For patients with stage III colon cancer, early discontinuation of adjuvant chemotherapy leads to worse outcomes—but early discontinuation of oxaliplatin did not. These findings, which came from an analysis of the large ACCENT and IDEA clinical trials databases, were presented at the 2022 ASCO Gastrointestinal Cancers Symposium.¹

Claire Gallois, MD

Early discontinuation of FOLFOX (fluorouracil, leucovorin, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) was defined as receipt of fewer than 75% of the planned treatments and was associated with a significant and clinically relevant decrease in disease-free and overall survival. Although early discontinuation of oxaliplatin alone before patients received a maximum of 75% of the planned cycles of oxaliplatin was not detrimental, patients who received less than 50% of the planned number of cycles of oxaliplatin did have poorer outcomes, said Claire Gallois, MD, of the Hopital Européen Georges Pompidou, Paris.

“In patients being treated with the [recommended] 6-month adjuvant regimen, it seems important to maintain the planned number of treatment cycles,” she said.

Chemotherapy relative dose intensity is known to be associated with prognosis in metastatic colorectal cancer and in localized colon cancer. Almost one-third of patients prescribed 6 months of adjuvant chemotherapy will discontinue treatment early. Lacking a standard definition for early treatment discontinuation, the generally accepted measure is a maximum of 75% of cycles. The prognostic impact of early treatment discontinuation is unclear, and any data on the topic have come from retrospective studies and are largely based on elderly patients and patients receiving fluoropyrimidine alone prior to 2006.

The importance of oxaliplatin in the treatment of early-stage colon cancer is well established, but many patients cannot tolerate a full course. Relative dose intensity of oxaliplatin less than 60% has been associated with poorer outcomes.^2,3

“In patients treated with 6 months of adjuvant chemotherapy, we may need to stop oxaliplatin early, mainly due to peripheral sensory neuropathy.…” said Dr. Gallois. “We need more robust data on the prognostic impact of early treatment discontinuation and oxaliplatin discontinuation while continuing fluoropyrimidine, according to the number of cycles received.”

Analysis of Large Databases

The current study examined the factors associated with early treatment discontinuation of all chemotherapy or of oxaliplatin alone. It sought to determine the impact of early treatment discontinuation on disease-free and overall survival.

Early treatment discontinuation was defined as a complete stop of all adjuvant chemotherapy before patients had received a maximum of 75% of cycles—translating to a maximum of nine cycles for FOLFOX and six cycles for CAPOX. Similarly, early oxaliplatin discontinuation was defined as the discontinuation of oxaliplatin alone, with a maximum of 75% of cycles, with continuation of fluoropyrimidine. This amounted to a maximum of nine cycles of oxaliplatin for patients being treated with FOLFOX and six cycles for those receiving CAPOX.

The study population drew from 28,623 patients with stage III colon cancer enrolled in 11 adjuvant clinical trials from the ACCENT and IDEA databases. The patients included were prescribed FOLFOX or CAPOX for 6 months for stage III colon cancer. The main exclusion criteria were treatment with fluoropyrimidine alone or targeted therapy, treatment duration less than 3 months, and discontinuation of chemotherapy due to recurrence.

In the final population, investigators analyzed 10,444 patients for early treatment discontinuation of chemotherapy and 7,243 for early discontinuation of oxaliplatin. In these two groups, 2,184 (20.9%) and 1,359 (18.8%), respectively, discontinued treatment before a maximum of 75% of the planned treatment.

Factors Observed With Early Treatment Discontinuation

Early treatment discontinuation in both groups was associated with female gender, older age, performance status > 0, and CAPOX regimen (for all, P < .001). Malnutrition (body mass index < 18.5 kg/m²) was associated as well with early discontinuation of the chemotherapy regimen (P < .001) but not oxaliplatin alone. There were no statistically significant differences in tumor or nodal stage, risk group, sidedness, histologic grade, lymph node ratio, mismatch repair status, and mutation (KRAS, BRAF) status.

“We can see in the multivariate analysis—adjusting for prognostic factors such as age, gender, year of enrollment, performance status, tumor, and nodal stage—that early treatment discontinuation was impacting disease-free survival [at 3 years] and overall survival [at 5 years],” Dr. Gallois said. Early treatment discontinuation resulted in a 3-year disease-free survival of 69.0% vs 78.8% (hazard ratio [HR] = 1.61; P < .0001), and a 5-year overall survival of 74.7% vs 84.7% (HR = 1.73; P < .001).

By regimen, worse disease-free survival was associated with discontinuation of both FOLFOX (HR = 1.64; P < .0001) and CAPOX (HR = 1.58; P < .0001), with no differences between the regimens. In the analysis according to risk group and regimen, patients who discontinued treatment early, in all subgroups, had worse disease-free and overall survival except for low-risk patients treated with CAPOX.

Early Discontinuation of Oxaliplatin

In contrast to the negative outcomes seen for early discontinuation of FOLFOX or CAPOX, in the same multivariate model, early discontinuation of oxaliplatin alone did not significantly impact disease-free or overall survival. The 3-year disease-free survival was approximately 78%, regardless of whether patients stopped treatment early or not. Overall survival at 5 years was 83% to 84%. No differences were observed according to regimen or risk group.

An examination of outcomes according to the number of cycles received, however, did reveal some differences. Although patients receiving 100% of cycles and more than 50% of cycles had similar outcomes, those receiving less than 50% had a 35% lower 3-year disease free survival (74% vs 78%), she reported.

Association With Adverse Events

Compared with fully treated patients, those discontinuing chemotherapy early were more likely to have nausea or vomiting (8.5% vs 3.6%) and diarrhea (16.1% vs 8.6%) but less likely to have peripheral sensory neuropathy (4.6% vs 13.2%). In patients who discontinued oxaliplatin early, more peripheral neuropathy was observed (26.8% vs 8.7%).

“If grade ≥ 2 neurotoxicity occurs at any time point, we stop oxaliplatin, according to good clinical practice. But after 3 months, for patients with grade 1 or 2 neurotoxicity, to avoid long-lasting neuropathy and improve quality of life, stopping oxaliplatin is likely a valid option that should not impair clinical outcomes,” Dr. Gallois concluded.

During the discussion, she noted that all patients in this analysis continued the fluoropyrimidine, and therefore she considers this aspect of treatment to be important. Dr. Gallois acknowledged that the impact on disease-free and overall survival could be confounded by other factors and suggested caution in interpreting the findings, as the study was not a randomized trial comparing treatment durations. 

DISCLOSURE: Dr. Gallois has received compensation from Amgen.

REFERENCES

1. Gallois C, Shi Q, Meyers JP, et al: Prognostic impact of early treatment discontinuation and early oxaliplatin discontinuation in patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer: An ACCENT/IDEA pooled analysis of 11 trials. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 11. Presented January 22, 2022.

2. Żok J, Bieńkowski M, Radecka B, et al: Impact of relative dose intensity of oxaliplatin in adjuvant therapy among stage III colon cancer patients on early recurrence: A retrospective cohort study. BMC Cancer 21:529, 2021.

3. Park D, Baek SJ, Kwak JM, et al: Analysis of reduced-dose administration of oxaliplatin as adjuvant FOLFOX chemotherapy for colorectal cancer. Ann Surg Treat Res 94:196-202, 2018.