A large multicenter study of more than 11,000 patients suggests that tweaking multi-drug chemotherapy treatments that are commonly used to treat metastatic or advanced gastrointestinal cancers can reduce side effects without affecting survival.
The findings, in the Journal of the National Comprehensive Cancer Network, showed that omitting the bolus, quick-delivery component of 5-fluorouracil (5-FU) and simply using its continuous infusion in first-line multidrug regimens could reduce treatment toxicity without compromising life expectancy.
Patients who initially received the short, intravenous bolus injection of 5-FU were significantly more likely to experience cytopenia than those just given 5-FU infusion during FOLFOX,FOLFIRI, and FOLFIRINOX multidrug regimens.
“The most significant benefit of this adjustment is that it makes the treatment more tolerable, potentially easing the chemotherapy experience for patients,” said lead researcher Shun Yu, MD, from NYU Langone Health medical center.
For decades, the most effective treatment for gastrointestinal cancers was the use of a 5-FU bolus injection followed by its continuous infusion, Yu explained.
However, the standard of care evolved into multi-drug regimens in the early 2000s following the discovery that adding to the two-component 5-FU backbone significantly improved patient outcomes.
“While the value of the 5-FU bolus was well established in the older single drug regimens, its role in these newer multi-drug combinations was never thoroughly tested and was largely just assumed,” he continued.
The 5-FU multidrug regimens FOLFOX, FOLFIRI, and FOLFIRINOX are now cornerstones in the treatment of gastrointestinal cancers and typically include a short intravenous bolus injection of 5-FU followed by a prolonged infusion over 46 to 48 hours.
The rationale behind this is that the bolus dose minimizes the time needed to reach a steady state therapeutic drug concentration. However, 5-FU has a half-life of eight to 20 minutes and therapeutic levels occur quickly with infusion.
To examine whether the bolus could be omitted, the team studied a U.S. database that used electronic health records from approximately 280 cancer clinics.
Patients included in the current study were aged at least 18 years and diagnosed with metastatic or advanced colorectal, pancreatic, or gastroesophageal malignancy between January 2011 and May 2022 for which they received FOLFOX, FOLFIRI, or FOLFIRINOX multidrug regimens.
Participants were categorized as receiving a “standard” dose of 5-FU bolus if they received a 400 mg/m2 ± 25% injection of 5-FU on the date of treatment plus infusion. The infusion dose of 5-FU was 2400 mg/m2 ± 25% and patients who did not get both a bolus and infusion dose were omitted from the bolus group.
Among 18,821 patients with GI cancers treated with 5-FU multi-drug regimens, 11,765 were ultimately included. Of these, 73.7% had colorectal cancer, 12.6% had gastroesophageal cancer, and 13.7% had pancreatic cancer.
Among the 5-FU regimens, 68.1% patients received FOLFOX, 18.2% received FOLFIRI, and 13.7% received FOLFIRINOX. Overall, 86.3% of patients received the standard-dose 5-FU bolus on the first day of their treatment.
Inverse probability treatment weighting (IPTW) was used to reduce imbalances in measured confounders between treatment groups.
Following IPTW analysis, patients who received the 5-FU bolus were significantly more likely to experience neutropenia—indicating a compromised immune system— than those who did not, at 22.7% versus 10.7%.
Patients who received the 5-FU bolus were also significantly more likely to experience thrombocytopenia, or bleeding issues, within 14 days of treatment, at 16.1% versus 11.2%, although this was not apparent in unadjusted analyses.
There were no differences in rates of anemia.
The researchers conclude: “Our data suggest that omitting the 5-FU bolus may lead to reduced treatment toxicity without compromising efficacy.”
