Pretreatment Strategies
In the absence of predictive biomarkers, investigation into the effect of targeted therapy on the pretreated primary tumor has been proposed, in order to aid in the identification of patients who may derive a benefit from CN.
Initially, cases have been described in which presurgical targeted therapy altered the surgical management of advanced RCC. A number of Phase II studies have recently been published that prospectively evaluated the clinical benefit of presurgical targeted agents in mRCC. One of the first trials reported on 50 patients with synchronous mRCC who were pretreated with bevacizumab. The outcome of presurgical treatment in this study population with high tumor burden and a large primary tumor mass was comparable to data from studies using the same agent after nephrectomy.
Pretreatment data from renal and other solid tumors revealed that sunitinib cessation as close as 24 h prior to surgery is without serious surgical adverse events. A potential size reduction of the primary tumor is most prominent in the first months of treatment, suggesting that up to three presurgical courses of sunitinib are required before an effect on downsizing can reliably be evaluated. Regardless of a modest objective RECIST response in the primary tumor, a presurgical approach with targeted therapy has several other potential benefits that may improve patient outcome. As mentioned previously, a high percentage of patients never receive systemic therapy after CN, and patients who start with targeted therapy prior to surgery may therefore have a benefit. In a multi-institutional experience, Kutikov et al. reported that 43 of 141 patients (31%) undergoing CN did not go on to receive systemic therapy due to rapid disease progression in 30%, patient refusal in 23% and perioperative death in 19%. While refusing therapy obviously reflects the individual choice of a patient, it would be of paramount importance to select out those who progress rapidly or die of surgical morbidity.
The importance of presurgical therapy for selection of patients who may not derive a benefit from additional CN has been previously evaluated in retrospective studies involving various targeted agents.
Recent OS data from a meta-analysis of two prospective Phase II studies support this paradigm, and suggest that a period of upfront sunitinib prior to planned CN may select out patients with primary refractory disease. This results in a subpopulation with a favorable outcome, which is particularly apparent in the MSKCC intermediate-risk population. Patients with a clinical benefit and intermediate MSKCC risk profile had a median OS of more than 2 years, while those with intermediate risk and progression at metastatic sites and those with poor risk irrespective of metastatic response had a median OS of <1 year. Patients with an initial poor MSKCC risk apparently did not benefit from pretreatment. It was argued that pretreatment may transfer patients from poor to intermediate risk, thereby potentially improving their outcome in combination with CN. The data from the two studies suggest that primary progression of disease at metastatic sites may further discriminate patients in combination with the surgical prognostic factors published by Culp et al.. Decrease of the primary tumor by more than 10% in largest diameter may be an additional discriminating factor predicting greater OS.
Excluding patients with progression at metastatic sites despite targeted therapy from CN makes sense, in that simply removing the primary tumor while metastatic sites progress seems counterintuitive. Approximately 20% of patients with mRCC are refractory to first-line therapy and progress rapidly. It is unlikely that these patients will benefit from upfront CN. On the other hand, there are concerns that progression of disease will occur post-sunitinib in the surgery-related treatment break. This is apparent in approximately 25% of surgical cases.
The majority of data in the presurgical setting have focused on sunitinib. More recent interim data from a Phase II study show that pazopanib also appears safe in this setting, with a toxicity profile justifying further evaluation.
To formally test the paradigm of presurgical therapy, a Phase III trial was designed to investigate the sequence of CN and systemic therapy. This prospective, randomized EORTC trial has opened in The Netherlands, Belgium, Italy, the UK and Canada, comparing immediate versus deferred CN in patients with synchronous mRCC (EORTC 30073; SURTIME) (Figure 1). The principal objective of the SURTIME trial is to investigate whether the sequence of CN influences outcome in patients who receive sunitinib for primary mRCC. While the primary end point focuses on PFS, secondary end points evaluate OS, safety and overall response to treatment. Particularly in the deferred nephrectomy arm, the proportion of patients who become unresectable and those who do not undergo CN because of progressive metastasis will be analyzed. In addition, a potential influence of CN and presurgical treatment on early disease progression will be investigated. The trial will enroll 458 patients over a 36-month period, with the final analysis performed after observation of 380 progressions or deaths and a minimum follow up of 1.5 years for all patients. In addition, tumor tissue and serum will be collected before and after pretreatment to identify genetic and protein profiles predictive of response.