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This educational proceedings publication is based on a symposium held on June 27-28, 2008, in Cambridge, Massachusetts.
Although upfront cytoreductive nephrectomy followed by systemic therapy remains the standard of care for metastatic renal cell carcinoma, the addition of novel targeted therapy has prompted a reevaluation of this treatment paradigm. The authors reviewed their experience with neoadjuvant systemic therapy administered before cytoreductive surgery for metastatic, locally recurrent, or regionally advanced renal cell carcinoma.
The authors compared patients treated with presurgical targeted therapy (with sunitinib, sorafenib, or bevacizumab) with a contemporary group that underwent up-front cytoreductive surgery.
The authors found no difference in any perioperative surgical parameters indicative of morbidity or mortality between the 2 groups. Laboratory models of renal cell carcinoma treated with systemic targeted therapy demonstrate specific protein expression profiles that correlate with response to therapy and the development of therapy resistance.
Surgery remains an integral part of the treatment of renal cell carcinoma in all stages of the disease. Resection followed by risk-based surveillance is the standard of care for localized and locally advanced disease. Cytoreductive nephrectomy (CN), followed by the timely administration of systemic therapy, is considered the standard of care for patients who present with metastases.1, 2 Randomized trials have demonstrated a survival advantage for patients who undergo cytoreductive surgery before the administration of immunotherapy, and the practice has largely been extended into the era of targeted therapy, in the absence of evidence-based data that would suggest control of the primary tumor in the setting of metastatic disease is no longer paramount.3, 4 Furthermore, metastasectomy, either as a primary therapy for a limited metastatic burden or as part of a surgical consolidation strategy after a partial response to systemic therapy, has also been associated with an improved prognosis.5
Despite extensive and intensive clinical research, the proper integration of surgery with systemic therapy remains elusive and problematic. To our knowledge, in the year 2008, there remains no effective adjuvant agent in the setting of locally advanced disease at high risk of recurrence after surgical therapy, despite extensive clinical studies evaluating the role of such agents as interferon, interleukin-2, chemotherapy, tumor vaccines, and hormones.6, 7 Current adjuvant strategies are focused on the role of the tyrosine kinase inhibitors sunitinib and sorafenib in ongoing clinical trials. In the setting of metastatic disease, despite the demonstrated improvement in survival associated with CN before systemic therapy, there remain a small but significant subset of patients who demonstrate either rapid progression of their metastatic disease in the postoperative period or a therapy-refractory phenotype; not only do these patients not derive benefit from control of their primary tumor, but the surgery also appears to hasten their demise because of excessive morbidity.8
Neoadjuvant or presurgical therapy is a novel therapeutic strategy that is now being investigated in the treatment of renal cell carcinoma in conjunction with the development of targeted molecular therapy that affects specific angiogenic and growth factor pathways important in renal cell carcinoma biology.9, 10 In part predicated on the success of this paradigm in other malignancies (such as colorectal, pancreatic, and urothelial cancers), presurgical therapy has the potential to provide real-time clinical feedback on the responsiveness of the patient's overall tumor burden to a given systemic therapy before committing the patient to what could be a highly morbid surgical procedure. Other potential benefits of this approach include local tumor down-staging, which may make subsequent surgical extirpation less morbid, and, in the case of locally advanced renal cell carcinoma, presurgical therapy, which may eliminate micrometastatic disease at its earliest stage, thus diminishing the risk of metastatic progression postoperatively. Potential detractions from the presurgical systemic therapy approach include the possibility that treatment-related morbidity may add to the complexity of the surgical procedure, increase the risk of perioperative morbidity and/or mortality, and, in the case of localized or locally advanced disease, unnecessarily delay potentially curative surgery in a nonresponding patient.
Herein, we review the published experience with presurgical targeted therapy before surgical resection of renal cell carcinoma at the University of Texas M. D. Anderson Cancer Center and elsewhere, with specific attention to safety, perioperative morbidity and mortality, local tumor effects, and outcomes. Furthermore, we report on interim results of ongoing translational experiments that examine the impact of targeted therapy response and resistance on tumor protein expression, with an eye toward the identification of novel molecular pathways that might prove important for therapeutic targeting in the salvage setting.
MATERIALS AND METHODS
By using an approved protocol through our institutional review board, we reviewed the perioperative clinical experience in patients at our institution undergoing surgery for renal cell carcinoma (recurrent disease or CN) after presurgical systemic therapy with targeted molecular agents (bevacizumab, sunitinib, sorafenib). These patients were matched to a contemporary cohort of patients undergoing CN or resection of recurrence, without receiving presurgical therapy. Parameters for the 2 groups that were examined and compared included length of presurgical systemic therapy, time from cessation of therapy to surgery, and type of therapy. Perioperative parameters that were examined included surgical time, blood loss, transfusion requirements, perioperative morbidity and mortality, and length of hospital stay. In patients undergoing CN as part of their treatment for metastatic renal cell carcinoma, survival outcomes between the 2 groups were also examined. In addition, as part of this review and presentation, we examined the published literature regarding the use of presurgical therapies in the treatment of renal cell carcinoma for localized, locally advanced, recurrent, and metastatic disease, to identify factors that might predict successful outcomes from the use of this approach.
The 44 patients treated with presurgical targeted agents and the 58 patients who underwent initial surgical resection were followed up for 12.1 months and 11.1 months, respectively, and were identically matched in terms of their clinical characteristics, burden of metastatic disease, and number of adverse prognostic factors.11 We found no significant differences between study groups in the type and length of surgical procedure, extent of lymph node dissection, estimated blood loss, incidence of blood transfusions, amount of blood products administered, or the length of hospital stay. In addition, a similar proportion of patients in each group received postsurgical systemic therapy. A total of 39 complications occurred in 33 (32.4%) of the study patients. There was no perioperative mortality, and we observed no statistically significant differences in the incidence of re-exploration; readmission; or thromboembolic, cardiovascular, pulmonary, gastrointestinal, infectious, or incision-related complications among patients treated with presurgical targeted molecular therapy and patients who underwent initial surgery. The results of a logistic regression analysis confirmed that presurgical targeted molecular therapy was not associated with increased perioperative mortality or morbidity. We evaluated numerous clinical variables, including patient age (10-year increments), sex, body mass index (<30 or >30 kg/m2), Eastern Cooperative Oncology Group performance status, number of Memorial-Sloan Kettering Cancer Center risk criteria, presurgical targeted therapy (bevacizumab or sunitinib/sorafenib), duration of presurgical therapy (1-week increments), interval between discontinuation of therapy and CN (1-week increments), intraoperative blood loss (200-mL increments), use of blood products, duration of surgery (1-hour increments), type of surgical procedure, and interval between CN and postsurgical systemic therapy (1-week increments), and found that only estimated blood loss of >1200 mL was associated with the occurrence of a complication after CN.
At the time of last follow–up, 8 (18.2%) of the 44 patients treated with presurgical targeted therapy and 18 (31.0%) of the 58 patients treated with initial surgery had died of renal cell carcinoma. Kaplan-Meier analysis revealed similar median cancer-specific survival among patients treated with presurgical targeted molecular therapies and patients treated with up-front CN (27.7 months vs 31.0 months; P = .697) (Fig. 1).
Current and potential future indications for presurgical therapy in the setting of locally advanced and metastatic renal cell carcinoma are listed in Table 1. There is no debate that patients who have unresectable disease are poor surgical candidates based on disease phenotype or presence of comorbid conditions or that those who refuse surgery have absolute indications for this approach. Patients with locally advanced disease, as well as those with adjacent organ involvement, tumor thrombi, or clinical evidence of regional lymph node metastases, could also potentially benefit from presurgical therapy in an attempt to surgically down-stage their disease and eliminate micrometastatic disease before surgery. In the setting of metastatic renal cell carcinoma, presurgical therapy offers the opportunity to confirm disease response to systemic therapy before committing the patient to a potentially morbid intervention. Aside from 2 case report series that describe tumor thrombi reduction in response to presurgical therapy, to our knowledge there are few studies in the literature regarding the primary tumor response to targeted therapy.12, 13 In a small series of 17 patients, van der Veldt et al14 reported that 4 patients achieved a partial response, 12 had stable disease, and 1 demonstrated disease progression. Overall, a volume reduction of 31% was noted in the primary tumor of responding patients.
Table 1. Potential Applications for Presurgical Targeted Therapy in the Management of Renal Cell Carcinoma
Locally advanced primary tumor
Large tumor in a solitary renal unit
Extensive bilateral tumors
Renal fossa recurrence
Metastatic renal cell carcinoma
Before cytoreductive nephrectomy
Before metastasectomy (surgical consolidation)
It is clear that both surgery and systemic therapy have a role in the management of locally advanced and metastatic renal cell carcinoma, but the proper integration of these 2 treatment modalities remains undefined. In the setting of locally advanced disease, the development of an effective systemic therapy that diminishes the risk of disease recurrence in conjunction with extirpative surgery remains elusive. To our knowledge to date, none of the systemic therapies that have demonstrated activity in the setting of metastatic disease has proved to be an effective and reliable adjuvant.6, 7 In the setting of metastatic disease, up-front CN followed by the administration of systemic therapy has been established as the standard of care, but in large part this treatment paradigm has developed as a consequence of the real lack of effective systemic therapies available in the past and the reality that the primary tumor rarely, if ever, responded to systemic therapy in conjunction with metastatic foci.15 With the development and implementation of targeted molecular therapy that can meaningfully affect the biology of both the primary tumor and metastases, the playing field has changed and, as a consequence, treatment paradigms must be reexamined.
The concept of neoadjuvant or presurgical therapy is an attractive treatment paradigm for many reasons. With the primary tumor left in situ during the administration of systemic therapy, there is real-time feedback provided on disease response to the selected treatment, which may allow adjustments in therapy (change to a different therapy, combine agents) to ensure maximal response. Locally advanced primary tumors may be down-staged, resulting in less morbid surgery and improved local control. In concert, patients not responding to systemic therapy can be “spared” highly morbid surgical interventions that have no hope of improving outcome. Lastly, tumor tissue, harvested at the time of surgery, can be rigorously interrogated with translational research techniques both to evaluate the effects of systemic therapy at a molecular level and to provide clues regarding pathways of resistance and novel therapeutic targets.
With that said, the presurgical paradigm must be rigorously tested in the context of clinical trials before being widely implemented. The potential delay in curative surgery for patients with localized and locally advanced disease must be measured against the potential benefits of presurgical therapy. The not insignificant toxic effects associated with the administration of targeted molecular therapy may result in the “deconditioning” of an otherwise fit surgical patient. The impact of therapy on perioperative morbidity and mortality must also be measured, because there is the potential for significant complications that might otherwise not be realized.
The available body of literature, which to our knowledge is modest at present, would suggest that the application of presurgical therapy is, at the very least, safe.11 In our retrospective series of patients undergoing CN or surgery for recurrent disease, the addition of presurgical targeted molecular therapy did not add to perioperative morbidity or mortality, even when administered up to the day before surgery, as was the case with some of the patients who received presurgical sunitinib. In particular, concerns regarding surgical site and wound healing appear unfounded based on our retrospective study, although surgical procedures that include an anastomosis (eg, enteric, vascular) were not evaluated in our study and need further consideration. Although this presurgical experience awaits prospective validation from ongoing clinical trials, it would appear from our retrospective analysis that a more important factor that would predict morbidity may be the time to resumption of therapy after surgery as opposed to the date of termination before surgery.
Although not a focus of our retrospective series, another purported benefit of presurgical therapy is the potential for primary tumor down-staging. The literature contains several, mostly anecdotal, case studies or small series that demonstrate primary tumor regression in response to targeted molecular therapy.12-14 These include reductions in tumor dimension and regression of tumor thrombi within the vena cava. Clinical response rates of approximately 31% have been cited in initial reports, although it remains unclear what impact, if any, these responses had on perioperative morbidity and ease of surgical resection. Although it is intriguing to consider the utilization of targeted molecular therapy as an adjunct to make the “unresectable” become resectable or to promote the regression of regionally advanced (atrial) tumor thrombi to the point that would obviate the need for cardiopulmonary bypass support, further study, in the context of clinical trials with informed patient consent, is necessary to confirm the utility of this approach. Particular attention should be focused on the treatment of tumor thrombi, because it is equally plausible to consider that instead of regression, necrosis and embolization of the pulmonary vasculature could be a possible consequence of presurgical therapy.
In the setting of metastatic renal cell carcinoma, the true benefit of presurgical therapy may be realized in patients who never see the inside of an operating room. Retrospective series that report on up-front CN all note a percentage of patients who do not receive systemic therapy because of rapid disease progression postoperatively or surgical morbidity or mortality. With a presurgical approach, only those patients who demonstrate response to therapy and remain good operative candidates would undergo surgery. Patients with treatment-refractory disease could be spared a highly morbid surgical procedure that is unlikely to affect their outcome.
Tissue, blood, and urine specimens harvested from patients treated with presurgical therapy can be used for translational research to confirm that the targeted therapy hits its target, examine downstream effects, and also search for novel molecular pathways that have not yet been exploited for therapeutic benefit. These and other studies that are focused on the identification and characterization of tissue-based, serum-based, and blood-based molecular markers that may predict response to a given therapy and patient outcome are the subject of intense investigation at the University of Texas M. D. Anderson Cancer Center and other institutions. In addition, we have developed xenograft models of human clear cell renal cell carcinoma from resected specimens, in which we have further evaluated the molecular changes in tumors that are associated with a response to targeted molecular therapy and the development of a resistant phenotype. Findings in these in vivo models, when correlated with findings from specimens harvested in our clinical research studies evaluating presurgical therapy, may translate into the rapid identification, characterization, and implementation of meaningful biomarkers associated with tumor response and patient outcome.
Neoadjuvant (presurgical) therapy is a novel treatment strategy for locally advanced and metastatic renal cell carcinoma that is worthy of further development. Initial experiences suggest that it is safe, with no increased risk of surgical morbidity or wound complications. Future presurgical studies in the locally advanced setting should focus on local tumor down-staging and effects on recurrence-free survival after surgery. In the setting of metastatic renal cell carcinoma, presurgical approaches can serve as a litmus test to reserve CN for only those who stand to benefit from the procedure. Finally, translational correlative studies with tissue harvested from patients treated with presurgical therapy will provide molecular readouts on the effectiveness of a given therapy on the tumor and perhaps provide clues toward novel molecular pathways that may emerge with therapy resistance.
The questions and discussion below follow from the oral presentation given at the Third Cambridge Conference on Innovations and Challenges in Renal Cancer and do not correspond directly to the written article, which is a more general review.
Dr. Michael Atkins: Do you have other data that show tissue findings and link those with changes in the tumor size, changes in imaging, or changes in blood?
Dr. Christopher G. Wood: Those studies are ongoing, but they appear to be able to allow us to predict who is responding to therapy and who is not.
Dr. W. Marston Linehan: Did you have trouble with wound healing?
Dr. Wood: No.
Dr. Brian Rini: Do you have a standard for when to restart therapy after surgery?
Dr. Wood: We start sunitinib approximately 1 month after surgery and bevacizumab a month after surgery.
Dr. Linehan: You do think that has affected your surgery much ?
Dr. Wood: It really has not. Recently, we have been operating more on patients who have received mTOR inhibitors, and there seems to be more of a desmoplastic reaction with the mTOR inhibitors compared with the VEGF inhibitors. I don't know whether that will pan out with subsequent surgeries.
Dr. David F. McDermott: What do you think should be the next adjuvant trial?
Dr. Wood: Axitinib.
Dr. Robert Figlin: It is hard to anticipate what the next trial should be in the absence of some information about the current 1800-patient trial. One option would be to join the sunitinib versus nothing trial that is international and finish that while you let things evolve.
Dr. Jeffrey Sosman: I would be concerned about moving forward quickly with subsequent trials without some idea of the dangers of giving a year of antiangiogenic therapy and then stopping. Conversely, it is going to be a long time from that trial.
Conflict of Interest Disclosures
The program was made possible by educational grants provided by Genentech, Novartis Pharmaceuticals, Pfizer, Inc., and Wyeth Pharmaceuticals. Program management and CME sponsorship were provided by InforMEDical Communications, Inc., Carlisle, Massachusetts.
Dr. Wood has served as a consultant for Bayer/Onyx; has served as consultant and received honoraria from Antigenics, Bristol-Myers Squibb, Ethicon, and Pfizer; and is a member of the Speaker's Bureau for Bayer/Onyx and Pfizer.