Postoperative chemotherapy relative dose intensity and overall survival in patients with colon cancer

Abstract

Purpose: Quantifying the association of chemotherapy relative dose intensity (RDI) with overall survival may enable supportive care interventions that improve chemotherapy RDI to estimate their magnitude of potential clinical benefit.

Methods: This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 12 cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposure was chemotherapy RDI. The primary outcome was overall survival. Restricted cubic splines estimated hazard ratios (HR).

Results: Chemotherapy regimen RDI was associated with overall survival in an L-shaped pattern (linear P = 0.006; nonlinear P = 0.057); the risk of death was flat above 85% but increased linearly below 85%. For example, a decrease in RDI from 85 to 75% was associated with an increased risk of death [HR: 1.20 (95% CI: 1.08, 1.52)], whereas an increase in RDI from 85 to 95% was not associated with the risk of death [HR: 1.06 (95% CI: 0.82, 1.38)].

Conclusion: If chemotherapy RDI is considered a potential surrogate of overall survival, supportive care interventions that improve chemotherapy RDI might confer a potential clinical benefit in this population.

Keywords: Adherence; Chemotherapy; Surrogate endpoint; Toxicity.

Figure 1.

Risk of all-cause mortality by chemotherapy regimen (FOLFOX) relative dose intensity on the relative hazard scale in 533 patients with colon cancer. Shaded regions indicate 95% confidence bands for mortality risk as a function of chemotherapy relative dose intensity. Estimates are adjusted for age, sex, and cancer stage. Three knots corresponding to the 10%, 50%, and 90% percentiles were placed at 68%, 88%, and 100% chemotherapy regimen RDI. The equation for the presented spline is log (HR) = −0.040 * spline parameter 1 + 0.034 * spline parameter 2 − 0.325 (if sex is female) + 0.282 (if age is ≥75 years) + 0.400 (if cancer stage is 3).

Figure 2.

Risk of all-cause mortality by chemotherapy drug relative dose intensity on the relative hazard scale in 533 patients with colon cancer. Shaded regions indicate 95% confidence bands for mortality risk as a function of 5-fluorouracil (red) and oxaliplatin (blue) chemotherapy relative dose intensity. Estimates are adjusted for age, sex, and cancer stage. Three knots corresponding to the 10%, 50%, and 90% percentiles were placed at 67%, 89%, and 100% for 5-fluorouracil RDI and 66%, 88%, and 100% for oxaliplatin RDI. The equation for the presented spline for 5-fluorouracil is log (HR) = log (HR) = −0.040 * spline parameter 1 + 0.032 * spline parameter 2 − 0.327 (if sex is female) + 0.300 (if age is ≥75 years) + 0.404 (if cancer stage is 3). The equation for the presented spline for oxaliplatin is log (HR) = −0.036 * spline parameter 1 + 0.032 * spline parameter 2 − 0.328 (if sex is female) + 0.279 (if age is ≥75 years) + 0.417 (if cancer stage is 3).