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Keywords:

  • infertility;
  • early menopause;
  • acute ovarian failure;
  • counseling;
  • amenorrhea;
  • Hodgkin disease;
  • breast cancer;
  • non-Hodgkin lymphoma;
  • leukemia

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND:

The authors sought to describe the age-specific impact of infertility and early menopause after chemotherapy among reproductive age women with cancer.

METHODS:

A total of 1041 women diagnosed with cancer between the ages of 18 and 40 years responded to a retrospective survey on reproductive health history. Five cancer types were included: leukemia, Hodgkin disease (HD), non-Hodgkin lymphoma (NHL), breast cancer, and gastrointestinal(GI) cancer. Survey questions addressed acute ovarian failure (cessation of menses after treatment), early menopause (menopause before 45 years old), and infertility (failed conception). Logistic regression was used to determine the proportions of acute ovarian failure and infertility based on age at diagnosis. Censored data methods were used to determine the probability of early menopause.

RESULTS:

Six hundred twenty women received chemotherapy alone. The percentage reporting acute ovarian failure was 8%, 10%, 9%, and 5% for HD, NHL, breast cancer, and GI cancer, respectively. Acute ovarian failure increased significantly with age at diagnosis (P < .05). In subjects not reporting acute ovarian failure, the incidence of infertility was at least 40% at age 35 years and increased significantly with age at diagnosis in HD and breast cancer (P < .05). The estimated probability of early menopause was at least 25% at age 30 years and increased significantly with younger age at diagnosis in HD, NHL, and GI cancer (P < .05).

CONCLUSIONS:

For patients to receive appropriate counseling, it is important that they understand the potential increased risk of infertility and early menopause beyond that of acute ovarian failure. These findings can provide improved, age-specific counseling regarding reproductive impairment for young women diagnosed with cancer. Cancer 2012;. © 2011 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

According to 2006 Surveillance, Epidemiology, and End Results (SEER) statistics, approximately 120,000 women younger than age 50 years develop cancer each year in the United States.1 Several studies have shown that loss of reproductive potential after cancer treatment can negatively impact quality of life in young survivors.2-4 Unfortunately, many young women unknowingly face reproductive compromise.5 Whereas about 7% of women across the United States report 12-month infertility,6 the rates of infertility in young cancer patients are unknown.

Studies conducted to date on reproductive compromise have focused on the resumption of menses, which may have underestimated the extent of gonadotoxicity.7 However, 2 additional phenomena, primary ovarian insufficiency and premature menopause, may compromise reproductive potential. Primary ovarian insufficiency (also known as premature ovarian failure) can be overt (menses are absent, as in acute ovarian failure, or irregular) or occult (the ovary is damaged but menses remain regular).8 Therefore, women may still menstruate, yet sustain partial ovarian injury that manifests as infertility when attempting conception.

The time period in a woman's life when conception is possible, her reproductive window, could be shortened if chemotherapy or radiation causes damage to her ovaries and decreases the number of viable eggs after treatment. It has been demonstrated, for instance, that women who continue to menstruate after treatment with chemotherapy for breast cancer remain at an increased risk of entering menopause early.9 Furthermore, evidence suggests that early menopause could be a sign of a shortened reproductive window. Before the onset of menopause, while menses are still present, subfertility often represents the first manifestation of incipient ovarian failure.10 In healthy women, fecundity decreases drastically about 10 years before the average age of menopause (51 years old).11, 12 Therefore, because cancer patients who have been exposed to chemotherapy have a higher incidence of early menopause, they may experience subfertility many years before what is expected naturally, and thus have a significantly narrowed window of opportunity for attempting conception.9

We sought to evaluate the percentage of reproductive age cancer survivors who have experienced some type of reproductive impairment, using a large and diverse sample of women who have undergone chemotherapy treatment for cancer during their reproductive years. We examined reproductive impairment by cancer type and from a comprehensive perspective, including women who have experienced acute ovarian failure, who have experienced infertility, and who have entered menopause early. Furthermore, we sought to examine the effect of age at treatment on the proportion of women who have experienced infertility and early menopause after treatment with chemotherapy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

We performed a retrospective survey study, using the California Cancer Registry to sample women across the state of California. All study procedures were reviewed and approved by the University of California at San Francisco Committee on Human Research.

Subjects

A computer-generated randomizer was used to sample reproductive age women from the cancer registry who had a history of leukemia, Hodgkin disease, non-Hodgkin lymphoma, breast cancer, or gastrointestinal (GI) cancer. These cancers were chosen for study because they are common, nongynecologic cancer groups that can be treated with systemic chemotherapy. Patients were included in the sample if they were 18 to 40 years of age at diagnosis, and were diagnosed between 1993 and 2007. Among 6709 patients initially selected for the study, 4147 patients were excluded because their contact information in the cancer registry was outdated. Letters were sent to the primary physicians of each of the remaining women before we attempted to reach the patients. Women were then also excluded if their physician thought participation in the study would cause undue psychological burden (because of severe comorbid mental illness) (30 patients). After exclusions, 2532 patients were contacted for participation in the study. Analyses of reproductive impairment included only women who reported treatment with chemotherapy alone (ie, no pelvic radiation, pelvic surgery, or bone marrow transplant).

Survey

A questionnaire was developed to query reproductive history before and after cancer treatment. The survey included information about acute ovarian failure, infertility, and early menopause. Acute ovarian failure was defined as amenorrhea for at least 1 year that began immediately after treatment. Infertility included only women who resumed menses after treatment and was defined 2 ways. The first, 12-month infertility, refers to trying to conceive with unprotected intercourse for at least 1 year with no resulting pregnancy, and is the more conservative estimate of infertility. The second refers to all women who had tried to conceive but were unable and includes both women with 12-month infertility as well as those who tried for <12 months but were unable to conceive. Early menopause was defined as entering menopause before age 45 years and therefore also includes women who experienced acute ovarian failure.

After an initial draft of the instrument was completed, 2 independent experts in survey methodology assessed it for readability and content validity—the extent to which our survey accurately assessed reproductive health history. The survey was then piloted on 20 patients from the University of California at San Francisco Reproductive Endocrinology Clinic and edited for ease of use and readability before being sent to our study population. The survey was made available in both English and Spanish. A professional translation company (American Language Services, Los Angeles, CA) was used to translate the survey and recruitment materials into Spanish. Paper surveys were created using Cardiff Teleform (Vista, CA), an automated scanning utility, allowing patients' answers to questions to be scanned directly into a deidentified database. An online version of the survey was also created (www.surveymonkey.com, Palo Alto, CA), enabling women to complete the survey online (in English or Spanish).

Recruitment

Women were contacted between January 2010 and September 2010. A contact letter was sent to potential participants, explaining the purpose of the survey and the source of the individual's personal contact information (the California Cancer Registry), and allowing women to opt out of further contact by reaching the University of California at San Francisco study coordinator. After 1 week, a second mailing was sent that included the written survey, a link to the online survey, a written consent form, a postage-paid return envelope, and an optional refusal postcard. Women were asked to complete and return a written consent form by mail and to return the survey by mail or complete it online. Women who did not reply within 3 weeks received a reminder follow-up phone call. Those who did not reply within 2 weeks of the reminder call were sent a reminder postcard with a link to the electronic survey.

Data Analysis

Survey data were merged with California Cancer Registry data using a unique, anonymous identifier code. Statistical analyses were performed using Stata version 11 (StataCorp, College Station, TX). Differences in diagnoses and demographic characteristics between women who did and did not respond were examined using cancer registry data.

Reproductive impairment was measured in those who reported having been treated with chemotherapy alone (ie, no pelvic radiation, pelvic surgery, or bone marrow transplant). Descriptive statistics were used to describe the percentage of women who had experienced the following 3 types of reproductive impairment: acute ovarian failure, infertility, and early menopause. The proportion of women of a given age at diagnosis who experienced reproductive impairment was described 2 ways, and participants were separated by cancer type during analysis to minimize heterogeneity of treatment between different cancer types. Logistic regression was used to estimate the proportions of women with acute ovarian failure and infertility as a function of cancer type and age at diagnosis. It was also used to generate plots of the proportion of women of a given age experiencing acute ovarian failure or infertility. Censored data methods were used to model the probability of early menopause, as some women in our sample had not reached our cutoff age for early menopause by the time of the survey. Interval censored regression analysis was used to determine the probability of entering menopause early, based on cancer type and age at diagnosis.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Patient Sample

Of the 2532 women who were contacted, 1378 women replied to our initial contact letter or survey. Of these, 337 refused and 1041 (41%) completed our survey. Forty-seven percent of respondents completed the survey online, and 53% completed it on paper. Reasons for declining included: a request to be removed from all cancer registry studies, no interest in further childbearing, the topic was too emotionally difficult to discuss, or the survey was too long. The average time to complete the survey was 26 minutes.

Table 1 compares all the women who completed our survey with those who were contacted, but did not compete it. Patients who completed the survey were 1.4 years younger at diagnosis than those who did not (P < .001), and were diagnosed with more aggressive cancers, as indicated by a SEER summary stage index (range of zero [in situ] to 7 [metastatic]) of 3.7 versus 3.4 (P < .001). There were no differences between responders and nonresponders in SEER socioeconomic index (calculated from median income and education for the census block group of residence at diagnosis, P = .8) or years since diagnosis (P = .2).

Table 1. Comparison of Survey Responders Versus Nonrespondersa
CharacteristicCompleted Survey, n=1041Nonresponder, n=1491Pb
  • a

    All data shown are mean (standard deviation).

  • b

    P value from t test comparing responders and nonresponders.

  • c

    Summary stage index = Surveillance, Epidemiology, and End Results (SEER) staging index. Scores range from 0 (in situ) to 7 (metastatic).

  • d

    SEER socioeconomic index was calculated from median income and education for the census block group of residence at diagnosis.

Age at diagnosis, y31.8 (6.7)33.2 (6.2)<.001
Age at survey, y41.3 (8.4)42.5 (8.0)<.001
Summary stage indexc3.7 (2.1)3.4 (2.1)<.001
Socioeconomic indexd2.5 (1.4)2.5 (1.3).8
Time since diagnosis, y9.5 (4.4)9.3 (4.4).2

Six hundred twenty of the 1041 respondents reported having been treated with only chemotherapy (ie, no pelvic radiation, pelvic surgery, or bone marrow transplant). The age and childbearing desires of patients who were treated with chemotherapy alone are listed in Table 2. Patients with a history of breast and GI cancers tended to be oldest at diagnosis and most likely to have had children before treatment. Between 49% and 65% of women reported that they would like to have had children after treatment. However, only 30% to 41% attempted pregnancy, and 9% to 24% were successful. These 620 patients who received chemotherapy alone were used in our analysis.

Table 2. Characteristics of Survey Respondents Who Received Chemotherapy
CharacteristicTotal Sample, N=620Type of Cancer
Leukemia, n=60Hodgkin, n=218Non-Hodgkin, n=123Breast, n=169Gastrointestinal, n=50
  1. Abbreviation: SD, standard deviation.

Age at diagnosis, y, mean (SD)31.2 (6.8)28.5 (7.2)27.5 (6.4)31.3 (6.1)36.0 (4.3)34.1 (5.4)
Age at survey, y, mean (SD)40.6 (8.5)36.8 (8.9)35.8 (7.5)40.3 (7.2)47.2 (6.0)44.2 (6.6)
Years since diagnosis, mean (SD)9.4 (4.4)8.3 (4.2)8.2 (4.2)9.0 (3.9)11.2 (4.5)10.1 (3.9)
Children before treatment, %504532516772
Desiring children after treatment, %576565514956
Attempted pregnancy, %363341383036
Had children after treatment, %19172421922

Acute Ovarian Failure and Infertility After Chemotherapy

The percentage of women treated with chemotherapy alone who experienced acute ovarian failure was the lowest among women with leukemia (3%) and highest among women with breast cancer (9%) and non-Hodgkin lymphoma (10%). Overall percentages of 12-month infertility among women who continued to menstruate after treatment were 20%, 18%, 15%, 27%, and 23% for women with leukemia, Hodgkin disease, non-Hodgkin lymphoma, breast cancer, and GI malignancies, respectively.

Age as a Predictor of Acute Ovarian Failure and Infertility After Chemotherapy

The proportion of women experiencing acute ovarian failure significantly increased with older age at diagnosis in patients with Hodgkin disease, Non-Hodgkin lymphoma, breast cancer, and GI malignancies (Fig. 1Top). For instance, the proportion experiencing acute ovarian failure with Hodgkin disease was 0.06 at age 20 years and 0.3 at age 35 years (P < .001). For women with breast cancer, the proportion was 0.32 at age 35 years and 0.55 at age 40 years (P < .001).

thumbnail image

Figure 1. Age is shown as a predictor of reproductive impairment after chemotherapy: (Top) proportion experiencing acute ovarian failure; (Middle) proportion experiencing infertility despite resuming menses; (Bottom) probability of early menopause despite resuming menses. *P < .05, **P < .1. GI, gastrointestinal malignancy; HD, Hodgkin disease, NHL, non-Hodgkin lymphoma.

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For women whose menses returned within 1 year of treatment, the proportion experiencing infertility (defined here by our less conservative estimate of infertility) significantly increased with older age at diagnosis in patients with breast cancer and Hodgkin disease, and there was a trend toward increase in women with non-Hodgkin lymphoma (Fig. 1, Middle). The proportion experiencing infertility with Hodgkin disease treatment was 0.18 at age 20 years and 0.57 at age 35 years (P = .007). For women with breast cancer, the incidence was 0.32 at age 35 years and 0.8 at age 40 years (P < .001).

Early Menopause After Chemotherapy

For women whose menses returned within 1 year of treatment, the probability of experiencing early menopause significantly increased with younger age at diagnosis in patients with Hodgkin disease, non-Hodgkin lymphoma, and GI malignancies, and there was a trend toward increase in women with breast cancer and leukemia (Fig. 1, Bottom). The probability of early menopause for women with Hodgkin disease was estimated to be 0.37 at age 20 years and 0.16 at age 35 years (P = .043). For women with non-Hodgkin lymphoma, the probability of early menopause was 0.56 at age 20 years and 0.16 at age 35 years (P < .001).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Our findings may have implications for family planning after chemotherapy treatment for cancer. For women diagnosed with cancer during their reproductive years, reproductive impairment can significantly impact quality of life long after cancer treatment. To make informed decisions about fertility preservation at the time of treatment, patients should better understand their risk of future reproductive impairment.

In this study, we demonstrate that rates of acute ovarian failure alone likely underestimate the effect of chemotherapy on reproductive function in women of reproductive age. Previous studies have largely focused on amenorrhea as a primary reproductive impairment outcome after cancer treatment.13 We have shown here, however, that chemotherapy is in addition associated with infertility and early menopause, essentially narrowing the reproductive window, even in women whose menses resume after treatment.

The percentage of women reporting acute ovarian failure after chemotherapy in our study is consistent with previous work in our field. Among breast cancer patients, the 9% experiencing acute ovarian failure in our patient population is consistent with the rate of 7% in patients younger than age 35 years reported by Kil and colleagues.14 In a prior study of 400 patients with Hodgkin disease, 7% reported acute ovarian failure, compared with 8% in our study.15 The relatively low rate of acute ovarian failure seen in leukemia is consistent with what has been learned from in vitro models, where it has been suggested that the agents used to treat the most common types of leukemia portend the least gonadotoxicity.16 Our age-specific proportions of acute ovarian failure are also similar to those seen by others. For instance, 55% of women who were 40 years old at diagnosis and treated with chemotherapy alone for breast cancer reported acute ovarian failure in our study. This is similar to Goodwin and colleagues' reported rate of approximately 50%.17

Although there is likely a significant biological component contributing to variability in rates of acute ovarian failure among disease and age-matched women,18 we have shown age to be a significant predictor. Our results, for instance, demonstrate that women who are 40 years old at the time of diagnosis for NHL are 3× more likely to experience acute ovarian failure than women who are age 18 at diagnosis.

The majority of women who remain amenorrheic 1 year after treatment will not regain ovarian function.14, 19-21 When women do not become menopausal at treatment and continue to menstruate, infertility and early menopause continue to significantly impact reproductive function. Women age 18 years at diagnosis for non-Hodgkin lymphoma have a 13% chance of acute ovarian failure; if they do continue to menstruate, they have an additional 9% chance of experiencing infertility and 60% probability of early menopause. It has been suggested that, because the majority of women younger than 35 years of age treated for breast cancer experience only temporary amenorrhea because of chemotherapy, many of these women can maintain fertility.22 In contrast, we found that at least 27% of all women with breast cancer in our study had infertility after treatment, despite the presence of menses.

Literature regarding the impact of chemotherapy on infertility is scarce. There have been numerous studies showing that women with prior diagnosis and treatment for cancer do successfully have children.23 However, there is often no information on the number of women actually attempting pregnancy. The percentage of 12-month infertility seen in all cancer types in our study was higher than the 7% 12-month infertility seen in the US population. Our results are consistent with rates of infertility seen in the Norwegian Cancer Registry, in which 25% of 184 women with similar time to follow-up for Hodgkin disease and attempting conception were unable to conceive.23 Notably, modern treatment for Hodgkin disease, which commonly includes AVBD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) or Stanford V (mechlorethamine, doxorubicin [Adriamycin], vinblastine, vincristine, bleomycin, etoposide, and prednisone), appears likely to have a significant and negative impact on fertility, in contrast to previous reports.24, 25

Our results suggest that fertility counseling for women who are nearer to 40 years old at the time of diagnosis could be different from that for a woman who is 18 years old. For instance, there appears to be a 4- to 5-fold increase in rates of infertility from age 18 to age 40 years in women with Hodgkin disease. Seventy percent of reproductive age women are concerned about infertility after a cancer diagnosis, and almost ⅓ of women will adjust their treatment plans based on fertility concerns.3 Our data could contribute to an improved ability to counsel women about future risk of infertility, based on predictors such as disease-type and age, and help to make more informed decisions about fertility preservation.

Women concerned about future fertility should also understand their risk of early menopause. Our results demonstrate age-specific rates of early menopause in women treated with chemotherapy for Hodgkin disease, non-Hodgkin lymphoma, and GI malignancies. Consistent with the work of Partridge and colleagues, we have demonstrated that the closer in age a patient is to natural menopause at the time of diagnosis, the lower the chance that chemotherapy will induce early menopause.9 For instance, 18-year-old women with Hodgkin disease are at a 2-fold increased risk of experiencing early menopause versus their 40 year-old counterparts. Although there are previous data alluding to the finding that younger patients exposed to chemotherapy are more likely to experience early menopause, this outcome is still surprising. Such results argue for the importance of counseling younger women about their risk of a shortened reproductive window. The reasons that young women may experience higher risks of early menopause yet lower risks of infertility and acute ovarian failure, although interesting, are beyond the scope of this paper and likely relate to duration of time elapsed since exposure.

This study has several important strengths and limitations. The outcomes chosen are comprehensive and inclusive, and not exclusively focused on amenorrhea. However, despite controlling for cancer type at diagnosis, lack of clearly defined treatment type and duration for each patient requires us to make generalizations and assumptions about what chemotherapy regimens patients likely received. We are limited to making reasonable inferences about treatment, based on cancer type and practice patterns at that time, as has been done by others with success.26 It is also possible that other, unmeasured, factors may play a role in our findings. For example, women who receive cancer treatment may postpone childbearing, leaving them older at the time they are trying to conceive. Age is an important prognosticator, but not a perfect predictor of reproductive impairment. Even within a given age group, prior studies have shown wide variability in an individual's ovarian reserve.18 Another limitation of this study has been the use of a retrospective rather than prospective survey, and using a historical cancer registry in which patients may be lost to follow-up.27 Nevertheless, as the National Cancer Institute's working group for the improvement of care of gynecologic malignancies indicated, cancer registries offer an effective means of rapidly acquiring large amounts of data for important cancer issues.28 Our response rate was consistent with those from previously published studies.3, 29 This study of a cancer registry has been most important in its ability to effectively identify a large sample of patients to demonstrate infertility as a missing metric in cancer survivorship research.

It is fundamental that patients understand their risk of future reproductive compromise, a risk that may include infertility and early menopause, in addition to acute ovarian failure. Counseling based on the risk of amenorrhea alone may give women an unrealistically low perception of their total risk of reproductive impairment, as we know that women can be menstruating and still be infertile. Patients should be given a chance to make an active decision about post-treatment family planning in the presence of the most comprehensive available information.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

This project was supported by National Institute of Health grant number TL1 RR024129. The National Institute of Health had no role in study design; in collection, analysis, and interpretation of data; in the writing of this report; or in the decision to submit this paper for publication.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES