Risk of disease progression in the first-line therapy of metastatic colorectal cancer to guide disease re-assessments - analysis of eleven trials by AIO and GONO

Abstract

Background: We evaluated the distribution and risk of disease progression (PD) in first-line therapy of unresected metastatic colorectal cancer (mCRC) patients receiving chemotherapy + biologics. The aim of the analysis is to provide guidance for the timing of disease reassessments during first-line therapy.

Patients and methods: Individual data of 2939 unresected patients from TRIBE, MOMA, TRIBE2, VALENTINO, ATEZOTRIBE, TRIPLETE, FIRE-3, XELAVIRI, PANAMA, FIRE-4 and FIRE-4.5 were analyzed. The frequency and risk of PD events were calculated for individual time points during therapy. RAS/BRAF profiling, tumor sidedness, type of therapy and early tumor shrinkage (ETS) were used to identify subgroups for risk assessment. A Cox regression model to predict first-line PFS was built.

Results: In the overall population, the maximum frequency of PD events was observed at 7.6 months, with an absolute PD risk of 19%. Then, the PD risk flattened, achieving a maximum of 23% at 14 months in RAS/BRAF wild-type patients (n=1786), 25% at 10 months in RAS mutant patients (n=973) and 35% at 8 months in BRAF mutant patients (n=180). ECOG-PS > 0, right sidedness, initially unresected primary tumor, higher number of organs involved by metastases and BRAF mutation were independently associated with higher risk of PD in first-line. The impact of baseline characteristics on PFS was mitigated after incorporation of ETS in the model.

Conclusions: The distribution of PD events does not follow a gaussian pattern, with the highest density observed between the third and fourth reassessment of a bimonthly surveillance schedule. In clearly unresectable patients, restaging should focus on the interval between 6-10 months and not on the initiation of systemic therapy. Our model might be helpful to schedule radiologic re-assessments according to baseline characteristics, early response and the expected duration of each treatment efficacy.

Keywords: Metastatic colorectal cancer; first-line chemotherapy; radiological surveillance.