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

Introduzione ed obiettivi: Il 40-50% dei pazienti con carcinoma renale parenchimale a cellule chiare localizzato sviluppa metastasi a distanza nel corso del follow-up dopo nefrectomia parziale o radicale. Al momento attuale, nessun trattamento chemio e/o immunoterapico adiuvante si è dimostrato efficace nel ridurre o dilazionare il rischio di progressione nei pazienti con carcinoma renale parenchimale a cellule chiare. I risultati favorevoli riportati negli ultimi anni con l’impiego degli inibitori delle tirosin-chinasi o di mTOR nel trattamento del carcinoma renali a cellule chiare metastatico ha lasciato ipotizzare anche un loro utilizzo adiuvante nei pazienti con maggiore rischio di progressione di malattia dopo nefrectomia parziale o radicale. Sono attualmente in fase di svolgimento 5 studi clinici randomizzati di fase III (ASSURE,STRAC, SORCE, EVEREST, PROTECT) che confrontano alcuni di questi farmaci (Sunitinib, Sorafenib, Everolimus, Pazopanib) al placebo. In questi studi di fase III sono stati utilizzati criteri di selezione estremamente variabili con evidenti conseguenze sul campione statistico necessario e sul numero di eventi attesi per il raggiungimento dell’obiettivo primario dello studio. Obiettivo della ricerca sarà quello di verificare l’appropriatezza dei diversi criteri utilizzati per selezionare i pazienti da arruolare nei diversi trials di adiuvante. Materiali e metodi: L’analisi è stata effettuata su un database multicentrico di 5463 pazienti sottoposti a nefrectomia radicale (NR) o nefrectomia parziale (NP) per carcinoma renale parenchimale in 16 centri italiani di urologia. Sono stati selezionati tutti i pazienti sottoposti a NR o NP per carcinoma renale non metastatico a cellule chiare. Sono stati esclusi dall’analisi tutti i pazienti sottoposti a nefrectomia citoriduttiva per malattia metastatica e tutti i pazienti con istotipo neoplastico non a cellule chiare. Per ogni singolo paziente sono state valutate le seguenti variabili cliniche e patologiche: stadio patologico del tumore primitivo, stadio patologico dei linfonodi regionali, grading nucleare secondo Fuhrman, performance status ECOG, dimensioni del tumore primitivo e necrosi coagulativa. La valutazioni delle suddette variabili ha consentito di riclassificare tutti i casi inclusi in analisi in accordo con i criteri di selezione identificati nei 5 RCTs attualmente in corso di realizzazione. Utilizzando i dati retrospettivi del database SATURN abbiamo calcolato e confrontare il numero di casi arruolabili in accordo con i criteri di inclusione riportati nei differenti trials di terapia adiuvante attualmente in corso. Inoltre, abbiamo calcolato il numero di eventi (pazienti in progressione di malattia) e la relativa sopravvivenza libera da progressione dei diversi sottogruppi suscettibili di arruolamento nei diversi trials. Analisi correlate In un sottogruppo di questi pazienti abbiamo eseguito la revisione centralizzata dei preparati istologici con l’obiettivo di valutare il ruolo prognostico addizionale di alcuni marcatori citogenetici testati con l’utilizzo della metodica FISH