Pulmonary function in childhood leukaemia survivors

Little is known of pulmonary function in survivors of acute lymphoblastic leukaemia (A.L.L.); this is despite the fact that some drugs used, most notably methotrexate, have well-recorded pulmonary toxicity, and the most common infections during therapy in most series are of upper and lower respiratory tract. As part of a survey of all cancer survivors attending the Royal Hospital for Sick Children in Edinburgh, 38 leukaemic patients, who had completed treatment 3 months to 14 years 6 months (median 6 years and 8 months) prior to survey were assessed with regards to their respiratory status. Each patient completed a questionnaire and had spirometry and lung volumes measured; 30 patients additionally had transfer factor for carbon monoxide (TCO) measured. There were 21 children, 11 adults, and 6 patients in the age range between child and adult. Of the 26 adults and children studied with complete data available, 17 (65%) had one or more low values for vital capacity (VC), total lung capacity (TLC), residual volume, or TCO. Mean VC, TLC and TCO were significantly lower than the mean of the predicted values (P less than .001). Gas transfer per unit lung volume (KCO) was normal in all cases. Few patients had symptoms of respiratory disease. There was an increased incidence of low TCO in patients diagnosed under 8 years of age. Impairment of lung growth could be a contributing factor to the observed abnormalities in pulmonary function. Impairment of pulmonary function in survivors of A.L.L. may be of significance for them in later life.     

Physical activity in survivors of childhood acute lymphoblastic leukaemia

Aim: To objectively measure levels of physical activity in children, following treatment for acute lymphoblastic leukaemia (ALL). Methods: Nineteen children who had completed treatment for ALL 6 months–5 years prior to study enrolment wore an accelerometer for 2 weekdays and 2 weekend days. Results: The children spent an average of 141 ± 74 min/day engaged in moderate to vigorous physical activity (MVPA), an amount similar to that previously documented in healthy children. Only three of the 19 subjects averaged less MVPA than the recommended amount (at least 60 min/day). MVPA levels were significantly higher on weekdays than weekend days (P= 0.006). Overall, boys engaged in significantly more MVPA than girls (P= 0.029). MVPA time was negatively correlated with age (r =?0.80) and age at diagnosis (r =?0.87). No trend between MVPA and time off treatment or body mass index was identified. Conclusions: Survivors of childhood ALL appear to be engaging in similar amounts of MVPA as those of the healthy children and are meeting recommended levels of physical activity.     

Lung function and exercise capacity in survivors of childhood leukaemia

The survival from acute lymphoblastic leukaemia in childhood is now approximately 60–70%, and from acute myeloid leukaemia, up to 50%. However, there is little information on the effects of intensive chemotherapy and radiotherapy used in the treatment of these conditions on lung function and exercise capacity in the long term. Seventy survivors of acute leukaemia from one centre in the UK were studied. Measurements of lung volumes, spirometry and transfer factor were made. Each child also performed a standard, symptom-limited maximal exercise test on a cycle ergometer. Predictive equations for indices of lung function and exercise tolerance were calculated from 146 age- and sex-matched control subjects. The results of the survivors of leukaemia were compared to these. There was a significant reduction of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), and transfer for carbon monoxide (DLCO; P < 0.05 for each measurement), in the survivors of leukaemia when compared to the control subjects. In addition, there was a mild but significant reduction of both maximal and submaximal indices of exercise capacity in the leukaemic group. A multivariate analysis was carried out to identify those variables acting independently to reduce lung volumes. For FEV1, FVC and TLC, these were craniospinal irradiation, cyclophosphamide and chest complications during treatment. For a reduction in DLCO, the significant factors were administration of anthracyclines, craniospinal irradiation and bone marrow transplantation. Survivors of acute leukemia have impaired pulmonary function and exercise capacity. Long-term cardiopulmonary follow-up may be necessary and new regimens devised which reduce long-term toxicity without compromising survival rates. © 1995 Wi1ey-Liss Inc.     

Physical performance in long-term survivors of acute leukaemia in childhood

The aim of this study was to assess the physical performance in long-term survivors of acute leukaemia in childhood and to evaluate the effects of anthracycline therapy. Electrocardiography, echocardiography and spiroergometry were carried out on 56 patients aged 9–28 years, of whom 44 patients had been treated with 15–483 mg/m² doxorubicin (or equivalent). Acute leukaemia had been diagnosed 1.5–16 years earlier. Of the patients 75% reached normal maximal oxygen uptake, 69% normal oxygen uptake at the anaerobic threshold and 95% normal maximal work rate. Of the patients 75% achieved adequate values for maximal heart rate and 78% normal blood lactate concentration. No difference was seen between patients treated with and without anthracyclines. Conclusion The results of this study provide little evidence for cardiopulmonary impairment in long-term survivors of ALL. Both the cardiac function, as evaluated by ECG and echocardiography, and the physical performance in spiroergometry are normal in a large number of these patients. Anthracycline treatment does not appear to have a negative effect on these parameters. Received: 30 October 1996 / Accepted in revised form: 7 October 1997     

Cerebral haemorrhage in long-term survivors of childhood acute lymphoblastic leukaemia

Modern treatment of childhood acute lymphoblastic leukaemia (ALL) has dramatically improved the prognosis for children with this disease. Therapeutic approaches consist of multimodal chemotherapy and radiotherapy with significant long-term side-effects. We report on 4 children out of a group of 120 newly diagnosed patients with ALL, who survived the disease for more than 2 years and developed a cerebral haemorrhage after chemotherapy and fractionated cranial irradiation. Following a period of 2–12 years the four children presented with acute neurological signs and symptoms, i.e. seizures, ataxia and hemiparesis. CT and MRI revealed intracerebral mass lesions, interpreted as haemorrhage. After neurosurgery the patients neurological state improved. Histological examination confirmed the suspected diagnosis of bleeding cavernous haemangioma or capillary telangiectases. There are two possibilities to explain these rare alterations: they may be pre-existent to the disease and therapy or they may be caused by irradiation. Conclusion Acute neurological symptoms in patients treated for ALL may be caused by spontaneous cerebral haemorrhaging of cavernous haemangiomas or capillary telangiectases induced by chemotherapy and/or radiotherapy. Received: 2 July 1996 and in revised form: 29 October 1996 / Accepted: 5 November 1996     

Physical function and fitness in long-term survivors of childhood leukaemia

OBJECTIVE: To evaluate the physical function and fitness in survivors of childhood leukaemia 5-6 years after cessation of chemotherapy. MATERIALS AND METHODS: Thirteen children (six boys and seven girls; mean age 15.5 years) who were treated for leukaemia were studied 5-6 years after cessation of therapy. Physical function and fitness were determined by anthropometry, motor performance, muscle strength, anaerobic and aerobic exercise capacity. RESULTS: On motor performance, seven of the 13 patients showed significant problems in the hand-eye co-ordination domain. Muscle strength only showed a significantly lower value in the mean strength of the knee extensors. The aerobic and the anaerobic capacity were both significantly reduced compared to reference values. CONCLUSION: Even 5-6 years after cessation of childhood leukaemia treatment, there are still clear late effects on motor performance and physical fitness. Chemotherapy-induced neuropathy and muscle atrophies are probably the prominent cause for these reduced test results. Physical training might be indicated for patients surviving leukaemia to improve fitness levels and muscle strength.     

Comparing thyroid ultrasonography to thyroid function in long-term survivors of childhood lymphoma

BACKGROUND: We studied the value of thyroid ultrasonography as a follow-up tool in survivors of childhood lymphomas and correlated morphologic abnormalities with thyroid function tests. PROCEDURE: A prospective follow-up study of 45 long-term survivors of histology-proved childhood lymphomas was performed. Mean age at diagnosis was 9.1 years (range 2.1-16.4 years) and mean follow-up duration 10.9 years (range 3.9-22.2 years). RESULTS: Among the 26 survivors of Hodgkin disease (HD) who received mantle field irradiation, 14 (54%) had abnormal ultrasonograms. Elevated thyroid-stimulating hormone (TSH) concentrations were found in 14 (54%), and 6 of them (42%) had normal thyroid functions. Six of twelve patients with normal ultrasonograms had abnormal thyroid function, and 5 of 11 patients with normal function had abnormal sonograms. Among the 19 non-HD survivors who did not receive radiotherapy, 18 (95%) had both normal sonograms and normal function. Thus thyroid gland abnormalities were detected in 54% of HD survivors after mantle field irradiation. No correlation between the abnormalities detected on ultrasonography and serum levels of TSH and thyroid hormones were found. CONCLUSIONS: Both ultrasound and thyroid function tests independently provide clinically useful information; the former examines gland morphologogy and the latter evaluates hormonal changes associated with thyroid disease. The high frequency of thyroid abnormalities detected by ultrasonography suggests that periodic thyroid ultrasonography is advisable in the follow-up of patients treated with mantle irradiation to screen for morphologic changes that may presage malignant transformation.     

Longitudinal growth and final height in long-term survivors of childhood leukaemia

Survival of children with acute lymphoblastic leukaemia (ALL) has increased considerably in recent years and data on the spontaneous growth and final height of these children are conflicting. Therefore, we analysed the longitudinal growth and final height in 52 survivors (33 females, 19 males) of childhood ALL. These children were diagnosed and treated in a single institution, all remained in first remission and were submitted to cranial irradiation with either 2400 or 1800 cGy. None of the patients received testicular or spinal irradiation. Median age at diagnosis was 4.2 (range 1.3–9.6) years in the first group (2400 cGy) and 3.9 (0.8–10.5) years in the second (1800 cGy). Standing height was measured at diagnosis, at the end of treatment (median 3.1 years after diagnosis), 6, 12, 24 months after the end of treatment, and finally at the completion of growth. In girls a significant decrease of mean height standard deviation score (SDS) during treatment and a catch up in growth after the end of therapy was followed by a second period of reduced growth. Mean final height SDS was significantly lower than the value at diagnosis in both groups of girls, but only in males treated with 2400 cGy. Mean overall loss in height SDS from diagnosis to final heigth was higher in females (–1.24) than in males (–0.40) (P=0.009). Females <-4 years of age at diagnosis showed a higher loss in final height than females >4 years. An unchanged or improved final height was evident in 8 cases, the other 44 cases showed a final height decrease between –0.1 and –2 SDS in 36 and >-2 SDS in 8, 6 of whom were females <-4 years at diagnosis and only 1 a female >4 years. Only females treated at a younger age showed a final height lower than midparental height (–5.7±1.8 cm,P<0.01), particularly those treated with 2400 cGy (–7.5±2.5 cm,P<0.05). Menarche occurred earlier than in the normal population (11.5±1.2 years) with no differences between the two radiation dosages.Conclusion Females, notably young girls, treated for ALL show a greater decrease in the final height than treated males. Early sexual maturation may contribute to the decrease in the final height. A better growth pattern seems to be shown by patients irradiated with the lower dosage.     

Cardiac function in survivors of acute lymphoblastic leukaemia and Hodgkin's lymphoma

Aim: The study objective was to assess plasma N‐terminal–pro‐brain natriuretic peptide (BNP) levels and to evaluate left ventricular mass as well as left ventricular systolic and diastolic functions in 44 children who had undergone treatment for acute lymphoblastic leukaemia and Hodgkin's lymphoma, with regard to gender, age at disease onset, time that had passed since therapy completion, cumulative dose of antracyclines and mediastinal radiotherapy applied. Methods: The median levels of pro‐BNP were found to be higher in the whole study group as compared with the control (55.9 ± 53.1 ng/mL vs. 38.5 ± 47.7 ng/mL, P= 0.059). The pro‐BNP values >80.0 ng/mL (standard deviation score (SDS)) were noted in 11/44 patients, including those exceeding 115.0 ng/mL (2 SDS) – in 6/44 patients. Results: No correlation was observed of pro‐BNP levels with the accumulated dose of antracyclines (r=?0.42, P= 0.79) or mediastinal radiotherapy (r= 0.197, P= 0.2). However, negative correlation was found between pro‐BNP and the time that had passed since therapy completion (r=?0.378, P= 0.009). In echocardiography, shortening and ejection fractions remained normal, whereas the indexed stroke volume was below 40 mL/m² in 16/44 patients. The E/A index below 1.5 was found in 6/44 cases. The left ventricular systolic mass remained within the normal range. Negative correlation was noted between isovolumetric diastolic time and pro‐BNP level. Conclusions: Increased levels of pro‐BNP after anti‐cancer treatment with the involvement of cardiotoxic substances may indicate the first symptoms of myocardial dysfunction, despite the lack of major echocardiographic disorders.     

Young female survivors of childhood leukaemia do not have increased somatic concerns

Objective: This study examined whether experience of cancer in childhood leaves a hypersensitivity to various somatic symptoms. Further, are self-reported somatic symptoms explained by medical late-effects or a worry of recurrence of the cancer?Methods: Of the total of 44 female survivors of leukaemia, 42 were compared with 69 age-matched healthy controls. We used a questionnaire to study self reported somatic symptoms and a face-to-face interview to explore worries about recurrence of the illness. Health status and medical late effects were evaluated by a paediatric haematologist. Results: In contrast to our assumptions, young survivors of leukaemia reported fewer somatic symptoms than healthy age-matched comparison subjects (p < 0.001). Late physical sequelae were uncommon except in the survivors of allogeneic bone marrow transplantation. Of the survivors, 52% were afraid of recurrence of the illness. The presence of physical or visible impairment and worry of recurrence were unrelated to frequency of somatic symptoms. Conclusions: The results suggest that experience of childhood leukaemia and its treatment does not result in increased somatic concerns or hypochondriacal tendencies.     

Male gonadal function in survivors of childhood Hodgkin and non-Hodgkin lymphoma

The aim of this study was to investigate the impact of therapy on long-term gonadal function of young people cured of childhood lymphomas and to assess whether a prepubertal state during the treatment protects the gonads from chemotherapy and/or radiotherapy late effects. Clinical evaluation, semen analysis, and endocrine status were studied in 20 survivors of childhood lymphomas. Five patients received Inverted Y radiotherapy, 2320 cGy (1550-4000); all 20 received chemotherapy as follows: MOPP/ABVD protocol, 9 patients; COMP protocol, 5 patients; MOPP protocol, 3 patients; other protocols, 3 patients. Semen analysis results were as follows: normal values, 4/20 patients; oligospermia, 8/20 patients; azoospermia, 8/20 patients; FSH above normal level, 10/20 patients; 4/5 who received Inverted Y irradiation were azoospermic and 1 was severely oligospermic. Treatment damage to the testis involves tubular germinal elements. Radiotherapy and chemotherapy combinations that included nitrogen mustard or cyclophosphamide were associated with high rates of oligospermia and azoospermia. MOPP/ABVD combination did not have a significant better outcome of sperm counts compared to MOPP alone. Age at chemotherapy did not correlate with the sperm count; hence a prepubertal state did not protect the gonad from the late effects of treatment.     

Detection of multidrug-resistant protein,P-glycoprotein in childhood leukaemia and lymphoma

Flow cytometric detection of surface P-glycoprotein, a multidrug-resistant gene product, with a monoclonal antibody, MRK 16, was performed on cells obtained from 18 children with leukaemia and lymphoma. Of 18 patients examined, 1 with malignant lymphoma at relapse showed a significant increase in P-glycoproteinpositive cells and a strong resistance to chemotherapy. Overexpression of P-glycoprotein in a case with B-cell type malignant lymphoma was confirmed by immunoprecipitation and Northern hybridization analysis. The present study suggests that an increased expression of surface P-glycoprotein might be involved in multidrug resistance at least in a certain case of childhood leukaemia and lymphoma.     

Intellectual abilities among survivors of childhood leukaemia as a function of CNS irradiation.

Twenty-eight children in remission at least 2 years after completing chemotherapy for acute lymphoblastic leukaemia were assessed on standardised psychological tests. It was found that 7 who never had central nervous system (CNS) irradiation and 9 having prophylactic CNS irradiation at least 6 months after diagnosis tended to perform at average or above levels, while those 10 each having prophylactic CNS irradiation (within 2 months of diagnosis) were generally of lower ability. Within the latter group, 3 children showed serious intellectual impairments, while the group as a whole functioned especially poorly on quantitative tasks and those involving speeded performance with abstract material. General language ability was not affected. Practical and theoretical implantation are discussed.     

Long-term pulmonary function in survivors of childhood Hodgkin disease and non-Hodgkin lymphoma

BACKGROUND: The aim of our study was to evaluate the long-term effects of chemotherapy and/or radiotherapy on lung function in 75 childhood Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) survivors several years after treatment. PATIENTS AND METHODS: We studied 37 HD and 38 NHL survivors. These patients were divided into two groups according to the treatment protocols applied. Group I consisted of 23 patients who were treated with both chemotherapy and thoracic irradiation and Group II consisted of 52 patients who were treated with chemotherapy and no thoracic irradiation. A detailed history of smoking habits, respiratory symptoms, and diseases was recorded. Complete physical examinations and pulmonary function tests [PFT, including spirometry, lung volume, and diffusion capacity for carbon monoxide (DLCO)] were performed on all subjects. RESULTS: No patients reported acute or chronic respiratory symptoms or diseases. Pulmonary function abnormality (reduced lung volume and diffusion capacity) was found in 13% of patients at a median 5 years after diagnosis. The percentage of predicted normal value of forced expiratory volume in the 1st sec (FEV(1)), residual volume (RV), and DLCO were significantly lower in Group I than these values for Group II. There were no significant differences in PFT parameters between patients with HD and NHL (P > 0.05). It appears that the risk of reduced lung function was greater the younger the patient in therapy. CONCLUSION: Chemotherapy or chemo-radiotherapy-induced pulmonary sequalae in childhood may remain asymptomatic for many years.     

Bone mineral metabolism and its relationship to leptin levels in survivors of childhood leukemia and lymphoma

Leptin has important effects on bone metabolism. Possible relationships between leptin and bone mineral density were evaluated in the survivors of the childhood leukemia and lymphoma. Twenty patients were included the study. Anthropometric parameters, growth hormone response to provocative test, serum calcium, phosphorus, alkaline phosphates, osteocalcin, leptin levels, urinary calcium and deoxyypyridinoline levels, and bone mineral density were obtained. Anthropometric parameters of patients were not significantly different from those of a control group. Growth hormone provocative test was abnormal in 3 patients who received cranial radiotherapy. The osteocalcin levels and bone mineral density of patients were significantly lower than in the control group (p=.001, p=.02). Nine patients were in the osteopenic and 7 were in the osteoporotic range. The leptin levels of patients were significantly lower (p=.01) than in the control group. Bone mineral density (BMD) was significantly correlated with leptin level, age, body mass index, and Tanner stage in simple correlation analysis. However, in multivariate analysis only age was significant (p<.000, r: .752). Markers of bone metabolism, BMD, and leptin levels were not related with the growth hormone status of patients and did not present a correlation with the cumulative doses of drugs. There are a few studies evaluating the relationship between BMD and leptin levels in childhood cancer. Although this study did not find any correlation between the leptin level and BMD, detailed studies of larger numbers of patients are necessary to evaluate causes of decreased leptin level and the possible role of leptin on osteopenia observed in survivors of childhood cancer.     

Cardiac functions by myocardial performance index and QT dispersion in survivors of childhood lymphoblastic leukaemia

AIM: Childhood leukaemia treatment contains multiple chemotherapeutic agents in high doses that can cause severe toxic effects on heart and other vital organs. In this respect patients taking cancer chemotherapy are followed for these adverse effects. Echocardiographic myocardial performance index (MPI) was reported as a new method of combined systolic and diastolic function for both adults and children, calculated as isovolumic relaxation time plus isovolumic contraction time divided by ejection time. In addition, it has been postulated that increased inter-lead differences in QT interval (QT dispersion) may be associated with an increased risk of cardiac death. The aim of this study was to determine the probable immediate and late adverse effects of childhood leukaemia treatment containing moderate dose of anthracyclines on heart by MPI and corrected QT dispersion (QTcD). METHODS: MPI and QTcD in 55 children with leukaemia and 38 healthy controls matched for age and sex were evaluated. RESULTS: There was no statistically significant difference between MPI values of patients and controls (20.7+/-13.1 (1-59.4) and 16.1+/-13.5 (0.3-77.5), P: 0.1, respectively). Also, there was no significant difference in MPI and QTc values between patients taking active treatment and those who completed the therapy and between the patients given a cumulative dose of anthracycline lower and higher than 250 mg/m2. But QTcD values were found to be higher in patients than controls (0.08+/-0.03 and 0.03+/-0.01, P<0.01, respectively). CONCLUSIONS: There was no overt cardiotoxicity in our children with leukaemia treated with protocols of ALL BFM 95 and TRALL 2000 (Modified BFM in Turkey) containing moderate dose of anthracyclines. However, they can cause subclinical cardiotoxicity and further monitoring and evaluation with such sensitive and noninvasive methods over a longer period of time are needed.