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Table of Contents
FPSI RECOMMENDATIONS
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 48-107

Fertility preservation for patients on gonadotoxic treatment: Recommendations for clinical practice by Fertility Preservation Society (India)


1 Mother and Child Hospital, D64, Defence Colony, New Delhi 110024, India
2 No1, Uma Admirality, Bannerghatta Road, Bangalore, India
3 Shreyas Hospital & Sushrut Assisted Conception Clinic, 2013 E, 6th Lane, Rajarampuri, Kolhapur 416 008, India

Date of Web Publication19-May-2021

Correspondence Address:
Dr. Nalini Kaul Mahajan
Mother and Child Hospital, D64, Defence Colony, New Delhi 110024
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2589-9597.315959

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  Abstract 


Aim: Objective of this document is to provide guidance to health care professionals on fertility preservation (FP) for Indian patients undergoing cancer treatment.
Participants: Extensive deliberations, discussion and brain storming was done with different reproductive medicine (RM) specialists, medical, radiation, surgical, gynaecological and oncologists and haematologists to develop the recommendations.
Evidence: A systematic review of the literature published up to December 2020 was carried out using PubMed and Cochrane Collaboration Library. International guidelines, cohort studies, case series, observational studies and randomized controlled trials currently available in literature were reviewed. Supplemental searches were made for individual conditions like lymphoma, leukaemia, haematological conditions, breast cancer, gynaecological cancers, immune disorders. Indian data on fertility preservation was limited to case series, hence opinion of experts was taken into account for the recommendations on fertility preservation in India. Cancer incidence and survival rates were taken from the Indian cancer registry (ICR). A panel of RM specialists across India reviewed the evidence and offered recommendations for Indian patients.
Process: Meetings were held with leading oncologists from major cancer institutes in India – Delhi: AIIMS, Medanta, Indraprastha Apollo hospital, Max SS hospital, Mumbai: Bombay Hospital; Miraj: Siddhivinayak hospital; Kolkata: Tata Medical Centre; Bangalore: Mazumdar Shaw Cancer Centre; Narayana Health City and HCG; The working group for the recommendation committee included members from the Fertility Preservation Society (India) and participating oncology experts.
Conclusions: The Fertility Preservation Society (India) recommends that oncologists should discuss the risk of infertility resulting from cancer treatment with patients of reproductive age group, at the earliest opportunity and provide initial information regarding the availability of FP. Patients with a good oncological prognosis at risk of infertility and interested in preservation of their fertility, should be referred to a reproductive medicine expert as early as possible after confirmatory diagnosis. Details of FP procedures including risks and subsequent reproductive outcome should be explained in detail by the reproductive medicine specialist. Genetic and social counselling should be made available to the patient to aid in taking an informed decision. Limiting factors in India include lack of awareness of FP options and availability, cost, lack of insurance coverage, experimental nature of some FP procedures.

Keywords: Chemotherapy, embryo, fertility preservation, gonadotoxicity, in vitro fertilization, Infertility, oocyte, premature ovarian insufficiency, radiotherapy, sperm and ovarian tissue cryopreservation pregnancy postgonadotoxic therapy


How to cite this article:
Kaul Mahajan N, Patil M, Jirge PR. Fertility preservation for patients on gonadotoxic treatment: Recommendations for clinical practice by Fertility Preservation Society (India). Onco Fertil J 2020;3:48-107

How to cite this URL:
Kaul Mahajan N, Patil M, Jirge PR. Fertility preservation for patients on gonadotoxic treatment: Recommendations for clinical practice by Fertility Preservation Society (India). Onco Fertil J [serial online] 2020 [cited 2021 Jul 26];3:48-107. Available from: https://www.tofjonline.org/text.asp?2020/3/2/48/315959




  Scope of Recommendations Top


Executive Summary 52

Definition of Fertility Preservation 52

Prioritised Clinical Questions for Developing the Recommendations 52

What the Recommendations do not Address? 53

Recommendation Development Methods 53

Interpreting the Recommendations 53

Limitations in India and Suggestions for Improvement 54

Disclaimer 54

Summary of Recommendations 55

Introduction 63

Context and Background 63

Aim 64

Indications for Fertility Preservation 64

Effect of Age on Fertility 65

Effect of Cancer and Cancer Therapy on Fertility 65

Effect of Chemotherapy in Female cancer Patients and Male Cancer Patients 65

Effect of Radiotherapy in Female and Male Cancer Patients 66

Effect of Radioactive Iodine in Men, pregnant and non-pregnant Women 67

General Recommendation 69

1.1: Are Indian patients with cancer interested in interventions to preserve fertility? 69

1.2:  Should oncologists discuss the effects of cancer treatment on fertility with all cancer patients of reproductive age? What would be an appropriate time to address this question and refer the patient for FP? 69

1.3:  Who should provide information on fertility preservation options? Oncologist/Counsellor/RM specialist? 71

1.4: Should FP be discussed with parents of pre-pubertal children? 72

In adolescents diagnosed with cancer should discussion on fertility effects of cancer treatment and fertility preservation, be discussed with patient and family individually or together?

1.5: What can health care providers do to educate patients on fertility after cancer treatment and FP? 73

1.6: Should ovarian reserve testing be done routinely prior to initiation of CT? 74

References 75

Fertility preservation in Men 77

2.1: What is the evidence supporting fertility preservation in men? 77

2.2: What is the role of fertility sparing surgeries in men? 78

References 78

Fertility Preservation in the Female 79

3.1: What are the fertility preservation options available for pre and post-pubertal females? 79

3.2: Effect of controlled ovarian stimulation (COS) on cancer prognosis? 82

3.3: Fertility sparing surgeries in gynaecological malignancies 83

References 85

Fertility Preservation in Breast Cancer 87

4.1: Routine use of GnRH analogue along with chemotherapy in young BC patients desiring children? 89

4.2: Ovarian stimulation in breast cancer patients – Is it different? 90

4.3: Should all breast cancer patients have testing for BRCA gene mutation and genetic counselling? 91

4.4: Role OTC before chemotherapy in breast cancer? 91

4.5: Breast feeding in breast cancer survivors 92

References 92

Fertility Preservation in Lymphoma and Leukaemias 94

5.1:  Methods of fertility preservation in pre-pubertal and post-pubertal males and females with lymphoma and leukemia 94

5.2: Can ovarian tissue cryopreservation be offered to patients with lymphoma and leukaemia? 96

5.3: Should ovarian suppression with GnRH agonist be advised to preserve ovarian function? 97

References 97

Fertility Preservation Options for Females and Males undergoing Radiotherapy 99

6.1: Methods of fertility preservation in patients planned for pelvic irradiation after surgery 99

References 100

After Treatment and Pregnancy in Cancer patients 101

7.1: After treatment 101

7.2: Effect of pregnancy on recurrence and survival outcomes in breast cancer 102

7.3: Pregnancy in women with gynecological cancer 103

7.4: Pregnancy in women with other cancers 103

7.5: Fatherhood after cancer 103

7.6: How to manage pregnancies diagnosed while undergoing anticancer therapy? 104

References 104

Conclusion 105


  Executive Summary Top



  Definition of Fertility Preservation Top


Fertility preservation (FP) refers to the preservation of gametes and gonadal tissue (oocyte, sperm, embryo, ovarian and testicular tissue) for use at a later, more convenient time to achieve pregnancy leading thereby, to an extension of the reproductive window.


  Prioritised Clinical Questions for Developing the Recommendations Top


1. General Recommendations

1.1. Are Indian patients with cancer interested in interventions to preserve fertility?

1.2. Should oncologists discuss the effects of cancer treatment on fertility with all cancer patients of reproductive age? What would be an appropriate time to address this question and refer the patient for FP?

1.3. Who should provide information on fertility preservation? Oncologist/Counsellor/RM specialist

1.4. Should FP be discussed with parents of pre-pubertal children?

In adolescents diagnosed with cancer should discussion on fertility effects of cancer treatment and fertility preservation, be discussed with the patient and family individually or together?

1.5. What can health care providers do to educate patients on fertility after cancer treatment and FP?

1.6. Should ovarian reserve testing be done routinely prior to initiation of chemotherapy (CT)?

2. Fertility Preservation in men

2.1. What are the fertility preservation options available for pre-pubertal and post-pubertal boys and men?

2.2. What is the role of fertility sparing surgeries in men?

3. Fertility Preservation in the Female

3.1. What are the fertility preservation options available for pre and post-pubertal girls and women?

3.2. What is the effect of controlled ovarian stimulation on cancer prognosis?

3.3. What is the role of fertility sparing surgeries/treatment in different gynaecological malignancies?

4. Fertility Preservation in Breast Cancer

4.1. Routine use of GnRH analogue along with chemotherapy in young breast cancer patients desiring children?

4.2. Ovarian stimulation in breast cancer patients?

4.3. Should all breast cancer patients have testing for BRCA gene mutation and genetic counselling?

4.4. Role of ovarian tissue cryopreservation (OTC) before chemotherapy in breast cancer?

4.5. Breast feeding in breast cancer survivors

5. Fertility Preservation in patients with Lymphoma and Leukemia

5.1. Methods of Fertility Preservation in pre-pubertal and post-pubertal males and females with lymphoma and leukemia

5.2. Can ovarian tissue cryopreservation be offered to patients with lymphoma and leukaemia?

5.3. Should ovarian suppression with GnRH agonist be advised to preserve ovarian function?

6. Fertility Preservation options for women and men undergoing Radiotherapy

6.1. Methods of fertility preservation in patients planned for pelvic irradiation after surgery

7. Pregnancy in Cancer patients

7.1 Treatment after cancer therapy for fertility

7.2: Effect of pregnancy on recurrence and survival outcomes in breast cancer?

7.3: Pregnancy in women with gynecological cancer

7.4: Pregnancy in women with other cancers

7.5: Fatherhood after cancer

7.6: How to manage pregnancies diagnosed while undergoing anticancer therapy?


  What the Recommendations Do not Address? Top


This recommendation does not seek to provide full safety and usage information on various aspects of fertility preservation for both male and female patients. The fertility preservation interventions recommended here should not be applied without consideration of the patient’s clinical profile and preferences. Each clinician should read further updated information regarding the fertility preservation techniques, contraindications, monitoring and providing reproductive assistance after completion of cancer therapy. All recommendations and practice points need to be considered in the context of regulations of each state in India. The recommendations do not include a formal analysis of cost, cost effectiveness or economic feasibility of the fertility preservation procedures in different parts of the country.


  Guideline Development Method Top


A systematic review of the literature published up to December 2020 was carried out using PubMed and Cochrane Collaboration Library. International guidelines, cohort studies, case series, observational studies and randomized controlled trials currently available in literature were reviewed. Supplemental searches were made for individual conditions such as lymphoma, leukaemia, haematological conditions, breast cancer, gynaecological cancers, immune disorders.

Indian data on fertility preservation was limited to case series, hence opinion of experts was taken into account for the recommendations on fertility preservation in India. Cancer incidence and survival rates were taken from the Indian cancer registry (ICR). A panel of RM specialists across India reviewed the evidence and the suggestions offered for Indian patients.

Process: Meetings were held with leading oncologists from major cancer institutes in India – Delhi: AIIMS, Medanta, Indraprastha Apollo hospital, Max SS hospital, Mumbai: Bombay Hospital; Miraj: Siddhivinayak hospital; Kolkata: Tata Medical Centre; Bangalore: Mazumdar Shaw Cancer Centre Narayana Health City and HCG; The working group for the recommendation committee included members from the Fertility Preservation Society (India) and participating oncology experts.


  Interpreting The Recommendations Top


GRADE of the recommendation



Quality of evidence



Categories of the guideline recommendations




  Limitations in India and Suggestions Top


Discussions with oncologists and RM specialists brought to light the constraints to FP faced in India

  1. Late diagnosis is a problem in India – especially in the rural setting. Cancer screening needs to be intensified in both urban and rural areas to identify the disease early and improve survival rates and quality of life of survivors. FP can be offered only in early stage cancers with a good prognosis
  2. Cost of procedure – cancer treatment is expensive, and patients are not left with sufficient funds for FP. Oncological treatment is the priority. Insurance should be made available for both cancer treatment and FP. All public institutions should have FP units and FP procedures should be offered free of charge to the economically weaker section of society
  3. Reluctance of family to discuss or implement FP – All oncology units should have a FP and genetic counsellor to facilitate discussion on fertility. Having a unit within the oncology department decreases the physical burden and increases patient comfort. Ideally a RM/FPspecialist should consult in the oncology unit
  4. Gender bias – gender bias is very common in the lower socio-economic groups where precious family resources would be spent on a male afflicted with cancer but not a female. This bias may take many years to improve; however if treatment is given free, families may be more willing to look after the girl child
  5. Information about effect of cancer treatment on fertility and FP options – through public awareness campaigns, association with non-Governmental Organizations (NGOs), articles in press, information leaflets in oncology outpatient department (OPD) and other out-patient areas will go a long way in increasing awareness. Patient information brochures on FP in cancer patients are available on the FPSI website.
  6. Information to oncologists about FP units providing services in their city
  7. Enhancing knowledge of oncologists, gynecologists and general physicians through CMEprograms is essential for counselling and timely patient referral
  8. Accreditation of centres performing FP procedures to ensure quality
  9. Training of RM specialists, embryologists and psychologists/social workers.



  Disclaimer Top


The Fertility Preservation Society (India) in collaboration with RM experts and oncologists from different cancer hospitals in India developed the evidence-based recommendations to improve the quality of healthcare, health outcomes and quality of life in patients with cancer, who are undergoing either gonadotoxic chemo or radiotherapy. The recommendations represents the integration of the best evidence available at the time of preparation, multidisciplinary, international clinical perspectives and patient preferences. In the absence of fertility preservation directives in India, these recommendations are prepared in an attempt to create awareness among both fertility experts and those providing care for cancer patients.

The aim of an evidenced-based recommedation is to aid healthcare professionals and consumers in decisions about appropriate and effective care, although recommedation are generalised, and application requires consideration of individual patient characteristics and preferences. All recommendations and practice points need to be considered in the context of regional regulations.

Adherence to the recommendations do not guarantee a successful or specific outcome in an individual or override the healthcare professional’s clinical judgment or patient preference in management of cancer patients and the fertility preservation services provided by the fertility experts. Ultimately, healthcare professionals must make their own clinical decisions on a case-by-case basis, using their clinical judgment, knowledge, and expertise, and taking into account the condition, circumstances, and perspectives of the individual patient, in consultation with the patient and/or the guardian.

The Fertility Preservation Society (India) is not liable for direct, indirect, special, incidental, or consequential damages related to the use of the information contained herein. Recommendations do not necessarily represent the views of all the members of the fertility preservation society, reproductive medicine experts and oncologist from different fraternity of practice. The information provided in this document does not constitute business, medical or other professional advice, and is subject to change.


  Summary of Recommendations Top





  Introduction Top


Innovative oncology treatments and better drugs have given a fresh lease of life to cancer patients, increasing the number of young cancer survivors. Statistics have shown that one in 1000 adults is a survivor of childhood cancer. Unfortunately, many of these young men and women face an unfulfilled life due to the gonadotoxicity of cancer therapy. Fertility preservation has become an integral part of onco-care in recent times and empowers cancer survivors to take charge of their reproduction.

Chemotherapy can result in varying degrees of damage to gametes resulting in oligospermia or azoospermia in males and premature ovarian insufficiency (POI), infertility or complete amenorrhoea in females. Direct radiotherapy additionally affects the reproductive organs. The degree of gonadotoxicity by CT or RT is dependent on the type of drug, dose and duration of treatment and female age.

Fertility preservation techniques in males include cryopreservation of semen and testicular tissue while in females, oocytes, embryos and ovarian tissue is cryopreserved. The technique used, depend on the pubertal status of patient and time available for the FP procedure prior to start of cancer treatment. and method used depends on the age, type and dose of adjuvant therapy, time available before chemotherapy/radiotherapy and the length of delay to childbearing post chemotherapy/radiotherapy. Pregnancy is usually recommended only 2 years after the last chemo or radiotherapy dose.

The field of oncofertility is in its nascent stages in India, this document attempts to bring about uniformity and evidence based practice across the country. It also documents the desire for FP across all socio-economic, ethnic and religious groups.


  Full Text Top



  Context and Background Top


There is heterogeneity in cancer incidence across India with higher prevalence in urban areas (annual percent change, 3.8%; P < .05).[1] The number of patients with cancer in India for the current year (2020) is 1,392,179 and the 5 leading cancers are breast, lung, mouth, cervix uteri, and tongue.[1]

Fertility preservation (FP) refers to the extension of the reproductive window through preservation of gametes and gonadal tissue (oocyte, sperm, embryo, ovarian and testicular tissue). Contemporary advances in assisted reproductive technology allow for safe long-term storage of gametes, permitting their use to achieve pregnancy at a later more convenient time. Initially used in oncofertility, use of FP has now been extended to women at risk of infertility due to decreasing ovarian reserve associated with age, medical disorders or genetic conditions [Table 1].
Table 1: Indications for fertility preservation

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The need and importance of FP and oncofertility is underscored by the knowledge of a rising cancer incidence in the young [Figure 1] and [Figure 2], the damaging effect of cancer treatments on gametes, increasing number of cancer survivors and their desire to live a fulfilled life, which includes having their biological offspring. The global upsurge in cancer has been attributed to rapid industrialization, urbanization, change in lifestyle and an increase in life expectancy. GLOBOCAN reports estimated 18.1 million new cancer cases in 2018, in India over 1.1 million new cancer patients were registered in the same year.[2] The highest incidence of adult cancer in India is seen in the North -Eastern region and the lowest in the rural region.[3] The commonest cancers encountered in India are Breast, Cervical, Ovary and Uterine cancers in females. Understandably, their treatment leads to damaging effects on reproduction. In males, the commonest cancers are lung followed by prostate, rectum and colon. The most frequent malignancies encountered in childhood (0-14years) are leukaemia and lymphomas. Interestingly, in contrast to adult cancers, incidence of childhood cancers is highest in Delhi and lowest in the North-East district of Meghalaya (NCR (NCDIR) 2016).[4] Since approximately 65% of the Indian population is under 35 years it is not surprising that there is an increase in the number of cancer patients diagnosed in their reproductive years. A trend in delaying childbirth has increased the number of women faced with a cancer diagnosis before they have completed their families. Median age of breast cancer diagnosis in Indian studies is a decade younger than their western counterparts. The incidence of Hereditary Breast and Ovarian Cancer (HBOC) syndrome associated with an inherently low ovarian reserve and Triple negative breast cancer is also higher than the West.[5],[6]
Figure 1: Female cancer 5 year trends in India (NCR)

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Figure 2: Male cancer 5 years trends in India (NCR)

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Intensive research in the area of cancer aetiology and pharmacogenetics has led to better-quality management resulting in vastly improved survival rates. Early detection through enhanced cancer screening programs has also contributed to this increase. Survival rates in early stage childhood lymphomas and leukaemia’s is almost 90%. Successful oncological treatments are however associated with a physical, emotional/psychological and social burden. Attention has been paid to alleviate the impact of cancer therapy on physical appearance; however, the damaging effect on reproductive ability though recognised, is rarely addressed as the treatment is geared towards survival.

Current data on pregnancy in cancer survivors suggests no increase in the risk of cancer progression with a good obstetric and neonatal outcome of pregnancy. This has created a pressing need for FP especially if the aim of cancer treatment is to provide survivors with a better quality of life. In Asian cultures this assumes even more importance as childlessness often leads to social ostracizing and abandonment. Fertility preservation is fast becoming the ‘standard of care’ for cancer survivors and non-cancer patients at risk of decreased fertility, intensifying the need for a document to provide guidance to health care professionals on FP for Indian patients given our racial, ethnic and cultural diversity.

Aim

Objective of this document is to provide guidance to health care professionals on fertility preservation for cancer patients in the Indian context.

Effect of age on fertility

The importance of a woman’s age lies in the fact the she has a finite number of oocytes which deplete with age. Thus the risk of developing permanent amenorrhea after CT increases in older women.[7] Women over 35 years also have an increased rate of aneuploid oocytes.

Effect of cancer and cancer therapy on fertility

Chemotherapy (CT) Chemotherapeutic drugs act by interrupting vital cell processes and arresting normal cellular proliferation cycle. Unfortunately, this action is not limited to cancer cells alone and can be quite disastrous to the metabolically active gonadal cells.[8] Cytotoxic agents produce DNA abnormalities and oxidative damage in the somatic as well as germ cells, leading to apoptosis. [Figure 3] illustrates the cytotoxic agents according to their gonadotoxicity.
Figure 3: Cytotoxic agents according to degree of toxicity. *Bevacizumab (VEGF inhibitor) ovarian failure reported in 34% of women receiving a bevacizumab- containing regimen.[9]

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In women

  1. Ovarian effects -chemotherapeutic drugs act on the ovary causing damage to the oocyte-granulosa cell complex, stroma, and blood vessels. This leads to apoptosis of the growing follicles and activation of the dormant follicles with subsequent apoptosis, resulting in a reduction of the ovarian reserve (OR).[10] The clinical manifestations range from complete amenorrhoea to premature menopause and varying degree of infertility, depending on the extent of follicular damage.[11],[12],[13] Type and dose of cytotoxic drug, age and OR of the woman at the time of cancer diagnosis, are important determining factors for the associated complications. The pre-pubertal ovary is less susceptible to damage by chemotherapeutic agents while older women have a lower ovarian reserve and hence, are more susceptible to premature ovarian failure (POF).[11],[14] Gonadotoxicity is highest with alkylating agents such as cyclophosphamide, a drug commonly used in the treatment of BC. Alkylating agents are responsible for the highest age-adjusted odds ratio (OR) of ovarian failure followed by other drug families.[15] Endocrine therapies (tamoxifen, aromatase inhibitors, and gonadotropin (GT)-releasing hormone analogues [GnRH-a]) are not gonadotoxic. Tamoxifen needs prolonged duration of administration, a woman is well past her reproductive prime by the time the treatment is completed [Figure 4]
  2. Effect on oocytes: Persistent unrepaired DNA double-strand breaks (DSB) activate apoptotic processes in the oocytes.[16] Most cytotoxic drugs have a mutagenic and teratogenic effect on oocytes exposed during maturation as seen in animal studies. This risk is maximum during oocyte maturation phase and minimum during the dormant phase. In humans, the maturation phase lasts approximately 6 months.[17] It is therefore recommended that conception should be delayed for 6 months after completing gonadotoxic treatments. No significant increase in miscarriage, congenital malformations, genetic abnormalities, or malignant neoplasms have been found when conception has taken place long after completion of therapy.[17],[18] FP techniques like oocyte and embryo cryopreservation are best carried out prior to CT however if a delay is unavoidable, then a wait of 6 months after treatment is mandatory. FP should not be performed between treatment cycles.[19] The exact safe interval from completion of treatment to oocyte collection for preservation has not been established.
Figure 4: Effect of radiotherapy and chemotherapy on female fertility

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In men

CT leads to Leydig cell dysfunction, germ cell failure, sexual and ejaculatory dysfunction. The germinal epithelium is more sensitive than the Leydig cells as a result of its high mitotic rate. Direct toxic effects of CT on spermatogonial stem cells (SSC’s) leads to gonadal dysfunction while later stage germ cells exhibit more resistance to damage. Alkylating agents can cause basal membrane thickening, interstitial fibrosis and germinal epithelium aplasia leading to azoospermia and high FSH in post-pubertal males. Testicular damage is based on drug type and dose. The pre-pubertal testes is also sensitive to CT even though it does not produce mature spermatozoa and CT in these boys can cause impaired fertility[20] [Figure 5]. Spermatogenesis has been shown to be impaired in patients with a variety of malignant diseases before gonadotoxic treatment.[21]
Figure 5: Effect of radiotherapy and chemotherapy on male fertility

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  Radiotherapy Top


  1. Women: The effects of radiotherapy are seen not only on the ovary but the uterus as well[8] [Figure 4]


    1. Ovarian effects: The human oocyte is highly sensitive to radiation, with an estimated median lethal dose (LD50) of <2 gray (Gy). The ‘fertility window’ is determined by the dose of radiation to the ovaries, the number of existing primordial follicles or ovarian reserve and age of the patient at the time of treatment. The dose of fractionated radiotherapy [Gy] at which premature ovarian failure occurs immediately after treatment in 97.5% of patients is termed the effective sterilizing dose (ESD). ESD decreases with increasing age, with only 6 Gy being required to cause permanent ovarian failure in women over 40. Ovarian failure has been reported in 90% of patients following TBI (10-15.75 Gy) and in 97% of females treated with total abdominal irradiation (20-30 Gy) during childhood.[22] It is best recommended to wait for one year after RT to start collecting oocytes for pregnancy purposes
    2. Uterine effect: RT causes reduced vascularity, fibrosis and hormone dependent endometrial insufficiency which eventually lead to infertility and adverse obstetric outcomes An increase in miscarriage, pre-term labour, intra-uterine growth retardation and low birth weight is seen especially if conception has occurred within a year of radiotherapy.[23],[24] Uterine growth starts at puberty and is completed almost 7 years after menarche i.e. around the age of twenty.[25] Radiation exposure to uterus at this critical juncture can lead to reduction in uterine size. Direct radiation reduces uterine volume and causes complete endometrial atrophy. Total body irradiation (TBI) of 12 Gy in adults is associated with significant uterine damage. Radiation doses of >25 Gy directly to the uterus in childhood appears to induce irreversible damage.[26] Increased perinatal mortality has been reported by Chiarelli et al 1999,[27] though they did not find any increase in spontaneous abortions or birth defects. There is no clarity on the dose of radiation to the uterus above which a pregnancy would not be sustainable. In colorectal cancers radiation damage to the gonads and uterus is inevitable and hence ovarian transposition and FP techniques should be strongly advised
    3. Irradiation of the vagina can result in sexual dysfunction and is due to loss of lubrication, anatomic impairment, and in some cases vaginal stenosis.


  2. Men: Type A spermatogonia are classified in the group of the most radiation- sensitive cells as they have a high mitotic rate. On the other hand Leydig cells are more radio-resistant. Transient sterility can be induced after external irradiation by a dose as low as 0.150 Gy to the testis[28] and permanent sterility is to be expected after a dose of 20Gy in fractionated doses.[29],[30] Radiation scatter from RT to pelvic organs can have an effect on testes and repeated irradiation has a cumulative effect. Testosterone production is lowered when Leydig cells are affected. High dose RT of pelvis can lead to erectile dysfunction by affecting the pelvic vessels [Figure 5].


Cranial irradiation for the treatment of brain tumours may induce infertility in both female and male patients by disruption of the hypothalamic-pituitary-gonadal axis and disturbance of gonadotropin secretion. Cranial irradiation in childhood can result in precocious puberty due to cortical disruption and loss of inhibition by the hypothalamus.

Effects of radioactive iodine

  1. Women - RAI is used in differentiated thyroid cancer (DTC). Though spontaneous conception rates after treatment of DTC are good recent studies indicate a rapid and profound effect on ovarian reserve, with only a partial recovery potential. With increasing age at first pregnancy this may have a bearing for FP[31]
  2. Men: The dose of I131 used in treatment of thyroid cancer causes discernible and dose- related germinal epithelium impairment leading to increase in FSH. These effects are transient and reverse within a year generally. Radiation dose to testis resulting from RAI treatment for hyperthyroidism may also cause small and transient damage, both to the germinal epithelium and Leydig cells[28]
  3. RAI & Pregnancy: The preliminary finding of an increased number of miscarriages in pregnancies, starting within 1 year after treatment with high I131 dose was not confirmed when larger numbers were taken into account. There have been sporadic observations of malformations in children born within a year of treatment. No teratogenic effect on offspring is reported in males so far.[32]



  References Top


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  2. Sahoo SS, Verma M, Parija PP. An overview of cancer registration in India: Present status and future challenges. Oncol J India 2018;2:86-9.
  3. Mohan S, Asthana S, Labani S, Popli G. Cancer trends in India: A review of population-based cancer registries (2005-2014). Indian J Public Health 2018;62:221-3.
  4. National Cancer Registry Program ICMR. Available from: https://www.ncdirindia.org/ncrp/.
  5. Singh J, Thota N, Singh S, Padhi S, Mohan P, Deshwal S, et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: Prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat 2018;170:189-96.
  6. Thakur KK, Bordoloi D, Kunnumakkara AB. Alarming burden of triple-negative breast cancer in India. Clin Breast Cancer 2018;18:e393-e399.
  7. Anderson RA, Wallace WH. Anti-Mu?llerian hormone, the assessment of the ovarian reserve, and the reproductive outcome of the young patient with cancer. Fertil Steril 2013;99:1469-75.
  8. Meirow D, Biederman H, Anderson RA, Wallace WH. Toxicity of chemotherapy and radiation on female reproduction. Clin Obstet Gynecol 2010;53:727-39.
  9. Loren AW, Mangu PB, Beck LN, Brennan L, Magdalinski AJ, Partridge AH, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013;31:2500-10.
  10. Roness H, Kalich-Philosoph L, Meirow D. Prevention of chemotherapy-induced ovarian damage: Possible roles for hormonal and non-hormonal attenuating agents. Hum Reprod Update 2014;20:759-74.
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  16. Di Giacomo M, Barchi M, Baudat F, Edelmann W, Keeney S, Jasin M. Distinct DNA – damage – dependant and independent responses drive the loss of oocytes in recombinant defective mouse mutants. Proc Natl Acad Sci U S A 2005;102:737-42.
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  19. Chung K, Donnez J, Ginsburg E, Meirow D. Emergency IVF versus ovarian tissue cryopreservation: Decision making in fertility preservation for female cancer patients. Fertil Steril 2013;99:1534-42.
  20. Vassilakopoulou M, Boostandoost E, Papaxoinis G, de La Motte Rouge T, Khayat D, Psyrri A. Anticancer treatment and fertility: Effect of therapeutic modalities on reproductive system and functions. Crit Rev Oncol Hematol 2016;97:328-34.
  21. Hallak J, Mahran AM, Agarwal A. Characteristics of cryopreserved semen from men with lymphoma. J Assist Reprod Genet 2000;17:591-4.
  22. Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005;62:738-44.
  23. Reulen RC, Zeegers MP, Wallace WH, Frobisher C, Taylor AJ, Lancashire ER, et al. Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 2009;18:2239-47.
  24. Fenig E, Mishaeli M, Kalish Y, Lishner M. Pregnancy and radiation. Cancer Treat Rev 2001;27:1-7.
  25. Holm K, Laursen EM, Brocks V, Müller J. Pubertal maturation of the internal genitalia: An ultrasound evaluation of 166 healthy girls. Ultrasound Obstet Gynecol 1995;6:175-81.
  26. Larsen EC, Schmiegelow K, Rechnitzer C, Loft A, Müller J, Andersen AN. Radiotherapy at a young age reduces uterine volume of childhood cancer survivors. Acta Obstet Gynecol Scand 2004;83:96-102.
  27. Chiarelli AM, Marrett LD, Darlington G. Early menopause and infertility in females after treatment for childhood cancer diagnosed in 1964-1988 in Ontario, Canada. Am J Epidemiol 1999;150:245-54.
  28. Ceccarelli C, Canale D, Vitti P. Radioactive iodine (131I) effects on male fertility. Curr Opin Urol 2008;18:598-601.
  29. Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Horwich A, et al. Guidelines on testicular cancer. Eur Urol 2005;48:885-94.
  30. Petersen PM, Giwercman A, Daugaard G, Rørth M, Petersen JH, Skakkeaek NE, et al. Effect of graded testicular doses of radiotherapy in patients treated for carcinoma-in-situ in the testis. J Clin Oncol 2002;20:1537-43.
  31. Yaish I, Azem F, Gutfeld O, Silman Z, Serebro M, Sharon O, et al. A single radioactive iodine treatment has a deleterious effect on ovarian reserve in women with thyroid cancer: Results of a prospective pilot study. Thyroid 2018;28:522-7.
  32. Sioka C, Fotopoulos A. Effects of I-131 therapy on gonads and pregnancy outcome in patients with thyroid cancer. Fertil Steril 2011;95:1552-9.



  1. General Information Top


Abstract

The desire to procreate is universal and progeny are very important in Indian culture. The overall consensus amongst oncologists is that Indian patients who are informed about fertility risks of cancer treatment are interested in FP and such discussions are a medico-legal necessity. Lack of awareness, availability and efficacy of FP procedures precludes discussions. Financial considerations too lead to the inability to take up the service. Counseling, initially by the oncologist and subsequently by the reproductive medicine specialist and genetic counselor if needed, are imperative prior to FP. Psycho-social counselors need to be involved in decision making to offer an unbiased environment for discussion. Details of the FP procedure including risks, benefits and cost should be explained and a detailed consent including consent for posthumous use of gametes, needs to be in place. Pubertal children and young adolescents should be involved in the discussion either individually or together with their parents. For pre-pubertal children counseling of parents is required.


  Full Text Top


1.1: Are Indian patients with cancer interested in interventions to preserve fertility?


  Summary of Evidence Top


When cancer is diagnosed patients are overwhelmed by the diagnosis and fertility concerns are farthest from their mind.[1] They are focussed on treatment of cancer rather than fertility issues. However once the shock starts wearing off they may want to discuss fertility.[2] Patients are concerned that if they pursue fertility preservation (FP), cancer treatment would be delayed which may lead to an increase in morbidity and mortality. In many instances the onco -physician finds it difficult to explain problems related to fertility and sexuality, either due to lack of time or personal discomfort. Many patients too are not aware that cancer treatment can affect their fertility. However, there has been recent evidence to suggests that many patients do discuss about fertility and fertility preservation.[4] A web based survey has shown that about 29% of the women with breast cancer had concerns about infertility and desired FP.[5]

Indian context

Oncologists are of the opinion that rural patients presented with more advanced stage cancers; however, most of them have early marriages and have completed their family and hence discussion on fertility preservation is often not required. In the urban setting, some patients are keen for fertility preservation, whereas others are more concerned about the treatment of cancer. Educated patients are more aware of effects of cancer treatment on fertility and of FP. Since progeny are very important in Indian culture even people from rural setting voice concerns about fertility. The overall consensus is that Indian patients who are informed about fertility risks of cancer treatment are interested in FP. Financial consideration is an important reason for not going ahead with procedure especially in women.

Recommendations



1.2: Should oncologists discuss the effects of cancer treatment on fertility with all cancer patients of reproductive age? What would be an appropriate time to address this question and refer the patient for FP?


  Summary of Evidence Top


Since treatment of cancer may lead to temporary or permanent impairment of fertility the onus is on the oncologist to provide this information to the patient since he/she is the first point of contact. The information can be imparted once cancer diagnosis, prognosis and treatment plan is confirmed. It has been observed that most oncologists give secondary preference to fertility and most of the time risk to fertility is not discussed.[6],[7],[8] Personal biases and beliefs of oncologists are often the reason for this lack of discussion. Some of the reasons quoted are - financial burden, adding to a patient’s emotional burden (they are already coping with cancer diagnosis and treatment), or patient is not interested in fertility.[9] Apart from this, lack of knowledge on fertility preservation techniques and crunch of time for these treatments, may prevent the oncologist from discussing fertility issues after cancer treatment. At times, even when the fertility issue is discussed, the amount of information provided on different methods of FP are insufficient.[6],[10],[11]

It is important and medico-legally sound to discuss treatment-induced infertility with the patient or parents of children or adolescents at the earliest possible opportunity. The oncologist may not feel it practical to raise this issue at the first encounter or immediately when sharing the diagnosis with the patient. Correct time for discussing this issue should be determined by the oncologist and referral to the reproductive medicine experts should be done at the earliest possible opportunity as FP procedures in women require a minimum of two weeks. Early referral in men too, it allows an opportunity of collecting more than one semen sample or testicular tissue if necessary. Further management should be a team approach involving medical oncologist, reproductive endocrinologist, and a counsellor.[12]

Indian context

Indian oncologists are of the opinion that the issue of infertility and FP should be addressed with all patients of reproductive age. It should be done as soon as diagnosis is confirmed, which would essentially be at the second visit before starting treatment rather than the first visit, as patient needs time to cope with the emotional trauma of the cancer diagnosis. The consensus is that for the rural Indian population discussions are not taking place in most centres currently. Though the need is less (patients have generally completed their family) discussion should be held. Patients should be given the freedom to decide on FP after giving the necessary information on procedure and cost. In the urban centres, information on the effect of cancer treatment on fertility is being given and in some centres FP discussion and referral is being advocated. Often educated patients or their families initiate the discussion on FP. Given the current status of FP in all international oncology guidelines, oncologists in India too believe that it is mandatory and a medico-legal liability. Referral for fertility preservation should be based on the patient’s interest. The referral should be guided by written protocols and should follow the pattern as described in [Figure 1].
Figure 1: Fertility preservation referral

Click here to view


Patients would have several questions in mind about FP before cancer treatment. Their question on whether FP options decrease the chance of successful cancer treatment, increase the risk of maternal or perinatal complications, or compromise the health of off- spring need to be addressed. A leading concern is transmission of cancer to the offspring.

A complete evaluation is mandatory before the patient is offered for FP [Figure 2].
Figure 2: Patient evaluation before offering fertility preservation

Click here to view


Recommendations



1.3: Who should provide information on fertility preservation options?

Oncologist/counsellor/RM specialist


  Summary of Evidence Top


Oncologist should provide information about effect of cancer treatment on fertility and the different options available for FP. If the patient is interested in fertility preservation then he/she should be referred to reproductive specialists and counsellor for detailed information on procedure and counselling. Referral to the RM expert should be as early as possible, especially in the female patients because of time required for FP procedures. Subsequently, FP management is benefited by regular inputs from the oncologist. While referring the patient to a RM expert. the experience in working with cancer patients should also be considered. Psychological counselling is essential before fertility preservation since the patient invariably exhibits moderate to severe distress about potential infertility and the success of the procedure performed. A structured, cognitive-behavioural counselling can reduce anxiety and depression.[13],[14],[15]

Indian context

Only about 20-25% of the patients referred accept and undergo fertility preservation. Oncologists acknowledge that primary counselling to advise for FP is their responsibility since they can determine oncological risk and prognosis. Though involvement of trained counsellors is important, availability is limited and patient burden is high in India. Patients expressing a desire for future fertility should then be referred to the reproductive medicine specialist for further detailed counselling. Oncologists in India concur with the statement that patients interested in FP should be referred to the reproductive medicine expert immediately once the oncological plan has been made.

Recommendations



1.4: Should FP be discussed with parents of pre-pubertal children?

In adolescents diagnosed with cancer should discussion on fertility effects of cancer treatment and fertility preservation, be discussed with patient and family individually or together?


  Summary of Evidence Top


There is risk to fertility in children and adolescents exposed to radiation and chemotherapy, which makes it necessary to address FP.[16],[17],[18],[19],[20],[21] Impaired future fertility is difficult for children to understand but it has the potential to induce psychological trauma when they become adults. This issue therefore needs to be discussed with parents especially in the paediatric group. When it comes to teenagers their wish for joint or individual discussion needs to be taken into account. Most of the times parents are concerned about their child’s future fertility and are receptive to information. Several studies confirm that adult survivors of paediatric cancer wish they had been given more information and options about fertility. They are often uncertain about their current fertility status and/or feel regret about no longer having an option.[22],[23] Parent’s concern about cancer treatment and uncertainty about making a decision given the experimental nature of FP techniques, sometimes prevents them from taking an affirmative step. This may create a situation where the child blames them for his/her infertility once they wish to start a family.

Parents must be informed that currently there are no standard modalities available for FP in prepubertal children due to sexual immaturity, and all available approaches for children are experimental. Till date there have been no live births reported after re-implantation of testicular tissue.[24],[25] For girls who require a highly gonadotoxic treatment, ovarian tissue cryopreservation (OTC) is the only technique that can be offered. Transplantation of ovarian tissue collected in pre-pubertal age has resulted in a pregnancy and childbirth.[26] Matthews et al. reported first women a case of thalassemia to have a baby where ovarian tissue was frozen pre-pubertally at the age of 9 years and was used after 14 years successfully. Thus OTC can be used as a therapeutic options for rare genetic diseases like thalassemia and girls who suffer from childhood cancer.[27]

Data in children born as a result of OTC and transplantation suggest that pregnancies are uncomplicated in majority of cases. Pregnancies are carried to term, babies have a normal birth weight and seem to be healthy. Long-term follow-up is necessary however, this information will be obtained only in the years to come.[28]

Indian context

Oncologists feel that discussion about FP with parents of paediatric and adolescent children is necessary; however it is not being done currently, particularly when patients are from a rural background. Personal bias regarding their financial ability, understanding implications of fertility procedure, possibility of time management - since they live far from facilities providing treatment, are in part responsible for the lack of discussion. In the urban setup oncologists are more inclined to give information. It is their opinion that the discussion on FP should be individualized based on the child’s prognosis. Most patients especially those from rural and poorly educated strata of society ask the doctor to decide whether they should go ahead with FP. Since FP procedures for prepubertal children are experimental and there is poor availability in India, pediatrics oncologists feel that they are unable to promote them. They are of the opinion that such procedures should only be done in an institution, under a research protocol free of charge.

For the adolescent patient, some oncologists feel that the counselling should be done together with parents, but others feel it should be done with the patient first and addressed together subsequently. The final consensus is that adolescents are very sensitive and do not like to have a discussion on sex or reproduction in front of parents, so the approach should be driven by child’s personality and should be individualized accordingly.

Recommendations



1.5: What can health care providers do to educate patients on fertility after cancer treatment and FP?


  Summary of Evidence Top


Patients would have several queries in mind about FP before cancer treatment. Their question on whether FP options decrease the chance of successful cancer treatment, increase the risk of maternal or perinatal complications, or compromise the health of off- spring, need to be answered. The main concern is about transmission of cancer to the offspring. The patients and parents of minors, should be provided with realistic expectations about their cancer prognoses. They should be informed about the success rates of fertility preservation interventions, cost of these interventions and given the option of declining FP interventions. Consideration about future pregnancy after completion of cancer treatment should ideally be provided by a maternal-fetal medicine expert. Opinion of cardiologist and pulmonologist should be sought regarding any risk to heart or lungs consequent to CT/RT. Potential legal and ethical issues, such as ownership of embryos and reproductive tissue in the event of a patient’s death or divorce should also be discussed by both the reproductive specialist and counsellor.

Apart from verbal communication[29] brochures with information regarding effects of cancer on fertility, FP options and costs are found to be useful.[30] Communication should be age appropriate. An adequate model of care document ensures that all patients are sufficiently empowered to make fully informed FP decisions and receive adequate reproductive follow-up care after cancer treatment, together with access to fertility-related psychosocial support. The counselling offered by a psychologist at different points of treatment helps improve communication between doctor and patient[31] and patients to make decision regarding FP.[32] With a multidisciplinary approach involving the oncologist, RM expert and counsellor, patients experience less distress and decision regret, and feel more positive about the future fertility.[33],[34],[35] Gaps in knowledge regarding suitability of procedures, steps involved in carrying out FP procedures and their success rates exist amongst all healthcare personnel. This was seen more in the paediatric and adolescent group.[6],[36],[37],[38] Perceived success rates of FP procedures and experimental nature of some procedures contribute to the opinion amongst oncologists that it is not a viable option. Socio-economic status and education also matters when making a decision. FP in cancer patients is often under-implemented. There are several barriers that prevent implementation of FP practice.[39],[40]

Perceived barriers to FP include

▪ Lack of referral pathways and models of care for oncofertility services

▪ Lack of collaboration between cancer and fertility doctors to deliver services

▪ Lack of adequately trained staff to deliver these services

▪ Cost of FP procedures

▪ Lack of social support for decision making

▪ Patients’ perception of cancer as a terminal non-curable illness and the need for immediate treatment

▪ Institutional policy, processes and resources

▪ Lack of consensus about the best way to deliver information to patients.

Indian context

Most of the information is provided by a busy oncologist. Trained counsellors should be available and information brochures and visual aids should be developed to improve communication and understanding. In India family support is good and family is involved in decision making.

Recommendations



1.6: Should ovarian reserve testing be done routinely prior to initiation of CT?


  Summary of Evidence Top


Chemo- and radiotherapy are potentially gonadotoxic resulting in iatrogenic premature ovarian insufficiency (POI). This decline in ovarian reserve post cancer therapy reduces the chances of spontaneous pregnancy making it mandatary to offer FP options to all women desirous of fertility.[41]

As each patient has a different ovarian reserve depending on genetic and environmental factors, it is compulsory to assess pre-treatment ovarian reserve by evaluating antimullerian hormone (AMH) and antral follicle count (AFC).[42],[43] AMH is a more reliable marker of ovarian reserve as it has less inter and intra-cycle variability. However, it may not be as reliable in women under 25 years as AMH levels rise from birth to 25 years after which there is a decline. AMH levels decrease after chemotherapy due to direct damage to the granulosa cells of growing follicles making AMH a valid marker of gonadotoxicity.[44.45] Pre-chemotherapy AMH could be a predictive marker of long term post-chemotherapy loss of ovarian function. Serum AMH levels before chemotherapy may guide clinicians to facilitate reproductive planning and taking decision regarding adjuvant endocrine therapy.

Recommendations




  References Top


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  2. Fertility Preservation in Men Top


Abstract

The degree of damage to the gonads by CT is variable depending on type of drug, dose and duration of treatment. Since it is difficult to quantify this damage FP is offered to all males undergoing gonadotoxic therapy. Fertility preservation techniques in pubertal males are established and include semen and testicular cryopreservation. In case ejaculation is not possible vibrators or electro-ejaculation can be used to acquire the semen sample. In per-pubertal children testicular tissue is cryopreserved, it is still experimental as maturation of sperms in vitro and/or re-implantation of testicular tissue is still under research. Hormonal therapy is not recommended in males. Risk of genetic damage in sperm collected after initiation of chemotherapy should be explained. Fertility preserving surgery needs to be considered when dealing with cancer of reproductive organs and sperm banking must be done prior to such surgery.


  Full Text Top


2.1: What is the evidence supporting preservation in men?


  Summary of Evidence Top


Cancer treatment can result in infertility due to gonadotoxicity of chemotherapeutic agents. There could be permanent or transient azoospermia. The different FP options are depicted in [Figure 1]. Sperm cryopreservation is an effective and proven method of FP in males treated for cancer.[1],[2],[3],[4],[5],[6],[7],[8]
Figure 1: Fertility preservation options in males

Click here to view


Testicular tissue or spermatogonial cryopreservation is still experimental but is the only option in pre-pubertal boys. Gonadal protection through hormonal manipulation is ineffective in FP in males.

Indian context

Seminal cryopreservation is easy and feasible, therefore should be offered to all patients before gonadotoxic therapy. Data on testicular tissue cryopreservation is still insufficient but may be offered to prepubertal males as it is the only option.

Recommendations



2.2: What is the role of fertility sparing surgeries in the males?


  Summary of Evidence Top


Partial orchiectomy can be done in selected patients when the testicular mass is small and radical orchiectomy may result in anorchia.[9] The German Testicular Cancer Study Group reported a 98.6% disease-free survival rate at 7-year follow-up after conservative surgery for tumours <2 cm in 73 patients.[10] However, the benefits must be weighed against the risk of tumour recurrence in these patients. In men with azoospermia undergoing orchidectomy sperms can be extracted from the epididymis and vas deferens of the orchiectomy specimen. Sperm may also be recovered from the contralateral noncancerous testicle at the time of orchiectomy in patients with azoospermia.[11] These sperms retrieved can be cryopreserved to preserve fertility.[12],[13] Sperm banking prior to surgery, even in patients undergoing partial orchiectomy is advisable.

Oncologic surgery for prostate, bladder, or colon cancer may damage nerves and affect potency or ejaculation, thus careful dissection during these surgeries to prevent nerve damage is necessary.

Recommendations




  References Top


  • Hourvitz A, Goldschlag DE, Davis OK, Gosden LV, Palermo GD, Rosenwaks Z. Intracytoplasmic sperm injection (ICSI) using cryopreserved sperm from men with malignant neoplasm yields high pregnancy rates. Fertil Steril 2008:90:557-63.
  • Romerius P, Ståhl O, Moëll C, Relander T, Cavallin-Ståhl E, Gustafsson H, et al. Sperm DNA integrity in men treated for childhood cancer. Clin Cancer Res 2010;16:3843-50.
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  • Ping P, Zhu WB, Zhang XZ, Yao KS, Xu P, Huang YR, et al. Sperm banking for male reproductive preservation: A 6-year retrospective multi-centre study in China. Asian J Androl 2010;12:356-62.
  • Navarro Medina P, Barroso Deyne E, Castillo Suárez M, Blanco Diez A, Lozano M, Artiles Hernández JL, et al. An analysis of our experience in cryopreservation of semen from cancer patients. Actas Urol Esp 2010;34:101-5.
  • Sabanegh ES Jr., Ragheb AM. Male fertility after cancer. Urology 2009;73:225-31.
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  • Schrader M, Mu?ller M, Sofikitis N, Straub B, Krause H, Miller K. “Onco-tese”: Testicular sperm extraction in azoospermic cancer patients before chemotherapy-new guidelines? Urology 2003;61:421-5.
  • Baniel J, Sella A. Sperm extraction at orchiectomy for testis cancer. Fertil Steril 2001;75:260-2.
  • Choi BB, Goldstein M, Moomjy M, Palermo G, Rosenwaks Z, Schlegel PN. Births using sperm retrieved via immediate microdissection of a solitary testis with cancer. Fertil Steril 2005;84:1508.



  3. Fertility Preservation in Women Top


Abstract

Established FP techniques in the post-pubertal female include oocyte and embryo cryopreservation and ovarian tissue cryopreservation (OTC). Options need to be tailored based on the patient’s age, type and stage of cancer, proposed onco- treatment and time available for FP. Oocyte and embryo cryopreservation require ovarian stimulation with gonadotrophins and egg retrieval under general anesthesia. Embryo CP requires fertilization of the oocyte by sperm from the husband or partner. Twelve to fourteen 14 days are required to complete the process. Efficacy of the procedure depends on the number of oocytes retrieved. In estrogen sensitive tumors Letrozole is added to the OS protocol to keep estradiol levels low. Safety of COS in cancer patients has been established. In per-pubertal girls and when there is paucity of time in older women only OTC is possible. In vitro follicular growth and oocyte maturation is still considered investigational. Oophoropexy or ovarian transposition is used for ovarian protection in case of pelvic radiotherapy. GnRH agonist induced pituitary suppression is used for ovarian protection in breast cancer patients undergoing CT. The fertility protective effect of GnRH analog in hematological cancer is still debated. Fertility sparing surgery is performed in cancer of reproductive organs. Definitive surgery is planned once patient completes her family. In the Indian context, centralized services for OTC need to be planned as expertise is limited to few centers.


  Full Text Top


3.1: What are the fertility preservation options available for pre and post –pubertal females?


  Summary of Evidence Top


Challenges associated with (FP) in pre and post pubertal girls diagnosed with malignancy are of varied nature. However, the option of FP needs to be considered, discussed and offered based on the type of malignancy, its prognosis, estimated risk of infertility following treatment for cancer; and feasibility and availability of FP. The current evidence strongly supports discussion and referral to reproductive medicine (RM) specialist for FP at diagnosis. Patients and parents both strongly feel that the future fertility concerns should be actively addressed and discussed.[1] In children and girls affected with malignancies of good prognosis, future fertility is often compromised due to chemotherapy and or radiotherapy. Hence, the ideal time for FP would be prior to commencing any chemotherapy.[2],[3] While the nature of some malignancies such as leukaemia and lymphomas may not permit adequate time or suitable option for FP, it can be comfortably performed without major changes in the treatment plan for many other malignancies.

The available options for FP in women [Figure 1] are oocyte cryopreservation, embryo cryopreservation, and ovarian cortical tissue cryopreservation. The pros and cons of each procedure are enumerated in [Table 1]. In addition, in-vitro maturation of oocytes and ovarian suppression may be offered selectively.[4] Maturity of the hypothalamo-pituitary-ovarian axis determines whether which or all of the above options can be considered in a particular individual. Despite FP, it has to be understood that not all will need to use the cryopreserved gamete/embryo/tissue. With appropriate reproductive counselling, many with presence of ovarian function may conceive spontaneously.
Table 1: Benefits and risks of different fertility preservation techniques in female cancer patients

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Figure 1: Fertility preservation techniques in females

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The role of fertility sparing surgeries have been discussed under section 3.3.


  Fertility Preservation in Prepubertal Girls Top


Ovarian tissue cryopreservation

The only proven method of preserving future fertility in prepubertal girls is ovarian tissue cryopreservation (OTC). It does not impose any delay in the definitive treatment of malignancy and is done as a minimally invasive laparoscopic procedure. It can be performed easily if the clinical condition of the child permits a surgical procedure. Part or a whole ovary is excised and thin strips of the cortex devoid of stromal tissue are cryopreserved. Orthoptic or heterotopic transplantation is performed at a later date to restore fertility. Appropriate tests to rule out presence of malignant cells in the ovaries are necessary before re-implanting the tissue to restore fertility.[4],[5],[6] Orthoptic transplantation provides an opportunity for natural conception. The lifespan of these cortical strips is usually limited.

Pre-pubertal ovaries contain only immature follicles and their viability and subsequent restoration of fertility is still not well understood. Two livebirths have been reported so far following cryopreservation of ovaries in premenarchal and prepubertal girls followed by re-implantation of the tissue in adulthood.[7],[8] It is increasingly being offered as a method of FP in many countries. An important limitation at present is the limited duration of ovarian function following transplantation. The American Society for Reproductive Medicine (ASRM) recently announced in a committee opinion that ovarian tissue cryopreservation (OTC) is no longer considered experimental and can be used in prepubertal patients or when there is not enough time for ovarian stimulation. This is a major step for the field and provides young patients with more options to preserve their future fertility.[9]


  Fertility Preservation in Post-Pubertal Girls and Young Women Top


Increasing acceptance of FP, availability of vitrification as a method of proven efficacy for cryopreserving oocytes and embryos and availabilty of safe and flexible ovarian stimulation protocols all have made fertility preservation in young women feasible. Oocyte or embryo cryopreservation and increasingly OTC are the most commonly offered methods of FP in young women with malignancies.

Oocyte and embryo cryopreservation

Early referral to reproductive specialist and co-ordinated treatment planning between the oncologists and fertility specialists are necessary to avoid any undue delay in initiating chemotherapy and or radiotherapy.

Both oocyte and embryo cryopreservation necessitate ovarian stimulation and transvaginal oocyte collection and hence a period of approximately two weeks are needed for completion of treatment. If the primary treatment for malignancy is surgery, ovarian stimulation and oocyte retrieval are planned in the immediate subsequent period, avoiding any delay in initiation of chemotherapy. Both oocyte and embryo cryopreservation are done with, well established protocols and vitrification is the method of choice. Embryo cryopreservation can be offered for people in stable relationship whilst oocyte cryopreservation offers reproductive autonomy to the person undergoing FP. Cryopreserved oocytes need to be fertilized with sperms after thawing; transfer of resultant embryos has a similar success rate as to that seen in infertile couples going through IVF.[10]

Ovarian tissue cryopreservation

When the time available before initiating chemotherapy or radiotherapy does not permit ovarian stimulation, ovarian tissue cryopreservation (OTC) is the choice for FP as has been discussed above, provided there is no risk of presence of malignant cells within the tissue. OTC is performed either by slow freezing protocol or vitrification and slow freezing/rapid thawing method remains the procedure of choice.[11],[12],[13]

Indian context

Indian oncologists believe that OTC should be centralised, as many centres in India are not trained for the same. At present OTC is being done in those ART clinics where facility for the same is available. Performing of OTC requires meticulous training and practice and such programs are still under development within the country. Centralised services and establishing appropriate awareness and access to the IVF centres in the surrounding geographical area are important for successful OTC services.

Criteria for ovarian tissue banking in India is highlighted in [Figure 2].
Figure 2: Criteria for cryopreservation of ovarian tissue

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In vitro maturation of oocytes

Collection of immature oocytes from unstimulated ovarian follicles can be performed as an alternative to ovarian stimulation when very little time is available for FP. Immature oocytes are matured in-vitro and subsequently vitrified.[14] Immature oocyte can also be collected during OCT. However, its safety and efficacy remains to be evaluated.[15] Procedure is not universally available as it requires expertise.


  Fertility Protection Top


Ovarian shielding alone in prepubertal girls or in combination with lateral ovarian transposition prior to pelvic radiation in the management of lymphomas or cervical cancer has gonad protective effect, which is variable.[16] Use of GnRH agonist as a gonad protectant prior to chemotherapy continues to be evaluated and evidence of low quality from RCTs suggests a reduction of POI and an increase in the probability of spontaneous pregnancy.[17],[18] It should not be offered as a sole option for FP.


  Future Perspective Top


Use of recombinant AMH concomitantly with chemotherapy may slow down the follicle burn out and premature ovarian insufficiency and may become a feasible option in future.[19] In vitro growth of follicles, development of artificial gametes and artificial ovaries are being explored as futuristic options to overcome the negative impact of cancer therapy on ovarian function. However, none of these options are currently available for clinical use.

Recommendations

Recommendations are provided in the context of efficacy of procedure in FP



3.2: Effect of Controlled Ovarian Stimulation (COS) on cancer prognosis?


  Summary of Evidence Top


COS in women with malignancies has two important concerns – possible delay in initiation of cancer treatment and possible negative impact of COS on the prognosis of malignancy, in particular in hormone responsive tumours.[20] Most of the data in this regard is from women treated for breast cancer. Use of random start protocols, and GnRH agonist for ovulation trigger reduce the time needed for COS and the risk of OHSS respectively.[21] Exposure to high estrogen levels during COS is an important safety concern in patients with breast cancer. Incorporation of letrozole[22] or tamoxifen[23] into the stimulation protocol is protective. Letrozole keeps the serum estradiol levels relatively low, while Tamoxifen is a Selective Estrogen Receptor Modulator. The safety of such strategies for COH has been proven in a large prospective study.[24] Turan et al. reported the safety and feasibility of double stimulation with the use of letrozole to increase the oocyte/embryo yield for fertility preservation.[25] In those who conceive after any form of assisted reproductive techniques in the subsequent years, disease free survival and overall survival is found to be similar to those who conceive spontaneously.[26]

Recommendations



3.3: Fertility sparing surgeries in gynaecological malignancies

What is the role of fertility sparing surgeries/treatment in different gynaecological malignancies?


  Summary of Evidence Top


Fertility sparing surgeries have been considered as an alternative to radical surgery for various gynaecological malignancies when diagnosed in very early stage and conservation of fertility is desired. The common malignancies encountered in women of reproductive age are of cervix, endometrium or ovary. Decision for conservative surgery should take into consideration the age of the individual, ooncological safety, patients desire for fertility, ovarian reserve, any pre-existing infertility factor, subsequent ante-natal and obstetric risks and pre-existing medical conditions. Meticulous clinical, surgical radiological and histopathological evaluation is necessary while choosing such an option. Such women should be counselled regarding possible need for a definitive surgery as a deferred procedure following pregnancy and childbirth. Fertility sparing surgeries in gynecological malignancies are illustrated in [Figure 3].
Figure 2: Criteria for cryopreservation of ovarian tissue

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Cervical cancer

Abdominal/transvaginal radical trachelectomy or cervical conization with pelvic lymph node dissection or sentinel node sampling is considered as the fertility sparing surgery in Stage IA and IB cervical cancers. Survival and recurrence are similar to that seen with definitive management.[27],[28] Subsequent pregnancies have a higher incidence of obstetric complications including preterm birth.[29]

Endometrial cancer

Conservative management can be considered in young women of reproductive age with complex endometrial hyperplasia, and early endometrial carcinoma (Stage I and Grade I).[30] With increasing incidence of diabetes and polycystic ovarian syndrome (PCOS), endometrial carcinoma is not uncommonly diagnosed in young women. Majority (73-81%) of patients respond well to treatment. The recurrence rate with conservative management is 18%–40%, concurrent ovarian malignancy being seen in 11-29% patients.[31] A pregnancy rate (PR) of 40% and live birth rates up to 47% have been reported.[32] Because of the high rate of recurrence, close surveillance with endometrial biopsy every 3 months and MRI is mandatory.

Amongst the progesterone agents daily oral medroxyprogesterone acetate (MPA) and megestrol acetate are preferred though levonorgestrel- releasing intrauterine system (LNG-IUS) is also being used. Currently, limited evidence exists regarding the role of LNG-IUS as an alternative to oral MPA or megestrol acetate. Performing IVF prior to commencing MPA and transferring frozen embryos following confirmation of resolution of the endometrial lesion is a practical approach to avoid indefinite delays in achieving pregnancy. Pooled LBR (52.57% vs 18.09% P=0.0399) of HR followed by progestogens are significantly higher than the LNG-IUS alone though there was no statistical difference in regression (98.06% vs 94.24%; P= 0.4098) and recurrence rates (4.79% vs 3.90% P=0.8561).[33] Following successful completion of family, definitive surgical treatment for endometrial cancer is advisable.[34]

Ovarian cancer

Unilateral epithelial carcinoma or germ cell tumour of the ovary when in early stage (Stage I, Grade I) and borderline ovarian tumours (BOT) can be effectively managed with conservative staging laparoscopic surgery or laparotomy, involving cystectomy or salpingooophorectomy.[35],[36]

The fertility sparing surgery offered is dependent on the stage of disease, histology, and preexisting ovarian reserve. Unilateral salingo-oopherectomy (USO) or cystectomy(C) with extensive staging is performed and patient is kept under surveillance. Rate of recurrence after cystectomy is as high as 25%, three times more than with oophorectomy. A more conservative approach bilateral cystectomy (BC) should be favoured for bilateral BOT, which are almost always serous, as no significant difference is seen in terms of recurrence rate when compared to USO with contralateral cystectomy (CC). Of the patients undergoing C, BC, USO and USO+CC the pooled recurrence estimates were respectively 25.3%, 25.6%, 12.5% and 26.1%.[37] The cumulative pregnancy rate was 55.7% with 45.4% for USO and 40.3.0% for C in this study.

Malignant ovarian tumors: Standard treatment for ovarian cancer is hysterectomy, BSO and pelvic and para-aortic lymphadenectomy with omentectomy and peritoneal biopsies. Non-epithelial malignant ovarian tumours, particularly germ-cell tumours, do well with fertility-sparing surgery. About 2.7% of patient’s epithelial ovarian cancers (EOC) are younger than 40 and present with stage I disease. FSS has also been tried for early stage epithelial ovarian malignancy. Prerequisites for conservative surgery include well-differentiated unilateral disease, with no sign of extra-ovarian metastasis. In a series of 572 women with stage (I) epithelial ovarian cancer no differences were seem in 5-year overall survival or disease-free survival between women who had undergone radical hysterectomy and those who had undergone fertility-sparing surgery.[38] A detailed discussion with the patients explaining the risk of recurrence is important and consent should be given with full understanding of this potential risk. Recurrence rate similar to radical surgery has been reported with satisfactory pregnancy rate. Even though IVF and oocyte or embryo cryopreservation prior to surgery has been attempted in bilateral tumours before definitive surgery or when chemotherapy becomes necessary following surgery, OTC should be avoided in ovarian carcinoma.

Other gynaecological malignancies

Vulvar and vaginal carcinomas are very rare and are treated usually with radiotherapy.  Fallopian tube More Details cancer should be treated similar to ovarian cancer.

Oophoropexy or transposition of ovaries protect the ovarian function to a variable extent from the effect of any pelvic radiation. This is most widely practised in the management of cervical cancer.

Most studies on ovarian transposition have been observational small and retrospective. Most of them were cases reports or case series. reports and most of the studies have been uncontrolled. A systematic review and meta-analysis which evaluated ovarian function after ovarian transposition found preservation of ovarian function in 50-90 %.[39] Whereas in another recent study the protection ranged from 20-100%.[40]

Indian context

Indian oncosurgeons agree that selectively fertility sparing surgeries should be offered after appropriate evaluation. In cervical cancer though radical trachelectomy can be done, practical experience with this modality is very limited at present in India. Though conservative treatment can be offered to women with stage 1, grade 1 endometrial cancer, most oncosurgeons in India prefer to proceed with definitive surgery. Those oncologists who offer conservative management prefer using megestrol acetate to MPA or LNG-IUS. For ovarian tumours conservative treatment is not offered by most oncosurgeons in India. In Germ cell tumours, FP may be offered by some if the patient is young.

Recommendations

Recommendations are for the role of fertility sparing surgeries:




  References Top


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  4. Fertility Preservation in Breast Cancer Top


Abstract

Chemotherapy for breast cancer reduces the ovarian reserve (OR) considerably, leading to a shortening of the reproductive window. Prolonged hormone therapy in estrogen sensitive cancers compounds the problem of low OR by virtue of advanced age. Fertility preservation is offered to all young BC patients who want to have a family after completion of treatment. Breast cancer patients who are The five-year-survival rate has increased considerably in breast cancer patients. The groups of breast cancer (BC) patients that need to be addressed include those with a recent diagnosis and would be subjected to chemotherapy, survivors with unmet reproductive needs and those in whom BC was diagnosed during pregnancy. Young women diagnosed with breast cancer during their reproductive life require cytotoxic chemotherapy and/or hormone therapy, which are responsible for decrease reproductive function, along with their age. Increasing number of patients have not completed childbearing when cancer is diagnosed which may be biologically aggressive disease and require treatment with adjuvant cytotoxic therapy which may impair gonadal function and threaten future fertility. BRCA mutation carriers who may have a lower ovarian reserve which is of concern during fertility preservation. Women with BRCA 1 are associated with low response to ovarian stimulation requiring higher doses of GT and also higher than average risk of chemotherapy-induced menopause. Early referral for fertility preservation is essential to ensure success. BRCA mutation carriers who have already been diagnosed with cancer are more likely to present with triple-negative tumours, which generally have poorer prognosis than other breast cancers. Moreover, two third of patients under 40 years generally present with a hormone receptor positive tumour and will therefore receive a ten-year treatment regimen with tamoxifen/Letrozole with or without a GnRH agonist. Pregnancy in patients with breast cancer should be avoided for at least two years following diagnosis. In hormone positive breast cancer patients, women should be fully informed about the risk of stopping tamoxifen prematurely as the earlier the interruption, the higher the risk of relapse. Early referral for fertility preservation is essential to ensure success. Use of aromatase inhibitors (Ais) in controlled ovarian stimulation (COS) may reduces concerns of estrogen exposure in women with breast cancer attempting FP via embryo or oocyte cryopreservation. Ovarian tissue cryopreservation can be used when there is insufficient time for COS. GnRH agonist is advised for ovarian protection. Pregnancy appears to be safe for breast cancer survivors and should be allowed keeping in mind the time period for risk of relapse., Sbut studies specific for women with BRCA mutations are lacking. Women with BRCA mutations should elect to use PGT - M during in- vitro fertilization (IVF) to avoid transmitting the mutation. Women with BRCA mutations should elect to use PGT - M during in- vitro fertilization (IVF) to avoid transmitting the mutation.


  Full Text Top



  BREAST Cancer (BA) Top


Cancer therapy leads to a signicant reduction in the reproductive lifespan of a woman; hence, there is a consensus on advising FP to young BC patients desirous of pregnancy after treatment.

Incidence

Breast cancer is the most common cancer amongst urban Indian women and the second most common in the rural population. The age adjusted rate (AAR) is 25.8 per 100,000 women with a mortality rate of 12.7 per 100,000 women. Delhi has the highest age adjusted incidence rate 41 per 100,000 women, followed by Chennai (37.9), Bangalore (34.4) and Thiruvananthapuram District (33.7) (NCDIR).[1] From 1982 to 2005 the incidence of breast cancer in metropolitan cities almost doubled.[2] An increase of 1.42% - 2.84% in the AAR was recorded from 1982 to 2014 in all the population based cancer registries (PBCRs). In terms of mortality to incidence rural registries reported a much higher ratio than urban registries (66 and 8 respectively).[3] BC occurs at a younger age in Indian women, atleast a decade earlier than in western women.[4]

Risk factors

Risk of BC in India has significant association with age at marriage, age at first childbirth, number of children, age at menarche, tobacco chewing, lifestyle, alcohol, smoking, deprivation status, obesity, family history, environmental compounds and genetic predisposition. The frequency of BRCA1/2 genetic mutations range from 2.9% to 24.0% among Indian familial breast cancer patients and 2.8% of early-onset breast cancer patients were found to have BRCA1/2 mutations.

Breast cancer can be either hormone (estrogen and progesterone) receptor positive or negative (HR+ve, HR –ve), Triple receptor negative (TNBC) and HER2/neu-positive. Younger women tend to have a higher incidence of triple receptor-negative (TN), HER2/neu-positive, poorly differentiated, aggressive breast tumors.[5] TNBC is highly prevalent among Indian women and occurs in about 20-43% of all patients with breast cancer. BRCA mutations are also increased and incidence of BRCA1 mutations is higher.[6],[7]

Treatment includes surgery, adjuvant systemic endocrine or CT, RT and tumor-reducing neoadjuvant therapy before surgery, when indicated. CT with gonadotoxic alkylating agents and anthracyclines or taxanes forms the standard of care. HR+ve tumors are managed with prolonged hormonal treatment for up to 10 years to reduce the risk of recurrence and improve survival rates.[8]

[Figure 1] gives the different treatment protocols and the options avaliable for fertility preservation in women with breast cancer.
Figure 1: Chemotherapy and fertility preservation options in breast cancer. BC: Breast cancer, ET: Endocrine therapy, OR: Ovarian reserve, CT: Chemotherapy, HR+: Hormone receptor positive, IVM: In vitro maturation, AMH: Anti-Mullerian hormone, eIVFG: Encapsulated in vitro follicular growth, F/B: Followed by, PGD: Preimplantation Genetic Diagnosis

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Chemotherapy induced amenorrhoea (CIA): Chemotherapy induced amenorrhea with CT regimens has been used as a marker of gonadotoxicity however resumption of menses is not an index of fertility. A systemic review and meta-analysis of 75 studies, revealed a pooled rate of 55% (95% confidence interval [CI]: 50%–60%). CIA increased with age being 26% (95% CI: 12%–43%) for women <35, 39% (95% CI: 31%–58%) for women 35–40, and 77% (95% CI: 71%–83%) in women over 40 years. Age over 40 years and use of tamoxifen were significant risk factors (strong evidence) while taxanes were not associated with a higher risk, but the level of evidence was weak. Inconclusive evidence existed for other potential risk factors such as trastuzumab, dose-dense therapy, duration of CT, smoking, educational level, and nulliparity.[9] Evaluation of the effect of the newer targeted therapies on CIA is currently not available in literature. The [Table 1] below gives the incidence of CIA in breast cancer patients.
Table 1: The rate of chemotherapy-induced amenorrhea in breast cancer patients

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Need for fertility preservation in breast cancer

FP is highly advocated for BC because the chemotherapeutic drugs used are highly gonadotoxic leading to a significant decrease in OR and shortening of the reproductive window. Endocrine therapy does not damage the follicles but is given for 10 years, and advanced age leads to a biological decrease in ovarian reserve.

The preferred methods of FP are oocyte and embryo freezing as there is sufficient time between surgery and CT to stimulate the ovaries for egg collection. Oocyte freezing is advocated as it gives reproductive autonomy to the woman.

4.1: Routine use of GnRH analogue along with chemotherapy in young BC patients desiring children?


  Summary of Evidence Top


Gonadotrophic releasing hormone agonist (GnRH-a) is used for protection of the ovary from gonadotoxicity of CT. The mechanism of action is thought to be through pituitary downregulation which in turn suppresses gonadotropin secretion putting the ovary in a prepubertal state.[11] Decreased blood flow to the ovaries and a direct action on the ovary have also been suggested as GnRH receptors are found on preovulatory follicles and corpus luteum.[5] Upregulation of anti-apoptotic molecules such as sphingosine-1-phosphate (S1P) in the ovary[12] and prevention of gonadotoxicity on oogonial stem cells[13] have also been suggested. The initial flare-up effect of the drug necessitates its administration at least 7–10 days prior to CT and it needs to be continued till 2 weeks after completion of therapy. Use of GnRH analogue decreases the rate of premature menopause (estimated by return of menses) in breast cancer patients, though its effect on fertility protection is controversial.[14],[15],[16] This protective effect has however not been demonstrated in patients with lymphoma or ovarian cancer.[17],[18] The protection of ovarian function in the young may provide a small window to consider FP with pooling of oocytes/embryos, if required.

Can we avoid fertility preservation using gonadotropin-releasing hormone analogue protection? Not enough data to support its use as an alternative to conventional methods of FP.[19]

Safety of gonadotropin-releasing hormone analogue co-administration Concerns have been raised regarding the return of ovarian function, especially in HR+ve BC patients. However the PROMISE trial which included 81% HR+ve patients reported no differences in 5-year DFS rates between CT alone arm versus CT plus GnRH-a (P = 0.519). The ASCO guidelines recommends suppression of ovarian function in HR+ve patients who resume menses.[20]

Recommendations on the use of gonadotropin-releasing hormone analogues in breast cancer. The National Comprehensive Cancer Network guidelines, the 2nd International Consensus Guidelines for Breast Cancer in Young Women, and the Italian Association of Medical Oncology, International Society of Fertility Preservation support the use of GnRH analogue in premenopausal breast cancer women who need to undergo chemotherapy.[21],[22],[23],[24] The ASCO guidelines 2013 state that there is insufficient evidence to recommend use.[20]

All Indian oncologists support the use of GnRH analogue to preserve fertility in 70% of pre-menopausal women.

Recommendations



4.2: Ovarian stimulation in Breast cancer patients – Is it different?


  Summary of Evidence Top


Ovarian stimulation

Protocol preferred is the GnRH antagonist protocol with gonadotrophin stimulation and GnRH agonist trigger as it reduces the risk of ovarian hyperstimulation syndrome. The use of letrozole in HR+ve BC with gonadotropins increases safety by keeping the estradiol levels low[25] though lower number of mature oocytes are recovered.[26] Tamoxifen has also been used to increase safety but number of studies are limited.[27] Random start protocol can be used when patient arrives late in the cycle, without compromising on oocyte numbers though the amount of gonadotrophin used and length of stimuation is increased.[28] Number of oocytes available in BC patients are similar to non-BC patients however women with BRCA mutations have a poorer response to OS.

When GnRHa is used instead of hCG for trigger, estradiol concentrations dropped significantly after the trigger than the HCG group (P=0.013) and the incidence of OHSS was also low. GnRHa trigger resulted in a higher number and percentage of mature oocytes and a higher number of cryopreserved embryos or oocytes compared with HCG.[29]

Safety of controlled ovarian stimulation

Rodgers et al. in a Swedish registry based study assessed the safety of hormonal stimulation in BC patients undergoing FP.[30] They concluded that it was safe to practice FP in young women with BC. Their study showed that women who received hormone stimulation did not have a higher relapse rate than unexposed controls adjusted for age and calendar period of diagnosis (incidence rate ratio [IRR], 0.59; 95% CI, 0.34–1.04). Results remained unchanged after adjustment for tumour size, ER status, affected lymph nodes, and CT treatment (IRR, 0.66; 95% CI, 0.37–1.17). A systematic review and meta-analysis reported no decline in relapse-free survival rates in women receiving letrozole with gonadotropins compared with women who did not undergo FP procedures (mean follow-up, 5.0 vs. 6.9 years; HR for recurrence, 0.77; 95% CI, 0.28–2.13).[30]

Recommendations



4. 3: Should all breast cancer patients have testing for BRCA gene mutation and genetic counselling?


  Summary of Evidence Top


BRCA1 mutation carriers are at a 50%–80% lifetime risk of BC and 40%–60% risk of ovarian cancer. Women with BRCA2 mutations also have a high risk of BC but lower risk of ovarian cancer (10%–20%). Fertility issues are extremely relevant in these young women as they may require cancer treatment at a young age or may be advised prophylactic bilateral salpingo-oophorectomy.[31] BRCA1/2 carriers have a higher risk of POI because their oocytes are more susceptible to CT-induced OR loss.[29] FP option of choice is oocyte freezing with preimplantation genetic diagnosis for mutation screening should be done before embryo transfer. Fertility drugs and IVF in BRCA carriers does not increase risk of intraepithelial ovarian cancer.[32],[33]

The patient must be made aware that the presence of a predisposing BRCA 1/2 mutation may impact clinical management and follow-up. Decision should be made whether family members also should be tested. The lifetime risk of ovarian cancer is 40-60% in BRCA 1 carriers as against 17-18% in BRCA2 and 1.4 % in general population.[34] There is also significant decline in ovarian reserve in BRCA1 mutation carriers >35 years of age.[35]

At the present time, the clinical utility and therapeutic implications of BRCA1/2 mutations in breast tumours are yet to be established and need further research.

Indian oncologists in the urban setting test for BRCA mutation in triple negative cancers and women less than 35 years. About 15 % of these patients are BRCA positive. In rural India usually patients are not tested for BRCA mutation.

Recommendations



4.4: Role OTC before chemotherapy in breast cancer?


  Summary of Evidence Top


Cryopreservation of ovarian tissue in BC can be considered if urgent neoadjuvant CT is required since it avoids delay of treatment. Collection of ovarian tissue and re-transplantation can be done laparoscopically. A live birth rate (LBR) of 30% has been reported.[36] Cryopreserved ovarian tissue can also be used for preservation of gonadal function. The success of OTC depends on the patient’s age, baseline OR, and expertize of the surgeon and scientist performing the procedure. In women with BRCA mutations, there are safety concerns because of increased risk of ovarian cancer.[31]

Recurrence

Recurrence for HR+ve cancer’s occurs within 5 years, but these cancers can recur even later. Women with TNBC have huge risk of recurrence within two to three years.

Indian contex

Oncologists feel that OTC may be a good option, when CT or RT has to be started immediately and there is no time for ovarian stimulation for oocyte or embyro freezing. Many patients decline OTC as it involves an operative procedure. If the patient has to undergo oncosurgery ovarian tissue can be collected at the same sitting.

Recommendations



4.5: Breast feeding in breast cancer survivors


  Summary of Evidence Top


Several studies have looked at feasibility of breast feeding and its impact on the prognosis of women with breast cancer. Clinicians need to counsel women who have been treated for breast cancer regarding future pregnancy and future breastfeeding.[37]

Indian oncologists are also of the opinion that breast feeding is not a contraindication in women breast cancer survivors.

Recommendations




  References Top


  • National Cancer Registry Program ICMR. Available from: https://www.ncdirindia.org/ncrp/.
  • Ali I, Wani WA, Saleem K. Cancer scenario in India with future perspectives. Cancer Ther 2011;8:56-70.
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  • Chopra I, Chopra A. Follow-up care for breast cancer survivors: Improving patient outcomes. Patient Relat Outcome Meas 2014;5:71-85.
  • de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): Survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 2014;15:1137-46.
  • Singh J, Thota N, Singh S, Padhi S, Mohan P, Deshwal S, et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: Prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat 2018;170:189-96.
  • Thakur KK, Bordoloi D, Kunnumakkara AB. Alarming burden of triple-negative breast cancer in India. Clin Breast Cancer 2018;18:e393-9.
  • Cardoso F, Harbeck N, Fallowfield L, Kyriakides S, Senkus E, ESMO Guidelines Working Group. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23 Suppl 7:vii11-9.
  • Zavos A, Valachis A. Risk of chemotherapy-induced amenorrhea in patients with breast cancer: A systematic review and meta-analysis. Acta Oncol 2016;55:664-70.
  • Mahajan N. Breast cancer and fertility: A review - Part 1. Onco Fertil J 2018;1:9.
  • Ataya K, Rao LV, Lawrence E, Kimmel R. Luteinizing hormone-releasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys. Biol Reprod 1995;52:365-72.
  • Roness H, Kalich-Philosoph L, Meirow D. Prevention of chemotherapy-induced ovarian damage: Possible roles for hormonal and non-hormonal attenuating agents. Hum Reprod Update 2014;20:759-74.
  • Blumenfeld Z, Evron A. Endocrine prevention of chemotherapy-induced ovarian failure. Curr Opin Obstet Gynecol 2016;28:223-9.
  • Blumenfeld Z, Zur H, Dann EJ. Gonadotropin-Releasing Hormone Agonist Cotreatment During Chemotherapy May Increase Pregnancy Rate in Survivors. Oncologist 2015;20:1283-9.
  • Lambertini M, Ceppi M, Poggio F, Peccatori FA, Azim HA Jr., Ugolini D, et al. Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: A meta-analysis of randomized studies. Ann Oncol 2015;26:2408-19.
  • Munhoz RR, Pereira AA, Sasse AD, Hoff PM, Traina TA, Hudis CA, et al. Gonadotropin-Releasing Hormone Agonists for Ovarian Function Preservation in Premenopausal Women Undergoing Chemotherapy for Early-Stage Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncol 2016;2:65-73.
  • Del Mastro L, Ceppi M, Poggio F, Bighin C, Peccatori F, Demeestere I, et al. Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: Systematic review and meta-analysis of randomized trials. Cancer Treat Rev 2014;40:675-83.
  • Demeestere I, Brice P, Peccatori FA, Kentos A, Dupuis J, Zachee P, et al. No Evidence for the Benefit of Gonadotropin-Releasing Hormone Agonist in Preserving Ovarian Function and Fertility in Lymphoma Survivors Treated With Chemotherapy: Final Long-Term Report of a Prospective Randomized Trial. J Clin Oncol 2016;34:2568-74.
  • Lambertini M, Falcone T, Unger JM, Phillips KA, Del Mastro L, Moore HC. Debated role of ovarian protection with gonadotro- pin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in women with cancer. J Clin Oncol 2017;35:804-5.
  • Loren AW, Mangu PB, Beck LN, Brennan L, Magdalinski AJ, Partridge AH, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013;31:2500-10.
  • Scherr D, Swindle PW, Scardino PT, National Comprehensive Cancer Network. National Comprehensive Cancer Network guidelines for the management of prostate cancer. Urology 2003;61:14-24.
  • Paluch-Shimon S, Pagani O, Partridge AH, Bar-Meir E, Fallowfield L, Fenlon D, et al. Second international consensus guidelines for breast cancer in young women (BCY2). Breast 2016;26:87-99.
  • Lambertini M, Cinquini M, Moschetti I, Peccatori FA, Anserini P, Valenzano Menada M, et al. Temporary ovarian suppression during chemotherapy to preserve ovarian function and fertility in breast cancer patients: A GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology. Eur J Cancer 2017;71:25-33.
  • Lambertini M, Del Mastro L, Pescio MC, Andersen CY, Azim HA Jr., Peccatori FA, et al. Cancer and fertility preservation: International recommendations from an expert meeting. BMC Med 2016;14:1.
  • Oktay K, Kim J, Bedoschi G, Turan V. Safety of letrozole-gonadotropin controlled ovarian stimulation protocol in women with breast cancer undergoing fertility preservation before or after tumor resection via embryo or oocyte cryopreservation: A prospective cohort study. Cancer Res 2015;75:abstract P5-15-02.
  • Revelli A, Porcu E, Levi Setti PE, Delle Piane L, Merlo DF, Anserini P. Is letrozole needed for controlled ovarian stimulation in patients with estrogen receptor-positive breast cancer? Gynecol Endocrinol 2013;29:993-6.
  • Meirow D, Raanani H, Maman E, Paluch-Shimon S, Shapira M, Cohen Y, et al. Tamoxifen co-administration during controlled ovarian hyperstimulation for in vitro fertilization in breast cancer patients increases the safety of fertility-preservation treatment strategies. Fertil Steril 2014;102:488-95.
  • Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: Random-start controlled ovarian stimulation. Fertil Steril 2013;100:1673-80.
  • Oktay K, Kim JY, Barad D, Babayev SN. Association of BRCA1 mutations with occult primary ovarian insufficiency: A possible explanation for the link between infertility and breast/ovarian cancer risks. J Clin Oncol 2010;28:240-4.
  • Rodgers RJ, Reid GD, Koch J, Deans R, Ledger WL, Friedlander M, et al. The safety and efficacy of controlled ovarian hyperstimulation for fertility preservation in women with early breast cancer: A systematic review. Hum Reprod 2017;32:1033-45.
  • Rodriguez-Wallberg KA, Oktay K. Fertility preservation and pregnancy in women with and without BRCA mutation-positive breast cancer. Oncologist 2012;17:1409-17.
  • Kotsopoulos J, Huzarski T, Gronwald J, Moller P, Lynch HT, Neuhausen SL, et al. Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: A case-control study. Breast Cancer Res Treat 2016;155:365-73.
  • Shapira M, Raanani H, Feldman B, Srebnik N, Dereck-Haim S, Manela D, et al. BRCA mutation carriers show normal ovarian response in in vitro fertilization cycles. Fertil Steril 2015;104:1162-7.
  • Herlihy NS. Caring for BRCA carriers: Strategies to promote health and preserve fertility. J Womens Health Gyn 2018;5:1-0.
  • Giordano S, Garrett-Mayer E, Mittal N, Smith K, Shulman L, Passaglia C, et al. Association of BRCA1 Mutations with Impaired Ovarian Reserve: Connection Between Infertility and Breast/Ovarian Cancer Risk. J Adolesc Young Adult Oncol 2016;5:337-43.
  • Van der Ven H, Liebenthron J, Beckmann M, Toth B, Korell M, Krüssel J, et al. Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: Tissue activity, pregnancy and delivery rates. Hum Reprod 2016;31:2031-41.
  • Azim HA Jr., Bellettini G, Gelber S, Peccatori FA. Breast-feeding after breast cancer: If you wish, madam. Breast Cancer Res Treat 2009;114:7-12.



  5. Fertility Preservation in Lymphoma and Leukaemia Top


Abstract

Leukemia and Lymphomas are the two commonest malignancies encountered in childhood in India. Survival rates quoted range from 50- 90%. Risk of gonadal dysfunction after chemotherapy (CT) is low in paediatric patients except for haematopoietic stem cell transplant (HSCT) where the rate of both premature ovarian insufficiency and testicular failure is high. For lymphomas; semen banking is advised since compromised semen parameters are present. In females FP requirement and modality is based on age, chemotherapy regime used and pre-treatment ovarian reserve. Women on ABVD regimen do not require FP. Acute leukemia requires urgent CT so oocyte and embryo freezing is not possible. Ovarian tissue cryopreservation can be done after stabilizing the patient, but carries the risk of reseeding of malignant cells. Semen cryopreservation is possible in the male patients, testicular tissue cryopreservation may be done bearing in mind the risk of testicular metastasis. Use of GnRH agonist for fertility protection is controversial though it is used to prevent menorrhagia in leukemia patients.


  Full Text Top


5.1: Methods of fertility preservation in pre-pubertal and post-pubertal males and females with lymphoma and leukemia


  Leukaemia Top


The most common forms of hematological malignancies that occur in young girls and women are acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL). Chronic lymphocytic leukemia (CLL) and Chronic myeloid leukemia (CML) and myeloma generally occur in older patients. Hematological malignancies account for 7-9% of estimated new cancer cases and deaths.[1] Leukemia and Lymphomas are the two commonest malignancies encountered in childhood in India. The incidence of childhood cancer (0-14 years) in India is 9 per million.[2] The proportion of childhood cancers relative to cancers in all age groups varied between 0.7-4.4% (NCR).[3] Leukemia is the most prevalent accounting for 40-50% of total childhood cancers while 15-20% are lymphomas. There is a male preponderance for both the cancers. (NCR).[3] Survival rates quoted range from 50- 90%. According to US data(2008-2014) from Leukemia and Lymphoma Society (LLS) 5 year survival rates are as follows:

ALL : 90.6 % (< 15 years age), AML : 68.8% (<15 years age) HL : 98.3% 5-yr survival (< 20 years age) and NHL : 84.3% 5-yr survival (< 20 years age). Long term outcomes reported from various centres in India are comparable to outcomes reported from western centres.[4]


  Lymphomas Top


  1. Hodgkins lymphoma: The age standardised rates (ASR) of Hodgkins lymphoma in India is 0.4/100000 population, whereas the global ASR varies between 0.3/100000 in less developed countries and 0.6/100000 in developed countries.[4] Children present at a younger age compared to West. All patients require combination chemotherapy, radiotherapy is usually reserved for a select subgroup depending on the protocol used.Treatment is geared towards reduction of long term side effects. Risk of relapse is maximum in the first five years though they should have a life-long follow up for late effects
  2. Non-Hodgkins Lymphoms: The age-adjusted incidence rates for NHL in men and women in India are 2.9/100,000 and 1.5/100,000, respectively. It presents at an earlier age (median age of 54 years), and is seen more in males. The estimated mortality rate due to NHL is higher in India.[5]


Effects of treatment on gonadal function

Risk of gonadal dysfunction after CT for lymphomas is low in paediatric patients. Effect of treatment of lymphomas is not associated with high gonadal toxicity in the reproductive age group except for haematopoietic stem cell transplant (HSCT) where the rate of premature ovarian insufficiency (POI) is 70- 100%[6] or testicular failure (50–90%) since aggressive chemotherapy and radiotherapy is needed to destroy pre-existing bone marrow.[7] Use of HSCT leads to high rates of POI and very low chances of conception after treatment (3-8 %). Literature from India suggests that multi-agent chemotherapy without radiotherapy may be sufficient to treat majority of Hodgkin lymphoma patients. Radiotherapy can be reserved for patients with bulky disease not responding to chemotherapy alone.[4]

CT frequently used for lymphomas is ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine). The rate of POI is less than 10 % in the reproductive age. The BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, oncovin, procarbazine, prednisolone) regime leads to POI rates of 50 % in patients < 30 years and MOPP (chlormethamine, oncovine: procarbazine, prednisilone) leads to POI rates of 20- 50 % in women in of reproductive age.[6],[8] Fertility preservation in women is generally not required with ABVD regime. Oocyte, embryo and ovarian tissue freezing is feasible and can be offered when patient has to go for BEACOPP or extended BEACOPP. Age of the woman and baseline ovarian reserve are important determinants. Role of GnRH agonist as an ovoprotective agent is controversial. There is an increased anaesthesia risk when OTC in done in a patient with mediastinal tumour.

FP for men

Since patients with lymphomas are known to have a compromised semen. Semen preservation should be advised.

CT for non-Hodgkin lymphoma

The CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) regime is used. POI rates are around 5 % and pregnancy rates after treatment are as high as 50 % Use of Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, methotrexate)leads to POI rates of 14 %, and pregnancy rates after treatment of 43 %.[9] Fertility preservation requirement are based on age and pre-treatment ovarian reserve.

2) Leukaemia (acute lymphocytic leukaemia (ALL), acute myeloid leukaemia (AML), chronic myeloblastic leukaemia (CML).

Current treatment protocols use lower doses or no alkylating agents and hence risk of infertility is low unless patient needs HSCT. The risk of infertility in patients with ALL or AML is very low. CML can be treated with tyrosine kinase inhibitors such as imatinib or rituximab. Effect of Tyrosine kinase inhibitors on gonadal function is uncertain at present due to lack of data. In vitro fertilization, egg freezing, and in vitro maturation are not recommended for patients with ALL.[10],[11],[12]

Fertility preservation

Most patients diagnosed with acute leukaemia must urgently undergo cytotoxic therapy hence ovarian stimulation is not possible. Unfortunately even OTC is difficult because of the poor general condition of the patient though it can be done it can be carried out once the patients’ condition is stable. Semen cryopreservation is possible in the male patients.

Indian context

Oncologists are of the opinion that FP may not be feasible in patients of acute leukaemia and late stages of lymphoma because of time constraints. In women with early stage lymphoma and chronic leukaemia it may be possible to delay treatment for FP. Semen banking is easy and feasible. For testicular tissue cryopreservation data is still insufficient and the risk of metastasis in testis also should be taken into consideration. Leukaemia and lymphoma may be associated with thrombocytopenia and coagulopathy. Oncologists are of the opinion that a checklist should be kept in all oncology units on the feasibility and methods of FP.

Recommendations



5.2: Can ovarian tissue cryopreservation be offered to patients with lymphoma and leukaemia?


  Summary of Evidence Top


For patients with leukaemia, for whom oocyte or embryo cryopreservation is difficult, ovarian tissue cryopreservation can be a useful method of FP, though the possibility of cancer cells in frozen ovarian tissue cannot be excluded. Cancer cells have been identified in ovarian cortical samples in more than 50% of women affected by acute leukaemia when tested using molecular biology studies.[13]

OTC can be a good options in patients with lymphoma.[14],[15],[16] There has been a growing evidence on safety of OTC in HL and NHL, though so far only low quality evidence is available on reseeding of malignant cell.[17] No relapse after OTC has been reported so far from more than 50 transplantations in lymphoma patients.

Greve et al. did not find any signs of viable malignant cells in pieces of ovarian cortex from 25 patients suffering from leukemia with the majority being in complete remission.[18] However, the ovarian cortex showed a positive RT-qPCR result in 4 of the 7 patients with a known molecular marker before transplantation.[18],[19] In leukemia patients OTC should be proposed only after careful evaluation of the surgical risks and abnormal haematological parameters. OTC can also be carried out after the first CT when patient’s condition has improved. Though less effective, it reduces the possibility of reseeding of cancer cells. There is an increased risk of miscarriage and fetal abnormalities if IVF is done after chemotherapy. This is because oocytes retrieved are genetically abnormal.

Most oncologists in India prefer using are also of the view that OTC should not be done in leukaemia patients as there is risk of contamination of the tissue with malignant cells. OTC can be offered to patients with lymphoma.

Recommendations



5.3: Should ovarian suppression with GnRH agonist to be advised preserve ovarian function?


  Summary of Evidence Top


Patients with leukaemia benifit from GnRH agonist co-administration to manage ovulation and menstrual bleeding during chemotherapy, though its effect on fertility protection in lymphomas is controversial.

In patients with lymphoma, GnRH agonist (GnRHa)-treated patients had a higher pregnancy rate than control patients,[20] and significant recovery of the regular ovulatory functions in the GnRHa-treated group following autologous HCT.[21] The FP effects of GnRHa on ovarian function preservation were not observed for patients with leukaemia. However some studies have reported that GnRHa had no fertility-preserving effects.[22],[23]

Two recent publications reported no significant benefit of GnRHa administration on POI and pregnancy rate after more than 5 years of follow-up.[24],[25] However, GnRHa during chemotherapy remains an option for women interested in preserving ovarian function and fertility.[26]

Some reports have shown that continuous use of combined oral contraceptives pills (COCP) can lower the rate of amenorrhea and premature ovarian failure. However they cannot be used as a primary method of FP with no prospective research comparing COC and GnRHa.[27],[28] As much evidence is lacking GnRHa therapy should be considered only when no other appropriate treatment options are available.

Indian context

Most oncologists in India prefer using GnRHa to prevent menorrhagia and are of the opinion that it may have some role in preserving ovarian function. A small number of physicians use COCPs.

Recommendations




  References Top


  • Salama M, Anazodo A, Woodruff TK. Preserving fertility in female patients with hematological malignancies: A multidisciplinary oncofertility approach. Ann Oncol 2019;30:1760-75.
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  • Kim SS. Assessment of long term endocrine function after transplantation of frozen-thawed human ovarian tissue to the heterotopic site: 10 year longitudinal follow-up study. J Assist Reprod Genet 2012;29:489-93.
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  • Bar-Joseph H, Ben-Aharon I, Rizel S, Stemmer SM, Tzabari M, Shalgi R. Doxorubicin-induced apoptosis in germinal vesicle (GV) oocytes. Reprod Toxicol 2010;30:566-72.
  • Silber S. Ovarian tissue cryopreservation and transplantation: Scientific implications. J Assist Reprod Genet 2016;33:1595-603.
  • Bastings L, Beerendonk CC, Westphal JR, Massuger LF, Kaal SE, van Leeuwen FE, et al. Autotransplantation of cryopreserved ovarian tissue in cancer survivors and the risk of reintroducing malignancy: A systematic review. Hum Reprod Update 2013;19:483-506.
  • Kyono K, Doshida M, Toya M, Sato Y, Akahira J, Sasano H. Potential indications for ovarian autotransplantation based on the analysis of 5,571 autopsy findings of females under the age of 40 in Japan. Fertil Steril 2010;93:2429-30.
  • Dolmans MM, Luyckx V, Donnez J, Andersen CY, Greve T. Risk of transferring malignant cells with transplanted frozen-thawed ovarian tissue. Fertil Steril 2013;99:1514-22.
  • Donnez J, Dolmans MM. Fertility preservation in women. Nat Rev Endocrinol 2013;9:735-49.
  • Greve T, Clasen-Linde E, Andersen MT, Andersen MK, Sørensen SD, Rosendahl M, et al. Cryopreserved ovarian cortex from patients with leukemia in complete remission contains no apparent viable malignant cells. Blood 2012;120:4311-6.
  • Zver T, Alvergnas-Vieille M, Garnache-Ottou F, Ferrand C, Roux C, Amiot C. Minimal residual disease detection in cryopreserved ovarian tissue by multicolor flow cytometry in acute myeloid leukemia. Haematologica 2014;99:e249-52.
  • Behringer K, Thielen I, Mueller H, Goergen H, Eibl AD, Rosenbrock J, et al. Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial. Ann Oncol 2012;23:1818-25.
  • Blumenfeld Z, Patel B, Leiba R, Zuckerman T. Gonadotropin-re- leasing hormone agonist may minimize premature ovarian failure in young women undergoing autologous stem cell transplantation. Fertil Steril 2012;98:1266-70.e1.
  • Behringer K, Wildt L, Mueller H, Mattle V, Ganitis P, van den Hoonaard B, et al. No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group. Ann Oncol 2010;21:2052-60.
  • Demeestere I, Brice P, Peccatori FA, Kentos A, Gaillard I, Zachee P, et al. Gonadotropin-releasing hormone agonist for the prevention of chemotherapy-induced ovarian failure in patients with lymphoma: 1-year follow-up of a prospective randomized trial. J Clin Oncol 2013;31:903-9.
  • Demeestere I, Brice P, Peccatori FA, Kentos A, Dupuis J, Zachee P, et al. No Evidence for the benefit of gonadotropin-releasing hormone agonist in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy: Final Long-term report of a prospective randomized trial. J Clin Oncol 2016;34:2568-74.
  • Demeestere I, Brice P, Peccatori FA, Kentos A, Dupuis J, Zachee P, et al. Reply to M. Lambertini, et al. J Clin Oncol 2017;35:805-6.
  • Lambertini M, Falcone T, Unger JM, Phillips KA, Del Mastro L, Moore HC. Debated role of ovarian protection with gonadotro- pin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in women with cancer. J Clin Oncol 2017;35:804-5.
  • Behringer K, Breuer K, Reineke T, May M, Nogova L, Klimm B, et al. Secondary amenorrhea after Hodgkin’s lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: A report from the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 2005;23:7555-64.
  • Blumenfeld Z, von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update 2008;14:543-52.



  6. Fertility Preservation Options for Women and Men Undergoing Radiotherapy Top


Abstract

Gonadotoxicity with radiotherapy (RT) depends on the irradiation field, dose, fractionation schedule, and patients age. Total body irradiation is associated with a high risk of gonadal failure in both sexes. Gonadal shielding is carried out to avoid scatter effects. Ovarian transposition is performed to preserve ovarian function if pelvic irradiation is planned. Success rates of the procedure vary between 20-100%. Sexual dysfunction resulting from RT is not addressed by oncologists. Fertility preservation is possible prior to RT.


  Full Text Top


6.1: Methods of fertility preservation in patients planned for pelvic irradiation after surgery


  Summary of Evidence Top


Radiation therapy to the abdomen and pelvis advised in Hodgkin’s disease, Ewing’s sarcoma, gynaecological cancer, and prostate cancer, may affect the fertility as gonads are very sensitive to RT. Gonadotoxicity depends on the age, dose, fractionation schedule, and irradiation field.[1],[2],[3] Total body irradiation is also associated with a high risk of gonadal failure in both sexes.[4],[5]

Most studies on ovarian transposition have been observational, small and retrospective. Most of them were cases reports or case series. A systematic review and meta-analysis which evaluated ovarian function and risks of OT found preservation of ovarian function in 50-90 %[6] whereas in another recent study the protection ranged from 20-100%.[7]

Shielding of the gonadal area is the standard procedure for reducing scatter radiation to the reproductive organs In both adult and prepubertal patients. Surgical ovarian transposition in females can be offered when pelvic irradiation is performed as it moves the ovaries out of the radiation field. Despite ovarian transposition there could be damage to the ovaries due to scatter radiation and damage to the blood vessels supplying the ovaries.[8]

In adult patients, sperm banking for males and embryo and oocyte banking for females, may also be considered prior to radiotherapy.

Indian context

In India gonadal shielding is the method of choice to prevent the gonadal damage due to radiotherapy, though a few centres do use ovarian transposition. Though most oncologists inform patients about RT induced gonadal damage, RT induced sexual dysfunction is rarely discussed. FP is not discussed when cranial irradiation is given. Oncologists are aware that FP is not effective after RT if gonads are exposed.

Recommendations




  References Top


  • Gosden RG, Wade JC, Fraser HM, Sandow J, Faddy MJ. Impact of congenital or experimental hypogonadotrophism on the radiation sensitivity of the mouse ovary. Hum Reprod 1997;12:2483-8.
  • Speiser B, Rubin P, Casarett G. Aspermia following lower truncal irradiation in Hodgkin’s disease. Cancer 1973;32:692-8.
  • Rodriguez-Wallberg KA, Oktay K. Fertility preservation medicine: Options for young adults and children with cancer. J Pediatr Hematol Oncol 2010;32:390-6.
  • Sklar C. Growth and endocrine disturbances after bone marrow transplantation in childhood. Acta Paediatr Suppl 1995;411:57-61.
  • Thibaud E, Rodriguez-Macias K, Trivin C, Espe?rou H, Michon J, Brauner R. Ovarian function after bone marrow transplantation during childhood. Bone Marrow Transplant 1998;21:287-90.
  • Gubbala K, Laios A, Gallos I, Pathiraja P, Haldar K, Ind T. Outcomes of ovarian transposition in gynaecological cancers; a systematic review and meta-analysis. J Ovarian Res 2014;7:69.
  • Hoekman EJ, Broeders EABJ, Louwe LA, Nout RA, Jansen FW, de Kroon CD. Ovarian function after ovarian transposition and additional pelvic radiotherapy: A systematic review. Eur J Surg Oncol 2019;45:1328-40.
  • Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006;24:2917-31.



  7: After Treatment Care and Pregnancy in Cancer Patients Top


Abstract

Pregnancy both spontaneous and after ART is safe after cancer treatment and should be allowed once risk of cancer relapse is reduced. Pregnancy does not increase the risk of relapse, no negative effect of pregnancy on disease-free survival or overall survival have been reported. Pregnancy complications ( pre-eclampsia, IUGR, prematurity, placenta previa and accreta, caesarean births) may be encountered, more so in patients exposed to pelvic RT. Children of cancer survivors are not at an increased risk of congenital malformations though an increase has been reported in offspring of male cancer survivors. Assessment of reproductive function, medical condition, psychological state, potential for conception and successful pregnancy in women planning pregnancy after cancer treatment must be carried out and a multidisciplinary team should be involved in pregnancy management.


  Full Text Top


In general, cancer survivors have reduced rates of subsequent pregnancy compared with the general population, although the rates are higher in males compared with female cancer survivors.[1] Apart from breast cancer, there is no data regarding the safety of pregnancy following cancer.[2],[3] It is still not known whether short intervals between treatment and conception might cause poor pregnancy outcomes. In women who conceived after more than 1 year after starting chemotherapy without radiation or more than 2 years after chemotherapy with radiation did not have an overall increased risk in pregnancy and due to pregnancy.[4]

7.1 After treatment care


  Summary of Evidence Top


It is important to assess the reproductive function, medical condition, psychological state, potential for conception and successful pregnancy in women planning pregnancy after cancer treatment. A multidisciplinary team consisting of an oncologist, obstetrician, RM specialists, physician and psychologist should be involved in the assessment.

In patients who have developed premature ovarian insufficiency (POI), embryos or ovarian tissue cryopreserved prior to cancer treatment may be used. In patients with POI frozen embryo replacement is recommended in a hormonal replacement treatment cycle. Women with oestrogen receptor positive breast cancer should have an FET preferably in an ovulatory cycle, to decrease exposure to high levels of estrogen. Patients with POI who have not had FP should be counselled for other options (Gamete donation).[5] Psychological, pre-conception antenatal and treatment option and implication counselling is important and should be offered to all patients.

High-dose pelvic irradiation can result in decreased uterine volume, impaired blood flow and endometrial scarring, leading to implantation failure and adverse pregnancy outcome.[6],[7] These effects are especially in evidence following RT exposure of the uterus during childhood and adolescence.

Radiotherapy-induced structural and functional changes to the uterus (> 5Gy) may also adversely affect maintenance of pregnancy, increasing the risk of placental attachment disorders (placenta accreta or placenta percreta), low birth weight, small for gestational age fetus and preterm birth.[8]

Recommendations



7.2: Effect of pregnancy on recurrence and survival outcomes in breast cancer?


  Summary of Evidence Top


Pregnancy in BC survivors does not jeopardize disease outcome. The optimal time for conception after completion of treatment needs to be determined and should take into account risk of relapse, age and decrease in OR. A period of 2 years after completion of treatment in ER negative tumours and 5 years in ER +ve tumours and when there is nodal involvement, is considered adequate and does not decrease DFS or OS. Safety of pregnancy in women with history of hormone (estrogen) receptor positive breast cancer also remains controversial. Advice on going through with pregnancy should be individualised after evaluating the status of the women as obstetric and neonatal complications are increased. Tamoxifen is teratogenic, so contraception is advised during administration and a washout period of 3 months is recommended before attempting conception.[9] Full oncological evaluation is mandatory prior to conception. ART can be used safely to attempt conception. Breast feeding should be encouraged though lactation may be inadequate. Data from a meta-analysis of 19 studies and 3 more recent reports consistently show that there is no negative effect of pregnancy on disease-free survival or overall survival in women after a previous diagnosis of breast cancer.[10] However, there is an association between maternal breast cancer and increased risk of preterm birth and low delivery weight.[11]

Indian context

Most nulliparous women want to go in for a pregnancy after completion of treatment for breast cancer. Tamoxifen is usually given to hormone receptor positive pre-menopausal patients after surgery for 10 years. If the patient is desirous of pregnancy it is interrupted at 5 years after counselling. In patients who are at risk of POI the tamoxifen is interrupted after 2 years and restarted again after delivery.

Recommendations



7.3 Pregnancy in women with Gynaecological cancer


  Summary of Evidence Top


Evidence on pregnancy outcomes after fertility-sparing treatment of endometrial cancer with hormonal treatment for grade 1 adenocarcinoma or endometrial hyperplasia is associated with increased risk of obstetric complications, and therefore require careful follow-up of these pregnancies.[12] There is a significant increased risk of recurrence in endometrial cancer after fertility-sparing treatment only (irrespective of pregnancy). This makes a regular follow-up by an oncologist necessary.[12]

Fertility sparing may be done in women with borderline ovarian tumours. Several births have been reported but the incidence of recurrence is much higher than other Gynaecological malignancies.[10] Most patients come to us at an advanced stage and a definitive radical surgery has to be performed. This makes it mandatory for counselling regarding the prognosis.

3 systematic reviews, have shown a significant risk of preterm birth rate (26.6%) after conservative treatment for cervical cancer.[13] Probably a transabdominal cerclage (TAC) of the uterine cervix reduces the risks of preterm birth.[14]

Indian context

Most patients of endometrial and cervical cancer are treated by oncologists, who invariably perform a definitive surgery. Onco-surgeons need to bear in mind that fertility sparing treatment is an option and definitive treatment can be offered after pregnancy and delivery. During the period of conservative treatment, a regular follow up is mandatory.

Recommendations



7.4 Pregnancy in other cancers


  Summary of Evidence Top


Women with any cancer other than gynaecological cancer have increased likelihood of adverse outcomes (postpartum haemorrhage, caesarean delivery, low APGAR score, and need for special neonatal care) in pregnancy.[15] When women with or without history of cancer were compared for obstetric risk after oocytes donation, the risk of preterm birth and pre-eclampsia was significantly higher in women with prior cancers.[16]

Recommendations



7.5 Fatherhood after cancer


  Summary of Evidence Top


In males when considering the safety of conception after RT and/or CT, three scenarios can be encountered: a) spontaneous conception in patients with continued spermatogenesis; b) ART conception with cryopreserved sperm; c) ART conception with post RT/CT residual spermatogenesis (ICSI ). A large retrospective study from US reported an anomaly prevalence of 2.7 % in the offspring of cancer survivors.[17] The limited available data on fatherhood after cancer are related to offspring from spontaneous conceptions or from IVF/ICSI with spermatozoa cryopreserved before the initiation of anticancer treatments. Until recently, none of the research reported an increased rate of congenital abnormalities or malignancies in children born from treated patients with subsequent spontaneous conceptions.[18] The offspring of male cancer survivors were more likely to have major congenital abnormalities than those of fathers without cancer.[19] The efficacy of ART is similar in patients treated for cancer as compared to non-cancer infertile males when ICSI is performed with cryopreserved sperms.[20]

Recommendations



7.6: How to manage pregnancies diagnosed while undergoing anticancer therapy?


  Summary of Evidence Top


All pre-menopausal patients and male cancer patients undergoing any form of systemic anti-cancer therapy (i.e. chemotherapy, hormonal therapy, immunotherapy or targeted therapy) should be advised to use active contraception until 6 months following the last administered dose.

If pregnancy occurs while on chemotherapy or tamoxifen, patient is advised termination of pregnancy due to the possible increased risk of fetal malformations.[9] It is safe to continue pregnancy if on monoclonal antibodies, which do not cross the placenta. If pregnancy is continued then trastuzumab or rituximab need to be stopped.[21] Tyrosine kinase inhibitors cross the placenta and are not safe hence pregnancy needs to be terminated.[22],[23],[24]

Recommendations




  References Top


  • Stensheim H, Cvancarova M, Møller B, Fossa? SD. Pregnancy after adolescent and adult cancer: A population-based matched cohort study. Int J Cancer 2011;129:1225-36.
  • Langagergaard V, Gislum M, Skriver MV, Nørgård B, Lash TL, Rothman KJ, et al. Birth outcome in women with breast cancer. Br J Cancer 2006;94:142-6.
  • De Sanctis V, Filippone FR, Alfò M, Muni R, Cavalieri E, Pulsoni A, et al. Impact of different treatment approaches on pregnancy outcomes in 99 women treated for Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2012;84:755-61.
  • Hartnett KP, Mertens AC, Kramer MR, Lash TL, Spencer JB, Ward KC, et al. Pregnancy after cancer: Does timing of conception affect infant health? Cancer 2018;124:4401-7.
  • European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D, et al. ESHRE Guideline: Management of women with premature ovarian insufficiency. Hum Reprod 2016;31:926-37.
  • Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE, et al. Stillbirth and neonatal death in relation to radiation exposure before conception: A retrospective cohort study. Lancet 2010;376:624-30.
  • van de Loo LE, van den Berg MH, Overbeek A, van Dijk M, Damen L, Lambalk CB, et al. Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors. Fertil Steril 2019;111:372-80.
  • Tarín JJ, García-Pérez MA, Cano A. Obstetric and offspring risks of women’s morbid conditions linked to prior anticancer treatments. Reprod Biol Endocrinol 2016;14:37.
  • Braems G, Denys H, De Wever O, Cocquyt V, Van den Broecke R. Use of tamoxifen before and during pregnancy. Oncologist 2011;16:1547-51.
  • Bentivegna E, Gouy S, Maulard A, Pautier P, Leary A, Colombo N, et al. Fertility-sparing surgery in epithelial ovarian cancer: A systematic review of oncological issues. Ann Oncol 2016;27:1994-2004.
  • Hartman EK, Eslick GD. The prognosis of women diagnosed with breast cancer before, during and after pregnancy: A meta-analysis. Breast Cancer Res Treat 2016;160:347-60.
  • Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: A systematic review. Gynecol Oncol 2012;125:477-82.
  • Zhang Q, Li W, Kanis MJ, Qi G, Li M, Yang X, et al. Oncologic and obstetrical outcomes with fertility-sparing treatment of cervical cancer: A systematic review and meta-analysis. Oncotarget 2017;8:46580-92.
  • Ishioka S, Kim M, Mizugaki Y, Kon S, Isoyama K, Mizuuchi M, et al. Transabdominal cerclage (TAC) for patients with ultra-short uterine cervix after uterine cervix surgery and its impact on pregnancy. J Obstet Gynaecol Res 2018;44:61-6.
  • Haggar F, Pereira G, Preen D, Woods J, Martel G, Boushey R, et al. Maternal and neonatal outcomes in pregnancies following colorectal cancer. Surg Endosc 2013;27:2327-36.
  • Marklund A, Nasiell J, Berger AS, Fagerberg A, Rodriguez-Wallberg KA. Pregnancy Achieved Using Donor Eggs in Cancer Survivors with Treatment-Induced Ovarian Failure: Obstetric and Perinatal Outcome. J Womens Health (Larchmt) 2018;27:939-45.
  • Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE, et al. Congenital anomalies in the children of cancer survivors: A report from the childhood cancer survivor study. J Clin Oncol 2012;30:239-45.
  • Dohle GR. Male infertility in cancer patients: Review of the literature. Int J Urol 2010;17:327-31.
  • Ståhl O, Boyd HA, Giwercman A, Lindholm M, Jensen A, Kjær SK, et al. Risk of birth abnormalities in the offspring of men with a history of cancer: A cohort study using Danish and Swedish national registries. J Natl Cancer Inst 2011;103:398-406.
  • García A, Herrero MB, Holzer H, Tulandi T, Chan P. Assisted reproductive outcomes of male cancer survivors. J Cancer Surviv 2015;9:208-14.
  • Pentsuk N, van der Laan JW. An interspecies comparison of placental antibody transfer: New insights into developmental toxicity testing of monoclonal antibodies. Birth Defects Res B Dev Reprod Toxicol 2009;86:328-44.
  • Azim HA Jr., Azim H, Peccatori FA. Treatment of cancer during pregnancy with 59. monoclonal antibodies: A real challenge. Expert Rev Clin Immunol 2010;6:821-6.
  • Azim HA Jr., Pavlidis N, Peccatori FA. Treatment of the pregnant mother with cancer: A systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: Hematological tumors. Cancer Treat Rev 2010;36:110-21.
  • Azim HA Jr., Peccatori FA, Pavlidis N. Lung cancer in the pregnant woman: To treat or not to treat, that is the question. Lung Cancer 2010;67:251-6.



  Conclusion Top


Introduction of advanced diagnostic techniques and chemotherapeutic agents has revolutionised cancer management leading to high survival rates. With increasing number of young survivors providing reproductive options has become vital to improve quality of life. Oncofertility is a fairly new discipline globally and it is only in recent years that an attempt has been made to provide guidelines for management of cancer patients requesting FP. Each country has its own dynamics - ethnicity, social customs and religious beliefs become inherent to management plans, hence the need for providing recommendations applicable to Indian patients. India is a diverse nation, local and regional issues come into play both in disease presentation and patient counselling. The recommendations presented in this document have been formulated after intense debate and discussion with oncologists and reproductive medicine specialists across the Indian states. The discussions brought into focus the desire of Indian patients for information on FP, across social and economic strata. A need to improve awareness amongst physicians and the public and setting up of centralised quality FP units was also recognised.

The Fertility Preservation Society (India) recommends that oncologists should discuss the risk of infertility resulting from cancer treatment with patients at the earliest opportunity and provide initial information regarding the availability of FP. Patients with a good oncological prognosis at risk of infertility and interested in preservation of their reproductive ability should be referred to a reproductive medicine expert as early as possible, after a confirmatory diagnosis. Details of FP procedures including risks and subsequent reproductive outcome should be explained in detail by the reproductive medicine specialist. Genetic and social counselling should be made available to patients to aid in taking an informed decision. Limiting factors in India include lack of awareness of FP options, availability, cost, lack of insurance coverage and the experimental nature of some FP procedures.


  Annexure I Top



  Members Of The Working Group Top


Dr. Nalini Mahajan (Founder President, Fertility Preservation Society (India)

Dr. Sabhyata Gupta (President, Fertility Preservation Society (India))

Dr. Gopinath P M (President Elect, Fertility Preservation Society (India))

Dr. Madhuri Patil (Vice-President, Fertility Preservation Society (India)

Dr. Padma Rekha Jirge (Secretary, Fertility Preservation Society (India)


  Acknowledgments Top


We gratefully acknowledge the contribution of our collaborating fertility experts and faculty from cancer hospitals. We also acknowledge the immense personal assistance by Prof Claus Y Andersen (Denmark).


  Participating Oncology Experts From` Top


Bangalore

Mazumdar Shaw Cancer Centre, Narayan Health City

HCG

Delhi

All India Institute of Medical Sciences

Medanta -The Medicity

Rajiv Gandhi Cancer Hospital

Indraprastha Apollo Hospital

Max Super Speciality Hospital

Kolkata

Tata Medical Centre

Mumbai

Bombay Hospital

Miraj

Sidhivinayak Cancer Hospital

Reproductive Medicine Experts

Senior RM specialist and members of FPSI

(Executive)

We thank Ferring Pharmaceuticals for their logistic support during the preparation of these guidelines.

Copyright information

No part of this document, may be reproduced by any process without written permission from Fertility Preservation Society (India)

Electronic documents: This work is copyright. You may download, display, print and reproduce this material in unaltered form only (retaining this notice) for your personal, non-commercial use, or use within your organisation.

Copies of the guideline can be downloaded from tofjonline.org /www.fpsind.com

Suggested citation: Fertility Preservation for Patients on Gonadotoxic Treatment

Recommendations for Clinical Practice by Fertility Preservation Society (India)


  Acknowledgement Top



  Oncologists Top


1. Bangalore

  • Mazumdar Shaw cancer centre, Narayana Health city - Dr. Sunil Bhat, Dr.Nataraj K S, Dr. Suchitra R.
  • HCG- Dr. Intezar Mehdi, Dr. Ramesh S Bilimagga, Dr. Brindha Sitaram, Dr. Govinda Babu, Dr. Nalini Rao, Dr. S Bhattacharya, Dr. Shekar Patil


2. Delhi

  • AIIMS- Dr. G. K. Rath, Dr. A. K. Mahapatra, Dr. Raja Pramanik
  • Indraprastha Apollo Hospital- Dr. Ramesh Sarin
  • Medanta -The Medicity - Dr.Sabhyata Gupta, Dr. A K Vaid, Dr. Shradha Chaudhri
  • Rajiv Gandhi Cancer Hospital- Dr. Rupinder Sekhon
  • Max SS – Col Ranga Rao Raju


3. Kolkata

  • Tata Medical Centre - Dr. V R Ramanan, Dr. Jaydip Bhowmik, Dr. Basumita Chakraborty, Dr. Rosina Ahmed, Dr. Arpita Bhattacharyya, Dr. Jaydip Ghosh, Dr. Arunabha Roy, Dr. Anik Ghosh, Dr. Rimpa Basu Achari, Dr. Gaurav Agarwal


4. Mumbai

  • Bombay Hospital- Dr.Rashmi Dalvi


Miraj

  • Sidhivinayak Cancer Hospital- Dr. Amita Gosavi, Dr, Yeshwanth Toro, Dr. M Khochikar, Dr. P V Chitale, Dr.V S Gosavi, Dr. SS Kale, Dr. Uday Phatak, Dr. Sandeep Nemani, Dr. Alok Pawaskar, Dr. Amit Grover, Dr. A P Udgaonkar



  REPRODUCTIVE MEDICINE EXPERTS: Top


Dr. Nalini Mahanjan

Dr. Sabhyata Gupta

Dr. P.M. Gopinath

Dr. Madhuri Patil

Dr. PadmaRekha Jirge

Dr. Neeta Singh

Dr. M Gouri Devi

Dr. S.N Basu

Dr. Umesh Jindal

Dr. Gautam Khastgir

Dr. Paapa Dasari

Dr. Sadhana Patwardhan

Dr. Shalu Gupta

Dr. Devika Gunasheela

Dr. Tanya Buckshee Rohatgi

Dr. Mala Raj

Dr. Nymphaea Walecha

Dr. Raja Priya Ayyappan

Dr. Ila Gupta

Dr. Padmaja Naidu

Dr. Shradha Chaudhari

Dr. K D Bakshi

Dr. Sudip Basu

Dr. Suparna Banerjee

Dr. Kaushiki Roy

Dr. Piya Roy




    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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  In this article
Abstract
Scope of Recomme...
Executive Summary
Definition of Fe...
Prioritised Clin...
What the Recomme...
Guideline Develo...
Interpreting The...
Limitations in I...
Disclaimer
Summary of Recom...
Introduction
Full Text
Context and Back...
Radiotherapy
References
1. General Infor...
Full Text
Summary of Evidence
Summary of Evidence
Summary of Evidence
Summary of Evidence
Summary of Evidence
Summary of Evidence
References
2. Fertility Pre...
FULL Text
Summary of Evidence
Summary of Evidence
References
3. Fertility Pre...
Full text
Summary Of Evidence
Fertility Preser...
Fertility Preser...
Fertility Protection
Future Perspective
Summary Of Evidence
Summary of Evidence
References
4. Fertility Pre...
Full Text
BREAST Cancer (BA)
Summary Of Evidence
Summary Of Evidence
Summary Of Evidence
Summary Of Evidence
Summary Of Evidence
References
5. Fertility Pre...
Full Text
Leukaemia
Lymphomas
Summary Of Evidence
Summary Of Evidence
References
6. Fertility Pre...
Full Text
Summary Of Evidence
References
7: After Treatme...
Full Text
Summary Of Evidence
Summary Of Evidence
Summary Of Evidence
Summary Of Evidence
Summary Of Evidence
Summary Of Evidence
References
Conclusion
Annexure I
Members Of The W...
Acknowledgments
Participating On...
Acknowledgement
Oncologists
REPRODUCTIVE MED...
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