Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE).

STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.

Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters.

Younger children are considered to be more vulnerable to late effects (LE), which prompted us to study LE in patients after haematopoietic stem cell transplantation (HSCT) for a haematological malignancy before the age of 3. In this multicentre EBMT study, cumulative incidence (CI) and severity of endocrine LE, central nervous system complications and secondary malignancies at 5, 10, 15 and 20 years of follow-up were assessed. Risk factors (RF) like gender, diagnosis, age at and year of HSCT, TBI- or chemo-conditioning and GVHD were analysed. CI of any LE was 0.30, 0.52, 0.66 and 0.72 at 5, 10, 15 and 20 years after HSCT, respectively. In 25% of the patients, LE were severe at a median follow-up of 10.4 years. In multivariate analysis, only TBI was a RF for having any LE and for thyroid dysfunction and growth disturbance. Female gender was a RF for delayed pubertal development. Some more insight could be gained by descriptive analysis regarding the role of TBI and GVHD on the severity of LE. Although only five selected LE have been studied and median follow-up is relatively short, the incidence and severity of these LE are considerable but not different from what has been found in older children and TBI is the main RF.

Sexually dimorphic and radiation dose dependent effect of cranial irradiation on body mass index.

OBJECTIVES: To investigate the relation between cranial irradiation received during treatment for childhood leukaemia and obesity at final height. DESIGN: Retrospective cross sectional study. SETTING: Paediatric oncology centres at Great Ormond Street Hospital for Children and the Royal Marsden Hospital. SUBJECTS: Survivors of childhood leukaemia who received cranial irradiation, were in continuous first remission, and had reached final height. An unirradiated group of patients from the United Kingdom acute lymphoblastic leukaemia XI trial was also included; these patients were in continuous first remission and had been followed for at least four years from diagnosis. MAIN OUTCOME MEASURES: Body mass index standard deviation score (BMI z score) at final height for irradiated patients and at most recent follow up for unirradiated patients. Regression analysis was used to examine the effect on BMI z score of sex, age at diagnosis, and the dose of radiation received. RESULTS: For cranially irradiated patients, an increase in the BMI z score at final height was associated with female sex and lower radiation dose, but not with age at diagnosis. Severe obesity, defined as a BMI z score of > 3 at final height, was only present in girls who received 18-20 Gy irradiation and had a prevalence of 8%. Both male and female unirradiated patients had raised BMI z scores at latest follow up and there was no association with age at diagnosis. CONCLUSIONS: These data are further evidence for a sexually dimorphic and dose dependent effect of radiation on the human brain.

Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT.

Few data are available on the long-term effect of bone marrow transplantation (BMT) on growth. This study examines those factors that play a role in the final height outcome of patients who underwent BMT during childhood. Data on 181 of 230 patients with aplastic anemia, leukemias, and lymphomas who had BMT before puberty (mean age, 9.8 +/- 2.6 years) and who had reached their final height were analyzed. An overall decrease in final height standard deviation score (SDS) value was found compared with the height at BMT (P < 10(7)) and with the genetic height (P < 10(7)). Girls did better than boys, and the younger in age the person was at time of BMT, the greater the loss in height. Previous cranial irradiation + single-dose total body irradiation (TBI) caused the greatest negative effect on final height achievement (P < 10(4)). Fractionation of TBI reduces this effect significantly and conditioning with busulfan and cyclophosphamide seems to eliminate it. The type of transplantation, graft-versus-host disease, growth hormone, or steroid treatment did not influence final height. Irradiation, male gender and young age at BMT were found to be major factors for long-term height loss. Nevertheless, the majority of patients (140/181) have reached adult height within the normal range of the general population.

Total body irradiation-induced osteochondromata.

Nine patients developed osteochondromata, a mean of 6 years after total body irradiation (TBI) given before bone marrow transplantation for childhood leukaemia. This represents 23% of patients receiving TBI during the period from 1981 to 1989 surviving > or =5 years after bone marrow transplantation. The patients were followed up for a mean of 12.5 years from diagnosis of leukaemia and a mean of 2.5 years from diagnosis of osteochondromata. No osteochondroma, including three lesions removed surgically, showed evidence of malignant change. Six patients received growth hormone for irradiation-induced growth hormone deficiency, but this did not appear to influence the natural history of the osteochondromata. Radiation-induced osteochondromata (RIO) are often multiple and are indistinguishable from the more common idiopathic type. The incidence of RIO after TBI was higher than that reported after local irradiation.

Survival and endocrine outcome after testicular relapse in acute lymphoblastic leukaemia.

Survival and endocrine status in a cohort of boys with acute lymphoblastic leukaemia (ALL) who started treatment between 1972 and 1987 and subsequently developed a testicular relapse were analysed. During this period there was a significant improvement in the overall event free survival for boys, but no significant decrease in the testicular relapse rate. Thirty three boys had an apparently isolated testicular relapse, whereas 21 boys had a combined relapse. The event free survival for boys with an isolated testicular relapse was 59% at six years (95% confidence interval (CI) 42 to 74%). The event free survival for the 16 patients with a combined relapse who received a second course of treatment was 32% (95% CI 17 to 60%). Those patients receiving adequate second line treatment for an isolated testicular relapse whose first remission was longer than or equal to two years had an event free survival of 82% (95% CI 63 to 93%) at six years. No boy relapsing within two years from diagnosis has survived. Endocrine late effects are significant, with 82% of the boys requiring hormonal treatment at some stage for induction of puberty or continuing pubertal maturation, or both. It is concluded that, despite the increasing intensity of initial treatment for ALL, isolated testicular relapse is treatable by conventional means in most patients. Careful endocrine follow up of these patients is essential as most will require hormone replacement treatment.

Clinic audit for long-term survivors of childhood cancer.

Follow up for survivors of childhood cancer is considered essential in order to document any continuing impact on growth, fertility and other systems, as well as provide appropriate care and information to individuals themselves. Appropriate follow up needs to take into account the survivors' own views about reasons for attendance and perceived satisfaction with the services provided. Information was sought from 93 survivors (more than five years from diagnosis) and 68 of their parents regarding current attendance, understanding of the purpose of the clinic and satisfaction, and future preferences. Patients' main reasons for attending were to gain reassurance that they were well and information about the disease. There were some discrepancies between the types of information patients would like from clinic attendance and what they remembered being given. Parents were more positive than patients. Our data suggest that (i) knowledge in survivors is poor and (ii) it may be possible to define a subgroup for whom less frequent follow up is appropriate. A key component of care must involve education of patients, both about their past and the implications for future health.

Secondary amenorrhoea after total body irradiation in pre-puberty.

Bone marrow transplant (BMT) has been used as part of the overall treatment of refractory malignant diseases. High dose cyclophosphamide and total body irradiation (TBI) are frequently used as conditioning for BMT. Initial regimens included a single fraction of TBI, with doses varying from 7.5-10 Gy, but this was associated with a high incidence of late sequelae including multiple endocrinopathies. A fractionated irradiation course over 3-4 days of a higher total dose, 12-15 Gy, of TBI is now used. Successfully treated patients with childhood cancer have an increased risk, of developing second tumours. We describe a patient successfully treated for AML who developed multiple endocrine dysfunction and a second benign ovarian tumour.

Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: effects of age and sex.

Cognitive outcome, as measured by verbal and performance IQs, was compared in 35 girls and 47 boys who were in first remission for acute lymphoblastic leukaemia. All children had received presymptomatic cranial radiotherapy and intrathecal methotrexate. The mean age at diagnosis was 4.2 years and the mean elapsed time from initial diagnosis to intellectual assessment was 7.1 years. Results showed that children irradiated before the age of 4 years were impaired in certain aspects of non-verbal ability, as well as in measures of short term memory and attention, calculated by factor scores derived from selected subtests of the IQ test. Subtests requiring verbal and non-verbal reasoning showed the greatest impairment after early diagnosis and treatment. In addition girls were selectively impaired in verbal IQ and other aspects of verbal ability, with the degree of impairment exacerbated by early treatment. No relationship was found between degree of impairment and either time since treatment or number of methotrexate injections. It is concluded that early age at irradiation increases the risk of impaired intellectual outcome, particularly in girls.

Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood.

PURPOSE: To perform a comprehensive assessment of the late effects of short-term intensive chemotherapy for childhood acute myeloid leukemia (AML) and myelodysplasia, and compare the sequelae of intensive chemotherapy alone with those of total-body irradiation (TBI). PATIENTS AND METHODS: Of 33 survivors studied, 26 (group A) received intensive chemotherapy including anthracyclines, one also received busulfan, cyclophosphamide (Bu/Cy), and bone marrow transplantation (BMT). Seven patients (group B) received chemotherapy, TBI, and BMT. Hearing, sight, growth, and endocrine, renal, and cardiac function were assessed. RESULTS: The mean height standard deviation score of 25 nontransplanted group A patients was +0.67 at diagnosis, -0.11 following treatment (P = .016), and +0.34 7 years later (P > .05), indicating no long-term growth impairment. The patients had normal gonadal function and the girls had normal uterine size and ovarian volume. The Bu/Cy patient had primary ovarian failure. Four group B children required growth hormone and four sex steroids for growth or gonadal failure. The girls had reduced uterine size and ovarian volume. Three had thyroid dysfunction and six had cataracts. Abnormalities of renal function were found in both groups and hearing loss in group A only. The mean cardiac shortening fraction was significantly reduced at 29.2% in group A and 28.6% in group B compared with 36% in normal subjects. Two group A patients have developed cardiac failure. CONCLUSION: Chemotherapy and TBI before BMT for AML has resulted in growth failure, gonadal and thyroid damage, and cataracts in most children, whereas chemotherapy alone caused cardiac, renal, and hearing abnormalities only.

Bone mineralization after treatment of growth hormone deficiency in survivors of childhood malignancy.

Having noted symptomatic osteoporotic vertebral collapse in young adult survivors of childhood malignancy, bone mineral density (BMD) was examined at three sites by dual-energy X-ray absorptiometry in 64 patients treated in childhood for intracranial malignancy (group 1; n = 21) or acute leukaemia (group 2; n = 43). Patients in group 1 were selected for growth hormone deficiency (GHD) by auxological and biochemical criteria before the end of puberty (Tanner stage V). Seven patients (six men; mean (+/- SEM) age at study, 28.0 +/- 2.9 years; mean age at diagnosis, 8.7 +/- 1.5 years) in this group had been treated with human pituitary growth hormone (GH) for 1-12 years; and 14 patients (nine men; mean age at study, 26.8 +/- 1.0 years; mean age at diagnosis, 10.7 +/- 1.4 years) had not received GH. Bone densities in group 1 were normal in the GH-treated patients at the femoral neck (98.4 +/- 3.8% of control), lumbar spine (100.4 +/- 6.1% of control) and Ward's triangle (101.0 +/- 6.1% of control) but markedly reduced in the untreated group (femoral neck, 81.2 +/- 2.6% of control (p = 0.002); lumbar spine, 79.1 +/- 4.1% of control (p = 0.04); Ward's triangle, 80.1 +/- 3.6% of control (p = 0.01)). The majority of patients in group 2 had been treated for acute lymphoblastic leukaemia (ALL) and were in three subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropsychological and neurological outcome after relapse of lymphoblastic leukaemia.

Fourteen children who relapsed after initial remission of leukaemia were studied. Six received a second course of cranial radiotherapy, while the remaining eight children were given total body irradiation before bone marrow transplantation. The postirradiation somnolence syndrome was common after cranial radiotherapy. All children had mild/soft neurological signs, mostly of coordination. None had a major motor disability. All but the youngest child had cataracts; two children required an operation for these. All children were growth hormone deficient. Verbal IQ, attention, and concentration were selectively reduced (with respect to normative levels). The time between the two treatments, age at relapse, and higher doses of radiotherapy all correlated with cognitive outcome, with girls showing greater impairments than boys. Only two children were performing at age appropriate levels on measures of academic achievement. It is concluded that neurological and neuropsychological morbidity is significantly increased by the current treatments prescribed after the relapse of leukaemia.