Adding mFOLFOX6 may allow less-invasive treatment of rectal cancer

Last Updated: 2015-07-24

By Will Boggs MD

NEW YORK (Reuters Health) - Adding cycles of mFOLFOX6 between chemoradiation and surgery increases the proportion of patients who achieve a pathological complete response, thereby opening the way to less-invasive surgical treatment, according to a new trial.

"Delivering FOLFOX after chemoradiotherapy but before surgery contributes to primary tumor response without compromising surgery," Dr. Julio Garcia-Aguilar from Memorial Sloan Kettering Cancer Center in New York told Reuters Health by email. "This approach may increase the proportion of patients who may eventually avoid a rectal resection."

Neoadjuvant chemoradiation before mesorectal excision induces tumor regression, increases the probability of achieving resection with negative margins, and reduces the risk of local recurrence, Dr. Garcia-Aguilar and colleagues note in the Lancet Oncology, online July 15.

Reasoning that chemotherapy after neoadjuvant chemoradiation might increase the tumor response, the researchers, from the Timing of Rectal Cancer Response to Chemoradiation Consortium, investigated the effect of delivering two, four, or six cycles of mFOLFOX6 between chemoradiation and surgery.

The phase 2, open-label trial included 292 patients with locally advanced rectal cancer at 17 institutions in the U.S. and Canada.

More cycles of mFOLFOX6 progressively increased the mean interval from completion of chemoradiation to total mesorectal excision: from 8.5 weeks without mFOLFOX6 to 19.3 weeks in the group that received six cycles of mFOLFOX6, the researchers found.

The proportion of patients achieving a pathological complete response increased from 18% with no mFOLFOX6 to 25% with two cycles, 30% with four cycles, and 38% with six cycles of mFOLFOX6. None of the patients experienced tumor progression during treatment.

The proportion of patients experiencing adverse events during mFOLFOX6 treatment also increased with increasing numbers of cycles.

There was no difference between groups in the proportion of patients who received sphincter-saving surgery and resection with negative margins. No patient died during or after surgery in any study group.

On multivariable analysis, the study group was the only independent predictor of pathological complete response, with the group receiving six cycles of mFOLFOX6 faring best.

"I see no reasons why not to try this approach in rectal cancer patients who would be candidates for neoadjuvant therapy," Dr. Garcia-Aguilar said. "This approach is particularly important if we believe that some rectal cancers can be eradicated completely by chemotherapy and radiation (we are testing this in a new study), because this approach - chemoradiation followed by FOLFOX - increases the proportion of responders."

"We need to wait for long term results - and probably larger studies - to determine if delivering systemic chemotherapy before rather than after surgery increases survival," Dr. Garcia-Aguilar concluded.

Dr. Andrés Cervantes from the University of Valencia in Spain, who co-wrote a linked editorial in the journal, cautioned that the new work is only a "hypothesis-generating study."

"This trial reinforces that extended chemotherapy in the preoperative treatment of rectal cancer should be studied in randomized phase III trials to confirm its potential value," he told Reuters Health by email.

The editorial, coauthored by Dr. Susana Roselló, concludes, "Although this hypothesis-generating trial does not modify practice, it opens several questions that may be relevant to answer in phase 3 trials. Could neoadjuvant chemotherapy affect the way we treat localized rectal cancer? Could chemotherapy replace chemoradiation in some patients? Can neoadjuvant chemotherapy increase the number of patients for whom a non-operative watch-and-wait approach can be recommended? Could neoadjuvant chemotherapy be better than adjuvant chemotherapy at controlling micrometastatic disease in patients with MRI-defined high-risk features? Patients are being enrolled into trials that aim to address these questions and some answers are expected in the near future."

The study was supported by the National Institutes of Health National Cancer Institute.

SOURCE: http://bit.ly/1HXkNrp and http://bit.ly/1MrwBbM

Lancet Oncol 2015.