- Email: [email protected]
Incidence of Chemotherapy-Induced Amenorrhea in Premenopausal Women Treated With Adjuvant FOLFOX for Colorectal Cancer
Original Study
Incidence of Chemotherapy-Induced Amenorrhea in Premenopausal Women Treated With Adjuvant FOLFOX for Colorectal Cancer Andrea Cercek,1 Cara L. Siegel,1 Marinela Capanu,2 Diane Reidy-Lagunes,1 Leonard B. Saltz1 Abstract The effect of FOLFOX chemotherapy on menses and fertility in young women with colon cancer is unknown. This study was a small retrospective survey in which patients were asked to answer questions pertaining to their menses before, during and after chemotherapy. In this study there appeared to be a trend toward FOLFOX induced amenorrhea during chemotherapy increasing with age. Larger prospective studies are needed to determine the effects of FOLFOX on menses and fertility. Background: Studies indicate that the incidence of young women diagnosed with colorectal cancer is rising, thus there is an increasing number of female colorectal cancer survivors of premenopausal and child-bearing age. Adjuvant FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy is the most widely used standard treatment for stage III and high-risk stage II colon cancer. We evaluated the incidence of FOLFOX-induced amenorrhea in women age 50 and younger treated with adjuvant therapy for colorectal cancer. Patients and Methods: A search of pharmacy records identified 119 women age 50 or younger who received adjuvant FOLFOX chemotherapy at Memorial SloanKettering for stage II or III colorectal cancer from January 2002 and January 2011. Eligible patients were mailed an anonymous questionnaire. The returned surveys were reviewed and the results tallied. Results: Seventy-three patients returned the questionnaire. Twenty-four patients were excluded from analysis: 19 were treated with pelvic radiotherapy, 2 patients had undergone bilateral oophorectomy, 2 had a hysterectomy, and 1 stopped menstruating before diagnosis. Forty-nine patient responses were analyzed. In total, 41% (n ¼ 20) experienced amenorrhea during chemotherapy. Sixteen percent had persistent amenorrhea 1 year after completion of chemotherapy. The incidence of amenorrhea during chemotherapy trended higher in patients aged older than 40 compared with patients aged 40 and younger (59% vs. 31% [P ¼ .075]). There was no statistically significant difference in persistent amenorrhea between the 2 age groups (24% vs. 13%; P ¼ .42). Conclusion: In this retrospective series, there appears to be a trend toward FOLFOX induced amenorrhea during chemotherapy increasing with age. Twenty-four percent of women older than the age of 40 were found to have persistent amenorrhea after FOLFOX therapy. Because of the small sample size, the study is underpowered to detect a statistically significant difference between older and younger patients. Prospective studies are planned to further characterize the effect of FOLFOX on early menopause and fertility. Clinical Colorectal Cancer, Vol. 12, No. 3, 163-7 ª 2013 Elsevier Inc. All rights reserved. Keywords: Colon cancer, FOLFOX chemotherapy, Menses, Young women
Introduction 1
Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 2 Division of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY Submitted: Oct 12, 2012; Revised: Feb 26, 2013; Accepted: Apr 15, 2013; Epub: Jul 17, 2013 Address for correspondence: Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, 300 East 66th St, New York, NY 10065 Fax: 646-888-4257; e-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2013.04.007
Colorectal cancer is the third most common cancer in women in the United States. It is estimated that in 2010, approximately 142,570 people were diagnosed with colorectal cancer and approximately 70,480 were women. Of the 70,480 women, 3% to 5% were younger than the age of 40.1 Recent analyses have indicated that the incidence rates of colorectal cancer in young women (age 20-49) increased 1.6% per year and up to 5.6% per year in women age 20 to 29 years from 1999 to 2005.The improvement in adjuvant treatment over the past several decades has improved overall survival.2 However,
Clinical Colorectal Cancer September 2013
- 163
Incidence of Chemotherapy Induced Amenorrhea in Young Women With Colon Cancer one of the potential effects of the treatment is ovarian failure and premature menopause. This results in an increased risk of osteoporosis and cardiovascular toxicities, and the loss of childbearing potential, which can have a major effect on the overall quality of life of young women surviving colorectal cancer. The standard adjuvant chemotherapy regimen in colorectal cancer is the biweekly infusion regimen of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin known by the acronym FOLFOX.3 Though this therapy has been shown to improve outcomes, multiple side effects of the treatment are recognized. Some of the known potential side effects include neurotoxicity, decreased blood counts, fatigue, and nausea and vomiting. In colorectal cancer, there are presently no studies published in the literature testing the effects of adjuvant chemotherapy on female fertility. To that end, as a first step, we conducted a survey to assess the incidence of loss of Figure 1 Questionnaire
164
-
Clinical Colorectal Cancer September 2013
menstrual cycle, and when lost, the incidence of recovery within 1 year of completion of chemotherapy, in patients age 50 and younger with resected stage II or III colorectal cancer treated with adjuvant FOLFOX chemotherapy.
Patients and Methods Eligible patients had stage II or III colorectal adenocarcinoma and were treated with FOLFOX chemotherapy (without pelvic radiation) at Memorial-Sloan Kettering Cancer Center. The women had to be 50 years of age or younger at the time of initiation of chemotherapy. For inclusion, there had to be a minimum of 6 months after completion of chemotherapy, and patients had to be free of known disease. Patients were invited to participate in the survey using mail, and had to be willing to complete the anonymous mail survey. The Institutional Review
Andrea Cercek et al Board reviewed this research plan and concluded that this retrospective survey analysis was exempt from requirements of waivers of authorization. We identified 119 eligible patients treated with FOLFOX after colon cancer resection (T1-3/N0-2) at Memorial-Sloan Kettering Cancer Center from January 2002 and June 2010. A total of 73 (61%) patients returned the survey. Of the 73 who responded, 24 women were excluded from the analyses: 19 received pelvic radiation, 2 had an oophorectomy, 2 had a hysterectomy, and 1 had stopped menstruating before diagnosis. Thus, a total of 49 patients met eligibility criteria. The patients were sent a survey, along with a letter explaining the purpose of the study and an addressed, stamped envelope. The survey consisted of a questionnaire with 10 questions. The survey questions are shown in Figure 1.
Treatment All patients had either stage II or III colorectal cancer, underwent resection, and then received FOLFOX chemotherapy. All patients were treated with postoperative FOLFOX, given in the standard modified mFOLFOX 6 schedule.4 Because the survey was anonymous, we were not able to ascertain the dosages and number of cycles that the patients received.
Statistical Methods The Fisher exact test was used to test for associations between amenorrhea during and after chemotherapy and age dichotomized at 40 years.
Results Patient Characteristics Patient characteristics are detailed in Table 1. Because of anonymity we were only able to report age ranges. The mean age range at diagnosis was 31-35 (range, 21-50) years. All patients had completed treatment at least 6 months earlier and 15 patients had completed treatment 1 year earlier. All patients were premenopausal and all reported regular menses at the start of chemotherapy.
Incidence of Amenorrhea Of the 49 patients that were included in this analysis, 20 patients (41%) experienced amenorrhea during chemotherapy. Eight
Table 1 Patient Characteristics Characteristic
Patients, n (%)
Menstruation Before Treatment Normal Abnormal
47 (96) 2 (4)
Age, years 21-25
2 (4)
26-30
8 (16)
31-35
8 (16)
36-40
14 (29)
41-45
6 (12)
46-50
11 (21)
Table 2 Incidence of Amenorrhea During and After Chemotherapy Loss of Menses Yes, n (%)
No, n (%)
P
During Chemotherapy All Ages, n [ 49
20 (41)
29 (59)
Younger than 40, n ¼ 32
10 (31)
22 (69)
40 and older, n ¼ 17
10 (59)
7 (41)
.075
After Chemotherapy All Ages, n [ 49
8 (16)
41 (84)
Younger than 40, n ¼ 32
4 (13)
28 (87)
40 and older, n ¼ 17
4 (24)
13 (76)
.423
(16%) of these 20 had persistent amenorrhea 1 year after completion of chemotherapy. Therefore, of the 20 patients experiencing loss of menses, this event proved to be transient in 12 (60%) and persistent in 8 (40%). In patients older than the age of 40, the overall incidence of chemically-induced amenorrhea (transient plus persistent) during chemotherapy was 59% (10 out of 17 patients), and 4 (24%) of these 17 experienced persistent loss of menses. For patients whose ages were 40 and younger, 31% (10 out of 32 patients) experienced at least transient ammenorhea, and 4 (13%) experienced persistent loss of menses. The overall incidence of amenorrhea during chemotherapy trended toward being higher in patients older than 40 vs. those aged 40 and younger (P ¼ .075) (Table 2). The incidence of persistent amenorrhea after completion of therapy did not appear to be statistically significantly higher in women older than 40 (24% vs. 13%; P ¼ .423) (Table 2). Of note, 2 women reported that they had attempted to become pregnant, 1 succeeded in doing so 18 months after completing treatment.
Discussion The ovaries have a relatively fixed number of follicles, and these are potentially sensitive to cytotoxic drugs. Damage to the follicles can lead to premature ovarian failure and infertility.5 The degree of damage to the theca and granulosa cells within the oocyte is largely dependent on the type of chemotherapeutic agent used. Alkylating agents such as cyclophosphamide, chlorambucil, and melphalan have the highest potential for gonadal damage, with reported incidence of ovarian failure as high as 70%. The effects of chemotherapy on ovarian function have been studied most extensively in breast cancer in which the reported incidences range from 30% to 70% depending on the regimen used. These data have indicated that the effects of 5-FU alone on ovarian function appear to be minimal, however, the risks of oxaliplatin are largely unknown.6-9 Previous studies in breast cancer have reported a wide variability in range of the risk of development of amenorrhea after chemotherapy. This might in part be because of the widely differing definitions of chemotherapy-related amenorrhea—some define it as cessation of menses lasting 3 to 6 months after chemotherapy and others list is as a cessation of 12 months.6,10 Data indicate that most
Clinical Colorectal Cancer September 2013
- 165
Incidence of Chemotherapy Induced Amenorrhea in Young Women With Colon Cancer
166
-
patients who have amenorrhea for 1 year after chemotherapy do not regain their menstrual cycle.7 In this patient survey, we attempted to obtain a general idea of the effect of adjuvant FOLFOX chemotherapy on the menstrual cycle in patients with early stage colorectal cancer. We used amenorrhea as a measure of premature ovarian failure. This is comparable with the approach used in studies evaluating chemotherapy-induced menopause in other types of solid tumors, including breast cancer.10 We sought to investigate whether age was associated with increased incidence of chemotherapy-induced amenorrhea. The trend toward increased incidence of amenorrhea and premature menopause with increased age was observed in our exploratory analysis. Because of the anonymous nature of the questionnaire, we could not evaluate patient characteristics such as tumor type and specifics of treatment dosing and duration. In breast cancer and many other tumor types, particularly hematologic malignancies, fertility preservation is often considered before initiation of chemotherapy. Studies in Hodgkin lymphoma showed that significantly fewer women treated with a gonadotropinreleasing hormone agonist during chemotherapy exhibited premature ovarian failure.11 Another possibility is embryo cryopreservation. Newer experimental options are also available to patients and these include oocyte cryopreservation and ovarian tissue cryopreservation. The latter option is an exciting investigational approach which involves the cryopreservation of ovarian tissue strips with subsequent reimplantation after completion of cancer therapy.12 These interventions are invasive, time-consuming, and expensive, however, and the relative benefits, risks, and costs would need to be considered in the context of the likelihood of infertility. The effect of FOLFOX on ovarian function and specifically on the menstrual cycle as a measure of potential fertility is not well studied. Recently a subset analysis of the National Surgical Adjuvant Breast and Bowel Project C-08 study evaluated the effects of FOLFOX vs. FOLFOX plus bevacizumab on ovarian failure. Among 179 patients, 84 received adjuvant FOLFOX and 95 received FOLFOX plus bevacizumab. Two percent of the FOLFOX-only group had ovarian failure compared with 34% of those who received bevacizumab. One of 5 women who had ovarian failure (22%) started menstruating after completion of treatment.13 In our small survey, most patients appear to maintain or at least regain ovarian function, and there is a trend toward increased incidence of amenorrhea during chemotherapy in women older than 40, but this does not translate into a statistically significant difference in incidence of persistent amenorrhea after completion of chemotherapy. Twenty-four percent of women age 40 or older reported persistent amenorrhea vs. 13% of patients younger than 40 years of age after FOLFOX treatment. Of note, we could not evaluate the relationship between loss of menses and continuous age; because of anonymity of the survey, the actual ages were not available. A potential criticism is that there might have been an inherent selection bias favoring the patients who regained their menses because they might have been more likely to complete the survey than patients who did not. The alternative, that loss of menses might stimulate a higher likelihood of response to the survey, is also possible. However, the results provide preliminary insight
Clinical Colorectal Cancer September 2013
into the incidence of chemotherapy-induced amenorrhea in patients with colorectal cancer who are treated with FOLFOX chemotherapy.
Conclusion Larger studies and prospective analyses are needed to provide more information on the effects of adjuvant colorectal chemotherapy on menses and fertility. These data will help physicians counsel their patient on menopausal symptoms and the clinical sequelae of early menopause, and inform young women on the effects of treatment on fertility. It will also assist in decision-making regarding selection of options for fertility preservation.
Clinical Practice Points Studies indicate that the incidence of young women diagnosed
with colorectal cancer is rising, thus there is an increasing number of female colorectal cancer (crc) survivors of premenopausal and child-bearing age. Adjuvant FOLFOX chemotherapy is the most widely used standard treatment for stage III and high-risk stage II colon cancer. We evaluated the incidence of FOLFOX induced amenorrhea in women age 50 and younger treated with adjuvant therapy for colorectal cancer. Eligible patients were mailed an anonymous questionnaire. The returned surveys were reviewed and the results tallied. In total, 41% experienced amenorrhea during chemotherapy. Sixteen percent had persistent amenorrhea one year after completion of chemotherapy. The incidence of amenorrhea during chemotherapy trended higher in patients age older than 40 compared to 40 or under (59% vs 31% (p ¼ 0.075)). There was no statistically significant difference in persistent amenorrhea between the two age groups, 24% vs 13% p ¼ 0.42, respectively). In this retrospective series, there appears to be a trend towards FOLFOX induced amenorrhea during chemotherapy increasing with age. Prospective studies are planned to further characterize the impact of FOLFOX on early menopause and fertility.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Surveillance Epidemiology and End Results. SEER Cancer Statistics Review, 19752007, based on November 2009 SEER data submission, posted to the SEER web site, 2010. National Cancer Institute [Web site]. Available at: http://seer.cancer. gov/csr/1975_2007/. Accessed: September 30, 2011. 2. Siegel RL, Jemal A, Ward E. Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiol Biomarkers Prev 2009; 18:1695-8. 3. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005; 325:476-87. 4. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluoruracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350: 2343-51. 5. Marhhom E, Cohen I. Fertility preservation options for women with malignancies. Obstet Gynecol Surv 2007; 62:58-72. 6. Gerber B, Dieterich M, Muller H, et al. Controversies in preservation of ovary function and fertility in patients with breast cancer. Breast Cancer Res Treat 2008; 108:1-7. 7. Petrek JA, Naughton MJ, Case LD, et al. Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study. J Clin Oncol 2006; 24:1045-51. 8. Walshe JM, Denduluri N, Swain SM. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 2006; 24: 5769-79.
Andrea Cercek et al 9. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996; 14:1718-29. 10. Fornier M, Modi S, Panageas KS, et al. Incidence of chemotherapy-induced, long term amenorrhea in patients with breast carcinoma age 40 years of younger after adjuvant anthracycline and taxane. Cancer 2005; 104:1575-9. 11. Blumenfeld Z, Avivi I, Eckman A, et al. Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian
failure in young female patients with Hodgkin lymphoma. Fertil Steril 2008; 89: 166-73. 12. Spanos CP, Mamopoulos A, Tsapas A, et al. Female fertility and colorectal cancer. Int Colorectal Dis 2008; 23:735-43. 13. Avastin [package insert and label information]. South San Francisco, CA: Genentech, Inc. Available at: http://druginserts.com/lib/rx/meds/avastin/. Accessed: September 30, 2011.
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Incidence of Chemotherapy-Induced Amenorrhea in Premenopausal Women Treated With Adjuvant FOLFOX for Colorectal Cancer Andrea Cercek,1 Cara L. Siegel,1 Marinela Capanu,2 Diane Reidy-Lagunes,1 Leonard B. Saltz1 Abstract The effect of FOLFOX chemotherapy on menses and fertility in young women with colon cancer is unknown. This study was a small retrospective survey in which patients were asked to answer questions pertaining to their menses before, during and after chemotherapy. In this study there appeared to be a trend toward FOLFOX induced amenorrhea during chemotherapy increasing with age. Larger prospective studies are needed to determine the effects of FOLFOX on menses and fertility. Background: Studies indicate that the incidence of young women diagnosed with colorectal cancer is rising, thus there is an increasing number of female colorectal cancer survivors of premenopausal and child-bearing age. Adjuvant FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy is the most widely used standard treatment for stage III and high-risk stage II colon cancer. We evaluated the incidence of FOLFOX-induced amenorrhea in women age 50 and younger treated with adjuvant therapy for colorectal cancer. Patients and Methods: A search of pharmacy records identified 119 women age 50 or younger who received adjuvant FOLFOX chemotherapy at Memorial SloanKettering for stage II or III colorectal cancer from January 2002 and January 2011. Eligible patients were mailed an anonymous questionnaire. The returned surveys were reviewed and the results tallied. Results: Seventy-three patients returned the questionnaire. Twenty-four patients were excluded from analysis: 19 were treated with pelvic radiotherapy, 2 patients had undergone bilateral oophorectomy, 2 had a hysterectomy, and 1 stopped menstruating before diagnosis. Forty-nine patient responses were analyzed. In total, 41% (n ¼ 20) experienced amenorrhea during chemotherapy. Sixteen percent had persistent amenorrhea 1 year after completion of chemotherapy. The incidence of amenorrhea during chemotherapy trended higher in patients aged older than 40 compared with patients aged 40 and younger (59% vs. 31% [P ¼ .075]). There was no statistically significant difference in persistent amenorrhea between the 2 age groups (24% vs. 13%; P ¼ .42). Conclusion: In this retrospective series, there appears to be a trend toward FOLFOX induced amenorrhea during chemotherapy increasing with age. Twenty-four percent of women older than the age of 40 were found to have persistent amenorrhea after FOLFOX therapy. Because of the small sample size, the study is underpowered to detect a statistically significant difference between older and younger patients. Prospective studies are planned to further characterize the effect of FOLFOX on early menopause and fertility. Clinical Colorectal Cancer, Vol. 12, No. 3, 163-7 ª 2013 Elsevier Inc. All rights reserved. Keywords: Colon cancer, FOLFOX chemotherapy, Menses, Young women
Introduction 1
Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 2 Division of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY Submitted: Oct 12, 2012; Revised: Feb 26, 2013; Accepted: Apr 15, 2013; Epub: Jul 17, 2013 Address for correspondence: Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, 300 East 66th St, New York, NY 10065 Fax: 646-888-4257; e-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2013.04.007
Colorectal cancer is the third most common cancer in women in the United States. It is estimated that in 2010, approximately 142,570 people were diagnosed with colorectal cancer and approximately 70,480 were women. Of the 70,480 women, 3% to 5% were younger than the age of 40.1 Recent analyses have indicated that the incidence rates of colorectal cancer in young women (age 20-49) increased 1.6% per year and up to 5.6% per year in women age 20 to 29 years from 1999 to 2005.The improvement in adjuvant treatment over the past several decades has improved overall survival.2 However,
Clinical Colorectal Cancer September 2013
- 163
Incidence of Chemotherapy Induced Amenorrhea in Young Women With Colon Cancer one of the potential effects of the treatment is ovarian failure and premature menopause. This results in an increased risk of osteoporosis and cardiovascular toxicities, and the loss of childbearing potential, which can have a major effect on the overall quality of life of young women surviving colorectal cancer. The standard adjuvant chemotherapy regimen in colorectal cancer is the biweekly infusion regimen of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin known by the acronym FOLFOX.3 Though this therapy has been shown to improve outcomes, multiple side effects of the treatment are recognized. Some of the known potential side effects include neurotoxicity, decreased blood counts, fatigue, and nausea and vomiting. In colorectal cancer, there are presently no studies published in the literature testing the effects of adjuvant chemotherapy on female fertility. To that end, as a first step, we conducted a survey to assess the incidence of loss of Figure 1 Questionnaire
164
-
Clinical Colorectal Cancer September 2013
menstrual cycle, and when lost, the incidence of recovery within 1 year of completion of chemotherapy, in patients age 50 and younger with resected stage II or III colorectal cancer treated with adjuvant FOLFOX chemotherapy.
Patients and Methods Eligible patients had stage II or III colorectal adenocarcinoma and were treated with FOLFOX chemotherapy (without pelvic radiation) at Memorial-Sloan Kettering Cancer Center. The women had to be 50 years of age or younger at the time of initiation of chemotherapy. For inclusion, there had to be a minimum of 6 months after completion of chemotherapy, and patients had to be free of known disease. Patients were invited to participate in the survey using mail, and had to be willing to complete the anonymous mail survey. The Institutional Review
Andrea Cercek et al Board reviewed this research plan and concluded that this retrospective survey analysis was exempt from requirements of waivers of authorization. We identified 119 eligible patients treated with FOLFOX after colon cancer resection (T1-3/N0-2) at Memorial-Sloan Kettering Cancer Center from January 2002 and June 2010. A total of 73 (61%) patients returned the survey. Of the 73 who responded, 24 women were excluded from the analyses: 19 received pelvic radiation, 2 had an oophorectomy, 2 had a hysterectomy, and 1 had stopped menstruating before diagnosis. Thus, a total of 49 patients met eligibility criteria. The patients were sent a survey, along with a letter explaining the purpose of the study and an addressed, stamped envelope. The survey consisted of a questionnaire with 10 questions. The survey questions are shown in Figure 1.
Treatment All patients had either stage II or III colorectal cancer, underwent resection, and then received FOLFOX chemotherapy. All patients were treated with postoperative FOLFOX, given in the standard modified mFOLFOX 6 schedule.4 Because the survey was anonymous, we were not able to ascertain the dosages and number of cycles that the patients received.
Statistical Methods The Fisher exact test was used to test for associations between amenorrhea during and after chemotherapy and age dichotomized at 40 years.
Results Patient Characteristics Patient characteristics are detailed in Table 1. Because of anonymity we were only able to report age ranges. The mean age range at diagnosis was 31-35 (range, 21-50) years. All patients had completed treatment at least 6 months earlier and 15 patients had completed treatment 1 year earlier. All patients were premenopausal and all reported regular menses at the start of chemotherapy.
Incidence of Amenorrhea Of the 49 patients that were included in this analysis, 20 patients (41%) experienced amenorrhea during chemotherapy. Eight
Table 1 Patient Characteristics Characteristic
Patients, n (%)
Menstruation Before Treatment Normal Abnormal
47 (96) 2 (4)
Age, years 21-25
2 (4)
26-30
8 (16)
31-35
8 (16)
36-40
14 (29)
41-45
6 (12)
46-50
11 (21)
Table 2 Incidence of Amenorrhea During and After Chemotherapy Loss of Menses Yes, n (%)
No, n (%)
P
During Chemotherapy All Ages, n [ 49
20 (41)
29 (59)
Younger than 40, n ¼ 32
10 (31)
22 (69)
40 and older, n ¼ 17
10 (59)
7 (41)
.075
After Chemotherapy All Ages, n [ 49
8 (16)
41 (84)
Younger than 40, n ¼ 32
4 (13)
28 (87)
40 and older, n ¼ 17
4 (24)
13 (76)
.423
(16%) of these 20 had persistent amenorrhea 1 year after completion of chemotherapy. Therefore, of the 20 patients experiencing loss of menses, this event proved to be transient in 12 (60%) and persistent in 8 (40%). In patients older than the age of 40, the overall incidence of chemically-induced amenorrhea (transient plus persistent) during chemotherapy was 59% (10 out of 17 patients), and 4 (24%) of these 17 experienced persistent loss of menses. For patients whose ages were 40 and younger, 31% (10 out of 32 patients) experienced at least transient ammenorhea, and 4 (13%) experienced persistent loss of menses. The overall incidence of amenorrhea during chemotherapy trended toward being higher in patients older than 40 vs. those aged 40 and younger (P ¼ .075) (Table 2). The incidence of persistent amenorrhea after completion of therapy did not appear to be statistically significantly higher in women older than 40 (24% vs. 13%; P ¼ .423) (Table 2). Of note, 2 women reported that they had attempted to become pregnant, 1 succeeded in doing so 18 months after completing treatment.
Discussion The ovaries have a relatively fixed number of follicles, and these are potentially sensitive to cytotoxic drugs. Damage to the follicles can lead to premature ovarian failure and infertility.5 The degree of damage to the theca and granulosa cells within the oocyte is largely dependent on the type of chemotherapeutic agent used. Alkylating agents such as cyclophosphamide, chlorambucil, and melphalan have the highest potential for gonadal damage, with reported incidence of ovarian failure as high as 70%. The effects of chemotherapy on ovarian function have been studied most extensively in breast cancer in which the reported incidences range from 30% to 70% depending on the regimen used. These data have indicated that the effects of 5-FU alone on ovarian function appear to be minimal, however, the risks of oxaliplatin are largely unknown.6-9 Previous studies in breast cancer have reported a wide variability in range of the risk of development of amenorrhea after chemotherapy. This might in part be because of the widely differing definitions of chemotherapy-related amenorrhea—some define it as cessation of menses lasting 3 to 6 months after chemotherapy and others list is as a cessation of 12 months.6,10 Data indicate that most
Clinical Colorectal Cancer September 2013
- 165
Incidence of Chemotherapy Induced Amenorrhea in Young Women With Colon Cancer
166
-
patients who have amenorrhea for 1 year after chemotherapy do not regain their menstrual cycle.7 In this patient survey, we attempted to obtain a general idea of the effect of adjuvant FOLFOX chemotherapy on the menstrual cycle in patients with early stage colorectal cancer. We used amenorrhea as a measure of premature ovarian failure. This is comparable with the approach used in studies evaluating chemotherapy-induced menopause in other types of solid tumors, including breast cancer.10 We sought to investigate whether age was associated with increased incidence of chemotherapy-induced amenorrhea. The trend toward increased incidence of amenorrhea and premature menopause with increased age was observed in our exploratory analysis. Because of the anonymous nature of the questionnaire, we could not evaluate patient characteristics such as tumor type and specifics of treatment dosing and duration. In breast cancer and many other tumor types, particularly hematologic malignancies, fertility preservation is often considered before initiation of chemotherapy. Studies in Hodgkin lymphoma showed that significantly fewer women treated with a gonadotropinreleasing hormone agonist during chemotherapy exhibited premature ovarian failure.11 Another possibility is embryo cryopreservation. Newer experimental options are also available to patients and these include oocyte cryopreservation and ovarian tissue cryopreservation. The latter option is an exciting investigational approach which involves the cryopreservation of ovarian tissue strips with subsequent reimplantation after completion of cancer therapy.12 These interventions are invasive, time-consuming, and expensive, however, and the relative benefits, risks, and costs would need to be considered in the context of the likelihood of infertility. The effect of FOLFOX on ovarian function and specifically on the menstrual cycle as a measure of potential fertility is not well studied. Recently a subset analysis of the National Surgical Adjuvant Breast and Bowel Project C-08 study evaluated the effects of FOLFOX vs. FOLFOX plus bevacizumab on ovarian failure. Among 179 patients, 84 received adjuvant FOLFOX and 95 received FOLFOX plus bevacizumab. Two percent of the FOLFOX-only group had ovarian failure compared with 34% of those who received bevacizumab. One of 5 women who had ovarian failure (22%) started menstruating after completion of treatment.13 In our small survey, most patients appear to maintain or at least regain ovarian function, and there is a trend toward increased incidence of amenorrhea during chemotherapy in women older than 40, but this does not translate into a statistically significant difference in incidence of persistent amenorrhea after completion of chemotherapy. Twenty-four percent of women age 40 or older reported persistent amenorrhea vs. 13% of patients younger than 40 years of age after FOLFOX treatment. Of note, we could not evaluate the relationship between loss of menses and continuous age; because of anonymity of the survey, the actual ages were not available. A potential criticism is that there might have been an inherent selection bias favoring the patients who regained their menses because they might have been more likely to complete the survey than patients who did not. The alternative, that loss of menses might stimulate a higher likelihood of response to the survey, is also possible. However, the results provide preliminary insight
Clinical Colorectal Cancer September 2013
into the incidence of chemotherapy-induced amenorrhea in patients with colorectal cancer who are treated with FOLFOX chemotherapy.
Conclusion Larger studies and prospective analyses are needed to provide more information on the effects of adjuvant colorectal chemotherapy on menses and fertility. These data will help physicians counsel their patient on menopausal symptoms and the clinical sequelae of early menopause, and inform young women on the effects of treatment on fertility. It will also assist in decision-making regarding selection of options for fertility preservation.
Clinical Practice Points Studies indicate that the incidence of young women diagnosed
with colorectal cancer is rising, thus there is an increasing number of female colorectal cancer (crc) survivors of premenopausal and child-bearing age. Adjuvant FOLFOX chemotherapy is the most widely used standard treatment for stage III and high-risk stage II colon cancer. We evaluated the incidence of FOLFOX induced amenorrhea in women age 50 and younger treated with adjuvant therapy for colorectal cancer. Eligible patients were mailed an anonymous questionnaire. The returned surveys were reviewed and the results tallied. In total, 41% experienced amenorrhea during chemotherapy. Sixteen percent had persistent amenorrhea one year after completion of chemotherapy. The incidence of amenorrhea during chemotherapy trended higher in patients age older than 40 compared to 40 or under (59% vs 31% (p ¼ 0.075)). There was no statistically significant difference in persistent amenorrhea between the two age groups, 24% vs 13% p ¼ 0.42, respectively). In this retrospective series, there appears to be a trend towards FOLFOX induced amenorrhea during chemotherapy increasing with age. Prospective studies are planned to further characterize the impact of FOLFOX on early menopause and fertility.
Disclosure The authors have stated that they have no conflicts of interest.
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