ASCO GI 2022: Key considerations about oxaliplatin for the treatment of mCRC

January 2022

Oxaliplatin is an important intravenous chemotherapy drug that is used to treat advanced colorectal cancer (CRC). It is usually given in combination with other chemotherapy drugs, like fluorouracil and leucovorin (e.g. FOLFOX – FOlinic acid + Fluorouracil + OXaliplatin). Oxaliplatin is considered the most neurotoxic chemotherapy agent, affecting the normal activity of the nervous system. This drug is the cause of peripheral neuropathy, which can sometimes be irreversible. Symptoms include pain, a pins-and-needles sensation, numbness, and weakness. As such, oxaliplatin’s efficacy in the treatment of mCRC is hampered by the dose-limiting neurotoxicity that may require dose reduction in order to prevent long-term neuropathy. The following two studies examine the benefit of oxaliplatin in the treatment regimen of different subgroups of patients with CRC.

a) Understanding the benefit of oxaliplatin among older patients

According to findings from the phase III JCOG1018 RESPECT study, adding oxaliplatin to 5-FU-based chemotherapy plus bevacizumab did not benefit older patients with metastatic colorectal cancer (mCRC). The study results showed that adding oxaliplatin did not increase patients’ progression-free survival (PFS) compared to 5-FU plus bevacizumab, and was associated with greater toxicity.

According to lead researcher Tetsuya Hamaguchi, MD, PhD, from Saitama Medical University International Medical Center in Japan, though 5-FU plus oxaliplatin with bevacizumab represents the standard, initial (first-line) therapy for patients with mCRC, since elderly patients are underrepresented in clinical trials, the benefit of this intensive first-line therapy in this subgroup of patients is not well understood.

Among the 251 patients with mCRC enrolled in the trial, 126 were randomly assigned to receive 5-FU plus bevacizumab with oxaliplatin and 125 were randomly assigned 5-FU plus bevacizumab alone. 5-FU-based chemotherapy was administered either as oral capecitabine or intravenous flourouracil plus leucovorin. The average age of participants in the oxaliplatin arm was 79 years, and 80 years in the no-oxaliplatin arm.

Patients who received oxaliplatin experienced more frequent adverse events compared to patients who did not receive oxaliplatin, including neutropenia (24% vs 15%), sensory neuropathy (57% vs 15%), fatigue (32% vs 21%), nausea (22% vs 10%) and diarrhea (16% vs 7%). The average PFS was 10 months in the oxaliplatin arm compared to 9.4 months in the no-oxaliplatin arm, while average overall survival (OS) was 19.7 months in the oxaliplatin arm and 21.3 months in the no-oxaliplatin arm. The overall response rate was 47.7% vs 29.5%, respectively.

Since oxaliplatin was associated with more adverse events and did not result in any significant improvements to PFS, the researchers concluded that 5-FU plus bevacizumab is the recommended initial treatment for elderly patients with mCRC.

b) Understanding the impact of removing oxaliplatin from adjuvant treatment for patients with stage III colon cancer

Among patients with high-risk stage III colon cancer, six months of oxaliplatin-based adjuvant chemotherapy (chemotherapy that follows surgery) is the standard treatment. While stopping adjuvant treatment entirely could worsen patient outcomes, there is currently a lack of data on the impact of stopping oxaliplatin only.

The study

A research team led by Claire Gallois, MD, of Hôpital Européen Georges Pompidou in Paris aimed to understand two key points in their study:

• the impact of stopping adjuvant treatment before the planned cycles have been completed;

• the impact of removing only oxaliplatin from treatment before the planned cycles have been completed.

Data from patients with stage III colon cancer who were enrolled in 11 relevant clinical trials within the ACCENT and IDEA databases were analyzed in this study. Both the Adjuvant Colon Cancer End Points (ACCENT) and the International Duration Evaluation of Adjuvant chemotherapy (IDEA) databases involve analyses of clinical data on the optimal use of adjuvant chemotherapy for patients with stage III disease. Patients were treated with a combination of leucovorin, fluorouracil, and oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX) prescribed for a duration of 6 months.

Findings

Once 75% of planned cycles had been completed, if oxaliplatin was removed it was not associated with worse disease-free survival (DFS) or overall survival (OS). However, if less than 50% of the planned oxaliplatin-containing chemotherapy cycles were completed and oxaliplatin was removed, patients experienced worse DFS.

In contrast, discontinuation of adjuvant treatment (stopping before 75% of planned chemotherapy cycles had been completed) was associated with a decrease in both DFS and OS.

Conclusion

Dr. Gallois concluded that among patients with high-risk stage III colon cancer prescribed a 6-month chemotherapy regimen, completing the planned number of treatment cycles appears to be important to DFS and OS outcomes. In patients who experience neurotoxicity due to treatment, the study findings do not support continuing oxaliplatin beyond 75% of the planned cycles. This underlines the central role of 5-FU-based chemotherapy in adjuvant chemotherapy for locally advanced stage III colon cancer.

Take away message:

Two studies evaluated the use of oxaliplatin in the treatment of different subgroups of patients with colorectal cancer. Since this chemotherapy drug is associated with potentially irreversible nerve damage, understanding the minimum effective dose that can be safely administered to patients without negatively impacting survival outcomes is an important step towards improving the quality of life for patients undergoing treatment.