Is fertility compromised in young adult cancer survivors?

Is fertility compromised in Young Adult Cancer Survivors?
Name of the Student
Professor’s Name

Is fertility compromised in Young Adult Cancer Survivors?
Introduction
1.1 Purpose of the Assignment
The main purpose of this assignment is to gather requisite knowledge about a clinical issue which would help to understand the treatment needs and care approaches much better under the current and present perspectives of need of such patients and their family members. This assignment would help in appraising various strategies which are currently used in providing certain therapeutic interventions and their pros and cons on the reproductive health of adult males and females. This assignment would not all appraise the treatment approaches but their effect on certain social endpoints related to the quality of life in such patients.
1.2 The Chosen Topic
The topic chosen for the present assignment is to study whether fertility is compromised in young adult cancer survivors, who receive various types of anti-cancer treatments like chemotherapy or radiotherapy. With the advancements in chemotherapeutic regimes and radiotherapy, the survival rates have improved for young adult individuals suffering from cancer.
However, the existing cancer therapies are documented to impose reproductive risks in such individuals. In this situation the long-term effects of cancer treatment regimes should be reviewed in the perspective of reproductive health of such cancer survivors.

This is because all such individuals who were suffering from cancer during their childhood or adolescent period, desires a productive and healthy lifestyle, when they grow up as adults.
1.3 Relevance of Topic Chosen
Cancer is a dreadful disease whether it occurs in childhood or in an advanced age irrespective of sex. The disease not only affects the individuals who suffer from the disease but also their family members who are emotionally and financially constrained by the situation. The focus of treatment by the clinicians is providing rapid and effective interventions to improve the prognosis of the disease. However, certain social aspects or demands of the patients are not considered a priority.
One such issue is the potential and desire for becoming a father or mother of a childhood cancer survivor patient, at later stages in their life. Such a situation must be thoroughly addressed by the care provider and should be given a priority while extending the necessary pharmacologic and non-pharmacologic interventions to such patients. The families of such individuals should be briefed about the possible complications of infertility and reproductive health and should be extended some sort of fertility preservation options.
1.4 Key Issues to be highlighted
This article would review the effects of chemotherapy and radiotherapy on the reproductive health of pre-pubertal boys and girls. This review would be helpful to plan treatment guidelines through these interventions, in a more focused and appropriate way based on gender, health care needs, comorbid conditions and base-line features of such affected individuals. Further, the assignment will also portray the needs of motivating and encouraging parents of such children on fertility prevention methods after due appraisal of the same.
1.5 Plan of Presentation of the Article
The article will first of all incorporate the current perspectives of cancer treatment with aetiology of cancer. After that the article would analyse and reflect the epidemiology and Burden of Illness (BOI) of Pre-Pubertal Cancer. Further, a literature survey would be done on the various chemotherapeutic and radiotherapy approaches which have already been implemented in management of childhood cancer and their implications on fertility would be evaluated. Finally, the article will provide a discussion and conclusion regarding the treatment modalities and future perspectives aimed at ensuring reproductive health in such individuals.

2. Background
2.1 Cancer and Current Perspectives
Cancer is a disease which affects individuals irrespective of age and gender. The progression of cancer depends with respect to the origin and the nature of tissues involved. The hallmark of any cancerous cell is metastasis, or invasion of cancerous cells in nearby or distant tissues. This leads to a rapid progression of cancer and decreases the prognosis of treatment. The progression of cancer is attributed to failure in apoptosis or programmed cell death of the cancerous cells or tissues. Recent research has endorsed the importance of microenvironment in the development and progression of cancer. Microenvironment refers to the immediate area surrounding a cancerous or a pre-cancerous cell. Hence, the therapeutic objective is not only to eliminate the cancerous cell or induce apoptosis, but should also aim to appropriately modify the cancer microenvironment, to improve prognostic outcomes (Wallace et al, 2011).
The most common treatment schedules implicated in the management of cancer are surgery, chemotherapy and radiotherapy. These procedures are intervened either independently or in association with each other depending upon the state and stage of cancer. Surgery or oncosurgery refers to the surgical removal of precancerous or cancerous cells and tissues, which lowers the potential for cancer. Chemotherapy refers to the management of cancer through induction of apoptosis with chemical or pharmacological interventions. On the other hand, radiotherapy uses infrared radiations to destroy the cancerous cell and their respective microenvironments. Proper implementation of such treatment regimes has increased the survival rates of individuals across various age groups and gender (Wallace et al, 2011).
Apart from the above treatment options, preservation of end organ health has gained importance, especially in cancer survivor patients. The most sought out requirement is the preservation of reproductive health organs and their functions in pre-pubertal children. Hence, fertility preservation programs are being implicated to enhance the quality of life of these individuals. Various forms of fertility preservation programs have been explored in the recent past. Out of them sperm and oocyte cryopreservation has been successfully implied to ensure preservation of fertility. In case of girls who are in the pre-pubertal stage, ovarian tissue cryopreservation has showed encouraging results, however, such interventions with pre-pubertal males, have still not been implied. Hence, these individuals have to depend upon the existing treatment approaches of surgery, chemotherapy or radiotherapy for the alleviation of cancer (Wallace et al, 2005).
2.2 Epidemiology and Burden of Illness of Pre-Pubertal Cancer
The most common forms of cancer which affects young adults include malignancies in the central nervous system, adenolymphomas, soft tissue carcinomas, bone cancer and Wilm’s tumour (affecting the kidneys). The major treatment schedules include oncosurgery, chemotherapy with alkylating agents, radiation therapy. It is noted that 80% of childhood cancer patients survive for at least 5 years. More importantly, one out of 640 individuals in the age group of 20 to 39 years is a long-term pre-pubertal cancer survivor (Stat bite, 2006).
Since the survival rates have drastically improved in such groups of individuals, the quality of life of these individuals during their later phases are gaining importance. However, the current treatment approaches have their own pros and cons which affect the reproductive health of such individuals. The major issue related to infertility with chemotherapeutic regimes or radiotherapy, is the changing recommendations and guidelines based on the safety profile of such treatments.
3. Literature Review
3.1 Methodology of Literature Survey
The methodology deployed in undertaking the assignment was to search through the internet and textbooks. The internet search was done from 2004 to 2015, for finding out the issues related to fertility in childhood cancer survivor patients. The articles which were assessed were published in indexed journals and high impact factors. The search strategy involved the key words “infertility”, “reproductive health”, “childhood cancer survivors”, “treatment with chemotherapy”, “treatment radiotherapy”. References were taken from “Pubmed” and various journals on cancer and oncology.
The articles were accepted based on large datasets and robust statistical interpretation. The philosophy of selecting articles with large dataset was to endorse the proper representation of the population, with minimum chances of experimental bias. Further, the statistical tests which were considered had a level of significance of minimum 0.05. Moreover, articles which incorporated measures like relative risk, odds ratio and confidence intervals in the study, were selected on a priority basis. This is because mere statistical tests of significance cannot portray the clinical relevance in all situations. Clinical relevance means the risk of inculcating a disease, the prevalence of side effects or the odds of having a particular finding, and the probable range of such findings (obtained through confidence intervals).
The textbooks were referred on the basis of acquiring knowledge on biochemistry and molecular biology of cancer. Such step was adopted to understand the current concepts till date regarding genesis, progression and management of cancer. The desired knowledge would be helpful for discussing future treatment options, based on the aetiology of the disease.
3.2 Issues Related to Predicting Infertility or Reproductive Health in Future
The major challenge in studying the reproductive health issues in pre-pubertal males and females affected by cancer is that the outcomes are hard to assess. This is because the fertility of an individual is affected by various confounding factors and relating the effects of chemotherapy or radiotherapy on reproductive health is extremely difficult. There is also a lack of prospective trials assessing the effects of chemotherapy or radiotherapy on infertility or reproductive health of a young adult (Green et al., 2009)
Although “Time to Pregnancy” studies are considered as the gold standard, it cannot be employed on a long term basis. Hence, various studies have explored different endpoints to predict the effects of chemotherapy or radiotherapy on infertility or reproductive health of a young adult. Such studies included assessment of menstrual function, reported pregnancy after intervention with chemotherapy or radiotherapy, antral follicle counts and assessment of ovarian volume through ultrasonography (van Beek et al., 2007). Apart from such diagnostic procedures, hormonal assay of inhibin B, anti-mullerian hormone, estradiol and follicle stimulating hormone have been done to study the integrity of reproductive cells (van Beek et al., 2007) (Green et al., 2009).
It is predicted that preservation of function of such reproductive cells will lead to improved fertility in cancer survivor children. Till date the most extensive results on the fertility issues of young adult cancer survivors comes from a large retrospective cohort study conducted on 20,720 individuals in whom cancer was not detected early in their childhood. These individuals had a diagnosis of cancer before the age of 21 years, and the survival pattern indicated the long term effects of cancer and cancer treatment regimes on the reproductive health of such individuals including oncofertility (Wo & Viswanathan, 2009).
3.3. Effects of radiotherapy on reproductive health
3.3.1 Females
Pelvic radiation is one of the common treatment modalities implicated in the management of cancer which occurs in the lower abdomen including the reproductive organs. The study of reproductive function in females is based on the structural morphology of the ovarian follicles. These follicles are very susceptible to be damaged by ionizing radiations due the finite number of non-renewable follicles (antral follicles) present at the time of birth. Radiation causes a release of free radicals in the vicinity of cancer cells or may directly damage the DNA of the follicle cells (Sudour et al., 2010).
Under both circumstances cell death occurs and since these cells are non-renewable their functional count remains reduced at later stages of their life leading to the speculated infertility. From a physiological aspect, the ovary produces oocytes before birth and such counts of oocytes typically peak during the 20th week of gestation. After such peak, the oocyte pool starts to decrease due to atresia of the follicles. It was reflected that radiation therapy with more than 2 Gy, expedites the atresia of follicles and reduces the count of antral follicles. In fact, such individuals are at high risk of premature ovarian failure (Sudour et al., 2010).
Wallace et al developed a mathematical predictive model of infertility due to radiation effects. He estimated that the mean radiation dose needed to cause ovarian failure at the age of 15 years is 16Gy. On the other hand, the mean radiation dose needed to cause ovarian failure at the age of 30 years is 12Gy (Sudour et al., 2010).
Apart from the ovaries, the uterus is also susceptible to radiation therapy. Radiotherapy causes atresia of uterine tissue and compromises the blood flow in a non-stochastic fashion which causes a decrease in uterine cavity (Critchley & Wallace, 2005). Such challenges in uterine morphology might impact implantation of a fertilized ovum and lead to issues of infertility (Critchley & Wallace, 2005).
Recent studies carried out in young adult females indicated that the relative risk of achieving pregnancy in female cancer survivors after 5 years of radiotherapy (with radiation dose of 5Gy to 10Gy) was 0.56. When the radiation dose was increased beyond 10 Gy the relative risk of achieving pregnancy dropped to 0.18. Form the above findings it is clearly reflected that, in young adult female cancer survivors the chances of getting pregnant reduces from 50% to 80%. Such comparisons were extrapolated from pregnancy which occurs in similar siblings who were not affected by cancer and did not receive any forms of radiation therapy (Wallace et al, 2005).
Another retrospective study clearly endorsed the finding that, radiation therapy was the most significant risk factor for causing infertility in childhood cancer survivors. Such conclusions were extrapolated from the reductions of spontaneous menstruation or the percentages of pregnancy. The odds ratio of such infertility predictive variables was estimated to be 17.6 when compared with those individuals who did not receive radiation therapy. Moreover, when other confounding variables associated with adjuvant therapy were standardized, it was noted that a radiation dose of less than 4Gy does not significantly reduce fertility in these individuals. The study further elucidated that ovarian transposition or shielding can provide possible benefits against radiotherapy (Wo & Viswanathan, 2009).
A study conducted on 1281 childhood female cancer survivors indicated that pelvic radiation before menarche was associated with stillbirths. The relative risk of stillbirth or neonatal death with a radiation dose of 2.5 Gy to 9.9 Gy was 5.8, in comparison to females who did not receive any forms of radiotherapy (Signorello et al, 2006). When the radiation dose was increased beyond 10 Gy the relative risk was estimated to be 19. Hence, the above studies clearly indicated there is a positive correlation between pelvic radiation dose and reproductive failure, in childhood female cancer survivors. Such dose dependent infertility may pave the way for combining low dose radiation coupled to other forms of oncotherapy to improve reproductive health outcomes in such individuals (Signorello et al, 2010).
Similar to pelvic radiation, hypothalamic-pituitary irradiation may result in fibrosis and atresia of the pituitary gland. Pituitary gland is essential for the maintenance of normal reproductive functioning in a female. It is the important source of liberation of progonadal hormones like Follicle stimulating Hormone (FSH) and Luteinizing hormone (LH). FSH helps in the development of Graffian follicles, and LH causes the graffian follicles to release ovum from the ovary by a process called ovulation (Green., 2011).
A failure in the development of follicles or compromise in release of LH will lead to anovulation. This will lead to a failure of fertilization, as the ovum from the ovaries would not be available to fertilize the sperm in the fallopian tube. Such phenomenon might be considered, as a predictive model of speculated infertility, in female childhood cancer survivors (Chen et al., 2011). Moreover, pituitary also acts a feedback mechanism for action of various hormones released from the mature Graffian follicles. A failure in FSH will lead to a decrease in the estrogen pulse, which is very vital for the release of LH from the pituitary. Such hormones also produce feedback control over the hypothalamus too. Hence, a dysfunction in hypothalamic function may occur due to direct or indirect effects of radiation therapy on the hypothalamic-pituitary axis (Chen et al., 2011).
The effects of hypothalamic –pituitary dysfunction include amenorrhea (failure of the menstrual cycle), elevated levels of prolactin and decreased titre of gonadotropins. A study reported that the relative risk of attaining pregnancy in female childhood cancer survivors, treated with 3 Gy was 0.61, compared to females who did not receive any dose of radiotherapy. Further studies indicated that after controlling for demographic variables the relative risk was estimated to be 0.67 with a radiation dose range of 2.2 to 2.7 Gy. The above studies demonstrate the chances of pregnancy is reduced by 33% to 39% in female childhood cancer survivors who received hypothalamic-pituitary radiotherapy compared to their counterparts who did not received hypothalamic-pituitary radiotherapy (Green et al., 2011).
3.3.2 Males
Testicular radiation is one of the common interventions applied for the management of childhood cancer in males. A functional testis in a male is important in ensuring the reproductive health in such individuals. A testis performs two major functions which include spermatogenesis (production of mature sperms from the spermatids) and steroidogenesis (synthesis of steroid hormone like testosterone in the body).
The immature spermatogonial in the tunica albugenia is responsible for the formation of mature sperms. On the other hand, the Leydig cells produce the main androgen, testosterone. Testosterone is mainly associated with the development of male secondary sexual features. Such features include a hoarseness of voice, development of pubic hairs and development of muscles. The spermatogonial cells are more sensitive to radiation therapy than the Leydig cells (Howell & Shalet, 2011).
Therefore it is predicted that the male childhood cancer survivors who are treated with radiotherapy will have more issues with infertility rather than experiencing any change in pubertal development or milestones and sexual developments of organs. Studies have indicated that a radiation dose of more than 0.1 Gy may lead to oligospermia (abnormal sperm count and abnormal cellular morphology). Such testicular radiations at doses of 0.35 Gy may also lead to azoospermia (failure in sperm production). However, the study does indicated with such small radiation doses azoospermia was reversible when the doses were withdrawn (Howell & Shalet, 2011).
Since the Leydig cells are less susceptible to testicular radiation, such low doses of radiation does not affect functioning of Leydig cells. However, a radiation dose of more than 12 Gy has been correlated with a significant failure in the development of male secondary sexual features and overall aspects of pubertal development (Howell & Shalet, 2011).
The relative risk of infertility in male childhood cancer patients compared to their counterparts who did not receive testicular radiation was estimated to be 0.12. Some studies have speculated that cancer therapies with radiation have greater potential to cause mutation in the DNA of spermatogonial cells or mature sperms (Howell & Shalet, 2011). Such speculation arises from the direct effect of radiations on DNA which can cause either a deletion mutation or an insertion mutation leading to the change of reading frame of the DNA. Such mutations may cause the formation of altered mRNA sequences and lead to formation of defective proteins which either leads to immature sperm cells or decreases the count of mature sperm cells by directly inducing cell death.
3.4 Effects of Chemotherapy
Chemotherapeutic agents behave differently on the imposition of risk of infertility. It may vary across gender, the dose of a drug, age of the patient, and the type of chemotherapeutic agent used to treat a patient. The alkylating agents impose more risk of infertility in boys compared to girls. The risk of alkylating agents on infertility can be predicted, as these agents destroy the primordial follicles in the ovary, in dose-dependent manner. On the other hand, the same agents act on the spermatogonial cells in a dose-independent manner, therefore increasing the risk of infertility (Reinmuth et al., 2013).
Moreover, older children are more to risk of developing infertility due to treatment and age related reproductive health variables. The chemotherapeutic agents like the alkylating agents, vincristine and procarbazine impose the greatest risks to infertility in both boys and girls. It is noted that such agents increases the risk of infertility in childhood cancer survivors by 90%. On the other hand agents like vinblastine and Adriamycin, increases the risk of infertility in childhood cancer survivors by 50% (Reinmuth et al., 2013).
3.4.1 Males
Chemotherapeutic agents, like the alkylating agents, cause significant impact on the testicular tissue. Tissue damage depends upon the type of chemotherapeutic agent and the dose administered. Studies have indicated that anti-metabolite therapy with methotrexate and mercaptopurine does not result in male infertility. On the other hand carboplatin and cisplatin based therapies impairs the process of spermatogenesis and leads to temporary infertility. The relative risk of infertility associated with non-Hodgkin lymphoma survivors was 0.34 (with a confidence of 0.28 to 0.41) who were treated with carboplatin and cisplatin based therapies, compared to their counterparts who did not receive such chemotherapeutic treatments. However, such chemotherapeutic regimes did not impact the fertility outcomes in patients suffering from neuroblastoma or Wilm’s tumour, compared to their healthy counterparts (Green et al, 2010).
A dose-response report indicated that dose of alkylating agent decreased the chances of fertility in male childhood cancer survivors. The risk was found to vary from 0.16 to 0.67. This means more the dose of a chemotherapeutic agent used to treat cancer, the lesser is the chance of individual’s ability of becoming a father in later stages in life. It is also reported that different chemotherapeutic agents impair fertility at different doses (Green et al, 2009).
3.4.2 Females
The chemotherapeutic agents mainly the alkylating agents’ cross-links with the DNA duplex strand and forms single stranded breaks, and such actions lead to a dysfunction of the ovaries. Similar to radiotherapy chemotherapeutic treatment has been associated with decrease in the number of matured graffian follicles with atresia and fibrosis of the stromal matrix. Such morphological changes occur due to absence of essential and presence of abnormal proteins due to breaks in the DNA strand which translates into faulty protein synthesis. The detrimental effects of chemotherapy are correlated to the age on a young adult female. This is because with age the number of follicles already decreases in number and hence chemotherapy causes even a greater decrease in the number of active or mature follicles leading to ovarian dysfunction and reproductive failure (Green et al, 2009).
Till date, there is no evidence which demonstrates that the ovaries of childhood females are protected through shielding effects. Various studies have indicated that the ovaries of young adult females are highly sensitive to chemotherapeutic treatment. The relative risk of conceiving reduces to 0.65 – 0.72 in young adult females who underwent chemotherapeutic treatment with alkylating agents compared to their counterparts who did not underwent any chemotherapeutic treatment with alkylating agents. Moreover, other chemotherapeutic agents like cyclosporine were highly correlated to infertility in young adult females in a dose-dependent manner. Studies done on paediatric female patients suffering from non-Hodgkin’s lymphoma indicated that reserves of anti-mullerian hormone were significantly reduced. Such decreased reserves of anti-mullerian hormone, may lead to underdevelopment of sex organs like the ovary (Green et al, 2009).
Trials are being conducted with various chemotherapeutic agents in order to ensure reproductive safety in young adult females who are survivors of childhood cancer. A recent study is currently being evaluated in Europe to find out the safety profile of decarbazine over procarbazine to ensure the reproductive health of young adult female patients suffering from Hodgkin’s lymphoma. It is postulated that decarbazine will be safer in ensuring reproductive health of young adult female patients suffering from Hodgkin’s lymphoma compared to procarbazine, but with similar efficacy to procarbazine. Although the endpoints of conception or pregnancy has been shown to be correlated with the dose of chemotherapeutic agents, till date no study have demonstrated that such dysfunction in reproductive health, leads to stillbirth or congenital defects in a child born to cancer survivor patients (Reinmuth et al, 2013).
Another study was recently conducted through an interviewing of the adult survivors who were listed in German Childhood Cancer Registry program. The endpoint which was analyzed was the fertility status. Fertility status was defined on the basis of attempts to conceive, number of confirmed pregnancies, associated reproductive functions like frequency of menstrual cycle and earlier fertility results. 618 childhood cancers were included for the study and out of them 384 were women. The responses were assessed on the basis of fertile/or probable fertility, or probable infertility (Reinmuth et al., 2013).
31% amongst 83 female survivors and 29% of amongst 117 male survivors reported that they were infertile based on earlier fertility tests. It was observed that “probably infertile” adult survivors received either pelvic radiotherapy or testicular radiotherapy compared to the “probably fertile” individuals. The adjusted odds ratio was 20.84 in women with a 95% confidence interval of 4.69 -87.29, while adjusted odds ratio was 12.22 in men, with a 95% confidence interval of 1.18 -126.70. Etoposide (> 500mg/m2) in women and carboplatin or cisplatin based therapies in both sexes were highly correlated to episodes of infertility. The decreased safety profile of these chemotherapeutic agents on reproductive health was also confirmed in post-pubertal males and females where fertility was decreased (Reinmuth et al., 2013).
3.5 Bone Marrow Transplantation and Associated Risks
Another risk factor for reproductive health in both males and females who are survivors of childhood include hematopoietic stem cell transplantation or commonly known as bone marrow transplantation. Such process requires administration of adjuvant chemotherapy which leads to their potential in alleviating infertility or possible infertility in both males and females. Bone marrow transplantation require high dose chemotherapeutic intervention or total body irradiation (Sanders, 2008).
Ovarian failure occurred in almost 65% to 84% post-pubertal females, who received paediatric transplants of bone marrow with the above doses of chemotherapeutic intervention or total body irradiation. The pre-pubertal effects of such regimes reflected incomplete pubertal development in 57% of individuals, who underwent hematopoietic stem cell transplantation. The major reproductive risks were attributed to the use of high dose conditioning regimes like cyclophosphamide with busulfan and individuals who are exposed to total body irradiation (Sanders, 2008).
Like in females, the effects of high dose chemotherapeutic intervention or total body irradiation, during bone marrow transplantation are evident in reproductive health of males. Azoospermia was reported in 48% to 85% post-pubertal individuals who underwent hematopoietic stem cell transplantation along with associated chemotherapy and total body irradiation during their childhood. The pre-pubertal effects of such regimes reflected incomplete pubertal development in 53% of male individuals who underwent hematopoietic stem cell transplantation. The major reproductive risks were attributed to the use of high dose conditioning regimes like cyclophosphamide with busulfan and individuals who are exposed to total body irradiation, similarly like in females (Sanders, 2008).
3.6 Fertility Preservation
Recent advances, like sperm and oocyte cryopreservation, has been successfully implied to avert such infertility issues. In case of girls who are in the pre-pubertal stage, ovarian tissue cryopreservation has showed encouraging results but such options with pre-pubertal males, have still not been implied. Thus, they are dependent upon the existing treatment regimes for management of cancer. Although these fertility preservation options are being explored, it is important to understand the risk of infertility with the existing treatments such as chemotherapy and radiotherapy (Quinn et al, 2009).
4. Discussion and Conclusion
From the various journal references and textbook knowledge it becomes apparent that cancer is a dreadful disease, irrespective of age and sex. The progression of cancer or metastasis depends on the origin and the nature of tissues involved. Recent research has endorsed the importance of tissue microenvironment in the development and progression of cancer. Such speculations are true and might stem from the observations that generation of free radicals may lead to mutation and cancer. For example, cancers of the haemopoietic system are more pronounced due to the presence of water in the extracellular spaces. Mutagens generate hydroxyl free radical from the water molecules, and acts indirectly on the cells of the haemopoietic system to induce carcinogenic effect.
Moreover, the progression of cancer is attributed to a failure in apoptosis or programmed cell death of the cancerous cells or tissues. The failure in apoptosis is chiefly attributed to presence of various growth factors in microenvironment of precancerous cells and due to an increased vascularity, either in those cells or microenvironment. The increased blood flow provides such cancerous tissue with oxygen, which further helps in the persistence and progression of cancerous cells. Therapeutic objective for managing cancer is based on inducing apoptosis, or destruction of cancerous cells. Recent approaches based on gene therapy, are being investigated in various human and murine models, which are aiming to modify the cancer microenvironment. However, the most common treatment schedules implicated in the management of cancer are surgery, chemotherapy and radiotherapy.
The current trends in management of cancer are to increase the life span of such individuals with increased safety profile of the chemotherapeutic and radiotherapy regimes. However, the social perspectives of a patient and the associated quality of life are not generally considered as treatment endpoints. With the advancements in chemotherapeutic regimes and radiotherapy, the survival rates have improved for young adult individuals suffering from cancer. However, the existing cancer therapies are documented to impose reproductive risks in such individuals. This hinders the social desire of such individuals or their family members, regarding the potential of their children (who are childhood cancer survivors) to enjoy fatherhood or motherhood in the future. Since, one out of 640 individuals in the age group of 20 to 39 years is a long-term pre-pubertal cancer survivor; maintenance of reproductive health should be a health care priority.
It is recognized through the analysis of literature that radiotherapy or chemotherapy can impose reproductive risk in a dose dependent or dose independent manner. The relative risks of suffering from infertility and pubertal developments are quite higher in children who receive such radiotherapy or chemotherapy regimes. Although, various chemotherapeutic alternatives or radiotherapy alternatives are being explored, no conclusive evidence has shown their impact on preserving reproductive health in childhood cancer survivors. Therefore, treatment options through new drug design and drug discovery must be encouraged and continued. On the other hand, newer approaches like gene therapy must be explored on the aspect of preserving reproductive health in childhood cancer survivors. At the same time such approaches must also ensure the efficacy and safety of treatment comparable to any chemotherapeutic or treatment regimes, if not superior.
In this regard considerable evidence has been accumulated on the initial success with gene therapy approaches. Such methods are based on the principle of inserting pro-apoptotic gene and inhibitors of vascular endothelial growth factors (VEGF). VEGF leads to the development of vascularity in the cancer cell microenvironment. Hence, anti-VEGF genes will help in prevention of vascularity and cutting off oxygen supply to either the cancerous cells or cancer cell microenvironment. On the other hand, insertion of pro-apoptotic gene helps in induction of apoptosis in cancerous cells. Such approaches would help in inducing death of cancerous cells and metastasis (progression of cancer in other tissues), in a very focused and targeted manner (Ledford, 2011).
This focused and targeted principle gene therapy will help in preventing systemic side effects which are evident with chemotherapy or radiotherapy. Adenovirus based gene therapy have been successfully implicated in adult patients suffering from ovarian cancer, however, till date, no studies with gene therapy have been initiated in pre-pubertal children (Ledford, 2011). Hence, gene therapy approaches must be expedited in childhood cancer patients. They should be evaluated, on the grounds of preserving the integrity of reproductive cells, and/or infertility in childhood cancer survivor patients.
With regard to the present chemotherapy and radiotherapy based regimes, consideration must be given in fixing the appropriate dose and duration of treatment. Treatments must not be generalized and should be modified on a case to case basis depending upon the body weight of the child, periodic assessment of reproductive viability through hormonal assays and follicular cell counts (in females) and spermatogonial cell counts(in males). Such stringent follow up and periodic assessment may help in improving the prognosis of future fertility in childhood cancer patients. Periodic assessments may also help to modify the initial treatment plan. This may involve dosage titration of the existing chemotherapy or radiotherapy regimes, change of such regimes, or intervention with combination of different regimes.
Apart from such approaches related to treatment and preserving the viability of the reproduction, the aspect of fertility preservation is gaining popularity. The current methods of preservation of gonadal function and integrity of gametes in childhood cancer patients pivot around hormonal and shielding manipulations. These interventions protect the testis or ovary from injury and maintain the reproductive of such organs. The primordial germ cells as evidenced in literature survey are highly sensitive to radiation therapy. However, shielding such cells during radiotherapy can only be implemented with selected radiations and is dependent on the anatomical location of the cancerous origin. Since, the primary objective of any cancer treatment is to eliminate a cancerous cell or a pro-cancerous cell, rather than protecting the reproductive viability in associated cells.
Such philosophy may encourage administration of radiotherapy along with removal of the gonads from the field of radiation through surgical interventions. This can be done by temporarily ablating out the gonads near the thigh or abdominal cavity. However, till date, such interventional modifications have not been reported. Preservation of gonadal function through hormonal manipulation have been carried out, and studied extensively. However, such interventions have not alleviated the issues like azoospermia or follicle atresia, in neither males nor females respectively (Wallace et al, 2005).
Interventions like xenotransplantation, auotransplantation or in vitro maturation, may be considered in pre-pubertal children, based on the initial findings in animal models. Such process can be intervened, as human spermatocytes are able to mature in vitro conditions, into mature and viable sprematids which are capable of fertilization. Testicular cryopreservation has been successfully implicated in male children who are survivors of childhood cancer (Wallace et al, 2011).
The current trends in preserving reproductive function of childhood cancer patients involve differential surgery. Such surgeries are being done in a conservative way in order to increase the viability of reproductive cells in near future after puberty. Surgical interventions are undertaken in early stages of cancer in such patients, so as to avoid the need of any chemotherapeutic or radiotherapy based interventions.
Apart from such interventional strategies, chemotherapeutic agents are considered which has the lowest possible risk of infertility in future. However, such conservative treatments may only be intervened in early stages of cancer. Procedures like unilateral adnexectomy are undertaken for preserving the functions of uterus related to implantation. When the cancer is in the early stages and the prognosis of such tumours are good, consideration must be give to therapy as single-agent chemotherapy. This is because treatment with single-agent chemotherapy, like methotrexate or actinomycin D, has been shown to preserve fertility (Wallace et al, 2011).
Further, administration of gonadotropin analogues has shown encouraging results in ensuring the function of reproductive cells. Intervention with such analogues has the potential to prevent follicle cell atresia and preserving their titre required for fertility potential. As per physiological mechanisms, these analogues may act as gonadotropin and induce either ovulation or act on the follicles to stimulate the release of oestrogen (Chen et al., 2011).
Such mechanism of action will lead to development of follicles into the mature Graffian follicle and also create the necessary oestrogen pulse required for the LH surge. These actions may lead to the maintenance of fertilization viability of reproductive cells and organs in girls. On the other hand, gonadal analogues may act on the male reproductive system and maintain the integrity of the spermatogonial cells, or maintain the effectiveness of Sertoli cell. Such functions will help in maintaining the fertilization viability of reproductive cells and organs in boys (Chen et al., 2011). Hence, intervention with such analogues must be considered with existing chemotherapeutic or radiotherapy regimes, and must be continued in the long term, if needed.
Decision of intervention should be selected based on the age or developmental maturity of an individual, the type of therapy recommended based on evidence based guidelines, the site of therapy where intervention is required, and the gender of the affected child (Wallace, et al, 2005).
The preservation of fertility in young adult cancer survivors has raised various ethical and social issues. Such issues include disclosure of reproductive effects of chemotherapy or radiotherapy, available options for fertility preservation with the available methods, the acceptance of such preservation options in the cultural perspective of the family of such affected children, and the desired consent of the parents or family members of such affected children in initiating treated interventions (Ginsberg et al, 2010).
Moreover, the crucial dilemma which exists amongst clinicians, and other health care providers, is to discuss the issue of counselling someone, who has not attained the reproductive age. However, medical ethics have felt the need to discuss such issues both with the affected child and their family members. Such discussions or counselling will not only create the necessary awareness and responsibility of being an adult fertile individual, but will also ensure adherence and compliance to treatment plan (Quinn et al., 2009).
Recent findings indicated that, such type of counselling and discussion with either the affected children or their parents is highly missing, in almost half the cases of childhood cancer. The studies indicated that either the physicians are not comfortable in discussing such issues with the individuals concerned or some physicians feel that parents would not be able to afford the fertility-preservation options. Moreover, the care givers also feel that treatment related to efficacy and safety is the key issue in treatment of cancer, and such issues of value addition like fertility prevention, is not under their professional priority (Quinn et al., 2009).
This is where I feel a person-centric approach or patient-centric approach must be implemented. The approach may be based on the interpersonal relations theory of Peplau. Moreover, various Clinical and Nursing Guidelines has recommended the importance of patient-centric approach in providing care to the patients (Koloroutis, 2010). The voice of the patient and their family must be respected and should be incorporated in the treatment as far as clinically possible. Such an action plan will help to maintain the social dignity of a cancer survivor and at the same time ensuring evidence based treatment.
5. References
Critchley HO & Wallace WH.(2005). “Impact of cancer treatment on uterine function”.
J Natl Cancer Inst Monogr; 34:64–8.
Chen H, Li J, Cui T, & Hu L.(2011). “Adjuvant gonadotropin releasing hormone analogues
for the prevention of chemotherapy induced premature ovarian failure in
premenopausal women”. Cochrane Database Syst Rev; 11:CD008018.
Ginsberg JP, Carlson CA, Lin K, Hobbie WL, Wigo E, Wu X, Brinster RL, & Kolon TF
(2010). “An experimental protocol for fertility preservation in prepubertal boys
recently diagnosed with cancer: a report of acceptability and safety”. Hum Reprod;
25:37–41
Green DM, Kawashima T, Stovall M, Leisenring W, Sklar CA,Mertens AC, Donaldson SS,
Byrne J, & Robison LL. (2009). “Fertility of female survivors of childhood cancer: a
report from the childhood cancer survivor study”. J Clin Oncol ; 27: 2677–85.
Green DM, Nolan VG, Kawashima T, Stovall M, Donaldson SS, Srivastava D, Leisenring W,
Robison LL, & Sklar CA.(2011). “Decreased fertility among female childhood cancer
survivors who received 22–27 Gy hypothalamic/pituitary irradiation: a report from the
Childhood Cancer Survivor Study”. Fertil Steril; 95:1922–7
Howell SJ, & Shalet SM. (2011). “Spermatogenesis after cancer treatment: damage and
recovery”. J Natl Cancer Inst Monogr; 34:12–7.
Koloroutis, M. (2010). Relationship-based care: A model for transferring practice.
Minneapolis, MN: Creative Care Management, Inc.
Ledford, H. (2011). “Cell therapy fights leukaemia”. Nature. doi:10.1038/news.2011.472.
Quinn GP, Vadaparampil ST, Lee JH, Jacobsen PB, Bepler G, Lancaster J, Keefe DL, &
Albrecht TL. (2009). “Physician referral for fertility preservation in oncology patients: a
national study of practice behaviours”. J Clin Oncol; 27:5952–7.
Reinmuth S, Hohmann C, Rendtorff R, Balcerek M, Holzhausen S, Müller A, Henze G, &
Borgmann-Staudt A. (2013). “Impact of chemotherapy and radiotherapy in childhood
on fertility in adulthood: the FeCt-survey of childhood cancer survivors in Germany”. J.
Cancer. Res. 39(12):2071-8
Sanders JE. (2008). “Growth and development after hematopoietic cell transplant in
children”. Bone Marrow Transplant ; 41:223–7.
Sudour H, Chastagner P, Claude L, Desandes E, Klein M, Carrie C, & Bernier V.(2010).
“Fertility and pregnancy outcome after abdominal irradiation that included or excluded
the pelvis in childhood tumor survivors”. Int J Radiat Oncol Biol Phys; 76: 867–73.
Stat bite .(2006). “Childhood cancer survival, 1975–2003”. J Natl Cancer Inst , 98:883.
Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE, Mertens AC,
Whitton JA, Robison LL, & Boice Jr JD.(2010). “Stillbirth and neonatal death in
relation to radiation exposure before conception: a retrospective cohort study”. Lancet;
376:624–30.
Signorello LB, Cohen SS, Bosetti C, Stovall M, Kasper CE, Weathers RE, Whitton JA,
Green DM, Donaldson SS, Mertens AC, Robison LL, & Boice Jr JD.(2006). “Female
survivors of childhood cancer: preterm birth and low birth weight among their
children”. J Natl Cancer Ins; 98:1453–61
van Beek RD, van den Heuvel-EibrinkMM, Laven JS, de Jong FH, Themmen AP, Hakvoort-
Cammel FG, van den Bos C, van den BergH, Pieters R, & deMuinck Keizer-
Schrama SM.(2007). “Anti-Mullerian hormone is a sensitive serum marker for
gonadal function in women treated for Hodgkin’s lymphoma during childhood”. J
Clin Endocrinol Metab; 92:3869–74.
Wo JY & Viswanathan AN. (2009). “Impact of radiotherapy on fertility, pregnancy, and
neonatal outcomes in female cancer patients”. Int J Radiat Oncol Biol Phys ;
73:1304–12.
Wallace WH, Thomson AB, Saran F, & Kelsey TW. (2005). “Predicting age of ovarian
failure after radiation to a field that includes the ovaries”. Int J Radiat Oncol Biol
Phys. 2005; 62:738–44.
Wallace WH. (2011). “Oncofertility and preservation of reproductive capacity in children and
young adults”. Cancer; 117:2301–10.