The researchers behind a new Cancer Research UK-funded clinical trial have suggested that giving colon cancer patients chemotherapy before surgery can reduce the risk of disease recurrence by more than a quarter.
There are over 40,000 new cases of bowel cancer diagnosed in the UK each year, and almost 17,000 deaths. Standard treatment is surgery followed by adjuvant oxaliplatin-fluoropyrimidine chemotherapy for those with moderate-to-high risk disease.
Dr Laura Magill, associate professor, Birmingham Clinical Trials Unit, University of Birmingham, highlighted that up to "1 in 3 colon cancer patients can see their cancer come back after surgery". She stressed that that figure is "far too high" and that new treatment strategies to stop colon cancer coming back were needed.
The authors of the new study, published in the Journal of Clinical Oncology,hypothesised that neoadjuvant chemotherapy (NAC) had potential advantages over standard postoperative chemotherapy for locally advanced colon cancer.
In the FOxTROT trial, researchers led from the Universities of Birmingham and Leeds set out to determine whether giving the first 6 weeks of chemotherapy preoperatively might safely reduce recurrence risk in patients with locally advanced but operable colon cancer.
Residual or Recurrent Disease Less With Preoperative Chemotherapy
A total of 1053 colon cancer patients from 85 hospitals in the UK, Denmark, and Sweden were involved in the study. Patients with radiologically staged T3-4, N0-2, M0 colon cancer were randomly allocated (2:1) between 15 May, 2008 and 23 December, 2016 to 6 weeks oxaliplatin-fluoropyrimidine preoperatively plus 18 postoperatively ("NAC group") or 24 weeks postoperatively ("control group").
Baseline characteristics were balanced across groups, median age was 63 years, and baseline CT suggested T4 disease in 268 (25%) and lymph-node involvement in 792 (75%). Median follow-up was 3.1 years.
The primary endpoint was residual disease or recurrence within 2 years. Secondary outcomes included surgical morbidity, histopathological stage, regression grade, completeness of resection and cause-specific mortality.
The authors rejoiced in the fact that the primary end point – to detect a reduction in residual or recurrent disease within 2 years - was "achieved" – and reported that residual or recurrent disease occurred less often in NAC group patients than in control patients (16.8% versus 21.2%). The authors said that this corresponded to a 28% lower recurrence rate with NAC than with standard treatment.
They added that chemotherapy toxicity was similar whether given before or after surgery, and surgical complications were, "if anything, less in the neoadjuvant chemotherapy group".
"Giving the first 6 weeks of chemotherapy to colon cancer patients before, instead of after surgery, cuts their risk of cancer coming back within 2 years by 28%," the authors pointed out, and added that "6 weeks of chemotherapy before surgery could be used to treat at least 5000 patients in the UK every year".
The researchers also said that there were "fewer serious postoperative complications" with NAC than in the control group, and that resection was more often histopathologically complete with NAC (94% versus 89%).
Timing is Everything
Dr Magill commented: "The standard approach has been to give chemotherapy after surgery to eradicate any cancer cells that might have spread before surgery. But our research shows that giving some of that chemotherapy before surgery increases the chances that all cancer cells will be killed."
The authors expressed that "6 weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy for operable colon cancer can be delivered safely, without increasing perioperative morbidity, and produces marked histopathological down-staging, fewer incomplete resections, and better 2-year disease control".
Matthew Seymour, professor of gastrointestinal cancer research, University of Leeds, said: "Timing is everything when it comes to treating colon cancer. The simple act of bringing forward chemotherapy, giving it before instead of after surgery, delivers some remarkable results.
"Delivering chemotherapy before surgery could prevent recurrences of cancer without the need for expensive new drugs or technologies. It was especially encouraging to find that patients who had chemotherapy before their surgery suffered fewer surgical complications," he said.
The authors proclaimed that patients with locally advanced but resectable colon cancer, selected using standard CT, may safely undergo 6 weeks of NAC prior to colon resection. They underlined that this "does not increase perioperative morbidity", and that "substantial" tumour regression is achieved.
Moreover, disease control is "significantly better" at 2 years than with the same chemotherapy given entirely postoperatively, the authors pointed out.
Scale Up Preoperative Chemotherapy
The authors proposed that 6-week neoadjuvant chemotherapy should be considered as a treatment option for fit, non-obstructed patients with operable, mismatch repair (MMR)-proficient colon cancer where there is radiological evidence of at least T3 disease.
"A growing body of evidence is showing the value of pre-operative chemotherapy in several other cancers, and we believe that our results could transform how we approach colon cancer in the clinic," said Dr Magill.
The scientists are now undertaking two further clinical trials - FOXTROT-2 and FOXTROT-3 - to investigate whether older patients also benefit from chemotherapy before surgery and to investigate if adding in more chemotherapy drugs before surgery further reduces the chances of recurrence.
Professor Dion Morton, professor of surgery at the University of Birmingham, said: "In many parts of the world cancer treatments can be prohibitively expensive. We wanted to go in the opposite direction, testing a treatment that could be used on the widest possible group of patients."
Professor Seymour encouraged "scaling up" this treatment worldwide, including in low and middle income countries, and exalted that this could "transform cancer care and save many thousands of lives".
The FOxTROT was funded by Cancer Research UK. Additional support was provided by the Birmingham and Leeds ECMC network, the RCS Eng and Rosetrees Trust, and the Swedish Cancer Society.
