MADRID, SPAIN (UroToday.com) - Dr. Axel Bex from the Netherlands Cancer Institute presented his state-of-the-art-lecture on the role of neoadjuvant/adjuvant therapy in advanced and metastatic renal cell carcinoma (RCC).
The results of several adjuvant randomized clinical trials with cytokines (IFN-alpha, HD IL-2, IL-2/IF-alpha) vs control have all been negative. There have been about 6 phase III adjuvant trials currently—S-TRAC, ASSURE, SORCE, EVEREST, PROTECT, and ATLAS. Of these, the ASSURE trial reported results recently while the remainder are ongoing. Unfortunately, the ASSURE trial did not report any benefit in disease-free survival or overall survival using sunitinib or sorafenib. Dr. Bex reported that several other subgroup analyses also showed no benefit.
Is there a possibility of a neoadjuvant phase III trial with disease-free survival or overall survival as an end point? Dr. Bex states that this is a challenge and no desire currently exists. Neoadjuvant therapy would delay definite surgical treatment in patients with localized RCC who can principally be curable by surgery alone. Additionally, negative adjuvant trials do not support a rationale for neoadjuvant approach to influence DFS or OS. Additionally, there has been no demonstrable downstaging reported with neoadjuvant therapy. Significant or relevant pathological complete remission in primary tumors or metastases has never been reported.
Therefore, the interest in neoadjuvant therapy currently lies in possibly downsizing locally advanced disease. The question is whether locally confined renal masses can be downsized to allow nephron-sparing surgery in patients who would otherwise be candidates for nephrectomy. Additionally, do locally infiltrative renal tumors become more amenable to nephrectomy when they are otherwise not operable? Dr. Bex then showed a table of several TKIs, which have been investigated to have an effect on downsizing. Of these, sunitinib has been shown to have a reduction in diameter by about 10-20%. Axitinib has been shown to have a reduction in diameter in about 30%.
However, do these reductions in size translate into improved resectability? This is difficult to assess. First, there is positive selection bias in reporting successful approaches. Second, it is questionable if downsizing of large locally advanced tumors by 10-30% eases surgery. Third, there is no universally accepted definition of unresectability. Fourth, the decision of unresectability is often based on imaging which is not always reliable. In one study, neoadjuvant sunitinib allowed cytoreductive surgery in 3-of-10 patients with advanced locally infiltrative tumors (Bex et al., World J Urol, 2009). However, in another study with 78 patients, RENAL nephrometry score changed by -1 (range -3 to +1), not necessarily showing us if neoadjuvant therapy eased partial nephrectomy (Lane et al., Urol Oncol 2014).
The rationale of neoadjuvant therapy for metastatic RCC is for surgical selection. The absence of progression on targeted therapy may indicate best candidates for surgery. In one study, patients with MSKCC intermediate risk and absence of progression at metastatic sites following pretreatment with sunitinib have the longest overall survival after cytoreductive nephrectomy (Powles et al., Eur Urol 2011).
Dr. Bex concluded with a few additional statements:
- Adjuvant trials: further reports pending, but ASSURE results are bad news.
- Neoadjuvant trials result in modest downstaging. Individual patients who otherwise face complex surgery with the chance of irresectability may profit from this approach, but there is no evidence to recommend neoadjuvant treatment routinely.
- Presurgical therapy may help to select long-term survivors among candidates for cytoreductive surgery. SURTIME, a EORTC-GU 30073, is one phase III study investigating the sequence of nephrectomy and sunitinib.
Presented by Axel Bex, MD, PhD at the 30th Annual European Association of Urology (EAU) Congress - March 20 - 24, 2015 - IFEMA - Feria de Madrid - Madrid, Spain
Netherlands Cancer Institute
Reported by Mohammed Haseebuddin, MD, medical writer for UroToday.com