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© 2002 American Society for Clinical Oncology Women Experience Greater Toxicity With Fluorouracil-Based Chemotherapy for Colorectal CancerByFrom the Mayo Clinic and Mayo Foundation, Rochester, MN; Geisinger Clinic & Medical Center Community Clinical Oncology Program, Danville, PA; and Saskatchewan Cancer Foundation, Allan Blair Memorial Center, Regina, Saskatchewan, Canada. Address reprint requests to Jeff Sloan, PhD, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; email: jsloan{at}mayo.edu
PURPOSE: The toxicity profile of fluorouracil (5-FU)–based chemotherapy given on 5 consecutive days at doses of 370 to 450 mg/m2 has been well documented. A meta-analysis of six North Central Cancer Treatment Group (NCCTG) cancer control trials involving 786 patients indicated that women treated with this type of regimen experienced more severe stomatitis and leukopenia than men. After these findings, an additional meta-analysis of the toxicity profiles on five NCCTG colorectal cancer treatment trials was undertaken. METHODS: Data for 1,093 women and 1,355 men from 12 different treatment arms were included. The primary end points were the incidence of stomatitis, leukopenia, alopecia, diarrhea, nausea, and vomiting, recorded with standard National Cancer Institute common toxicity criteria. Fisher’s exact test was used to compare incidence and severity across sexes, supplemented by Forrest meta-analysis plots and logistic regression. RESULTS: The incidence of four out of six toxicities studied was significantly greater for women than men; the exceptions were severe nausea and vomiting. Overall, almost half of the women compared with a third of the men experienced severe toxicity (P < .0001). Logistic regression confirmed the univariate findings while adjusting for the effects of study, dose, body mass index, and age. The differences were consistent across treatment cycles. Response rates and survival distributions were the same for both sexes. CONCLUSION: This study confirms an earlier finding that women receiving 5-FU–based chemotherapy in a 5-day bolus schedule experience toxicity more frequently and with more severity than men. These data raise the question of whether the recommended initial dose of 5-FU–based chemotherapy for women should be lower than that for men.
FLUOROURACIL (5-FU) HAS been the focus of considerable research as a chemotherapeutic agent for colorectal cancer.1 A MEDLINE search revealed that more than 350 articles on 5-FU treatment were published from 1996 to 2000 in the cancer literature alone. Three commonly used regimens in North America are the so-called Mayo, Roswell Park, and low-dose infusion regimens. Infusional administration of 5-FU was originally developed at Wayne State for 5-day infusions and at The Cancer Center of Boston for protracted infusions. The phase III studies of The Cancer Center of Boston were performed by the Mid-Atlantic Oncology Program and subsequently by other groups, including the National Cancer Institute of Canada. Although their activity rates are similar, their side effect profiles are distinct. On the basis of published reports, the Mayo regimen is associated with more stomatitis and neutropenia,2 the Roswell Park regimen with more diarrhea,3 and the low-dose infusion regimen with more hand/foot syndrome.4 Although large clinical trials have been performed attempting to find an optimal 5-FU–based regimen on the basis of activity and toxicity, there has been little work comparing the effect of sex on these outcomes. A study published in the New England Journal of Medicine suggests that the 5-year survival rate for women is 10% higher than that of men after adjuvant 5-FU–based chemotherapy for colon cancer.5 The relative order of magnitude for the sex effect was as profound as that for the less phenotypically apparent genetic markers studied involving allelic loss and microsatellite instability. However, another review article suggests that the optimal dose has been found, but it makes no mention of sex-associated differences in efficacy or toxicity.6 A previous meta-analysis of 5-FU–related chemotherapy toxicity compared two different 5-FU administration methods—regimens in which 5-FU was given as a bolus versus as a continuous infusion.4 In this analysis of more than 1,200 patients from seven different trials, the effects of a wide variety of potential prognostic factors for treatment-related toxicity were explored. Among the findings was a suggestion that sex was a predictive factor for severe nonhematologic toxicity. Five other studies have appeared that included specific analyses of potential sex differences for 5-FU–related toxicity. In one study, data from 53 patients (23 men and 30 women) treated with 5-FU–based chemotherapy indicated that women experienced more toxicity than men. This study suggests that women are more prone to dihydropyrimidine dehydrogenase deficiency syndrome.1 Studies by Weinerman7 and Weinerman et al,8 involving 310 and 87 patients, respectively, observed that women receiving 5-FU–based chemotherapy reported a 6% and 14% higher incidence of stomatitis, respectively, compared with men. A 1996 Anti-Cancer Treatment Congress abstract based on 439 patients reported that women experienced a greater incidence of leukopenia.9 In contrast, a publication by Cascinu et al10 in Supportive Care in Cancer in 1997, involving 258 patients, demonstrated no difference between sexes in 5-FU–induced diarrhea. A further pharmacokinetic study of 22 patients indicated that the 5-FU area under the curve concentrations differed between sexes.11 Hence, the relatively sparse literature is inconsistent with respect to the existence of a sex effect for 5-FU–based toxicity. This study was predicated on an initial meta-analysis of five North Central Cancer Treatment Group (NCCTG) cancer control studies of various agents aimed at reducing chemotherapy-induced stomatitis.12 These data, which included those of 786 patients, indicated that women reported a 12% greater incidence of stomatitis and a doubling of the incidence of severe stomatitis, from 11% to 22%. These results left us the question as to whether stomatitis was the only toxicity for which women reported a greater incidence in response to 5-FU–based chemotherapy. The previous work hence produced a working hypothesis for this study: do women experience more severe toxicity than men from 5-FU–based chemotherapy? To address this question, we did a semi–meta-analysis of the toxicity on 5-FU–based studies conducted by the NCCTG colorectal cancer program. This project was performed collaboratively by the NCCTG Quality of Life Research Program, the NCCTG Cancer Control, and the NCCTG Gastrointestinal Cancer Programs.
Statistical Considerations We used stomatitis as the primary end point in this study to confirm our findings from the previous meta-analyses. To answer our working hypothesis regarding other types of toxicity, we included secondary end points of the five most commonly reported toxicity types related to 5-FU chemotherapy (leukopenia, alopecia, nausea, vomiting, and diarrhea). Physicians rated end points for each toxicity type and all side effects consistent with the National Cancer Institute common toxicity criteria. Both the incidence of any grade and the incidence of severe (grade  3) toxicity were analyzed. For these analyses, the toxicity data used were those recorded for treatment cycles 1, 2, and 3. For each treatment arm in each protocol, we estimated the mean dose administered in cycles 1, 2, and 3. In addition, the percentage of patients who experienced any or severe/very severe toxicity for each cycle by sex was calculated. Statistical methods for this patient level semi–meta-analysis took into account treatment arm, sex, and cycle number. Graphical methods included simple bar charts and meta-analytic Forrest plots.13 Other analyses included comparison of binomial proportions by use of Fisher’s exact test, cross-tabulations and relative risks, and logistic regressions. Logistic regression was used to examine sex differences in the presence of potentially confounding covariates, including age (65 years and older or not), body mass index, study number, leukopenia (presence or absence), and treatment regimen (five indicator variables for the protocol). Additional models included the seven regimens (six indicator variables) instead of study protocol and included the same variables as in the previous model. The first step in the logistic regression modeling estimated the saturated model (ie, the model with all variables included), and the second step excluded the treatment regimens. Cox regression models were used to test sex differences in survival per treatment arm and by groups of protocols. Group 1 included patients with adjuvant therapies, and group 2 included patients with advanced cancer. Classification tables were used to observe the distribution of all toxicity types by sex and cycle; similar procedures were used to calculate response rates for each protocol and treatment arm by sex.
Studies Included
NCCTG 83-46-52 was a randomized trial in advanced colorectal cancer exploring six different schedules of 5-FU alone or administered with different modulators, including methotrexate, cisplatin, and high- and low-dose leucovorin. Data from the three treatment arms included in this analysis called for treatment over 5 consecutive days every 5 weeks with single-agent 5-FU 500 mg/m2 daily (hereafter referred to as treatment arm A); 5-FU 425 mg/m2 and leucovorin 20 mg/m2, known as the Mayo regimen (treatment arm E); or 5-FU 370 mg/m2 with leucovorin 200 mg/m2 (treatment arm D).14,15 The incidence of severity of patient-reported stomatitis was measured by the Eastern Cooperative Oncology Group performance status questionnaire by use of a scale ranging from 0 to 4. The second trial (NCCTG 87-46-51) was a randomized phase III trial of adjuvant treatment for resectable stage II and III adenocarcinoma of the colon. Patients in this study were randomized to treatment with the Mayo regimen or with interferon gamma or to a no-treatment control arm. Only data from the patients treated with the 5-FU–based Mayo regimen are included in this analysis (arm B).16 Patient-reported toxicity based on an ordinal measure was obtained; categories ranged from 1 to 4. The third trial (NCCTG 88-46-51) randomized patients with advanced metastatic colorectal cancer to one of two treatment programs. Patients received either the Mayo regimen or the regimen of 5-FU 600 mg/m2 with leucovorin 500 mg/m2 weekly for 6 of every 8 weeks, commonly called the Roswell Park regimen. Only the patients randomized to the Mayo regimen are included here (arm A).17 Toxicity levels were measured by a physician report designed by the Eastern Cooperative Oncology Group that categorized the severity of stomatitis from 0 to 3. The fourth study (NCCTG 89-46-51) was a phase III adjuvant treatment trial for resectable stage II or III colon cancer that called for 5-FU combined with levamisole plus or minus leucovorin for either 6 or 12 months. Patients randomized to 5-FU plus levamisole were treated with 5-FU 450 mg/m2 for 5 consecutive days followed by weekly treatment for a duration of either 6 or 12 months (arms A and B). The 5-FU was given with levamisole 150 mg daily for 3 days every 2 weeks. Patients randomized to the three-drug regimen received 5-FU 370 mg/m2 with leucovorin 20 mg/m2, both administered daily for 5 days. Levamisole was also administered at 150 mg daily for 3 consecutive days every 2 weeks. A second randomization assigned treatment for either 6 or 12 months (arms C and D).18 For purposes of analysis, the original four treatment arms involving this study were grouped into two. For patients enrolled in arms A and B, only their experiences over the first 5 weeks of treatment were used. Some expected toxicities were stomatitis, diarrhea, and dermatitis. A five-point scale measurement of toxicity grade was used, ranging from 0 to 4. The fifth study (NCCTG 89-46-52) was a randomized trial in advanced colorectal cancer that involved intensive-course 5-FU combined with the L-isomer of leucovorin, oral leucovorin, or an intravenous (D,L) racemic mixture of leucovorin. In all three regimens, the 5-FU was given at 370 mg/m2 for 5 consecutive days at 1, 4, and 8 weeks followed by every 5 weeks thereafter. The oral leucovorin was administered in four divided doses taken orally before 5-FU for a total daily dose of 500 mg/m2 (arm B). The (D,L) leucovorin was administered at 200 mg/m2 (arm C) and the L-leucovorin at 100 mg/m2 (arm A) on each day of 5-FU therapy.19 A four-point Eastern Cooperative Oncology Group performance status toxicity scale was used, with values ranging from 0 to 3. All toxicity criteria in all studies were converted into one scale graded from 0 to 5. The studies included in this study were NCCTG treatment trials; this is different from our previous work, which included NCCTG cancer control trials. The hypothesis generation was presented in our other study.12 It is true, however, that some patients were enrolled onto both treatment and cancer control trials, so there is a small amount of overlap (440 of 2,448; 18%) between the two data sets. The previous hypothesis-generating study, however, looked only at stomatitis, whereas this study’s hypothesis was that women would have more toxicity (not just mucositis) than men. As such, this analysis represents an independent validation of the previous hypothesis-generating study.
Individual sample sizes from the 12 treatment arms ranged from 53 to 226 patients. The proportion of women ranged from 35% to 54% per treatment arm and was 45% overall. In total, 2,448 patients’ data were included in the meta-analysis (1,093 women and 1,355 men). Table 2 indicates the broad range of 5-FU dose levels and chemotherapy combinations that were included. All regimens included 5-FU bolus chemotherapy given on days 1 to 5 of the treatment cycle. Figure 1 presents the incidence rates for each of the six toxicity types by sex. Roughly 98% of both men and women experienced toxicity of some kind. Individually, the incidence rates of the six toxicity types are higher among women than men. By toxicity type, women experienced 8% more stomatitis, 14% more leukopenia, 12% more alopecia, 7% more nausea, 7% more vomiting, and 4% more diarrhea than men (all Pvalues < .02). Further examination of incidence of any toxicity broken down by sex and cycle indicates that women experience more toxicity than men consistently across all cycles of treatment and for all toxicity types (data not shown).
Stomatitis incidence rates for each trial by sex are given in Table 3 for any toxicity grade 1 or higher, and Table 4 lists severe or very severe stomatitis incidence of grade 3 or higher. Incidence rates of stomatitis were higher among women compared with men. The highest incidence of grade 3 and 4 stomatitis is seen in the trials with the highest doses of 5-FU and leucovorin. Furthermore, the trial in which we noted the greatest difference between the incidence of stomatitis by sex (study 88-46-51) prescribed the highest dose of 5-FU combined with leucovorin. Figure 2 presents a Forrest meta-analysis plot for the differences in stomatitis incidence rates between men and women.13 For these plots, the rate in men was subtracted from the rate in women. Results for each individual treatment arm are represented by a circle and related confidence bands. The size of the circle is proportional to the sample size of the treatment arm. The aggregated results across all studies are displayed at the bottom of the graph. The vertical reference line represents equality of stomatitis incidence across sexes. Ten of 12 treatment arms indicated that women had more stomatitis than men.
The mean percentage of prescribed 5-FU dose actually received by each patient was calculated for each cycle. One hundred percent of men and women received a full dose at cycle 1. For cycles 2 and 3, women received an equal or smaller mean percentage of 5-FU dosage than men. The proportion of women and men who had dose reduction on the basis of protocol-specified criteria in cycle 2 was 46% and 34%, respectively (P < .0001). In cycle 3, the proportion of women and men experiencing dose reduction was 51% and 38%, respectively (P < .0001). As indicated in Table 5, women consistently experienced more toxicity than men across treatment cycles 1 to 3. For example, in cycle 1, 93% of women experienced any toxicity type (hematologic and nonhematologic, grade 1 or higher) compared with 85% of men.
The incidence of severe toxicity by sex is presented in Fig 3. The rightmost pair of bars indicates that half the women experienced some form of severe toxicity, compared with 40% of men (P < .0001). Severe leukopenia was experienced by almost twice as many women as men (P < .0001). As previously noted, of the six toxicity incidence rates studied, stomatitis and leukopenia showed the largest difference between men and women. A closer examination of severe/very severe toxicity by cycle indicates that women experienced more toxicity than men at cycle 1, ie, 8% more stomatitis, 8% more leukopenia, and 6% more diarrhea (all P values < .001). Moreover, women experienced a greater incidence of severe leukopenia on all 12 treatment arms studied (Fig 4). In each of the 12 different treatment arms, at least 10% more women than men experienced some form of severe toxicity (Fig 5).
Logistic regression was used to examine the potential effect of additional variables on the observed sex-related difference in toxicity rates. Table 6 reports the results for the saturated and reduced models for the incidence of any and severe/very severe stomatitis. The saturated models for any toxicity grade of stomatitis indicated significant effects of sex, body surface area, and leukopenia. The reduced model indicated the same significant effects as those from the full model. In Table 6 for severe/very severe stomatitis, all effects were significant for both full and reduced models. In particular, older (> 60 years) patients more often experienced severe/very severe stomatitis. Overall, we observed that sex differences were significant in terms of incidence of any stomatitis (Tables 3 and 6) and severe/very severe stomatitis (Tables 4 and 6).
Additional logistic regression models were fit, including the 5-FU regimens combined with leucovorin doses (data not shown). These models were consistent with the ones listed in Table 6; for example, the odds ratio for a male effect was 0.76 (P = .009) and was 0.60 (P = .0004) for any and severe/very severe stomatitis. Overall, although other variables significantly contributed to the toxicity incidence, none altered the sex estimates or effect sizes. The response rates to treatment in the advanced measurable disease protocols were the same for men and women across all studies (Table 7). Such data were not available for adjuvant treatment arms. Survival analysis indicated that there is no difference in survival by sex for either adjuvant (P = .72) or advanced (P = .91) cancer patients. The 5-year survival rate for adjuvant cancer patients is similar for men (67%) and women (66%), and the corresponding survival rate for advanced cancer patients is also similar for men (2%) and for women (3%).
The results of this study provide strong data to support the conclusion that women do experience more severe toxicity than men while receiving bolus 5-FU–based chemotherapy. Women not only report a greater incidence of a wide variety of toxicity types, but they also seem to experience them with greater average severity. The differential between incidence rates for men and women was consistent with previous results indicating that women report a greater incidence of stomatitis across all treatment regimens. Even in cycles 2 and 3, when men received an equal or greater 5-FU dosage than women, women still experienced more toxicity than men during these cycles. The first challenge to such a sweeping conclusion derived from a retrospective data analysis is to address the questions regarding the veracity and generalizability of the results. The studies involved in this analysis were conducted by a large group of investigators. Several of these have produced changes in clinical practice. Regarding the toxicity findings, the effect sizes observed are large and are consistent across a range of studies, treatments, and time periods and are not mere artifacts of statistical modeling. Given the evidence presented in this article for the existence of a sex-dependent toxicity difference, it is reasonable to seek explanations for potential mechanisms. Levels of dihydropyrimidine dehydrogenase have been reported to differ between the sexes, although the data are inconsistent.1,20,21 This may be causative, although it has been postulated that the differences in toxicity profiles across sexes might be related to thymidylate synthase levels.22-24 However, there is no report of sex differences in thymidylate synthase levels. However, one might speculate that a potential source for sex differences in toxicity is related to a perceived differential in reporting of subjective symptoms between men and women.25,26 The literature is consistent on this issue, with the preponderance of evidence suggesting that this stereotype is unsubstantiated.27 Our data would speak against this conclusion. Additionally, sex-related differences in leukopenia were consistently observed. This objectively measured toxicity parameter is not subject to potential subjective reporting bias. A basic question arises regarding the relationship between toxicity incidence and treatment efficacy. We do not know whether the increasing toxicity is related to health improvement or whether it is related to increasing death rates. It could be argued that the increased toxicity in women implies that they are receiving a higher biologic dose of antitumor therapy, which could imply a better cure rate or a higher likelihood of response. Conversely, if the toxicity causes excessive dose reductions, it could be argued that women are receiving a lower actual dose and thus receiving suboptimal treatment. Further research efforts are required to address this question. However, the facts that survival in the adjuvant setting and response rates in the advanced setting were not different by sex and that treatment of patients was individualized through dose adjustments based on each patient’s experience after cycle 1 suggest that similar treatment outcomes will occur across sexes. Another potential source of confounding lies in the perception that women have been understudied relative to men and therefore participate in clinical trials in different ways and numbers than men. This would bring the generalizability of our results into question. A recent review article of a congressional research investigation study refuted this argument. In an analysis of 100,455 trials found in MEDLINE from 1966 to 1998, the proportion of clinical trials involving women only and men only were 12.2 and 11.4, respectively, suggesting that the study samples can be considered representative for men and women.28 Our results are sufficiently provocative and convincing that we believe it is time to begin to systematically ascertain the underlying mechanism for increased 5-FU–related toxicity among women. Further study is warranted to try to discern the mechanisms for these differences in toxicity profiles. Perhaps there are pharmacologic differences in 5-FU metabolism and clearance across sexes. In this regard, the current intergroup advanced colorectal cancer trial N9741 randomizes patients between two regimens containing 5-FU combined with either oxaliplatin or irinotecan, and one regimen of irinotecan and oxaliplatin without 5-FU. Exploratory pharmacogenetic studies performed as part of this trial may help to identify underlying genetic polymorphisms that account for sex-based and other variations within the treated population in toxicity patterns.29 It may be time to consider designing sex-specific dose-seeking studies to answer this question. An example of such dose-specific modeling has been applied recently to a study with amonafide.30 In this study, the goal was to investigate a pharmacodynamic dosing strategy for amonafide to decrease toxicity. It is not unreasonable to investigate such differences, given the long history of dose-seeking studies for 5-FU. Despite the considerable amount of work performed to date on determining dosage for 5-FU, there remains considerable variability in dose recommendations and dose tolerability.6 The challenge of such research would be to reduce 5-FU–based chemotherapy doses for women sufficiently to reduce the toxicity incidence while retaining efficacy. In conclusion, we believe that the accumulated data provide sufficient evidence that women do indeed experience a greater incidence and severity of 5-FU–related toxicity when they are treated on a day 1 to 5 schedule. The open question and challenge before us is to decide what we can do to alleviate this burden for women receiving 5-FU–based chemotherapy.
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and the Mayo Clinic and was supported in part by Public Health grant nos. CA-15083, CA-25224, CA-37404, CA-63826, and CA-35448 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.
1. Milano G, Etienne M, Pierrefite V, et al: Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity. Br J Cancer 79: 627-630, 1999[CrossRef][Medline] 2. O’Connell M: A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: A Mayo Clinic/North Central Cancer Treatment Group study. Cancer 63: 1026-1030, 1989[CrossRef][Medline]
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Petrelli N, Herrera L, Rustum Y, et al: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5: 1559-1565, 1987 4. Toxicity of fluorouracil in patients with advanced colorectal cancer: Effect of administration schedule and prognostic factors—Meta-Analysis Group in Cancer. J Clin Oncol 16: 3537-3541, 1998[Abstract]
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Watanabe T, Wu TT, Catalano PJ, et al: Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 344: 1196-1206, 2001
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Michael M, Zalcberg J: The optimal 5-fluorouracil regimen for the adjuvant therapy of colon cancer: Where to from here? Ann Oncol 11: 915-918, 2000 7. Weinerman B: Increased incidence of toxicity (T) in elderly females treated with 5FU, leucovorin (Ful). Proc Am Soc Clin Oncol 15: 225, 1996 (abstr 541) 8. Weinerman B, Rayner H, Venne A, et al: Increased incidence and severity of stomatitis (S), in women treated with 5 fluorouracil (F), and leucovorin (L). Proc Am Soc Clin Oncol 17: 305a, 1998 (abstr 1176) 9. Seitz J, Cunningham D, Rath U, et al: Tomudex (ZD1694) is effective first line therapy for advanced colorectal cancer (CRC), but in contrast to 5-fluorouracil (5FU) + leucovorin (LV) gender, age or cycle number does not predict for severe toxicity. Anti-Cancer Treatment 6th International Congress, Paris, France, February 6-9, 1996 (abstr) 10. Cascinu S, Barni S, Labianca R, et al: Evaluation of factors influencing 5-fluorouracil-induced diarrhea in colorectal cancer patients: An Italian Group for the Study of Digestive Tract Cancer (GISCAD) study. Support Care Cancer 5: 1314-1317, 1997 11. Puchalsky TA, Ryan DP, Supko JG, et al: Pharmacokinetic (PK), pharmacodynamic (PD), and pharmacogenetic study of weekly intravenous (IV) bolus 5-fluorouracil (5FU) in combination with leucovorin (LV) in patients with colorectal adenocarcinoma (CRC). Proc Am Soc Clin Oncol 20: 91a, 2001 (abstr 360)
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Sloan A, Loprinzi C, Novotny P, et al: Sex differences in fluorouracil-induced stomatitis. J Clin Oncol 18: 412-420, 2000 13. Boes H: Forrest plot, a graphical presentation of a meta-analysis: Communications at the meta-analysis unit meeting. Brussels, Belgium, European Organization for the Research and Treatment of Cancer Data Center, January 1994 14. Poon M, O’Connell M, Moertel C, et al: Biochemical modulation of fluorouracil: Evidence of a significant improvement of survival and quality of life in patients with advanced colorectal cancer. J Clin Oncol 7: 1407-1418, 1989[Abstract]
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Poon M, O’Connell M, Wieand H, et al: Biochemical modulation of fluorouracil with leucovorin: Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9: 1967-1972, 1991
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O’Connell M, Mailliard J, Kahn M, et al: Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 15: 246-250, 1997 17. Buroker TR, O’Connell MJ, Wieand HS, et al: Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 12: 14-20, 1994[Abstract]
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O’Connell M, Laurie J, Kahn M, et al: Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 16: 295-300, 1998
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Goldberg R, Hatfield A, Kahn M, et al: Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol 15: 3320-3329, 1997 20. Mayr J, Riemer S, Habeck N, et al: Analysis of dihydropyrimidine dehydrogenase (DPD) in peripheral white blood cells of healthy donors using ELISA and quantitative real-time RT-PCR on the light cycler instrument and correlation of results with DPD activity. Proc Am Soc Clin Oncol 20: 89a, 2001 (abstr 354) 21. Diasio RB: The role of dihydropyrimidine dehydrogenase (DPD) modulation in 5-FU pharmacology. Oncology (Huntingt) 12: 23-27, 1998 22. Ito K, Kato T, Nakazato H, et al: Thymidylate synthase expression predicts response to adjuvant chemotherapy in curatively resected colorectal carcinoma patients in clinical trials. Proc Am Soc Clin Oncol 19: 254a, 2000 (abstr 988)
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Cascinu S, Aschele C, Barni S, et al: Thymidylate synthase protein expression in advanced colon cancer: Correlation with the site of metastasis and the clinical response to leucovorin-modulated bolus 5-fluorouracil. Clin Cancer Res 5: 1996-1999, 1999
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Edler D, Kressner U, Ragnhammar P, et al: Immunohistochemically detected thymidylate synthase in colorectal cancer: An independent prognostic factor of survival. Clin Cancer Res 6: 488-492, 2000 25. Kim K, Moser D, Garvin B, et al: Differences between men and women in anxiety early after acute myocardial infarction. Am J Crit Care 9: 245-253, 2000 26. Cecile M, van Wijk G, Huisman H, et al: Gender differences in physical symptoms and illness behavior: A health diary study. Soc Sci Med 49: 1061-1074, 1999 27. Macintyre S, Ford G, Hunt K: Do women ’over report’ morbidity? Men’s and women’s responses to structured prompting on a standard question on long standing illness. Soc Sci Med 48: 89-98, 1999 28. Meinert C, Gilpin A, Unlap A, et al: Gender representation in trials. Control Clin Trials 21: 462-475, 2000[CrossRef][Medline] 29. Morton RF, Goldberg RM, Sargent DJ, et al: Oxaliplatin (OXAL) or CPT-11 combined with 5FU/leucovorin (LV) in advanced colorectal cancer (CRC): An NCCTG/CALGB study. Proc Am Soc Clin Oncol 20: 125a, 2001 (abstr 495) 30. Ratain MJ, Mick R, Janisch L, et al: Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender. Pharmacogenetics 6: 93-101, 1996[Medline] Submitted July 10, 2001; accepted November 19, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
