Metastasectomy After Targeted Therapy in Patients With Advanced Renal Cell Carcinoma

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1 Metastasectomy After Targeted Therapy in Patients With Advanced Renal Cell Carcinoma Jose A. Karam, Brian I. Rini,* Leticia Varella, Jorge A. Garcia, Robert Dreicer, Toni K. Choueiri, Eric Jonasch, Surena F. Matin, Steven C. Campbell, Christopher G. Wood and Nizar M. Tannir** From the Departments of Urology (JAK, SFM, CGW) and Genitourinary Medical Oncology (EJ, NMT), University of Texas M. D. Anderson Cancer Center, Houston, Texas, Department of Medical Oncology, Dana Farber Cancer Institute (TKC), Boston, Massachusetts, and Department of Solid Tumor Oncology, Taussig Cancer Institute (BIR, LV, JAG, RD) and Department of Urology (SCC), Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio Purpose: Metastasectomy is often incorporated in overall treatment in patients with metastatic renal cell carcinoma. While this approach was studied in the immunotherapy era, only a few cases have been described in the targeted therapy era. Thus, we evaluated the role of metastasectomy in patients with metastatic renal cell carcinoma who received prior targeted therapy. Materials and Methods: We retrospectively evaluated the records of patients who underwent consolidative metastasectomy after targeted therapy at 3 institutions from 2004 to All patients received at least 1 cycle of targeted therapy before surgical resection of all visible disease. Results: We identified 22 patients. Metastasectomy sites included the retroperitoneum in 12 patients, lung in 6, adrenal gland in 2, bowel in 2, and mediastinum, bone, brain and inferior venal caval thrombus in 1 each. A total of 6 postoperative complications were observed in 4 patients within 12 weeks after surgery, which resolved with appropriate management. Postoperatively 9 patients received at least 1 targeted therapy. In 11 patients recurrence developed a median of 42 weeks after metastasectomy and another 11 experienced no recurrence at a median of 43 weeks. At a median followup of 109 weeks 21 patients were alive and 1 died of renal cell carcinoma 105 weeks after metastasectomy. Conclusions: In a cohort of select patients with a limited tumor burden after treatment with targeted agents consolidative metastasectomy is feasible with acceptable morbidity. Significant time off targeted therapy and long-term tumorfree status are possible with this approach. Key Words: kidney; carcinoma, renal cell; neoplasm metastasis; drug therapy; reoperation Abbreviations and Acronyms mrcc metastatic RCC NED no disease evidence RCC renal cell carcinoma Submitted for publication May 29, Study received institutional review board approval at each center. * Financial interest and/or other relationship with Pfizer, Bayer and Genentech. Financial interest and/or other relationship with Genentech. Financial interest and/or other relationship with GlaxoSmithKline, Pfizer, Novartis, Genentech and Bayer/Onyx. Financial interest and/or other relationship with Pfizer, Genentech and Novartis. Financial interest and/or other relationship with Pfizer. Financial interest and/or other relationship with Pfizer and Novartis. ** Correspondence: Department of Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1374, Houston, Texas (telephone: ; ntannir@mdanderson.org). APPROXIMATELY a third of patients diagnosed with RCC present with metastasis at initial diagnosis and in up to 40% with localized RCC metastatic disease develops after radical or partial nephrectomy. 1,2 Targeted therapy, the current standard of care in patients with mrcc, is notable for a higher objective response with an improved reduction in tumor burden and survival rate than historical treatments. 3 7 However, a complete response to systemic therapy alone remains extremely rare. Metastatic RCC has long been a disease for which resection of metastatic deposits can be considered for overall patient treatment. 8 Generally /11/ /0 Vol. 185, , February 2011 THE JOURNAL OF UROLOGY Printed in U.S.A by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI: /j.juro

2 440 METASTASECTOMY AFTER TARGETED THERAPY FOR RENAL CELL CANCER patients who undergo metastasectomy tend to have a better outcome independent of the risk score. 9 In the immunotherapy era patients with a good performance status and a solitary resectable metastasis were considered good candidates for metastasectomy. Several retrospective studies of immunotherapy use before metastasectomy showed that 24% to 100% of patients were disease free 1 to 4 years after surgery Kim et al noted a potential benefit from integrating metastasectomy and immunotherapy. 10 Patients treated with immunotherapy who underwent metastasectomy had better outcomes than those who achieved an initial complete or partial response to immunotherapy but did not undergo consolidative metastasectomy. One group prospectively evaluated the role of metastasectomy after immunotherapy. 8 This study included 38 patients with mrcc treated with immunotherapy with a median followup of 11.1 years. All patients had stable disease or a response after therapy. All patients underwent metastasectomy and 76% achieved NED status after surgery. In this group median time to progression was 1.8 years and median survival was 4.7 years. Of the patients 21% remained disease free at last followup. The high response rate to targeted therapy has expanded the pool of patients who are potentially eligible for metastasectomy. Those initially not considered candidates for this approach due to metastasis number, site or anatomy may be rendered surgically resectable after a response to systemic therapy. To date only case reports have described patients with mrcc who achieved long-term disease-free survival after treatment with sunitinib and resection of residual metastasis. 16 To our knowledge the role of metastasectomy in patients with advanced RCC who achieve NED status after a response to targeted therapy has not been prospectively studied. We report the results of a multi-institutional, retrospective study of this approach in a select group of patients with mrcc who received targeted therapy, followed by complete surgical resection of metastatic disease. PATIENTS AND METHODS This retrospective analysis included patients who underwent metastasectomy for RCC at 3 our academic institutions from October 2004 to August Appropriate institutional review board approval was obtained at each center. To be included in this study patients had metastatic RCC of any histological type and had received at least 1 cycle of targeted therapy, followed by metastasectomy aiming to resect all visible disease. The decision to perform metastasectomy was made on an individual basis, was not prospectively specified and varied among institutions. Patients underwent routine laboratory evaluations and computerized tomography of the chest, abdomen and pelvis at regular intervals according to the systemic therapy schedule while on treatment. For analysis purposes the retroperitoneum was considered to include any retroperitoneal nodes, peri-adrenal tissue, retroperitoneal musculature or recurrence in the renal fossa. The lung was considered to include the lung, pleura or diaphragm. Clinical, pathological and treatment related data are shown in descriptive fashion. The median and range, and mean SD were used to summarize continuous variables. RESULTS Patient Demographics and Disease Characteristics Included in analysis were 19 men (86.4%) and 3 women (13.6%) with a mean age of years (median 55.5, range 41 to 71). Table 1 lists demographics and baseline patient characteristics. Table 2 shows risk stratification based on the criteria of Motzer 17 and Heng 18 et al. In addition to the metastasectomy of interest after targeted therapy, all patients underwent nephrectomy for RCC, including 21 with nephrectomy before metastasectomy and 1 with nephrectomy 9 weeks after metastasectomy, and 6 underwent prior metastasectomy. Five patients had evidence of metastasis before nephrectomy. In 17 patients metastatic disease developed a median of 85.3 weeks (range 13.0 to ) after nephrectomy, including 11 with metastasis 1 year or later after nephrectomy. Preoperative Targeted Therapy Table 3 lists therapies administered before metastasectomy. A total of 17 patients received only 1 preoperative therapy and 5 received 2 preoperative therapies each. The median duration of preoperative therapy was 45.6 weeks (range 11.7 to 177.0) and median time from the last preoperative therapy dose to metastasectomy was 27 days (range 3 to 103). According to Response Criteria In Solid Tumors, 19 while on targeted therapy and before metastasectomy, 4 patients had a partial response, 11 had stable disease and 4 had progressive disease, defined as an increase in index lesion size without new metastasis. Information was incomplete in 3 patients. Metastasectomy Table 4 lists details of surgery related parameters. Median time from metastatic disease diagnosis to metastasectomy was 61 weeks (range 15 to 259). Metastasectomy sites included the retroperitoneum in 12 patients, lung in 6, adrenal gland in 2, bowel in 2, and mediastinum, bone, brain and inferior venal caval thrombus in 1 each. Four patients underwent metastasectomy at more than 1 site. At pathological evaluation of the metastasectomy specimen 20 patients had viable tumor while 2 had no evidence of

3 METASTASECTOMY AFTER TARGETED THERAPY FOR RENAL CELL CANCER 441 Table 1. Patient demographics and tumor characteristics No. Pts (%) Race: White 17 (77.3) Hispanic 3 (13.6) Black 2 (9.1) Nephrectomy: Rt 11 (50.0) Lt 11 (50.0) Initial RCC diagnosis stage: T2 5 (22.7) T3a 7 (31.9) T3b 7 (31.9) T4 1 (4.5) Tx 2 (9) Initial RCC diagnosis nodes: N0 5 (22.7) N1/2 3 (13.6) Nx 14 (63.7) Initial RCC diagnosis metastasis: M0 8 (36.4) M1 5 (18.2) Mx 9 (45.4) Nephrectomy histology: Clear cell 15 (68.2) Papillary 2 (9.1) Chromophobe 2 (9.1) Unclassified 2 (9.1) Unknown 1 (4.5) Nephrectomy Fuhrman grade: 1 1 (4.5) 2 2 (9.1) 3 9 (40.9) 4 7 (31.8) Unknown 3 (13.6) Nephrectomy sarcomatoid elements: Yes 2 (9.1) No 18 (81.8) Unknown 2 (9.1) Nephrectomy histological necrosis: Yes 3 (13.6) No 17 (77.3) Unknown 2 (9.1) Radiation therapy history: Yes (brain) 4 (18.2) No 18 (81.8) tumor. The latter 2 patients did not undergo preoperative biopsy of metastasis due to the site of the masses. However, on radiography each had growth of the masses during observation. Also, the masses were reduced with targeted therapy and pathological evaluation of the metastasectomy specimen revealed fibrosis and/or necrosis consistent with a treatment effect. One patient had a microscopic positive margin after resection of retroperitoneal metastasis. Perioperative Complications In 4 patients a total of 6 postoperative complications were observed, including chylous ascites in 4, atrial fibrillation in 1 and ileus in 1, within 12 weeks after surgery, which resolved with appropriate manage- Table 2. Patient risk classification Classification No. First Systemic Therapy No. Metastasectomy Motzer et al: 17 Good 4 4 Intermediate Poor 0 0 Missing 5 8 Heng et al: 18 Good 6 5 Intermediate Poor 2 1 Missing 3 5 ment. No bleeding, thromboembolic or wound complications were noted in this period. One patient experienced 3 of these complications (chylous ascites, ileus and atrial fibrillation). In this patient an intraperitoneal drain was placed during surgery, which remained in place until ascites resolved. He also received octreotide and total parenteral nutrition. Atrial fibrillation was transient with no etiology found and no treatment needed. The other 3 patients experienced chylous ascites, including 1 with a drain placed intraperitoneally during surgery and 2 who required temporary percutaneous paracentesis. In 1 patient an intraoperative cavotomy was repaired by primary closure with no sequelae. There were no perioperative deaths. Outcomes All 22 patients were rendered tumor free after metastasectomy. At a median followup of 109 weeks (range 10 to 283) after metastasectomy 21 patients were alive and 1 died of RCC 105 weeks after metastasectomy. At a median of 43 weeks (range 10 to 197) after metastasectomy 11 patients (50%) had no tumor recurrence. In the other 11 patients (50%) tumor recurred during the study period a median of 42 weeks (range 6 to 145) after metastasectomy. Three patients had distant and local recurrences, 7 had distant recurrence only and 1 had local recur- Table 3. Preoperative and postoperative therapies No. Preop Therapy No. Postop Therapy Sunitinib 10 5 Sorafenib 5 3 Bevacizumab interleukin Sorafenib interferon-alfa 3 0 Bevacizumab 1 1 Bevacizumab erlotinib 1 0 Bevacizumab sunitinib 1 0 Interleukin ABT Foretinib 1 0 Everolimus 0 4 Sunitinib gemcitabine 0 2 Pazopanib 0 1

4 442 METASTASECTOMY AFTER TARGETED THERAPY FOR RENAL CELL CANCER Table 4. Metastasectomy parameters Value Median cc estimated blood loss (range) 475 (0 3,000) Median mins operative time (range) 210 (77 425) Median days hospital stay (range) 6 (1 17) No. pts transfused 5 Median cm metastasis (range) 3 (1 12) No. pos surgical margin: Microscopic 1 Macroscopic 0 No. intraop cavotomy 1 No. postop complication: Chylous ascites 4 Atrial fibrillation 1 Ileus 1 rence only. Ten patients had evidence of disease at last followup at a median of 108 weeks (range 18 to 283). A patient with a microscopic positive surgical margin after retroperitoneal disease resection is currently alive 138 weeks after metastasectomy without tumor recurrence or postoperative therapy. There was no correlation between the response according to Response Criteria In Solid Tumors and disease recurrence. Postoperative Targeted Therapy Postoperatively 9 patients received at least 1 targeted therapy, including sunitinib in 5, sorafenib in 2 and everolimus in 2. Eight of these patients restarted targeted therapy at disease recurrence and 1 restarted therapy 2 weeks postoperatively with no evidence of recurrence at that time. Six patients received a second postoperative targeted therapy at last followup, including sunitinib plus gemcitabine in 2, and everolimus, sorafenib, pazopanib and bevacizumab in 1 each. Five patients received the same therapeutic agent and 4 received a different drug postoperatively. Median time to initiate targeted therapy after metastasectomy was 55.3 weeks (range 2 to 226.7). DISCUSSION To our knowledge we report the largest experience with presentations and outcomes in patients with mrcc treated in a multimodality setting with targeted therapy and metastasectomy. Of the 22 patients 21 were alive and half were disease-free at the time of analysis. Also, half of the patients did not receive any systemic therapy after metastasectomy. Four patients underwent surgery at 2 metastatic sites. While we typically advocate metastasectomy in the setting of solitary metastasis, they were counseled to undergo surgery since the metastases were at close anatomical sites that were amenable to surgery at the same time and they did not experienced new metastasis while on therapy. Complications were noted in 18% of patients but were reversible with appropriate management. No perioperative deaths occurred. Preoperative targeted therapy in patients with advanced RCC has been retrospectively studied by several groups. Thomas et al studied 19 deemed to have unresectable disease who were treated with sunitinib. 20 Of the patients 11% had a partial response, 37% had stable disease and no complete responses were noted. Four patients (21%) subsequently underwent nephrectomy with no unexpected surgical morbidity. Margulis et al compared 44 patients treated with targeted therapy before cytoreductive nephrectomy with a contemporary cohort of 58 who underwent only cytoreductive nephrectomy and found no significant difference in the complication rate postoperatively (39% vs 28%, p 0.28). 21 In contrast, Jonasch et al reported a prospective, phase II preoperative trial of 8 weeks of bevacizumab with or without erlotinib in 50 patients with mrcc. 22 Bevacizumab therapy was stopped 4 weeks before surgery. A total of 42 patients with no disease progression after 8 weeks of therapy underwent cytoreductive nephrectomy and had a median progression-free survival of 11 months. Two perioperative deaths occurred but were not attributable to bevacizumab based therapy. Three patients experienced wound dehiscence, resulting in the discontinuation of bevacizumab based therapy. More recently Cowey et al performed a prospective trial of 1 month of preoperative sorafenib in 30 patients with RCC, including 17 with localized disease and 13 with metastasis. 23 Two of the 28 evaluable patients had a partial response and 26 had stable disease. All patients underwent cytoreductive nephrectomy as planned. Postoperatively 1 patient had a myocardial infarction and another experienced superficial wound breakdown, which was managed conservatively. No delayed wound healing, excessive bleeding or surgical dehiscence was noted. These trials show the feasibility of preoperative targeted therapy but did not specifically address metastatic disease resection. Only a few groups have investigated the role of targeted therapy before the resection of metastatic disease. Rini et al described 2 patients who achieved tumor burden reduction with sunitinib therapy and underwent subsequent metastasectomy with a longterm response. 16 Thomas et al described their experience with 19 patients who underwent a total of 21 operations, including radical nephrectomy in 9, partial nephrectomy in 3, resection of local recurrence in 6 and metastasectomy in 3, and experienced partial response or stable disease with targeted therapy before surgery. 24 They found that this approach was

5 METASTASECTOMY AFTER TARGETED THERAPY FOR RENAL CELL CANCER 443 feasible and relatively safe. At the time of the study 16 patients were alive at a median followup of 8 months, including 8 with disease progression. Major complications developed in 3 patients, including death in 1 due to disseminated intravascular coagulation associated with partial hepatectomy, anastomotic bowel leak in 1 and dialysis for 10 months in 1. Two minor complications were also noted in patients who did not receive postoperative targeted therapy, including a wound seroma and a ventral hernia. In our study complications occurred exclusively in patients who underwent retroperitoneal surgery. Caution must be exercised during these surgeries since postoperative adhesions and anatomical distortions are typically noted in the original nephrectomy field. Careful hemostasis and lymphostasis are required in these cases to avoid chylous ascites. Also, targeted therapy can obliterate normal tissue planes, rendering surgery more difficult. 25 In our small series we observed no excessive bleeding, or arterial or venous thromboembolic events during the study period but investigators must be cautioned about the increased risk of vascular complications during treatment with antivascular endothelial growth factor therapy. 26,27 A recent review extensively discussed preoperative targeted therapy for a multitude of cancers and concluded that available data are not sufficient to make general recommendations on their use in the perioperative setting. 28 The group also called for careful use of these agents before surgery as well as further study in prospective fashion to further elucidate their safety profiles in the preoperative setting. Several questions remain unanswered in the era of targeted therapy when treating a patient with mrcc who is a potential candidate for metastasectomy, such as whether targeted therapy is needed, the initial choice and treatment duration with a targeted agent, and whether to resume therapy postoperatively with the same agent or a new one in the setting of NED. A potential advantage of treating select patients with targeted therapy before metastasectomy is that this approach could act as a litmus test in those who already have metastasis and are at risk for further metastasis. As such, most patients in whom metastasis develops while on targeted therapy would no longer be eligible for surgery. Our report has limitations. 1) Although to our knowledge this is the largest experience with targeted therapy before metastasectomy, it is a retrospective study that included a small number of patients with a relatively short followup. 2) Metastasectomy was done in different organ systems and selected on an individual basis. 3) The type and duration of targeted therapy before metastasectomy were not prospectively standardized. CONCLUSIONS We report that consolidative metastasectomy is feasible with acceptable morbidity in a cohort of select patients with a limited tumor burden after targeted therapy. Metastasectomy was well tolerated and half of the patients had NED status at last followup. Significant time off targeted therapy and the potential for durable remission may be achievable with this approach. Longer followup in the current patient cohort and a prospective trial of up front targeted therapy followed by metastasectomy are needed before recommending this multimodality approach as routine care in patients with mrcc. REFERENCES 1. Pantuck AJ, Zisman A and Belldegrun AS: The changing natural history of renal cell carcinoma. J Urol 2001; 166: Flanigan RC: Debulking nephrectomy in metastatic renal cancer. Clin Cancer Res 2004; 10: 6335S. 3. Motzer RJ, Hutson TE, Tomczak P et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: Escudier B, Eisen T, Stadler WM et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: Hudes G, Carducci M, Tomczak P et al: Temsirolimus, interferon alfa, or both for advanced renalcell carcinoma. N Engl J Med 2007; 356: Motzer RJ, Escudier B, Oudard S et al: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. 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