The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer

Abstract

Background: Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC).

Methods: Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions.

Results: Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8-10.5) and 4.2 months (95% CI: 3.4-4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21-0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36-0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS.

Conclusion: The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC.

Trial registration: ClinicalTrials.gov NCT01290926.

Conflict of interest statement

Competing Interests: The authors of this manuscript have read the journal's policy and have the following competing interests: Institut Jules Bordet sponsored this study. Bayer Healthcare AG funded this study by furnishing both a grant and sorafenib but played no further role. AH, PF, M. Paesmans, LA, MM had access to the raw data. The corresponding author had the final responsibility to submit for publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AH played an advisory role and received honoraria from Sirtex, Roche, Bayer, Sanofi and Amgen; M. Paesmans played an advisory role and received honoraria from Merck, Roche, Bayer, Sanofi and Amgen; M. Piccart played an advisory role and received honoraria from Roche & Bayer; PF played an advisory role and received honoraria from Sirtex, Roche, Bayer. All other co-authors have no conflicts of interest to disclose. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials

Figures

Fig 1. Classes of metabolic responses.

Class 1: no metabolic unresponsive lesion; Class 2: minority of unresponsive lesion among whole body target tumour load; Class 3: majority of whole body target tumour load does not respond; Class 4: all target lesions are non-responding, or, presence of progressive lesions [progression defined as >25% increase of FDG uptake on second PET, or appearance of a new lesion].

Fig 2. Consort Diagram.

Fig 3. PFS* (A) and OS* (B) distribution according to the 4 classes of metabolic response.

Class 1: no metabolic unresponsive lesion; Class 2: minority of unresponsive lesion among whole body target tumour load; Class 3: majority of whole body target tumour load does not respond; Class 4: all target lesions are non-responding, or, presence of progressive lesions [progression defined as >25% increase of FDG uptake on second PET, or appearance of a new lesion]. *from date of the second FDG PET-CT.

Fig 4. PFS and OS distribution according to the dichotomized mR classifications.