Oxaliplatin not recommended in initial therapy for elderly patients with metastatic colorectal cancer

The JCOG1018 RESPECT study is a randomised phase III trial of mFOLFOX7 or CapeOX plus bevacizumab versus 5-FU/l-LV or capecitabine plus bevacizumab as initial therapy in elderly patients with metastatic colorectal cancer. The trial demonstrated that the addition of oxaliplatin did not result in a survival benefit but came at the cost of higher toxicity and is thus not recommended in this elderly patient population.

Fluoropyrimidine plus oxaliplatin with bevacizumab is one of the standard intensive initial therapies for patients with metastatic colorectal cancer (mCRC). Since elderly patients are often under-represented in clinical trials, the benefit of intensifying initial therapy is not yet clear in this group. Therefore, the randomised controlled JCOG1018 RESPECT trial was conducted by Hamaguchi et al. to confirm the superiority of the addition of oxaliplatin in terms of progression-free survival (PFS).

RESPECT Study design

JCOG1018 is a randomised phase III study of mFOLFOX7 or CapeOX plus bevacizumab versus 5-fluorouracil/Leucovorin or capecitabine plus bevacizumab as first-line treatment in elderly patients with mCRC. Key eligibility criteria included unresectable metastatic colorectal cancer, and histologically confirmed adenocarcinoma, aged 70-74 years with ECOG performance status (PS) 2 or 75 or older with ECOG PS 0-2. Furthermore, all patients should have preserved major organ functions and no contraindication to use bevacizumab (BEV). Eligible patients were randomised (1:1) to either no addition of oxaliplatin or addition. Whether using 5-FU + levoleucovorin calcium (5-FU/l-LV) or capecitabine (Cape) was declared before study entry; options included 5-FU/l-LV+BEV, Cape+BEV, mFOLFOX7+BEV, or CapeOX+BEV. 5-FU/l-LV regimen omitted bolus 5-FU from the original sLV5FU regimen. The dose of capecitabine was adjusted by estimated creatinine clearance. The primary endpoint was PFS.

Results

Between September 2012 and March 2019, 251 patients were randomised. Of them, 125 patients were allocated to no addition of oxaliplatin and 126 patients to addition. Median age was 79 years and most patients had an ECOG PS of 0 or 1. Median PFS did not differ between both treatment groups and was 9.4 months in patients not receiving oxaliplatin versus 10.0 months in patients receiving oxaliplatin (HR[90.5%CI]: 0.837[0.673–1.042], one-sided p= 0.086). Furthermore, the addition of oxaliplatin did not result in a prolongation of overall survival (OS), with a median OS of 21.3 months in the no addition group and of 19.7 months in addition of oxaliplatin (HR[95%CI]: 1.058 [0.808–1.386]). The overall response rates were 47.7% and 29.5% in the with and without oxaliplatin arms, respectively. Finally, also the proportion of patients whose EQ-5D quality of life scores improved from baseline to post-treatment in overall score did not differ between both arms (odds ratio[95%CI]: 0.94[0.51-1.75], p= 0.849). Although the addition of oxaliplatin did not translate into improved survival outcomes or a better quality of life, it did came at the cost of higher toxicity. Neutropenia (24% vs. 15%), nausea (22% vs. 10%), diarrhoea (16% vs. 7%), fatigue (32% vs. 21%) and sensory neuropathy (57% vs. 15%) where all higher with the addition of oxaliplatin. Finally, more treatment-related deaths were reported in the oxaliplatin arm (3 deaths vs. 1 death in the no-addition arm).

Conclusion

In this trial of elderly patients with metastatic colorectal cancer, 93% of patients were at least 75 years old. In this patient population, the addition of oxaliplatin to fluoropyrimidine with bevacizumab did not prolong the PFS but came at the cost of more frequent and more severe adverse events. Therefore, the combination of fluoropyrimidine plus bevacizumab is the recommended first-line therapy for elderly mCRC patients.

Reference

Hamaguchi T, Takashima A, Mizusawa J, et al. A randomized phase III trial of mFOLFOX7 or CapeOX plus bevacizumab versus 5-FU/l-LV or capecitabine plus bevacizumab as initial therapy in elderly patients with metastatic colorectal cancer: JCOG1018 study (RESPECT). Presented at ASCO GI 2022; Abstract 10. JCOG1018 study (RESPECT)