Three months of adjuvant capecitabine plus oxaliplatin represents a potential option for select patients with high-risk stage II colorectal cancer due to its convenience, reduced toxicity, and cost, although noninferiority to the 6-month standard duration was not demonstrated.
Three months of adjuvant capecitabine plus oxaliplatin (CAPOX) represents a potential option for select patients with high-risk stage II colorectal cancer (CRC) due to its convenience, reduced toxicity, and cost, although noninferiority to the 6-month standard duration was not demonstrated, according to data from a study published in the Journal of Clinical Oncology.1
A total of 3,273 eligible patients were randomized to receive either 3 or 6 months of adjuvant treatment with a doublet chemotherapy regimen; 62% of these patients received CAPOX, while 38% were given fluorouracil, leucovorin, and oxaliplatin (FOLFOX). Results showed that the 5-year disease-free survival (DFS) rates for 3 vs 6 months of adjuvant treatment were 80.7% and 83.9%, respectively (hazard ratio [HR], 1.17; 80% CI, 1.05-1.31). The confidence intervals were noted to have crossed the noninferiority HR limit of 1.2; as such, noninferiority for 3 months of treatment had not been met (P = .39).
Additionally, the duration effect was surmised to be dependent on the chemotherapy regimen, but a test of interaction proved to be negative. The HR for CAPOX was 1.02 (80% CI, 0.88-1.17), while it was 1.41 (80% CI, 1.18-1.68) for FOLFOX.
“If oxaliplatin-containing adjuvant treatment is recommended in these patients, then the balance between efficacy and toxicity has to be carefully considered,” the study authors wrote. “Although noninferiority could not be demonstrated for 3-month treatment in the overall study population, the absolute difference in DFS between 3-month and 6-month CAPOX treatment is only 0.3%, and 3-month treatment results in significantly less toxicity, meaning that [when] balancing efficacy and toxicity, 3-month CAPOX can be considered.”
The addition of oxaliplatin to fluoropyrimidine has previously been shown to improve the efficacy of adjuvant chemotherapy treatment for patients with colon cancer. Six months of adjuvant FOLFOX or CAPOX has since become the standard of care for patients with stage III disease based on positive findings from pivotal trials. However, it has been acknowledged that oxaliplatin also results in significant neurotoxicity.
In light of that information, a total of 6 randomized trials were launched to evaluate whether the duration of adjuvant chemotherapy could be reduced to 3 months to decrease toxicity without impacting efficacy. To prospectively examine individual patient data from these trials, the International Duration of Adjuvant Chemotherapy collaboration was formed and data regarding patients with stage III colon cancer were published.
The analysis published in the Journal of Clinical Oncology looked at data from patients with high-risk stage II disease who were included in 4 of the 6 studies: the phase 3 SCOT trial (NCT00749450), the phase 3 TOSCA trial (NCT00646607), the phase 3 HORG trial (NCT01308086), and the phase 3 ACHIEVE2 trial (UMIN000013036).
All of these studies looked at whether 3 months of treatment with an adjuvant chemotherapy doublet was noninferior to what had been the standard 6 months of treatment in this population. In all 4 studies, the choice of CAPOX or FOLFOX had not been randomized; this was chosen by the treating clinician prior to randomization to 3 or 6 months of treatment.
From June 2007 through January 2017, a total of 3,332 patients were enrolled and randomly assigned into the 4 studies, although 59 were excluded from the modified intent-to-treat (mITT) population because they did not receive chemotherapy. Additionally, 24 patients with rectal cancer from the SCOT trial received preoperative short-course radiotherapy and were excluded. As such, 3,273 patients comprised the mITT population. By December 2018, the time of the statistical analysis, the median DFS follow-up was 60.2 months (range, 59.8-60.5).
The median age of patients enrolled across the 4 studies was 64 years (range, 20-85), and the majority were male (56.5%; n= 1,850), had an ECOG performance status of 0 (87.5%), and presented with T3 disease (66.2%). The percentage of patients with T4 disease varied from 14% in the HORG trial to 50% in the SCOT trial, while the percentage of those with poorly differentiated tumors ranged from 12% in ACHIEVE2 to 57% in HORG. Characteristics were noted to be well balanced across the randomized arms, with no large differences noted between CAPOX and FOLFOX subsets.
Overall, 90% of patients who received 3 months of treatment received all planned treatment vs 65% of those assigned to receive a 6-month duration (P <.0001). A total of 553 DFS events were observed, exceeding the 542 required for 80% power. Notably, no evidence of nonproportional hazards or of heterogeneity in HRs across individual trials was observed.
Investigators planned for 4 subgroup comparisons: chemotherapy regimen (CAPOX vs FOLFOX), T-stage (T4 vs T1 to 3), poorly differentiated tumor (yes vs no), and unacceptable nodal harvest. Chemotherapy regimen was the only subset to demonstrate a notable difference in duration effect.
Patients assigned to receive 3 months of treatment with CAPOX had a 5-year DFS rate of 81.7% (95% CI, 79.2%-84.3%) vs 79.2% (95% CI, 75.9%-82.7%) with FOLFOX. Among those who were assigned to received 6 months of treatment, the 5-year DFS rate was 82.0% (95% CI, 79.3%-84.7%) with CAPOX vs 86.5% (95% CI, 83.7%-89.3%) with FOLFOX.
“For CAPOX, 3-month treatment is noninferior to 6-month treatment, but for FOLFOX, chemotherapy of 6-month duration is superior to 3-month treatment,” the study authors wrote. “Similarly, in high-risk stage II patients and stage III patients, giving 6-month chemotherapy treatment results in significantly more toxicity. This is especially true for neurotoxicity that has been shown to last for significant periods of time and affect the quality of life.”
Additionally, an exploratory analysis looked at the impact of the number of high-risk factors on DFS for the SCOT, ACHIEVE2, and HORG studies. Investigators compared those with just 1 risk factor to those with 2 or more risk factors. Results indicated that patients with 2 or more risk factors experienced a significantly worse DFS vs those with just 1 risk factor, at 74.8% vs 87.3%, respectively. Moreover, when looking at all 4 studies, investigators demonstrated that patients with T4 disease experienced worse outcomes than those with T3 disease.
In terms of safety, patients who received 6 months of treatment experienced significantly more adverse effects (AEs) than those who were given 3 months. The most common AEs reported were diarrhea, peripheral neuropathy, hand–foot syndrome, and mucositis. Additionally, peripheral neuropathy that was grade 2 or higher in severity was reported in 13% of patients in the 3-month treatment arm and 36% of those in the 6-month arm.
“Although noninferiority ha not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest that the standard of care for high-risk stage II colon cancer can be considered to be either 3-month CAPOX (if considered for oxaliplatin-based chemotherapy) or 6-month single-agent fluoropyrimidine,” the study authors concluded.