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Clinical benefit of a treatment demonstrated in patients with metastatic cancer leads to an optimistic and, understandably, logical belief that the same treatment is likely to be active against those apparently quiescent malignant cells that lead to disease recurrences after removal of the primary cancer. Thus, a simple paradigm has directed the development of adjuvant systemic therapy of solid tumors: administration of the systemic treatment regimen found to be active in the metastatic disease to a subset of patients at high risk of disease recurrence. Delaying of events (ie, fewer relapses or fewer deaths at a selected time point, in those receiving the adjuvant treatment) indicates the benefit derived from the adjuvant treatment. Successes using this classic paradigm have been many, but most often they are modest in effect and at times have required meta-analyses to extract a convincing evidence of treatment efficacy. Unfortunately, though quite understandably, the apparent simplicity and a promise of success of the process, confounded by the limits of available technology, has curtailed motivation to a deeper inquiry into the likely critical differences in the complexities of 2 related but distinct phenomena—the biology of established and visible growing metastatic tumors, and the biology of the apparently quiescent malignant cells in transition. In 2007, 2 vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI), sunitinib and sorafenib, were found to extend the progression-free survival of patients with advanced renal cell carcinoma (RCC) and received the US Food and Drug Administration approvals for treatment of advanced RCC.1,2 Following the classic paradigm of adjuvant therapy development outlined herein, the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN) investigators designed the study E2805, also known as ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma. It enrolled patients who had undergone surgical removal of their clear cell or non–clear cell RCC and were then at a high risk of recurrence.3 The study looked for a longer disease-free survival (DFS) as the clinical benefit from the adjuvant treatment. The clinical trial, led by ECOG-ACRIN with participation of the other National Cancer Institute National Clinical Trial Network members, accrued with a remarkable efficiency, despite requiring critical protocol amendments on the way. Tolerance of and compliance with the doses of sunitinib and sorafenib that were administered in the metastatic disease studies were found to be critical problems in the adjuvant setting. Sunitinib and sorafenib dosing was revised, allowing titration of the dose based on tolerance. The Initial planned accrual of 1332 patients was increased to 1923 to have enough patients with adequate drug exposure. The results of the study, based on the entire study population (1943) were published in March 2016 by Haas et al.3 The median (mean) DFS was 70.0 months (69.6 months) for sunitinib, 73.4 months (73.2 months) for sorafenib, and 79.6 months (79.2 months) for placebo. The median DFS did not differ significantly among the groups. Events had been reported for 284 of 647 patients (43.8%) prescribed sunitinib, 284 of 649 patients (43.7%) prescribed sorafenib, and 287 of 647 patients (44.3%) prescribed placebo. Thus, the adjuvant treatment of RCC with sorafenib or sunitinib showed no DFS benefit relative to placebo, despite a clear progression-free survival benefit that had been demonstrated in the metastatic RCC. Notably, substantial treatment discontinuations occurred in ASSURE: proportions of patients receiving the intended dose at cycle 3 were 262 of 629 patients (42%) receiving sunitinib, 193 of 630 (31%) receiving sorafenib, and 560 of 633 (88%) receiving placebo. The treatment discontinuation problem remained after the mid-study changes in dosing. Among the patients starting at full dose, the overall rates of treatment discontinuation were 193 of 438 patients (44%) prescribed sunitinib, 199 of 441 patients (45%) prescribed sorafenib, and 47 of 444 patients (11%) prescribed placebo. The overall discontinuation rates among the patients starting at reduced dose were 65 of 191 patients (34%) prescribed sunitinib, 56 of 189 patients (30%) prescribed sorafenib, and 18 of 189 patients (10%) prescribed placebo. However, other studies have also evaluated adjuvant treatment of RCC using VEGF TKIs. Using the same adjuvant therapy development paradigm—directed by the proven efficacy of antiangiogenic therapies, VEGF TKI sunitinib and sorafenib in patients with metastatic renal-cell carcinoma—adjuvant treatment trial S-TRAC (Sunitinib as Adjuvant Treatment for Patients at High Risk of Recurrence of Renal Cell Carcinoma Following Nephrectomy) was developed by Pfizer and an international group of investigators.4 Results of this randomized, doubleblind, phase 3 trial that assigned 615 patients with locoregional, high-risk clear cell renal cell carcinoma to receive either sunitinib (50 mg/d) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable Related article Opinion