Abstract
Keywords
The overall increase in cancer prevalence and the significant increase in long-term survival have brought about a worldwide interest in the attempts to preserve fertility in young patients exposed to gonadotoxic chemo- and radiotherapy. Malignancy is currently estimated to occur in one out of 49 women under the age of 40 years in the western developed world [1,2]. In the last two decades the survival rates for many of the malignancies that affect young adults have significantly improved. For many of these malignancies survival rates now exceed 80–90% [2–7]. Therefore, the remote effects of cancer treatment have recently gained a ubiquitous worldwide interest, and the protection against iatrogenic infertility caused by chemotherapy has assumed high priority. Indeed, fertility preservation has become the focused interest not only among reproductive endocrinologists, but also among hematologists, oncologists, gynecologists, endocrinologists, rheumatologists, family physicians and all healthcare providers [4–7], and the protection against iatrogenic amenorrhea caused by chemotherapy assumes ubiquitous interest.
Premature ovarian failure after breast cancer treatment
Similarly to other malignant diseases, the rates of reported premature ovarian failure (POF) after treatment of women with breast cancer in the reproductive age differ significantly depending on the patients' age and the chemotherapeutic protocol. Preclinical studies have found that temporary ovarian suppression with a gonadotropin-releasing hormone analog (GnRH-a) during chemotherapy can minimize gonadotoxicity in women and Phase II studies have shown that GnRH-a may protect the ovaries of 67–96% of women with breast cancer undergoing chemotherapy [3]. The Prevention of Menopause Induced by Chemotherapy: a Study in Early Breast Cancer Patients – Gruppo Italiano Mammella 6 (PROMISE-GIM6) study is a prospective, randomized, multicenter, Phase III study of 18–45-year old, premenopausal patients with stage I–III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy [3]. Patients with previous chemotherapy, radiotherapy, with evidence of distant metastases, other malignancies in the previous 5 years (except basal or squamous cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix), and pregnancy or lactation were excluded [3]. Patients received adjuvant or neoadjuvant treatment with anthracycline-based, anthracycline plus taxane-based or cyclophosphamide/methotrexate/fluorouracil-based chemotherapy [3]. Patients with hormone-sensitive tumors whose ovarian function had returned (indicated by the occurrence of at least one menstrual cycle, premenopausal levels of estradiol, or both) during the 12-month period of observation after the end of chemotherapy received, in addition to tamoxifen (a monthly depot), controlled release of triptorelin 3.75 mg every month for at least 2 years.
The study end point was the incidence of chemotherapy-induced POF in the treatment group compared with the control group (chemotherapy without GnRH-a). POF was defined as amenorrhea and menopausal follicle-stimulating hormone levels 1 year after the end of chemotherapy. Menstrual activity, follicle-stimulating hormone and estradiol levels were assessed every 3 months from the end of chemotherapy for 1 year, and annual follow-up was planned to record pregnancies, recurrences and deaths (last follow-up: October 2010) [3]. To avoid the exclusion of patients with missing data, an intention-to-treat analysis including all of the randomized patients was performed in which missing values were imputed using the multiple imputation method [3]. Logistic regression was used for imputation of categorical and continuous variables. The prospective statistical calculations, a power of 90% and a two-sided error of 5% required the enrollment of 280 patients, were performed. The multivariate logistic regression evaluated the effects of the GnRH-a treatment, age and type of chemotherapy on the development of POF [3].
Results
The analysis showed a POF rate of 25.9% in the control (chemotherapy-alone) group versus 8.9% in the treatment (chemotherapy and GnRH-a) group, an absolute difference of −17% (95% CI: −26% to −7.9%; p < 0.001). The number needed to treat (i.e., the number of patients that had to be treated with GnRH-a to prevent POF in one patient) was six. Multivariate analysis showed that only treatment with GnRH-a was associated with a significant reduction of the risk of developing POF (odds ratio = 0.28; 95% CI: 0.14–0.59; p < 0.001) [3]; the median number of administered chemotherapy cycles and median cumulative doses of cyclophosphamide, anthracyclines and taxanes were similar in both groups. At the time of the last annual follow-up, one pregnancy occurred in the control group versus three (one term, one premature delivery and one termination of pregnancy) in the treatment group [3].
Significance
This important study, which is so far the largest Phase III study to evaluate the role of a GnRH-a in preserving ovarian function during chemotherapy for breast cancer, shows that the administration of the GnRH-a, before and in parallel to chemotherapy, can significantly decrease the occurrence of POF in young women with breast cancer, from 25.9 to 8.9% [3].
The resumption of menses was higher in hormone receptor-negative patients who did not receive tamoxifen (74% in the controls and 93% in the treatment group) than in hormone receptor-positive patients who received tamoxifen starting from the end of chemotherapy (44% in the controls and 55% in the treatment group), confirming that the administration of tamoxifen after chemotherapy is associated with an increased incidence of POF [3]. This finding suggests that the hormone receptor-positive patients may suffer POF more than the hormone receptor-negative patients; therefore they may benefit more from the GnRH-a cotreatment. Indeed, this study, and the study by Recchia et al. [8], has demonstrated that the outcome of hormone receptor-positive patients treated with GnRH-a in parallel to chemotherapy and afterwards is not significantly different from the outcome of hormone receptor-negative patients similarly treated. This contradicts the raised but unsubstantiated fear that administration of GnRH-a may possibly decrease the efficiency of chemotherapy in eradicating the malignant cells [3,8]. Furthermore, a meta-analysis [9], based on 11,906 young breast cancer patients randomized in 16 trials, found that the addition of GnRH-a to tamoxifen, chemotherapy or both reduced recurrence by 12.7% (p < 0.02) and death after recurrence by 15% (p < 0.03), contradicting the unsubstantiated hypothetical speculation. More than 250 patients have been treated over the last two decades in our medical center with GnRH-a in parallel to chemotherapy for different indications and the survival rate was not lower than the survival of those who did not receive the GnRH-a cotreatment [4–6].
A strength of the current study is the definition of POF in keeping with that of WHO, which defines menopause as amenorrhea of 12 months. Other studies that evaluated patients as soon as 6 months after chemotherapy did not find a difference between the group that received GnRH-a cotreatment and the control group, which received only chemotherapy [10–12]. Since resumption of ovarian function may occur as late as a year or more after ending chemotherapy, an early assessment of the outcome at 6 months, as in the studies by Gerber et al. [10] and Leonard et al. [11], may underestimate the true effect of GnRH-a treatment. Indeed, in the study by Gerber et al., the number of patients resuming cyclic menstruation at 2 years after chemotherapy was significantly higher than those with ‘two menses at 6 months’ as chosen by the authors to define resuming ovarian function [10]. Furthermore, the gonadotropin levels of the patients in the control group were significantly higher (‘p = 0.015’), in the menopausal range, as compared with the patients receiving goserelin in parallel to chemotherapy [10], casting a serious discrepancy between the conclusion and the results of this study [12].
The only weakness of this study, as the authors themselves point out, as well as most other studies evaluating the role of GnRH-a in preserving ovarian function, is the lack of data concerning fertility and the long-term maintenance of ovarian function.
Preservation of ovarian function despite chemotherapy
Several options have been put forward for preserving female fertility: ovarian transposition, cryopreservation of embryos, unfertilized meta-phase-II oocytes and ovarian tissue, and administration of gonadotropin-releasing hormone-agonistic analogs in an attempt to decrease the gonadotoxic effects of chemotherapy by simulating a prepubertal hormonal milieu [3–8]. Unfortunately, none of the suggested methods is ideal and none guarantees future fertility in survivors. IVF and embryo cryopreservation, the only noninvestigational, ubiquitously agreed upon and clinically established method, necessitates postponing chemotherapy for at least 2 weeks, and is frequently not applicable to the very young and single patient. In the last two decades, cryopreservation of unfertilized ova has gained recent popularity and increased success due to the vitrification method, but it also does not guarantee future fertility [5–7]. However, although cryopreservation and transplantation of ovarian tissue several years after the chemotherapeutic insult, when the patient is cured from her malignancy, has generated at present 18 successful deliveries, it is not unequivocally safe and successful [13]. The in vitro maturation of primordial follicles to fertilizable meta-phase-II oocytes is a promising endeavor with enormous potential but it must overcome many technological obstacles, and is not clinically available yet. Therefore, GnRH-a has been used by many groups of clinicians for decreasing the gonadotoxic effects of chemotherapy [3–8,14–21] by simulating a prepubertal hormonal milieu, with the rationale and philosophy that preventing POF in survivors is preferable to treating it after it occurs.
To date, 16 studies (13 retrospective and three prospective randomized controlled trials) have reported on more than 1000 patients treated with GnRH-a in parallel to chemotherapy, showing a significant decrease in the rate of hypergonadotropic amenorrhea and menopause in survivors [3–8,14–21] versus seven studies including 409 patients reporting no beneficial effect of the GnRH-a. Overall, female patients exposed to gonadotoxic chemotherapy and concurrent GnRH-a preserved their cyclic ovarian function in over 90% of cases as compared with 41% of controls, with a pregnancy rate of 19% in the treated patients [16].
Four recently published meta-analyses have concluded that GnRH-a are beneficial and decrease the risk of POF in survivors [16–19]. The first of them [22] found a significant beneficial role for the agonists on both preservation of ovarian function and conception: 68% increase in the rate of preserved ovarian function. Among the GnRH-a-treated women, 22% achieved pregnancy compared with 14% without GnRH-a (relative risk = 1.65; 95% CI: 1.03–2.6). This meta-analysis concluded that GnRH-a cotreatment improves ovarian function and the ability to achieve pregnancy, and that premenopausal women exposed to gonadotoxic chemotherapy should be counseled about ovarian preservation options, including the use of GnRH-a cotreatment, in keeping with the recently published recommendation of the multicenter FertiPROTEKT network of more than 70 centers in Germany, Switzerland and Austria involved in fertility preservation [7,101].
The study by Del Mastro et al. is the most recent and convincing prospective, multicenter, open-label, Phase III, randomized controlled trial [3]. At 1 year after chemotherapy, POF was observed in 32.3% of patients in the chemotherapy-alone arm compared with only 13.5% in the patients who were treated with chemotherapy and GnRH-a (p = 0.0002), with a 19% absolute reduction (95% CI: 8–29). Cyclic menstrual activity and premenopausal estradiol levels were observed in 58% of patients in the chemotherapy-alone arm versus 77% in the chemotherapy and GnRH-a arm (p = 0.006) [3]. Logistic regression analysis showed that GnRH-a was independently associated with a higher probability of cyclic ovarian function preservation (p = 0.001) [3].
In summary, there are four prospective, peer-reviewed studies, in addition to the 13 nonrandomized controlled trials and four meta-analyses, concluding that the addition of GnRH-a to chemotherapy can significantly preserve ovarian function and fertility in premenopausal women facing gonadotoxic chemotherapy.
Although no randomized trials assessed the role of embryo or oocyte cryopreservation strategies for fertility preservation, many opponents to the use of GnRH-a refer to cryopreservation of ovarian tissue as an established method of fertility preservation. Although ovarian tissue cryopreservation has promising results and bears great potential, its strength of evidence is not high, since it is based on nonrandomized, case–control or observational studies. On the other hand, the role of GnRH-a therapy in preserving ovarian function has been now assessed both in randomized trials and in nonrandomized, case–control studies [3–8,14–21].
An argument put forward by opponents to GnRH-a claims that prepubertal children receiving high-dose chemotherapy given before hematopoietic stem cell transplantation still suffer from ovarian failure. This argument is only partially correct. Remérand et al. have described four spontaneous pregnancies and deliveries in a patient after prepubertal high dose busulfan and cyclophosphamide conditioning and allogeneic bone marrow transplant (BMT), demonstrating that successful pregnancies are possible in patients undergoing prepubertal hematopoietic stem cell transplantation [22]. Similarly, the only published case of repeated spontaneous pregnancies and two successful deliveries after repeated autologous BMTs combined with GnRH-a treatment during the gonadotoxic chemotherapy has been recently described in a postpubertal lymphoma patient, suggesting that the prepubertal hormonal milieu induced by the GnRH-a cotreatment might have contributed to the preserved fertility despite repeated BMTs [23]. Only 0.6% of patients conceive after one autologous or allogeneic BMT, according to an extensive survey, involving 37,362 female patients [24]. Thus, the estimated odds for pregnancy after two BMTs are negligible (theoretically 0.006 × 0.006 = 0.000036) [23]. Similarly, another study on 619 patients [25], found that only 3% conceived after one BMT. Thus, theoretically, according to this study, the estimated odds for conceiving after two stem cell transplantations are 0.03 × 0.03 = 0.0009, approximately 1/1000 [23,25]. Thus it may be hypothesized that the GnRH-a cotreatment, started before and continued along the gonadotoxic conditioning chemotherapy simulated the prepubertal hormonal milieu, and might have minimized the gonadotoxic effect and augmented the probability of ovulations, conceptions and deliveries [23].
Another argument put forward by opponents to the GnRH-a cotreatment during gonadotoxic chemotherapy was that 8% of prepubertal children exposed to gonadotoxic chemotherapy may suffer POF by the age of 40 years and therefore the rationale for creating a prepubertal milieu is illogical. Indeed, recent publications [26,27] have found that 8% of the survivors of childhood cancer may experience POF by the age of 40 years, compared with <1% in the general population. This is in keeping with the published results whereby young female patients in the reproductive age treated with GnRH-a in addition to chemotherapy suffer POF in approximately 7–11% of cases (simulating prepubertal exposure), whereas those similarly treated but without GnRH-a have a 30–60% risk for POF [3–8,14–21]. Thus, this argument does not contradict the use of GnRH-a cotreatment; on the contrary, it strongly supports the rationale of generating a prepubertal milieu during the gonadotoxic insult of chemotherapy [4–6].
Another concern raised is that the agonist may reduce the efficiency of chemotherapy. However, a meta-analysis [9] based on 11,906 young breast cancer patients randomized in 16 trials found that the addition of GnRH-a to tamoxifen, chemotherapy or both reduced recurrence by 12.7% (p < 0.02) and death after recurrence by 15% (p < 0.03). These data strongly contradict the previously raised theoretical unbiased speculation. Furthermore, the results of Del Mastro et al. [3] and Recchia et al. [8] have demonstrated improved 5- and 10-year survival rates with GnRH-a as compared with survival rates after similar protocols without GnRH-a.
Future perspective
Maximizing patients' odds for future fertility will necessitate the combination of ovarian cryopreservation, GnRH-a administration and follicular aspiration, and all these modalities should be offered to all such patients. Last but not least, it may appear ethically incorrect to deprive patients from all the information regarding possible fertility preservation. Since most methods involving ovarian or egg cryopreservation are not clinically established or 100% successful, these young patients deserve to be given treatment that will minimize gonadal damage and preserve ovarian function and, thus, increase their future fertility [4–8]. In addition, combining different treatments for a specific patient may increase the likelihood of their future fertility being preserved. There is currently no contraindication for ovarian biopsy combined with GnRH-a administration and follicular aspiration, as recently published [4–8]. In cases where the chemotherapy has caused POF, as is often the case after total body irradiation and BMT, the patient will still have cryopreserved ova, embryos or primordial follicles. However, when conventional chemotherapy regimens, such as for young lymphoma patients, are used, GnRH-a cotreatment may preserve ovarian function and prevent POF without the need for cryopreservation.
Executive summary
The administration of a gonadotropin-releasing hormone analog (GnRH-a) in parallel to gonadotoxic chemotherapy to young, premenopausal women can significantly decrease the rate of premature ovarian failure and possibly preserve future fertility.
The preservation of ovarian function may also prevent osteoporosis, vaginal dryness, dyspareunia and other menopausal symptoms in young women who are survivors of gonadotoxic chemotherapy.
The administration of this cotreatment is beneficial to both hormone receptor-positive and hormone receptor-negative patients with breast cancer. There are no data in support of the raised fear that GnRH-a administration may lower the efficiency of chemotherapy in eradication of malignant cells. Hormone receptor-positive patients may suffer premature ovarian failure more than hormone receptor-negative patients; therefore they may benefit more from the GnRH-a cotreatment in parallel to the gonadotoxic chemotherapy.
The long-term effect of GnRH-a cotreatment on fertility preservation needs to be demonstarted through the publication of additional studies with long-term follow-up.
Since none of the methods used for preservation of fertility guarantees future success, all the methods should be offered to young premenopausal women before administration of gonadotoxic chemotherapy. It is possible to combine GnRH-a and cryopreservation of embrya, unfertilized ova and ovarian tissue to maximize a patient's future fertility potential.
Assessment of ovarian function should be done 1 year after ending chemotherapy. Earlier assessment may be inaccurate since in some women it may take up to 12 months to resume cyclic ovarian function.
The beneficial effect of GnRH-a cotreatment may not be detected in protocols with very low gonadotoxicity (e.g., doxorubicin/cyclophosphamide in young women with breast cancer, or doxorubicin/bleomycin/vinblastine/dacarbazine in young Hodgkin lymphoma patients), or in protocols with very high gonadotoxicity (e.g., conditioning before allogeneic stem cell transplantation, escalated bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone in Hodgkin lymphoma, or in women older than 40 years with breast cancer exposed to gonadotoxic chemotherapy).
Footnotes
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.