5-FU Bolus Omission May Reduce Toxicity, Maintain Efficacy in GI Cancers

"The most significant benefit of this adjustment is that it makes the treatment more tolerable, potentially easing the chemotherapy experience for patients,” according to study author Shun Yu, MD.

Decreases in toxicity without a negative effect on overall survival (OS) outcomes occurred when omitting the 5-fluorouracil (5-FU) bolus from multi-agent chemotherapy regimens for patients with gastrointestinal (GI) cancers, according to data from a real-world study published in the Journal of the National Comprehensive Cancer Network.¹

After conducting an inverse probability of treatment weighted (IPTW) analysis, investigators noted that treatment without the 5-FU bolus did not confer an OS improvement (HR, 0.99; 95% CI, 0.91-1.07; P = .74). No significant differences in OS outcomes were reported across subgroups based on age, sex, ECOG performance status, cancer type, regimen, and other characteristics.

Investigators observed no differences in OS outcomes among patients who received the 5-FU bolus vs those who did not when stratifying by year of treatment (HR, 0.98; 95% CI, 0.91-1.06; P = .62), the type of chemotherapy regimen (HR, 0.97; 95% CI, 0.90-1.05; P = .51), or the type of cancer (HR, 0.98; 95% CI, 0.91-1.06; P = .62). Additionally, no significant differences in OS outcomes occurred when adjusting for oxaliplatin and irinotecan doses (HR, 0.98; 95% CI, 0.86-1.11; P = .78) and the administration of monoclonal antibodies or immunotherapy (HR, 1.00; 95% CI, 0.93-1.09; P = .83).

Among patients who received the 5-FU bolus and those who did not, respectively, the rate of any-grade neutropenia within 2 weeks of treatment per unadjusted analysis was 22.3% vs 14.6% (P <.01), and the rate of grade 3/4 neutropenia was 8.2% vs 6.0% (P <.01). Additionally, the rates of anemia in each group were 80.0% vs 81.7% (P = .33), and the rates of thrombocytopenia were 14.9% vs 16.4% (P = .07). Based on IPTW analysis, the rates of neutropenia were 22.7% vs 10.7%, respectively (P <.01), and the rates of thrombocytopenia were 16.1% vs 11.2% (P <.01).

When adjusting for oxaliplatin and irinotecan doses, investigators reported an increased risk of neutropenia (P = .02) and thrombocytopenia (P <.01) when the 5-FU bolus was administered. Additionally, 29.1% of patients who received the 5-FU bolus required granulocyte colony-stimulating factor compared with 19.6% who received treatment with the bolus omitted (P <.01).

“The true value of our findings lies in the empirical evidence they provide, which supports what many of us have long suspected. The most significant benefit of this adjustment is that it makes the treatment more tolerable, potentially easing the chemotherapy experience for patients,” study author Shun Yu, MD, a medical oncologist specializing in GI Oncology at NYU Langone Health, stated in a press release on these findings.² “[Although] 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.”

Investigators used the Flatiron Health database to assess real-world outcomes among patients with GI cancers who received multi-agent treatment at approximately 280 cancer clinics and 800 sites of care across the United States. Patients were included in the analysis if they received treatment with leucovorin calcium plus fluorouracil and oxaliplatin (FOLFOX); leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI); or leucovorin calcium in combination with fluorouracil, irinotecan hydrochloride, and oxaliplatin (FOLFIRINOX).

Additionally, patients 18 years and older with colorectal (CRC), pancreatic, or gastroesophageal cancers who were diagnosed between January 2011 and May 2022 were included. Only patients with metastatic disease were eligible for inclusion if they had CRC or pancreatic cancer; those with metastatic and/or unresectable gastroesophageal cancers were included.

The study involved the use of Cox proportional hazards and Kaplan-Meier analyses to evaluate OS outcomes in patients who received the 5-FU bolus (n = 10,148) compared with those who did not (n = 1617). Additionally, investigators used IPTW analysis to adjust for potential treatment selection bias.

Overall, the analysis included 11,765 patients; the median age was 63 years (range, 18-85). Additionally, most patients were male (59.6%), White (64.2%), and had an ECOG performance status of 0 or 1 (90.3%). The most common cancer types across the study population included CRC (n = 8670), gastroesophageal cancer (n = 1481), and pancreatic cancer (n = 1614). Regarding treatment regimens, patients commonly received FOLFOX (n = 8014) followed by FOLFIRI (n = 2137) and FOLFIRINOX (n = 1614).

Among patients who received treatment without the 5-FU bolus and those who were treated with the bolus, respectively, the median OS per unadjusted analysis was 23.6 months vs 24.5 months in the CRC subgroup (P = .13), 10.4 months vs 10.2 months in the gastroesophageal cancer group (P = .84), and 8.9 months vs 9.5 months in the pancreatic cancer cohort (P = .84). Across the entire study population, unadjusted analysis indicated a median OS of 20.3 months among patients who received the bolus vs 14.0 months among those who did not (HR, 0.74; 95% CI, 0.69-0.79; P <.01).

“This study offers solid evidence for not using a 5-FU bolus with FOLFOX/FOLFIRI/FOLFIRINOX regimens in advanced GI cancers,” Elena Gabriela Chiorean, MD, clinical director of Gastrointestinal Medical Oncology and a professor in the Clinical Research Division at Fred Hutch Cancer Center, as well as a professor of medicine and the clinical research director of Gastrointestinal Medical Oncology at the University of Washington School of Medicine, said in the press release.² “This large study shows that omitting the bolus 5-FU has no detrimental effect on survival but reduces [adverse] effects and health care costs.”

References

1. Peng C, Saffo S, Oberstein PE, et al. Omission of 5-fluorouracil bolus from multidrug regimens for advanced gastrointestinal cancers: a multicenter cohort study. J Natl Compr Canc Netw. Published online September 5, 2024. doi:10.6004/jnccn.2024.7029
2. New study in JNCCN supports chemotherapy option that reduces side effects for people with gastrointestinal cancers. News release. National Comprehensive Cancer Network. September 5, 2024. Accessed October 11, 2024. https://tinyurl.com/yyzhu3rt