Abstract
This secondary analysis of the PETACC-3 trial examines the association of sex with incidence and severity of chemotherapy-related toxic effects in patients with stage II and III colorectal cancer treated with fluorouracil and leucovorin with or without irinotecan hydrochloride.
Sex is one of several known factors responsible for the wide interpatient variability in the dose-effect relationship of drugs.1 It affects both pharmacokinetics and pharmacodynamics.2 Data on the clinical impact of sex on chemotherapy-related toxic effects are lacking for colorectal cancer (CRC). The aim of this study is to evaluate the association of sex with incidence and severity of chemotherapy-related toxic effects in patients with stage II and III CRC treated with adjuvant fluorouracil and leucovorin or FOLFIRI (a combination therapy consisting of leucovorin, fluorouracil, and irinotecan hydrochloride) in the previously reported PETACC-3 trial.3
Methods
We conducted a retrospective analysis on treatment-emergent adverse events, defined as all adverse events (AEs) that developed or worsened during the on-treatment period, graded according to the National Cancer Institute of Canada Common Toxicity Grading and considered as possibly or probably treatment-related by the local investigator. Data analysis was performed at the European Organization for Research and Treatment of Cancer (EORTC) Headquarters in Brussels, Belgium, independently of any commercial interest. Primary analysis was the comparison of rates of any grade treatment-emergent adverse events (nonhematological AEs with a frequency of ≥5% of treated patients and hematological AEs) by sex in the pooled treatment arms. Secondary analyses were performed on rates of grade 3 or 4 AEs, as well as subgroup analyses according to regimen (fluorouracil/leucovorin or FOLFIRI), age (<50, 50-64, ≥65 years) and body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) (<18.5, 18.5 to <25, ≥25). In the pooled treatment arms as well as in all subgroups, rates of AEs and grade 3 or 4 AEs were compared between men and women using Fisher exact test; P values are 2-sided and considered significant if less than .05. The PETACC-33 trial was approved by an independent ethics committee at each center and was conducted in accordance with the Declaration of Helsinki, and this subgroup analysis was approved by EORTC Gastrointestinal Group. Patient consent was not required because data used was deidentified.
Results
Among the 2974 included participants, 1656 were men (55.7%) and 1318 women (44.3%). Women were slightly younger (277 [21.0%] younger than 50 years vs 288 men [17%] younger than 50 years), had a lower BMI (593 [45.0%] with BMI ≥25 vs 874 men [53.0%] with BMI ≥25) and body surface area (1284 [97.0%] ≤ 2 m2 vs 1254 men [76.0%] with body surface area ≤2 m2). Results of the primary comparison of all-grade AEs in the pooled treatment arms are displayed in Table 1. Women had significantly higher rates of all-grade nausea, vomiting, constipation, cramping, stomatitis, cholinergic syndrome, lethargy, alopecia, leukopenia, neutropenia and anemia. Overall toxic effects and differences between women and men were numerically increased with FOLFIRI (Table 2). Significantly higher rates of all-grade constipation, nausea, vomiting, alopecia, leukopenia, neutropenia, and anemia in women were observed regardless of treatment (fluorouracil/leucovorin or FOLFIRI). The significantly higher risk for leukopenia, anemia, alopecia, and vomiting for women was not affected by age. Grade 3 or 4 AEs significantly more frequent in women in pooled treatment arms (Table 1) were alopecia, stomatitis, diarrhea, nausea, leukopenia, neutropenia, and anemia. Under treatment with FOLFIRI, but not fluorouracil and leucovorin, significant differences between men and women were seen for grade 3 or 4 alopecia, stomatitis, diarrhea, and lethargy (Table 2). The higher incidence of grade 3 or 4 neutropenia in women treated with FOLFIRI was independent of age and BMI. Dose reductions were more frequent in women vs men (341 [25.9%] vs 279 [16.8%]; P < .001), especially under treatment with FOLFIRI.
Table 1. Adverse Events With Statistically Significant Sex Differences in Pooled Treatment Arms in 2974 Patientsa.
| Characteristic | No. (%) | Asymptotic Difference, % (95% Confidence Limits) | P Valuea | |
|---|---|---|---|---|
| Female (n = 1318) | Male (n = 1656) | |||
| Nonhematological Adverse Events | ||||
| Diarrhea | ||||
| All grade | 705 (53.5) | 809 (48.9) | 4.6 (1.0 to 8.3) | .01 |
| Grade 3-4 | 131 (9.9) | 122 (7.4) | 2.6 (0.5 to 4.6) | .01 |
| Constipation | ||||
| All grade | 149 (11.3) | 123 (7.4) | 3.9 (1.8 to 6.0) | <.001 |
| Grade 3-4 | 4 (0.3) | 8 (0.5) | −0.2 (−0.6 to 0.3) | .57 |
| Nausea | ||||
| All grade | 814 (61.8) | 889 (53.7) | 8.1 (4.5 to 11.6) | <.001 |
| Grade 3-4 | 54 (4.1) | 44 (2.7) | 1.4 (0.1 to 2.8) | .03 |
| Vomiting | ||||
| All grade | 429 (32.5) | 405 (24.5) | 8.1 (4.8 to 11.4) | <.001 |
| Grade 3-4 | 47 (3.6) | 42 (2.5) | 1.0 (−0.2 to 2.3) | .11 |
| Cramping | ||||
| All grade | 251 (19.0) | 224 (13.5) | 5.5 (2.8 to 8.2) | <.001 |
| Grade 3-4 | 16 (1.2) | 9 (0.5) | 0.7 (0.0 to 1.4) | .07 |
| Stomatitis | ||||
| All grade | 480 (36.4) | 501 (30.3) | 6.2 (2.8 to 9.6) | <.001 |
| Grade 3-4 | 34 (2.6) | 20 (1.2) | 1.4 (0.4 to 2.4) | .01 |
| Cholinergic syndrome | ||||
| All grade | 123 (9.3) | 106 (6.4) | 2.9 (1.0 to 4.9) | .004 |
| Grade 3-4 | 1 (0.1) | 4 (0.2) | −0.2 (−0.4 to 0.1) | .39 |
| Lethargy | ||||
| All grade | 556 (42.2) | 612 (37.0) | 5.2 (1.7 to 8.8) | .004 |
| Grade 3-4 | 36 (2.7) | 31 (1.9) | 0.9 (−0.2 to 2.0) | .14 |
| Alopecia | ||||
| All grade | 549 (41.7) | 431 (26.0) | 15.6 (12.2 to 19.0) | <.001 |
| Grade 3-4 | 18 (1.4) | 6 (0.4) | 1.0 (0.3 to 1.7) | .003 |
| Hematological Adverse Events | ||||
| Leukopenia | ||||
| All grade | 654 (49.6) | 645 (38.9) | 10.7 (7.1 to 14.3) | <.001 |
| Grade 3-4 | 53 (4.0) | 40 (2.4) | 1.6 (0.3 to 2.9) | .01 |
| Neutropenia | ||||
| All grade | 818 (62.1) | 886 (53.5) | 8.6 (5.0 to 12.1) | <.001 |
| Grade 3-4 | 293 (22.2) | 215 (13.0) | 9.3 (6.5 to 12.0) | <.001 |
| Anemia | ||||
| All grade | 1056 (80.1) | 820 (49.5) | 30.6 (27.4 to 33.8) | <.001 |
| Grade 3-4 | 20 (1.5) | 8 (0.5) | 1.0 (0.3 to 1.8) | .01 |
The Holm-Bonferroni correction for multiple testing was applied for primary analysis. No multiple testing adjustment was done for secondary analysis. P values for the primary analysis of all grade AEs, which are below the statistical level of significance for the Holm-Bonferroni procedure, are highlighted.
Table 2. Adverse Events With Statistically Significant Sex-Differences in 1481 Patients Treated With FOLFIRI.
| Characteristic | No. (%) | Asymptotic Difference, % (95% Confidence Limits) | P Valuea | |
|---|---|---|---|---|
| Female (n = 657) | Male (n = 824) | |||
| Nonhematological Adverse Events | ||||
| Diarrhea | ||||
| All grade | 430 (65.4) | 481 (58.4) | 7.1 (2.1 to 12.0) | .01 |
| Grade 3-4 | 91 (13.9) | 83 (10.1) | 3.8 (0.4 to 7.1) | .03 |
| Constipation | ||||
| All grade | 86 (13.1) | 70 (8.5) | 4.6 (1.4 to 7.8) | .01 |
| Grade 3-4 | 2 (0.3) | 4 (0.5) | −0.2 (−0.8 to 0.5) | .70 |
| Nausea | ||||
| All grade | 480 (73.1) | 518 (62.9) | 10.2 (5.5 to 14.9) | <.001 |
| Grade 3-4 | 44 (6.7) | 37 (4.5) | 2.2 (−0.2 to 4.6) | .07 |
| Vomiting | ||||
| All grade | 303 (46.1) | 294 (35.7) | 10.4 (5.4 to 15.5) | <.001 |
| Grade 3-4 | 40 (6.1) | 39 (4.7) | 1.4 (−1.0 to 3.7) | .30 |
| Cramping | ||||
| All grade | 159 (24.2) | 135 (16.4) | 7.8 (3.7 to 12.0) | <.001 |
| Grade 3-4 | 12 (1.8) | 6 (0.7) | 1.1 (−0.1 to 2.3) | .06 |
| Stomatitis | ||||
| All grade | 267 (40.6) | 247 (30.0) | 10.7 (5.8 to 15.6) | <.001 |
| Grade 3-4 | 24 (3.7) | 10 (1.2) | 2.4 (0.8 to 4.1) | .003 |
| Cholinergic syndrome | ||||
| All grade | 120 (18.3) | 106 (12.9) | 5.4 (1.7 to 9.1) | .004 |
| Grade 3-4 | 1 (0.2) | 4 (0.5) | −0.3 (−0.9 to 0.2) | .39 |
| Lethargy | ||||
| All grade | 321 (48.9) | 315 (38.2) | 10.6 (5.6 to 15.7) | <.001 |
| Grade 3-4 | 27 (4.1) | 15 (1.8) | 2.3 (0.5 to 4.1) | .01 |
| Cardiovascularb | ||||
| All grade | 54 (8.2) | 41 (5.0) | 3.2 (0.7 to 5.8) | .01 |
| Grade 3-4 | 18 (2.7) | 17 (2.1) | 0.7 (−0.9 to 2.3 | .40 |
| Alopecia | ||||
| All grade | 384 (58.4) | 324 (39.3) | 19.1 (14.1 to 24.2) | <.001 |
| Grade 3-4 | 17 (2.6) | 5 (0.6) | 2.0 (0.7 to 3.3) | .002 |
| Rash | ||||
| All grade | 42 (6.4) | 28 (3.4) | 3.0 (0.8 to 5.2) | .01 |
| Grade 3-4 | 1 (0.2) | 1 (0.1) | 0.0 (−0.4 to 0.4) | >.99 |
| Hematological Adverse Events | ||||
| Leukopenia | ||||
| All grade | 438 (66.7) | 432 (52.4) | 14.2 (9.3 to 19.2) | <.001 |
| Grade 3-4 | 43 (6.5) | 30 (3.6) | 2.9 (0.6 to 5.2) | .01 |
| Neutropenia | ||||
| All grade | 512 (77.9) | 552 (67.0) | 10.9 (6.4 to 15.5) | <.001 |
| Grade 3-4 | 245 (37.3) | 174 (21.1) | 16.2 (11.5 to 20.8) | <.001 |
| Anemia | ||||
| All grade | 581 (88.4) | 468 (56.8) | 31.6 (27.5 to 35.8) | <.001 |
| Grade 3-4 | 12 (1.8) | 5 (0.6) | 1.2 (0.1 to 2.4) | .046 |
No multiple testing adjustments were done for subgroup analyses.
Cardiovascular adverse events include cardiac dysrhythmia, abnormal cardiac function, tachycardia, chest pain, myocardial ischemia, venous edema, hypotension.
Discussion
This analysis is the largest to date that systematically addresses the association of sex with all types of toxic effects of standard fluorouracil with or without irinotecan chemotherapy in CRC. It demonstrates a statistically significant and clinically relevant greater risk of nonhematological and objectively measurable hematological AEs in women. Female sex has previously been identified as a risk factor for irinotecan-induced neutropenia.4 As UGT1A1 polymorphisms do not vary with sex,5 they cannot explain the observed differences in toxic effects caused by irinotecan. These differences must be either pharmacokinetic, as demonstrated for fluorouracil, or pharmacodynamic. In an age of personalized medicine, and also considering growing knowledge about sex-related differences in molecular profiles and disease biology,6 the potential effect of sex on efficacy and toxic effects of systemic treatments in oncology deserves more awareness and further investigation. Drug targets, but also the optimal dose necessary to hit a target with an acceptable level of toxic effects, may be different between men and women.
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