Abstract
Purpose
Metastasectomy is often incorporated in the overall management of patients with metastatic renal cell carcinoma (mRCC). While this approach has been studied in the immunotherapy era, only a few cases have been described in the targeted therapy era. Therefore, we evaluated the role of metastasectomy in patients with mRCC who received prior targeted therapy.
Patients and Methods
Patients who underwent consolidative metastasectomy following targeted therapy at three institutions from 2004 to 2009 were evaluated in this retrospective study. All patients received at least one cycle of targeted therapy prior to surgical resection of all visible disease.
Results
Twenty-two patients were identified. Sites of metastasectomy included the retroperitoneum in 12 patients, lung in 6 patients, adrenal gland in 2 patients, bowel in 2 patients, and mediastinum, bone, brain, and IVC thrombus in 1 patient each. A total of 6 postoperative complications were observed in 4 patients within 12 weeks from surgery, all of which resolved with appropriate management. Postoperatively, nine patients received at least one targeted therapy. Eleven patients recurred at a median of 42 weeks from metastasectomy and another eleven patients have not experienced a recurrence at a median of 43 weeks from metastasectomy. Twenty-one patients were alive at a median follow-up of 109 weeks and one patient died of RCC 105 weeks after metastasectomy.
Conclusions
In a cohort of selected patients with limited tumor burden after treatment with targeted agents, consolidative metastasectomy is feasible with acceptable morbidity. Significant time off targeted therapy and long-term tumor-free status are possible with this approach.
Keywords: renal cell carcinoma, targeted therapy, metastasectomy
Approximately one third of patients diagnosed with renal cell carcinoma (RCC) present with metastases at initial diagnosis, and up to 40% of patients with localized RCC develop metastatic disease after radical or partial nephrectomy1, 2. Targeted therapy is the current standard of care for patients with metastatic RCC (mRCC), notable for higher objective responses, with improved tumor burden reduction and survival rates, compared to historical treatments 3-7. However, complete responses to systemic therapy alone remain extremely rare.
mRCC has long been a disease where resection of metastatic deposits can be considered in the overall management of patients8. In general, patients who undergo metastasectomy tend to have better outcomes, independent of their risk score9. In the immunotherapy era, patients with a good performance status and a solitary resectable metastasis were considered good candidates for metastasectomy. Several retrospective studies investigated the use of immunotherapy prior to metastasectomy, and reported that 24-100% of patients were free of disease 1-4 years after surgery 10-15. Kim et al10 showed a potential benefit from integration of metastasectomy and immunotherapy, as patients treated with immunotherapy who underwent a metastasectomy had better outcomes than those who achieved an initial complete or partial response to immunotherapy, but did not undergo consolidative metastasectomy.
One study has prospectively evaluated the role of metastasectomy following immunotherapy8. This study included 38 patients with mRCC treated with immunotherapy with a median follow-up of 11.1 years, all of whom had either stable disease or response after therapy. All patients underwent metastasectomy and 76% achieved NED (no evidence of disease) status after surgery. In this group, the median time to progression was 1.8 years and median survival was 4.7 years; twenty-one percent of the patients remained free of disease at last follow-up.
The high response rates to targeted therapy have expanded the pool of patients potentially eligible for metastasectomy. Patients initially not considered candidates for this approach due to number, location or anatomy of metastases, 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 metastases16. The role of metastasectomy in patients with advanced RCC achieving NED status following response to targeted therapy has not been prospectively studied.
We report the results of a multi-institutional retrospective study to evaluate 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 three academic institutions (MD Anderson Cancer Center, Cleveland Clinic Foundation, and Dana Farber Cancer Institute) from October 2004 to August 2009. Appropriate Institutional Review Board approval was obtained at each center. To be included in this study, patients had to have metastatic RCC of any histologic type, and had to have received at least one 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 computed tomography scans 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, periadrenal tissue, retroperitoneal musculature, or recurrence in the renal fossa. The lung was considered to include lung, pleura, or diaphragm. Clinical, pathological, and treatment-related data are presented in a descriptive fashion. Medians (with ranges) and means (with standard deviation) were used to summarize continuous variables.
Results
Patient demographics and disease characteristics
Twenty-two patients were included in this analysis. Demographics and baseline patient characteristics are shown in table 1. Risk stratification based on the criteria of Motzer et al 17 and Heng et al 18 is shown in table 2. All patients had a nephrectomy for RCC (21 patients had a nephrectomy prior to metastasectomy, and one patient had a nephrectomy 9 weeks after metastasectomy) and 6 patients had a prior metastasectomy, in addition to the metastasectomy of interest that followed targeted therapy. Five patients had evidence of metastases prior to nephrectomy, and 17 patients developed metastatic disease at a median of 85.3 weeks (range, 13.0-1152.3) after nephrectomy, with 11 of the 17 developing metastases one year or later after nephrectomy.
Table 1. Patient demographics and tumor characteristics.
| Variable | Number of patients | Percentage (%) |
|---|---|---|
| Total number of patients | 22 | 100 |
|
| ||
| Age (years) | ||
| Median, range | 55.5 | 41-71 |
| Mean, standard deviation | 56.9 | 9.4 |
|
| ||
| Gender | ||
| Male | 19 | 86.4 |
| Female | 3 | 13.6 |
|
| ||
| Race | ||
| White | 17 | 77.3 |
| Hispanic | 3 | 13.6 |
| Black | 2 | 9.1 |
|
| ||
| Nephrectomy | ||
| Right | 11 | 50.0 |
| Left | 11 | 50.0 |
|
| ||
| Stage at initial RCC diagnosis | ||
| T2 | 5 | 22.7 |
| T3a | 7 | 31.9 |
| T3b | 7 | 31.9 |
| T4 | 1 | 4.5 |
| Tx | 2 | 9 |
|
| ||
| Nodes at initial RCC diagnosis | ||
| N0 | 5 | 22.7 |
| N1/2 | 3 | 13.6 |
| Nx | 14 | 63.7 |
|
| ||
| Metastasis at initial RCC diagnosis | ||
| M0 | 8 | 36.4 |
| M1 | 5 | 18.2 |
| Mx | 9 | 45.4 |
|
| ||
| Histology at nephrectomy | ||
| Clear cell | 15 | 68.2 |
| Papillary | 2 | 9.1 |
| Chromophobe | 2 | 9.1 |
| Unclassified | 2 | 9.1 |
| Unknown | 1 | 4.5 |
|
| ||
| Fuhrman grade at nephrectomy | ||
| 1 | 1 | 4.5 |
| 2 | 2 | 9.1 |
| 3 | 9 | 40.9 |
| 4 | 7 | 31.8 |
| Unknown | 3 | 13.6 |
|
| ||
| Sarcomatoid elements at nephrectomy | ||
| Yes | 2 | 9.1 |
| No | 18 | 81.8 |
| Unknown | 2 | 9.1 |
|
| ||
| Histologic necrosis at nephrectomy | ||
| Yes | 3 | 13.6 |
| No | 17 | 77.3 |
| Unknown | 2 | 9.1 |
|
| ||
| History of radiation therapy | ||
| Yes (all brain) | 4 | 18.2 |
| No | 18 | 81.8 |
Table 2. Patient risk classification.
| Motzer et al criteria | Heng et al criteria | |||
|---|---|---|---|---|
| Risk Classification | At first systemic therapy | At time of metastasectomy | At first systemic therapy | At time of metastasectomy |
| Good | 4 | 4 | 6 | 5 |
| Intermediate | 13 | 10 | 11 | 11 |
| Poor | 0 | 0 | 2 | 1 |
| Missing | 5 | 8 | 3 | 5 |
Preoperative targeted therapy
Therapies administered prior to metastasectomy are summarized in table 3. Seventeen patients received only 1 preoperative therapy and 5 patients received two preoperative therapies each. The median duration of preoperative therapy was 45.6 weeks (range, 11.7-177.0) and the median time from last dose of preoperative therapy to metastasectomy was 27 days (range, 3-103). While on targeted therapy and prior to metastasectomy, 4 patients had a partial response, 11 patients had stable disease, and 4 patients had progressive disease (increase in the size of index lesion without development of new metastases), per RECIST (REsponse Criteria In Solid Tumors) (information was incomplete for 3 patients)19.
Table 3. Therapies received preoperatively and postoperatively.
| Therapy | Number of therapies given: | |
|---|---|---|
| Preoperatively | Postoperatively | |
| Sunitinib | 10 | 5 |
|
| ||
| Sorafenib | 5 | 3 |
|
| ||
| Bevacizumab + interleukin-2 | 3 | 0 |
|
| ||
| Sorafenib + interferon alfa | 3 | 0 |
|
| ||
| Bevacizumab | 1 | 1 |
|
| ||
| Bevacizumab + erlotinib | 1 | 0 |
|
| ||
| Bevacizumab + sunitinib | 1 | 0 |
| Interleukin-2 | 1 | 0 |
|
| ||
| ABT-510 | 1 | 0 |
|
| ||
| Foretinib | 1 | 0 |
| Everolimus | 0 | 4 |
| Sunitinib + gemcitabine | 0 | 2 |
|
| ||
| Pazopanib | 0 | 1 |
Metastasectomy
Details about surgery-related parameters are shown in table 4. Median time from diagnosis of metastatic disease to performing the metastasectomy was 61 weeks (range, 15-259). Sites of metastasectomy included the retroperitoneum in 12 patients, lung in 6 patients, adrenal gland in 2 patients, bowel in 2 patients, and mediastinum, bone, brain, and IVC thrombus in 1 patient each. Four patients underwent metastasectomy at more than one site. At pathologic evaluation of the metastasectomy specimen, 20 patients had viable tumor while 2 patients had no evidence of tumor. These two patients did not have a preoperative biopsy of the metastases due to the location of the masses; however both had radiographic growth of the masses during observation. In addition, the masses decreased in size with targeted therapy, and pathologic evaluation of the metastasectomy specimen revealed fibrosis and/or necrosis consistent with treatment effect. One patient had a microscopic positive margin after resection of retroperitoneal metastases.
Table 4. Metastasectomy operative parameters.
| Parameter | Value |
|---|---|
| Estimated blood loss (median, range in cc) | 475 (0-3000) |
|
| |
| Operative duration (median, range in minutes) | 210 (77-425) |
|
| |
| Length of hospital stay (median, range in days) | 6 (1-17) |
|
| |
| Number of patients transfused | 5 |
|
| |
| Size of metastasis (median, range in cm) | 3 (1-12) |
|
| |
| Positive surgical margin | |
| Microscopic | 1 |
| Macroscopic | 0 |
|
| |
| Intraoperative complications | |
| Cavotomy | 1 |
|
| |
| Postoperative complications | |
| Chylous ascites | 4 |
| Atrial fibrillation | 1 |
| Ileus | 1 |
Perioperative complications
A total of 6 postoperative complications (4 chylous ascites, 1 atrial fibrillation, and 1 ileus) were observed in 4 patients within 12 weeks from surgery, all of which resolved with appropriate management. There were no bleeding, thromboembolic, or wound complications noted within this period. One patient experienced 3 of these complications (chylous ascites, ileus and atrial fibrillation). This patient had an intraperitoneal drain placed during surgery, which was kept in place until the ascites resolved. He also received octreotide and total parenteral nutrition. The atrial fibrillation was transient, with no etiology found, and no treatment was needed. The three other patients experienced chylous ascites (1 patient had a drain placed intraperitoneally during surgery, and 2 patients required temporary percutaneous paracentesis). One patient had an intraoperative cavotomy that was repaired by primary closure with no sequelae. There were no perioperative deaths.
Outcomes
All 22 patients were rendered tumor-free after metastasectomy. Twenty-one patients were alive at a median follow-up of 109 weeks (range, 10-283) after metastasectomy and one patient died of RCC 105 weeks after metastasectomy. Eleven patients (50%) have not experienced tumor recurrence at a median of 43 weeks from metastasectomy (range, 10-197). The other eleven patients (50%) developed tumor recurrence during the study period at a median of 42 weeks from metastasectomy (range, 6-145): three patients had both distant and local recurrences, seven patients had distant recurrences only, and one patient had local recurrence only. Ten patients had evidence of disease at last follow-up (median follow-up of 108 weeks; range, 18-283). Of note, a patient with a microscopic positive surgical margin after resection of retroperitoneal disease is currently alive at 138 weeks from metastasectomy without tumor recurrence and without postoperative therapy. There was no correlation between response by RECIST and disease recurrence.
Postoperative targeted therapy
Postoperatively, 9 patients received at least one targeted therapy (5 sunitinib, 2 sorafenib, 2 everolimus). Eight of these patients restarted targeted therapy at disease recurrence and one patient restarted therapy 2 weeks postoperatively with no evidence of recurrence at the time. Six patients received a second postoperative targeted therapy at last follow-up (2 sunitinib + gemcitabine, 1 everolimus, 1 sorafenib, 1 pazopanib, 1 bevacizumab). Five patients received the same therapeutic agent, and four patients received a different drug postoperatively. The median time to initiate targeted therapy after metastasectomy was 55.3 weeks (range, 2-226.7).
Discussion
To our knowledge, we report the largest experience detailing the presentation and outcomes of patients with mRCC treated in a multimodality setting with targeted therapy and metastasectomy. Twenty-one of the 22 patients were alive, and half of them were disease-free at the time of analysis. In addition, half of the patients did not receive any systemic therapy after metastasectomy. Four patients underwent surgery in the presence of 2 metastatic sites. While we typically advocate metastasectomy in the setting of solitary metastases, these patients were counseled to undergo surgery as their metastases were in close anatomical locations (amenable to surgery at the same time), and they did not experienced new metastases while on therapy. Complications were noted in 18% of the patients, but were reversible with the appropriate management, and no perioperative deaths were observed.
The use of preoperative targeted therapy in patients with advanced RCC has been retrospectively studied by several groups. Thomas et al20 studied nineteen patients deemed to have unresectable disease who were treated with sunitinib: 11% had a partial response, 37% had stable disease and no complete responses were noted. Four patients (21%) subsequently underwent a nephrectomy, with no unexpected surgical morbidity. Margulis et al21 compared 44 patients treated with targeted therapy prior to cytoreductive nephrectomy with a contemporary cohort of 58 patients who underwent only cytoreductive nephrectomy and did not find any significant difference in the rate of complications postoperatively (39% versus 28%, respectively, p=0.28). In contrast, Jonasch et al22 reported a prospective phase II presurgical trial of 8 weeks of bevacizumab with or without erlotinib in 50 patients with mRCC. Bevacizumab therapy was stopped 4 weeks prior to surgery. Forty-two patients who did not demonstrate 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 discontinuation of bevacizumab-based therapy. More recently, Cowey et al23 conducted a prospective trial of 1 month of preoperative sorafenib in 30 patients with RCC (17 with localized disease and 13 with metastases). Of the 28 evaluable patients, 2 had a partial response and 26 had stable disease. All patients underwent cytoreductive nephrectomy as planned. Postoperatively, one patient had a myocardial infarction and another patient experienced superficial wound breakdown that was managed conservatively. No delayed wound healing, excessive bleeding or surgical dehiscences were noted. These trials demonstrate the feasibility of pre-operative targeted therapy, but do not specifically address resection of metastatic disease.
Only a few studies have investigated the role of targeted therapy prior to resection of metastatic disease. Rini et al16 described 2 patients who achieved tumor burden reduction with sunitinib therapy, and had subsequent metastasectomy with long-term responses. Thomas et al24 described their experience in 19 patients who underwent 21 operations (9 had radical nephrectomy, 3 had partial nephrectomy, 6 had resection of local recurrence and 3 had metastasectomy) and experienced partial response or stable disease with targeted therapy prior to surgery. These investigators found that such approach was feasible and relatively safe. At the time of reporting, 16 patients were alive at a median follow up of 8 months, including 8 patients with disease progression. Major complications occurred in 3 patients and included death in 1 patient due to disseminated intravascular coagulation associated with partial hepatectomy, anastomotic bowel leak in 1 patient, and dialysis for 10 months in another patient. Two minor complications were also noted in patients who did not receive postoperative targeted therapy, and included a wound seroma and a ventral hernia.
In the present analysis, complications occurred exclusively in the patients who underwent retroperitoneal surgery. Caution must be exercised during these surgeries, because postoperative adhesions and anatomical distortions are typically encountered in the original field of nephrectomy. Careful hemostasis and lymphostasis are required in these particular cases to avoid the occurrence of chylous ascites. In addition, it has been reported that use of targeted therapies can obliterate normal tissue planes, rendering surgery more difficult25. In this small series, we did not observe any excessive bleeding or arterial or venous thromboembolic events during the study period, but investigators have to be cautioned about the increased risk of vascular complications during treatment with anti-VEGF therapies26, 27. A recent review extensively discussed the use of preoperative targeted therapy in a multitude of cancers and concluded that the available data are not sufficient to make general recommendations on their use in the perioperative setting. In addition, the authors called for careful use of these agents prior to surgery and for further study in a prospective fashion to further elucidate their safety profile in the presurgical setting28.
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 or not, 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. One potential advantage of treating selected patients with targeted therapy prior to metastasectomy is that this approach could act as a litmus test for patients who already have a metastasis and are at risk of developing further metastases. As such, most patients who develop metastases while on targeted therapy would no longer be eligible for surgery.
Our report has some limitations. First, although this is the largest experience investigating targeted therapy prior to metastasectomy, it is a retrospective study that included a small number of patients with a relatively short follow-up. Second, metastasectomy was performed in different organ systems and was selected on an individual basis. Third, the type and duration of targeted therapy prior to metastasectomy were not prospectively standardized.
Conclusion
In this report, we demonstrated that in a cohort of selected patients with limited tumor burden after treatment with targeted therapy, consolidative metastasectomy is feasible with acceptable morbidity. Metastasectomy was well tolerated, and half the patients had no evidence of disease at last follow-up. Significant time off targeted therapy and the potential for a durable remission may be achievable with this approach. A longer follow up of the current patient cohort and a prospective trial evaluating upfront targeted therapy followed by metastasectomy will be necessary before recommending this multimodality approach for the routine care of patients with mRCC.
Abbreviations
- RCC
renal cell carcinoma
- mRCC
metastatic renal cell carcinoma
- NED
no evidence of disease
Footnotes
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References
- 1.Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol. 2001;166:1611. [PubMed] [Google Scholar]
- 2.Flanigan RC. Debulking nephrectomy in metastatic renal cancer. Clin Cancer Res. 2004;10:6335S. doi: 10.1158/1078-0432.CCR-sup-040026. [DOI] [PubMed] [Google Scholar]
- 3.Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115. doi: 10.1056/NEJMoa065044. [DOI] [PubMed] [Google Scholar]
- 4.Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125. doi: 10.1056/NEJMoa060655. [DOI] [PubMed] [Google Scholar]
- 5.Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271. doi: 10.1056/NEJMoa066838. [DOI] [PubMed] [Google Scholar]
- 6.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. Lancet. 2008;372:449. doi: 10.1016/S0140-6736(08)61039-9. [DOI] [PubMed] [Google Scholar]
- 7.Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103. doi: 10.1016/S0140-6736(07)61904-7. [DOI] [PubMed] [Google Scholar]
- 8.Daliani DD, Tannir NM, Papandreou CN, et al. Prospective assessment of systemic therapy followed by surgical removal of metastases in selected patients with renal cell carcinoma. BJU Int. 2009;104:456. doi: 10.1111/j.1464-410X.2009.08490.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Eggener SE, Yossepowitch O, Kundu S, et al. Risk score and metastasectomy independently impact prognosis of patients with recurrent renal cell carcinoma. J Urol. 2008;180:873. doi: 10.1016/j.juro.2008.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Kim B, Louie AC. Surgical resection following interleukin 2 therapy for metastatic renal cell carcinoma prolongs remission. Arch Surg. 1992;127:1343. doi: 10.1001/archsurg.1992.01420110091018. [DOI] [PubMed] [Google Scholar]
- 11.Krishnamurthi V, Novick AC, Bukowski RM. Efficacy of multimodality therapy in advanced renal cell carcinoma. Urology. 1998;51:933. doi: 10.1016/s0090-4295(98)00033-8. [DOI] [PubMed] [Google Scholar]
- 12.Pogrebniak HW, Haas G, Linehan WM, et al. Renal cell carcinoma: resection of solitary and multiple metastases. Ann Thorac Surg. 1992;54:33. doi: 10.1016/0003-4975(92)91136-w. [DOI] [PubMed] [Google Scholar]
- 13.Sella A, Swanson DA, Ro JY, et al. Surgery following response to interferon-alpha-based therapy for residual renal cell carcinoma. J Urol. 1993;149:19. doi: 10.1016/s0022-5347(17)35986-4. [DOI] [PubMed] [Google Scholar]
- 14.Sherry RM, Pass HI, Rosenberg SA, et al. Surgical resection of metastatic renal cell carcinoma and melanoma after response to interleukin-2-based immunotherapy. Cancer. 1992;69:1850. doi: 10.1002/1097-0142(19920401)69:7<1850::aid-cncr2820690729>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- 15.Tanguay S, Swanson DA, Putnam JB., Jr Renal cell carcinoma metastatic to the lung: potential benefit in the combination of biological therapy and surgery. J Urol. 1996;156:1586. doi: 10.1016/s0022-5347(01)65454-5. [DOI] [PubMed] [Google Scholar]
- 16.Rini BI, Shaw V, Rosenberg JE, et al. Patients with metastatic renal cell carcinoma with long-term disease-free survival after treatment with sunitinib and resection of residual metastases. Clin Genitourin Cancer. 2006;5:232. doi: 10.3816/CGC.2006.n.042. [DOI] [PubMed] [Google Scholar]
- 17.Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289. doi: 10.1200/JCO.2002.20.1.289. [DOI] [PubMed] [Google Scholar]
- 18.Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27:5794. doi: 10.1200/JCO.2008.21.4809. [DOI] [PubMed] [Google Scholar]
- 19.Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205. doi: 10.1093/jnci/92.3.205. [DOI] [PubMed] [Google Scholar]
- 20.Thomas AA, Rini BI, Lane BR, et al. Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma. J Urol. 2009;181:518. doi: 10.1016/j.juro.2008.10.001. [DOI] [PubMed] [Google Scholar]
- 21.Margulis V, Matin SF, Tannir N, et al. Surgical morbidity associated with administration of targeted molecular therapies before cytoreductive nephrectomy or resection of locally recurrent renal cell carcinoma. J Urol. 2008;180:94. doi: 10.1016/j.juro.2008.03.047. [DOI] [PubMed] [Google Scholar]
- 22.Jonasch E, Wood CG, Matin SF, et al. Phase II presurgical feasibility study of bevacizumab in untreated patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:4076. doi: 10.1200/JCO.2008.21.3660. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Cowey CL, Amin C, Pruthi RS, et al. Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J Clin Oncol. 2010;28:1502. doi: 10.1200/JCO.2009.24.7759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Thomas AA, Rini BI, Stephenson AJ, et al. Surgical resection of renal cell carcinoma after targeted therapy. J Urol. 2009;182:881. doi: 10.1016/j.juro.2009.05.014. [DOI] [PubMed] [Google Scholar]
- 25.Shuch B, Riggs SB, LaRochelle JC, et al. Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm. BJU Int. 2008;102:692. doi: 10.1111/j.1464-410X.2008.07660.x. [DOI] [PubMed] [Google Scholar]
- 26.Je Y, Schutz FA, Choueiri TK. Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol. 2009;10:967. doi: 10.1016/S1470-2045(09)70222-0. [DOI] [PubMed] [Google Scholar]
- 27.Choueiri TK, Schutz FA, Je Y, et al. Risk of Arterial Thromboembolic Events With Sunitinib and Sorafenib: A Systematic Review and Meta-Analysis of Clinical Trials. J Clin Oncol. 2010 doi: 10.1200/JCO.2009.27.2757. [DOI] [PubMed] [Google Scholar]
- 28.Bose D, Meric-Bernstam F, Hofstetter W, et al. Vascular endothelial growth factor targeted therapy in the perioperative setting: implications for patient care. Lancet Oncol. 2010;11:373. doi: 10.1016/S1470-2045(09)70341-9. [DOI] [PubMed] [Google Scholar]