A phase 3 trial, FOxTROT, showed that 6 weeks of neoadjuvant chemotherapy with oxaliplatin-fluoropyrimidine in patients with locally advanced colon cancer resulted in better disease control at 2 years when compared with adjuvant chemotherapy.
Marked tumor down-staging and increased complete resection rates were also reported with neoadjuvant chemotherapy.
Further study is needed before adopting neoadjuvant chemotherapy in patients with locally advanced colon cancer as the standard of care over up-front surgical resection.
For patients with colon cancer, the standard approach to therapy has been to give chemotherapy after surgery, to eliminate any cancer cells that may have spread. However, up to a third of people with colon cancer have a recurrence after surgery.
In other cancers, preoperative chemotherapy has shown some value, and thus colon cancer investigators wondered if this might help patients with colon cancer as well. Now, results of the phase 3 FOxTROT trial indicate that it does. In fact, the chance of recurrence at 2 years was reduced by 28% for patients getting preoperative chemo over that for patients who received chemo postoperatively. The study was published in the Journal of Clinical Oncology.
Design of FOxTROT
The trial was funded by Cancer Research UK and conducted among 85 hospitals in the UK, Denmark, and Sweden.
Enrolled were 1053 patients (median age, 63 years) with radiologically staged T3-4, N0-2, M0 colon cancer. The study was conducted between May 15, 2008, and December 23, 2016; median follow-up was 3.1 years.
The patients were randomly assigned to the neoadjuvant oxaliplatin-fluoropyrimidine chemotherapy group—receiving 6 weeks of chemotherapy preoperatively plus 18 weeks postoperatively—or to the control group, which received 24 weeks of chemotherapy postoperatively.
The primary outcome was residual disease or recurrence within 2 years. Secondary endpoints included surgical morbidity, histopathologic stage, regression grade, resection completeness, and cause-specific mortality.
Of the 699 patients who received chemotherapy before surgery, 606 (87%) completed treatment. Surgery was performed in 98.1% (686/699) of the patients who received neoadjuvant chemotherapy and in 99.2% (351/354) of the patients in the control group.
Preoperative chemo delivered safely
The study results indicated that 6 weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy could be delivered safely. In the neoadjuvant chemotherapy arm, 30 patients (4.3%) developed obstructive symptoms requiring expedited surgery. However, overall, fewer serious postoperative complications were reported with neoadjuvant chemotherapy than with the control therapy.
Preoperative chemo met the primary outcome
The primary outcome was achieved. The rates of residual or recurrent disease within 2 years were 16.9% and 21.5% for the neoadjuvant chemotherapy and control groups, respectively.
Neoadjuvant chemotherapy produced “marked” tumor and node downstaging and histologic tumor regression, along with fewer incomplete resections.
For the neoadjuvant chemotherapy and control groups, the complete resection rates were 94% and 89%, respectively. Mismatch repair (MMR)–deficient cancers had a lower response than did MMR-proficient cancers.
The authors noted that histologic regression after neoadjuvant chemotherapy is a “strong predictor of lower postoperative recurrence risk,” and therefore it could potentially be used as a guide for postoperative therapy.
A 2021 study by Chinese investigators reported that tumor regression grade is a prognostic factor in predicting long-term outcomes of patients with metastatic colon cancer treated with preoperative chemotherapy. The 276-patient study included patients with locally advanced cancer and metastatic cancer. The 3-year overall survival in the entire cohort for patients with complete or good tumor regression grade response was 80.0%; it was 68.8% and 43.3% for moderate and poor response, respectively.
Study author Laura Magill, PhD, associate professor at the Birmingham Clinical Trials Unit, University of Birmingham, England, commented on the implications of the FOxTROT study:
"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.” — Laura Magill, PhD"
— Laura Magill, PhD
Andrew H. Ko, FASCO, MD, associate editor of the Journal of Clinical Oncology, and professor of clinical medicine at UCSF Cancer Center in San Francisco, also put the study in context. He stated that, for patients with clinical stage T3+ operable, MMR-proficient colon cancer, “a short course of neoadjuvant chemotherapy is a reasonable treatment option.”
However, he noted that further study and validation are needed “before adopting this as the preferred standard of care over up-front surgical resection.”
While this is a trial offers hope, the OPTICAL trial did not demonstrate improved disease-free survival with the use of neoadjuvant chemotherapy therapy. The trial included 752-patients with radiologically staged locally advanced colon cancer, who were randomly assigned to three months of neoadjuvant FOLFOX or CAPOX followed by surgery and three additional months of chemotherapy, or immediate surgery followed by adjuvant chemotherapy given at the discretion of the treating clinicians. In preliminary results, the pathologic complete response rate with neoadjuvant chemotherapy therapy was 7%. Despite a lower pathologic disease stage overall, disease-free survival for neoadjuvant chemotherapy was similar to that of surgery plus adjuvant chemotherapy.
The FOxTROT investigators are planning two further clinical trials, FOXTROT-2 and FOXTROT-3, to see whether older patients also benefit from chemotherapy before surgery. An additional objective is to test whether adding more chemotherapy drugs before surgery further reduces the risk of cancer recurrence.
What this means for you
A short course of neoadjuvant chemotherapy may be considered for select patients with locally advanced colon cancer, such as those with potentially compromised surgical margins. However, further study is needed before adopting this as the preferred treatment over initial surgery followed by adjuvant chemotherapy.