Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer ASCO Clinical Practice Guideline

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 145,600 new cases of CRC will be diagnosed in the United States in 2019 and about 51,020 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) Colon Cancer, has been the standard of care since the 1990s. Adjuvant treatment with an ELOXATIN® (Oxaliplatin) based chemotherapy regimen has been considered standard intervention since 2004, for patients with Stage III colon cancer, following surgical resection, and has been proven to decrease the chance of recurrent disease. Chemotherapy regimens have included (FOLFOX – Leucovorin, 5-FluoroUracil, ELOXATIN®) or CAPOX/XELOX (XELODA®/Capecitabine and ELOXATIN®), given over a period of 6 months. ELOXATIN® can however be associated with neuropathy which can be long lasting or permanent, depending on the duration of therapy. Additional toxicities with longer duration of chemotherapy include diarrhea, fatigue as well as more office visits.

This ASCO Clinical Practice Guideline was based on the IDEA Collaboration, which is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials, which included 12,834 patients from 12 countries. The goal of this study was to determine if 3 months of adjuvant chemotherapy would be as effective as 6 months of therapy and would be non-inferior. Approximately, 40% of patients received CAPOX regimen and 60% received FOLFOX regimen. The Primary endpoint was Disease Free Survival (DFS).

In an exploratory subgroup analyses by risk of recurrence within the high-risk group defined in the IDEA Collaboration (T4 – tumor invades through the visceral peritoneum including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum or tumor directly invades or adheres to other adjacent organs or structures and/or N2 – metastasis in 4 or more regional lymph nodes), superior DFS was found with 6 months versus 3 months duration of ELOXATIN® based adjuvant chemotherapy. In the low-risk group however, (T1-tumor invades submucosa, T2-tumor invades muscularis propria, or T3-tumor invades through the muscularis propria into the pericolorectal tissues and N1-metastasis in 1-3 regional lymph nodes), DFS was noninferior with 3 months versus 6 months duration of adjuvant chemotherapy.

In prespecified subgroup analysis by type of ELOXATIN®-based chemotherapy, 3 months of treatment was non-inferior to 6 months for patients treated with CAPOX regimen. However, 3 months of treatment was inferior to 6 months, for patients treated with FOLFOX regimen. It has been hypothesized that the protracted delivery of a Fluoropyrimidine with CAPOX might have been more effective than the twice-monthly 5-FUinfusions with FOLFOX as an adjuvant therapy. Grade 2 or more neurotoxicity was significantly lower for patients who received 3 months of adjuvant therapy versus 6 months (P <0.0001), regardless of the treatment regimen (17% vs 48% for FOLFOX and 15% vs 45% for CAPOX/XELOX, respectively).

It was concluded from this study that a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with Stage III Colon Cancer, taking into consideration choice of treatment regimen and duration of therapy. In patients treated with adjuvant CAPOX/XELOX regimen, 3 months of therapy was as effective as 6 months, particularly in the low risk subgroup. In patients treated with FOLFOX, 6 months of adjuvant therapy compared to 3 months, resulted in a higher rate of Disease Free Survival, particularly in the high-risk subgroup.

Guideline Question: What is the optimal duration (3 months vs 6 months) of ELOXATIN®-based chemotherapy for patients with completely resected Stage III Colon Cancer?

Target Population: Patients with completely resected Stage III Colon Cancer. Target Audience: Medical oncologists, general surgeons, colorectal surgeons, surgical oncologists, and oncology Advanced Practice Providers who treat patients with Colon Cancer.

Methods: A multidisciplinary Expert Panel which included clinicians with expertise in colorectal surgery and medical oncology as well as a patient representative and an ASCO guidelines health research expert, was convened to develop clinical practice guideline recommendations, based on a systematic review of the medical literature from April 2004 to August 2018, for Phase III randomized clinical trials (RCTs) that included a comparison of two or more durations of treatment with FOLFOX or CAPOX chemotherapy.

Recommendations for patients with Stage III resected Colon Cancer who are being offered treatment with ELOXATIN®-based chemotherapy.

Recommendation 1: For patients with High-risk (T4 and/or N2) Stage III resected Colon Cancer, adjuvant ELOXATIN®-based chemotherapy should be offered for a duration of 6 months.

Recommendation 2: For patients with Low-risk (T1, T2, or T3 and N1) Stage III resected Colon Cancer, adjuvant ELOXATIN®-based chemotherapy may be offered for a duration of 3 months or 6 months, after a discussion with the patient of the potential benefits and risks of harm associated with the options for treatment duration.

Recommendation 3: A shared decision-making approach should be used for duration of ELOXATIN®-based chemotherapy for patients with Stage III resected Colon Cancer, taking into account a patient’s tumor characteristics, completeness of surgical resection, number of lymph nodes examined, comorbidities, functional status, performance status, values and preferences, age at diagnosis, life expectancy, potential years at risk for long-term sequelae of treatment, and including a discussion of the potential for benefit and risks of harm associated with treatment duration.

Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline.Lieu C, Kennedy EB, Bergsland E, J Clin Oncol. 2019;37:1436-1447.