Systemic therapy for chromophobe renal cell carcinoma: A systematic review

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Clinical-Kidney cancer

Systemic therapy for chromophobe renal cell carcinoma: A systematic review Dimitrios Papanikolaou, M.D., M.Sc.a,*, Pinelopi Ioannidou, M.D., M.Sc.b, Periklis Koukourikis, M.D., M.Sc.a, Kyriakos Moysidis, M.D., Ph.D.a, Soultana Meditskou, M.D., Ph.D.c, Dimitrios Koutsoumparis, M.D.d, Konstantinos Hatzimouratidis, M.D., Ph.D.a, Eudoxia Hatzivassiliou, M.Sc., Ph.D.d a

Second Department of Urology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece c Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece d Laboratory of Biological Chemistry, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece b

Received 22 August 2019; received in revised form 25 October 2019; accepted 20 November 2019

Abstract Background: Chromophobe renal cell carcinoma (chRCC) subtype accounts for almost 5% of total RCC cases. It carries the best prognosis among the rest of RCC types. However, patients with metastatic chRCC disease have worse prognosis than patients with advanced clear cell RCC. Furthermore, available data regarding systemic therapy for chRCC patients are scarce and confusing. Aim: The aim of this systematic review is to search for and critically appraise studies that investigate the results of systemic therapies in patients diagnosed with metastatic chRCC disease. Methods: Search strategy included PUBMED, CENTRAL, clinicaltrials.gov databases, and abstracts of major conferences with a focus on urologic oncology (till March 2019). Studies investigating patients that were treated with systemic therapy for advanced chRCC disease were included. Primary outcomes were progression-free survival and objective response rate. Secondary outcome was overall survival. Screening of available studies was carried out by 2 groups of reviewers, as well as the quality assessment of the included studies. Results: The systematic search yielded 369 studies, of which 15 studies (2 randomized control trials and 13 cohort studies), involving 183 patients, met the eligibility criteria. The 2 randomized control trials that directly compared sunitinib vs. everolimus, suggested an advantage for sunitinib without being statistically significant. Furthermore, sunitinib seems to be superior than sorafenib at least in terms of objective response rate. Regarding mTOR inhibitors, they may have a role in a specific subset of chRCC patients, that needs to be further explored. Finally, as far as immunotherapy is concerned, available data suggest that chRCC seems to be resistant to recent immune check point inhibitors, since just a few tumor responses were observed with the administered immunotherapy regiments. Conclusion: The optimum therapy for metastatic chRCC is still missing, as results from ongoing trials are awaited. More studies, of high quality and adequate sample size, that will be based on the specific biology of chRCC, have to be carried out in order to identify the best treatment. Ó 2019 Elsevier Inc. All rights reserved.

Keywords: Renal cell carcinoma; RCC; Chromophobe; Systemic therapy; Antineoplastic agents

1. Introduction Renal cancer is the sixth most common cancer in men and 10th most common cancer in women, accounting for Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. *Corresponding author. Tel.: +30-2313-323586. E-mail address: [email protected] (D. Papanikolaou). https://doi.org/10.1016/j.urolonc.2019.11.006 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.

5% and 3% of new cancer cases, respectively [1]. The incidence of kidney cancer is still increasing worldwide. Highest incidence rates are found in North America, Northern European, and Eastern European countries, whereas the lowest are found in South-East Asia and Africa [2,3]. Renal cancer has a peak incidence between 60 and 70 years old; there is a male predominance with a male to female ratio almost equal to 2:1 [2]. As far as mortality is concerned,

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rates seem to be stabilized or even decreasing in the developed countries [4]. Lower mortality rates are found in the most developed countries with advanced health care systems, where access to optimal therapies is available [5]. Nowadays, most of new cases are diagnosed incidentally as a result of the available imaging technologies. However, even in this setting, 17% of new cases are with distant metastases at the time of diagnosis, affecting their possibilities of survival [6]. In this regard, renal cancer is the most lethal cancer of the urinary system, with a 5-year relative survival reaching 73%, in comparison to prostate 99% and urinary bladder 77% [7]. Renal cell carcinoma (RCC) comprises a rather heterogeneous group of tumors, with clear cell subtype (clear cell RCC − ccRCC) being the dominant one as it accounts for 70% to 75%. Other common subtypes are papillary RCC (pRCC) accounting for 10% to 16%, and chromophobe RCC (chRCC) accounting for 5% [8]. ChRCC was first reported by Thoenes in 1985, who described 12 RCCs that consisted of “chromophobe” cells [9]. ChRCC subtype affects both sexes equally, with an incidence that peaks during the sixth decade of life [10]. The majority of patients present with Stage I or Stage II disease; 6% to 7% present with advanced disease that mostly affects the liver (unlike ccRCC) or lungs [11]. It carries the best prognosis between the rest of RCC subtypes, as 5-year and 10-year diseasefree survival reach 83.9% and 77.9%, respectively [12]. Previous studies show that every 1 out of 5 patients with RCC will present with metastatic disease, whereas another 21% that was metastases free at the time of diagnosis will finally develop metastases [13]. As far as chRCC is concerned, the proportion of patients with metastatic disease is lower, accounting only for 6% of total cases [11]. However, according to a study, patients with metastatic chRCC disease have poor prognosis; they present more often with sarcomatoid features and show lower response rates to immunotherapy [14]. Surgical approaches are common for all RCC subtypes; however, differences exist in terms of systemic therapy as the various histological subtypes have a different molecular background. Latest European Association of Urology Guidelines on RCC present a therapeutic strategy for the treatment of advanced ccRCC. Patients are first categorized into favorable risk or intermediate/poor risk based on International Metastatic Renal Cancer Database Consortium. For patients categorized as poor/intermediate risk, they are primarily treated with ipilimumab or nivolumab (both monoclonal antibodies targeting immune checkpoint blockade). As far as patients with favorable risk disease are concerned, first line therapy includes the usage of sunitinib or pazopanib (both tyrosine kinase inhibitors). Further drugs are available for second and third line treatments, boosting the survival of those patients [15]. However, data regarding systemic therapy of nonccRCC subtypes are scarce; no phase III trials for these patients have been reported. As a result, recommendations

regarding systemic treatment of non-ccRCC are weak. Both mTOR inhibitors and Vascular Endothelial Growth Factor (VEGF)-targeted therapies have been offered with poorer oncological outcomes [15,16]. A phase II trial that evaluated the efficacy of sunitinib vs. everolimus in patients with non-ccRCC showed a slight advantage in patients treated with sunitinib. However, no superiority was proven with both drugs presenting poor outcomes [17]. Despite the fact that non-ccRCC subtypes account for more than 20% of total RCC cases, little consensus around best practice exists [18]. It is now well understood that non-ccRCC is a heterogeneous group of different histological subtypes that have different molecular backgrounds that need different treatments. The hallmark of chromophobe tumors is the loss of multiple chromosomes including 1, 2, 6, 10, 13, 17, and 21 which can be found exclusively in chRCC tumors and help in the diagnosis of difficult histological cases [19,20]. After the whole genome analysis of chRCC was completed, it was proven that it is a completely different disease from ccRCC, highlighting the need for disease-specific therapy [21]. Future trials, that will be based on studies about the molecular mechanisms that underlie the disease, need to be tailored in order to optimize results. Information on chRCC is constantly increasing since the genetic background of the tumor is better understood. However, when it comes to patients presenting with metastatic chRCC disease, available information is confusing, thus producing an obstacle for the treating physicians. The aim of this systematic review is to search for and critically evaluate studies that investigate the results of systemic therapies in patients diagnosed with metastatic chRCC disease. 2. Materials and methods We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in order to report this systematic review and we also took into consideration the methods outlined in the Cochrane Handbook for Systematic Reviews of Healthcare interventions [22,23]. We did not register a protocol for this systematic review. 2.1. Information sources Major electronic databases including MEDLINE (PubMed, until 3 March 2019) and Cochrane (until 3 March 2019) were searched. Further investigation included searching the clinical trial registration platform clinicaltrials.gov and abstracts of major conferences with focus on urologic oncology. In order to ensure literature saturation, we scanned the reference lists of reviews that focused on chRCC for any information on studies that may have escaped our search. No language restriction and no publication date criteria were used. When there was more than one publication from one study, we aimed to select the most comprehensive study, in terms of data.

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2.2. Search strategy In order to conduct our search, we used the following search terms "Carcinoma, Renal Cell"[Mesh], kidney carcinoma, RCC, kidney tumor, chromophobe, chromophobe RCC, nonclear RCC, nonccRCC, metastatic RCC, advanced RCC. Further details of our search strategy regarding PUBMED are presented on Appendix A. After MEDLINE strategy was finalized, it was translated to the syntax of other databases. 2.3. Eligibility criteria Inclusion and exclusion criteria were decided by the researchers considering the research question. Studies will be selected according to the criteria outlined below. 2.3.1. Participants Study population consisted of patients diagnosed with chRCC metastatic disease that are receiving systemic therapy. Patients were eligible despite if they were or were not operated previously or after the therapy. Patients could be treatment naive, or they could have received previous systemic therapies. 2.3.2. Intervention Targeted agents available for systemic therapy that were evaluated included tyrosine kinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, tivozanib, and lenvatinib), mTOR inhibitors such as everolimus and temsirolimus, bevacizumab (monoclonal antibody against circulating VEGF), immunotherapy agents such as nivolumab, ipilimumab, pembrolizumab, interferon (IFN), intereleukin-2 (IL-2), as well as any other different systemic treatment agents that were found during the systemic search. In case of studies with comparators, the comparators could be anyone from the previously described agents or placebo. Results for each agent had to be presented separately, and not as a group of drugs with similar pharmacokinetics (for example, everolimus and temsirolimus are both mTOR inhibitors). 2.3.3. Outcome Primary outcomes were overall progression-free survival (PFS) and objective response rate (ORR), evaluated in accordance with Response Evaluation Criteria In Solid Tumors (RECIST v1.1) [24]. If possible, responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Secondary outcome evaluated was overall survival (OS). 2.3.4. Study type As chRCC is a rare disease any type of studies focusing on metastatic non-ccRCC patients including randomized control

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trials (RCTs), quasi-RCTS, nonrandomized comparative studies, prospective and retrospective cohort studies were considered eligible. Studies with mixed populations of non-ccRCC and chRCC were considered eligible as long as outcomes for chRCC populations were reported separately. 2.3.5. Language There were no language restriction criteria, as long as information could be provided by the authors of the article. 2.3.6. Exlusion criteria - Case reports. - Studies focusing on ccRCC patients. - Studies that included chRCC patients along with other non-ccRCC but did not report the outcomes of each subgroup separately, were not included. - Studies carried out in the neoadjuvant setting. 2.4. Study selection process All relevant studies were imported in Mendeley reference manager (v 1.19.2 for Mac). Eligibility assessment was performed independently in an unblinded standardized manner by 2 groups of researchers. Studies that were considered as eligible by both researchers were then analyzed comprehensively. Disagreements between the 2 groups were resolved by discussion, and where no agreement was reached, a third partner acted as an arbitrator. 2.5. Data extraction Data were collected in data extraction sheets that were designed a priori. As previously, 2 independent reviewers carried out this process, after proper training on randomly selected studies. In case of disagreements they were resolved by discussion; if no agreement was reached, a third author would decide. The following details were collected: study design, participants’ characteristics, agent evaluated, outcome characteristics, number of previous systemic treatments. Due to the great heterogeneity of the results, a metaanalysis was not possible to be conducted. 2.6. Quality assessment Risk of bias assessment was performed by 2 reviewers in a blinded manner. As 2 studies were RCTs they were evaluated in accordance to Cochrane collaboration risk of bias tool, using the Revised Cochrane risk of bias tool for randomized trial ROB 2.0 [25]. The rest of the eligible studies were observational (prospective or retrospective cohort studies), so they were evaluated using the NewcastleOttawa Scale (NOS). NOS is based on a “star system,” where each of the studies that are evaluated is judged on 3 different categories: selection of study groups, comparability of study groups, and ascertainment of the outcome of

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interest [26]. Any disagreements regarding the quality assessment were arbitrated by a third reviewer. 3. Results The systematic search yielded 369 results after removal of the duplicates (Cochrane: 38, Pubmed: 320, clinicaltrials.gov: 10, and manual searching: 7). After screening of the titles and abstracts, 308 were excluded as irrelevant. From the remaining 61 studies, full text assessment was made. In the end, 15 studies fulfilled the criteria for inclusion in the systematic review. Full details of the study selection process are presented in the PRISMA flow diagram which can be found in Appendix B. All of the studies that were found to be eligible were written in English and were published from 2002 to 2019. General characteristics of the included studies are presented in Table 1. 3.1. Study characteristics As far as the characteristics of the included studies are concerned, 2 of the studies were RCTs, 7 were prospective cohort studies, and the rest were retrospective cohort studies. A total of 183 patients with chRCC were studied, treated with 10 different agents or combinations. The study with the biggest sample of chRCC patients was the study of Keizman et al. (n = 36 pts), while the studies with the smallest sample were the studies of Lee et al. and Procopio et al. (n = 3 pts, respectively). Twelve studies recruited exclusively non-ccRCC patients, while the rest 3 studies had patients of mixed histology (both ccRCC and non-ccRCC). Patients were recruited from 8 different countries (USA, South Korea, Israel, Turkey, Italy, Spain, Canada, and UK). The summary of outcomes of all the included studies are presented in Table 2. Armstrong et al. [27]: The ASPEN trial, was an RCT comparing the efficacy of sunitinib and everolimus in nonccRCC patients. A total of 16 patients with chRCC histology were randomized. As far as ORR is concerned, everolimus was superior with 33.3% vs. 10%, while in terms of PFS a superiority of everolimus was also found with 11.4 (95% CI: 5.7−19.4) vs. 5.5 (95% CI: 3.2−19.7) months. However, in terms of OS, sunitinib was found superior with 31.5 vs. 13.2 months. Tannir et al. − ESPN RCT [28]: Regarding the ESPN trial, it was a crossover RCT trial, comparing the efficacy of sunitinib vs. everolimus in non-ccRCC patients. Twelve patients with chRCC were randomized into 2 different groups. Data regarding the PFS and Response evaluation according to RECIST were not available; in terms of OS there was a benefit toward sunitinib with 31.9 months vs. 25.1 for everolimus. Choueiri et al. [29]: In this retrospective study, they evaluated the efficacy of sunitinib vs. sorafenib. Seven patients of chRCC histology received sunitinib vs. 5 patients taking sorafenib. In this study, sorafenib showed a

superiority in terms of PFS and ORR with 27.5 vs. 8.0 and 40% (2 PR) vs. 14.2% (1 PR), respectively. No data regarding OS were available. Keizman et al. [30]: A multicenter retrospective study comparing the efficacy of sunitinib in chRCC (n = 36) and ccRCC (n = 36) patients. Median OS and PFS for chRCC patients was 26 months and 10 months, respectively. An ORR of 27.7% was noted. Tannir et al. [31]: In this prospective phase II trial they tested the efficacy of sunitinib in non-ccRCC patients that have received a maximum of 2 previous systemic therapies. In the 5 patients with chRCC histology, median PFS was 12.7 months, whereas OS was available as the data for the whole group reaching 16.8 months. ORR was 40% as only 2 PR were noted. Lee et al. [32]: A multicenter prospective phase II study where efficacy of sunitinib was tested. Three patients were of chRCC histology; 1 SD and 2 PR responses were noted, thus reaching an ORR of 33.3%. Two of the patients were continuing treatment at the time the results were posted, so no data on median OS and PFS were available. Procopio et al. [33]: In this prospective study, they evaluated the efficacy of sorafenib in a mixed population of patients with advanced RCC, which they were previously untreated or they have relapsed after previous therapies. Three patients were of chRCC histology; no data were available regarding OS and PFS and ORR was 0% as no PR or CR were seen. Stadler et al. [34]: In the multicenter prospective phase III ARCCS trial, they tested the efficacy of sorafenib in advance non-ccRCC patients that they have previously received at least one systemic therapy. ORR in the 29 chRCC patients was 3.4%; results regarding OS were not available whereas PFS was available only for the whole population of non-ccRCC patients reaching 8.5 months. Campbell et al. [35]: A single center retrospective study “evaluating” the efficacy of cabozantinib in non-ccRCC patients that they have progressed on previous therapies. ORR regarding the 6 patients with chRCC histology was 16.6%. Data on median PFS and OS were available only as a sum for the whole group (30 patients), reaching 8.6 months (95% CI: 6.1−14.7) and 25.4 months (95% CI: 15.3−35.4), respectively. Koh et al. [36]: A prospective multicenter phase II study “evaluating” the efficacy of everolimus in metastatic nonccRCC patients. ChRCC was diagnosed in 8 patients, who had previously received at least one systemic therapy. PFS and OS of these patients were 13.1 months and 21.6 months, respectively. ORR was 25% with confirmed 2 PR. Voss et al. [37]: A single center phase II prospective study investigating the efficacy of everolimus plus bevacizumab in treatment naive metastatic non-ccRCC patients. Bevacizumab is a recombinant monoclonal antibody directed against VEGF-A, used for the treatment of metastatic RCC. Data regarding OS and PFS for the 6 patients with chRCC were not available; however, 3 patients

Table 1 General characteristics of the included studies Author

Type of study [identificator]

Population

Patients (n)

Non-ccRCC

64

Procopio et al. (2007) [33]

Single Center Prospective

Mixed

136

Stadler et al. (2007) [34]

Multicenter Prospective (Phase III) [ARCCS]

Non-ccRCC

212

Choueiri et al. (2008) [29]

Retrospective

Non-ccRCC

53

Lee et al. (2012) [32]

Multicenter Prospective (Phase II) [NCT01219751]

Non-ccRCC

31

Tannir et al. (2012) [31]

Single Center Prospective

Non-ccRCC

57

Koh et al. (2013) [36]

Multicenter Prospective Phase II

Tannir et al. (2014) [28]

RCT (phase II) Multicenter [ESPN] [NCT01185366]

Non-ccRCC

68

Voss et al. (2016) [37]

Single center Prospective (phase II)

Non-ccRCC

35

Everolimus + bevacizumab Keizman et al. (2016) [30]

0 Multicenter Retrospective

Mixed

72

49

Papillary (n = 18) Chromophobe (n = 12) Collecting duct (n = 26) Unclassified (n = 8) Clear cell (n = 103) Papillary (n = 14) Chromophobe (n = 3) Bellini ducts (n = 1) Sarcomatoid (n = 1) Unclassified (n = 4) Papillary (n = 170) Chromophobe (n = 29) Collecting Duct (n = 10) Oncocytoma (n = 3) Papillary (n = 41) Chromophobe (n = 12) Papillary (n = 12) Chromophobe (n = 3) Translocational (n = 1) Unclassified (n = 5) Papillary (n = 27) Chromophobe (n = 5) Collecting Duct (n = 6) Unclassified (n = 8) Sarcomatoid (n = 7) Other (n = 4) Papillary (n = 29) Chromophobe (n = 8) Collecting Duct (n = 2) Sarcomatoid (n = 4) Unclassified (n = 6) Papillary (n = 27) Chromophobe (n = 12) Unclassified Translocational Sarcomatoid Papillary (n = 5) Chromophobe (n = 5) Medullary (n = 2) Unclassified (n = 23) Clear cell (n = 36) Chromophobe (n = 36)

Prior systemic treatments 0−2

Chemotherapy/IFN2a / IL -2 or combination IFN2a + IL-2 Sorafenib

1

Sorafenib

≥1

Sunitinib/Sorafenib

0−1

Sunitinib

0−1

Sunitinib

0−≤2

Everolimus

≥1

Everolimus vs. Sunitinib

0−1 (crossover)

Sunitinib

0

5

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Single center Retrospective

Agent

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Motzer et al. (2002) [38]

Subgroups

6

Table 1 (Continued) Author

Type of study [identificator]

Population

Patients (n)

Non-ccRCC

108

Koshkin et al. (2018) [39]

Multicenter Retrospective

Non-ccRCC

41

McKay et al. (2018) [40]

Multicenter Retrospective

Mixed

43

Campbell et al. (2018) [35]

Single center Retrospective

Non-ccRCC

30

McDermott et al. (2019) [41]

Multicenter Prospective (phase II) [NCT02853344]

(2 cohorts) Cohort B: NonccRCC

165

Papillary (n = 70) Chromophobe (n = 16) Translocational (n = 8) Minor clear cell (n = 13) Sarcomatoid (n = 16) Unclassified (n = 22) Papillary (n = 16) Chromophobe (n = 5) Collecting Duct (n = 4) Translocational (n = 1) Unclassified (n = 14) Mucinous Tubular (n = 1) Clear Cell (n = 7) Papillary (n = 14) Chromophobe (n = 10) Translocational (n = 3) Unclassified (n = 9)

Papillary (n = 17) Chromophobe (n = 6) Translocational (n = 2) Unclassified (n = 3) Other (n = 2) Papillary (n = 118) Chromophobe (n = 21) Unclassified (n = 26)

Prior systemic treatments

Everolimus vs. Sunitinib

0

Nivolumab

0−3

PD-1 (n = 29) PD-L1 (n = 1) PD-1/PDL1 + Ipilimumab (n = 4) PD-1/PD-L1 + VEGFtargeted therapy (n = 9) Cabozantinib

0−3

0−≥1

Pembrolizumab

0

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RCT Multicenter [ASPEN] [NCT01108445]

Agent

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Armstrong et al. (2016) [27]

Subgroups

Table 2 Summary of outcomes of the included studies Study (type)

Motzer et al. (Retrospective)

Agent

IFN

Prior treatments

Patients chRCC/total

IL-2 IFN + IL-2 Sorafenib

0−≥2

3/64 2/64 3/136

Stadler et al. (Prospective)

Sorafenib

≥1

Choueiri et al. (Retrospective)

Sunitinib

PFS (mo) median (95%CI)

55 (40−80) 29 (19−59)

NA

59 (32−79)a

NA

NA

29/212

63

NA

8.5a

0−1

7

56 (35−75)

NA

8.9

Sorafenib

0−1

5

Lee et al. (Prospective)

Sunitinib

0−1

3/31

53 (18−76)a

NA

4.9 15.1 *36.3*

Tannir et al. (2012) (Prospective)

Sunitinib

0−≤2

5/57

57 (22−85)a

16.8 (10.7−26.3)a

12.7 (8.5−NA)

Koh et al. (Prospective)

Everolimus

≥1

8/49

57 (23−75)

21.6

13.1

Tannir et al. (2014) (RCT)

Sunitinib

0−1 (crossover)

6/68

60 (28−76)a

31.6

8.9

Everolimus Everolimus + bevacizumab

0

6/68 5/35

58 (23−73)a 54 (19−75)a

25.1 NA

NA NR [6 month PFS: 75%]

Keizman et al. (Retrospective)

Sunitinib

0

36

64 (26−87)

26 (§10)

10 (§9) median

Armstrong et al. (RCT)

Sunitinib Everolimus Nivolumab

0 0 0−3

10/51 6/57 5/41

59 (24−100) 64 (29−90) 58 (33−82)a

31.5 (14.8−NR) 13.2 (9.7−37.9) NR

5.5 (3.2−19.7) 11.4 (5.7−19.4) NA (3.5)a

Procopio et al. (Prospective)

Voss et al. (Prospective)

Koshkin et al. (Retrospective)

27.5

Response evaluation RECIST

ORR

DCR

PR:1/12

8%

8%

CR:0 PR:0 SD:1 PD:2 CR:0 PR:1 b SD:16 PD:1 PR:1 SD:6 PR:2 SD:3 CR:0 PR:1 SD:2 PD:0 CR:0 PR:2 SD:3 PD:0 CR:0 PR:2 SD:4 PD:1 NA

0%

33.3%

3.4%

58.6%

14.2%

100%

40%

100%

33.3%

100%

40%

100%

25%

75%

NA

NA

NA 40%

NA 80%

27.7%

77.7%

10% 33.3% 0%

NA NA 60%

NA CR:0 PR:2 SD:2 PD:1 CR:0 PR:10 SD:18 PD:8 CR or PR:1 CR or PR:2 CR:0 PR:0

7

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7/64

OS (mo) median (95%CI)

D. Papanikolaou et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−13

0−5

Age (range)

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4.1 (2.9−5.6)a NR 62 (22−86)a Pembrolizumab McDermott et al. (Prospective)

0

21/165

8.6 (6.1−14.7)a 25.4 (15.3−35.4)a 58.4 (25−81)a Cabozantinib Campbell et al. (Retrospective)

≥0

6/30

NA 12.9 (7.4−NR)a 57 (24−75)a 10/43 0−3 PD-1/PD-L1 Monotherapy or in combination McKay et al. (Retrospective)

CR = complete response; DCR = disease control rate; IFN = interferon; IL-2 = Interleukin-2; NA = not available; NR = not reached; ORR = objective response rate (by RECIST criteria); OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; SD = stable disease. a Data from general group. b Three more patients are mentioned with unconfirmed partial response.

33.3% 9.5%

16.6%

40% 0%

SD:3 PD:1 CR:0 PR:0 SD:4 PD:6 CR:0 PR:1 SD:2 PD:3 CR:1 PR:1 SD:10 PD:9

DCR ORR Response evaluation RECIST PFS (mo) median (95%CI) OS (mo) median (95%CI) Age (range) Patients chRCC/total Prior treatments Agent Study (type)

Table 2 (Continued)

50%

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remained on treatment for more than 12 moths achieving a 6 months PFS of 75%. ORR was 40% as 2 PRs were confirmed. Motzer et al. [38]: A retrospective study investigating the efficacy of IFN, IL-2, or their combination in patients with non-ccRCC histology that have failed previous systemic therapies. Median OS for the 12 chRCC patients was 29 months, while data regarding PFS were not available. As only 1 PR was confirmed ORR was 8%. Koshkin et al. [39]: A multicenter retrospective study evaluating the activity of nivolumab in metastatic nonccRCC patients that they were previously untreated, or they have relapsed after previous therapies. Five patients with chRCC histology were included. ORR was 0% as no responses were noted. Median PFS for the whole cohort population was 3.5 months, while OS was not reached. McKay et al. [40]: A multicenter retrospective analysis exploring the efficacy of PD1/PD-L1 inhibitors in 43 patients with non-ccRCC histology. The majority were treated with monotherapy, and the rest were treated in combination with ipilimumab or another VEGF-targeted therapy. No objective response was seen at the 10 patients diagnosed with chRCC (only SD was observed in 4 patients). Data were not available regarding PFS whereas OS was not reached. McDermott et al. [41]: A prospective multicenter phase II study investigating the efficacy of pembrolizumab in 165 treatment naive metastatic non-ccRCC patients. ORR for the 21 patients with chRCC histology was 9.5% as 1 CR and 1 PR were confirmed. Data regarding OS were not reached at the time they presented the results; median PFS was 4.1 months for the whole group. 3.2. Risk of bias assessment of the included studies All of the studies were critically assessed. Different tools for assessing the quality of the included studies were used, as the eligible studies differed in terms of methodology. In this regard, from the 14 eligible studies 2 were RCTs, while the rest were Cohort studies, either prospective or retrospective. As far as the RCTs are concerned, the ESPN and ASPEN trials, they were evaluated using the ROB 2.0 risk of bias assessment tool by Cochrane [27,28]. Details of the assessment are provided in Fig. 1. Regarding the cohort studies, they were evaluated using the NOS for assessing the quality of Cohort studies. Details of the quality assessment are provided in Table 3. Regarding the length of follow-up time (at the outcome assessment category of NOS), we considered that a followup time of at least 6 months was considered sufficient. In this way, ORR and PFS (the main outcomes of interest) could be easily assessed. All the studies, both retrospective and prospective were methodologically correct. In this regard, the available results about the efficacy of each specific agent in treating metastatic chRCC can be trustworthy. However, it should

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it provided evidence both from observational and RCT studies. 4.1. Principal findings

Fig. 1. Risk of bias table of the 2 RCTs included in the systematic review. Green point (+): low risk of bias; Yellow point (?): unclear risk of bias; Red point ( ): high risk of bias. (Color version of figure is available online.)

be pointed out that due to the rarity of the disease, the number of the included patients is relatively small and therefore, concrete conclusions cannot be drawn. 4. Discussion Up to date, the majority of studies that evaluated systemic therapies on patients with advanced renal cancer focused almost exclusively on patients diagnosed with ccRCC. As a result, drugs approved for the treatment of advanced disease were tested only in a small number of patients diagnosed with non-ccRCC, without distinguishing the different histologic subtypes of non-ccRCC. Nevertheless, it was recently established that each histological subtype of non-ccRCC is a separate disease entity that needs to be treated with distinct targeted agents in order to increase efficacy. In this regard, the last few years studies that focused on metastatic nonccRCC patients were published, both of retrospective and prospective design. Since chRCC is a rare histological subtype, little is known of the efficacy of the available systemic therapies. In this regard, this is the first systematic review that tried to search for and critically appraise studies that investigate the role of systemic therapies in patients that are diagnosed with advanced chRCC disease. It was conducted in accordance to PRISMA guidelines and

In our review 15 studies were found to be eligible that evaluated the efficacy of different systemic treatments for patients with metastatic chRCC. The total number of patients was 183, which were treated with 10 different agents, offered as monotherapy or as a combination. ASPEN and ESPN trials were the only RCTs that compared the efficacy of sunitinib and everolimus in nonccRCC patients [27,28]. The two studies showed that the efficacy of sunitinib is better than everolimus in terms of OS (31.9 vs. 25.1 and 31.5 vs. 13.2 months). However, we need to assess these findings with precaution, because the quality of the studies was not optimal and the fact that when the data were evaluated in a meta-analysis, the superiority of sunitinib was not proven to be statistically significant [42]. The study by Colomba et al. was not included in the systematic review, since chRCC patients were grouped in those receiving antiangiogenic (sunitinib, sorafenib, pazopanib, and bevacizumab) and those treated with mTOR inhibitors (temsirolimus or everolimus) [43]. However, their results need to be mentioned as it compares data from 91 chRCC patients. Antiangiogenic therapies apparently offer an advantage both in terms of ORR and OS, although, this was not proven to be statistically significant, as previously mentioned. The efficacy of sunitinib was also evaluated vs. sorafenib in the study of Choueiri et al., where a superiority of sorafenib was found in terms of PFS and ORR with 27.5 vs. 8.0 and 40% vs. 14.2%, respectively [29]. However, the retrospective nature of the study in combination with the small number of participants and the moderate risk for systemic bias, make it necessary to approach the results with caution. Three more studies in the systematic review evaluated specifically the efficacy of sunitinib. PFS ranged from 10 months in the study of Keizman et al. (36 pts) to 12.7 in the study of Tannir et al. (5 pts) [30−32]. ORR ranged from 27.7% to 40% while results on OS ranged from 16.8 to 26 months. In the studies of Procopio et al. (3 pts) and Stadler et al. (29 pts) that evaluated the efficacy of sorafenib, results cannot confirm the superiority of sorafenib shown by Choueiri et al. [33,34]. Data on PFS and OS were not available in both studies, whereas, ORR was 0% to 3.4%. Taking into account results from all the aforementioned studies, the number of patients of each study and the study design, a superiority of sunitinib vs. sorafenib, at least in terms of ORR, seems to exist. However, no firm conclusions can be reached as data are extracted from studies with different study design, without a prospective randomized comparison and the sample size is small. Cabozantinib, another tyrosine kinase inhibitor, was evaluated for its efficacy in non-ccRCC by Campbell et al. [35]. In terms of efficacy outcomes for the 6 patients with

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Study

Representativeness of exposed cohort

Selection of nonexposed cohort

Ascertainment of exposure

Demonstration

Comparability

Assessment of outcome

Follow-up long enough

Not available Not available

Secure record* Secure record*

Yes* Yes*

No No

Record linkage* Record linkage*

Yes* Yes*

Tannir et al. (2012) Lee et al. (2012) Koh et al. (2013) Voss et al. (2016)

Truly representative* Truly representative* Truly representative* Truly representative*

Not available Not available Not available Not available

Secure record* Secure record* Secure record* Secure record*

Yes* Yes* Yes* Yes*

No No No No

Record linkage* Record linkage* Record linkage* Record linkage*

Yes* Yes* Yes* Yes*

McDermott et al. (2019) Truly representative* Retrospective Cohort studies Motzer et al. (2002) Truly representative* Choueiri et al. (2008) Truly representative* Keizman et al (2016) Truly representative*

Not available

Secure record*

Yes*

No

Record linkage*

Secure record* Secure record* Secure record*

Yes* Yes* Yes*

No No Study controls for any factor**

Secure record*

Yes*

Secure record* Secure record*

Yes* Yes*

Koshkin et al. (2018)

Truly representative*

Not available Not available Drawn from the same community* Not available

McKay et al. (2018) Campbell et al. (2018)

Truly representative* Somewhat representative*

Not available Not available

Length of follow-up of at least 6 months is considered acceptable for assessment of objective response rate (ORR). Lost of follow-up <10% is considered acceptable.

Total score

Yes*

Complete* 11/29 lost follow up (37%) Complete* Complete* Complete* 1/36 lost follow up (2.7%)* Complete*

6 5

6

Record linkage* Record linkage* Record linkage*

Yes* Yes* Yes*

Complete* Complete* Complete*

6 6 9

No

Record linkage*

Yes*

5

No No

Record linkage* Independent blind assessment*

Yes* Yes*

1/5 lost to follow up (20%) Complete* Complete*

6 6 6 6

6 6

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Prospective Cohort studies Procopio et al. (2007) Truly representative* Stadler et al. (2007) Truly representative*

Adequacy of follow-up

D. Papanikolaou et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−13

Table 3 Summary of quality assessment based on the Newcastle-Ottawa scale (NOS)

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chRCC, it had a low ORR of 16.6%. Data on median PFS and OS were available only as a sum for the whole group (30 patients), reaching 8.6 months (95% CI: 6.1−14.7) and 25.4 months (95% CI: 15.3−35.4), respectively. As it seems from PFS data, SD can be achieved for at least 6.1 months, which correlates with the better results of disease control rate that reach 50%. However, data regarding OS need to be considered with precaution, due to the confounding effect of previous or later therapies that could easily affect OS. The efficacy of everolimus, an mTOR inhibitor, in advanced non-ccRCC patients was investigated by Koh et al. in a prospective study of 49 patients [36]. ChRCC was diagnosed in 8 patients, that had previously received at least one systemic therapy. PFS of these patients was 13.1 months with 25% ORR, consistent to the PFS of 13.2 months found in the ASPEN trial [27]. OS was 21.6 months, similar to the OS of 25.1 months in the ESPN trial, greater than the OS of 13.2 months of the ASPEN trial [28]. Despite the fact that, in this phase II study, OS did not differ in terms of tumor histology, patients diagnosed with chRCC had longer PFS, suggesting that these patients may benefit from everolimus treatment. As previously mentioned, targeting the mTOR pathway could be helpful in a subset of patients with chRCC, which present mutations in the mTOR pathway [21]. To further support this statement, a case of a patient who remained without disease for 8 years after temsirolimus therapy is reported. In this patient, mutations were identified in TSC2, a critical negative regulator of mTOR [44]. Bevacizumab, a recombinant monoclonal antibody that is directed against VEGF-A, is approved for the treatment of advanced RCC. In the study by Voss et al. 5 patients with chRCC that were treatment naive were treated with everolimus plus bevacizumab [37]. Despite the fact that PFS was not reached, 3 out of 5 patients remained on treatment for more than 12 months, achieving a disease control rate of 80%. ORR was 40%, since 2 patients have shown a PR to therapy. The combination of bevacizumab with everolimus might offer a small benefit in terms of ORR (40% vs. 25%) than the administration of everolimus alone as in the study by Koh et al. [36]. However, numbers are small in order to reach firm conclusions and as toxicity is expected to be higher when using drug combinations, they should always be administered with caution. As far as immunotherapy is concerned, 4 studies evaluating its efficacy were found. A retrospective analysis by Motzer et al. of 12 patients with metastatic chRCC, tested the efficacy IFN, IL-2, or their combination [38]. None of the agents used resulted in substantial antitumor activity as only 1 patient showed PR (ORR: 8%). Results on PFS were not available. Furthermore, the available OS of 29 months could be easily affected by previous or subsequent chemotherapy regimens, so it is not trustworthy. These results are in agreement with previous studies, where INF has been substituted by newer targeted therapy agents and IL-2 has

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shown low response rates ranging from 7% to 27% in ccRCC patients [15]. Results from “Select” Trial, evaluating patients treated with high doses of IL-2, have been promising showing durable remissions and prolonged survival both in poor and intermediate risk patients [45]. However, the trial focused mainly on patients with ccRCC and given the considerable toxicity of high dose IL-2, it is necessary to address results with prudence when referring to non-ccRCC patients. Recent advances in immunotherapy have resulted to the approval of immune check point inhibitors such as nivolumab and ipilimumab in the ccRCC metastatic setting. However, data on their activity in patients with non-ccRCC are limited, including patients with chRCC. In our review 3 studies evaluated the efficacy of recent immunotherapy agents. As it is indicated by the first 2 studies of Koshkin et al. and McKay et al., the efficacy of immune checkpoint inhibitors in metastatic chRCC is low, as no responses were observed. However, the small sample size and the retrospective nature of both studies again highlight the need to address results with caution. In the prospective KEYNOTE-427 trial that evaluated the efficacy of pembrolizumab, results were more promising as responses were observed in 9.5% of patients [41]. However, these 3 trials reveal also the possibility of chRCC subtype being resistant to immunotherapy- at least with the agents that have been tested so far − in contrast to the rest non-ccRCC subtypes that achieved better ORR. Pembrolizumab, an anti-PD-1 agent, has proven its efficacy in patients with metastatic ccRCC in the KEYNOTE-426, a phase III trial, where its combination with axitinib resulted in better OS, PFS and higher ORR than treatment with sunitinib alone [46]. However, its efficacy in non-ccRCC needs to be further evaluated. The last few years there has been an emerging interest in the treatment of metastatic non-ccRCC. As a result, there are many ongoing trials that investigate therapies aimed for metastatic non-ccRCC patients, with the interest focusing mostly in recent immunotherapy regiments. CheckMate 920 (NCT02982954) is a phase 3b/4 trial which evaluates the safety and efficacy of ipilimumab and nivolumab combination in non-ccRCC patients; preliminary results are available from an interim analysis [47]. Two more ongoing phase II trials that evaluate treatment combinations of immune check point inhibitors are NCT03177239 (ANZUP1602) that evaluates the efficacy of nivolumab as a monotherapy or in combination with ipilimumab and NCT03075423 (SUNIFORECAST) that evaluates the efficacy of the combination of ipilimumab and nivolumab vs. sunitinib. Further trials that evaluate the combination of immunotherapy and angiogenesis inhibitors are NCT03635892 where nivolumab is combined with cabozantinib and NCT03866382 that tests the efficacy of triple combination nivolumab, ipilimumab and cabozantinib. The efficacy of cabozantinib post immunotherapy is tested in NCT03685448 trial (ANZUP1802), while its efficacy is evaluated vs. sunitinib in trial NCT03541902. Finally, the last 2 phase II ongoing trials focus on tyrosine kinase inhibitors

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and everolimus; NCT02915783 aims to demonstrate the efficacy of lenvatinib in combination with everolimus while in NCT01767637 (PINCR) the activity of pazopanib is evaluated [48]. As many patients within these trials will be of chRCC histology, their results may help optimizing treatment of advanced chRCC. The present systematic review tried to be as concise as possible strictly adhering to the PRISMA statement guidelines. However, the review has several limitations. First of all, the majority of the studies were of moderate quality, regarding risk of bias assessment, which could affect the validity of the results. Second, clinical and methodological heterogeneity among the included studies was present, although they were methodologically correct. Furthermore, heterogeneities were present regarding the number of agents used, or the line of treatment which could also affect results. Trying to deal with this issue, we have chosen as primary goals ORR and PFS as they are not affected by subsequent or crossover therapies offering an excellent alternative for assessing drugs’ efficacy [49]. Furthermore, the majority of studies included were retrospective with the potential to introduce many confounders. Finally, due to the rarity of metastatic chRCC disease, the sample size is relatively small and therefore concrete conclusions cannot be drawn. However, despite its limitations, this study provides treating physicians with information on how to approach patients with metastatic chRCC. 5. Conclusion The optimum-targeted therapy for chRCC is still missing. Available data from direct comparison of sunitinib and everolimus suggest an advantage for sunitinib without being statistically significant. Furthermore, sunitinib seems to be superior than sorafenib at least in terms of ORR. Regarding mTOR inhibitors, they may be superior for a specific subset of patients with chRCC. As cost for DNA sequencing is decreasing, new data could help to identify these patients. As far as immunotherapy is concerned, available data suggest that chRCC seems to be resistant to recent immune check point inhibitors as just a few responses were observed. Results from ongoing trials are expected, whereas new trials that are based on underlying mechanisms of the disease are needed, in order to identify the optimum therapy for chRCC patients. Conflict of interest The authors declare they have no conflicts of interest. Ethical approval This article does not contain any studies with human participants performed by any of the authors.

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