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The Outcome of Patients Treated with Sunitinib Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer
EUROPEAN UROLOGY 60 (2011) 448–454
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Kidney Cancer Editorial by Simon P. Kim and R. Houston Thompson on pp. 455–456 of this issue
The Outcome of Patients Treated with Sunitinib Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer Thomas Powles a, Christian Blank b, Simon Chowdhury c, Simon Horenblas b, John Peters d, Jonathan Shamash a, Naveed Sarwar a, Ekaterini Boleti e, Anju Sahdev a, Tim O’Brien c, Dan Berney a, Luis Beltran d, Paul Nathan f, John Haanen b, Axel Bex b,* a
Bart Cancer Institute, Queen Mary University of London, St Bartholomew’s Hospital London, UK
b
Departments of Surgical and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
c
Department of Uro-oncology, Guys and St Thomas’s Hospital, London, UK
d
Department of Surgery, Whipps Cross Hospital, London, UK
e
Department of Medical Oncology, The Royal Free Hospital London, UK
f
Department of Medical Oncology, Mount Vernon Hospital, London, UK
Article info
Abstract
Article history: Accepted May 9, 2011 Published online ahead of print on May 17, 2011
Background: The role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma (ccRCC) is controversial. Objective: To determine the outcome of patients with metastatic ccRCC who receive sunitinib prior to planned nephrectomy. Design, setting, and participants: The study combined the data from two prospective phase 2 studies that assessed upfront sunitinib (12–16 wk) prior to nephrectomy in previously untreated patients with metastatic renal cell carcinoma (RCC). Sunitinib was discontinued during the perioperative period (median: 29 d). Intervention: Sunitinib 50 mg in six weekly cycles (4 wk on, 2 wk off). Measurements: Progression-free (PFS) and overall survival (OS) using the Kaplan-Meier method. Results and limitations: Twenty-one patients (32%) had Memorial Sloan-Kettering Cancer Centre (MSKCC) poor-risk disease; 45 (68%) had intermediate-risk disease. Nephrectomy was not performed in 19 (29%), most commonly due to disease progression (n = 12). The PFS for the cohort was 6.3 mo (95% confidence interval [CI], 5.1–8.5). Seventeen (36%) patients progressed during the treatment break, 13 (76%) of whom stabilised upon reinitiating of sunitinib. The OS for the cohort was 15.2 mo (95% CI, 10.3–NA). The OS for the intermediate MSKCC risk group was significantly longer than that for the poor-risk group (26.0 mo [95% CI, 13.6–NA] and 9.0 mo [95% CI, 5.8–20.5], respectively; p < 0.01). In multivariate analysis, progression of disease prior to planned nephrectomy (hazard ratio [HR]: 5.34; 95% CI, 3.17–13.27), high Fuhrman grade (HR 3.27; 95% CI, 1.38–7.72), and MSKCC poor risk at diagnosis (HR 4.75; 95% CI, 2.05–11.02) were associated with short survival ( p < 0.01). However, in the absence of randomised studies it is not possible to determine if this approach is beneficial. Conclusions: Upfront sunitinib prior to planned nephrectomy in intermediate-risk disease is associated with a median survival of >2 yr despite frequent progression during treatment break. Progression in metastatic sites prior to planned surgery and MSKCC poor-risk disease was associated with a poor outcome.
Keywords: Sunitinib Nephrectomy Metastatic renal cancer FDG-PET
# 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. The Netherlands Cancer Institute, Division of Surgical Oncology, Department of Urology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel. +31 20 512 2553; Fax: +31 20 512 2554. E-mail address: [email protected] (A. Bex). 0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2011.05.028
EUROPEAN UROLOGY 60 (2011) 448–454
1.
Introduction
449
cycles (study A) of sunitinib (50 mg by mouth once daily, 4 wk on, 2 wk off) prior to a planned nephrectomy. After the nephrectomy, patients
Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is established as first-line therapy in metastatic clear cell renal cell carcinoma (ccRCC) [1,2]. In the landmark trial of Motzer et al, patients had a median overall survival >2 yr [1]. The vast majority of these patients had a nephrectomy prior to starting targeted therapy. Cytoreductive nephrectomy in metastatic renal cell carcinoma (RCC) in the era of vascular endothelial growth factor TKIs is controversial [3]. Its role was established in the era of immune therapy, but retrospective data suggest that it is of benefit in selected patients in the TKI era [4–6]. Prospective phase 3 studies in this area are under way (CARMENA and SURTIME). A potential treatment option is to give a period of targeted therapy prior to cytoreductive nephrectomy [7–11]. This approach appears safe, potentially results in patients commencing systemic therapy more quickly to obtain disease control, and may also downsize the primary tumour, facilitating surgery [7]. In addition to this, the upfront approach selects patients with rapidly progressive disease, sparing them from nephrectomy and giving them the option to switch to other systemic therapies instead [12]. However, there are concerns that the treatment break during surgery, which is approximately 1 mo, causes tumour rebound and may have a detrimental effect on progression-free (PFS) and overall survival (OS) [7–10]. Data from the immune therapy era also suggest that nephrectomy may aid response to primary therapy and outcome [4,5]. These concerns require attention in the era of targeted therapy. In this manuscript, two single-arm, phase 2, prospective studies evaluating upfront sunitinib prior to nephrectomy are assessed together to address outcome. The studies were almost identical in terms of patient characteristics, design, and end points. Studies have already reported on the safety of this approach [7]. We report the OS and PFS for this cohort. 2.
Methods and patients
Patients in this combined meta-analysis were from two independent
continued on sunitinib until progression. Imaging with computed tomography (CT) of the chest, abdomen, and pelvis was performed prior to therapy and before and after surgery in both studies. Imaging took place on a 12-wk basis after surgery. Radiologic analysis was performed centrally. The degree of necrosis, grade, and T stage (American Joint Committee on Cancer/Union Internationale Contre le Cancer classification) of the tumour was assessed. Patients with symptomatic progression of metastatic disease prior to nephrectomy did not undergo surgery. Symptomatic progression was defined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 in conjunction with worsening of one of the MSKCC criteria [12,13]. Those patients who progressed during the treatment break were rechallenged with sunitinib irrespective of symptoms. Those patients who did not have a nephrectomy, for either surgical reasons or through patient choice, continued on sunitinib until progression. The design of these studies is described in detail in the previous publication [7,14]. The primary end point of both studies focused on the primary response of the renal tumour (RECIST v1.1). In study A (n = 44), surgery took place 14 d after the last dose of sunitinib therapy (day 28, cycle 3). Sunitinib was planned to start a minimum of 14 d after the surgery. In study B, nephrectomy took place 24 h after the last dose of the second cycle of sunitinib and was restarted 3 wk later.
2.2.
Statistics of the combined analysis
Analysis of both studies took place centrally in December 2010. The OS, which was a secondary end point in both studies, was the primary focus of this meta-analysis. The OS and PFS were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were also performed. Factors significant in the univariate model ( p < 0.1) were taken forward in the multivariate model. Factors included age, gender, study design, MSKCC prognostic score, platelets, neutrophils, number of sites of metastatic disease, and grade. This analysis was initially performed at the time of commencing sunitinib. Multivariate analysis was also performed at the time of planned surgery to identify prognostic factors at this time point. Additional factors in this second model included response of the metastatic sites and primary renal tumour to therapy.
3.
Results
3.1.
Patient characteristics at diagnosis
prospective trials. Both studies were approved by established independent ethical committees (study A: European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2006-004511-21, study B: EudraCT 2006006491-38). The two trials are complete and have almost identical inclusion criteria and design. Patients had untreated, newly diagnosed, biopsy-proven, metastatic ccRCC. None of the patients had previously received systemic therapy or had undergone nephrectomy. All patients were treated with sunitinib (two or three cycles) prior to planned
A total of 66 patients with clear-cell tumours were enrolled in these two studies (44 from study A and 22 from study B). The characteristics of these patients are summarised in Table 1. The characteristics of the patients in the two studies were similar, except more patients in study A had MSKCC poor-risk disease.
nephrectomy.
3.2. 2.1.
Patient characteristics at surgery
Studies
The safety data for these studies were combined and reported in 2009 [7]. This occurred to establish the safety of this upfront approach prior to the multicentre randomised SURTIME (European Organisation for Research and Treatment of Cancer) study opening. This was justified because the two studies were almost identical in terms of design, end points, and patient population. Only patients with either intermediate- or poor-risk (Memorial Sloan-Kettering Cancer Centre [MSKCC] criteria [13]) disease were included. Patients were given either two cycles (study B) or three
All but one of the patients were assessable radiologically for best response prior to surgery (one died of pneumonia within 4 wk of starting therapy). Patient characteristics at surgery are presented in Table 2. The median reduction in longest diameter of the primary tumour was 13% (range: 38% reduction to 8% increase). No patients had progression of the renal tumour by RECIST criteria or became inoperable. The number of patients with pathologic T4 disease at the time
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Table 1 – Patient characteristics prior to study entry
Patients, No. (%) Age, yr median (range) Gender, no. (%) Male Female MSKCC prognostic risk, no. (%) Intermediate Poor Metastatic sites, no. (%) 1 2 3 Radiologic T stage at diagnosis, no. (%) T1 T2 T3 T4 Clear cell grade at biopsy, no. (%) 1 2 3 4
Combined data
Study A: Two sunitinib cycles
Study B: Three sunitinib cycles
66 58.5 (37–78)
44 (66) 61 (44–76)
22 (33) 52 (37–78)
51 (77) 15 (23)
34 (77) 10 (23)
17 (77) 5 (23)
45 (68) 21 (32)
24 (54) 20 (46)
21 (95) 1 (5)
18 (27) 26 (39) 22 (34)
13 (29) 18 (41) 13 (29)
5 (23) 8 (36) 9 (40)
4 18 36 8
(6) (27) (55) (12)
4 12 21 7
(9) (27) (48) (16)
0 6 (27) 15 (68) 1 (5)
3 28 29 6
(4) (42) (44) (9)
3 20 18 3
(7) (45) (41) (7)
0 8 (36) 11 (50) 3 (13)
MSKCC = Memorial Sloan-Kettering Cancer Center.
of surgery was lower than the number with radiologic T4 stage at diagnosis. Whether this is related to genuine downstaging or discrepancies between pathology and radiology staging remains unknown.
Overall, a clinical benefit (by RECIST) occurred in 48 (73%) evaluable patients, while 17 (27%) had progression of disease at metastatic sites prior to or at the time of planned surgery. Forty-seven (71%) patients underwent nephrec-
Table 2 – Clinical and radiologic features at the time of surgery Overall Patients, No. (%) Best overall response (RECIST v1.1), no. (%) PR SD PD Not evaluable Best response of renal tumour (RECIST v 1.1), no. (%) PR SD PD Not evaluable Nephrectomy, no. (%) No nephrectomy, No. (%) Reason for no nephrectomy, no. (%) Disease progression Unfit for surgery Patient choice Died of infection presurgery, no. (%) Pathologic stage at surgery [21], no. (%) T1 T2 T3 T4 Tumour grade at surgery, no. (%) 1–2 >2 Percent necrosis at surgery, no. (%) 0–25 26–50 >50 NA
66
Intermediate-risk disease
Poor-risk disease
45 (68)
21 (32)
13 35 17 1
(20) (52) (26) (2)
11 21 12 1
(24) (46) (26) (2)
2 (10) 14 (66) 5 (24) 0
4 61 0 1 47 19
(6) (92)
(9) (89)
(2) (71) (29)
4 40 0 1 35 10
(2) (77) (23)
0 21 (100) 0 0 12 (53) 9 (43)
12 1 5 1
(63) (5) (26) (5)
7 1 1 1
(70) (10) (10) (10)
5 (55) 0 4 (45) 0
1 18 25 3
(2) (38) (53) (10)
1 13 18 3
(3) (37) (51) (9)
0 5 (42) 7 (58) 0
16 (33) 31 (66)
11 (31) 24 (69)
5 (42) 7 (58)
11 14 21 1
9 11 14 1
2 (17) 3 (25) 7 (58) 0
(23) (30) (45) (2)
(25) (31) (40) (3)
RECIST = Response Evaluation Criteria In Solid Tumors; PR = partial response; SD = stable disease; PD = progressive disease; NA = not applicable.
451
EUROPEAN UROLOGY 60 (2011) 448–454
[()TD$FIG]
(26.0 mo [95% CI, 13.6–NA] and 9.0 mo [95% CI, 5.8–20.5], respectively; p < 0.01) (Fig. 2c). 3.4.
Fig. 1 – Flow diagram of patient pathway.
The median duration off therapy for surgery was 29 d (range: 22–96 d). One patient did not restart sunitinib for 96 d due to impaired renal function postoperatively. A significant proportion of patients had progression of disease by RECIST (17 of 45 assessable patients [36%]) after the surgery-related treatment break. Eight of these individuals had new sites of disease. These data include three patients with progression of disease prior to surgery who had a nephrectomy. Reintroduction of sunitinib therapy resulted in stabilisation of disease or better in 13 (76%) of these 17 patients at the first evaluation by CT-scan. One patient achieved partial response to therapy again after restarting treatment. 3.5.
tomy. Ten (22%) of those with intermediate risk and 9 (42%) with poor risk did not undergo surgery. The main reasons for not performing nephrectomy was progression at metastatic sites (63%) and patient choice (26%). One patient did not have a nephrectomy due to thromboembolic disease while on sunitinib. These data are summarised in Figure 1. 3.3.
Progression-free and overall survival
The PFS for the cohort was 6.3 mo (95% confidence interval [CI], 5.1–8.5) (Fig. 2a). The PFS for the intermediate- and poor-risk patients was 8.1 (95% CI, 5.0–11.1) and 6.0 mo (95% CI, 4.0–7.5), respectively (Fig. 2b). The OS for the cohort was 15.2 mo (95% CI, 10.3–NA). One patient died of respiratory failure during the operative or perioperative period. There was one treatment-related death (pneumonia within the first 3 wk of therapy) and one suicide (in the absence of progression of disease). The OS for the intermediate MSKCC risk group (n = 45) was significantly longer than seen in poor-risk patients (n = 21)
Progression during surgery-related treatment interruption
A correlation between the response in the renal tumour or
metastatic sites and outcome
Both the lack of response in the primary tumour (less than the median response of 13%) and progression at metastatic sites (measured by RECIST) at the time of planned surgery was associated with shorter survival (hazard ratio [HR]: 2.8 [95% CI, 1.4–5.8] and 6.5 [95% CI, 3.2–13.3], respectively) (Fig. 2d and 2e). 3.6.
Multivariate analysis
In the multivariate analysis performed at the time of study entry, a high Fuhrman tumour grade at diagnosis (HR: 3.68; 95% CI, 1.62–8.37) and poor MSKCC prognosis at time of study entry (HR: 2.25; 95% CI, 1.14–4.43) were associated with poor prognosis, which are in line with studies in metastatic RCC. Subsequent analysis performed at the time of planned surgery showed progression of disease at metastatic sites, grade, and MSKCC prognostic score were associated with poor outcome (HR: 5.34 [95% CI, 2.74–11.62];
Table 3 – Univariate and multivariate analysis Analysis performed at study entry
UVA, HR (95% CI) Raised platelets (above median) Male gender Raised neutrophils (above median) Increased tumor grade (3 + 4) MSKCC score (poor) Metastatic sites Study design A vs B Progression prior to planned surgery Primary tumour reduction above the median (13%)
1.49 1.42 1.17 1.94 2.25 1.85 1.06 NA NA
(0.76–2.90) (0.72–2.80) (0.60–2.28) (0.97–3.89) (1.14–4.43)* (0.69–4.93) (0.51–2.20)
MVA, HR (95% CI) NS NS NS 3.68 (1.62–8.37)* 4.29 (1.92–9.60)* NS NS NA NA
Analysis performed at time of planned nephrectomy UVA, HR (95% CI)
MVA, HR (95% CI)
1.55 1.38 1.19 2.02 2.63 1.62 1.12 6.48 2.81
NS NS NS 3.27 (1.38–7.72)* 4.75 (2.05–11.02)* NS NS 5.34 (2.74–11.62)* NS
(0.79–3.05) (0.74–2.91) (0.60–2.28) (0.99–4.12) (1.31–5.25)* (0.63–4.15) (0.55–2.36) (3.17–13.27)* (1.36–5.81)*
UVA = univariate analysis; MVA = multivariate analysis; HR = hazard ratio; CI = confidence interval; MSKCC = Memorial Sloan-Kettering Cancer Center; NA = not applicable; NS = not significant. * p < 0.05.
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EUROPEAN UROLOGY 60 (2011) 448–454
HR: 3.27 [95% CI, 1.38–7.72]; and HR: 4.75 [95% CI, 2.74–11.62], respectively) (Table 3). 3.7.
Sunitinib toxicity prior to planned nephrectomy and
surgical complications
Grade 3 or higher sunitinib-related toxicity (CTCv4) occurred in 12 (19%) patients and 14 (22%) required
a dose reduction to 37.5 mg prior to surgery. The most commonly encountered toxicities were mucositis (15%), hand-foot syndrome (11%), fatigue (9%), hypertension (6%), and diarrhoea (6%). Surgical complications included one death (2%); grade I–IV complications (Clavien-Dindo classification) occurred in 12 (26%) patients, including 6 (13%) cases of delayed wound healing (Table 4).
Fig. 2 – (a) Overall (OS) and progression-free survival (PFS); (b) PFS and Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate- and poor-risk patients; (c) OS of MSKCC intermediate- and poor-risk patients; (d) reduction in primary and overall survival; (e) OS of patients prior to planned surgery.
EUROPEAN UROLOGY 60 (2011) 448–454
Table 4 – Surgical complications Surgical complications*** (Clavien-Dindo classification)
No. (%)
Details
0 1
35 (74) 8 (17)
– Delayed wound healing (n = 6); oedema (n = 2) – Postoperative bleeding Renal failure and hypotension Respiratory failure
2 3 4 5
4.
0 1 2 1
(0) (2) (4) (2)
Discussion
These prospective data report on the OS of patients treated with upfront sunitinib prior to nephrectomy. They show that patients have OS data in line with those seen using standard approaches. In the pivotal randomised phase 3 study, the OS for the intermediate-risk group was 20.7 mo (95% CI, 18.2– 25.6 mo) compared to 26.0 mo (95% CI, 13.6–NA) in our series [1]. These results are particularly encouraging because few patients had access to second-line therapy (n = 7). The PFS periods are comparatively short; this may be due, in part, to a high proportion of patients who progressed during the 4-wk treatment interruption for surgery (36%). This tumour rebound during treatment interruptions is supported by in vivo data [15]. It is difficult to shorten this treatment break because of concerns regarding delayed wound healing and surgical recovery [7–10]. This progression is of concern as it may facilitate the development of sunitinib resistance. It also raises treatment dilemmas, such as: Should sunitinib continue at this progression or should it be switched to a different agent? As the majority of patients achieve subsequent stabilisation of disease when restarting sunitinib (76%), this seems a logical first therapeutic step. Overall, this treatment break had a marked effect on PFS (Fig. 1); however, this is not reflected in the OS results. This upfront approach, which commences treatment quickly and potentially selects those with refractory disease, may be attractive for specific individuals with intermediate-risk disease, particularly the subset who go on to have debulking nephrectomy, where the median OS is yet to be reached (Fig. 2e). Also, the subset of patients with refractory disease can be quickly switched to alternative therapy with a different mode of action, such as mammalian target of rapamycin inhibitors, with this approach [16,17]. The poor-risk group requires particular attention. Our approach with upfront sunitinib showed that the OS data (9.0 mo; 95% CI, 5.8–20.5) were in line with prospective data from the phase 3 trial (5.3 mo; 95% CI, 4.2–10.0) [1]. It remains unclear if this group benefits from nephrectomy at all. Figure 1e suggests that in the poor-risk group, this approach does not result in prolonged survival in any patients questioning its use. Temsirolimus has more robust randomised data than sunitinib in the poor-risk untreated population [16], although sunitinib has been used widely in expanded access programmes [2].
453
Radiologic responses, using RECIST, have not been successful in predicting outcome of sunitinib treatment in RCC [18]. Alternative criteria, such as a less marked reduction in tumour size required to define response (10% rather than 30%), hold promise [19,20]. Our results show for the first time that a response in the primary tumour correlated with OS; however, this response was not significant in the multivariate model. One of the areas of concern with this upfront approach is the delayed wound healing noted in our and other studies [8–10] (Table 4). This needs close attention, and targeted therapy should not be started too soon after surgery; at least 14 d postsurgery is recommended. This work has a number of shortcomings. Although the two studies were remarkably similar in all aspects, they were not initially designed with the intention of combining the data. However, central meta-analysis of all aspects of the studies was performed to reduce potential bias. This showed there was no difference in response rate, PFS, or outcome for the two studies. Also, the studies were modest in size and not powered to investigate OS; therefore, results should be interpreted with caution and require validation. 5.
Conclusions
Despite the high progression rate during the surgeryrelated treatment break, the OS with this approach is in line with those seen in the pivotal trials. Progression on sunitinib prior to planned nephrectomy has a poor outcome and alternative treatments should be considered. Author contributions: Thomas Powles had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Powles, Shamash, Chowdhury, Bex. Acquisition of data: Powles, Bex. Analysis and interpretation of data: Powles, Bex. Drafting of the manuscript: Powles, Hannen, Blank, Bex. Critical revision of the manuscript for important intellectual content: Hannen, Blank, Chowdhury, Powles, Shamash, Bex, Sahdev, Sarwar. Statistical analysis: Powles, Sarwar, Shamash, Bex. Obtaining funding: Powles, Bex. Administrative, technical, or material support: Peters, O’Brien, Boleti, Horenblas, Nathan, Sarwar, Sahdev, Berney, Betran. Supervision: Bex, Powles. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: T. Powles and A. Bex have participated on advisory boards for Pfizer and received an educational grant from Pfizer for this work. Funding/Support and role of the sponsor: Study data and material were sponsored by Queen Mary University of London.
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Acknowledgement statement: The authors would like to thank the
[10] Jonasch E, Wood CG, Matin SF, et al. Phase II presurgical feasibility
Experimental Cancer Medicine Centres at Barts and the London and
study of bevacizumab in untreated patients with metastatic renal
University College Hospital for their support.
cell carcinoma. J Clin Oncol 2009;27:4076–81. [11] Hellenthal NJ, Underwood W, Penetrante R, et al. Prospective clinical trial of preoperative sunitinib in patients with renal cell
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Kidney Cancer Editorial by Simon P. Kim and R. Houston Thompson on pp. 455–456 of this issue
The Outcome of Patients Treated with Sunitinib Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer Thomas Powles a, Christian Blank b, Simon Chowdhury c, Simon Horenblas b, John Peters d, Jonathan Shamash a, Naveed Sarwar a, Ekaterini Boleti e, Anju Sahdev a, Tim O’Brien c, Dan Berney a, Luis Beltran d, Paul Nathan f, John Haanen b, Axel Bex b,* a
Bart Cancer Institute, Queen Mary University of London, St Bartholomew’s Hospital London, UK
b
Departments of Surgical and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
c
Department of Uro-oncology, Guys and St Thomas’s Hospital, London, UK
d
Department of Surgery, Whipps Cross Hospital, London, UK
e
Department of Medical Oncology, The Royal Free Hospital London, UK
f
Department of Medical Oncology, Mount Vernon Hospital, London, UK
Article info
Abstract
Article history: Accepted May 9, 2011 Published online ahead of print on May 17, 2011
Background: The role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma (ccRCC) is controversial. Objective: To determine the outcome of patients with metastatic ccRCC who receive sunitinib prior to planned nephrectomy. Design, setting, and participants: The study combined the data from two prospective phase 2 studies that assessed upfront sunitinib (12–16 wk) prior to nephrectomy in previously untreated patients with metastatic renal cell carcinoma (RCC). Sunitinib was discontinued during the perioperative period (median: 29 d). Intervention: Sunitinib 50 mg in six weekly cycles (4 wk on, 2 wk off). Measurements: Progression-free (PFS) and overall survival (OS) using the Kaplan-Meier method. Results and limitations: Twenty-one patients (32%) had Memorial Sloan-Kettering Cancer Centre (MSKCC) poor-risk disease; 45 (68%) had intermediate-risk disease. Nephrectomy was not performed in 19 (29%), most commonly due to disease progression (n = 12). The PFS for the cohort was 6.3 mo (95% confidence interval [CI], 5.1–8.5). Seventeen (36%) patients progressed during the treatment break, 13 (76%) of whom stabilised upon reinitiating of sunitinib. The OS for the cohort was 15.2 mo (95% CI, 10.3–NA). The OS for the intermediate MSKCC risk group was significantly longer than that for the poor-risk group (26.0 mo [95% CI, 13.6–NA] and 9.0 mo [95% CI, 5.8–20.5], respectively; p < 0.01). In multivariate analysis, progression of disease prior to planned nephrectomy (hazard ratio [HR]: 5.34; 95% CI, 3.17–13.27), high Fuhrman grade (HR 3.27; 95% CI, 1.38–7.72), and MSKCC poor risk at diagnosis (HR 4.75; 95% CI, 2.05–11.02) were associated with short survival ( p < 0.01). However, in the absence of randomised studies it is not possible to determine if this approach is beneficial. Conclusions: Upfront sunitinib prior to planned nephrectomy in intermediate-risk disease is associated with a median survival of >2 yr despite frequent progression during treatment break. Progression in metastatic sites prior to planned surgery and MSKCC poor-risk disease was associated with a poor outcome.
Keywords: Sunitinib Nephrectomy Metastatic renal cancer FDG-PET
# 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. The Netherlands Cancer Institute, Division of Surgical Oncology, Department of Urology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel. +31 20 512 2553; Fax: +31 20 512 2554. E-mail address: [email protected] (A. Bex). 0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2011.05.028
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1.
Introduction
449
cycles (study A) of sunitinib (50 mg by mouth once daily, 4 wk on, 2 wk off) prior to a planned nephrectomy. After the nephrectomy, patients
Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is established as first-line therapy in metastatic clear cell renal cell carcinoma (ccRCC) [1,2]. In the landmark trial of Motzer et al, patients had a median overall survival >2 yr [1]. The vast majority of these patients had a nephrectomy prior to starting targeted therapy. Cytoreductive nephrectomy in metastatic renal cell carcinoma (RCC) in the era of vascular endothelial growth factor TKIs is controversial [3]. Its role was established in the era of immune therapy, but retrospective data suggest that it is of benefit in selected patients in the TKI era [4–6]. Prospective phase 3 studies in this area are under way (CARMENA and SURTIME). A potential treatment option is to give a period of targeted therapy prior to cytoreductive nephrectomy [7–11]. This approach appears safe, potentially results in patients commencing systemic therapy more quickly to obtain disease control, and may also downsize the primary tumour, facilitating surgery [7]. In addition to this, the upfront approach selects patients with rapidly progressive disease, sparing them from nephrectomy and giving them the option to switch to other systemic therapies instead [12]. However, there are concerns that the treatment break during surgery, which is approximately 1 mo, causes tumour rebound and may have a detrimental effect on progression-free (PFS) and overall survival (OS) [7–10]. Data from the immune therapy era also suggest that nephrectomy may aid response to primary therapy and outcome [4,5]. These concerns require attention in the era of targeted therapy. In this manuscript, two single-arm, phase 2, prospective studies evaluating upfront sunitinib prior to nephrectomy are assessed together to address outcome. The studies were almost identical in terms of patient characteristics, design, and end points. Studies have already reported on the safety of this approach [7]. We report the OS and PFS for this cohort. 2.
Methods and patients
Patients in this combined meta-analysis were from two independent
continued on sunitinib until progression. Imaging with computed tomography (CT) of the chest, abdomen, and pelvis was performed prior to therapy and before and after surgery in both studies. Imaging took place on a 12-wk basis after surgery. Radiologic analysis was performed centrally. The degree of necrosis, grade, and T stage (American Joint Committee on Cancer/Union Internationale Contre le Cancer classification) of the tumour was assessed. Patients with symptomatic progression of metastatic disease prior to nephrectomy did not undergo surgery. Symptomatic progression was defined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 in conjunction with worsening of one of the MSKCC criteria [12,13]. Those patients who progressed during the treatment break were rechallenged with sunitinib irrespective of symptoms. Those patients who did not have a nephrectomy, for either surgical reasons or through patient choice, continued on sunitinib until progression. The design of these studies is described in detail in the previous publication [7,14]. The primary end point of both studies focused on the primary response of the renal tumour (RECIST v1.1). In study A (n = 44), surgery took place 14 d after the last dose of sunitinib therapy (day 28, cycle 3). Sunitinib was planned to start a minimum of 14 d after the surgery. In study B, nephrectomy took place 24 h after the last dose of the second cycle of sunitinib and was restarted 3 wk later.
2.2.
Statistics of the combined analysis
Analysis of both studies took place centrally in December 2010. The OS, which was a secondary end point in both studies, was the primary focus of this meta-analysis. The OS and PFS were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were also performed. Factors significant in the univariate model ( p < 0.1) were taken forward in the multivariate model. Factors included age, gender, study design, MSKCC prognostic score, platelets, neutrophils, number of sites of metastatic disease, and grade. This analysis was initially performed at the time of commencing sunitinib. Multivariate analysis was also performed at the time of planned surgery to identify prognostic factors at this time point. Additional factors in this second model included response of the metastatic sites and primary renal tumour to therapy.
3.
Results
3.1.
Patient characteristics at diagnosis
prospective trials. Both studies were approved by established independent ethical committees (study A: European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2006-004511-21, study B: EudraCT 2006006491-38). The two trials are complete and have almost identical inclusion criteria and design. Patients had untreated, newly diagnosed, biopsy-proven, metastatic ccRCC. None of the patients had previously received systemic therapy or had undergone nephrectomy. All patients were treated with sunitinib (two or three cycles) prior to planned
A total of 66 patients with clear-cell tumours were enrolled in these two studies (44 from study A and 22 from study B). The characteristics of these patients are summarised in Table 1. The characteristics of the patients in the two studies were similar, except more patients in study A had MSKCC poor-risk disease.
nephrectomy.
3.2. 2.1.
Patient characteristics at surgery
Studies
The safety data for these studies were combined and reported in 2009 [7]. This occurred to establish the safety of this upfront approach prior to the multicentre randomised SURTIME (European Organisation for Research and Treatment of Cancer) study opening. This was justified because the two studies were almost identical in terms of design, end points, and patient population. Only patients with either intermediate- or poor-risk (Memorial Sloan-Kettering Cancer Centre [MSKCC] criteria [13]) disease were included. Patients were given either two cycles (study B) or three
All but one of the patients were assessable radiologically for best response prior to surgery (one died of pneumonia within 4 wk of starting therapy). Patient characteristics at surgery are presented in Table 2. The median reduction in longest diameter of the primary tumour was 13% (range: 38% reduction to 8% increase). No patients had progression of the renal tumour by RECIST criteria or became inoperable. The number of patients with pathologic T4 disease at the time
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Table 1 – Patient characteristics prior to study entry
Patients, No. (%) Age, yr median (range) Gender, no. (%) Male Female MSKCC prognostic risk, no. (%) Intermediate Poor Metastatic sites, no. (%) 1 2 3 Radiologic T stage at diagnosis, no. (%) T1 T2 T3 T4 Clear cell grade at biopsy, no. (%) 1 2 3 4
Combined data
Study A: Two sunitinib cycles
Study B: Three sunitinib cycles
66 58.5 (37–78)
44 (66) 61 (44–76)
22 (33) 52 (37–78)
51 (77) 15 (23)
34 (77) 10 (23)
17 (77) 5 (23)
45 (68) 21 (32)
24 (54) 20 (46)
21 (95) 1 (5)
18 (27) 26 (39) 22 (34)
13 (29) 18 (41) 13 (29)
5 (23) 8 (36) 9 (40)
4 18 36 8
(6) (27) (55) (12)
4 12 21 7
(9) (27) (48) (16)
0 6 (27) 15 (68) 1 (5)
3 28 29 6
(4) (42) (44) (9)
3 20 18 3
(7) (45) (41) (7)
0 8 (36) 11 (50) 3 (13)
MSKCC = Memorial Sloan-Kettering Cancer Center.
of surgery was lower than the number with radiologic T4 stage at diagnosis. Whether this is related to genuine downstaging or discrepancies between pathology and radiology staging remains unknown.
Overall, a clinical benefit (by RECIST) occurred in 48 (73%) evaluable patients, while 17 (27%) had progression of disease at metastatic sites prior to or at the time of planned surgery. Forty-seven (71%) patients underwent nephrec-
Table 2 – Clinical and radiologic features at the time of surgery Overall Patients, No. (%) Best overall response (RECIST v1.1), no. (%) PR SD PD Not evaluable Best response of renal tumour (RECIST v 1.1), no. (%) PR SD PD Not evaluable Nephrectomy, no. (%) No nephrectomy, No. (%) Reason for no nephrectomy, no. (%) Disease progression Unfit for surgery Patient choice Died of infection presurgery, no. (%) Pathologic stage at surgery [21], no. (%) T1 T2 T3 T4 Tumour grade at surgery, no. (%) 1–2 >2 Percent necrosis at surgery, no. (%) 0–25 26–50 >50 NA
66
Intermediate-risk disease
Poor-risk disease
45 (68)
21 (32)
13 35 17 1
(20) (52) (26) (2)
11 21 12 1
(24) (46) (26) (2)
2 (10) 14 (66) 5 (24) 0
4 61 0 1 47 19
(6) (92)
(9) (89)
(2) (71) (29)
4 40 0 1 35 10
(2) (77) (23)
0 21 (100) 0 0 12 (53) 9 (43)
12 1 5 1
(63) (5) (26) (5)
7 1 1 1
(70) (10) (10) (10)
5 (55) 0 4 (45) 0
1 18 25 3
(2) (38) (53) (10)
1 13 18 3
(3) (37) (51) (9)
0 5 (42) 7 (58) 0
16 (33) 31 (66)
11 (31) 24 (69)
5 (42) 7 (58)
11 14 21 1
9 11 14 1
2 (17) 3 (25) 7 (58) 0
(23) (30) (45) (2)
(25) (31) (40) (3)
RECIST = Response Evaluation Criteria In Solid Tumors; PR = partial response; SD = stable disease; PD = progressive disease; NA = not applicable.
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[()TD$FIG]
(26.0 mo [95% CI, 13.6–NA] and 9.0 mo [95% CI, 5.8–20.5], respectively; p < 0.01) (Fig. 2c). 3.4.
Fig. 1 – Flow diagram of patient pathway.
The median duration off therapy for surgery was 29 d (range: 22–96 d). One patient did not restart sunitinib for 96 d due to impaired renal function postoperatively. A significant proportion of patients had progression of disease by RECIST (17 of 45 assessable patients [36%]) after the surgery-related treatment break. Eight of these individuals had new sites of disease. These data include three patients with progression of disease prior to surgery who had a nephrectomy. Reintroduction of sunitinib therapy resulted in stabilisation of disease or better in 13 (76%) of these 17 patients at the first evaluation by CT-scan. One patient achieved partial response to therapy again after restarting treatment. 3.5.
tomy. Ten (22%) of those with intermediate risk and 9 (42%) with poor risk did not undergo surgery. The main reasons for not performing nephrectomy was progression at metastatic sites (63%) and patient choice (26%). One patient did not have a nephrectomy due to thromboembolic disease while on sunitinib. These data are summarised in Figure 1. 3.3.
Progression-free and overall survival
The PFS for the cohort was 6.3 mo (95% confidence interval [CI], 5.1–8.5) (Fig. 2a). The PFS for the intermediate- and poor-risk patients was 8.1 (95% CI, 5.0–11.1) and 6.0 mo (95% CI, 4.0–7.5), respectively (Fig. 2b). The OS for the cohort was 15.2 mo (95% CI, 10.3–NA). One patient died of respiratory failure during the operative or perioperative period. There was one treatment-related death (pneumonia within the first 3 wk of therapy) and one suicide (in the absence of progression of disease). The OS for the intermediate MSKCC risk group (n = 45) was significantly longer than seen in poor-risk patients (n = 21)
Progression during surgery-related treatment interruption
A correlation between the response in the renal tumour or
metastatic sites and outcome
Both the lack of response in the primary tumour (less than the median response of 13%) and progression at metastatic sites (measured by RECIST) at the time of planned surgery was associated with shorter survival (hazard ratio [HR]: 2.8 [95% CI, 1.4–5.8] and 6.5 [95% CI, 3.2–13.3], respectively) (Fig. 2d and 2e). 3.6.
Multivariate analysis
In the multivariate analysis performed at the time of study entry, a high Fuhrman tumour grade at diagnosis (HR: 3.68; 95% CI, 1.62–8.37) and poor MSKCC prognosis at time of study entry (HR: 2.25; 95% CI, 1.14–4.43) were associated with poor prognosis, which are in line with studies in metastatic RCC. Subsequent analysis performed at the time of planned surgery showed progression of disease at metastatic sites, grade, and MSKCC prognostic score were associated with poor outcome (HR: 5.34 [95% CI, 2.74–11.62];
Table 3 – Univariate and multivariate analysis Analysis performed at study entry
UVA, HR (95% CI) Raised platelets (above median) Male gender Raised neutrophils (above median) Increased tumor grade (3 + 4) MSKCC score (poor) Metastatic sites Study design A vs B Progression prior to planned surgery Primary tumour reduction above the median (13%)
1.49 1.42 1.17 1.94 2.25 1.85 1.06 NA NA
(0.76–2.90) (0.72–2.80) (0.60–2.28) (0.97–3.89) (1.14–4.43)* (0.69–4.93) (0.51–2.20)
MVA, HR (95% CI) NS NS NS 3.68 (1.62–8.37)* 4.29 (1.92–9.60)* NS NS NA NA
Analysis performed at time of planned nephrectomy UVA, HR (95% CI)
MVA, HR (95% CI)
1.55 1.38 1.19 2.02 2.63 1.62 1.12 6.48 2.81
NS NS NS 3.27 (1.38–7.72)* 4.75 (2.05–11.02)* NS NS 5.34 (2.74–11.62)* NS
(0.79–3.05) (0.74–2.91) (0.60–2.28) (0.99–4.12) (1.31–5.25)* (0.63–4.15) (0.55–2.36) (3.17–13.27)* (1.36–5.81)*
UVA = univariate analysis; MVA = multivariate analysis; HR = hazard ratio; CI = confidence interval; MSKCC = Memorial Sloan-Kettering Cancer Center; NA = not applicable; NS = not significant. * p < 0.05.
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EUROPEAN UROLOGY 60 (2011) 448–454
HR: 3.27 [95% CI, 1.38–7.72]; and HR: 4.75 [95% CI, 2.74–11.62], respectively) (Table 3). 3.7.
Sunitinib toxicity prior to planned nephrectomy and
surgical complications
Grade 3 or higher sunitinib-related toxicity (CTCv4) occurred in 12 (19%) patients and 14 (22%) required
a dose reduction to 37.5 mg prior to surgery. The most commonly encountered toxicities were mucositis (15%), hand-foot syndrome (11%), fatigue (9%), hypertension (6%), and diarrhoea (6%). Surgical complications included one death (2%); grade I–IV complications (Clavien-Dindo classification) occurred in 12 (26%) patients, including 6 (13%) cases of delayed wound healing (Table 4).
Fig. 2 – (a) Overall (OS) and progression-free survival (PFS); (b) PFS and Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate- and poor-risk patients; (c) OS of MSKCC intermediate- and poor-risk patients; (d) reduction in primary and overall survival; (e) OS of patients prior to planned surgery.
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Table 4 – Surgical complications Surgical complications*** (Clavien-Dindo classification)
No. (%)
Details
0 1
35 (74) 8 (17)
– Delayed wound healing (n = 6); oedema (n = 2) – Postoperative bleeding Renal failure and hypotension Respiratory failure
2 3 4 5
4.
0 1 2 1
(0) (2) (4) (2)
Discussion
These prospective data report on the OS of patients treated with upfront sunitinib prior to nephrectomy. They show that patients have OS data in line with those seen using standard approaches. In the pivotal randomised phase 3 study, the OS for the intermediate-risk group was 20.7 mo (95% CI, 18.2– 25.6 mo) compared to 26.0 mo (95% CI, 13.6–NA) in our series [1]. These results are particularly encouraging because few patients had access to second-line therapy (n = 7). The PFS periods are comparatively short; this may be due, in part, to a high proportion of patients who progressed during the 4-wk treatment interruption for surgery (36%). This tumour rebound during treatment interruptions is supported by in vivo data [15]. It is difficult to shorten this treatment break because of concerns regarding delayed wound healing and surgical recovery [7–10]. This progression is of concern as it may facilitate the development of sunitinib resistance. It also raises treatment dilemmas, such as: Should sunitinib continue at this progression or should it be switched to a different agent? As the majority of patients achieve subsequent stabilisation of disease when restarting sunitinib (76%), this seems a logical first therapeutic step. Overall, this treatment break had a marked effect on PFS (Fig. 1); however, this is not reflected in the OS results. This upfront approach, which commences treatment quickly and potentially selects those with refractory disease, may be attractive for specific individuals with intermediate-risk disease, particularly the subset who go on to have debulking nephrectomy, where the median OS is yet to be reached (Fig. 2e). Also, the subset of patients with refractory disease can be quickly switched to alternative therapy with a different mode of action, such as mammalian target of rapamycin inhibitors, with this approach [16,17]. The poor-risk group requires particular attention. Our approach with upfront sunitinib showed that the OS data (9.0 mo; 95% CI, 5.8–20.5) were in line with prospective data from the phase 3 trial (5.3 mo; 95% CI, 4.2–10.0) [1]. It remains unclear if this group benefits from nephrectomy at all. Figure 1e suggests that in the poor-risk group, this approach does not result in prolonged survival in any patients questioning its use. Temsirolimus has more robust randomised data than sunitinib in the poor-risk untreated population [16], although sunitinib has been used widely in expanded access programmes [2].
453
Radiologic responses, using RECIST, have not been successful in predicting outcome of sunitinib treatment in RCC [18]. Alternative criteria, such as a less marked reduction in tumour size required to define response (10% rather than 30%), hold promise [19,20]. Our results show for the first time that a response in the primary tumour correlated with OS; however, this response was not significant in the multivariate model. One of the areas of concern with this upfront approach is the delayed wound healing noted in our and other studies [8–10] (Table 4). This needs close attention, and targeted therapy should not be started too soon after surgery; at least 14 d postsurgery is recommended. This work has a number of shortcomings. Although the two studies were remarkably similar in all aspects, they were not initially designed with the intention of combining the data. However, central meta-analysis of all aspects of the studies was performed to reduce potential bias. This showed there was no difference in response rate, PFS, or outcome for the two studies. Also, the studies were modest in size and not powered to investigate OS; therefore, results should be interpreted with caution and require validation. 5.
Conclusions
Despite the high progression rate during the surgeryrelated treatment break, the OS with this approach is in line with those seen in the pivotal trials. Progression on sunitinib prior to planned nephrectomy has a poor outcome and alternative treatments should be considered. Author contributions: Thomas Powles had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Powles, Shamash, Chowdhury, Bex. Acquisition of data: Powles, Bex. Analysis and interpretation of data: Powles, Bex. Drafting of the manuscript: Powles, Hannen, Blank, Bex. Critical revision of the manuscript for important intellectual content: Hannen, Blank, Chowdhury, Powles, Shamash, Bex, Sahdev, Sarwar. Statistical analysis: Powles, Sarwar, Shamash, Bex. Obtaining funding: Powles, Bex. Administrative, technical, or material support: Peters, O’Brien, Boleti, Horenblas, Nathan, Sarwar, Sahdev, Berney, Betran. Supervision: Bex, Powles. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: T. Powles and A. Bex have participated on advisory boards for Pfizer and received an educational grant from Pfizer for this work. Funding/Support and role of the sponsor: Study data and material were sponsored by Queen Mary University of London.
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Acknowledgement statement: The authors would like to thank the
[10] Jonasch E, Wood CG, Matin SF, et al. Phase II presurgical feasibility
Experimental Cancer Medicine Centres at Barts and the London and
study of bevacizumab in untreated patients with metastatic renal
University College Hospital for their support.
cell carcinoma. J Clin Oncol 2009;27:4076–81. [11] Hellenthal NJ, Underwood W, Penetrante R, et al. Prospective clinical trial of preoperative sunitinib in patients with renal cell
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