Key words
breast cancer - premature ovarian failure - chemotherapy - gynecolocic malignancies
- irradiation - infertility
Introduction
Cure rates for oncologic disease in children, teenagers and premenopausal patients
have improved significantly in recent years with the increasing administration of
chemotherapy. With many women postponing having a family until later in life and because
of the long-term consequences of premature ovarian failure there is now a legitimate
interest in maintaining ovarian function, irrespective of the type of tumor. It is
important to differentiate between maintaining ovarian function (hormone production)
and preserving fertility (the opportunity to have children). Affected women with premature
ovarian failure can suffer from concomitant subjective symptoms (hot flushes, attacks
of sweating, sleep disturbance, loss of libido, etc.) und objective symptoms (osteoporosis,
cardiovascular events, genital atrophy, drop in mental performance, cognitive dysfunction,
mental instability, vaginal atrophy, dyspareunia, loss of vitality, etc.), which can
irreversibly impair their quality of life over the long term [1], [2].
Histologically verifiable changes to the ovary following chemotherapy range from a
lower number of follicles to their complete absence and fibrosis.
According to the WHO definition, the absence of menstruation for more than one year
is defined as amenorrhea or menopause. Synonyms for ovarian insufficiency include
chemotherapy-induced amenorrhea (CIA), premature ovarian failure (POF) and amenorrhea.
The following methods can be used to preserve fertility: drug-induced ovarian suppression
prior to oncologic systemic therapy, cryopreservation of oocytes and ovarian tissue,
or the surgical relocation of the ovaries out of the radiation field prior to the
planned radiation of the pelvis. Depending on the stage of disease, an organ-preserving
approach may be possible during surgery of the gynecologic malignancy in patients
who may wish to have children. This review focuses on the importance of a carefully
differentiated approach, according to the affected organ and stage of disease. All
premenopausal women, particularly very young women and women without children should
be informed as early as possible about the options of preserving fertility and ovarian
function. Associated networks of oncology centers and centers of reproductive medicine
such as the Fertiprotekt network in Germany (http://fertiprotekt.com) can offer additional
counselling and advice.
Prevalence and Risk Factors
Prevalence and Risk Factors
The prevalence of permanent gonadal injury (infertility) for various therapy regimens
is [3], [4], [5], [6]:
-
High (> 80%) for:
-
pelvic radiotherapy (dose per ovary > 10 Gy, dose per testis > 4 Gy)
-
whole body irradiation [7]
-
high-dose chemotherapy with stem cell transplants and cyclophosphamide/busulfan
-
CMF, FEC, FAC (6 cycles respectively in women aged > 40 years)
-
Intermediate for:
-
CMF, FEC, FAC (6 cycles respectively in women aged 30 – 39 years)
-
AC, EC (4 cycles respectively in women aged > 40 years)
-
taxane-based combinations
-
Low (< 20%) for:
-
ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)
-
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)
-
treatment for acute myeloid leukemia
-
treatment for acute lymphocytic leukemia
-
CMF, FEC, FAC (6 cycles respectively in women aged < 30 years)
-
AC, EC (4 cycles respectively in women aged < 40 years)
-
Unknown/doubtful for:
-
taxane, vincristine, MTX, 5-FU, oxaliplatin, irinotecan, capecitabine
The therapy reported to have the highest cure rate in the guidelines should always
be used, irrespective of the potential ovarian damage. It is important to avoid any
relevant delay of oncologic therapy, even if the delay is for fertility-preserving
measures [8].
Preservation of Ovarian Function in Patients with Breast Cancer
Preservation of Ovarian Function in Patients with Breast Cancer
Around 25% of all cases of breast cancer develop in premenopausal patients and 12%
of cases are women under the age of 40 years [18], [19].
Does ovarian function recover?
Estrogens play a very important role in the tumorigenesis of breast cancer. Conversely,
the suppression of hormone production (= ovarian function suppression, OFS) is therapeutically
very effective to treat hormone-sensitive tumors [1]. For hormone receptor-positive women with high-risk breast cancer, chemotherapy
with additional OFS can significantly improve breast cancer-specific survival by 5 – 10%
[20], [21]. Studies have shown that disease-free 10-year survival rates (78.4 vs. 67%, p = 0.022)
and overall survival (90.8 vs. 79.7%, p = 0.041) were significantly higher for women
who had CIA compared to women without CIA [22]. The existing data indicate that amenorrhea (CIA, GnRH therapy) after chemotherapy
improves prognosis. At present it is not clear how long the amenorrhea should be maintained.
Depending on the patientʼs age and the administered cytostatic drugs and their dosages,
CIA occurs after administration of the standard chemotherapy combinations currently
in use in 50 – 60% of cases; CIA can be reversible or irreversible [5]. For patients aged < 35, 35 – 40 and > 40 years the CIA rate was 26% (95% CI: 12 – 43%),
39% (95% CI: 31 – 58%) and 77% (95% CI: 71 – 83%), respectively [23]. Older age (> 40 years) and tamoxifen intake have been confirmed as independent
risk factors for CIA.
There are no concerns about the return of menstruation in women with hormone receptor-negative
tumors.
Are there parameters which predict chemotherapy-induced amenorrhea (CIA)?
Generally speaking, the younger the patient, the lower the risk of CIA. Although the
data are not conclusive, predicting the risk of CIA is possible using anti-Mullerian
hormone (AMH), inhibin and follicle-stimulating hormone (FSH) [24], [25], [26], [27]. Determining the number of follicles and their size can be helpful but is subjective
[28]. AMH, number of follicles and levels of other hormones are strongly age-dependent.
Anthracycline-taxane-based chemotherapy regimens are currently the standard therapy.
Although taxane-based regimens tend to have somewhat higher amenorrhea rates, their
CIA rates do not differ significantly from those for FAC/FEC regimens [29], [30]. In all studies age was the decisive predictor for the occurrence of CIA. Recently,
genetic polymorphisms have been discussed as possible causes for CIA [31], [32], [33]. According to the study by Reimer et al. published in 2016, women with a heterozygote
variant of the drug metabolism enzyme SLCO1B1*5 had significantly lower CIA rates.
Before starting chemotherapy the indications for chemotherapy must be critically assessed
using multigene assays, where necessary [34], [35], [36]. Endocrine therapy alone may be sufficient.
GnRH analogs for functional protection of the ovary during chemotherapy?
It is still not clear how cytostatic drugs exert their harmful effect on the ovaries.
As follicular development from primordial follicle to small preantral follicle is
independent of GnRH, the cytotoxic effect on proliferating cells should only play
a subordinate role. While the Ataya hypothesis assumes that the primary harmful effect
is exerted on the proliferating granulosa cells, the Meirow hypothesis postulates
that alkylating substances primarily destroy the dormant pregranulosa cells and the
oocytes surrounding them through the induction of apoptosis [37].
Several randomized studies have investigated the effect of chemotherapy on ovarian
function with and without GnRH analogs ([Table 1]). Four studies reported a benefit from the administration of GnRHa on the CIA rate,
while three studies found no benefit. The biggest study (POEMS [38]) reported an inexplicable but significant improvement in the disease-free survival
of hormone receptor-negative patients and in overall survival following the additional
administration of GnRHa. Because of bias during follow-up (only 135 of 218 patients),
the unclear definition of hormone receptors, and the different effects of chemotherapy,
this study must be viewed critically [39]. [Table 1] additionally shows that the overall pregnancy rate was very low.
Table 1 Randomized clinical studies on the use of GnRHa to protect ovarian function during
chemotherapy.
|
Author
|
Patients (n)
|
Mean age (years)
|
Hormone receptor-positive (%)
|
% POF*
GnRH/no GnRH
|
Pregnancies (n)
|
|
* POF = premature ovarian failure
|
|
Badawy [42]
|
78
|
30
|
Not specified
|
10/67 p < 0.001
|
Not specified
|
|
Sverrisdottir [43]
|
285
|
45
|
45
|
64/90 p = 0.006
|
Not specified
|
|
Del Mastro [44]
|
281
|
39
|
81
|
9/26 p < 0.001
|
3/1
|
|
Gerber [45]
|
60
|
37
|
0
|
30/43 n. s.
|
1/1
|
|
Munster [46]
|
49
|
39
|
73
|
12/10 n. s.
|
1/1
|
|
Elgindy [47]
|
100
|
33
|
0
|
24/48 n. s.
|
2/1
|
|
Moore [38]
|
218
|
38
|
0 (≤ 10%)
|
8/22 p = 0.02
|
22/12
|
Recent meta-analyses came to the conclusion that the administration of GnRHa can be
recommended for premenopausal patients for whom chemotherapy is indicated and who
wish to preserve ovarian function [40], [41]. The additional administration of GnRHa resulted in a significantly higher rate
of menstruation recovery after 6 (OR: 2.41; 95% CI: 1.40 – 4.15; p = 0.002) and 12
months (OR: 1.85; 95% CI: 1.33 – 2.59; p = 0.0003) and a higher pregnancy rate (OR:
1.85; 95% CI: 1.02 – 3.36; p = 0.04) [2].
Other options for fertility preservation
Advances in reproductive medicine (ART) have led to a change in thinking about fertility
preservation prior to chemotherapy. At present, cryopreservation of fertilized oocytes
and mature oocytes is a well-established procedure, while the cryopreservation of
immature oocytes is still considered to be in its experimental stages [48], [49]. Cryopreservation of ovarian tissue is another procedure for preserving fertility
[17], [50]. All ART procedures cost more than € 2000, and health insurance companies usually
do not fund the procedures.
Cryopreservation of embryos or pronuclear fertilized oocytes (2PN) has the highest
success rates in terms of healthy live births [51]. But this requires the woman to have a partner.
For women without a partner, the options are cryopreserving mature oocytes or ovarian
tissue. Follicular stimulation with gonadotropins can be done at the same time as
administering tamoxifen or an aromatase inhibitor (letrozole). The time to follicle
puncture from the start of stimulation treatment in the luteal phase with recombinant
FSH and the simultaneous administration of GnRH antagonists has decreased to a maximum
of 14 days. This period is considered oncologically acceptable. By using GnRH agonists
to induce ovulation prior to egg collection (“agonist trigger”) it is usually possible
to avoid ovarian hyperstimulation (OHSS). The administration of a GnRH depot preparation
on the day of egg collection quickly achieves the desired ovarian insufficiency required
for chemotherapy.
Vitrification is currently the standard method to cryopreserve unfertilized oocytes,
as it achieves very high survival rates even though the spindle apparatus is vulnerable
to ice crystal formation. The formerly used slow freezing protocol is no longer used
because of the low cryo survival rates of approximately 30% of unfertilized oocytes.
Although survival rates of > 85% have been achieved for 2PN and embryos after slow
freezing, this method is also being replaced by vitrification.
The laparoscopic extraction of ovarian tissue (up to and including an entire ovary)
and the subsequent cryopreservation of this tissue is becoming increasingly important.
To date, more than 86 successful term pregnancies following the transplantation of
previously cryopreserved ovarian tissue have been reported worldwide [49], [52], [53]. Slow freezing of ovarian tissue appears to offer superior results compared to vitrification.
After chemotherapy has been completed, the ovarian cortex chips are transplanted either
orthotopically into perforations in the (contralateral) ovary, subperitoneally into
the pelvic wall or heterotopically, e.g. into subcutaneous fat tissue [54]. The short duration between the procedure and the start of therapy is an advantage.
The encouraging results reported by different working groups show that cryopreservation
of ovarian tissue with subsequent transplantation is well on the way to becoming an
established procedure for fertility preservation. Associated problems include the
risk of tumor cell dissemination, e.g. in patients with leukemia, and the retransplantation
of ovarian tissue in women with BRCA 1/2 mutations [8], [55], [56].
Preservation of Ovarian Function in Patients with Cervical, Ovarian and Uterine Tumors
Preservation of Ovarian Function in Patients with Cervical, Ovarian and Uterine Tumors
Ovarian tumors
In unilateral borderline tumors of the ovary (BTO) and even in very early ovarian
cancer (EOC, FIGO I) fertility-preserving surgery can be an option after adequate
staging (rinse cytology, omentectomy, appendectomy and, where necessary, peritoneal
sampling) [55], [57], [58], [59], [60]. An unremarkable uterus and unremarkable contralateral ovary are the preconditions
for organ-sparing procedures. Ovarian biopsy is only recommended for macroscopic anomalies.
However, cohort studies for both pathologies have reported an increased risk of recurrence
after fertility preservation.
After treatment of BTO and a median follow-up of 88 months (range: 14 – 205) studies
report invasive recurrence in 16% of cases, with recurrence developing after a median
of 22 months (range: 3 – 74) [61]. Independent prognostic factors for recurrence include invasive implants, FIGO Ic,
G3 and young patient age. Currently the risk of recurrence is reported to be 12 – 29%,
depending on FIGO stage, inclusion criteria, systemic therapy and follow-up, and the
reported pregnancy rates are 30% [60], [62], [63]. But no difference with regard to survival was found between patients with FIGO
stage 1 disease who had fertility-preserving surgery and patients with FIGO stage
1 disease who underwent radical surgery [63], [64]. In two thirds of cases, recurrence after fertility preservation developed at extraovarian
sites and was usually lethal. Patients therefore need to be informed in detail about
their individual risk of recurrence.
80% of germ cell tumors (malignant mullerian mixed tumor, MMMT) are diagnosed in women
under the age of 30 years, and 70 – 75% of these tumors are stage 1. A conservative
approach is appropriate in most cases and has a good prognosis [65]. The risk of recurrence reported in the literature ranges from 9.8 to 27.4% [66].
It is not clear whether there are differences in the risk of recurrence between carriers
of BRCA 1/2 gene mutations and non-mutation carriers. In Scandinavia, cryopreservation
with retransplantation of ovarian tissue instead of fertility-preserving surgery is
already considered “safe” [50], [67].
At present there are no confirmed data on a possible connection between ovulation
induction and recurrence. Rates of spontaneous pregnancies of between 33 – 100% have
been reported after fertility-sparing adnexal-preserving surgery [68].
Definitive removal of the adnexa with or without hysterectomy can be always be carried
out for “safety reasons” after patients have completed their reproductive planning.
However, it is currently not clear whether this improves overall survival.
Cervical cancer
Early detection and appropriate treatment of cervical dysplasias is the best way to
preserve fertility. As described in the S3 guideline “Cervical Cancer”, conization
is sufficient to treat patients with stage IA cervical cancer (synonym: early stromal
invasion, micro-carcinoma) with up to one risk factor (L1, V1, G3) who wish to preserve
their fertility (in patients with L1, conization may be supplemented by laparoscopic
pelvic lymphadenectomy).
A number of different techniques for fertility preservation are currently used. Radical
vaginal trachelectomy (RVT) as described by Dargent – a combination of laparoscopic
lymphadenectomy and vaginal resection of the cervix together with the proximal part
of the vagina and the parametrium/paracolpium – is used to treat patients with FIGO
stage IB1 cervical carcinoma (tumor size ≤ 4.0 cm) who wish to preserve their fertility
[69]. A German multicenter study with 100 patients reported a recurrence-free survival
of 90% after a median follow-up of 29 months for patients with early cervical cancer
(≤ 2 cm) [70]. The results for 379 patients presented by 6 working groups showed a 4% rate of
pelvic recurrence [71], [72]. Recent meta-analyses on RVT confirm the reported recurrence and mortality rates
of 5 and 2%, respectively (tumor size ≤ 2 cm) and 11 and 4%, respectively (tumor size
> 2 cm) [73], [74], [75]. In patients with adenocarcinoma, the risk of recurrence is 13% and mortality is
also higher compared to mortality rates for squamous cell carcinoma [76].
Radical trachelectomy can also be carried out using an abdominal approach (RAT) [77].
As tumor size (≤ 2 cm vs. > 2 cm), lymph node involvement and lymphatic invasion are
the most significant factors which affect the decision for or against a fertility-sparing
approach, the first step should consist of pelvic and paraaortal lymphadenectomy [78].
Early closure of the cervical os is recommended to prevent very early premature births,
which have a reported incidence of up to 50% after RVT/RAT [79]. However, a high percentage of infertile women (> 15%) has been reported because
of cervical stenosis following trachelectomy [80].
Laparoscopic lymphadenectomy followed by neoadjuvant (radio-)chemotherapy with administration
of GnRH analogs for ovarian protection and subsequent conization is a less well established
fertility-preserving option for women with cervical cancer. This option can be expanded
by the additional cryopreservation of ovarian tissue or oocytes [73].
The ovaries can be preserved in patients with advanced disease requiring radical surgery.
If the ovaries are retained, they should be marked with metal clips, moved cranially
and fixed outside the lesser pelvis ([Fig. 1]). This will protect them if radiochemotherapy is indicated. The risk of ovarian
failure increases significantly when the radiation dose is higher than 10 Gy. More
than 70% of patients who received radiation doses of more than 20 Gy developed ovarian
failure [81]. There is insufficient data on the benefits of administering GnRH for ovarian protection,
and GnRH administration is therefore not an established procedure.
Fig. 1 Radiotherapy planning for a 29-year-old patient with cervical cancer for whom radio-chemotherapy
was indicated. CT of the abdomen in the (a) frontal plane and (b) sagittal plane shows the new location of the ovaries outside the lesser pelvis.
c, d Ovaries outside the irradiated area, inside the 10% isodoses (images were kindly
provided by Prof. Dr. G. Hildebrandt, Director of the Department of Radiation Therapy
of Rostock Medical University).
Uterine cancer
The option of organ preservation is rare for histologically confirmed complex hyperplasia
(CHP) or early endometrial cancer (EEMC). In most cases, the patients are obese. Progestational
therapy (e.g. 400 – 600 mg/d medroxyprogesterone acetate or 160 mg/d megestrol acetate
for 3 – 6 months) may be indicated in young premenopausal patients with CHP/well differentiated
EEMC and no infiltration of the myometrium. The remission rates are reported to be
comparable for levonorgestrel-containing IUDs but the weight gain is significantly
lower [82]. The remission rates for progestational therapy are high with reported rates of
81% and a remission duration of 6 months, but recurrence occurs in up to 50% of cases
[83]. Because of these high rates of recurrence, women wishing to have children should
have children as soon as possible after pathological remission (hysteroscopy and curettage).
In addition, they should optimize lifestyle factors (diet, control of diabetes, weight
loss). MRI ([Fig. 2]) can be useful in addition to ultrasound to determine the extent of myometrium infiltration
by EMC.
Fig. 2 MRI in a 27-year-old patient with a well differentiated endometrioid adenocarcinoma
and infiltration of the myometrium. After histologic confirmation of the diagnosis
following hysteroscopy and fractionated curettage, preoperative staging was done with
MRI to assess the possibility of preserving the uterus.
Hysteroscopic resection of EEMC together with the underlying myometrium and adjacent
endometrium followed by 6 months of progestational therapy resulted in complete pathological
regression in 89% of cases. There were two (8%) cases of recurrence, and the median
duration of response was 95 (8 – 175) months. 87% of the women who wanted to have
children gave birth to healthy children [84]. These data are encouraging but are not yet the standard.
Retention of Ovarian Function in Children, Adolescents, and Young Adults (CAYAs) with
Oncologic Disease
Retention of Ovarian Function in Children, Adolescents, and Young Adults (CAYAs) with
Oncologic Disease
CAYAs treated with chemotherapy for lymphoma, leukemia, myeloma, Wilms tumor, sarcoma,
etc. have a higher risk (RR: 1.48 [95% CI: 1.23 – 1.78]; p < 0.0001) of infertility
once they reach the age of fertility and are more likely to be treated for sterility
compared to persons who did not have chemotherapy [10]. Pelvic irradiation, therapy with alkylating agents, and high-dose chemotherapy
were particularly strong predictors of infertility [11]. It is difficult to make proper recommendations for fertility preservation. A comparison
of 25 different recommendations for fertility preservation in CAYAs showed a wide
range of sometimes divergent recommendations, which suggests a lack of evidence [12], [13]. The current recommendations are cryopreservation of ovarian tissue and oocytes,
depending on patient age and the planned type of chemotherapy [14], [15], [16], [17].
Fertility-preserving Measures in Male Cancer Patients
Fertility-preserving Measures in Male Cancer Patients
Before starting therapy, cryopreservation of sperm is possible in postpubertal adolescents
aged 13 and above, who are Tanner stage ≥ 3 and have a testis volume of 10 ml or above.
Sperm cells can be obtained by ejaculation, electrostimulation or microsurgical testicular
sperm extraction (TESE). Cryopreservation of mature testicular tissue is also possible
although, because of the potential for testicular metastasis, this is associated with
a risk of retransplanting malignant cells [9].
After completing therapy, the extraction of vital sperm from patients with persisting
azoospermia with TESE has been reported to be successful in up to 50% of patients.
However, patients should wait at least 2 years after completing treatment to see whether
spermatogenesis recovers, unless they have additional pathologies such as hypogonadism
or ejaculation disorders. Hormone replacement therapy with testosterone is indicated
in patients with hypogonadism [6].
Summary
With the significant improvement in cure rates for oncologic disease in children,
teenagers and young adults, preserving fertility and gonadal function has become a
central aspect of therapy planning.
Developments in reproductive medicine which can preserve fertility in postpubertal
women and men with oncologic disease include the cryopreservation of oocytes and sperm
and the cryopreservation of ovarian tissue (even from prepubertal girls) and testicular
tissue. The highest pregnancy rates are achieved by the cryopreservation of embryos,
but this assumes that the patient has a partner.
For premenopausal patients with hormone receptor-positive breast cancer, (temporary)
chemotherapy-induced amenorrhea is associated with an improved prognosis. Depending
on patient age, CIA is reversible; the administration of a GnRHa prior to starting
chemotherapy is recommended if the patient wishes to retain ovarian function [40], [41].
Women of reproductive age with a primary diagnosis of cervical cancer, endometrial
cancer or ovarian cancer who wish to have children can opt for a fertility-sparing
surgical approach, depending on their cancer stage.
All patients should be informed about the consequences for reproduction before they
start therapy and be informed about the options of preserving their fertility, e.g.
through the Fertiprotekt network.
