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Late reproductive effects of cancer treatment in female survivors of childhood malignancy
Current Obstetrics & Gynaecology (2003) 13, 369--372 c 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0957-5847(03)00065-9
Late reproductive effects of cancer treatment in female survivors of childhood malignancy Kate I.L. Patrick*,W. Hamish B.Wallacew and Hilary O. D. Critchleyz *Specialist Registrar in Obstetrics and Gynaecology, Simpson Centre for Reproductive Health, Royal Inf|rmary of Edinburgh; wConsultant Paediatric Oncologist and Senior Lecturer, Section of Child Life and Health, Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh; zConsultant Gynaecologist, Royal Inf|rmary of Edinburgh, Section of Obstetrics and Gynaecology, Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, UK
KEYWORDS childhood cancer; late effects; pregnancy
Summary In the last three decades, there has been a substantial improvement in survival rates of childhood cancers. As a result, we are encountering long-term sequlae of both the primary illness and of the therapy employed in treatment. The challenges include management of disorders of gonadal function, such as pubertal delay or failure, impaired menstruation, premature menopause and compromised fertility. When female survivors achieve a pregnancy, there is an increased risk of pregnancy loss, pre-term labour and intra-uterine growth retardation.Caesarean section, if required, may be complicated if the patient has had previous abdominal or pelvic surgery or radiotherapy. A multidisciplinary approach is a vital component of the management of all long-term survivors of childhood cancer, particularly of pregnancies in female patients. c 2003 Elsevier Ltd. All rights reserved.
INTRODUCTION Treatment of childhood cancers has improved signif|cantly over the last four decades, such that 80% of children with cancer will be alive 5 years from diagnosis. Forty years ago, the survival rate for the most prevalent childhood malignancy, acute lymphoblastic leukaemia, was under 10%. The number of long-term survivors is therefore increasing, and it has been estimated that by the year 2010, one in 250 young adults will have been treated for cancer in childhood. This dramatic improvement in prognosis of all childhood malignancies has brought new challenges in the management of these children. As a result, there has been a change in emphasis from ‘cure at any cost’ to one in which quality of life during and after treatment has become important. Therefore, whilst still striving to improve survival, attention must be directed to minimizing adverse effects of treatment, both in the short and long term. These late effects are diff|cult to predict with certainty; however, potential adverse effects on reproductive function must be recognized. Newer chemotherapeutic and radiation treatments aim to minimize gonadal destruction.The goal is not only to maintain gonadal function to allow normal secondary sexual development, but also to preserve reproductive
Correspondence to: HODC. Tel.: +44(0) 131 242 6439; Fax: +44(0) 131 242 6440; E-mail: [email protected]
function if possible. The case described below highlights some of the issues that complicate the survival of children who have been successfully treated for cancer. It is of particular importance to acknowledge that the greatest challenge is not simply the achievement of conception, but rather the effective, multidisciplinary management of a high-risk pregnancy in a survivor of childhood cancer.
CASE PROFILE A 29-year-old woman presented for booking at 10 weeks’ gestation in her f|rst pregnancy. Her past medical history was complicated as a result of treatment of a childhood malignancy. At the age of 2 years, she underwent an extensive laminectomy to excise an abdominal, retroperitoneal neuroblastoma. Adjuvant therapy consisted of both chemotherapy and radiation. She was given two courses of vincristine and cyclophosphamide. Radiotherapy was given to her at 2 years of age, to a 12 by 9 cm f|eld in the region of the left flank with a 4 mega voltage linear accelerator.The total dose of radiation was 16 Gy in 20 fractions over 7 weeks.The f|eld of treatment crossed the midline to prevent the development of scoliosis, and the left ovary was likely to have been within the radiation f|eld.The right ovary and uterus would have been outside the area of treatment but may have received a scatter dose.
370
She underwent a number of further surgical procedures in her childhood and adolescence having developed a flaccid paralysis and urinary dysfunction after the primary extensive laminectomy operation. Subsequently, she underwent permanent urinary diversion with bilateral cutaneous ureterostomies. Despite exposure to abdominal irradiation, puberty occurred spontaneously and was not delayed. Menarche occurred at the age of 11 years. Her menstrual cycle was regular and of normal duration, with her menses lasting for 5 days. At the age of 18 years, she commenced the oral combined contraceptive pill to avoid an unplanned pregnancy. At the age of 26 years, shortly before her marriage, she ceased the pill, having been counselled that she may have diff|culty conceiving spontaneously. The couple failed to conceive spontaneously after 2.5 years of unprotected intercourse. Investigations were commenced after the f|rst 12 months of primary infertility, and revealed that her cycle was ovulatory and her husband’s semen analysis was normal. In view of her previous extensive pelvic surgery, a diagnostic laparoscopy was not performed nor did the patient undergo a hysterosalpingogram. Prescription of oral clomiphene was an interim shortterm measure with clinicians anticipating that in-vitro fertilization would be required to achieve a pregnancy. She conceived following a single cycle of clomiphene citrate. The f|rst and second trimesters of the pregnancy were uncomplicated. Her antenatal serology was normal, as were her 10 -week booking and 18 -week fetal anomaly ultrasound scans. In particular, there was no evidence of uterine artery notching seen on the 18 -week ultrasound, and serial ultrasound scans of biometry in the early third trimester conf|rmed satisfactory growth of the fetus. At 31 weeks’ gestation, she developed a symptomatic urinary tract infection that was successfully treated with oral antibiotics. In view of her previous urological surgery and risk factors for recurrent urinary tract infection in pregnancy, she was commenced on prophylactic antibiotics for the remainder of gestation. Computed tomography (CT) of her pelvis was booked for 34 weeks’ gestation because of her clinically small pelvis, history of pelvic radiotherapy and Trendeleberg gait. At 33 weeks’ gestation, prior to planned CT pelvimetry, our patient presented with pre-term spontaneous rupture of the membranes. Initial management was conservative with intravenous antibiotics, intramuscular steroids and regular fetal monitoring. Three days after admission, she began to experience palpable and painful uterine contractions. In view of the now prolonged period of ruptured membranes, a co-existing low-grade maternal temperature and an uncomplicated fetal tachycardia, a vaginal examination was performed. The cervix was 4 cm dilated and it was decided to augment
CURRENT OBSTETRICS & GYNAECOLOGY
labour with a syntocinon infusion. Despite active management with oxytocin, dilatation of the cervix did not progress beyond 5 cm. In view of the failed augmentation and a persisting maternal pyrexia associated with a fetal tachycardia, the decision was made to perform a Caesarean section.The surgical team consisted of two obstetric consultants, a senior registrar in obstetrics and gynaecology and a consultant urologist. Prior to performing a suprapubic transverse abdominal incision, both ureters had stents inserted in view of the transverse course of each ureter to the lower midline ureterostomy site (midway between the symphysis pubis and the umbilicus).The Caesarean section was complicated by the presence of dense pelvic adhesions resulting from her multiple pelvic operations and previous pelvic irradiation. A healthy male was delivered in good condition with a birthweight of 2150 kg (weight just under 50th centile for gestation). His subsequent course in the neonatal unit was uncomplicated. The surgical closure of the uterine incision was diff|cult due to distortion of the pelvic anatomy. Extensive exploration of the incision site revealed that, in fact, delivery had inadvertently taken place through an extraperitoneal incision in the right upper vaginal fornix (laparoelytrotomy). A satisfactory repair was performed but in keeping with the complex nature of the surgery, intra-operative blood loss was substantial (3.5 litres) and a f|ve-unit blood transfusion was given peri-operatively. The maternal post-operative course was complicated by transient non-specif|c pyrexia treated successfully with antibiotics, and by vaginal pain which resolved spontaneously. A secondary post-operative complication of a retropubic abcess, requiring surgical drainage, was followed by a satisfactory recovery. Several months post partum, dysparunia and vaginal scarring necessitated a Z vaginoplasty. The procedure was a success and our patient was able to resume comfortable sexual intercourse. Permanent contraception remains a need for this patient. At the time of her post-partum vaginal surgery, she had a levonorgestrel-releasing intrauterine system (LNG-IUS) inserted for effective longterm contraception.
DISCUSSION The survival rate for children who are treated for cancer has improved dramatically over the past three decades as many childhood cancers are now treatable with multi-agent chemotherapy, in combination with radiation and surgery. Problems with fertility are well documented in the survivors. Adverse effects of chemotherapy or radiotherapy may be mediated through the hypothalamo-pituitary-ovarian axis, the ovary or the uterus. This case clearly identif|es the reproductive challenges that face survivors of childhood
LATE EFFECTS OF CANCERTREATMENT
malignancies.This patient was exposed to both systemic chemotherapy and abdominal radiotherapy. Cyclophosphamide, an alkylating agent, is known to be toxic to the gonads.The ovary is chemosensitive although the extent of damage varies according to drug type, dosage and age of the patient at the time of treatment. Females are generally less susceptible to the deleterious effects of chemotherapy compared with males. Nevertheless, ovarian dysfunction is well recognized following combination chemotherapy. Ovarian damage is drug and dose dependent, and is related to age at time of treatment, with progressively smaller doses required to produce ovarian failure with increasing age.Total body, abdominal or pelvic irradiation may cause ovarian and uterine damage, and the degree of impairment is related to the radiation dose, fractionation schedule and age at time of treatment. In the ovary, the female gamete pool is complete at birth with as many as two million primordial follicles present. Depletion of primordial follicles is proportional to the oocyte pool; consequently, the size of the remaining pool will determine the fertile window and dictate the time until menopause. This means that the younger the child at the time of radiotherapy, the larger the oocyte pool and hence the later the onset of menopause. The human oocyte is very sensitive to radiation, with an estimated LD50 of less than 2 Gy. Permanent menopause may be induced in women over 40 years of age following treatment with 6 Gy, while signif|cantly higher doses are required to completely destroy the oocyte pool and induce ovarian failure in young women and children. There are no data as regards the threshold chemotherapy doses for ovarian damage. The impact of these drugs is made harder to def|ne because multiple agents are often used together. In our patient’s case, the spontaneous onset of puberty at the correct time was reassuring but not in itself an indication of normal future ovarian function. It would not have been possible to assess ovarian toxicity by gonadotrophin assessment prior to the onset of puberty. Once puberty has been established, elevated gonadotrophins, an undetectable oestradiol and failure of pubertal progression signal severe early ovarian failure, and treatment with oestrogen replacement would be indicated. As it was, our patient occupied the group of patients least likely to suffer severe ovarian chemotoxicity. She was a small infant at the time of her chemotherapy, and whilst her gamete pool would have been going through age-related exponential decline since birth, her overall number of ovarian primordial follicles at the time of therapeutic insult would have been high.Chemotherapy does not have a deleterious effect on the developing uterus, nor is it associated with an increased miscarriage rate in subsequent successful pregnancies. Our patient did not receive total body irradiation. In fact, the pelvis was not a direct target during her treat-
371
ment.Young women exposed to radiotherapy below the diaphragm may suffer potential reproductive problems, including risk of ovarian failure and impaired development of the uterus. Study of our patient’s anterior abdominal and posterior lower spinal f|eld diagrams reveals that it is likely that her pelvic organs were irradiated to some degree. The younger the patient is at the time of treatment, the greater her oocyte pool and the greater the surviving number of oocytes. Also, the younger the patient is at the time of treatment, the later the onset of menopause. As we have noted previously, our patient would have sustained less primordial follicle destruction than a post-pubertal patient receiving the same adjuvant therapy. Whilst ovarian radiotoxicity is inversely related to age, the uterus is more vulnerable in younger patients. The magnitude of the risk to uterine function is related to the radiation f|eld, total dose and fractionation schedule of radiotherapy. Pre-term labour and lowbirthweight infants are reported after flank abdominal radiation. Female long-term survivors, exposed to total body irradiation (14 Gy) and bone marrow transplant, are at risk of impaired uterine growth and blood flow, early pregnancy loss and pre-term labour even if a pregnancy is achieved. The uterus of these young women is often reduced to 40% of the normal adult size. The uterine volume correlates with the age at which radiotherapy was administered. Thus when a pre-pubertal, immature uterus is exposed to radiotherapy, there is a likelihood of reduction in elasticity of the myometrium and a reduction in overall uterine volume. The reproductive consequences of uterine radiation damage are due to reduced uterine elasticity, f|brosis and vascular damage. As a result, there is an increased rate of miscarriage, pre-term delivery and intra-uterine growth retardation. Consequently, all pregnancies in women who are survivors of childhood cancer must be considered to be high risk, and multidisciplinary team management is usually indicated. Our patient had co-existing urological morbidity as a result of her primary surgical management as a 2-yearold child.The secondary urinary neuropathy led to multiple reconstructive procedures and, ultimately, to permanent urinary diversion. A urologist was closely involved throughout her pregnancy. An anaesthetic opinion was sought antenatally, given her history of spinal surgery, to assess her suitability for a regional anaesthetic in labour. In fact, she underwent a general anaesthetic for her Caesarean section as it was anticipated that the procedure would be long and complicated. Avery important aspect of our patient’s case is the impact of multiple pelvic surgical procedures on the delivery itself. An attempt was made to achieve a vaginal delivery because of her complex surgical history. When the Caesarean section was organized, an experienced multidisciplinary team of
372
CURRENT OBSTETRICS & GYNAECOLOGY
obstetricians, anaesthetists, a urologist and a neonatal paediatrician was present. Her pelvic anatomy was clearly distorted and this led to an inadvertent laparoelytrotomy being performed. An inexperienced surgeon may not have identif|ed this complication. An intra-operative vaginal examination was performed in order to ensure that the uterus, cervix and vagina had been returned to their normal anatomical relationship. The intra-operative blood loss and postoperative abcess are peri-operative complications that are in keeping with a procedure of this complexity. At this stage, our patient is not planning to have another pregnancy.The risk of future premature delivery is significant and the associated neonatal morbidity has been fully discussed.The surgical aspect of a subsequent delivery would be more complicated than her previous delivery, and might result in unacceptably high maternal complications. Her need for effective long-term contraception is a major issue for this patient. She has found a LNG-IUS a very acceptable contraceptive option to meet this need. In summary, therefore, this case prof|le highlights the need for multidisciplinary involvement in the care of patients who are survivors of childhood cancer. After treatment with chemotherapy and/or radiotherapy and/ or surgery, typical concerns will centre on future fertility prospects, sexual functioning and optimal hormone replacement. If pregnancy is achieved (either spontaneously or with assistance), there will be risks of early pregnancy loss, premature delivery and anxiety about optimal mode of delivery. These diverse needs of patients will be best served from a multidisciplinary approach. In due course, the availability of evidence-based guidelines for the management of long-term childhood cancer survivors will be an invaluable contribution to their care.
PRACTICE POINTS *
*
The pre-pubertal ovary is vulnerable to chemotherapy Uterine size and function may be affected by radiotherapy, particularly before puberty
*
*
*
* *
*
*
*
Ovarian function is diff|cult to assess until activation of the hypothalamic pituitary gonadal axis at puberty Even if puberty occurs spontaneously, ovarian activity may be short lived Survivors of childhood cancer often have multisystem problems Pregnancies in these patients are high risk Multidisciplinary pre-conceptual, antenatal, intra- and post-partum care is vital Surgery in these patients may be complex due to previous surgery and radiotherapy Each patient has a conundrum of medical problems exclusive to them Strictly individualized medical care should be tailored for each patient
FURTHER READING Bath LE, Critchley HOD, Chambers SE, Anderson RA, Kelnar CT, Wallace WH. Ovarian and uterine characteristics after total body irradiation in Childhood and adolescence: response to sex steroid replacement. Br J Obstetr Gynaecol 1999; 106: 1265--1272. Bath LE, Wallace WHB, Critchley HOD. Late effects of the treatment of childhood cancer on the female reproductive system and the potential for fertility preservation. Br J Obstetr Gynaecol 2002; 109: 107--114. Critchley HOD, Bath LE, Wallace WHB. Radiation damage to the uterusFreview of the effects of treatment of childhood cancer. Hum Fertil 2002; 5: 61--66. Critchley HOD, Wallace WHB, Mamtora M, Higginson J, Anderson DC, Shalet SM. Abdominal irradiation in childhood; the potential for pregnancy. Br J Obstetr Gynaecol 1992; 99: 392--394. Davies H, Greenfield D, Ledger W. Reproductive medicine in a late effects of cancer clinic. Hum Fertil 2003; 6: 9--12. Mertens AC, Yasui Y, Neglia JP et al. Late mortality experience in fiveyear survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 2001; 19: 3163--3172. Peleg D, Perhtz Y, Pansky S, Levit A, Ben-Ami M. Accidental delivery through a vaginal incision (laparoelytrotomy) during Caesarean section in the second stage of labour. Br J Obstetr Gynaecol 2001; 108: 659--660. Thomson AB, Critchley HOD, Kelnar CJH, Wallace WHB. Late reproductive sequelae following treatment of childhood cancer and options for fertility. Best Prac Res Clin Endo Metab 2002; 2: 311--334. Wallace WHB, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod 2003; 18: 117--121. Wallace WHB, Blacklay A, Eiser C et al. Developing strategies for longterm follow up of survivors of childhood cancer. BMJ 2001; 323: 271--274.
Late reproductive effects of cancer treatment in female survivors of childhood malignancy Kate I.L. Patrick*,W. Hamish B.Wallacew and Hilary O. D. Critchleyz *Specialist Registrar in Obstetrics and Gynaecology, Simpson Centre for Reproductive Health, Royal Inf|rmary of Edinburgh; wConsultant Paediatric Oncologist and Senior Lecturer, Section of Child Life and Health, Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh; zConsultant Gynaecologist, Royal Inf|rmary of Edinburgh, Section of Obstetrics and Gynaecology, Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, UK
KEYWORDS childhood cancer; late effects; pregnancy
Summary In the last three decades, there has been a substantial improvement in survival rates of childhood cancers. As a result, we are encountering long-term sequlae of both the primary illness and of the therapy employed in treatment. The challenges include management of disorders of gonadal function, such as pubertal delay or failure, impaired menstruation, premature menopause and compromised fertility. When female survivors achieve a pregnancy, there is an increased risk of pregnancy loss, pre-term labour and intra-uterine growth retardation.Caesarean section, if required, may be complicated if the patient has had previous abdominal or pelvic surgery or radiotherapy. A multidisciplinary approach is a vital component of the management of all long-term survivors of childhood cancer, particularly of pregnancies in female patients. c 2003 Elsevier Ltd. All rights reserved.
INTRODUCTION Treatment of childhood cancers has improved signif|cantly over the last four decades, such that 80% of children with cancer will be alive 5 years from diagnosis. Forty years ago, the survival rate for the most prevalent childhood malignancy, acute lymphoblastic leukaemia, was under 10%. The number of long-term survivors is therefore increasing, and it has been estimated that by the year 2010, one in 250 young adults will have been treated for cancer in childhood. This dramatic improvement in prognosis of all childhood malignancies has brought new challenges in the management of these children. As a result, there has been a change in emphasis from ‘cure at any cost’ to one in which quality of life during and after treatment has become important. Therefore, whilst still striving to improve survival, attention must be directed to minimizing adverse effects of treatment, both in the short and long term. These late effects are diff|cult to predict with certainty; however, potential adverse effects on reproductive function must be recognized. Newer chemotherapeutic and radiation treatments aim to minimize gonadal destruction.The goal is not only to maintain gonadal function to allow normal secondary sexual development, but also to preserve reproductive
Correspondence to: HODC. Tel.: +44(0) 131 242 6439; Fax: +44(0) 131 242 6440; E-mail: [email protected]
function if possible. The case described below highlights some of the issues that complicate the survival of children who have been successfully treated for cancer. It is of particular importance to acknowledge that the greatest challenge is not simply the achievement of conception, but rather the effective, multidisciplinary management of a high-risk pregnancy in a survivor of childhood cancer.
CASE PROFILE A 29-year-old woman presented for booking at 10 weeks’ gestation in her f|rst pregnancy. Her past medical history was complicated as a result of treatment of a childhood malignancy. At the age of 2 years, she underwent an extensive laminectomy to excise an abdominal, retroperitoneal neuroblastoma. Adjuvant therapy consisted of both chemotherapy and radiation. She was given two courses of vincristine and cyclophosphamide. Radiotherapy was given to her at 2 years of age, to a 12 by 9 cm f|eld in the region of the left flank with a 4 mega voltage linear accelerator.The total dose of radiation was 16 Gy in 20 fractions over 7 weeks.The f|eld of treatment crossed the midline to prevent the development of scoliosis, and the left ovary was likely to have been within the radiation f|eld.The right ovary and uterus would have been outside the area of treatment but may have received a scatter dose.
370
She underwent a number of further surgical procedures in her childhood and adolescence having developed a flaccid paralysis and urinary dysfunction after the primary extensive laminectomy operation. Subsequently, she underwent permanent urinary diversion with bilateral cutaneous ureterostomies. Despite exposure to abdominal irradiation, puberty occurred spontaneously and was not delayed. Menarche occurred at the age of 11 years. Her menstrual cycle was regular and of normal duration, with her menses lasting for 5 days. At the age of 18 years, she commenced the oral combined contraceptive pill to avoid an unplanned pregnancy. At the age of 26 years, shortly before her marriage, she ceased the pill, having been counselled that she may have diff|culty conceiving spontaneously. The couple failed to conceive spontaneously after 2.5 years of unprotected intercourse. Investigations were commenced after the f|rst 12 months of primary infertility, and revealed that her cycle was ovulatory and her husband’s semen analysis was normal. In view of her previous extensive pelvic surgery, a diagnostic laparoscopy was not performed nor did the patient undergo a hysterosalpingogram. Prescription of oral clomiphene was an interim shortterm measure with clinicians anticipating that in-vitro fertilization would be required to achieve a pregnancy. She conceived following a single cycle of clomiphene citrate. The f|rst and second trimesters of the pregnancy were uncomplicated. Her antenatal serology was normal, as were her 10 -week booking and 18 -week fetal anomaly ultrasound scans. In particular, there was no evidence of uterine artery notching seen on the 18 -week ultrasound, and serial ultrasound scans of biometry in the early third trimester conf|rmed satisfactory growth of the fetus. At 31 weeks’ gestation, she developed a symptomatic urinary tract infection that was successfully treated with oral antibiotics. In view of her previous urological surgery and risk factors for recurrent urinary tract infection in pregnancy, she was commenced on prophylactic antibiotics for the remainder of gestation. Computed tomography (CT) of her pelvis was booked for 34 weeks’ gestation because of her clinically small pelvis, history of pelvic radiotherapy and Trendeleberg gait. At 33 weeks’ gestation, prior to planned CT pelvimetry, our patient presented with pre-term spontaneous rupture of the membranes. Initial management was conservative with intravenous antibiotics, intramuscular steroids and regular fetal monitoring. Three days after admission, she began to experience palpable and painful uterine contractions. In view of the now prolonged period of ruptured membranes, a co-existing low-grade maternal temperature and an uncomplicated fetal tachycardia, a vaginal examination was performed. The cervix was 4 cm dilated and it was decided to augment
CURRENT OBSTETRICS & GYNAECOLOGY
labour with a syntocinon infusion. Despite active management with oxytocin, dilatation of the cervix did not progress beyond 5 cm. In view of the failed augmentation and a persisting maternal pyrexia associated with a fetal tachycardia, the decision was made to perform a Caesarean section.The surgical team consisted of two obstetric consultants, a senior registrar in obstetrics and gynaecology and a consultant urologist. Prior to performing a suprapubic transverse abdominal incision, both ureters had stents inserted in view of the transverse course of each ureter to the lower midline ureterostomy site (midway between the symphysis pubis and the umbilicus).The Caesarean section was complicated by the presence of dense pelvic adhesions resulting from her multiple pelvic operations and previous pelvic irradiation. A healthy male was delivered in good condition with a birthweight of 2150 kg (weight just under 50th centile for gestation). His subsequent course in the neonatal unit was uncomplicated. The surgical closure of the uterine incision was diff|cult due to distortion of the pelvic anatomy. Extensive exploration of the incision site revealed that, in fact, delivery had inadvertently taken place through an extraperitoneal incision in the right upper vaginal fornix (laparoelytrotomy). A satisfactory repair was performed but in keeping with the complex nature of the surgery, intra-operative blood loss was substantial (3.5 litres) and a f|ve-unit blood transfusion was given peri-operatively. The maternal post-operative course was complicated by transient non-specif|c pyrexia treated successfully with antibiotics, and by vaginal pain which resolved spontaneously. A secondary post-operative complication of a retropubic abcess, requiring surgical drainage, was followed by a satisfactory recovery. Several months post partum, dysparunia and vaginal scarring necessitated a Z vaginoplasty. The procedure was a success and our patient was able to resume comfortable sexual intercourse. Permanent contraception remains a need for this patient. At the time of her post-partum vaginal surgery, she had a levonorgestrel-releasing intrauterine system (LNG-IUS) inserted for effective longterm contraception.
DISCUSSION The survival rate for children who are treated for cancer has improved dramatically over the past three decades as many childhood cancers are now treatable with multi-agent chemotherapy, in combination with radiation and surgery. Problems with fertility are well documented in the survivors. Adverse effects of chemotherapy or radiotherapy may be mediated through the hypothalamo-pituitary-ovarian axis, the ovary or the uterus. This case clearly identif|es the reproductive challenges that face survivors of childhood
LATE EFFECTS OF CANCERTREATMENT
malignancies.This patient was exposed to both systemic chemotherapy and abdominal radiotherapy. Cyclophosphamide, an alkylating agent, is known to be toxic to the gonads.The ovary is chemosensitive although the extent of damage varies according to drug type, dosage and age of the patient at the time of treatment. Females are generally less susceptible to the deleterious effects of chemotherapy compared with males. Nevertheless, ovarian dysfunction is well recognized following combination chemotherapy. Ovarian damage is drug and dose dependent, and is related to age at time of treatment, with progressively smaller doses required to produce ovarian failure with increasing age.Total body, abdominal or pelvic irradiation may cause ovarian and uterine damage, and the degree of impairment is related to the radiation dose, fractionation schedule and age at time of treatment. In the ovary, the female gamete pool is complete at birth with as many as two million primordial follicles present. Depletion of primordial follicles is proportional to the oocyte pool; consequently, the size of the remaining pool will determine the fertile window and dictate the time until menopause. This means that the younger the child at the time of radiotherapy, the larger the oocyte pool and hence the later the onset of menopause. The human oocyte is very sensitive to radiation, with an estimated LD50 of less than 2 Gy. Permanent menopause may be induced in women over 40 years of age following treatment with 6 Gy, while signif|cantly higher doses are required to completely destroy the oocyte pool and induce ovarian failure in young women and children. There are no data as regards the threshold chemotherapy doses for ovarian damage. The impact of these drugs is made harder to def|ne because multiple agents are often used together. In our patient’s case, the spontaneous onset of puberty at the correct time was reassuring but not in itself an indication of normal future ovarian function. It would not have been possible to assess ovarian toxicity by gonadotrophin assessment prior to the onset of puberty. Once puberty has been established, elevated gonadotrophins, an undetectable oestradiol and failure of pubertal progression signal severe early ovarian failure, and treatment with oestrogen replacement would be indicated. As it was, our patient occupied the group of patients least likely to suffer severe ovarian chemotoxicity. She was a small infant at the time of her chemotherapy, and whilst her gamete pool would have been going through age-related exponential decline since birth, her overall number of ovarian primordial follicles at the time of therapeutic insult would have been high.Chemotherapy does not have a deleterious effect on the developing uterus, nor is it associated with an increased miscarriage rate in subsequent successful pregnancies. Our patient did not receive total body irradiation. In fact, the pelvis was not a direct target during her treat-
371
ment.Young women exposed to radiotherapy below the diaphragm may suffer potential reproductive problems, including risk of ovarian failure and impaired development of the uterus. Study of our patient’s anterior abdominal and posterior lower spinal f|eld diagrams reveals that it is likely that her pelvic organs were irradiated to some degree. The younger the patient is at the time of treatment, the greater her oocyte pool and the greater the surviving number of oocytes. Also, the younger the patient is at the time of treatment, the later the onset of menopause. As we have noted previously, our patient would have sustained less primordial follicle destruction than a post-pubertal patient receiving the same adjuvant therapy. Whilst ovarian radiotoxicity is inversely related to age, the uterus is more vulnerable in younger patients. The magnitude of the risk to uterine function is related to the radiation f|eld, total dose and fractionation schedule of radiotherapy. Pre-term labour and lowbirthweight infants are reported after flank abdominal radiation. Female long-term survivors, exposed to total body irradiation (14 Gy) and bone marrow transplant, are at risk of impaired uterine growth and blood flow, early pregnancy loss and pre-term labour even if a pregnancy is achieved. The uterus of these young women is often reduced to 40% of the normal adult size. The uterine volume correlates with the age at which radiotherapy was administered. Thus when a pre-pubertal, immature uterus is exposed to radiotherapy, there is a likelihood of reduction in elasticity of the myometrium and a reduction in overall uterine volume. The reproductive consequences of uterine radiation damage are due to reduced uterine elasticity, f|brosis and vascular damage. As a result, there is an increased rate of miscarriage, pre-term delivery and intra-uterine growth retardation. Consequently, all pregnancies in women who are survivors of childhood cancer must be considered to be high risk, and multidisciplinary team management is usually indicated. Our patient had co-existing urological morbidity as a result of her primary surgical management as a 2-yearold child.The secondary urinary neuropathy led to multiple reconstructive procedures and, ultimately, to permanent urinary diversion. A urologist was closely involved throughout her pregnancy. An anaesthetic opinion was sought antenatally, given her history of spinal surgery, to assess her suitability for a regional anaesthetic in labour. In fact, she underwent a general anaesthetic for her Caesarean section as it was anticipated that the procedure would be long and complicated. Avery important aspect of our patient’s case is the impact of multiple pelvic surgical procedures on the delivery itself. An attempt was made to achieve a vaginal delivery because of her complex surgical history. When the Caesarean section was organized, an experienced multidisciplinary team of
372
CURRENT OBSTETRICS & GYNAECOLOGY
obstetricians, anaesthetists, a urologist and a neonatal paediatrician was present. Her pelvic anatomy was clearly distorted and this led to an inadvertent laparoelytrotomy being performed. An inexperienced surgeon may not have identif|ed this complication. An intra-operative vaginal examination was performed in order to ensure that the uterus, cervix and vagina had been returned to their normal anatomical relationship. The intra-operative blood loss and postoperative abcess are peri-operative complications that are in keeping with a procedure of this complexity. At this stage, our patient is not planning to have another pregnancy.The risk of future premature delivery is significant and the associated neonatal morbidity has been fully discussed.The surgical aspect of a subsequent delivery would be more complicated than her previous delivery, and might result in unacceptably high maternal complications. Her need for effective long-term contraception is a major issue for this patient. She has found a LNG-IUS a very acceptable contraceptive option to meet this need. In summary, therefore, this case prof|le highlights the need for multidisciplinary involvement in the care of patients who are survivors of childhood cancer. After treatment with chemotherapy and/or radiotherapy and/ or surgery, typical concerns will centre on future fertility prospects, sexual functioning and optimal hormone replacement. If pregnancy is achieved (either spontaneously or with assistance), there will be risks of early pregnancy loss, premature delivery and anxiety about optimal mode of delivery. These diverse needs of patients will be best served from a multidisciplinary approach. In due course, the availability of evidence-based guidelines for the management of long-term childhood cancer survivors will be an invaluable contribution to their care.
PRACTICE POINTS *
*
The pre-pubertal ovary is vulnerable to chemotherapy Uterine size and function may be affected by radiotherapy, particularly before puberty
*
*
*
* *
*
*
*
Ovarian function is diff|cult to assess until activation of the hypothalamic pituitary gonadal axis at puberty Even if puberty occurs spontaneously, ovarian activity may be short lived Survivors of childhood cancer often have multisystem problems Pregnancies in these patients are high risk Multidisciplinary pre-conceptual, antenatal, intra- and post-partum care is vital Surgery in these patients may be complex due to previous surgery and radiotherapy Each patient has a conundrum of medical problems exclusive to them Strictly individualized medical care should be tailored for each patient
FURTHER READING Bath LE, Critchley HOD, Chambers SE, Anderson RA, Kelnar CT, Wallace WH. Ovarian and uterine characteristics after total body irradiation in Childhood and adolescence: response to sex steroid replacement. Br J Obstetr Gynaecol 1999; 106: 1265--1272. Bath LE, Wallace WHB, Critchley HOD. Late effects of the treatment of childhood cancer on the female reproductive system and the potential for fertility preservation. Br J Obstetr Gynaecol 2002; 109: 107--114. Critchley HOD, Bath LE, Wallace WHB. Radiation damage to the uterusFreview of the effects of treatment of childhood cancer. Hum Fertil 2002; 5: 61--66. Critchley HOD, Wallace WHB, Mamtora M, Higginson J, Anderson DC, Shalet SM. Abdominal irradiation in childhood; the potential for pregnancy. Br J Obstetr Gynaecol 1992; 99: 392--394. Davies H, Greenfield D, Ledger W. Reproductive medicine in a late effects of cancer clinic. Hum Fertil 2003; 6: 9--12. Mertens AC, Yasui Y, Neglia JP et al. Late mortality experience in fiveyear survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 2001; 19: 3163--3172. Peleg D, Perhtz Y, Pansky S, Levit A, Ben-Ami M. Accidental delivery through a vaginal incision (laparoelytrotomy) during Caesarean section in the second stage of labour. Br J Obstetr Gynaecol 2001; 108: 659--660. Thomson AB, Critchley HOD, Kelnar CJH, Wallace WHB. Late reproductive sequelae following treatment of childhood cancer and options for fertility. Best Prac Res Clin Endo Metab 2002; 2: 311--334. Wallace WHB, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod 2003; 18: 117--121. Wallace WHB, Blacklay A, Eiser C et al. Developing strategies for longterm follow up of survivors of childhood cancer. BMJ 2001; 323: 271--274.