- Email: [email protected]
Preoperative Tyrosine Kinase Inhibition as an Adjunct to Debulking Nephrectomy
Oncology Preoperative Tyrosine Kinase Inhibition as an Adjunct to Debulking Nephrectomy Chirag Amin, Eric Wallen, Raj S. Pruthi, Benjamin F. Calvo, Paul A. Godley, and W. Kimryn Rathmell OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
Since the introduction of tyrosine kinase inhibitors (TKI), treatment of metastatic renal cell carcinoma (RCC) has undergone dramatic changes. However, the use of TKI therapy in adjunctive settings remains to be defined. We present a single-institution experience of patients who received preoperative TKI before nephrectomy for metastatic or unresectable disease. The records of 9 patients with locally advanced or metastatic RCC treated with TKI therapy before nephrectomy at the University of North Carolina were reviewed. All procedures and radiographic images were performed at 1 institution. The cases were surveyed for the effect of TKI on tumor burden and surgical approach and timing. The patients received systemic therapy with either sorafenib or sunitinib before proceeding to nephrectomy on clinical trials for metastatic disease or as the standard of care. The surgery was well tolerated by all patients, without an apparent effect from TKI therapy on the surgical technique or complications. Responses were observed in the primary tumor, as well as in the metastatic sites. Neoadjuvant TKI therapy can induce responses in the primary tumor and has the potential advantage of cytoreduction when administered before nephrectomy for RCC. This setting also potentially provides an opportunity to evaluate the TKI responsiveness of patients with metastatic disease. However, prospective trials evaluating adjunctive surgical approaches to locally advanced and metastatic RCC are needed to determine the significant benefits of TKI therapy and to define the optimal agent, timing of therapy, and disease stage to derive benefit for preoperative therapy. UROLOGY 72: 864 – 868, 2008. © 2008 Elsevier Inc.
R
enal cell carcinoma (RCC) is the 7th leading cancer among males and the 10th leading cause of death from cancer in the United States for both sexes.1 Surgical resection of nonmetastatic RCC remains the primary definitive treatment even in the setting of bulky retroperitoneal lymphadenopathy or locally invasive T4 lesions. Even in the metastatic setting, cytoreductive nephrectomy is an important modality for palliation or with the intent to improve survival. Two studies have investigated the benefit of cytoreductive nephrectomy followed by systemic treatment with cytokine therapy vs cytokine alone. These investigations, and a subsequent meta-analysis, have demonstrated a small, but reproducible, improvement in overall survival, although the extent of this benefit for patients in the era of tyrosine kinase inhibitor (TKI) therapy is unknown.2-4
This study was supported in part by research funding from the Doris Duke Charitable Fund (to W. K. R.). From the Division of Hematology and Oncology, Division of Urology, Lineberger Comprehensive Cancer Center, and Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Reprint requests: W. Kimryn Rathmell, M.D., Ph.D., Department of Hematology/ Oncology, Lineberger Comprehensive Cancer Center, 450 West Drive, CB 7295, Chapel Hill, NC 27599. E-mail: [email protected] Submitted: December 19, 2007, accepted (with revisions): January 29, 2008
864
© 2008 Elsevier Inc. All Rights Reserved
Until recently, therapeutic options for advanced RCC were essentially limited to cytokine therapy with interferon-␣ or interleukin-2. Both have been investigated in the adjuvant setting, with available data providing no evidence to support this practice. In fact, a trend toward worse outcomes with adjuvant treatment has been suggested in some analytic subsets.5-7 The utility of preoperative systemic therapy for cytoreduction has not been explored extensively owing to the rare objective responses to cytokine therapy and the anticipation that a decline in performance status with cytokine therapy would preclude a prompt transition to surgery.8,9 Recently, however, systemic therapy for advanced RCC has undergone a significant evolution with the advent of targeted therapeutics. Specifically, the development of receptor tyrosine kinase inhibitors, such as sorafenib (Nexavar, Bayer AG, Berlin, Germany, and Onyx Pharmaceuticals, Emeryville, CA) and sunitinib (Sutent, Pfizer Oncology, New York, NY), which act to inhibit multiple kinases, including vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and others.10-12 Both small molecule inhibitors are now approved by the Food and Drug Administration in the United States for the broad indication of advanced RCC. 0090-4295/08/$34.00 doi:10.1016/j.urology.2008.01.088
Although neither of these therapies is curative, they have shown substantial improvements in response and progression-free survival for patients with metastatic disease.13,14 Although the introduction of TKI therapy appears to signify a new era in the treatment of RCC, significant questions remain regarding the safety, utility, and feasibility in various clinical settings.15,16 These compounds provide a novel family of agents with an unprecedented ability to achieve tumor reduction in RCC. Although complete responses are not seen with these agents, significant activity, including a reduction in tumor burden, can be achieved in patients with advanced disease. Efforts to examine the ability of these agents to reduce recurrence after successful nephrectomy for patients with high-risk disease are underway. However, the greatest effect from these new drugs might be in the initial reduction in tumor volume that can be achieved within the first few cycles of treatment. Even for those patients with more widely distributed disease, the opportunity to debulk, evaluate the response to systemic therapy, and stabilize more rapidly growing sites before cytoreduction could provide a clinical benefit. These outcomes require a thorough examination in the clinical trial setting; however, many issues remain regarding the safety of preoperative treatment with antiangiogenic treatment, the expectation of response in the primary tumor, and the risk of causing patient deterioration to the point that nephrectomy can no longer be considered. At the University of North Carolina at Chapel Hill, we have collected our institutional experience with patients who received systemic treatment with a TKI before nephrectomy. This unique cohort of patients has provided early evidence of the safety of nephrectomy in this difficult population, an indication of the activity of these drugs against the primary tumor, and suggested a possible treatment alternative for patients with difficult-to-manage primary tumors.
MATERIAL AND METHODS Patient Subjects We reviewed the cumulative single-institution experience of patients who received therapy with a TKI (either sorafenib or sunitinib) for ⱖ4 weeks before nephrectomy for RCC. A total of 9 patients met these criteria at the analysis. All therapy and surgical resection was completed at the University of North Carolina at Chapel Hill.
Response Assessment All patients had pretreatment and posttreatment computed tomography imaging data available. The response was calculated by measuring the largest diameter of the primary tumor and any lymph nodes on the pre- and posttreatment computed tomography scans. For all patients, including those who underwent an extended treatment period with TKI before nephrectomy, the posttreatment measurement was made at the conclusion of treatment. UROLOGY 72 (4), 2008
Statistical Analysis Descriptive analyses of the patient and therapy characteristics are provided.
RESULTS Patient Characteristics The patients described in this study received systemic therapy with a TKI for a variety of indications related to advanced RCC before proceeding to nephrectomy. Most patients were initially considered to have unresectable disease because of the bulk of local or metastatic disease or at diagnosis had another contraindication to immediate surgical resection and thus were treated with primary systemic therapy for their locally advanced or metastatic disease. This group of patients included those treated with TKI therapy on locally available clinical trials using conventional dosages and those treated with commercial products after Food and Drug Administration approval of the drugs. The cohort consisted of 5 men and 4 women with a median age of 57 years. The patients received a variety of therapies, including sunitinib, sorafenib, or sorafenib in combination with interferon. Four patients required a dose reduction because of adverse events, including rash/ hand foot syndrome, hypertension, and fatigue. The patients received treatment for a mean duration of 107 days (median 47, range 23-262). Because this was a diverse set of retrospective cases, the treatment duration is highly individualized. As a rule, patients were treated for a minimum of 2 cycles of therapy before undergoing repeat imaging; however, surgical preferences had to be considered for several patients and others were treated to achieve maximal tumor shrinkage. Most tumors were of the clear cell histologic type, although papillary and chromophobe subtypes were represented (Table 1). No patients proceeded to surgery because of medication intolerance. Nephrectomy was performed a minimum of 2 days after cessation of TKI therapy, and the surgical approach was determined by the treating urologic surgeon. In this group, 5 patients underwent hand-assisted laparoscopic nephrectomy and 4 open radical nephrectomy. Patient Outcome The details of the surgical approach and operative times are provided in Table 2. The surgical approaches were typical for the institution and included patients undergoing open radical nephrectomy, laparoscopic radical nephrectomy, and vena caval thrombectomy. The operative times were consistent with historical surgical times recorded at University of North Carolina at Chapel Hill compared with untreated patients undergoing surgery by the same surgeons (mean 195 min, median 137) with longer operative times corresponding to the open procedures and more complex masses, in particular, 1 case with an involved inferior vena cava thrombectomy. The operative times in unselected patients during the same 865
Table 1. Patient characteristics Treatment Duration (d)
Pt. No.
Sex
Age (y)
Treatment
1 2 3 4 5 6 7 8 9 Mean Median
Male Male Female Male Female Female Male Female Male
57 73 60 53 50 46 72 64 57 59 57
Sorafenib Sunitinib Sunitinib Sorafenib Sunitinib Interferon plus sorafenib Sorafenib Sorafenib Sorafenib
32 72 217 47 235 262 23 43 38 107 47
Pathologic Finding Clear cell Chromophobe Clear cell Mixed (clear/papillary) Clear cell Clear cell Papillary Clear cell Clear cell
Pt. No. ⫽ Patient number.
Table 2. Posttreatment parameters Pt. No.
Interval After Systemic Therapy Before Surgery
Reduction (%)
Surgery
OR Time (min)
Hospital Stay (d)
1 2 3 4 5 6 7 8 9 Mean Median
19 2 8 2 68 36 6 4 3 16 6
18.6 8.8 2 4.9 17.9 54 0.82 5.13 8.4 12.9 8
LN LN R LN R LN R ⫹ VT LN R
137 188 110 120 382 118 390 190 121 195 137
3 2 7 2 13 3 19 2 4 6.11 3
LN ⫽ Laparoscopic nephrectomy; R ⫽ radical nephrectomy; VT ⫽ vena caval thrombectomy; OR ⫽ total operative time.
3-year period were reviewed and averaged 211 minutes for open radical nephrectomy and 182 minutes for laparoscopic nephrectomy. Thus, in this small subgroup, TKI therapy did not seem to have a meaningful detrimental effect on the operation itself. Before nephrectomy, TKI therapy was discontinued an average of 16 days before surgery (median 6, range 2-68). The mean hospital admission was 6 days (median 3). The individual hospital stays are detailed in Table 2. The longer hospitalizations were associated with more involved surgical procedures. At follow-up, no patient had issues with wound healing. Patients with residual measurable metastatic disease were offered to resume TKI therapy after a 2-month postoperative wound check. Tumor Response For the group as a whole, a modest (mean 12.9%, median 8%) decrease occurred in the size of the primary tumor before surgical resection. The responses in the primary tumor were quite varied, ranging from 0.82% for essentially stable disease to 54% with a partial response using the Response Evaluation Criteria in Solid Tumors. Two patients who presented with primary tumors associated with bulky retroperitoneal lymphadenopathy had substantial reductions in the size of the kidney tumor and/or lymph nodes (Fig. 1C). Because of the reduction in tumor size and, in particular, the substantial reductions in the 866
bulky lymphadenopathy, these patients were able to undergo a complete resection of all disease. Retroperitoneal lymph nodes can frequently present a difficult problem to approach, particularly when encasement of major vessels has occurred. Bulky nodal involvement can substantially impair the ability to completely resect the involved nodes with negative margins and also dramatically increases the risk of recurrence after surgery. With their initial presentation, these patients would have had to undergo surgery in which it would have been difficult or impossible to achieve complete clearance. In contrast, both were free of evidence of recurrence and not receiving systemic therapy ⬎1 year after nephrectomy. Two examples of the responses are provided in Fig. 1, demonstrating the effect of the treatment response on both the primary tumor (Fig. 1A,B; patient 1) and lymphadenopathy (Fig. 1C,D; patient 5).
COMMENT With the advent of targeted therapy for RCC, preoperative systemic therapy presents an attractive modality for treating advanced RCC for multiple reasons. First, targeted agents are better tolerated than most immunotherapeutic agents in a broader range of patients, with improved tumor response and progression-free survival, and patients remain fit for a major surgical intervention. We UROLOGY 72 (4), 2008
Figure 1. Computed tomography scans demonstrating responses in primary tumor and extrarenal tissue with preoperative treatment. (A) Pretreatment renal mass demonstrating solid mass with significant enhancement. (B) Posttreatment image of same mass demonstrating decrease in tumor size and central contrast enhancement. (C) Pretreatment renal tumor and associated large lymph node conglomerate. (D) Posttreatment image of same mass demonstrating marked improvement in lymphadenopathy and primary mass.
have observed and documented in this analysis that a substantial response can be achieved in the primary tumor, as well as in the extrarenal tissues. Provocatively, preoperative treatment could provide the opportunity for downstaging of the primary tumor itself and, perhaps, improvement of surgical resectability, thereby decreasing surgical complications, improving surgical recovery, and limiting the hospital stay. This series was limited by being a retrospective analysis of a small patient sample. However, the primary interest in conducting this analysis was to address, with a series of cases, the potential of preoperative TKI therapy for use in advanced RCC. One of the primary concerns of preoperative TKI is the potential to make conditions worse for surgical resection because of bleeding complications or poor wound healing. In this series, surgery was well tolerated with low perioperative morbidity, even though most resections were performed within 1 week after the cessation of TKI therapy. Moreover, compared with our institutional standards, the operative times and surgical approaches were not affected by the use of TKI therapy. Additional studies are needed to clarify the optimal timing of the discontinuation of the drug, especially because the half-lives for both medications differ. The half-life for sorafenib is 25-48 hours, and a long terminal clearance is characteristic.17 In contrast, sunitinib and its active metabolite have a half-life of 40-60 hours and 80-100 hours, respectively.18 UROLOGY 72 (4), 2008
CONCLUSIONS Our review of this single-institution series of patients suggests that systemic TKI therapy in advance of open or laparoscopic nephrectomy could be a potentially safe alternate use of these systemic agents. Overall, the potential for tumor downstaging, improving the surgical field, and providing the opportunity to judge the responsiveness of a patient’s tumor before committing to surgery suggest that the preoperative venue might be an ideal setting to maximize the effect of TKI therapy for RCC. These preliminary findings support at least the exploration of neoadjuvant TKI therapy in clinical trials for localized, regional, or metastatic RCC. Despite these encouraging findings, the routine use of TKIs as neoadjuvant therapy for patients who should proceed with definitive surgical resection cannot yet be recommended outside of a clinical trial. Ultimately, the outcomes of clinical trials ongoing at centers, including our own, are necessary to demonstrate a benefit calculated in reductions in recurrence or improved overall survival and a better assessment of tolerability of neoadjuvant TKI therapy. Acknowledgment. To the courageous patients and their families who made this analysis possible. References 1. American Cancer Society. Cancer facts and figures 2007. Available from: http://www.cancer.org, 2007. Accessed 9/1/2007.
867
2. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345: 1655-1659. 3. Pantuck AJ, Belldegrun AS, Figlin RA. Nephrectomy and interleukin-2 for metastatic renal-cell carcinoma. N Engl J Med. 2001; 345:1711-1712. 4. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: A randomised trial. Lancet. 2001;358:966-970. 5. Pizzocaro G, Piva L, Colavita M, et al. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: A multicentric randomized study. J Clin Oncol. 2001;19:425431. 6. Atzpodien J, Schmitt E, Gertenbach U, et al. Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: Results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer. 2005;92:843-846. 7. Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: A Cytokine Working Group randomized trial. J Clin Oncol. 2003;21: 3133-3140. 8. Bex A, Horenblas S, de Gast GC. The timing of immunotherapy and nephrectomy in multimodality treatment of metastatic renal cell carcinoma. Technol Cancer Res Treat. 2003;2:205-210. 9. Wood CG. The role of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma. Urol Clin North Am. 2003;30:581-588.
868
10. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9:327-337. 11. Wilhelm S, Chien DS. BAY 43-9006: Preclinical data. Curr Pharm Des. 2002;8:2255-2257. 12. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099-7109. 13. Escudier B, Eisen T, Stadler WM. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. 14. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007; 356:115-124. 15. Rini BI, Campbell SC. The evolving role of surgery for advanced renal cell carcinoma in the era of molecular targeted therapy. J Urol. 2007;177:1978-1984. 16. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24: 16-24. 17. Clark JW, Eder JP, Ryan D, et al. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res. 2005;11:5472-5480. 18. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24:25-35.
UROLOGY 72 (4), 2008
METHODS
RESULTS
CONCLUSIONS
Since the introduction of tyrosine kinase inhibitors (TKI), treatment of metastatic renal cell carcinoma (RCC) has undergone dramatic changes. However, the use of TKI therapy in adjunctive settings remains to be defined. We present a single-institution experience of patients who received preoperative TKI before nephrectomy for metastatic or unresectable disease. The records of 9 patients with locally advanced or metastatic RCC treated with TKI therapy before nephrectomy at the University of North Carolina were reviewed. All procedures and radiographic images were performed at 1 institution. The cases were surveyed for the effect of TKI on tumor burden and surgical approach and timing. The patients received systemic therapy with either sorafenib or sunitinib before proceeding to nephrectomy on clinical trials for metastatic disease or as the standard of care. The surgery was well tolerated by all patients, without an apparent effect from TKI therapy on the surgical technique or complications. Responses were observed in the primary tumor, as well as in the metastatic sites. Neoadjuvant TKI therapy can induce responses in the primary tumor and has the potential advantage of cytoreduction when administered before nephrectomy for RCC. This setting also potentially provides an opportunity to evaluate the TKI responsiveness of patients with metastatic disease. However, prospective trials evaluating adjunctive surgical approaches to locally advanced and metastatic RCC are needed to determine the significant benefits of TKI therapy and to define the optimal agent, timing of therapy, and disease stage to derive benefit for preoperative therapy. UROLOGY 72: 864 – 868, 2008. © 2008 Elsevier Inc.
R
enal cell carcinoma (RCC) is the 7th leading cancer among males and the 10th leading cause of death from cancer in the United States for both sexes.1 Surgical resection of nonmetastatic RCC remains the primary definitive treatment even in the setting of bulky retroperitoneal lymphadenopathy or locally invasive T4 lesions. Even in the metastatic setting, cytoreductive nephrectomy is an important modality for palliation or with the intent to improve survival. Two studies have investigated the benefit of cytoreductive nephrectomy followed by systemic treatment with cytokine therapy vs cytokine alone. These investigations, and a subsequent meta-analysis, have demonstrated a small, but reproducible, improvement in overall survival, although the extent of this benefit for patients in the era of tyrosine kinase inhibitor (TKI) therapy is unknown.2-4
This study was supported in part by research funding from the Doris Duke Charitable Fund (to W. K. R.). From the Division of Hematology and Oncology, Division of Urology, Lineberger Comprehensive Cancer Center, and Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Reprint requests: W. Kimryn Rathmell, M.D., Ph.D., Department of Hematology/ Oncology, Lineberger Comprehensive Cancer Center, 450 West Drive, CB 7295, Chapel Hill, NC 27599. E-mail: [email protected] Submitted: December 19, 2007, accepted (with revisions): January 29, 2008
864
© 2008 Elsevier Inc. All Rights Reserved
Until recently, therapeutic options for advanced RCC were essentially limited to cytokine therapy with interferon-␣ or interleukin-2. Both have been investigated in the adjuvant setting, with available data providing no evidence to support this practice. In fact, a trend toward worse outcomes with adjuvant treatment has been suggested in some analytic subsets.5-7 The utility of preoperative systemic therapy for cytoreduction has not been explored extensively owing to the rare objective responses to cytokine therapy and the anticipation that a decline in performance status with cytokine therapy would preclude a prompt transition to surgery.8,9 Recently, however, systemic therapy for advanced RCC has undergone a significant evolution with the advent of targeted therapeutics. Specifically, the development of receptor tyrosine kinase inhibitors, such as sorafenib (Nexavar, Bayer AG, Berlin, Germany, and Onyx Pharmaceuticals, Emeryville, CA) and sunitinib (Sutent, Pfizer Oncology, New York, NY), which act to inhibit multiple kinases, including vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and others.10-12 Both small molecule inhibitors are now approved by the Food and Drug Administration in the United States for the broad indication of advanced RCC. 0090-4295/08/$34.00 doi:10.1016/j.urology.2008.01.088
Although neither of these therapies is curative, they have shown substantial improvements in response and progression-free survival for patients with metastatic disease.13,14 Although the introduction of TKI therapy appears to signify a new era in the treatment of RCC, significant questions remain regarding the safety, utility, and feasibility in various clinical settings.15,16 These compounds provide a novel family of agents with an unprecedented ability to achieve tumor reduction in RCC. Although complete responses are not seen with these agents, significant activity, including a reduction in tumor burden, can be achieved in patients with advanced disease. Efforts to examine the ability of these agents to reduce recurrence after successful nephrectomy for patients with high-risk disease are underway. However, the greatest effect from these new drugs might be in the initial reduction in tumor volume that can be achieved within the first few cycles of treatment. Even for those patients with more widely distributed disease, the opportunity to debulk, evaluate the response to systemic therapy, and stabilize more rapidly growing sites before cytoreduction could provide a clinical benefit. These outcomes require a thorough examination in the clinical trial setting; however, many issues remain regarding the safety of preoperative treatment with antiangiogenic treatment, the expectation of response in the primary tumor, and the risk of causing patient deterioration to the point that nephrectomy can no longer be considered. At the University of North Carolina at Chapel Hill, we have collected our institutional experience with patients who received systemic treatment with a TKI before nephrectomy. This unique cohort of patients has provided early evidence of the safety of nephrectomy in this difficult population, an indication of the activity of these drugs against the primary tumor, and suggested a possible treatment alternative for patients with difficult-to-manage primary tumors.
MATERIAL AND METHODS Patient Subjects We reviewed the cumulative single-institution experience of patients who received therapy with a TKI (either sorafenib or sunitinib) for ⱖ4 weeks before nephrectomy for RCC. A total of 9 patients met these criteria at the analysis. All therapy and surgical resection was completed at the University of North Carolina at Chapel Hill.
Response Assessment All patients had pretreatment and posttreatment computed tomography imaging data available. The response was calculated by measuring the largest diameter of the primary tumor and any lymph nodes on the pre- and posttreatment computed tomography scans. For all patients, including those who underwent an extended treatment period with TKI before nephrectomy, the posttreatment measurement was made at the conclusion of treatment. UROLOGY 72 (4), 2008
Statistical Analysis Descriptive analyses of the patient and therapy characteristics are provided.
RESULTS Patient Characteristics The patients described in this study received systemic therapy with a TKI for a variety of indications related to advanced RCC before proceeding to nephrectomy. Most patients were initially considered to have unresectable disease because of the bulk of local or metastatic disease or at diagnosis had another contraindication to immediate surgical resection and thus were treated with primary systemic therapy for their locally advanced or metastatic disease. This group of patients included those treated with TKI therapy on locally available clinical trials using conventional dosages and those treated with commercial products after Food and Drug Administration approval of the drugs. The cohort consisted of 5 men and 4 women with a median age of 57 years. The patients received a variety of therapies, including sunitinib, sorafenib, or sorafenib in combination with interferon. Four patients required a dose reduction because of adverse events, including rash/ hand foot syndrome, hypertension, and fatigue. The patients received treatment for a mean duration of 107 days (median 47, range 23-262). Because this was a diverse set of retrospective cases, the treatment duration is highly individualized. As a rule, patients were treated for a minimum of 2 cycles of therapy before undergoing repeat imaging; however, surgical preferences had to be considered for several patients and others were treated to achieve maximal tumor shrinkage. Most tumors were of the clear cell histologic type, although papillary and chromophobe subtypes were represented (Table 1). No patients proceeded to surgery because of medication intolerance. Nephrectomy was performed a minimum of 2 days after cessation of TKI therapy, and the surgical approach was determined by the treating urologic surgeon. In this group, 5 patients underwent hand-assisted laparoscopic nephrectomy and 4 open radical nephrectomy. Patient Outcome The details of the surgical approach and operative times are provided in Table 2. The surgical approaches were typical for the institution and included patients undergoing open radical nephrectomy, laparoscopic radical nephrectomy, and vena caval thrombectomy. The operative times were consistent with historical surgical times recorded at University of North Carolina at Chapel Hill compared with untreated patients undergoing surgery by the same surgeons (mean 195 min, median 137) with longer operative times corresponding to the open procedures and more complex masses, in particular, 1 case with an involved inferior vena cava thrombectomy. The operative times in unselected patients during the same 865
Table 1. Patient characteristics Treatment Duration (d)
Pt. No.
Sex
Age (y)
Treatment
1 2 3 4 5 6 7 8 9 Mean Median
Male Male Female Male Female Female Male Female Male
57 73 60 53 50 46 72 64 57 59 57
Sorafenib Sunitinib Sunitinib Sorafenib Sunitinib Interferon plus sorafenib Sorafenib Sorafenib Sorafenib
32 72 217 47 235 262 23 43 38 107 47
Pathologic Finding Clear cell Chromophobe Clear cell Mixed (clear/papillary) Clear cell Clear cell Papillary Clear cell Clear cell
Pt. No. ⫽ Patient number.
Table 2. Posttreatment parameters Pt. No.
Interval After Systemic Therapy Before Surgery
Reduction (%)
Surgery
OR Time (min)
Hospital Stay (d)
1 2 3 4 5 6 7 8 9 Mean Median
19 2 8 2 68 36 6 4 3 16 6
18.6 8.8 2 4.9 17.9 54 0.82 5.13 8.4 12.9 8
LN LN R LN R LN R ⫹ VT LN R
137 188 110 120 382 118 390 190 121 195 137
3 2 7 2 13 3 19 2 4 6.11 3
LN ⫽ Laparoscopic nephrectomy; R ⫽ radical nephrectomy; VT ⫽ vena caval thrombectomy; OR ⫽ total operative time.
3-year period were reviewed and averaged 211 minutes for open radical nephrectomy and 182 minutes for laparoscopic nephrectomy. Thus, in this small subgroup, TKI therapy did not seem to have a meaningful detrimental effect on the operation itself. Before nephrectomy, TKI therapy was discontinued an average of 16 days before surgery (median 6, range 2-68). The mean hospital admission was 6 days (median 3). The individual hospital stays are detailed in Table 2. The longer hospitalizations were associated with more involved surgical procedures. At follow-up, no patient had issues with wound healing. Patients with residual measurable metastatic disease were offered to resume TKI therapy after a 2-month postoperative wound check. Tumor Response For the group as a whole, a modest (mean 12.9%, median 8%) decrease occurred in the size of the primary tumor before surgical resection. The responses in the primary tumor were quite varied, ranging from 0.82% for essentially stable disease to 54% with a partial response using the Response Evaluation Criteria in Solid Tumors. Two patients who presented with primary tumors associated with bulky retroperitoneal lymphadenopathy had substantial reductions in the size of the kidney tumor and/or lymph nodes (Fig. 1C). Because of the reduction in tumor size and, in particular, the substantial reductions in the 866
bulky lymphadenopathy, these patients were able to undergo a complete resection of all disease. Retroperitoneal lymph nodes can frequently present a difficult problem to approach, particularly when encasement of major vessels has occurred. Bulky nodal involvement can substantially impair the ability to completely resect the involved nodes with negative margins and also dramatically increases the risk of recurrence after surgery. With their initial presentation, these patients would have had to undergo surgery in which it would have been difficult or impossible to achieve complete clearance. In contrast, both were free of evidence of recurrence and not receiving systemic therapy ⬎1 year after nephrectomy. Two examples of the responses are provided in Fig. 1, demonstrating the effect of the treatment response on both the primary tumor (Fig. 1A,B; patient 1) and lymphadenopathy (Fig. 1C,D; patient 5).
COMMENT With the advent of targeted therapy for RCC, preoperative systemic therapy presents an attractive modality for treating advanced RCC for multiple reasons. First, targeted agents are better tolerated than most immunotherapeutic agents in a broader range of patients, with improved tumor response and progression-free survival, and patients remain fit for a major surgical intervention. We UROLOGY 72 (4), 2008
Figure 1. Computed tomography scans demonstrating responses in primary tumor and extrarenal tissue with preoperative treatment. (A) Pretreatment renal mass demonstrating solid mass with significant enhancement. (B) Posttreatment image of same mass demonstrating decrease in tumor size and central contrast enhancement. (C) Pretreatment renal tumor and associated large lymph node conglomerate. (D) Posttreatment image of same mass demonstrating marked improvement in lymphadenopathy and primary mass.
have observed and documented in this analysis that a substantial response can be achieved in the primary tumor, as well as in the extrarenal tissues. Provocatively, preoperative treatment could provide the opportunity for downstaging of the primary tumor itself and, perhaps, improvement of surgical resectability, thereby decreasing surgical complications, improving surgical recovery, and limiting the hospital stay. This series was limited by being a retrospective analysis of a small patient sample. However, the primary interest in conducting this analysis was to address, with a series of cases, the potential of preoperative TKI therapy for use in advanced RCC. One of the primary concerns of preoperative TKI is the potential to make conditions worse for surgical resection because of bleeding complications or poor wound healing. In this series, surgery was well tolerated with low perioperative morbidity, even though most resections were performed within 1 week after the cessation of TKI therapy. Moreover, compared with our institutional standards, the operative times and surgical approaches were not affected by the use of TKI therapy. Additional studies are needed to clarify the optimal timing of the discontinuation of the drug, especially because the half-lives for both medications differ. The half-life for sorafenib is 25-48 hours, and a long terminal clearance is characteristic.17 In contrast, sunitinib and its active metabolite have a half-life of 40-60 hours and 80-100 hours, respectively.18 UROLOGY 72 (4), 2008
CONCLUSIONS Our review of this single-institution series of patients suggests that systemic TKI therapy in advance of open or laparoscopic nephrectomy could be a potentially safe alternate use of these systemic agents. Overall, the potential for tumor downstaging, improving the surgical field, and providing the opportunity to judge the responsiveness of a patient’s tumor before committing to surgery suggest that the preoperative venue might be an ideal setting to maximize the effect of TKI therapy for RCC. These preliminary findings support at least the exploration of neoadjuvant TKI therapy in clinical trials for localized, regional, or metastatic RCC. Despite these encouraging findings, the routine use of TKIs as neoadjuvant therapy for patients who should proceed with definitive surgical resection cannot yet be recommended outside of a clinical trial. Ultimately, the outcomes of clinical trials ongoing at centers, including our own, are necessary to demonstrate a benefit calculated in reductions in recurrence or improved overall survival and a better assessment of tolerability of neoadjuvant TKI therapy. Acknowledgment. To the courageous patients and their families who made this analysis possible. References 1. American Cancer Society. Cancer facts and figures 2007. Available from: http://www.cancer.org, 2007. Accessed 9/1/2007.
867
2. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345: 1655-1659. 3. Pantuck AJ, Belldegrun AS, Figlin RA. Nephrectomy and interleukin-2 for metastatic renal-cell carcinoma. N Engl J Med. 2001; 345:1711-1712. 4. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: A randomised trial. Lancet. 2001;358:966-970. 5. Pizzocaro G, Piva L, Colavita M, et al. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: A multicentric randomized study. J Clin Oncol. 2001;19:425431. 6. Atzpodien J, Schmitt E, Gertenbach U, et al. Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: Results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer. 2005;92:843-846. 7. Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: A Cytokine Working Group randomized trial. J Clin Oncol. 2003;21: 3133-3140. 8. Bex A, Horenblas S, de Gast GC. The timing of immunotherapy and nephrectomy in multimodality treatment of metastatic renal cell carcinoma. Technol Cancer Res Treat. 2003;2:205-210. 9. Wood CG. The role of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma. Urol Clin North Am. 2003;30:581-588.
868
10. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9:327-337. 11. Wilhelm S, Chien DS. BAY 43-9006: Preclinical data. Curr Pharm Des. 2002;8:2255-2257. 12. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099-7109. 13. Escudier B, Eisen T, Stadler WM. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. 14. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007; 356:115-124. 15. Rini BI, Campbell SC. The evolving role of surgery for advanced renal cell carcinoma in the era of molecular targeted therapy. J Urol. 2007;177:1978-1984. 16. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24: 16-24. 17. Clark JW, Eder JP, Ryan D, et al. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res. 2005;11:5472-5480. 18. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24:25-35.
UROLOGY 72 (4), 2008