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The post-treatment quality of life (QOL) impacts of receiving pre-cancer-treatment infertility counseling and of pursuing fertility preservation have not been described in large-scale studies of reproductive age women with cancer.
1041 women diagnosed between the ages of 18 and 40 responded to a retrospective survey and reported whether they received infertility counseling before cancer treatment and whether they took action to preserve fertility. Five cancer types were included: leukemia, Hodgkin’s disease, non-Hodgkin lymphoma, breast cancer, and gastrointestinal cancer. Validated QOL scales were used: Decision Regret Score (DRS), Satisfaction with Life Scale (SWLS), and World Health Organization QOL BREF (WHOQOL-BREF).
560 women (61%) whose treatment could affect fertility were counseled by the oncology team, 45 (5%) were counseled by fertility specialists, 36 (4%) took action to preserve fertility. Pre-treatment infertility counseling by a fertility specialist and an oncologist resulted in lower regret than counseling by an oncologist alone (8.4 vs. 11.0, P<0.0001). The addition of fertility preservation (6.6 vs. 11.0, P<0.0001) was also associated with even lower regret scores than counseling by an oncologist alone.. Further improvements were similarly seen in SWLS with the addition of fertility specialist counseling (23.0 vs. 19.8, P=0.09) or preserving fertility (24.0 vs. 19.0, P=0.05).
Receiving specialized counseling about reproductive loss and pursuing fertility preservation is associated with less regret and greater QOL for survivors, yet few patients are exposed to this potential benefit. Reproductive aged women should have expert counseling and be given the opportunity to make active decisions about preserving fertility.
Loss of reproductive potential after cancer treatment negatively impacts quality of life (QOL) in young survivors.1, 2 Recent studies have shown that the potential iatrogenic loss of fertility – the loss of a potential child – has profound impact on young women and may be, at times, more stressful than the cancer diagnosis itself.3,4 This represents a large-scale survivorship issue -according to 2006 SEER statistics, approximately 120,000 women under age 50 develop cancer each year in the United States.5 As recently as 2009, however, only 34–72% of reproductive-age women treated for cancer recall having a discussion about the effects of cancer treatment on future fertility.6 Oncologists have cited many reasons for lack of such a discussion with patients, including: lack of knowledge, insufficient time to discuss the issue, perceptions that patients can not delay treatment, or the perception that if patients did not raise the issue themselves they were not interested.7 Furthermore, most patients have this discussion just before starting cancer treatment and therefore believe they have no time to pursue a fertility consultation without delaying planned treatments.8 Yet, the risk of treatment associated infertility and premature menopause is a top concern for patients.9–11
Studies have shown that up to 75% of young women are interested in the opportunity to have children after a cancer diagnosis.3 If women are not informed of the risks to their fertility, they may lose their ability to take action towards preserving their fertility before cancer treatment.12, 13
Over the past two decades significant advancements have been made in the technology of egg and embryo cryopreservation, and young women with cancer are increasingly being informed about the option to utilize such technology for fertility preservation. The American Society of Clinical Oncology now recommends that patients who might desire children after treatment should be counseled about fertility preservation options.12 The effectiveness of fertility counseling and fertility preservation on long-term regret and QOL in a large population of reproductive age female cancer survivors has not been reported. Our study aims to first evaluate whether receiving pre-cancer-treatment infertility counseling from an oncology team is associated with improved post-treatment QOL. Second, we aim to evaluate whether seeing a fertility doctor or taking action to preserve fertility is associated with even greater improvements in QOL than only receiving counseling from the oncology team.
We performed a retrospective survey study, using the California Cancer Registry (CCR) to sample women across the state. All study procedures were approved by University of California, San Francisco Committee on Human Research.
A computer-generated randomizer was used to sample reproductive age women from the cancer registry that had a history of leukemia, Hodgkin’s disease, non-Hodgkin lymphoma, breast cancer, or gastrointestinal (GI) cancer. These cancers were chosen for study because they are common, non-gynecologic cancer groups that may be treated with fertility compromising chemotherapy or radiation. Patients were included in the sample if they were 18–40 years of age at diagnosis, and were diagnosed between 1993 and 2007. Among 6709 patients initially selected, 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 (due to severe co-morbid mental illness) (30 patients). After exclusions, 2532 patients were contacted for participation in the study. Analyses of QOL included only women who reported treatment with potential to compromise fertility (i.e., systemic chemotherapy, pelvic radiation, pelvic surgery, or bone marrow transplant).
The survey was created at UCSF and assessed for readability and content validity – the extent to which our survey accurately assessed reproductive health history and quality of life - by two independent experts in survey methodology. It was then piloted on 20 patients from the UCSF Center for Reproductive Health for content and readability. The final survey included questions about demographic information, past obstetric and gynecological history, cancer type and treatment, and fertility preservation actions and post-treatment QOL.
Post-treatment QOL was conceptualized to include satisfaction with treatment choices and satisfaction with life, in addition to a more traditional assessment. QOL was assessed with three validated scales: the Decision Regret Scale (DRS), the Satisfaction with Life Scale (SWLS), and the World Health Organization QOL BREF (WHOQOL-BREF).14–16 The DRS, which was used to assess satisfaction with treatment decisions, is a five-item scale that measures regret regarding a specific medical decision. The decision of interest in our study was centered on whether participants regretted their decision to undergo (or not undergo) fertility preservation. Scores range from 5 to 25, with higher scores representing greater regret. The SWLS is a five-item scale that was developed to assess satisfaction with people’s lives as a whole. Participants respond to each item ranging from 1 (strongly disagree) to 7 (strongly agree). Summing the items results in a total score ranging from 5 (low satisfaction) to 35 (high satisfaction) Overall OOL was measured with the WHOQOL-BREF, an abbreviated version of the longer WHO QOL scale. It includes 26 items covering four domains: physical (daily living, sleep and rest, and work capacity), psychological (self-esteem, body image and memory), social (personal relationships, social support and sexual activity), and environmental (financial resources, health care resources, and physical environment). Higher scores reflect better QOL.
The survey was made available in both English and Spanish. A professional translation company (American Language Services, Los Angeles, CA) translated the study materials into Spanish using two independent translators. A third bilingual person checked translations. Paper surveys were created using Cardiff Teleform (Vista, CA). Patients could also complete the survey online through Surveymonkey.com (LLC, Palo Alto, CA).
Women were contacted between January 2010 and September 2010. A contact letter was sent to potential participants, explaining the purpose of the survey, the source of the individual’s personal contact information (the CCR), and allowing women to opt out of further contact by reaching the UCSF study coordinator. After one 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 three weeks received a reminder follow-up phone call. Those who did not reply within two weeks of the reminder call were sent a reminder post-card with a link to the electronic survey.
Survey data was merged with CCR data with a unique, anonymous identifier code. Statistical analyses were performed using STATA Version 11 (College Station, TX). Statistical significance was defined by two-sided P-values less than 0.05. Power analyses revealed that our sample size would permit us to detect a difference of 1 or greater in DRS, SWLS, and WHO QOL-BREF scores between women counseled by their oncologist versus not. It would also permit us to detect a difference in each scale of 3 or more between women who saw a fertility specialist or preserved their fertility versus those who only received counseling from the oncology team.
Initially, Student’s t-tests were used to compare the characteristics of responders and non-responders. Multivariate logistic regression analyses were conducted where appropriate to determine the odds of counseling and fertility preservation.
Analyses of QOL included only women who reported treatment with potential to compromise fertility (i.e., systemic chemotherapy, pelvic radiation, pelvic surgery, or bone marrow transplant). T-tests were used to compare QOL outcome scales between groups. First, we sought to examine the impact of receiving pre-cancer treatment infertility counseling on QOL, by comparing mean QOL scores of women who were and were not counseled by their oncology team. Second, we evaluated whether mean QOL scores were higher after seeing a fertility doctor or taking action to preserve fertility than after only receiving counseling from the oncology team. Decision regret scores were calculated only for women who had been counseled about fertility risks by an oncologist. Multivariate linear regression was used to examine differences in QOL first between women who did and did not receive oncology team counseling and then between those who preserved fertility or saw a fertility specialist versus those who were only counseled by the oncology team, adjusting for the effect of disease type, age at diagnosis, and pretreatment parity.
Of the 2532 women who were contacted, 1378 women replied to our initial contact letter or survey. Of these 337 refused to participate and 1041 (41%) completed our survey. 47% of participants completed it online and 53% on paper. Reasons for declining included: a request to be removed from all cancer registry studies, no interest in further childbearing, the topic of infertility was too emotionally difficult to discuss, or the survey was too long. The average time to complete the survey was 26 minutes. Of the 1041 women who completed the survey, 918 reported treatment with the potential to compromise their fertility and were included in QOL analyses.
Table 1 shows comparisons of the 1041 responders and 1491 non-responders, based on disease and demographic data in the cancer registry. Patients who completed the survey were 1.4 years younger at diagnosis than those who did not (P<0.0001), and were diagnosed with more aggressive cancers, as indicated by a SEER summary stage index (range of 0 (in situ) to 7 (metastatic)) of 3.7 vs. 3.4 (P=0.0008). There were no differences between responders and non-responders in socioeconomic status (calculated from median income and education for the census block group of residence at diagnosis, P=0.8) or years since diagnosis (P=0.2).
The age and childbearing desires of the 918 participants who reported treatment with potential to affect fertility are listed in Table 2. Patients with a history of breast and gastrointestinal cancers tended to be oldest at diagnosis and most likely to have had children before treatment. Depending on the type of cancer, between 47–63% of respondents reported desiring to have children after treatment, with the highest rates among women with leukemia (59%) and Hodgkin’s (63%). These latter two groups were also composed of women with the lowest mean ages.
Of the 918 patients who reported treatment with the potential to affect fertility, 560 (61%) were counseled about potential reproductive loss by a member of the oncology team. Overall, 46 of the 918 women (5%) visited a fertility specialist, and 36 women (4%) took action to preserve their fertility. Eight preserved embryos; nine preserved eggs; one had an oophoropexy; and 18 used ovarian suppression therapy under the care of a fertility specialist.
Of the 560 women who were counseled by their oncology team, 505 (90%) were only counseled by the oncology team and took no further action (i.e., neither visited fertility specialist nor preserved fertility). 40 women (7%) were counseled by the oncology team and went on the visit a fertility specialist. 30 women (5%) who received counseling from the oncology team went on to pursue fertility preservation. These latter two groups of women were used to examine the QOL impact of pursuing further counseling and fertility preservation beyond being counseled by the oncology team alone.
Of the 918 women who had treatment with potential to impact fertility, those less than 35 years old at diagnosis were more likely to preserve their fertility than older women (OR 11.0, 95% CI 1.5–81.9). Women without children at diagnosis were more likely to take action to preserve their fertility than those with children (OR 4.6, 95% CI 1.6–13.5).
We found no significant differences in SWLS between women who were counseled about their risk of infertility by the oncology team compared to those who were not (20.2 vs. 19.8, P=0.57; Table 3). However, there was a trend toward SWLS being improved by as many as 3 points when women who were counseled by an oncology team also went on to see a fertility specialist (23.0 vs. 19.8, P=0.09; Table 4). This trend remained after controlling for cancer type as well as age and parity at diagnosis. Furthermore, women who were counseled by an oncologist and took action to preserve their fertility were found to have an even greater improvement in SWLS scores than those women who were only counseled about infertility by an oncologist (24.0 vs. 19.8, P=0.05).
Women who had been counseled by their oncology team had slightly higher physical WHOQOL-BREF subscale scores compared to those who were not counseled though this difference was no longer seen after adjusting for age, cancer type, and parity (16.3 vs. 15.8, P=0.12; Table 3). Women who were counseled by an oncologist and visited a fertility specialist had significantly higher physical domain scores than those women who were counseled by an oncologist, but did not see a fertility specialist (17.7 vs. 16.2, P=0.01; Table 4), and this remained significant after adjustment for other potential confounders. Women who were counseled by an oncologist and who preserved their fertility also had significantly higher physical domain scores than women who received only infertility counseling by their oncologist (17.6 vs. 16.2). This relationship remained a trend after controlling for age, cancer type, and parity (P=0.08).
In the domain of psychological health, a significant difference was noted only between women who had been counseled by their oncology team compared to those who had not (15.7 vs. 15.3, P=0.03; Table 3) and this difference remained a trend after controlling for confounders (P=0.08; Table 3). Women who had been seen by a fertility specialist (17.0 vs. 16.3, P=0.09) and those that had taken action to preserve their fertility (17.2 vs. 16.3, P=0.09) each showed trends toward higher environmental subscale scores versus those who were counseled about infertility by an oncologist but who did not do either of these things. Again, these trends remained regardless of age, cancer type, or parity at diagnosis. No statistically significant differences were noted in the social domain.
Receiving counseling from a fertility specialist and preserving fertility both appear to decrease regret. Women counseled about their risk of infertility from cancer therapy by both an oncology team and a fertility specialist had significantly less regret about their decision to preserve fertility than those counseled only by an oncology team (DRS = 8.4 vs. 11.0, P<0.0001; Table 4). Among those women who were counseled by their oncologist, the largest difference in regret was noted between women who took action to preserve their fertility and those who did not (DRS = 6.6 vs. 11.0, P<0.0001). These differences remained significant after adjustment for age at diagnosis, cancer type, and parity at diagnosis.
Receiving pre-cancer-treatment counseling about reproductive loss significantly improved quality of life after cancer treatment for reproductive age women. Receiving pre-cancer-treatment counseling from a fertility specialist and attempting to preserve one’s fertility were both associated with even greater improvements in quality of life than being counseled by only the oncology team.
Visiting a fertility specialist and preserving one’s fertility were associated with improvement in one’s overall satisfaction with life after cancer treatment. The differences noted in SWLS are likely to represent a clinically significant difference. The increases in SWLS between those who visit a fertility doctor or preserve fertility and those who do not are similar to differences in SWLS seen in other groups of young cancer survivors whose quality of life has been affected by access to healthcare resources. For instance, cancer survivors who reside in urban areas have been shown to have higher satisfaction with life, as well as lower levels of depression, anxiety, and distress than those survivors in rural areas with limited access to health services and resources.15 The increase in SWLS of two to three points between rural and urban survivors is very similar in magnitude to the increase between those who visit a fertility doctor or preserve fertility and those who do not. Being able to visit a fertility specialist or preserve fertility before cancer treatment commences could have the same magnitude of impact on satisfaction with life for cancer survivors as being moved from a relatively healthcare-resource-poor rural area to a relatively resource abundant urban setting.
We also found differences in several domains of the WHOQOL-BREF based on counseling history and whether action was taken to preserve fertility. Previous studies have shown that a one to two point difference in the raw score in each of the four domains of the WHOBREF-QOL represents a clinically significant difference in the domain score.16 Physical health was significantly improved in women who were counseled by a reproductive endocrinologist and in those women who took action to preserve their fertility, again supporting the notion that escalated fertility care, beyond only receiving counseling from an oncologist, is associated with improved QOL. These differences appear clinically significant and are similar in magnitude to those differences seen in women with gynecologic cancers who report pain and anemia versus those who do not.17
While trends were observed suggesting positive differences in the environmental and psychological domains as a result of counseling, they do not appear as great in magnitude as the benefits to physical health and were not statistically significant. However, as others have pointed out, issues like infertility, the perceived safety (or lack thereof) of conceiving after treatment, the potential for delays in treatment to pursue fertility preserving options and changes in sexual functioning after treatment are complicated and impact many facets of psychological, social, and environmental health.15 Further research into the impact of reproductive loss after cancer treatment on particular facets of social, environmental, and psychological health is needed.
Counseling by a fertility specialist about reproductive loss before treatment reduces long-term regret about having or not having preserved one’s fertility. We found patients reported greater differences in regret after pre-treatment counseling by a fertility specialist than after being counseled by an oncologist alone, supporting the notion that pursuing escalated fertility care is likely to provide additional QOL benefits beyond discussing infertility with one’s oncology team. In prior studies, patients have reported a preference for learning about potential reproductive loss from a focused visit with a fertility doctor.18 Regret is lessened further after taking action to preserve fertility. The magnitude of reduction in regret suggests that having the opportunity to take action to preserve fertility may add to the benefits seen with counseling.
The differences in regret are likely clinically significant. The two- to five-point differences found in DRS are similar to those cited as significant in other studies. For instance, DRS scores in men who chose more aggressive radiation treatment for prostate cancer treatment was an average of three points less than men who opted out.14
Thirty-nine percent of patients in our study did not recall being told about the risk of treatment to their fertility. This is consistent with counseling rates reported in other studies.4 An area for improvement in patient care may be implementing more frequent referral to reproductive health specialists. While rates of referral to a fertility specialist (five percent) in our study appear low, the rates are similar to those seen in other studies. For instance, in 2009, a survey of 249 oncologists at major academic centers in the USA reported that only six percent of oncologists always refer reproductive age women for fertility preservation.19 Our rate of women taking action to preserve their fertility (four percent), is also consistent with other published rates.20 We have observed that 80% of the patients who visited a fertility specialist took action to preserve fertility. This is consistent with a previous retrospective case-control study, which showed that about 67% of patients who are referred to a fertility specialist take action to preserve their fertility.21
This study has several important strengths and limitations. A significant proportion of the eligible participants in our study were not reached. However, the response was similar to that seen in several other registry-based studies of young female cancer survivors, with rates of 26–51%.4, 10, 22, 23 And, given the importance of survivorship issues, the National Cancer Institute recently recommended the use of cancer registries as a means of conducting studies that could rapidly yield information about life after treatment.24, 25 Despite the benefits of registry-based studies, the possibility of sampling bias remains a concern in this study. While women who responded were slightly younger at diagnosis than those who did not, there were no differences with regard to socioeconomic status. It is also likely, given the consistency of our counseling and preservation rates with other studies, that we achieved a relatively accurate sampling of the population, with regard to previous exposure to fertility preservation. However, other important confounding factors that were not controlled for include the absence of information regarding current disease state (i.e., recurrence or not), and residual side effects. Patients’ disease may have recurred, or they may have received the most aggressive treatment, which resulted in chronic toxicities – all of the above can contribute to reduced satisfaction with life and QOL.
It is difficult to predict exactly which women will choose to utilize fertility preservation in the future. However, with as few as four percent of eligible patients currently accessing the potential long-term benefit of fertility preservation services, a primary focus of future research and policy decisions could be upon continuing to improve access in an equitable manner. For instance, this study showed that older women are less likely to preserve their fertility. However, women reported higher regret and lower QOL if they were not counseled or if they did not preserve fertility, regardless of their age. Gaps in access could lead to missed opportunities to intervene and potentially improve quality of life for certain patients. Disparities in access to fertility preservation and counseling - based on ethnicity, education level, and gender identity - have been noted in other studies, suggesting that there are important areas upon which to focus efforts to improve care.27,28
While counseling by the oncology team is paramount, incremental benefits were seen in regret, satisfaction with life, and physical domains of quality of life as intervention was escalated from infertility counseling by oncologists toward taking action to preserve fertility. Reproductive age women should be encouraged to discuss future childbearing goals and to learn about the risks of their cancer treatment to their fertility during pre-treatment counseling with the oncology team. However, there is additional benefit to a pre-cancer-treatment referral to a reproductive endocrinologist and access to the opportunity to preserve fertility. As advanced cancer treatments increasingly help to prolong life, there is a need to refer for fertility counseling services and fertility preservation, as they now appear to offer a significant chance to improve quality of life post-treatment for our patients.
Conflict of Interest Disclosures
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. The authors have no conflicts of interest to declare.