Making Fluorouracil “Sexy” Again

The antimetabolite 5-fluorouracil (5-FU) was patented by Charles Heidelberger in 1957 and continues to be a mainstay of gastrointestinal cancer therapy more than 60 years later. It should be noted that Dr Heidelberger also gave us 5-fluoro-2′-deoxyuridine (FUDR) and trifluoro-thymidine (now the main ingredient of TAS-102) and various other antiviral antimetabolites. These drugs are all rationally synthesized analogs of known DNA bases and nucleosides. Despite their apparent straightforward chemistry, we continue to learn how to best use 5-FU and other such agents in the clinic more than 60 years after their introduction.

In this issue of JNCI, Wagner and colleagues (1), using the remarkable ACCENT (Adjuvant Colon Cancer Endpoints) database, add further to this clinical knowledge. This database, assembled by the late and greatly missed Dan Sargent, Chief Statistician and Statistics Chair at Mayo Clinic, includes more than 34 000 patient records from randomized adjuvant colon cancer trials. Using these data, the authors report that female patients treated with 5-FU–based therapy have more hematologic toxicity, including leukopenia and neutropenia (but not thrombocytopenia or anemia), and some greater nonhematologic toxicity (all with hazard ratio [HR] = 1.50 to approximately 3). Data on other relevant cancer-related outcomes, such as recurrence, disease-free survival (DFS), or overall survival (OS), are not reported in the study. Of interest, a prior analysis by the ACCENT investigators of a similar number of patients demonstrated improved disease-free survival (HR = 1.12, P < .0001) and OS (HR = 1.13, P < .0001) for female patients, with a small improvement in time to recurrence (HR = 1.05, P = .0073), though unadjusted 5-year recurrence-free survival rates were 67% vs 66% (2). Regardless, these toxicity data certainly raise questions about standard body surface area (BSA)-based dosing practices for 5-FU and if men are, in fact, somewhat underdosed.

5-FU metabolism is highly variable, with an estimated intra-patient variability as high as 50% (3). Sex appears to be an important factor in this variability, with consistent data suggesting lower clearance of 5-FU in women (4,5). Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in catabolism of pyrimidines, namely uracil and thymine, but also, critically, 5-FU. DPD converts 80%-85% of 5-FU to 5,6-dihydro-5-fluorouracil, which is then converted to the major metabolite, α-fluoro-β-alanine (FBAL), thought to be responsible for some unique toxicities, in particular palmoplantar erythrodysesthesia (hand-foot syndrome) (6). Importantly, DPD plays a crucial role in determining the amount of available 5-FU for conversion to the active nucleotides fluorodeoxyuridine monophosphate, fluoroudeoxyridine diphosphate, and fluorodeoxyuridine triphosphate. However, DPD is expressed variably and undergoes diurnal activity fluctuations (7). In addition, DPD deficiency (full or partial) is observed in 3%-8% of the population, classically due to DPYD polymorphisms (8). Finally, DPD levels have been reported to be 15% lower in women, perhaps a clinically meaningful contributor to the aforementioned lower clearance (9).

Some of this inherent variability could be reduced through the combination of oral fluoropyrimidines with reversible DPD inhibitors, including UFT (uracil and tegafur combination) and S-1 (CDHP, 5-chloro-2.4-dihydroxypyridine), or eniluracil, an irreversible DPD inhibitor. The use of such agents produce a more consistent and predictable pool of available 5-FU. Because tumor expression of DPD may also be variable, with higher levels predicting 5-FU resistance, a strategy that includes robust DPD inhibition may also yield therapeutic gains. Yet, prospective, phase III randomized trials of UFT, S-1, and eniluracil in colon cancer have failed to show survival benefit compared with FU with or without leucovorin.

Therapeutic drug monitoring presents an additional future avenue for mitigation of toxicity and optimization of efficacy. One of the few prospective studies randomly assigned 208 patients with metastatic colorectal cancer to “conventional dosing” or pharmacokinetically (PK) guided dosing using an unconventional dose schedule: 5-FU 1500 mg/m²/wk over an 8-hour infusion with folinic acid 200 mg/m² weekly. In the PK-guided arm, the response rate was improved (33.7% vs 18.3%) with lower toxicity rates and a non-statistically significant different OS (22 vs 16 months, P = .08) (10). A nonrandomized study from the same group compared 118 patients with metastatic colorectal cancer who received FOLFOX (5-FU, Leucovorin, and Oxaliplatin) and PK-guided 5-FU dosing with 39 patients who received standard BSA-based dosing. Again, toxicity was lower and efficacy seemed to be greater, with 80% of patients in the PK-guided arm requiring dose adjustments to achieve the target range (3). Although these data are a far cry from definitive or practice changing, it supports the premise that PK-guided dosing of 5-FU merits further attention.

Nonetheless, the important issue of sex differences has been largely ignored in oncology trials, perhaps because our randomized trials are generally one order of magnitude smaller than cardiovascular trials and oncology trials are underpowered for subset analyses. But, we must, in this day and age, pay more attention to the issues of sex and outcomes, be they positive or negative. We call on our clinical trial colleagues to report on these factors and, to the extent possible, power subset analyses to address important sex-based differences.

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Disclosures: The authors have no relevant disclosures. The authors contributed equally to this opinion piece.