World J Urol (2011) 29:355–360 DOI 10.1007/s00345-010-0642-3
ORIGINAL ARTICLE
Response of renal lesions during systemic treatment with sunitinib in patients with metastatic renal cell carcinoma: a single center experience with 14 patients C. Seidel • M. Fenner • A. S. Merseburger • C. Reuter • P. Ivanyi • F. La¨nger • A. Ganser V. Gru¨nwald
•
Received: 6 November 2010 / Accepted: 29 December 2010 / Published online: 22 January 2011 Ó Springer-Verlag 2011
Abstract Purpose The tyrosine kinase inhibitor (TKI) sunitinib induces partial remissions (PR) in a substantial proportion of patients with metastatic renal cell carcinoma (mRCC). Only little is known about the activity of sunitinib in renal lesions in patients with metastatic disease, as most patients with synchronous metastases receive palliative nephrectomy. Methods Fourteen patients with clear cell mRCC with renal lesions and sunitinib therapy (50 mg OD, 4/2 scheme) were retrieved retrospectively from clinic records. Tumor assessment consisted of CT scans at least every two cycles, analyzed according to RECIST. In 5 of 14 patients, renal tumors were considered as the primary tumor, while the remaining patients had kidney metastases. In total, 65 target lesions were evaluated. Results The median progression-free survival (PFS) of sunitinib was 8.7 months (range: 2.7–40.2). Median overall survival (OS) from initiation of TKI therapy was 26 months (range: 3–55). Best response according to RECIST consisted of partial remission (PR) in 4 patients, stable disease (SD) in 7 patients, a complete remission
C. Seidel M. Fenner C. Reuter P. Ivanyi A. Ganser V. Gru¨nwald (&) Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany e-mail:
[email protected] A. S. Merseburger Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany F. La¨nger Institute of Pathology, Hannover Medical School, Hannover, Germany
(CR) in 1 patient, and 2 patients with progressive disease (PD). Analyzing the response of renal lesions only, 1 patient had PD, 8 patients had SD, 4 patients had PR, and 1 had a CR. Palliative nephrectomy was performed after two courses of sunitinib in 2 patients. Conclusions In our cohort, similar responses of renal tumors and peripheral metastases were achieved with sunitinib treatment. Our results support the use of sunitinib to control renal tumor lesions in metastatic patients. Keywords Sunitinib Renal cell carcinoma Renal lesions Primary RECIST
Introduction Up to 30% of patients with newly diagnosed renal cell carcinoma present with metastatic disease, and 40% of the remainder subsequently develop metastases [1]. Immunotherapy with interferon rarely induced objective responses in renal lesions [2]. The inclusion of palliative nephrectomy prior to immunotherapy has shown survival benefit in two randomized controlled trials in patients with metastatic RCC [3, 4]. Palliative nephrectomy, therefore, became the standard of care in patients with mRCC [5, 6]. TKIs and mTOR (mammalian target of rapamycin) inhibitors have replaced immunotherapy as the treatment of choice for most mRCC [7, 8]. Although no prospective clinical trial has yet shown a survival benefit for patients receiving nephrectomy prior to systemic treatment in the TKI era, patients suitable for surgery with mRCC will be operated as the mainstay of therapy. This is due to the evidence from the previous cytokine era described previously, which also reported complete remissions following primary tumor removal. In the pivotal trial exploring
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sunitinib in mRCC, 91% of patients had a nephrectomy prior to systemic therapy [9]. Sunitinib is considered standard therapy in first-line treatment of mRCC and is associated with a PFS of 11.8 months and objective remissions in 39% of patients [9]. However, its activity in renal lesions has never been reported prospectively so far. A retrospective analysis of 22 patients without nephrectomy prior to start of treatment with sunitinib revealed a 31% volume reduction of the primary tumor, suggesting distinct biological activity [10]. In another series, 19 patients with either advanced or metastatic RCC received sunitinib [11]. Sixteen percent of patients achieved objective responses, and a nephrectomy was performed in 21% of patients. These preliminary data suggest clinical activity for sunitinib in mRCC patients without prior nephrectomy. To further explore the efficacy of sunitinib in mRCC patients with primary or metastatic lesions of the kidney, we retrospectively analyzed the overall tumor response as well as the response of renal tumor lesions only in 14 patients treated at our institution.
Methods Fourteen patients with mRCC and renal lesions receiving first-line TKI treatment with sunitinib 50 mg (4/2 scheme) between December 2005 and September 2010 were identified at our institution and included in this analysis. In one patient, only renal lesions were analyzable during sunitinib treatment. Five patients received prior interferon therapy. Data were summarized retrospectively, in accordance with the regulatory agreement of the local ethics committee and the Declaration of Helsinki. Patient demographics and disease characteristics are described in Table 1. Tumor assessment was made according to local practice, which included CT scans of the chest and abdomen every two treatment cycles. Early assessment was additionally performed in four patients after cycle one. The overall tumor response was evaluated according to RECIST criteria version 1.1 [12]. We analyzed the response of sole renal lesions and overall tumor response, respectively. The response of renal lesions was analyzed according to RECIST criteria, i.e., assessment of the sum of the largest diameter compared to either baseline or the corresponding value at time of best response. Tumors of the kidney were considered as primary when growing at the initial anatomical site without previous resection. Renal lesions where defined as metastases, which appeared after previous nephrectomy during the course of disease. Nine patients had one single renal lesion, while in one case multiple lesions with 5 metastases of the kidney were
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World J Urol (2011) 29:355–360 Table 1 Patient demographics and disease characteristics MSKCC 0
4
33%
1
5
42%
2
3
25%
Prior Interferon therapy
5
PFS under Sunitinib
8.7
range (2.7–40.3)
CS from first-line TKI
25.9
range (3.1–55)
Dear cell
13
93%
Papillary
1
7%
Histology
Age (range)
59 (40–72)
Male
9
64%
Female
5
36%
11 3
79% 21%
Renal
14
100%
Lung
8
57%
Liver
4
29%
Lymph nodes
8
57%
Adrenal gland
7
50%
Other
6
43%
1–3
4
29%
4–6
7
50%
7–9
3
21%
ECCG 0 1 Metas organ sites
Number of target lesions
analyzed. Three patients had two renal lesions and one patient had 3 renal lesions. Statistics Statistical analyses were performed using the Statistical Package for the Social Sciences software ver. 17.0 (SPSS, Inc., Chicago, IL). OS and PFS were calculated by the Kaplan–Meier method with 95% confidence intervals. Logrank tests were applied for statistical analysis. A two-sided P B 0.05 was regarded as significant.
Results The 14 mRCC patients were treated with sunitinib for a median of 6 cycles (range: 2–17). Dose reductions due to adverse events were necessary in 3 patients (37.5 mg in two patients, 25 mg in one patient). Two patients underwent palliative nephrectomy after two courses of sunitinib for tumor debulking. The median PFS was 8.7 months (range: 2.7–40.2), with a median OS from start of sunitinib
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treatment of 26 months (range: 3–55). Six patients are still alive, with one patient still on sunitinib therapy. The median duration from the end of sunitinib treatment until death or to the present day is 10.1 months (range: 0–26.3 months). Sixty-five target lesions were evaluated, including 23 renal lesions (35%). Considering the overall tumor response during sunitinib treatment according to RECIST, 2 patients (14%) had progressive disease, 7 patients (50%) had stable disease, 4 patients (29%) had a partial remission, and one patient achieved a complete remission (7%) as best response. The median reduction of the tumor diameter of all target lesions was 18%. Hereby the best response was a complete remission, while one patient with progressive disease had a 43% size increase of the sum of target lesions. Considering the response of renal lesions only, 1 patient (7%) had an increase of its index lesions C20%, 8 patients (62%) had disease stabilization, 4 patients (31%) showed tumor shrinkage of renal lesions C30%, and one patient (7%) had a complete disappearance. The median size reduction of primary tumors in the kidney was 21%, and the median tumor shrinkage of metastatic lesions in the kidney was 24%. The median PFS of patients with primary tumors in the kidney was 8.7 months (with one patient still on treatment) compared to 11.2 months for patients with metastatic lesions in the kidney (P = 0.4). The median OS of patients with primary tumors in the kidney was 10.7 months, compared to 25.9 months for patients with metastatic lesions in the kidney (P = 0.18). Two patients with primary RCC received nephrectomy after two courses of sunitinib treatment. One patient presented with synchronous bone metastases, which required
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radiotherapy. During the course of local therapy, the patient developed rapid disease progression with new lung lesions, which triggered the decision to initiate sunitinib treatment. After 2 courses, tumor shrinkage of metastatic and the renal primary were detected by 17 and 21%, respectively (Fig. 1). The patient received subsequent nephrectomy based on susceptible disease. On histology, a partial necrosis with remaining vital tumor tissue was reported (Fig. 2). Treatment with sunitinib was maintained for 10 months, reporting a PR as best response to therapy. After disease progression, treatment was switched to everolimus and disease stabilization was achieved for 7 more months. Intermittently, resection of a CNS metastasis with hypofractionated stereotactic postoperative radiotherapy was required (40 Gy). However, at time of disease progression, experimental treatment with dovitinib was offered within a clinical trial, but PD was noted after two courses requiring spine surgery. Subsequent therapy was applied by everolimus and radiotherapy to bone and CNS. However, the patient died 4 months later, which accumulates to an overall survival of 30.4 months since initial diagnosis. The second patient had synchronous lung metastases and received up-front sunitinib in the absence of tumor complaints. After 2 courses of sunitinib, progressive disease was noted with new lung lesions, whereas the renal lesion remained stable. Due to the enormous primary lesion, palliative debulking nephrectomy was performed. However, the patient died 11.6 months after initial diagnosis. During this period 4 different treatment regimens were applied, without any clinical response. After progression of sunitinib, treatment was continued with everolimus (best response: PD) and subsequently exposed to
Fig. 1 Similar response of a renal primary lesion compared with the response of a metastatic lesion of the left mediastinum after two courses of sunitinib shown on CT scans. Median tumor reduction was 21% for the renal lesion and 17% for the mediastinal lesion
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Fig. 2 a Biopsy of bone lesions before sunitinib treatment without necrosis (HE, OM 509). b After two cycles of sunitinib, this patient underwent nephrectomy and histology revealed necrosis (N) in about 30% within remaining vital tumor (HE, OM 2009)
dovitinib (best response: PD). Last line of therapy consisted of sorafenib. But again, disease control could not be achieved and the patient died subsequently due to further disease progression, rendering this patient intrinsically resistant.
Discussion Sunitinib is a potent drug for the treatment of patients with mRCC. Objective tumor responses have been reported in 39% of patients, but only 9% of patients had an intact primary at the start of treatment and whether patients had renal metastases was not reported [9]. However, control of renal lesions within the remaining kidney may be essential to maintain renal function and prevent local complications. The sunitinib expanded access program enrolled 4,622 patients until December 2007 of whom 490 had intact primaries and received systemic treatment. In this cohort of patients, first-line therapy with sunitinib was associated with a PFS of 12 months in patients with prior nephrectomy (N = 1,020) and 6.5 months in patients without prior nephrectomy (N = 146) [13]. However, whether these data reflect patient selection rather than a real decrease in antitumor activity in primary tumors remains unknown. A prospective phase II trial of sunitinib reported a PFS of 4.9 months in patients with unresectable primaries, suggesting an inferior outcome [14]. Other studies have demonstrated the feasibility of neoadjuvant treatment [15, 16]. Hereby, Wood et al. found no difference by comparing a study group treated with presurgical targeted therapy (with sunitinib, sorafenib, or bevacizumab) with a contemporary group that underwent up-front cytoreductive surgery in terms of any perioperative surgical parameters indicative of morbidity or mortality. Kaplan–Meier analyses also revealed similar median cancer-specific survival among patients treated with either presurgical targeted molecular therapies or up-front nephrectomy. Jonasch et al. demonstrated that presurgical treatment with bevacizumab therapy yields clinical outcomes comparable to postsurgical
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treatment with antiangiogenic therapy in patients with mRCC with a median PFS of 11.0 months. Median OS was 25.4 months. These results have spurred the initiation of large randomized trials that explore the role of targeted therapies in conjunction with nephrectomy in these patients [17]. In our analysis, renal lesions responded to VEGFRtargeted treatment with sunitinib in terms of growth arrest and tumor shrinkage. With a median PFS of 8.7 months (range: 2.7–40.2), our patient cohort had a reasonable outcome. Disease control was achieved in 86% of patients, including objective responses in 36% (N = 5). Response of renal lesions was similar to response of metastases in other locations in our analysis. However, whether the presence of unresected primary correlates with inferior survival remains unknown. In our patient cohort, patients with metastases to the kidney had a beneficial OS compared with patients with primary tumors (25.9 vs. 10.7 months), which did not reach significance (P = 0.18). However, these subgroups remain very small, which may limit the statistical power to detect differences. However, our findings are supported by subgroup analyses of the aforementioned trials. Certainly, additional studies are needed to validate clinical response of renal primaries or metastases, which is currently under investigation in the clinic. The French CARMENA trial prospectively explores the role of sunitinib with or without palliative nephrectomy in metastatic RCC. Tumor burden was thought to have predictive value in patients with renal lesions. However, no correlation was found between treatment response and disease burden, defined by the sum of renal and non-renal target lesions (P = 0.41). Recently, a retrospective analysis addressed the relevance of tumor load and response to TKI. In metastatic RCC, the amount of tumor tissue removed by debulking nephrectomy predicts PFS of subsequent TKI treatment, suggesting to differentiate between renal and metastatic tumor load [18]. Despite the prevailing role of palliative nephrectomy in metastatic RCC, it is of at most importance to define the
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optimal time point for tumor resection in conjunction with systemic treatment. To date, there is only limited data on preoperative use of sunitinib in metastatic RCC, rendering preoperative treatment feasible. In our analysis, local tumor complications such as bleeding or invasive tumor growth into neighboring organs were not observed, supporting the applicability of sunitinib in such a setting. However, the schedule of palliative nephrectomy and systemic treatment needs to be defined prospectively, which is currently addressed by the EORTC 30073 phase III trial. The main goal of this important study is to test whether immediate or deferred resection of the renal primary is appropriate in the context of sunitinib treatment. An interesting clinical question will be whether susceptibility to TKI is an useful marker for the selection of subsequent nephrectomy. One of our patients showed rapid tumor progression defined by new lung lesions and required up-front systemic therapy. When tumor shrinkage was achieved during sunitinib treatment, a palliative nephrectomy was performed and sunitinib treatment resided until disease progression. This case indicates the interdisciplinary treatment approach required for optimal treatment in mRCC patients and underscores the relevance of local and systemic treatment approaches. In contrast to this susceptible tumor, another patient failed to respond to any line of therapy given. This may apply to a subgroup of patients of up to 20% in firstline treatment [19, 20]. The clinical course of intrinsic resistance remains largely undefined; however, there is some data supporting the notion that probability of PFS at 3 and 6 months predicts OS in metastatic RCC [21]. Hence, selection of susceptible patients may play a future role in palliative nephrectomy. In conclusion, sunitinib has significant antitumor activity in patients with either renal primaries or renal metastases. In our series, treatment outcome measured by PFS remained similar to the previously published efficacy of sunitinib and further supports its use in these patients. The precise role of perioperative systemic treatment and palliative debulking nephrectomy in the era of TKI has not yet been defined. Patients initially appearing with metastatic disease, therefore, should be treated within a clinical trial in order to answer this important clinical task. To date, the decision on palliative nephrectomy is given individually rather than on a broad base of evidence. Our series supports the feasibility of this approach with a low local complication rate and raises the question whether renal primaries and metastases may reflect a different clinical scenario. Conflict of interest Christoph Seidel: none. Martin Fenner: none. Axel S. Merseburger: Invited speaker for Pfizer, participating in a clinical trial for Bayer; Advisory Board: Bayer. Christoph Reuter: none. Philip Ivanyi: none. Florian La¨nger: none. Arnold Ganser: none. Viktor Gru¨nwald: Honoraria: Bayer, Glaxo Smith Kline, Novartis, Pfizer, Roche; Advisory: Novartis, Roche, Pfizer, Glaxo Smith Kline.
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