FOxTROT trial supports use of neoadjuvant chemotherapy for operable colon cancer

CHICAGO — Administering chemotherapy 6 weeks before surgery for colon cancer was safe and reduced postoperative morbidity without adding to the cost or burden of treatment, according to recent findings from the FOxTROT trial.

Despite these benefits, the trial failed to meet its primary endpoint of recurrent- and persistent-free disease 2 years after surgery.

“There was a trend towards improved 2-year relapse rate, which reached the target HR but did not reach our predetermined significance level,” Matthew T. Seymour, MD, professor of gastrointestinal cancer research at the University of Leeds School of Medicine, said during a presentation. “There was also highly significant downstaging and a reduced risk of incomplete resection.”

According to Seymour, little progress has been made in postoperative adjuvant therapy for colon cancer since oxaliplatin was introduced 15 years ago in the MOSAIC trial. Neoadjuvant chemotherapy, he added, offers potential benefits.

“A response in the tumor might reduce the risk of incomplete surgical resection,” Seymour said. “Neoadjuvant therapy means that we can treat micrometastases 2 to 4 months sooner than we do with postoperative adjuvant therapy. It [also] gives us an opportunity to assess response and to personalize treatment, perhaps in the postoperative phase.”

Seymour and colleagues launched the FOxTROT trial in 2008 to further investigate the benefits of neoadjuvant chemotherapy. The researchers enrolled 1,052 patients with operable, non-obstructed colon cancer who had CT scan-predicted T3- or T4-stage disease and no metastases. The study was conducted across 85 centers in the United Kingdom, Denmark and Sweden.

Patients were randomly assigned in a 2:1 ratio to receive 6 weeks of neoadjuvant chemotherapy with modified FOLFOX (folinic acid, fluorouracil and oxaliplatin), followed by 18 weeks of postoperative modified FOLFOX (intervention arm; n = 698), or 24 weeks of postoperative modified FOLFOX (control arm; n = 354).

“The primary research question was: Does neoadjuvant chemotherapy increase the cure rate? And the outcome to measure that was relapse or persistent disease measured out to 2 years following randomization,” Seymour said.

Secondary outcomes included complete resection rates, perioperative safety, and tumor downstaging and regression.

There were two “dealer’s choices” within the trial. Physicians could choose to replace modified FOLFOX with XELOX (oxaliplatin [Eloxatin] and capecitabine [Xeloda]) as the chemotherapy backbone for patients who did not receive panitumumab. They could also shorten the duration of chemotherapy from 24 weeks to 12 weeks in older, low-risk patients.

A substudy was also conducted to assess the benefit of adding panitumumab (Vectibix, Amgen) to neoadjuvant chemotherapy. Patients with KRAS wildtype tumors were randomly assigned to neoadjuvant therapy with or without the agent. The primary endpoint of this analysis was histological response, which will be reported later this year, according to Seymour.

Of the 1,052 patients, 98.2% in the intervention arm and 97.7% in the control arm moved forward with attempted curative resection. However, 4% and 27%, respectively, did not receive postoperative chemotherapy because the patient was too unwell, refused treatment, or had a tumor that was considered low risk. In both treatment arms, 28% of patients received XELOX and 6% received the shorter chemotherapy regimen.

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There were “no surprises” in terms of chemotherapy toxicity profiles, according to Seymour. In addition, there was no association between neoadjuvant chemotherapy and greater surgical morbidity.

“In fact, there were fewer major surgical complications,” Seymour said.

Patients who received neoadjuvant chemotherapy had a substantially lower risk for anastomotic leaks or intraabdominal abscesses (4.7% vs. 7.4%) and complications requiring additional surgery (4.3% vs. 7.1%).

There was a nonsignificant increase in the 2-year recurrent- and persistent-free disease rate, which was 13.6% in the intervention arm and 17.2% in the control arm. The lack of clinical significance was attributed to the low recurrence rate in the control arm, Seymour said.

“When the trial was powered, we were anticipating between 25% and 32% recurrence rate at 2 years,” he added. “... Thanks to the lower event rate, we did not reach the specified significance level.”

Neoadjuvant therapy was associated with a substantial reduction in failed resections. The risk for undergoing surgery without achieving a microscopically complete resection was 4.8% in the intervention arm and 11.1% in the control arm. There were also reductions in tumor stage, tumor size and nodal status (P < .0001). At the time of surgery, there was a higher complete response rate (3.5% vs. 0%) and fewer cases of no regression (33.9% vs. 78.8%) in the intervention arm compared with control arm (P < .0001).

In a sensitivity analysis, there was no evidence that panitumumab impacted the overall study findings, including tumor regression or 2-year relapse rates, according to Seymour.

Results of an exploratory subgroup analysis suggested that neoadjuvant therapy was less effective in patients with deficient mismatched repair (MMR) status (n = 173). Nearly 74% of these patients had no tumor regression vs. 26.6% of patients with proficient MMR status. Seymour also reported that proficient MMR status was associated with a “borderline significant” increase in 2-year recurrent- and persistent-free disease. However, these findings need to be validated, he said.

“To conclude, this FOxTROT trial did not reach the target significance for its primary endpoint,” Seymour said. “In that sense, it was a negative trial. However, what we have shown with some confidence is that moving 6 weeks of chemotherapy ahead of the surgery, which does not involve a major addition to either the cost or the patient burden of treatment, was safe. We saw less major post-operative morbidity; we saw significantly downstaged tumors and a reduced rate of incomplete resections; and we saw a strong trend towards improved 2-year cancer control. On that basis, we feel that this approach can be considered a new therapeutic option for locally-advanced operable colon cancer.” – by Stephanie Viguers

Reference:

Seymour MT, Morton D. Abstract 3504. Presented at: ASCO Annual Meeting; May 31- June 4, 2019; Chicago.

Disclosures: Morton and Seymour report receiving research funding on behalf of their institutions from Amgen.