Biggest Change Since 2004 in NCCN Colon Cancer Chemo Guide

Nick Mulcahy

March 23, 2018

ORLANDO, Florida — The National Comprehensive Cancer Network's (NCCN's) colon cancer guidelines have been changed to indicate that patients with low-risk stage III colon cancers can be treated with a shorter schedule of adjuvant chemotherapy.

The change is based on results from the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration. IDEA compared 3 months of treatment with the standard of 6 months of oxaliplatin-based chemotherapy regimens. Treatment was either FOLFOX (leucovorin, fluorouracil, oxaliplatin) or CAPEOX (capecitabine/oxaliplatin; also known as XELOX).

The results were first presented at the 2017 American Society of Clinical Oncology (ASCO) annual meeting, as reported by Medscape Medical News.

It was announced at the meeting that the IDEA results are due to be published soon in the New England Journal of Medicine.

"I believe we will have the first...important changes [in adjuvant chemotherapy] since 2004," commented Axel Grothey, MD, of the Mayo Clinic Cancer Center in Rochester, Minnesota.

The 2004 date is a reference to the adoption of 6 months of therapy with FOLFOX4 as standard of care, based on results from the MOSAIC trial.

In IDEA, investigators randomly assigned 12,834 patients to receive either 3 or 6 months of a chemotherapy regimen based on clinician/patient choice (this was not a comparison of the two regimens) to examine noninferiority of the shorter regimen.

The efficacy analysis, based on 3-year disease-free survival (DFS), failed to meet the prespecified noninferiority threshold. The 3-year DFS in the 3-month arm was lower than that in the 6-month arm by 0.9% (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.00 - 1.15). To show noninferiority, the upper limit of the 95% CI had to be 1.12 or less, so noninferiority was not established. But the failure was by such a slim margin that the investigators championed the briefer schedule.

The shorter duration is worth championing, the investigators said, because of reduced toxicity. There was dramatic reduction in neurotoxicity with 3 months of treatment (reported by 17% patients on FOLFOX and 15% on CAPEOX, 15%) compared with 6 months (48% and 45%, respectively; P < .0001).

The NCCN guidelines now incorporate the 3-month regimen of adjuvant chemotherapy. The guidelines also reflect the fact that different risk groups performed differently with the different regimens in the trial.

Specifically, the NCCN's stage III colon cancer treatment recommendations are differentiated on the basis of risk status:

  • Low-risk stage III is defined as pathologic stages T1-3N1. For these patients, the preferred treatments are CAPEOX for 3 months or FOLFOX for 3 to 6 months.

  • High-risk stage III disease is defined as pathologic stages T4N1-2 and AnyTN2. For these patients, the preferred treatments are CAPEOX for 3 to 6 months or FOLFOX for 6 months.

The guidelines note that rates of neurotoxicity of grade 3+ are lower for patients who receive 3 months vs 6 months of treatment (3% vs 16% for FOLFOX; 3% vs 9% for CAPEOX).

Despite the fact that the recommendations stratify patients on the basis of risk status, the number of patients who can judiciously be treated with less chemotherapy is huge, said speakers at last year's ASCO meeting.

In the United States, 20,000 patients per year have low-risk stage III tumors. It is not recommend that these patients receive more than 3 months of chemotherapy with an oxaliplatin-based regimen, said Grothey.

"That translates to hundreds of thousands of patients worldwide," he added.

History of Chemo in This Setting

At the NCCN meeting, Grothey also reviewed the history of chemotherapy in this setting.

He noted in particular the practice-changing results from the international randomized MOSAIC trial in 2004, which compared FOLFOX4 (LV5FU2 + oxaliplatin) with LV5FU2 alone. Both groups received 6 months of therapy.

Among previously untreated stage III patients (60% of total), 5-year DSF (the primary endpoint) was 66.4% for the FOLFOX4 group vs 58.9% for the LV5FU2 group — an absolute difference of 7.5% (P = .005). Eventually, a statistically significant improvement in overall survival was also seen with FOLFOX4.

But there was a problem with 6 months of treatment with the more potent FOLFOX4, said Grothey — the treatment was associated with peripheral sensory neuropathy. Among 811 evaluable patients from MOSIAC, after 3 years of treatment, 12% had experienced grade 1 neuropathy, 2.8% had experienced grade 2 neuropathy, and 0.7% had experienced grade 3 neuropathy.

Eventually, CAPEOX, the other oxaliplatin-based adjuvant chemotherapy, joined FOLFOX4 as standard of care.

In both treatments, oxaliplatin is associated with cumulative dose-dependent neurotoxicity, said Grothey. "It's debilitating for many patients, both short and long term," and the effects be permanent, he added.

Shorter duration of treatment would likely help with adverse events without a significant loss of efficacy, he suggested. That possibility led to IDEA, which has been a collaborative, international effort consisting of six large, well-designed studies conducted under the umbrella of a single analytical group led by the Mayo Clinic.

Dr Grothey has disclosed no relevant financial relationships.

National Comprehensive Cancer Network (NCCN) 23rd Annual Conference. Presented March 22, 2018.

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

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