Monitoring metabolic response using FDG PET-CT during targeted therapy for metastatic colorectal cancer.

INTRODUCTION: The introduction of targeted drugs has had a significant impact on the approach to assessing tumour response. These drugs often induce a rapid cytostatic effect associated with a less pronounced and slower tumoural volume reduction, thereby impairing the correlation between the absence of tumour shrinkage and the patient's unlikelihood of benefit. The aim of the study was to assess the predictive value of early metabolic response (mR) evaluation after one cycle, and its interlesional heterogeneity to a later metabolic and morphological response assessment performed after three cycles in metastatic colorectal cancer (mCRC) patients treated with combined sorafenib and capecitabine. METHODS: This substudy was performed within the framework of a wider prospective multicenter study on the predictive value of early FDG PET-CT response assessment (SoMore study). A lesion-based response analysis was performed, including all measurable lesions identified on the baseline PET. On a per-patient basis, a descriptive 4-class response categorization was applied based upon the presence and proportion of non-responding lesions. For dichotomic response comparison, all patients with at least one resistant lesion were classified as non-responding. RESULTS: On baseline FDG PET-CT, 124 measurable "target" lesions were identified in 38 patients. Early mR assessments showed 18 patients (47 %) without treatment resistant lesions and 12 patients (32 %) with interlesional response heterogeneity. The NPV and PPV of early mR were 85 % (35/41) and 84 % (70/83), respectively, on a per-lesion basis and 95 % (19/20) and 72 % (13/18), respectively, on a dichotomized per-patient basis. CONCLUSIONS: Early mR assessment performed after one cycle of sorafenib-capecitabine in mCRC is highly predictive of non-response at a standard response assessment time. The high NPV (95 %) of early mR could be useful as the basis for early treatment discontinuation or adaptation to spare patients from exposure to non-effective drugs.

Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours.

AIM: The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a phase I, dose-escalation trial. METHODS: Twenty-seven patients in four cohorts received docetaxel on day 1 (cohorts 1 and 4: 75 mg/m2; cohorts 2 and 3: 100 mg/m2) plus sorafenib on days 2-19 (cohorts 1 and 2: 200 mg twice-daily (bid); cohorts 3 and 4: 400 mg bid) in 21-day cycles. RESULTS: Most common adverse events (AEs) (grade 3-5) included neutropenia (89%), leucopaenia (81%), hand-foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration-time curve (AUC)(0-24) increased by 5% (cohort 1), 54% (cohort 2), 36% (Cohort 3) and 80% (cohort 4) with docetaxel plus sorafenib, while C(max) increased by 16-32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease. CONCLUSION: Dose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75 mg/m2 plus sorafenib 400mg bid (with dose reductions for dermatological toxicities) is proposed for phase II.