Status Report: Expert Reviews Guideline-Based Options in Advanced CRC

Jason Harris
Published: Wednesday, Jun 13, 2018
Rona D. Yaeger, MD

Rona D. Yaeger, MD

Three months of adjuvant chemotherapy could be a viable option for most patients with advanced colorectal cancer (CRC), and the addition of targeted therapy should be considered for those with metastatic disease. All patients diagnosed with CRC should be tested for mismatch repair deficiency (dMMR) and microsatellite instability (MSI) to screen for Lynch syndrome and potential treatment with immune checkpoint immunotherapy.

That was the bird’s eye view of standard therapy for patients with advanced or metastatic disease that Rona D. Yaeger, MD, provided at the 3rd Annual School of Gastrointestinal Oncology™ (SOGO®) in April. Yaeger, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, led her audience through a review of pivotal developments that have shaped the National Comprehensive Cancer Network guidelines in the past several years.

The most debatable recommendation concerns recently published data from the IDEA trial suggesting that a shorter course of treatment is safe and effective. “As we think now about adjuvant therapy,” she said, “the question is, do we need to continue therapy for the entire 6 months of treatment? This has become increasingly important because of the cumulative neuropathy that develops with the oxaliplatin, which can be hard to detect while patients are on treatment and can catch up with you after patients have received most of the course of treatment.”

In the landmark MOSAIC trial, investigators established that combination therapy of bolus plus continuous infusion fluorouracil with leucovorin (LV5FU2) would be improved by adding oxaliplatin (FOLFOX4). Patients with stage III disease who received FOLFOX4 experienced a statistically significant disease-free survival (DFS) benefit of 7.5% compared with those treated with LV5FU2 (P = .005).1

However, the rate of grade 3 peripheral sensory neuropathy was 12.5% in the FOLFOX4 group compared with 0.2% in the LV5FU2 group. Eighteen months after study completion, the rate of grade 3 neuropathy was 24.1% versus 0.7%, respectively.1

These results inspired investigators and clinicians to reconsider the necessity of 6 months of adjuvant treatment for these patients. In IDEA, a prospective pooled analysis of 6 phase III trials, patients with stage III disease were randomly assigned to investigator’s choice of FOLFOX (5-fluorouracil plus leucovorin and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) for 3 or 6 months. The primary endpoint was noninferiority for the 3-month regimen.

DFS rate in the 3-month arm was 74.6% versus 75.5% in the 6-month arm (HR, 1.07; 95% CI, 1.00-1.15). The 3-year difference in DFS was –0.9% (95% CI, –2.4 to 0.6). The prespecified boundary for noninferiority was 1.12, so IDEA technically did not con rm noninferiority for the broad population.2

However, in the subgroup analysis, the DFS rate for the FOLFOX arm was 81.9% in the 3-month arm and 83.5% in the 6-month arm for patients with low-risk disease (tumor stage 1-3; nodal status 1). The DFS rate was slightly better for low-risk patients in the CAPOX group assigned to 3 months versus 6 months of treatment (85.0% vs 83.1%, respectively).3 “Even with 3 months, they have a better disease-free survival,” Yaeger said.

In patients with high-risk disease, the DFS rate in the FOLFOX group was slightly poorer with 3 months of treatment (61.5% vs 64.7%), but there was no clear difference between 3 and 6 months of CAPOX (64.1% vs 64.0%).

“There’s been a lot of discussion about this trial, and it leads us to have longer conversations and more informed discussions with our patients,” Yaeger said. “But it’s reasonable to consider 3 months of treatment based on patient choice and based on the risk of disease.”

The findings raise the question of whether CAPOX is a better regimen, she said, noting that combination is more frequently administered in Europe, where familiarity may result in higher adherence rates.

Targeted Therapies in Metastatic Disease

Combination therapy is the preferred modality for metastatic CRC (mCRC), according to NCCN guidelines. Yaeger said the FOLFOX or FOLFIRI (5-fluorouracil plus leucovorin and irinotecan) chemotherapy regimens produce equal outcomes with similar response rates in about 50% of patients. “Whatever regimen is chosen, the other can be used in a second-line setting,” she added.

SWOG 80405 explored investigator’s choice of FOLFOX or FOLFIRI combined with cetuximab (Erbitux) or bevacizumab (Avastin) as first-line therapy for patients with mCRC and KRAS wild-type tumors (codons 12 and 13). Cetuximab targets EGFR; bevacizumab, VEGF.

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