Dr. Rohit Kabre, MD Radiation Oncology, Hinduja Hospital

1. FERTILITY PRESERVATION
FOR PATIENTS WITH CANCER
Dr Rohit.S.Kabre
Radiation Oncology

2. Outline
• Introduction
• Treatment modalities & their cytotoxic effects
• Psycho-social effect of infertility
• Fertility preservation options
• Recommendations from ASCO guidelines
• Facilities available

3. Cancer burden in reproductive age group
population
• Every year 250,000 children all over the world get
diagnosed with cancer
• In India, it is estimated that nearly 40-50,000 new
childhood cancer cases occur each year.
• Increase in incidence rates for all cancers combined
is largest in people aged 0-24 where rates have
increased by a fifth (20%)
• In 2010, every 250th adult was a survivor of
childhood cancer.
• Approximately, 40-80% of females face possible
infertility as a result of their cancer treatment

4. Malignancies encountered in
Reproductive age group
• Breast Cancer
• Ovarian tumors
• Lymphomas/leukemias
• Paediatric solid tumors
• Testicular cancers
• Brain tumors
• PNET
• Bone Tumors

6. • Multi-modality Treatment is current standard of care in
treating malignancies.
• Both chemotherapy and radiotherapy have a major
impact on reproductive potential.
• Infertility causes being
1. disruption of the hypothalamic-pituitary-gonadal axis
2. direct immunological or cytotoxic injury to the
germinal epithelium within the testis
3. Anorexia-cachexia syndrome
4. psychological issues such as anxiety and depression.

7. Chemotherapy
• Degree of ovarian damage dependent upon the type of the
chemotherapeutic agent used, dose , age and baseline
ovarian reserve.
• MOA-apoptosis of the growing follicles and activation of
the resting follicle with subsequent apoptosis, leading to a
burn-out effect &Fibrosis of stromal blood vessels
• clinical manifestation ranges from a complete amenorrhea
to premature menopause and varying degree of infertility
• The incidence of temporary or definitive chemotherapy-
induced amenorrhea ranges from 22% to 61% in women
under 40 years of age and from 61% to 97% in those over
40

8. Effects of Cytotoxic drugs on the ovary

9. • Alkylating agents - highest age-adjusted odds ratio of
ovarian failure rates
• Platinum-based compounds- medium risk of amenorrhea
• Anthracycline antibiotics- amenorrhea and fertility risk is
medium to low
• Vinca alkaloids do not seem to increase the risk of ovarian
failure, though animal experiments show a high rate of
oocyte aneuploidy
• Anti-metabolites- do not seem to affect the ovary based on
the limited current data available.
• little available information regarding the impact of targeted
agents on fertility at any level of evidence, exception is
bevacizumab

10. Effects of cytotoxic drugs on Testis
• The testicular vasculature is permeable-> drugs can freely
reach the Leydig and Sertoli cells(functional damage) and
the spermatogonia.
• sperm count diminishes with a time course that depends
on the sensitivities of the different spermatogenic cells and
their kinetics of maturation to sperm
• spermatocytes relatively insensitive while differentiating
spermatogonia are extremely susceptible
• induced azoospermia can be either temporary or
prolonged, depending on the survival of stem
spermatogonia and their ability to proliferate.

11. Radiation Therapy
• Unlike chemotherapy, radiotherapy affects both
the ovary and the uterus.
• median lethal dose (LD50) of <2 Gy for human
oocyte.
• effective sterilizing dose (ESD) dose of
fractionated radiotherapy at which POF occurs.
• ESD decreases with increasing age, being 20.3 Gy
at birth, 18.4 Gy at 10 years, 16.5 Gy at 20 years,
and 14.3 Gy at 30 years, with only 6 Gy being
required to cause permanent ovarian failure in
women over 40.

12. Effects of Radiation on Uterus
• Radiation leads to reduced vascularity,
damage to myometrium leading to fibrosis
and hormone dependent endometrial
insufficiency, resulting in adverse
reproductive outcomes.
• Increased rates of infertility, miscarriage,
preterm labor, intra-uterine growth retardation
and low birth weight have been reported by
especially if conception occurs within a year.

13. Effects of Radiation on the testis
• Despite significant advances, radiation therapy has
detrimental and irreversible effects on the testis
• Very small doses (as low as 0.1 Gy) lead to histological
changes in spermatogonia number and shape.
• Exposure to 2–3 Gy of radiation leads to significant
spermatocyte damage.
• Doses in the 4–6 Gy range lead to significant spermatid injury.
• As to its effect on ejaculated sperm concentration, radiation
doses less than 0.8 Gy typically lead to oligospermia, doses
0.8–2 Gy often result in transient azoospermia, and exposure
to doses greater than 2 Gy may lead to irreversible
azoospermia

14. • timeline for radiation injury to be reflected in
semen analyses is approximately 60–70 days
after exposure.
• The larger the dose of radiation, the more
precipitous the decline in sperm concentration
and the longer the period of time required for
recovery of spermatogenesis
• reach nadir by 4–6 months after the
conclusion of radiation therapy.

15. • Prognostic factors favoring more rapid or
complete recovery of spermatogenesis include
normal semen parameters prior to therapy and
younger age at the time of treatment
Radiation dosage Time to complete recovery*
<1 Gy 9–18 months
2–3 Gy 30 months
>4 Gy >5 years
*return to pre-irradiative sperm concentration

16. Oncofertility-Unmet need
• Growing Increase in cancer incidence and cancer
survivourship in reproductive age group coupled
with demographic trend of initiating pregnancy
later in life has made fertility preservation an
important facet in Quality of life.
• Only about 50 % of cancer survivors report
receiving counseling regarding the cancer
treatment’s impact on their fertility and future
options for childbearing

17. Psycho-social effect of Infertility on
Survivorship
• Adult survivors of childhood cancer report
increased anxiety regarding finding a mate
• Infertility is associated with diagnosis of
depression 2 times that of fertile population.
• Informed decision reduces reproductive regret &
psychological distress in these young men and
women.
• A strong factor in long-term emotional well-being
of cancer survivors is the ability to parent a child.

19. Fertility sparing treatment
modifications
• Opt for surveillance or less gonadotoxic chemotherapy on
case-by-case basis.
• Incorporation Oncotype DX for breast cancer patients
• Timing for treatment for breast cancer: chemotherapy delay 1
month for ovarian stimulation/oocyte retrieval
• Tamoxifen delay for pregnancy
• “Ferto-protective adjuvant therapy” during or prior to
chemotherapy with an agent that can prevent loss of ovarian
reserve ex-GnRH analogues.
• Less aggressive resection for ovarian cancer & cervical cancer
• Oophoropexy for radiation shielding.

20. Assisted Reproductive Technologies
• In vitro handling of human oocytes and sperm or
embryos for the purpose of establishing a
pregnancy
• Currently, IVF with ICSI is the most successful
method for achieving pregnancy from banked
sperm.
1. single cycle can take 2 to 3 weeks to complete
and necessitates a delay in cancer treatment.
2. rising estradiol levels during ovarian stimulation
tackled by letrozole/tamoxifen use

21. Embryo cryopreservation
• ovarian hyperstimulation->surgical oocyte retrieval->
IVF an essential component.
• embryo banking is the most successful form of fertility
preservation and should be offered to all women who
are married, or who are open to the idea of using
donor sperm.
• Limitations-
1. High estradiol levels during stimulation may have a
negative effect on estrogen-sensitive tumors
2. delay cancer treatment
3. Non applicability in prepubertal patients.

22. Oocyte cryopreservation
• with appropriate counseling, is recommended
for patients facing infertility due to
chemotherapy or other gonadotoxic
therapies.
• When a woman is unmarried or does not have
a partner mature oocyte cryopreservation is
preferred
• cryopreservation (slow freezing) or
vitrification (rapid freezing) is an option

23. Sperm Cryopreservation
• strongly advisable to complete sperm banking
before starting therapy to avoid increased genetic
damage in sperm collected after the start of
therapy
• collection of three or four samples with
approximately 48-hour periods of abstinence
between sampling is ideal
• If sperm count or motility is impaired or sample
amounts are limited, IVF is necessary or else IUI is
feasible.
• conception rates of IUI are lower than with IVF.

24. Ovarian Tissue Cryopreservation
• entails the surgical removal of ovarian tissue containing
numerous primordial follicles or whole ovary
cryopreservation of tissue slicessubsequent grafting
back to the site of the ovary.
• excellent emerging method suitable for premenarchal
girls Large number of immature oocyte in ovarian
cortex
• reported success with ovarian tissue transplantation
that has resulted in at least 12 patients with 28
subsequent live births in humans.
• concern for reintroduction of malignant cells back into
the host, particularly for patients treated for leukemia.

25. Testicular Tissue Cryopreservation
• Testicular cells have been harvested before
sterilizing cytotoxic therapy and later injected
back into the testicular tubules.
• When the provided sample reveals azoospermia,
surgical testicular sperm extraction prior to
cancer treatment is an option
• To date, there has not yet been a report of
successful transplantation of testicular tissue in a
male patient,

26. Oophoropexy
• ovaries are surgically translocated away from the direct
beam( para-colic gutter, anterior abdominal wall)
• region can be further shielded using lead blocks
• beneficial in preserving ovarian function and future
fertility in an adult population
• Laparoscopic or robotic approach allows for shortened
hospital stay and earlier return to normal activity.
• Ex- CSI, pelvic radiation
• Avoided if chemotherapy is contemplated.
• Procedure done close to period of initiation of Rx- risk
of remigration

27. GnRH agonist & antagonist
• GnRH agonist protective effect –
1. pituitary desensitization that ensues after 7 to 14 days
later -->reduce the number of primordial follicles
destroyed by toxic agents
2. may reduce the blood flow to the ovary and reduce
delivery of chemotherapeutic agents
• Human studies- conflicting evidence.
• GnRH antagonists rapid inhibition of gonadotropin and
sex steroids secretion leasing to immediate
downregulation.
• insufficient evidence to definitively recommend this
therapy.

28. ASCO clinical practice guideline on
fertility preservation
• To preserve the full range of options, fertility preservation
approaches should be discussed as early as possible, before
treatment starts.
• refer patients who express an interest in fertility
preservation (and patients who are ambivalent) to
reproductive specialists.
• Document fertility preservation discussions in the medical
chart
• No patient should be excluded from consideration for
discussion of fertility preservation for any reason, including
age, prognosis, socioeconomic status, or parity
• concerns such as need to initiate chemotherapy quickly
should not dissuade patients from banking sperm.

29. Adult Males
• At present sperm cryopreservation (sperm banking) as
the only established fertility preservation method
• Do not recommend hormonal therapy in men; it is not
successful in preserving fertility
• Inform patients that other methods (eg, testicular
tissue cryopreservation, which does not require sexual
maturity, for the purpose of future reimplantation or
grafting of human testicular tissue) are experimental
• Advise men of a potentially higher risk of genetic
damage in sperm collected after initiation of therapy

30. Adult Females
• Present both embryo and oocyte cryopreservation as established
fertility preservation methods
• Discuss the option of ovarian transposition (oophoropexy) when
pelvic radiation is performed as cancer treatment
• Inform patients of conservative gynecologic surgery and radiation
options
• Inform patients that there is insufficient evidence regarding the
effectiveness of ovarian suppression (GnRH analogs) as a fertility
preservation method, and these agents should not be relied on to
preserve fertility
• Inform patients that other methods (eg, ovarian tissue
cryopreservation, which does not require sexual maturity, for the
purpose of future transplantation) are still experimental

31. Children
• Use established methods of fertility preservation
(semen cryopreservation and oocyte
cryopreservation) for post pubertal minor
children, with patient consent, if appropriate, and
parent or guardian consent
• Present information on additional methods that
are available for children but are still
investigational
• Refer for experimental protocols when available

32. Facilities available
• Embryo cryopreservation
• Oocyte cryopreservation
• Sperm banking
• Testicular & Ovarian tissue cryopreservation.

33. THANK YOU