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Commentary on Surgical resection of renal cell carcinoma after targeted therapy
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P. Russo / Urologic Oncology: Seminars and Original Investigations 28 (2010) 228 –232
radical nephrectomy (T4N0) had a median survival of 48 months, whereas the 64 patients who underwent nonsurgical treatment had a median survival of 6 months. For the 85 patients with adjacent organ invasion and concomitant nodal metastases, radical nephrectomy and nonsurgical treatment had the same poor outcome. These data were obtained (1988 –2004) prior to the widespread use of contemporary systemic chemotherapies, such as TKI and mTOR inhibitors, and likely represents the maximum therapeutic impact that could be obtained from operative interventions alone. Missing from these data is information regarding cancer related selection factors (performance status, presence or absence of symptoms, hemoglobin levels, corrected calcium levels, LDH levels). These factors segregate metastatic patients into distinct risk groups with greatly different survival distributions, for example, some good risk patients surviving ⬎70 months without systemic treatment [1,2]. In addition, the authors present no data as to why surgical resection was not attempted in the 64 patients. Were they suffering from significant medical co-morbidities and/or systemic symptoms (poor risk) that rendered them nonsurgical candidates? Today, as tyrosine kinase and mTOR inhibitors are increasingly being utilized in the treatment of advanced and metastatic renal cancer, including patients now enrolled in neoadjuvant and adjuvant clinical trials, surgical judgment will be increasingly tested to determine the optimum timing for these massive operations. It is also conceivable that some patients may be treated medically for prolonged periods of time with either stable or only slowly progressive metastatic disease and never undergo such operations. Although this study may be subject to some uncertainties of case selection, it strongly suggests a limited role for surgical intervention alone in patients with adjacent organ involvement and nodal metastases. In this poor risk patient population, contemporary systemic agents may convert select patients into candidates for surgical consolidation. doi:10.1016/j.urolonc.2009.11.017 Paul Russo, M.D., F.A.C.S.
References [1] Eggener SE, Yossepowitch O, Pettus JA, et al. Renal cell carcinoma recurrence following nephrectomy for localized disease: Predicting survival from time to recurrence. J Clin Oncol 2006;24:3101– 6. [2] Eggener S, Yossepowitch O, Kundu S, et al. Risk score and metastasectomy independently impact prognosis in patients with recurrent renal cell carcinoma. J Urol 2008;180:873– 8.
Commentary on Surgical resection of renal cell carcinoma after targeted therapy. Thomas AA, Rini BI, Stephenson AJ, Garcia JA, Fergany A, Krishnamurthi V, Novick AC, Gill IS, Klein EA, Zhou M, Campbell SC, Glickman Urological and Kidney Institute, Cleveland, OH. J Urol 2009;182:881– 6 The development of targeted agents for renal cell carcinoma has renewed interest in consolidative surgery due to the robust clinical responses seen with these agents. The integration of targeted therapy and surgery requires careful consideration due to the potential for increased perioperative morbidity. We retrospectively identified patients with renal cell carcinoma treated with sunitinib, sorafenib, or bevacizumab plus interleukin-2 before tumor resection. Between June 2005 and August 2008, 19 patients were treated with targeted therapy and subsequently underwent resection. Surgical extirpation involved an open and a laparoscopic approach in 18 and 3 cases, respectively, for locally advanced (8), locally recurrent (6), and metastatic disease (3). Two patients with extensive bilateral renal cell carcinoma were also treated to downsize the tumors to enable partial nephrectomy. Perioperative complications were noted in 16% of patients. One patient had a significant intraoperative hemorrhage and disseminated intravascular coagulopathy from a concomitant liver resection. An anastomotic bowel leak and abscess were noted postoperatively in another patient who underwent en bloc resection of a retroperitoneal recurrence and adjacent colon. Two patients (11%) had minor wound complications, including a wound seroma and a ventral hernia. Pathologic analysis of 20 specimens revealed clear cell, chromophobe, and unclassified renal cell carcinoma in 80%, 5%, and 10% of cases, respectively. One patient (5%) had a pathologic complete response. Surgical resection of renal cell carcinoma after targeted therapy is feasible with low morbidity in most patients. However, significant complications can occur, raising concern for possible compromise of tissue and/or vascular integrity associated with surgery in this setting.
Commentary The authors report a preliminary experience of 21 operations in 19 patients previously treated systemic targeted therapies (including sunitinib, n ⫽ 12, sorafenib n ⫽ 3, and bevacizumab/Il-2 n ⫽ 4) followed by subsequent surgical resections in patients with either stable disease or partial clinical response. Operations included 9 radical nephrectomies, 3 partial nephrectomies, 6 local tumor recurrence resections, and 3 metastasectomies. Open operations were performed in 18 cases and laparoscopic operations in 3. Only 1 patient had a complete pathologic response to the systemic therapy and 80% had conventional clear cell carcinoma in the resected specimen. Three patients had major complications (16%), including 2 major postoperative bleeds leading to 1 postoperative death, and anastomotic bowel
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leak. At a median follow-up of 8 months, 16 patients (84%) were alive, 8 of whom (42%) had disease progression. Nine patients (50%) with metastatic disease or later disease progression were continued on systemic targeted therapy. With numerous multikinase and mTOR inhibitors now FDA approved for use in metastatic renal cancer, surgeons will be consulted by medical oncology colleagues to consider surgical intervention to consolidate a partial clinical response either in the primary renal tumor, areas of local recurrence, or metastatic sites. Decisions concerning the resumption of systemic therapies or active surveillance after complete surgical resection are currently made based on the patient’s overall performance status and level of drug-related toxicity. Clinical trials utilizing these same agents in the neoadjuvant and adjuvant setting have been initiated in the USA and Europe. I predict the role of the surgeon in metastatic renal cancer will continue to expand, particularly since the likelihood of a complete pathologic remission is low as evidenced by this and other studies. doi:10.1016/j.urolonc.2009.11.018 Paul Russo, M.D., F.A.C.S.
Commentary on Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: An expanded-access trial. Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R, Royal Marsden Hospital NHS Trust, London, UK. Lancet Oncol 2009;10:757– 63 Results from clinical trials have established sunitinib as a standard of care for first-line treatment of advanced or metastatic renal-cell carcinoma (RCC); however, many patients, particularly those with a poorer prognosis, do not meet inclusion criteria, and little is known about the activity of sunitinib in these subgroups. The primary objective of this trial was to provide sunitinib on a compassionate-use basis to trial-ineligible patients with RCC from countries where regulatory approval had not been granted. Previously treated and treatment-naive patients at least 18 years of age with metastatic RCC were eligible. All patients received open-label sunitinib 50 mg orally once daily on schedule 4 –2 (4 weeks on treatment, 2 weeks off). Safety was assessed regularly, tumor measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, which consisted of all patients who received at least 1 dose of sunitinib. This study is registered with ClinicalTrials.gov, NCT00130897. As of December, 2007, 4,564 patients were enrolled in 52 countries; 4,371 patients were included in the modified ITT population. This population included 321 (7%) patients with brain metastases, 582 (13%) with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, 588 (13%) non-clear-cell RCC, and 1,418 (32%) aged 65 years or more. Patients received a median of 5 treatment cycles (range 1–25). Reasons for discontinuation included lack of efficacy (n ⫽ 1,168 [27%]) and adverse events (n ⫽ 362 [8%]). The most common treatment-related adverse events were diarrhea (n ⫽ 1,936 [44%]) and fatigue (n ⫽ 1,606 [37%]). The most common grade 3– 4 adverse events were fatigue (n ⫽ 344 [8%]) and thrombocytopenia (n ⫽ 338 [8%]) with incidences of grade 3– 4 adverse events similar across subgroups. In 3,464 evaluable patients, the objective response rate (ORR) was 17% (n ⫽ 603), with subgroup ORR as follows: brain metastases (26 of 213 [12%]), ECOG performance status 2 or higher (29 of 319 [9%]), non-clear-cell RCC (48 of 437 [11%]), and age 65 years or more (176 of 1056 [17%]). Median progression-free survival was 10.9 months (95% CI 10.3–11.2) and overall survival was 18.4 months (17.4 –19.2). In a broad population of patients with metastatic RCC, the safety profile of sunitinib 50 mg once-daily (initial dose) on schedule 4 –2 was manageable, and efficacy results were encouraging, particularly in subgroups associated with poor prognosis who are not usually entered into clinical trials. Funding by Pfizer Inc.
Commentary The authors evaluate 4,371 patients, who were protocol ineligible because of brain metastases, poor performance status, age greater than 65, and non-clear-cell histology, who were given 50 mg po qd of sunitinib in an expanded access trial. Patients received a median of 5 treatment cycles and had the sunitinib discontinued because of lack of efficacy (27%) and adverse events (8%), including diarrhea and fatigue. The total incidence of cardiac disorders was 1% and congestive heart failure incidence was ⬍1%. Median progression-free survival was 10.9 months, overall survival was 18.4 months, and the objective response rate was 17%. This study highlights the benefits achieved in an expanded access trial where the toxicities of sunitinib were manageable in a patient population expected to have far more side effects. This information should be very useful to medical oncologists for counseling and treating their more complicated metastatic renal cancer patients. doi:10.1016/j.urolonc.2009.11.019 Paul Russo, M.D., F.A.C.S.
P. Russo / Urologic Oncology: Seminars and Original Investigations 28 (2010) 228 –232
radical nephrectomy (T4N0) had a median survival of 48 months, whereas the 64 patients who underwent nonsurgical treatment had a median survival of 6 months. For the 85 patients with adjacent organ invasion and concomitant nodal metastases, radical nephrectomy and nonsurgical treatment had the same poor outcome. These data were obtained (1988 –2004) prior to the widespread use of contemporary systemic chemotherapies, such as TKI and mTOR inhibitors, and likely represents the maximum therapeutic impact that could be obtained from operative interventions alone. Missing from these data is information regarding cancer related selection factors (performance status, presence or absence of symptoms, hemoglobin levels, corrected calcium levels, LDH levels). These factors segregate metastatic patients into distinct risk groups with greatly different survival distributions, for example, some good risk patients surviving ⬎70 months without systemic treatment [1,2]. In addition, the authors present no data as to why surgical resection was not attempted in the 64 patients. Were they suffering from significant medical co-morbidities and/or systemic symptoms (poor risk) that rendered them nonsurgical candidates? Today, as tyrosine kinase and mTOR inhibitors are increasingly being utilized in the treatment of advanced and metastatic renal cancer, including patients now enrolled in neoadjuvant and adjuvant clinical trials, surgical judgment will be increasingly tested to determine the optimum timing for these massive operations. It is also conceivable that some patients may be treated medically for prolonged periods of time with either stable or only slowly progressive metastatic disease and never undergo such operations. Although this study may be subject to some uncertainties of case selection, it strongly suggests a limited role for surgical intervention alone in patients with adjacent organ involvement and nodal metastases. In this poor risk patient population, contemporary systemic agents may convert select patients into candidates for surgical consolidation. doi:10.1016/j.urolonc.2009.11.017 Paul Russo, M.D., F.A.C.S.
References [1] Eggener SE, Yossepowitch O, Pettus JA, et al. Renal cell carcinoma recurrence following nephrectomy for localized disease: Predicting survival from time to recurrence. J Clin Oncol 2006;24:3101– 6. [2] Eggener S, Yossepowitch O, Kundu S, et al. Risk score and metastasectomy independently impact prognosis in patients with recurrent renal cell carcinoma. J Urol 2008;180:873– 8.
Commentary on Surgical resection of renal cell carcinoma after targeted therapy. Thomas AA, Rini BI, Stephenson AJ, Garcia JA, Fergany A, Krishnamurthi V, Novick AC, Gill IS, Klein EA, Zhou M, Campbell SC, Glickman Urological and Kidney Institute, Cleveland, OH. J Urol 2009;182:881– 6 The development of targeted agents for renal cell carcinoma has renewed interest in consolidative surgery due to the robust clinical responses seen with these agents. The integration of targeted therapy and surgery requires careful consideration due to the potential for increased perioperative morbidity. We retrospectively identified patients with renal cell carcinoma treated with sunitinib, sorafenib, or bevacizumab plus interleukin-2 before tumor resection. Between June 2005 and August 2008, 19 patients were treated with targeted therapy and subsequently underwent resection. Surgical extirpation involved an open and a laparoscopic approach in 18 and 3 cases, respectively, for locally advanced (8), locally recurrent (6), and metastatic disease (3). Two patients with extensive bilateral renal cell carcinoma were also treated to downsize the tumors to enable partial nephrectomy. Perioperative complications were noted in 16% of patients. One patient had a significant intraoperative hemorrhage and disseminated intravascular coagulopathy from a concomitant liver resection. An anastomotic bowel leak and abscess were noted postoperatively in another patient who underwent en bloc resection of a retroperitoneal recurrence and adjacent colon. Two patients (11%) had minor wound complications, including a wound seroma and a ventral hernia. Pathologic analysis of 20 specimens revealed clear cell, chromophobe, and unclassified renal cell carcinoma in 80%, 5%, and 10% of cases, respectively. One patient (5%) had a pathologic complete response. Surgical resection of renal cell carcinoma after targeted therapy is feasible with low morbidity in most patients. However, significant complications can occur, raising concern for possible compromise of tissue and/or vascular integrity associated with surgery in this setting.
Commentary The authors report a preliminary experience of 21 operations in 19 patients previously treated systemic targeted therapies (including sunitinib, n ⫽ 12, sorafenib n ⫽ 3, and bevacizumab/Il-2 n ⫽ 4) followed by subsequent surgical resections in patients with either stable disease or partial clinical response. Operations included 9 radical nephrectomies, 3 partial nephrectomies, 6 local tumor recurrence resections, and 3 metastasectomies. Open operations were performed in 18 cases and laparoscopic operations in 3. Only 1 patient had a complete pathologic response to the systemic therapy and 80% had conventional clear cell carcinoma in the resected specimen. Three patients had major complications (16%), including 2 major postoperative bleeds leading to 1 postoperative death, and anastomotic bowel
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leak. At a median follow-up of 8 months, 16 patients (84%) were alive, 8 of whom (42%) had disease progression. Nine patients (50%) with metastatic disease or later disease progression were continued on systemic targeted therapy. With numerous multikinase and mTOR inhibitors now FDA approved for use in metastatic renal cancer, surgeons will be consulted by medical oncology colleagues to consider surgical intervention to consolidate a partial clinical response either in the primary renal tumor, areas of local recurrence, or metastatic sites. Decisions concerning the resumption of systemic therapies or active surveillance after complete surgical resection are currently made based on the patient’s overall performance status and level of drug-related toxicity. Clinical trials utilizing these same agents in the neoadjuvant and adjuvant setting have been initiated in the USA and Europe. I predict the role of the surgeon in metastatic renal cancer will continue to expand, particularly since the likelihood of a complete pathologic remission is low as evidenced by this and other studies. doi:10.1016/j.urolonc.2009.11.018 Paul Russo, M.D., F.A.C.S.
Commentary on Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: An expanded-access trial. Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R, Royal Marsden Hospital NHS Trust, London, UK. Lancet Oncol 2009;10:757– 63 Results from clinical trials have established sunitinib as a standard of care for first-line treatment of advanced or metastatic renal-cell carcinoma (RCC); however, many patients, particularly those with a poorer prognosis, do not meet inclusion criteria, and little is known about the activity of sunitinib in these subgroups. The primary objective of this trial was to provide sunitinib on a compassionate-use basis to trial-ineligible patients with RCC from countries where regulatory approval had not been granted. Previously treated and treatment-naive patients at least 18 years of age with metastatic RCC were eligible. All patients received open-label sunitinib 50 mg orally once daily on schedule 4 –2 (4 weeks on treatment, 2 weeks off). Safety was assessed regularly, tumor measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, which consisted of all patients who received at least 1 dose of sunitinib. This study is registered with ClinicalTrials.gov, NCT00130897. As of December, 2007, 4,564 patients were enrolled in 52 countries; 4,371 patients were included in the modified ITT population. This population included 321 (7%) patients with brain metastases, 582 (13%) with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, 588 (13%) non-clear-cell RCC, and 1,418 (32%) aged 65 years or more. Patients received a median of 5 treatment cycles (range 1–25). Reasons for discontinuation included lack of efficacy (n ⫽ 1,168 [27%]) and adverse events (n ⫽ 362 [8%]). The most common treatment-related adverse events were diarrhea (n ⫽ 1,936 [44%]) and fatigue (n ⫽ 1,606 [37%]). The most common grade 3– 4 adverse events were fatigue (n ⫽ 344 [8%]) and thrombocytopenia (n ⫽ 338 [8%]) with incidences of grade 3– 4 adverse events similar across subgroups. In 3,464 evaluable patients, the objective response rate (ORR) was 17% (n ⫽ 603), with subgroup ORR as follows: brain metastases (26 of 213 [12%]), ECOG performance status 2 or higher (29 of 319 [9%]), non-clear-cell RCC (48 of 437 [11%]), and age 65 years or more (176 of 1056 [17%]). Median progression-free survival was 10.9 months (95% CI 10.3–11.2) and overall survival was 18.4 months (17.4 –19.2). In a broad population of patients with metastatic RCC, the safety profile of sunitinib 50 mg once-daily (initial dose) on schedule 4 –2 was manageable, and efficacy results were encouraging, particularly in subgroups associated with poor prognosis who are not usually entered into clinical trials. Funding by Pfizer Inc.
Commentary The authors evaluate 4,371 patients, who were protocol ineligible because of brain metastases, poor performance status, age greater than 65, and non-clear-cell histology, who were given 50 mg po qd of sunitinib in an expanded access trial. Patients received a median of 5 treatment cycles and had the sunitinib discontinued because of lack of efficacy (27%) and adverse events (8%), including diarrhea and fatigue. The total incidence of cardiac disorders was 1% and congestive heart failure incidence was ⬍1%. Median progression-free survival was 10.9 months, overall survival was 18.4 months, and the objective response rate was 17%. This study highlights the benefits achieved in an expanded access trial where the toxicities of sunitinib were manageable in a patient population expected to have far more side effects. This information should be very useful to medical oncologists for counseling and treating their more complicated metastatic renal cancer patients. doi:10.1016/j.urolonc.2009.11.019 Paul Russo, M.D., F.A.C.S.