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CANCER THERAPY

by Dr. Keshav Malhotra

INTRODUCTION

Cancer therapy has advanced and with this it has increased the number of long term cancer survivor worldwide. It had been suggested that by 2010 1 in 250 adult would be a childhood cancer survivor. in india alone the number of patients who would develop cancer in their lifetime is set to go up from 9.79 lacs in 2010 to 11.4 lacs by 2020, out of these more than 140,000 would be diagnosed in their reproductive age. Fertility preservation has now become an important aspect of care for patients with cancer. With the increase in long term survival, quality of lives post remission is also an important factor to considered by patients these days. There are some guidelines which suggest that fertility preservation should be done prior to initiation of chemotherapy or radiotherapy but its a sad truth that very few actually implement it in practice. There are now numerous techniques for fertility preservation, while oocyte and embryo cryopreservation have proven their efficacy, ovarian tissue cryopreservation is an upcoming modality, for the men sperm freezing and testicular tissue freezing are available but does impose a lot of challenges in prepubertal age groups.We know that both chemotherapy and radiotherapy have negative effects on male and female fertility, and in this era the counselling for patients specially those with good prognosis fro long term survival should have a multidiscipline counselling involving both oncologists and gynaecologists. the emphasis in the management of cancer has tremendously evolved and changed from cure at any cost to improving the quality of life post treatment.

Effect of cancer therapies on fertility
Chemotherapeutic agents produce a varied effect on fertility and it involves different pathophysiological pathways, which makes it difficult to predict the effect, also makes it difficult to understand and thus counsel. we have a basic understanding that the chemotherapeutic agents target proliferating cells like bone marrow and ovarian follicles etc, the reported rates of premature ovarian failure in such patients differs considerably. It is a known dilemma for oncologist that women are born with their full complement of eggs which decreases with time till they achieve menopause, and both chemotherapy and radiotherapy accelerate that decline, if the eggs survive they might lose their functional competence as the dNA in such eggs might have been compromised due to the therapy, and though this response in varied in women, ovarian dysfunction post chemotherapy is quite common specially when using alkylating agents. Cancer survivors post chemotherapy can conceive naturally as there have been reports in literature regarding the same but we know that chemotherapeutic agents can be mutagenic and teratogenic and thus conception in such women should be delayed otherwise there is a risk of congenital malformations specially if conception happens within 3 months post treatment as suggested by animal models. However in humans the Live birth rates in survivors are similar to their siblings, there has been no reports of significant increase in malformations, abortions, genetic defects when conception has taken place long after finishing therapy. Risk has been proposed to be maximum during oocyte maturation and not when they’re dormant, therefore it is suggested that a woman should wait about 6 months after finishing treatment in order to conceive and even if preservation isn’t done before treatment it should be done 6 months post it and not in between, the safety guidelines for this are yet to be established. In men the chemotherapeutic agents have a profound effect on the seminiferous tissues, which is the crux of spermatogenesis but leydig cells tend to tolerate chemotherapy better and thus post treatment even though these men might be rendered as oligo-asthenozoospermic they still produce testosterone.

There have been various studies which have stated that gonads might be highly sensitive to irradiation and the damage induced by radiotherapy depends on the field of exposure the dosage and also the age of the patient at time of exposure. The human egg is highly susceptible to damage due to irradiation and the LD 50 which is the lethal dosage to kill half of the pool of oocytes has been shown to be < 2 Gy Wallace et al, 2003. Wallace 2005 also studied the sterilising dosage which is when 97.5% of the oocytes are lost and this varies with age which is shown in the chart. it is not just the ovaries that are susceptible to damage, the uterus also undergoes changes post irradiation, and radiation can cause reduction in blood flow, fibrosis and even endometrial insufficiency and atrophy. a dosage of about 12 Gy can cause significant effects on the uterus, there have been studies which have reported an increase in miscarriage rate, IUGR, preterm deliveries, and even low weight at birth apart from an increase in the incidence of infertility within a year of irradiation. A radiation dosage of 25gy and above can cause permeant and irreversible uterine damage in childhood cases.

In men a radiation dosage of 0.1-1.2 gy could result in detectable damage but a dosage of 4Gy causes permanent damage. As far as paediatric oncology is concerned, post radiation testicular dysfunction is one of the commonest issues specially in common cancers like leukemia. Treatment for it includes irradiation with doses going as high as 24Gy which can render the child as azoospermic. A total body irradiation dose for bone marrow conditioning before transplant is also 14.4 Gy and can cause permanent damage but leydig cell function might get spared. The various chemo and radiotherapy options and their effect on fertility both male and female are mentioned in the tables.



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