et al. [30]
Favorable: 16% Intermediate: 56% pts Poor: 14% Undetermined: 14% Intermediate risk: 14 (61%) Poor risk: 3 (13%) Favorable: 36% Intermediate: 44% Poor: 9% Missing: 11%
50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest (4/2) Sunitinib 50 mg orally once daily on schedule 4–2 (4 weeks on treatment, 2 weeks off) Oral sunitinib 50 mg/day in repeated 6 weekly cycles (4 weeks on and 2 weeks off)
Previous systemic therapy: 62%
Papillary type I = 2 papillary type II = 10 pRCC type not specified = 13 N/R
N/R
0 = 24 (45%) 1 = 26 (49%) 2 = 3 (6%) N/R
N/R
PS was 0 in 14 (56%) pts 1 in 11 (44%) pts
Favorable: 5 Intermediate: 14 Poor: 4 Undetermined: 4 HENG risk groups: Favorable: 11%, Intermediate: 56% Poor: 33%. N/R
0 = 42% 1 = 43% 2 = 12% 3 = 3%
ii. Retrospective studies Choueiri et al. [18] Retrospective study
53
Papillary = 41 (77%) Chromophobe = 12 (23%)
Yildiz et al. [29]
Retrospective
63
Paglino et al. [31]
Retrospective
21
Papillary RCC = 46 pts (88%) Chromophobe = 10 pts. Unclassified = 7 pts N/R
Lee et al. [32]
Retrospective
74
Papillary = 100%
N/R
Casuscelli et al. [33]
Retrospective
16
Papillary type II = 100%
N/R
*
N/R
Previous nephrectomy: 89% Previous antiangiogenic therapy: 5% Previous immunotherapy: 68%
Previous nephrectomy: 89% Previous immunotherapy: 61.9% Previous chemotherapy: 3.5% N/R
Oral sunitinib 50 mg/day in repeated 6 weekly cycles (4 weeks on and 2 weeks off)
Previous nephrectomy: 78%
Oral sunitinib 50 mg/day in repeated 6 weekly cycles (4 weeks on and 2 weeks off)
N/R
N/R: not reported.
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Table 2 baseline characteristics of included trials.
5
Disease control rate (DCR)
Objective response rate (ORR)
Median (PFS)
Median (OS)
ORR and PFS
58%
5%
16.8 months (95% CI: 10.7, 26.3).
Lee et al. [16]
ORR
91%
36%
For the entire group: 2.7 months [95% CI: 1.4, 5.4]. For patients with papillary histology: 1.6 months (95% CI: 1.4, 5.4). For patients with chromophobe histology: 12.7 months (95% CI: 8.5, NA) With a median follow up duration of 18.7 months (95% CI 13.7–23.7 months), the median PFS was 6.4 months (95% CI 4.2–8.6 months) and the 1-year PFS rate was 40%
Molina et al. [17]
ORR
69%
4%
Tannir et al. [28]
ORR and PFS
N/R
ORR in first line was 12% (2 pts had chromophobe, 1 pt had papillary type 1 and 1 pt had 99% sarcomatoid)
Ravaud et al. [27] Plimack et al. [35]
ORR ORR and PFS
60% 35%
4% 0%
Gore et al. [30]
ORR and PFS
86%
11%
Progression-free survival: 7.8 (95% CI 6.3–8.3) months
ii. Retrospective studies Choueiri et al. [18] ORR and PFS
78%
10%
Yildiz et al. [29]
ORR and PFS
63.5%
11.1%
Paglino et al. [31]
ORR and PFS
52.4%
14.3%
Lee et al. [32]
ORR and PFS
70%
N/R
Progression-free survival for entire study: 8.6 months Sunitinib-treated PRCC patients had a PFS of 11.9 months Median PFS was 7.6 months (95% CI, 5.5–9.7 months) and 1-year PFS rate was 33.7% The median progression-free survival was 4.1 months Median PFS = 5 months Factors associated with PFS were sunitinib-induced HTN (HR 0.31, P = 0.002), pre-treatment NLR > 3 (HR 5.3, P = 0.001), and active smoking (HR 2.5, P = 0.01)
Casuscelli et al. [33]
PFS
N/R
N/R
• DCR = (CR + PR = SD). • ORR = (CR + PR).
The median progression-free survival was 5.5 months (95% CI, 2.5–7.1) in all 23 patients, and 5.6 months for the 8 papillary patients (95% CI, 1.4–7.1). Median PFS in first line was 6.1 mos (95% CI: 4.7, 10.8) Median PFS in second line was 1.8 mos (95% CI: 1.5, NA) N/R Median PFS was 1.6 months (95% CI, 1.3–12)
Median PFS = 8.9 months
The median OS times of the poor and intermediate risk groups were 7.7 months (95% CI 7.3–8.1 months) and 25.6 months (95% CI 4.5–46.9 months), respectively. Median OS had not been reached in the favorable risk group. N.B. Patients with prior nephrectomy had a tendency of better OS (HR 0.37, 95% CI 0.1–1.4, P = 0.19), but it did not meet statistical significance. Prior exposure to cytokines did not affect PFS or OS N/R
Median OS with first line was not reached
N/R Median OS of 10.8 months (95% CI, 6.2-NE) Fewer disease sites, better performance status, prior nephrectomy, and normal baseline albumin and LDH levels correlated with longer OS. Overall survival: 13.4 (95% CI 10.7–14.9)
Overall survival time (for the entire study): 19.6 months
Median OS was 22.0 months (95% CI, 13.4–30.6 months) and 1-year OS rate was 64.7% Median overall survival was 14.6 months Median OS = 12 months Factors associated with OS were sunitinib-induced hypothyroidism (HR 0.4, P = 0.024), past nephrectomy (HR 0.41, P = 0.02), pre-treatment NLR > 3 (HR 2.25, P = 0.036), and active smoking (HR 2.3, P = 0.027) Median OS = 15 months
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Primary endpoint
i. Prospective studies Tannir et al. [37]
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Study
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Table 3 Summary of efficacy measures.
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Hypertension
Thromboembolism
Proteinuria
Anemia and leukopenia
thrombocytopenia
Fatigue
Hepatotoxicty/ hypothyroidism
GI toxicity
Mucocutaneous
Bleeding
Lee et al. [16]
23 (74%)
N/R
12 (39%)
Anemia = 23 (77%) Neutropenia = 28 (93%) Leucopenia = 26 (87%)
27 (90%)
21 (67%)
Elevated ALT = 16(54%) Elevated AST = 23(77%) Hyperbilirubinemia = 8 (27%)
Stomatitis = 27 (88%) Alopecia = 6 (19%) HFSR = 23 (65%) Rash = 3 (10%)
17 (55%)
Molina et al. [17]
6 (26%)
2 (9%)
N/R
19 (83%)
11 (48%)
Elevated ALT = 17 (74%) Elevated AST = 16 (70%) Elevated AP = 14 (61%)
Mucositis = 9 (39%) Skin (HFSR + other) = 11 (48%)
N/R
Gore et al. [30]
22%
N/R
N/R
Anemia = 21(91%) Neutropenia = 10 (43%) Leucopenia = 16 (70%) Lymphopenia = 5 (22%) Anemia = 15% Neutropenia 15%
Anorexia = 18 (58%) Nausea = 14 (45%) Vomiting = 11 (35%) Constipation = 11 (36%) Diarrhea = 13 (42%) Epigastric pain = 14 (45%) Vomiting = 7 (30%) Diarrhea = 6 (26%)
22%
37%
N/R
Epistaxis = 13%
Lee et al. [32]
43%
N/R
N/R
N/R
N/R
N/R
Hypothyroidism: 30%
Mucosal inflammation = 28% Stomatitis = 27% Rash = 15% HFSN = 24% N/R
Diarrhea = 44% Anorexia = 26% Nausea = 34% Vomiting = 25% Constipation = 13% N/R
N/R
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Table 4 Summary of all-grade toxicities.
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[18,29,31–33]. No phase III clinical trials and only one Meta analysis published in abstract form about systemic therapy-in general-in non clear cell RCC were found [34]. 4.1.1. Prospective clinical trials Only six phase II clinical trials involving sunitinib in non clear cell RCC met the inclusion criteria. They are summarized in Tables 2–4. • Four phase II studies involving sunitinib treatment for all subtypes of non clear cell RCC (Papillary, chromophobe, translocation and unclassified). These four studies included fifty seven [37], thirty one [16], twenty three [17], and thirty three [28] patients. • Two phase II studies involving sunitinib treatment for papillary RCC only. These two studies included twenty eight [27] and twenty three [35] patients. • One expanded access program including 588 patients with non clear cell RCC [30]. 4.1.2. Retrospective studies • Three retrospective studies involving sunitinib treatment for all subtypes of non clear cell RCC. These three studies included fifty three [18], sixty three [29] and twenty one [31] patients. • Two retrospective studies involving sunitinib treatment for papillary RCC only. These two studies included seventy four [32] and sixteen patients [33]. 4.2. Studies and patients characteristics (Table 2) All the studies included advanced disease that was not amenable to local resection. All 9 trials reported ECOG Performance Status. The vast majority (90% to 100%) of patients had ECOG scores of 0 or 1, and no more than 10% of patients had a score equal to or greater than greater than 2. MSKCC scoring system was evaluated in the majority of studies and the majority of patients lie either in the favorable or intermediate group. The dose schedule used by sunitinib in almost all studies was: Sunitinib 50 mg daily on a 4-week on, 2week off schedule. The majority of included patients had prior nehrectomy (range 68–89%). A considerable proportion of included patients had received prior systemic therapy (immune/chemo/targeted therapy), ranging from (15–65%). Median PFS was reported in 8 out of the 9 studies and there was inter- trial variability in median PFS (Table 3). Median reported PFS ranged from 8.2 to 16.5 months. 4.3. Progression free survival and overall survival (PFS and OS) Median PFS was reported in eleven out of the twelve studies and there was inter- trial variability in median PFS (Table 3). Median reported PFS ranged from 1.6 to 8.9 months. One study reported that sunitinib-induced HTN was associated with better PFS [32]. Some studies reported
differential PFS outcomes according to histology (papillary vs. chromophobe) [37], while the rest of the studies do not show such a difference. Median OS was reported in nine studies and it ranged from 12 months to 22 months, was not reported in two studies and it was not reached in one study (Table 3). Fewer disease sites, better performance status, prior nephrectomy was reported to correlate with better overall all survival [16,35]; while the use of prior cytokine therapy was not related to better survival [16]. 4.4. Tumor response Response assessment was done by RECIST (Response Evaluation in Solid Tumors) in all studies. The DCR (Disease Control Rate defined as complete response + partial response + stable disease) was reported in ten studies, and it ranged from 35% to 91%. The ORR (objective response rate defined as complete response + partial response) was reported in ten studies and it ranged from 0% to 36%. Stable disease was the major response subtype in most of the studies. 4.5. Toxicities All-grade toxicities (grades 1–4) were reported in four trials, while high-grade toxicities were reported in five trials (Tables 4–5). The more common all grade toxicities included hypertension, mucocutaneous toxicities, gastrointestinal, hepatic and hematologic toxicities. The most common grade 3 or 4 toxicities were gastrointestinal toxicities, mucocutaneous toxicities and hematologic toxicities. Treatment-related toxicities have resulted in treatment interruption and/or discontinuation in a number of studies (Table 6). Noted toxicity-related reasons for treatment discontinuation included hepatotoxicity, hypertension/cardiac toxicities and hematologic toxicities; however, detailed reasons for patient withdrawal were not available in all studies.
5. Discussion According to FDA approval data, a number of agents have been approved for advanced RCC: this includes sunitinib, pazopanib, bevacizumab/interferon, high dose interleukin (in selected patients), temsirolimus (in poor risk patients), in addition to a number of other agents in second and third lines of treatment including Everolimus, sorafenib and axitinib. Additionally, many other agents are in the developmental pipeline with multiple Phase II and III trials and results are eagerly awaited. However the available phase III studiesupon which FDA approval has been based-included mainly clear cell RCC and for non clear cell RCC, we do not have similar level of evidence or diversity of armamentarium for the choice of proper systemic treatment.
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Hypertension
Thromboembolism
Proteinuria
Hematologic Toxicities
Mucocutaneous
Fatigue
Hepatotoxicity
GI toxicity
Tannir et al. [37]
16
1
N/R
Anemia = 5 Neutropenia = 12 Leucopenia = 3
Mucositis = 6 HFSR = 1 Rash = 1
16
Hypoalbuminemia =1 Hyperlipidemia = 1
Lee et al. [16]
1 (3%)
N/R
4 (13%)
Anemia = 2 (7%) Leucopenia = 2(7%) Neutropenia = 10 (33%) Thrombocytopenia = 8(27%)
Stomatitis = 2(7%) Alopecia = 0% HFSR = 9 (29%) Rash = 0%
1 (3%)
AST elevation = 1(3%) ALT elevation = 2(7%) Hyperbilirubinemia = 0%
Molina et al. [17]
1 (4%)
2 (9%)
N/R
Mucositis = 1(4%) Other = 3 (13%)
0%
AST elevation = 0% ALT elevation = 2(9%) AP elevation = 0%
Plimack et al. [35]
Hypertension (3 pts) 5%
N/R
N/R
Mucositis (3 pts)
N/R
N/R
N/R
N/R
N/R
Anemia = 4(17%) Leucopenia = 1(4%) Lymphopenia = 2(4%) Neutropenia = 2(9%) Thrombocytopenia = 1(4%) Neutropenia (3 pts) and thrombocytopenia (2 pts) Anemia = 4% Neutropenia = 6% Thrombocytopenia = 8%
Diarrhea = 3 Nausea = 3 Anorexia = 2 Vomiting = 2 Dysphagia = 1 Anorexia = 1 (3%) Nausea = 0% Vomiting = 0% Constipation = 0% Diarrhea = 0% Epigastric Pain = 2 (7%) Diarrhea = 6 (26%) Vomiting = 0%
Mucosal inflammation = 3% Stomatitis = 3% HFSR = 6% Rash = 1%
8%
Epistaxis = 1%
Diarrhea = 5% Anorexia = 2% Nausea = 2% Vomiting = 3% Constipation =
