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Vive La Difference: Sex and Fluorouracil Toxicity

St Vincent’s Cancer Center, New York, NY

C OLORECTAL CANCER is an important disease, with 135,400 cases occurring in the United States in 2001. This is also a disease that effects both men and women in approximately equal numbers.¹ There is an increasing role for chemotherapy in colorectal cancer; for at least 10 years, adjuvant chemotherapy has been used based on improved survival in patients with resected colon cancer at high risk for recurrence.² Chemotherapy is also widely used in cases with metastatic colorectal cancer^3,4, and fluorouracil (5-FU) is still, after more than 40 years, the mainstay of both adjuvant and advanced-disease chemotherapy regimens in colon cancer.

In this issue of the Journal of Clinical Oncology, Sloan et al⁵ address an issue important to clinicians by exploring variations in toxicity between men and women receiving 5-FU for the treatment of large bowel cancer. Sloan et al have produced a well-written meta-analysis of five North Central Cancer Therapy Group (NCCTG) clinical trials in which bolus schedules of 5-FU and leucovorin were used. Therapeutic outcome and toxicity were analyzed in 1,093 women and 1,355 men who participated in three advanced-disease and two adjuvant chemotherapy trials. The compelling result reported by Sloan et al is convincing evidence supporting important differences in the degrees of toxicity experienced by men and women in these clinical trials. The major end points of this study were the incidence of stomatitis, leukopenia, alopecia, diarrhea, nausea, and vomiting. With the exception of severe nausea and vomiting, women experienced more toxicity from 5-FU than men. Almost 50% of women, as opposed to approximately 40% of men (P < .001), experienced severe (grade 3 or greater) toxicity.⁵ Because the goal of cancer treatment in general, and chemotherapy administration in particular, is to benefit patients by improving survival and by palliating cancer-related symptoms, while minimizing negative impacts on quality of life, the implication of a very commonly used therapy having significantly more toxicity in women than in men is great.

In considering the results reported by Sloan et al,⁵ clinicians must ask several questions. First, should we believe these results? Is 5-FU truly more toxic in women? Secondly, if we believe these results, how can we explain them? Are there biologic, pharmacologic, pharmacogenomic, or other reasons for these findings? Finally, if it is necessary to use 5-FU in women and if women are at more risk for toxicity, are there ways that we may manage that toxicity while maintaining the potential for benefit from 5-FU–based chemotherapy in women?

First, should we believe these data? I believe both the data and the interpretation of the data. One may have a great deal of confidence in the size of this database. There were a large number of cases (n > 2,400) included. Data capture was excellent, and there are no detectable flaws in the analyses and interpretation of these data. One could ask did women receive higher doses, or more dose-intense chemotherapy than men, which could explain increased toxicity. The answer to this question is no. All doses and dose reductions were protocol-mandated, and there were no differences in doses planned or delivered between men and women. Women experienced significantly greater grade 3 or worse toxicity in all cycles of therapy. This is an important finding suggesting an intrinsic sensitivity to this chemotherapy in women, because women experienced greater cycle 1 toxicity and, therefore, had greater cycle 2 and 3 dose reduction than men. Women still experienced increased toxicity in later cycles of therapy even though they were receiving lower doses of fluorinated pyrimidine. Another concern would be a reporting bias. Do women, compared with men, report worse grades of such toxicity as mucositis and diarrhea? Although there may be a subjective component to the definition of mucositis and diarrhea, that is not the case with leukopenia, and women experienced worse grades of leukopenia than men. Finally, in one highly subjective toxicity, severe nausea, there was not a significant difference between men and women supporting the lack of sex-based reporting bias.

If we are able to feel very comfortable in believing these data, how can we explain the increased toxicity in women? It could be that women and their tumors are more sensitive to 5-FU, and lower doses of the drug have an increased pharmacologic or antitumor effect in women. If this were the case, one might expect to see increased antitumor effect in women than in men. This was not the case, because the meta-analysis shows that 5-year survivals in both advanced disease (3% and 2%) and in adjuvant studies (66% and 67%) were no different between women and men.

There has been much interest in understanding the relationship of molecular markers in tumor cells to response after treatment with fluorinated pyrimidine chemotherapy. Work by a number of translational scientists^6-8 has suggested that low levels of the 5-FU target enzyme thymidylate synthase (TS) and low levels of dipyrimidine dehydrogenase (DPD), the major catabolizing enzymes of 5-FU, result in improved tumor response and survival with fluorinated pyrimidine therapy. One could hypothesize that the same low levels of these enzymes favoring tumor response would, in normal tissue, predispose to toxicity. Sloan et al⁵ reports there are no studies that show consistent differences in TS levels between the sexes. Might there be consistent differences in DPD activity between men and women? There are data showing that the area under the curve, a measurement of plasma 5-FU level, is increased in women compared with men. Profound DPD deficiency is very infrequent, with approximately 20 cases in the literature.^7,9 When it occurs, it may result in lethal toxicity after 5-FU therapy. Severe DDP deficiency, therefore, has little relevance to the modestly increased toxicity in women demonstrated by Sloan. Much of the work done with TS levels and response to fluorinated pyrimidine has been performed by measuring TS or TS m-RNA in tumor specimens. Recently, there has been interest in defining genetic polymorphisms of TS expression in normal tissue. High- and low-expression¹⁰ genotypes have been defined. This work has been aimed at correlating TS levels and response to chemotherapy. It would, therefore, be appropriate to examine normal tissue TS polymorphisms by sex to see whether there are differences that may correlate with toxicity. In summary, there are no easy answers to the causes of increased toxicity of fluorinated pyrimidines in women. The reasons for this finding are likely multifactorial, including pharmacokinetic and possibly pharmacogenic factors.

Given the fact that 5-FU (as given in the NCCTG studies) is more toxic in women than men, what is a clinician to do if 5-FU is part of the appropriate therapy for a woman? Perhaps the first thing to do is to avoid 5-day bolus 5-FU/leucovorin schedules, which were the predominant schedules of therapy in the studies analyzed by Sloan. There are alternative doses and schedules that produce more modest toxicity in all patients. Infusional fluorinated pyrimidines are clearly an option. In a Southwest Oncology Group (SWOG) phase II study,¹¹ 620 cases with advanced colorectal cancer were randomized to low-dose continuous-infusion 5-FU, high-dose weekly infusions of the drug, and the 5-day bolus 5-FU/leucovorin regimen similar to that used in many of the NCCTG studies. Although toxicity was not analyzed by sex, it was significantly different between the infusional and bolus regimens. Grade 3 or worse toxicity in the weekly 24-hour and continuous low-dose infusion regimens varied between 6% and 11%. In contrast, the 5-day bolus regimen resulted in 47% grade 3 or worse toxicity.¹¹ A similar Eastern Cooperative Oncology Group study,¹² with over 1,100 cases, evaluated weekly high-dose 24-hour infusion (2,600 mg/m²) 5-FU regimens versus bolus 5-FU/leucovorin regimens. Grade 4 or greater toxicity was seen in 11% of infusional cases versus 22% to 30% in the bolus arms. Another alternative approach for the use of fluorinated pyrimidines in colon cancer is the oral prodrug of 5-FU, capecitabine. Capecitabine⁴ has been shown to produce equal therapeutic benefit to 5-day bolus 5-FU/leucovorin but with relatively modest toxicity.

In summary, 5-FU is a commonly used agent in a variety of gastrointestinal and other malignancies. Sloan et al⁵ has provided clinicians and clinical investigators with valuable information on sex and the toxicity produced by this agent, effectively drawing our attention to the important finding of toxicity differences between sexes. In support of these findings are emerging data (K. Chansky, personal communication, December 2001) from SWOG. In an analysis of toxicity data from 1,074 patients on four SWOG studies using 5-FU, women were shown to experience a greater number of different types of toxicities (P = .009) and a greater number of severe toxicities (P = .02) than men. As a result of this evolving evidence of sex differences in toxicity, translational scientists have had a challenge presented to them to understand the mechanisms resulting in increased toxicity in women. Clinicians, having been made aware of the potential for negatively effecting quality of life in women treated with certain doses and schedules of 5-FU, may choose not to use this drug in women if there are alternative therapies available. If 5-FU is the appropriate drug for a woman, oncologists are now aware of a number of options for delivering 5-FU in ways that may both minimize toxicity and maintain efficacy.

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