Elevated body mass index (BMI) is associated with reduced average relative dose intensity of adjuvant chemotherapy in colorectal cancer: the OCTOPUS trials consortium


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Corinna Slawinski, Lee Malcomson, Hui Guo, Jorge Barriuso, Andrea Harkin, Timothy Iveson, Andrew Renehan

Abstract

Background

Adjuvant chemotherapy (ACT) for colorectal cancer (CRC) is dosed according to body surface area (BSA). Dose capping is common for patients with a BSA ≥2.2m2, and may reduce relative dose intensity (RDI). A RDI <85% is associated with reduced cancer survival, hence, dose-capping-related RDI reductions might reduce survival in obesity. Big-data with deeply phenotyped dosing schedules may better elucidate these relationships.

Method

We included individual-level participant data from two CRC-ACT randomised-trials (MOSAIC: 5-fluorouracil/leucovorin (5FU) (control arm); SCOT: 5FU/Oxaliplatin (mFOLFOX6) & capecitabine/oxaliplatin (CAPOX) regimens), with derivable BMI and ACT data. BSA was calculated with the Mosteller formula using actual body weight (ABW). Dose capping was defined as receipt of <95% of the standard ABW-derived 1st cycle dose. Average RDI (ARDI) was defined as a percentage of actual to expected dose intensity (DI; cumulative dose (mg/m2 of BSA) divided by treatment duration in weeks) averaged across drug regimens. ARDI was dichotomised as <85% or ≥85%. Statistical analysis consisted of ordinal tests for trend and multivariable logistic regression, to explore BMI-ARDI relationships by regimen.

Results

A combined total of 6865 patients were eligible. Proportions of underweight, normal, overweight and obese BMI were 3.3%, 49.5%, 35.0% and 12.3% for MOSAIC; 1.3%, 36.0% 40.4% and 22.2%, for SCOT. Proportions of patients dose capped and receiving ARDI <85% are presented in Table 1.

Compared with normal BMI, obese was associated with increased odds of receiving <85% ARDI in MOSAIC-5FU (OR: 2.36; 95%CI: 1.46, 3.83; p <0.001) and SCOT-CAPOX (OR: 1.44; 95%CI: 1.20, 1.71; p <0.001), but not SCOT-FOLFOX.

Table 1: Proportions of patients dose capped and receiving ARDI <85%

Trial/Regimen

BMI Category (kg/m2)

<18.5

18.5-24.9

25-29.9

>=30

Ptrend

Dose caped (%)

MOSAIC-5FU

0

3.50

6.25

31.85

<0.001

SCOT- CAPOX

32.00

38.61

47.94

74.30

<0.001

SCOT- mFOLFOX6

8.33

7.75

16.39

46.29

<0.001

ARDI <85% (%)

MOSAIC-5FU

22.22

11.60

15.36

23.70

0.002

SCOT-CAPOX

45.10

50.97

50.64

58.72

<0.001

SCOT-mFOLFOX6

62.50

58.58

55.53

58.93

0.5458


Conclusion

Obesity was associated with increased odds of receiving <85% ARDI in MOSAIC-5FU and SCOT-CAPOX regimens, suggesting potentially sub-optimal dosing. 

Impact statement

Sub-optimal chemotherapy dosing of obese patients might reduce CRC survival. Further work will explore BMI-ARDI-survival relationships.