Keywords
radiotherapy - ovarian insufficiency - ovarian function - ovarian radiation
Palavras-chave
radioterapia - insuficiência ovariana - função ovariana - radiação ovariana
Introduction
Radiation is an integral component of therapy for a variety of tumors that may affect
young people. Most of these tumors are associated with high cure rates; therefore,
treatment results in potential risk for survivorship issues.[1]
[2]
[3] For young women, premature ovarian insufficiency and decreased reproductive potential
are important risks related to this treatment, with consequences regarding bone and
cardiovascular health.[4]
[5]
[6] Total body craniospinal axis, whole abdominal, or pelvic irradiation potentially
expose the ovaries to irradiation.[7]
[8]
[9] Radiotherapy is now a well-known cause of ovarian damage. The amount of injury is
related to several variables, including the total radiation dose, the fractionation
schedule, and age at the time of treatment.[10]
The human ovary contains a limited number of primordial oocytes that reaches a peak
at 5 months after conception and declines with increasing age in a biexponential fashion.
This decline culminates in the menopause, when the number of oocytes is < 1,000, at
an average age of 51 years old.[11] The ovaries are highly radiosensitive organs. Some authors have suggested that doses > 6 Gy
in total body irradiation in young women induce premature ovarian insufficiency, whereas
prepubertal women can tolerate even higher radiation doses.[2] In a large cohort of childhood cancer survivors, 215 cases (6.3%) developed premature
ovarian insufficiency. Radiotherapy to the ovaries was the most significant risk factor
for premature ovarian insufficiency, especially at doses ≥ 1,000 Gy, and exposure
to the alkylating agents procarbazine and cyclophosphamide, at older ages.[12] Presumably, this reflects the number of oocytes at the time of exposure: a younger
patient has more oocytes and, therefore, a wider fertility window.
Wallace et al.[13] created a mechanism to predict ovarian insufficiency according to the age of the
patient and to the fractionated radiation dose received by the ovaries. In that model,
they reported sterilizing dose of radiation for a known age at treatment and the age
of ovarian insufficiency for total body radiation maximum dose of 3, 6, 9, and 12
Gy. This is the first model to predict with reliability the age at which ovarian insufficiency
will supervene for any patient after treatment with a known dose of radiotherapy received
by the ovaries. However, the described model does not allow an accessible evaluation
of the decrease of the time for ovarian insufficiency for other doses and has limited
use in clinical practice. Therefore, the present study aimed to review the model created
by Wallace et al. and to develop a mathematical model to facilitate the prediction
of ovarian insufficiency in the era of modern computed tomography (CT) radiotherapy
planning.
Methods
The present study was approved by the Ethics Committee of the involved institutions
(CAAE number: 77681317.3.0000.5128). To correlate ovarian radiation dose with ovarian
function, we used the formula described by Wallace et al.:[13] √g(z) = 10,[2]
[10]
[14] where “g(z)” and “z” represent oocyte survival rate and the radiation dose (in Gray),
respectively. To solve the differential equation, we applied the fourth order of Runge-Kutta
method using a Matlab algorithm and obtained the number of oocytes at a given age
and calculated the residual number after irradiation at any dose.[14] The Runge–Kutta is an iterative method used in temporal discretization for the approximate
solutions of ordinary differential equations. It has enabled a more accurate estimate
of the radiosensitivity of the human oocyte. We considered 701,200 the initial number
of oocytes at birth and 1,000 the number necessary at menopause.[15]
For the statistical analysis, R software, version 3.4.2 (R Foundation, Vienna, Austria)
was used. The loss of ovarian function (LOF) was defined as the percentage of decrease
in the time to ovarian insufficiency compared with the time expected for a woman at
the same age without irradiation exposition. Assuming that oocyte decay after irradiation
was the same as that for nonirradiated oocytes, we simulated the remaining time for
women aged between 10 and 50 years old for exposure to 0.5 Gy to doses that cause
immediate ovarian insufficiency. From these remaining times, we could obtain a simple
equation relating dose and time until menopause.
To define the relationship between loss of ovarian function and dose, a linear regression
was fitted.[16] To verify the performance of the model, a cross-validation was performed with the
leave-one-out method. At the end of the cross-validation process, the root-mean-square
error (RMSE) was calculated.
Discussion
The equation proposed in the present study can be considered a readily accessible
way to predict ovarian insufficiency after radiotherapy with a known dose received
by the ovaries. For example, if the ovaries were exposed to 4 Gy at age 27, the patient
would have a decrease in time to ovarian insufficiency of 47% [2.7 + (11.08 × 4)]
to what would be expected in women of the same age without radiation exposure. In
other words, considering 51 years old as the median age of natural menopause, if a
27-year-old patient was exposed to 4 Gy, she would lose 11 years of ovarian function,
and would enter menopause at 40 years old.
With no biochemical markers available to predict premature ovarian insufficiency,
such a model that determines the extent of radiotherapy-induced damage and allows
an assessment of the “fertile window” will have a significant impact on reproductive
counseling for young women with cancer. For those young women who are at risk of a
very early menopause, it is possible to consider counseling them on the options currently
available to preserve their fertility before their treatment starts. Making decisions
about preserving future fertility requires that patients receive information from
their doctors.
Limitation of radiation dose to the ovary is practiced in adult women with cervical
cancer in childbearing age submitted to adjuvant radiotherapy. In the era of radiotherapy,
treatment planning based on CT and sophisticated external beam irradiation techniques,
such as intensity modulated radiotherapy (IMRT) and volumetric modulated arc radiotherapy
(VMAT), sharp dose gradients against normal tissue with a considerable reduction of
ovarian radiation dose are possible.[17] In order to minimize the effects of induced menopause, ovarian transposition can
be surgically performed and modern radiation techniques can spare the ovaries from
high radiations doses ([Figure 5]).[18]
[19]
[20] Calculation of the dose of radiation received by each ovary, combined with a more
accurate estimate of the radiosensitivity of the human oocyte, could facilitate our
ability to provide more scientific fertility counseling to young women at risk of
premature menopause following the successful treatment of cancer. Wallace et al.[13] reported the first model to predict the age of ovarian insufficiency after treatment
with a known dose of radiotherapy. In their publication, they provided a table with
the predicted age of onset of ovarian insufficiency for ages of treatment from 0 to
30 years old for fixed doses of 3, 6, 9, and 12 Gy.[13] Our mathematical model has a sharp CI and yields similar results to those of the
table developed by Wallace et al. We observed by our model that the pattern of oocyte/ovarian
function loss occurs with different patterns for women younger or older than 40 years
old. This can be explained by an increased rate of oocyte loss that occurs around
the age of 37 years old, when ∼ 25,000 follicles remain.[21]
[22]
Fig. 5 Computed tomography planning with volumetric arc therapy (VMAT) (Monaco TPS – version
5.51) of a 27-year-old patient in adjuvant radiation for cervical cancer. Isodose
(blue color wash) of 4 Gy does not touch the transposed ovary (white arrow).
It is important to note that we did not consider the ovaries receiving different doses,
and the results can only be applied to both ovaries receiving the same radiation dose.
We acknowledge that this is a predictive model based on preclinical work and that
it does not take into account the current use of combined modality treatments. The
results do not contemplate the chemotherapy impact on oocytes damage. Radiotherapy
is frequently used in combination with chemotherapy for the treatment of cancer. Potentially
gonadotoxic chemotherapy may be a contributory factor to the development of premature
menopause. It is also important to consider the effect of radiation towards the uterus
in terms of fertility. Radiation towards the uterus reduces the size of the organ,
makes it less elastic, and, therefore, enhances the risk of spontaneous abortion and
premature birth.[3]
[4]
[23]
Conclusion
In summary, the present study enables counseling women on their reproductive potential
following the successful treatment of their cancer. We have constructed a mathematical
model that could be used to quickly estimate ovarian insufficiency after radiotherapy.
More studies with clinical outcomes and follow-up of the patients are needed to validate
and optimize the proposed model.
