Influence of Sex on Toxicity and Treatment Outcome in Small-Cell Lung Cancer
http://www.100md.com
《临床肿瘤学》
the Division of Medical Oncology, Department of Medicine, Princess Margaret Hospital
University of Toronto
Cancer Care Ontario, Toronto
the National Cancer Institute of Canada Clinical Trials Group
Queens University, Kingston, Ontario
the British Columbia Cancer Agency, Vancouver, British Columbia, Canada
ABSTRACT
PATIENTS AND METHODS: This was a sex-based retrospective analysis of four SCLC trials conducted by the National Cancer Institute of Canada Clinical Trials Group between 1987 and 1999. The 1,006 patients (648 males and 358 females) received similar chemotherapy consisting of cyclophosphamide-doxorubicin-vincristine and etoposide-cisplatin. Toxicities examined included myelosuppression, stomatitis, vomiting, and infection. Other end points included dose reductions and omissions, response, and survival.
RESULTS: Women experienced significantly more hematologic toxicity than men (grade 3 and 4 anemia, 16.3% v 7.6%, respectively, P < .001; grade 3 and 4 leukopenia, 80.4% v 69.2%, respectively, P = .0001). However, toxic death rates were similar for men and women (1.5% v 1.1%, respectively, P = .58). Women also had significantly more stomatitis and vomiting of all grades. Despite increased toxicity, 76% of females versus 73.4% of males received all six treatment cycles (P = .38), but 52% of females versus 43.4% of males had treatment delayed for 2 weeks or more (P = .022). Only 31.8% of females and 28.2% of males had at least one cycle of chemotherapy dose reduction (P = .23). The overall response rate was 80.3% for females and 66.9% for males (P < .0001), and the median survival time was 1.31 years for females compared with only 0.91 year for males (P < .0001).
CONCLUSION: Women experience more chemotherapy-related toxicity in the treatment of SCLC, but they also have increased response rates and survival.
INTRODUCTION
Small-cell lung cancer (SCLC) accounts for approximately 15% to 20% of all bronchogenic carcinomas. Demographic studies suggest that women are more likely than men to suffer from SCLC, whereas men are more likely to be diagnosed with non–small-cell lung cancer.3 Interestingly, sex has been found to be an independent prognostic factor for survival for all subtypes of lung cancer, with women surviving longer than men (P < .0001).5 Specifically, with respect to SCLC, prognostic studies of several of the large cooperative group databases have shown in both univariate and multivariate analyses that female sex is associated with a favorable outcome.5-10 However, this has not been observed in all analyses.11
Treatment of both limited- and extensive-stage SCLC involves chemotherapeutic drugs that are associated with significant side effects. In fact, virtually all patients treated will experience some form of toxicity. Patients give informed consent to treatment after a discussion based on the risks and benefits, including an assessment of treatment-related toxicity. Generally this information is applied to the population as a whole, and little, if any, information is given to patients on the role sex can play in treatment toxicity. Traditionally, results from clinical trials and information on drug pharmacokinetics and toxicity have been generalized and applied to both sexes. Only since 1993 has the American Congress required sex-specific analysis of the safety and efficacy of drugs in clinical trials. Legislation now states that clinical trials must be "designed and carried out in a manner sufficient to provide for an analysis of whether the variables being studied in the trial affect women differently than other subjects in the trial."12
Emerging data suggest that sex-specific pharmacokinetics and toxicity exist for certain chemotherapeutic drugs. Clearance rates and differences in area under the plasma concentration-time curve (AUC) ratios have been reported for doxorubicin and etoposide, which are two drugs that are used frequently in SCLC.13,14 Similarly, Milano et al15 have shown that the capacity to clear fluorouracil is lower in women compared with men, and sex-related differences in drug toxicity profiles and significant variations in both the frequency and severity of toxicity have been found in men and women.16-19 Although few sex-related studies of cisplatin have been undertaken, at least one study has shown that women experience significantly more nausea and vomiting after cisplatin than men.20,21
On the basis of these observations derived from the treatment of other tumors, we hypothesized that women would also experience more frequent and more severe toxicity than men during SCLC chemotherapy. We elected to undertake this sex-based retrospective analysis of treatment delivery and toxicity in four prospectively randomized SCLC trials conducted by the National Cancer Institute of Canada Clinical Trials Group and to correlate these parameters with outcome. The trials were selected because patients in seven of the eight study arms examined received similar chemotherapy regimens with variations only in schedule and radiation treatment. We report here the results of this analysis.
PATIENTS AND METHODS
Treatment
The chemotherapy regimens and doses used in the four trials are listed in Table 2. BR.3 compared three cycles of cyclophosphamide, doxorubicin, and vincristine (CAV) followed by three cycles of etoposide and cisplatin (EP) with alternating CAV with EP for three cycles each in limited SCLC. After three courses of chemotherapy, responding patients underwent prophylactic cranial irradiation (PCI) on days 8 through 15 (20 Gy in five fractions). Responding patients were further randomized after the sixth cycle of chemotherapy to receive thoracic radiotherapy consisting of either 37.5 Gy in 15 fractions or 25 Gy in 10 fractions.
BR.4 compared CAV every 3 weeks for six cycles to three cycles of CAV alternating with three cycles of EP in patients with extensive SCLC. Stable and responding patients received PCI on day 8 of cycle 3.
BR.6 compared the timing of thoracic irradiation in limited-stage SCLC. All patients received three cycles of CAV alternating with three cycles of EP and were randomly assigned to receive early thoracic irradiation (40 Gy in 15 fractions) administered concurrently with the first cycle of EP (cycle 2) or with the last cycle of EP (cycle 6).
BR.8 compared three cycles of CAV alternating with three cycles of EP to a dose-intensive weekly chemotherapy regimen in extensive SCLC. Patients with a complete response received PCI (25 Gy in 10 fractions) after chemotherapy. The intensive treatment arm was not included in our analysis.
Assessment
The primary end points of the study consisted of hematologic toxicity (leukocyte count, hemoglobin, and platelets), stomatitis, vomiting, and infection. Toxicity was reported and graded according to the National Cancer Institute of Canada Clinical Trials Group expanded common toxicity criteria from grades 0 to 4. All toxicities (grade 1 and above), as well as severe toxicities (grade 3 and above), were examined.
Secondary end points included assessment of the number of dose reductions required and the number of omitted cycles. Response rates, survival, and toxic deaths were also examined. Standard response criteria were used, and survival was measured from the date of randomization until the date of death or last follow-up examination.
Statistical Analyses
Fisher’s exact test was used to compare toxicity between the sexes. Logistic regression was performed to examine for potentially confounding covariates, including age, body surface area (BSA), PS, pretreatment lactate dehydrogenase (LDH), and individual trial. Survival curves were estimated by the Kaplan-Meier method.26 The total dose and dose reductions of chemotherapy were calculated using all included patients from the start to completion of the last cycle of chemotherapy.
RESULTS
Toxicity
Hematologic toxicities of anemia (55.9% of females v 38.6% of males, P < .0001) and leukopenia (92.7% of females v 84.7% of males, P = .0002) were significantly higher in female patients (Table 4). This was consistent when examined both for all toxicity levels and for grade 3 and 4 toxicity. Despite greater leukopenia, there was no significant difference in infection rates or toxic death rates (10 deaths in males, 1.5%; and four deaths in females, 1.1%; P = .58).
Females also experienced more nonhematologic toxicities than men (Table 4), including stomatitis (16.8% v 8.3%, respectively, P < .0001) and vomiting (76.8% v 67.2%, respectively, P = .0014). Logistic regression analysis was performed to adjust the comparisons between sexes by the following baseline characteristics: age (≤ 65 v > 65 years), baseline BSA (< 2 v ≥ 2 m2), PS (ECOG 0 to 1 v 2 to 3), baseline LDH, and trial (Table 5). After adjusting for the effect of these variables, female sex was still a significant predictor for increased anemia, leukopenia, stomatitis, and vomiting.
Chemotherapy Treatment Delivery
Treatment received and dose reductions required are listed by sex in Table 6. Despite experiencing more toxicity, 76% of female and 73.4% of male patients received all six cycles (P = .38). Only 31.8% of females and 28.2% of males had one or more cycles of chemotherapy reduced (P = .23). However, more females than males had treatment delays of 2 weeks or more (52% v 43.4%, respectively, P = .022), likely because of their increased toxicity.
Response and Survival
Females had a superior overall response rate (Table 7) compared with males (80.3% v 66.9%, respectively, P < .0001), and they also had more complete responses. As shown in Figure 1, women had significantly better survival (P < .0001). After adjusting for age, baseline BSA, PS, baseline LDH, and trial, female sex was still a highly significant predictor for survival.
DISCUSSION
Sex-related toxicity has been reported previously for fluorouracil in the treatment of gastrointestinal cancers, where it has been shown that females experienced greater hematologic toxicity and nonhematologic toxicity including stomatitis, alopecia, nausea, vomiting, and diarrhea.16-19
Patients in our study received two regimens, CAV and EP. Few sex-related studies of cisplatin have been undertaken, but one study has shown that women experience significantly more nausea and vomiting after cisplatin than men.20 This is consistent with our results. Another study showed that female sex was a negative predictor for complete antiemetic control with 5-hydroxytryptamine-3 antagonists in patients receiving doxorubicin or cyclophosphamide.21 However, sex differences have not been observed with the new class of antiemetics, neurokinin-1 antagonists.27 Pharmacokinetic studies of the chemotherapeutic agent etoposide have been shown to vary slightly in women, although significant differences in AUC ratios have not been reported.14 However, it is possible that small differences in etoposide AUC may have contributed to the excess toxicity experienced by the women in our analysis.
There are fewer sex-related studies for the agents in the CAV regimen. Dobbs et al13 showed that in patients with normal liver biochemistry, men had a higher rate of clearance of doxorubicin than women. Similarly, older women have been shown to have a lower rate of clearance of another anthracycline, epirubicin, than do men of any age.28 As with etoposide, lower clearance and a higher doxorubicin AUC might be expected to result in excess toxicity for women treated with the CAV regimen. Gemcitabine, a drug that is used extensively in non–small-cell lung cancer, although not in SCLC, has been reported to have a higher clearance rate in men when compared with women of the same age.29 There have been no published sex-based studies of vincristine. However, rates of neuropathy were not significantly different in men and women in our study.
Another possible reason for the increased toxicity seen in women may have to do with influence of body mass index (BMI). Women generally have a higher baseline BMI than men because of increased body fat,30 and this may affect drug distribution and potentially increase toxicity. Obesity and high BMI have been shown to be associated with a decrease in drug clearance and a resultant increase in the elimination half-life for both doxorubicin and cyclophosphamide.31,32 A study of 262 patients treated for limited and extensive SCLC found no effect of BMI levels on toxicity.33 However, this study was not designed to evaluate sex differences, but rather, it evaluated obesity.
It has been suggested that women overreport morbidity and disability compared with men, resulting in a reporting bias with respect to toxicity.34 However, this has been shown not to be the case when studied and when other possible confounding variables are examined.35,36 Clearly, this was not the case in our study because women had higher toxicity rates and grades not only in subjective areas, such as nausea, but also in objective areas, including leukopenia and anemia, in which self-reporting of symptoms is not subject to patient bias.
Our results show that women not only experience more frequent toxicity, but they also suffer from more severe toxicity. Despite this, the overall doses of chemotherapy delivered to females were not significantly different from those received by their male counterparts. Although more female patients required dose delays because of toxicity, treatment compliance remained high, with equal proportions of men and women completing six cycles of chemotherapy. Despite similar treatment delivery, females in our study had significantly better outcomes with respect to both response rates and overall survival. These results are consistent with the previous studies7-9 that have shown that female sex is one of the strongest prognostic indicators in SCLC. These findings raise the possibility of sex-based differences in drug pharmacodynamics for agents used in SCLC. Sex-based differences in outcome may also be a result of altered tumor biology between the sexes, although this remains unproven. Women smokers have been shown to have a higher rate of some forms of lung cancer, such as adenocarcinoma, thus raising the possibility of estrogens playing a role in carcinogenesis.37 Women smokers also seem to be more susceptible to the carcinogenic effects of smoke than men.3 Finally, men have been shown to have a greater allele loss for marker HSAS on chromosome 11p(LOH11B), which has been associated with a poorer survival in non–small-cell lung cancer.38 Thus, it is possible that inherent biologic differences may also play a role in explaining toxicity and efficacy differences between the sexes, and further study is warranted.
Further investigation into the mechanism for increased toxicity in women is warranted to determine whether differences between the sexes may be seen in pharmacokinetics and pharmacogenomic profiles. Our current system of dosing by BSA, although well established, has never been validated in adults29 and is not sex specific. It may be a suboptimal tool for maximizing drug activity and decreasing side effects. Recent attempts have been made to develop individualized dosing of drugs, such as amonafide, based on a pharmacodynamic model involving phenotype, sex, and pretreatment WBC levels.39 Carboplatin dosing is also often adjusted for sex because of the inclusion of glomerular filtration rate calculations in the Calvert formula.40 It is possible that such individualized dosing protocols for the other drugs used in the treatment of SCLC might minimize the potential for toxicity in women.
In conclusion, women experience more toxicity when treated for SCLC, although they do not receive fewer chemotherapy cycles, and they have an improved outcome compared with men. The cause for this is likely multifactorial, and further studies are needed to identify the mechanisms that lead to these sex-specific effects.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer J Clin 54:8-29, 2004
2. National Cancer Institute of Canada: Canadian Cancer Statistics 2003. Toronto, Canada, National Cancer Institute of Canada, ISDN 0835-2976, 2003
3. Payne S: ‘Smoke like a man, die like a man’: A review of the relationship between gender, sex and lung cancer. Soc Sci Med 53:1067-1080, 2001
4. Haugen A: Women who smoke: Are women more susceptible to tobacco-induced lung cancer Carcinogenesis 23:227-229, 2002
5. Ferguson MK, Skosey C, Hoffman PC, et al: Sex-associated differences in presentation and survival in patients with lung cancer. J Clin Oncol 8:1402-1407, 1990
6. Wolf M, Holle R, Hans K, et al: Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): The role of sex as a predictor for survival. Br J Cancer 63:986-992, 1991
7. Spiegelman D, Maurer LH, Ware JH, et al: Prognostic factors in small-cell carcinoma of the lung: An analysis of 1,521 patients. J Clin Oncol 7:344-354, 1989
8. Osterlind K, Hansen HH, Hansen M, et al: Long-term disease-free survival in small-cell carcinoma of the lung: A study of clinical determinants. J Clin Oncol 4:1307-1313, 1986
9. Albain KS, Crowley JJ, LeBlanc M, et al: Determinants of improved outcome in small-cell lung cancer: An analysis of the 2,580-patient Southwest Oncology Group database. J Clin Oncol 8:1563-1574, 1990
10. Paesmans M, Sculier JP, Lecomte J, et al: Prognostic factors for patients with small cell lung carcinoma: Analysis of a series of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer 89:523-533, 2000
11. Mennecier B, Lebitasy MP, Moreau L, et al: Women and small cell lung cancer: Social characteristics, medical history, management and survival—A retrospective study of all the male and female cases diagnosed in Bas-Rhin (Eastern France) between 1981 and 1994. Lung Cancer 42:141-152, 2003
12. Meinert CL, Gilpin AK, Unalp A: Gender representation in trials. Control Clin Trials 21:462-475, 2000
13. Dobbs NA, Twelves CJ, Gillies H, et al: Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry. Cancer Chemother Pharmacol 36:473-476, 1995
14. Kaul S, Srinivas NR, Mummaneni V, et al: Effects of gender, age, and race on the pharmacokinetics of etoposide after intravenous administration of etoposide phosphate in cancer patients. Semin Oncol 23:23-29, 1996
15. Milano G, Etienne MC, Cassuto-Viguier E, et al: Influence of sex and age on fluorouracil clearance. J Clin Oncol 10:1171-1175, 1992
16. Zalcberg J, Kerr D, Seymour L, et al: Hematological and non-hematological toxicity after 5-flurouracil and leucovorin in patients with advanced colorectal cancer is significantly associated with gender, increasing age and cycle number. Eur J Cancer 34:1871-1875, 1998
17. Stein BN, Petrelli NJ, Douglass HO, et al: Age and sex are independent predictors of 5-flurouracil toxicity: Analysis of a large-scale phase III trial. Cancer 75:11-17, 1995
18. Sloan JA, Loprinzi CL, Novotny PJ, et al: Sex differences in fluorouracil-induced stomatitis. J Clin Oncol 18:412-420, 2000
19. Sloan JA, Goldberg RM, Sargent DJ, et al: Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 20:1491-1498, 2002
20. Liaw CC, Wang CH, Chang HK, et al: Gender discrepancy observed between chemotherapy-induced emesis and hiccups. Support Care Cancer 9:435-441, 2001
21. Hesketh PJ, Gandara DR, Hesketh AM, et al: Dose-ranging evaluation of the antiemetic effect of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide. Support Care Cancer 4:141-146, 1996
22. Feld R, Evans WK, Coy P, et al: Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross resistant chemotherapy combinations in patients with limited small-cell carcinoma of the lung. J Clin Oncol 5:1401-1409, 1987
23. Evans WK, Feld R, Murray N, et al: Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer. Ann Intern Med 107:451-458, 1987
24. Murray N, Coy P, Pater J, et al: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. J Clin Oncol 11:336-344, 1993
25. Murray N, Livingston RB, Shepherd FA, et al: Randomized Study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: An intergroup study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 17:2300-2308, 1999
26. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
27. Hesketh PJ, Grunberg SM, Gralla, et al: The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—The Aprepitant Protocol 052 Study Group. J Clin Oncol 21:4112-4119, 2003
28. Wade JR, Kelman AW, Kerr DJ, et al: Variability in the pharmacokinetics of epirubicin: A population analysis. Cancer Chemother Pharmacol 29:391-395, 1992
29. Grochow LB: Individualized dosing of anti-cancer drugs and the role of therapeutic monitoring, in Growchow LB, Ames MM (eds): A Clinician’s Guide to Chemotherapy Pharmacokinetics and Pharmacodynamics. Lippincott, Williams and Wilkins, Baltimore, MD, 1998, pp 3-16
30. Williamson DF: Descriptive epidemiology of body weight and weight change in U.S. adults. Ann Intern Med 119:646-649, 1993
31. Rodvold KA, Rushing DA, Tewksbury DA: Doxorubicin clearance in the obese. J Clin Oncol 6:1321-1327, 1998
32. Powis G, Reece P, Ahmann DL, et al: Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemother Pharmacol 20:219-222, 1987
33. Georgiadis MS, Steinberg SM, Hankins LA, et al: Obesity and therapy-related toxicity in patients treated for small-cell lung cancer. J Natl Cancer Inst 87:361-366, 1995
34. Hibbard JH, Pope CR: Another look at sex differences in the use of medical care: Illness orientation and the types of morbidities for which services are used. Women Health 11:21-36, 1986
35. 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
36. Gijsbers van Wijk CM, Huisman H, Kolk AM: Gender differences in physical symptoms and illness behavior: A health diary study. Soc Sci Med 49:1061-1074, 1999
37. Baldini EH, Strauss GM: Women and lung cancer: Waiting to exhale. Chest 112:229S-234S, 1997
38. Schreiber G, Fong KM, Peterson B, et al: Smoking, gender, and survival association with allele loss for the LOH11B lung cancer region on chromosome 11. Cancer Epidemiol Biomarkers Prev 6:315-319, 1997
39. Ratain MJ, Mick R, Janisch L: Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender. Pharmacogenetics 6:93-101, 1996
40. Calvert AH, Newell DR, Gumbrell LA: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989(Simron Singh, Wendy Parul)
University of Toronto
Cancer Care Ontario, Toronto
the National Cancer Institute of Canada Clinical Trials Group
Queens University, Kingston, Ontario
the British Columbia Cancer Agency, Vancouver, British Columbia, Canada
ABSTRACT
PATIENTS AND METHODS: This was a sex-based retrospective analysis of four SCLC trials conducted by the National Cancer Institute of Canada Clinical Trials Group between 1987 and 1999. The 1,006 patients (648 males and 358 females) received similar chemotherapy consisting of cyclophosphamide-doxorubicin-vincristine and etoposide-cisplatin. Toxicities examined included myelosuppression, stomatitis, vomiting, and infection. Other end points included dose reductions and omissions, response, and survival.
RESULTS: Women experienced significantly more hematologic toxicity than men (grade 3 and 4 anemia, 16.3% v 7.6%, respectively, P < .001; grade 3 and 4 leukopenia, 80.4% v 69.2%, respectively, P = .0001). However, toxic death rates were similar for men and women (1.5% v 1.1%, respectively, P = .58). Women also had significantly more stomatitis and vomiting of all grades. Despite increased toxicity, 76% of females versus 73.4% of males received all six treatment cycles (P = .38), but 52% of females versus 43.4% of males had treatment delayed for 2 weeks or more (P = .022). Only 31.8% of females and 28.2% of males had at least one cycle of chemotherapy dose reduction (P = .23). The overall response rate was 80.3% for females and 66.9% for males (P < .0001), and the median survival time was 1.31 years for females compared with only 0.91 year for males (P < .0001).
CONCLUSION: Women experience more chemotherapy-related toxicity in the treatment of SCLC, but they also have increased response rates and survival.
INTRODUCTION
Small-cell lung cancer (SCLC) accounts for approximately 15% to 20% of all bronchogenic carcinomas. Demographic studies suggest that women are more likely than men to suffer from SCLC, whereas men are more likely to be diagnosed with non–small-cell lung cancer.3 Interestingly, sex has been found to be an independent prognostic factor for survival for all subtypes of lung cancer, with women surviving longer than men (P < .0001).5 Specifically, with respect to SCLC, prognostic studies of several of the large cooperative group databases have shown in both univariate and multivariate analyses that female sex is associated with a favorable outcome.5-10 However, this has not been observed in all analyses.11
Treatment of both limited- and extensive-stage SCLC involves chemotherapeutic drugs that are associated with significant side effects. In fact, virtually all patients treated will experience some form of toxicity. Patients give informed consent to treatment after a discussion based on the risks and benefits, including an assessment of treatment-related toxicity. Generally this information is applied to the population as a whole, and little, if any, information is given to patients on the role sex can play in treatment toxicity. Traditionally, results from clinical trials and information on drug pharmacokinetics and toxicity have been generalized and applied to both sexes. Only since 1993 has the American Congress required sex-specific analysis of the safety and efficacy of drugs in clinical trials. Legislation now states that clinical trials must be "designed and carried out in a manner sufficient to provide for an analysis of whether the variables being studied in the trial affect women differently than other subjects in the trial."12
Emerging data suggest that sex-specific pharmacokinetics and toxicity exist for certain chemotherapeutic drugs. Clearance rates and differences in area under the plasma concentration-time curve (AUC) ratios have been reported for doxorubicin and etoposide, which are two drugs that are used frequently in SCLC.13,14 Similarly, Milano et al15 have shown that the capacity to clear fluorouracil is lower in women compared with men, and sex-related differences in drug toxicity profiles and significant variations in both the frequency and severity of toxicity have been found in men and women.16-19 Although few sex-related studies of cisplatin have been undertaken, at least one study has shown that women experience significantly more nausea and vomiting after cisplatin than men.20,21
On the basis of these observations derived from the treatment of other tumors, we hypothesized that women would also experience more frequent and more severe toxicity than men during SCLC chemotherapy. We elected to undertake this sex-based retrospective analysis of treatment delivery and toxicity in four prospectively randomized SCLC trials conducted by the National Cancer Institute of Canada Clinical Trials Group and to correlate these parameters with outcome. The trials were selected because patients in seven of the eight study arms examined received similar chemotherapy regimens with variations only in schedule and radiation treatment. We report here the results of this analysis.
PATIENTS AND METHODS
Treatment
The chemotherapy regimens and doses used in the four trials are listed in Table 2. BR.3 compared three cycles of cyclophosphamide, doxorubicin, and vincristine (CAV) followed by three cycles of etoposide and cisplatin (EP) with alternating CAV with EP for three cycles each in limited SCLC. After three courses of chemotherapy, responding patients underwent prophylactic cranial irradiation (PCI) on days 8 through 15 (20 Gy in five fractions). Responding patients were further randomized after the sixth cycle of chemotherapy to receive thoracic radiotherapy consisting of either 37.5 Gy in 15 fractions or 25 Gy in 10 fractions.
BR.4 compared CAV every 3 weeks for six cycles to three cycles of CAV alternating with three cycles of EP in patients with extensive SCLC. Stable and responding patients received PCI on day 8 of cycle 3.
BR.6 compared the timing of thoracic irradiation in limited-stage SCLC. All patients received three cycles of CAV alternating with three cycles of EP and were randomly assigned to receive early thoracic irradiation (40 Gy in 15 fractions) administered concurrently with the first cycle of EP (cycle 2) or with the last cycle of EP (cycle 6).
BR.8 compared three cycles of CAV alternating with three cycles of EP to a dose-intensive weekly chemotherapy regimen in extensive SCLC. Patients with a complete response received PCI (25 Gy in 10 fractions) after chemotherapy. The intensive treatment arm was not included in our analysis.
Assessment
The primary end points of the study consisted of hematologic toxicity (leukocyte count, hemoglobin, and platelets), stomatitis, vomiting, and infection. Toxicity was reported and graded according to the National Cancer Institute of Canada Clinical Trials Group expanded common toxicity criteria from grades 0 to 4. All toxicities (grade 1 and above), as well as severe toxicities (grade 3 and above), were examined.
Secondary end points included assessment of the number of dose reductions required and the number of omitted cycles. Response rates, survival, and toxic deaths were also examined. Standard response criteria were used, and survival was measured from the date of randomization until the date of death or last follow-up examination.
Statistical Analyses
Fisher’s exact test was used to compare toxicity between the sexes. Logistic regression was performed to examine for potentially confounding covariates, including age, body surface area (BSA), PS, pretreatment lactate dehydrogenase (LDH), and individual trial. Survival curves were estimated by the Kaplan-Meier method.26 The total dose and dose reductions of chemotherapy were calculated using all included patients from the start to completion of the last cycle of chemotherapy.
RESULTS
Toxicity
Hematologic toxicities of anemia (55.9% of females v 38.6% of males, P < .0001) and leukopenia (92.7% of females v 84.7% of males, P = .0002) were significantly higher in female patients (Table 4). This was consistent when examined both for all toxicity levels and for grade 3 and 4 toxicity. Despite greater leukopenia, there was no significant difference in infection rates or toxic death rates (10 deaths in males, 1.5%; and four deaths in females, 1.1%; P = .58).
Females also experienced more nonhematologic toxicities than men (Table 4), including stomatitis (16.8% v 8.3%, respectively, P < .0001) and vomiting (76.8% v 67.2%, respectively, P = .0014). Logistic regression analysis was performed to adjust the comparisons between sexes by the following baseline characteristics: age (≤ 65 v > 65 years), baseline BSA (< 2 v ≥ 2 m2), PS (ECOG 0 to 1 v 2 to 3), baseline LDH, and trial (Table 5). After adjusting for the effect of these variables, female sex was still a significant predictor for increased anemia, leukopenia, stomatitis, and vomiting.
Chemotherapy Treatment Delivery
Treatment received and dose reductions required are listed by sex in Table 6. Despite experiencing more toxicity, 76% of female and 73.4% of male patients received all six cycles (P = .38). Only 31.8% of females and 28.2% of males had one or more cycles of chemotherapy reduced (P = .23). However, more females than males had treatment delays of 2 weeks or more (52% v 43.4%, respectively, P = .022), likely because of their increased toxicity.
Response and Survival
Females had a superior overall response rate (Table 7) compared with males (80.3% v 66.9%, respectively, P < .0001), and they also had more complete responses. As shown in Figure 1, women had significantly better survival (P < .0001). After adjusting for age, baseline BSA, PS, baseline LDH, and trial, female sex was still a highly significant predictor for survival.
DISCUSSION
Sex-related toxicity has been reported previously for fluorouracil in the treatment of gastrointestinal cancers, where it has been shown that females experienced greater hematologic toxicity and nonhematologic toxicity including stomatitis, alopecia, nausea, vomiting, and diarrhea.16-19
Patients in our study received two regimens, CAV and EP. Few sex-related studies of cisplatin have been undertaken, but one study has shown that women experience significantly more nausea and vomiting after cisplatin than men.20 This is consistent with our results. Another study showed that female sex was a negative predictor for complete antiemetic control with 5-hydroxytryptamine-3 antagonists in patients receiving doxorubicin or cyclophosphamide.21 However, sex differences have not been observed with the new class of antiemetics, neurokinin-1 antagonists.27 Pharmacokinetic studies of the chemotherapeutic agent etoposide have been shown to vary slightly in women, although significant differences in AUC ratios have not been reported.14 However, it is possible that small differences in etoposide AUC may have contributed to the excess toxicity experienced by the women in our analysis.
There are fewer sex-related studies for the agents in the CAV regimen. Dobbs et al13 showed that in patients with normal liver biochemistry, men had a higher rate of clearance of doxorubicin than women. Similarly, older women have been shown to have a lower rate of clearance of another anthracycline, epirubicin, than do men of any age.28 As with etoposide, lower clearance and a higher doxorubicin AUC might be expected to result in excess toxicity for women treated with the CAV regimen. Gemcitabine, a drug that is used extensively in non–small-cell lung cancer, although not in SCLC, has been reported to have a higher clearance rate in men when compared with women of the same age.29 There have been no published sex-based studies of vincristine. However, rates of neuropathy were not significantly different in men and women in our study.
Another possible reason for the increased toxicity seen in women may have to do with influence of body mass index (BMI). Women generally have a higher baseline BMI than men because of increased body fat,30 and this may affect drug distribution and potentially increase toxicity. Obesity and high BMI have been shown to be associated with a decrease in drug clearance and a resultant increase in the elimination half-life for both doxorubicin and cyclophosphamide.31,32 A study of 262 patients treated for limited and extensive SCLC found no effect of BMI levels on toxicity.33 However, this study was not designed to evaluate sex differences, but rather, it evaluated obesity.
It has been suggested that women overreport morbidity and disability compared with men, resulting in a reporting bias with respect to toxicity.34 However, this has been shown not to be the case when studied and when other possible confounding variables are examined.35,36 Clearly, this was not the case in our study because women had higher toxicity rates and grades not only in subjective areas, such as nausea, but also in objective areas, including leukopenia and anemia, in which self-reporting of symptoms is not subject to patient bias.
Our results show that women not only experience more frequent toxicity, but they also suffer from more severe toxicity. Despite this, the overall doses of chemotherapy delivered to females were not significantly different from those received by their male counterparts. Although more female patients required dose delays because of toxicity, treatment compliance remained high, with equal proportions of men and women completing six cycles of chemotherapy. Despite similar treatment delivery, females in our study had significantly better outcomes with respect to both response rates and overall survival. These results are consistent with the previous studies7-9 that have shown that female sex is one of the strongest prognostic indicators in SCLC. These findings raise the possibility of sex-based differences in drug pharmacodynamics for agents used in SCLC. Sex-based differences in outcome may also be a result of altered tumor biology between the sexes, although this remains unproven. Women smokers have been shown to have a higher rate of some forms of lung cancer, such as adenocarcinoma, thus raising the possibility of estrogens playing a role in carcinogenesis.37 Women smokers also seem to be more susceptible to the carcinogenic effects of smoke than men.3 Finally, men have been shown to have a greater allele loss for marker HSAS on chromosome 11p(LOH11B), which has been associated with a poorer survival in non–small-cell lung cancer.38 Thus, it is possible that inherent biologic differences may also play a role in explaining toxicity and efficacy differences between the sexes, and further study is warranted.
Further investigation into the mechanism for increased toxicity in women is warranted to determine whether differences between the sexes may be seen in pharmacokinetics and pharmacogenomic profiles. Our current system of dosing by BSA, although well established, has never been validated in adults29 and is not sex specific. It may be a suboptimal tool for maximizing drug activity and decreasing side effects. Recent attempts have been made to develop individualized dosing of drugs, such as amonafide, based on a pharmacodynamic model involving phenotype, sex, and pretreatment WBC levels.39 Carboplatin dosing is also often adjusted for sex because of the inclusion of glomerular filtration rate calculations in the Calvert formula.40 It is possible that such individualized dosing protocols for the other drugs used in the treatment of SCLC might minimize the potential for toxicity in women.
In conclusion, women experience more toxicity when treated for SCLC, although they do not receive fewer chemotherapy cycles, and they have an improved outcome compared with men. The cause for this is likely multifactorial, and further studies are needed to identify the mechanisms that lead to these sex-specific effects.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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