The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer

PLoS One. 2015 Sep 30;10(9):e0138341. doi: 10.1371/journal.pone.0138341. eCollection 2015.

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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Capecitabine / administration & dosage
  • Colorectal Neoplasms* / diagnostic imaging
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / mortality
  • Disease-Free Survival
  • Female
  • Glucose-6-Phosphate / administration & dosage
  • Glucose-6-Phosphate / analogs & derivatives*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds / administration & dosage
  • Positron-Emission Tomography*
  • Prospective Studies
  • Radiography
  • Sorafenib
  • Survival Rate

Substances

  • Phenylurea Compounds
  • Niacinamide
  • 2-fluoro-2-deoxyglucose-6-phosphate
  • Glucose-6-Phosphate
  • Capecitabine
  • Sorafenib

Associated data

  • ClinicalTrials.gov/NCT01290926

Grant support

Institut Jules Bordet sponsored this study. Bayer Healthcare AG furnished 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.