Metabolic Switch in Hepatocellular Carcinoma Patients Treated with Sorafenib: a Proof-of-Concept Trial.

BACKGROUND: Sorafenib is a multikinase inhibitor used to treat advanced hepatocellular carcinoma (HCC). Recently, a preclinical trial has shown that response to sorafenib is associated with a metabolic shift towards aerobic glycolysis. To test this observation in humans, we decided to conduct a proof-of-concept trial investigating the role of metabolic shift detected on [18F]FDG PET/CT in predicting survival and tumor response in HCC patients treated with sorafenib. METHODS: We prospectively enrolled advanced HCC patients candidate to sorafenib and undergoing [18F]FDG PET/CT at baseline, at 24 h, and at day 7 following treatment start. Response evaluation was obtained after 8 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST). All clinical variables and metabolic parameters (i.e., SUVmax; metabolic tumor volume, MTV; total lesion glycolysis, TLG; and their variations, Δ) were compared with those of treatment response and correlated to progression-free (PFS) and overall survival (OS). RESULTS: For this proof-of-concept trial, between August 2016 and August 2018, 13 patients (10 male, 3 female, median age 69) were enrolled. Considering the entire cohort, we demonstrated a significant negative correlation between ΔSUVmax at 24 h and 1 week (rho = - 0.733, p = 0.016). The metabolic shift, as expected, demonstrated median SUVmax, MTV, and TLG after 1 week lower in patients with a stable disease than a progressive disease (p = 0.019). Metabolic parameters and ECOG performance status (PS) resulted significantly correlated to PFS and OS at univariate analysis. On multivariate analysis, only median MTV at 1 week resulted as an independent prognostic factor for PFS (p = 0.033). CONCLUSIONS: As hypothesized, [18F]FDG PET/CT resulted in able to evaluate metabolic shift at 24 h and early treatment response already 1 week after treatment start. Moreover, metabolic parameters and ECOG PS resulted in predictive and prognostic factors to PFS and OS, with MTV at 1 week appearing as an independent predictive factor for PFS.

Maintenance Therapy With Panitumumab Alone vs Panitumumab Plus Fluorouracil-Leucovorin in Patients With RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Few studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined. OBJECTIVE: To determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen. DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m2 at day 1, leucovorin calcium, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus, followed by 600-mg/m2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018. INTERVENTIONS: Patients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites. MAIN OUTCOMES AND MEASURES: The prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A. RESULTS: Overall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07; P = .01). During maintenance, arm A had a higher incidence of grade 3 or greater treatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B. CONCLUSIONS AND RELEVANCE: In patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02476045.