Gonadal function after 12-Gy testicular irradiation in childhood acute lymphoblastic leukaemia

Gonadal function was assessed in 15 boys with acute lymphoblastic leukaemia (ALL) who had received testicular irradiation. The dose to the testes was 12 Gy in 12, 15 Gy in 1, and 24 Gy in 2 cases. All of those who had received 12 or 15 Gy had normal Leydig cell function, although high levels of gonadotropins suggest subclinical Leydig cell damage. The 2 who had 24 Gy had Leydig cell failure. All who were old enough to produce a semen specimen were azoospermic.     

Gonadal function after testicular radiation for acute lymphoblastic leukaemia.

Pubertal maturation, growth, and gonadal function were assessed in 13 boys with acute lymphoblastic leukaemia who had received direct testicular irradiation three to nine years earlier as treatment for testicular relapse or prophylaxis against this complication. Six boys had reached Tanner stage III-V puberty, five of whom had normal growth velocities and bone ages equivalent to chronological age. One boy exhibited maturational arrest on entering stage IV. The remaining seven children (54%) showed evidence of complete pubertal delay or arrested development in stage II, with absence of the pubertal growth spurt and often with delayed bone age. Basal gonadotrophins were abnormally high in all 13 boys, and those with delayed puberty had prepubertal concentrations of testosterone. Testicular irradiation given before puberty causes permanent Leydig cell damage in a high proportion of subjects, necessitating testosterone supplementation. The extent of damage may be related to the age at which radiation is delivered.     

Testicular relapse in childhood acute lymphoblastic leukaemia in Malaysia, 1967–82

From 1967–82,9 children with testicular relapse (TR) of acute lymphoblastic leukaemia (ALL) were diagnosed out of 99 boys treated, an incidence of 9.1%. The median time from the onset of ALL until diagnosis was 28 months (range 3–41 months). All were asymptomatic; six were detected on routine examination while three were diagnosed only on biopsy. Routine biopsy prior to stopping chemotherapy is useful in detecting occult TR. Biopsies should be done on both the testes regardless of the clinical findings. The age, leucocyte count and hepatosplenomegaly at diagnosis of ALL were not found to be significant factors in influencing relapse. Eight-children were in bone marrow remission at the time of TR, but three had preceding or concurrent meningeal leukaemia while in the other five the testis was the first and only site of relapse. Radiotherapy was effective in local disease control but failed to prevent bone marrow relapse in all except two patients despite continuation of chemotherapy. The median time from onset of TR until bone marrow relapse was 7 months (range 3–13 months) and the median time until death, was 11 months (range 6–18 months). The frequency of testicular relapse may be related to the intensity of either the initial induction therapy or the consolidation chemotherapy. Further studies are required to determine whether the incidence of testicular relapse will decline with more intensive early treatment.     

Gonadal function after combination chemotherapy for Hodgkin's disease in childhood.

The effect of quadruple chemotherapy (mustine, vincristine, procarbazine, and prednisolone) on gonadal function was investigated in 15 males and 2 females treated for Hodgkin''s disease during childhood. The 2 females have regular menstrual cycles with evidence of ovulation in one. Twelve of the males have shown normal progression of pubertal development since completing their treatment. Nine out of 10 late pubertal or adult subjects had small testes but only one developed gynaecomastia. All 4 prepubertal subjects had normal basal and peak gonadotrophin responses to luteinising hormone-releasing hormone. Nine of the 12 subjects studied during puberty or adulthood had either an increased basal serum follicle-stimulating hormone (FSH) level or an exaggerated FSH response to luteinising hormone-releasing hormone. Each of the 6 males who provided semen for analysis was azoospermic after an interval of between 2.4 and 8 (mean 5.3) years after completion of treatment. We conclude that severe testicular damage is common after treatment with mustine, vincristine, procarbazine, and prednisolone in childhood. The germinal epithelium is particularly vulnerable and the resultant azoospermia is likely to be irreversible. The Leydig cells are less susceptible to cytotoxic-induced damage. Pubertal development is normal and there is no indication for androgen replacement therapy.     

Cyclic chemotherapy in acute lymphoblastic leukaemia of childhood: 5-Year survivals

Of 31 children with acute lymphoblastic leukaemia treated with a cyclical scheme of chemotherapy, 19% survived for over 5 years, 16% remained in continuing haematological remission for 5 years, and 13% remained leukaemia free for 5 years. These findings are relevant to potential cure, unlike the median remission duration, which is a measure of palliation.A relation between the percentage of PAS-positive blast cells at diagnosis and duration of control of the disease still pertains for the long-term results in this series of patients.     

Ovarian function following the treatment of childhood acute lymphoblastic leukaemia

Ovarian function was assessed in 40 long term survivors who had received standard United Kingdom Acute Lymphoblastic Leukaemia (UKALL) protocols and were in first clinical and haematological remission. A menstrual and pregnancy history was taken (median age at assessment: 18.8 (12–34.7) years) and the acquisition of adult secondary sexual characteristics confirmed in each patient. Basal bloods were taken for follicle stimulating hormone (FSH), luteinizing hormone (LH), and serum oestradiol estimations. Serum progesterone concentration was measured in those patients who were in the luteal phase of their menstrual cycle at assessment. In addition, menstrual cycle profiles of salivary progesterone concentrations were derived from daily samples in 12 patients. All patients achieved adult sexual development; median age at menarche was early at 12.4 (9.0–14.6) years and 37 of them have regular menses. Ten patients have had 14 live births, and evidence of ovulation was seen in a further 11 patients assessed in the luteal phase of the menstrual cycle. Four patients had damaged ovaries, two of whom show evidence of ovulation; three of the four received craniospinal irradiation and one received cyclophosphamide as part of her chemotherapy regimen. None of these patients has yet developed total ovarian failure or required sex steroid replacement therapy. The medium term outlook for ovarian function is good for the majority of childhood ALL survivors. The spinal component of craniospinal irradiation is a major risk factor for ovarian damage, and cyclophosphamide may be a contributory factor. A premature menopause remains a possibility if significant follicular depletion has occurred at the time of cytotoxic treatment. © 1993 Wiley-Liss, Inc.     

Haemoglobin and prognosis in childhood acute lymphoblastic leukaemia.

Two hundred and nine children presenting consecutively with acute lymphoblastic leukaemia to a regional paediatric oncology unit were investigated to determine the prognostic significance of various factors at diagnosis. There was a strong positive correlation between the pretreatment haemoglobin level and the percentage of bone marrow blast cells in S phase of the cell cycle as assessed by flow cytometry. Patients with T- and B-cell leukaemia had significantly higher haemoglobin levels than non-B non-T patients. In patients with total white cell counts less than 20 X 10(9)/l, aged less than 13 years, and no mediastinal mass, there was no association of haemoglobin with length of first remission. However, among those with white blood counts greater than 20 +/- 10(9)/l there was a strong positive trend towards shorter remission with higher haemoglobin levels. Children with high white blood counts at diagnosis and low haemoglobin levels may have a better prognosis than predicted by the white blood count alone.     

Pneumomediastinum complicating childhood acute lymphoblastic leukaemia

A case of pneumomediastinum that developed in a 10 year old girl receiving induction chemotherapy for acute lymphoblastic leukaemia is reported. Three factors were identified that may have been associated with this complication: the patient suffered recurrent vomiting during her induction chemotherapy; she had travelled by air the day before the pneumo mediastinum was diagnosed; and was septic with Enferobacter at time of diagnosis. The pneumomediastinum resolved over 2 weeks without specific treatment and without further complications.     

Memory after treatment for acute lymphoblastic leukaemia.

Long term survivors of acute lymphoblastic leukaemia (ALL) often experience cognitive difficulties, which may be related to impairment of memory function. Memory ability has been studied in a group of survivors of ALL along with sibling controls and in children who have received treatment for other forms of cancer. Children in the ALL group were found to have significant deficits in memory function in tasks which required the application of strategic planning behaviour. These deficits are potentially remediable by educational strategies.     

Rhinocerebral zygomycosis in childhood acute lymphoblastic leukaemia

The hazards associated with invasive candidiasis and aspergillosis in oncology patients are well recognised. These conditions typically present late in treatment, often after prolonged or recurrent episodes of neutropenia. We report the occurrence of Absidia corymbifera infection causing rhinocerebral zygomycosis in two children with acute lymphoblastic leukaemia, early in the induction phase of treatment and within a 3-month interval, in the same oncology unit. The initial presentation of facial pain was rapidly followed by the development of cranial nerve palsies, cavernous sinus thrombosis, diabetes insipidus, seizures and death within 9 days of symptom onset, despite aggressive management with high-dose liposomal amphotericin (Ambisome), surgical debridement and local instillation of amphotericin solution. These cases highlight the need for awareness of zygomycosis as a potentially lethal fungal infection that can present even with short duration exposure to the usual risk factors. Their occurrence within a limited time period raises questions as to the relative importance of environmental exposure. The failure of medical and surgical intervention to impact on the course illustrates the need to develop appropriate preventative strategies which may have to incorporate measures to reduce the environmental exposure of susceptible patients. Received: 23 February 2000 / Accepted: 11 October 2000     

Cognitive function after two doses of cranial irradiation for acute lymphoblastic leukaemia.

The cognitive function of 23 children given cranial irradiation in a dose of 24 Gy was compared with that of 41 given 18 Gy. No significant differences were found in intellectual function or in mean number of intelligence quotient points lost between patients in the two treatment groups. A reduction in the dose of cranial irradiation does not seem to alleviate long term neuropsychological deficits.     

Academic career after treatment for acute lymphoblastic leukaemia.

AIM: To evaluate academic career in long term survivors of childhood acute lymphoblastic leukaemia (ALL), in comparison to their healthy siblings. PATIENTS: Ninety four children treated for ALL with cranial irradiation 18 or 25 Gy and intrathecal methotrexate as CNS prophylaxis. Median age at evaluation was 20 years; median follow up since diagnosis was 15 years at the time of the study. METHODS: Patients and their 134 siblings completed a questionnaire on school career. The percentage of referrals to special primary schools for learning disabled, and the final level of secondary education in patients and siblings were compared, using a six point classification. Within the patient group, the effect of possible risk factors (age at diagnosis, irradiation dose, and gender) was investigated. RESULTS: Significantly more patients than siblings were placed in special educational programmes. A significant difference was found for level of secondary education. No effect of gender or irradiation dose was found, but younger age at diagnosis was significantly related to both referrals and school levels. CONCLUSION: Treatment for childhood ALL with cranial irradiation and chemotherapy at a young age is clearly associated with poorer academic career.     

Randomized comparison of rotational chemotherapy in high-risk acute lymphoblastic leukaemia of childhood — follow up after 9 years

A frequent change of drug combinations may circumvent drug resistance in the treatment of patients with acute lymphoblastic leukaemia (ALL). In study COALL 85/89 201 children with high-risk ALL were randomized to receive over a period of 8 months rotational chemotherapy with six drug combinations given either in slow rotation (SR) (each combination given twice in succession) or in rapid rotation (RR) (cach combination given once with a repetition of the drug combinations). Treatment of central nervous system leukaemia consisted of cranial irradiation and intrathecal methotrexate. Both SR and RR treatment groups were then given continuation chemotherapy of oral 6-mercaptopurine and methotrexate until 2 years after the date of diagnosis. The 9-year eventfree survival (EFS) rate for the whole group is 69%±3%, and the survival rate 75%±3% at a median follow up of 5.8 years. Failure to achieve remission at day 28 was the most important prognostic factor (EFS 12%±7% vs. 75%±3% in the remission group). In the RR group, 11/100 patients were not in remission at day 28 opposed to 7/101 patients in the SR group. Children aged <1 year (6/6 relapses) or aged >=10 years had a worse prognosis (EFS 64%±5% vs. 77%±4% in patients 1–10 years old). After 5 years EFS was inferior in the RR group attributable to a significantly higher relapse rate in children with a WBC>=100/nl. The EFS at 9 years for all patients, however, is similar in both groups (SR 72%±5% vs. RR 67±5%).     

Endocrine function after antineoplastic therapy in 22 children with acute lymphoblastic leukaemia.

In 22 children who were in complete remission after acute lymphoblastic leukaemia endocrinological investigations were performed 5-12 weeks after cessation of therapy. The children had received central nervous system irradiation (tele-Co60, 850-1800 rad), and long term, aggressive cytostatic drug therapy during 21 to 36 months. Growth hormone, TSH, thyroxine, LH, FSH, cortisol secretion, and urinary concentrating capacity were found to be normal, with a few exceptions where borderline results were obtained.     

Small bowel function in acute lymphoblastic leukaemia

Small bowel function before, during, and after treatment for acute lymphoblastic leukaemia was studied in 26 children. A significant impairment of D-xylose absorption was found during treatment. Permeability studies showed a significant decrease in mannitol and a significant increase in lactulose concentrations; five of 20 children tested had evidence of lactose malabsorption, three of whom were symptomatic. Intestinal function abnormalities were greater in children whose methotrexate treatments were separated by 7 day than by 16 day intervals. Only five (19%) children had no abnormal tests. Abnormalities of small bowel function may be treatment induced and this has implications for morbidity from gastrointestinal symptoms, impairment of the mucosal barrier, and malabsorption of both nutrients and drugs leading to malnutrition and suboptimal drug concentrations.