Limitations of selection criteria of ongoing randomized controlled trials testing targeted therapies in an adjuvant setting of patients with renal cell carcinoma

Introduction and objectives: 40-50% of patients who underwent partial or radical nephrectomy for localized clear cell renal cell carcinoma (CCRCC) develop metastases during the follow-up period. Until now adjuvant chemotherapy and/or adjuvant immunotherapy failed to demonstrate significant advantages to reduce the risk of progression in CCRCC. Recently, new targeted therapies such as tyrosine kinase or mTOR inhibitors showed good results in the treatment of metastatic diseases. Therefore, the use of this new category of drugs was tested also in an adjuvant setting of high-risk patients to prolong the progression-free survival after partial nephrectomy (PN) or radical nephrectomy (RN). Indeed, 5 randomized control trials (ASSURE, STRAC, SORCE, EVEREST, PROTECT) are currently ongoing with the aim to test the role of some of these drugs (Sunitib, Sorafenib,Everolimus, Pazopanib) in comparison with placebo. The wide variability of the inclusion criteria used to enroll patients can affect the sample size and consequently the number of expected events according to the planned primary endpoint. In our study we tested the appropriateness of the eligibility criteria used to recruit participants for clinical trials on adjuvant medical therapy and we tested whether the simultaneous presence of loss of chromosomes 9p and 14q was associated with a different risk of recurrence in the subgroup of patients suitable for adjuvant therapy with targeted therapies. Materials and methods: Clinical records of 5,463 patients with RCC who received PN or RN were gathered from the databases of 16 Italian Urology Clinics. We selected all non-metastatic cases. Moreover, all patients who underwent cytoreductive nephrectomy for metastatic disease and those with non-clear cell RCC were excluded. The following pathological variables were assessed: local extension and dimension of primary tumor, regional lymph nodes involvement, Fuhrman’s nuclear grade and coagulative necrosis. All the included cases were reclassified according the eligibility criteria of each ongoing RCT testing adjuvant targeted therapies. For each category we calculated the frequencies and the progression-free survival. Events were defined as patients who developed distant metastases during the follow-up period. Finally, we evaluated the loss of chromosomes 9p and 14q in 175 patients who underwent PN or RN for non-metastatic ccRCC. We generated different multivariable models with the intent of demonstrating the independent predictive role of cytogenetic abnormalities once adjusted for the effects of the most common tools used to stratify patients in ongoing phase 3 trials evaluating the efficacy of adjuvant therapies. Results: The most selective criteria were used in the context of STRAC study. Indeed, using the high risk and very high risk categories according to UISS system, only 12% of our patients resulted suitable for randomization. At a median follow-up of 60 months, the percentage of observed events were 36% for high-risk and 68% for very high risk category, respectively. Conversely, the less selective criteria were used in ASSURE, EVEREST and SORCE trials in which the enrolled patients ranged between 41-43% of cases. In particular, the inclusion of patients in pT1b G3-4 or pT2 categories regardless the Fuhrman grading resulted in a very limited number of events ranging between 13-21% of cases. Similarly, the inclusion of intermediate risk patients according to Leibovich criteria in the SORCE trial is associated with only 20% of events. Concerning the cytogenetic analyses performed in a small subgroup of cases, no cytogenetic abnormalities were observed in 135 cases (77.1%), and loss of chromosome 9p or 14q was detected in 14 cases (8%) and 9 cases (5.1%), respectively. The contemporary presence of both cytogenetic alterations was reported in 17 cases (9.7%). The median follow-up duration was 36 mo (interquartile range: 21–78). The simultaneous loss of both chromosomes 9p and 14q turned out to be an independent predictor of DFS, once adjusted for the effects of pT and nuclear grade (hazard ratio [HR]: 4.579; 95% confidence interval [CI], 1.767–11.868), Leibovich score (HR: 3.704; 95% CI, 1.565–8.768), or UCLA Integrated Staging System (UISS; HR: 3.194; 95% CI, 1.351–7.553). Conclusions: Ongoing RCTs testing the adjuvant effect of targeted therapies in patient who underwent radical or partial nephrectomy for non-metastatic RCC were strongly limited by the used selection criteria. Indeed, in the majority of these trials the researchers enrolled categories with a very limited risk to progress influencing significantly the number of events needed to demonstrated a statistically significant differences between treatment arms and placebo ones. Moreover, loss of chromosomes 9p and 14q was an independent predictor of DFS in patients who underwent PN or RN for nonmetastatic ccRCC, once adjusted for the effects of either Leibovich score or UISS, demonstrating that the recurrence-free survival of patients suitable for adjuvant protocols could be strongly influenced by the cytogenetic characteristics of the tumor