Doxorubicin cardiotoxicity in children: reduced incidence of cardiac dysfunction associated with continuous-infusion schedules.

We retrospectively reviewed the medical records of 97 children (59 boys and 38 girls) with a median age of 13 +/- 4 years who had been treated with continuous infusion of doxorubicin at a dosage of 60 mg/m2 over 24 h (61 patients) or at a dosage of 75 mg/m2 over 72 h (36 patients). The drug was administered every 3 weeks. The cardiac status of patients was evaluated as a baseline and every 6 months during, and following therapy (median, 30.5 months). The evaluations included M-mode and two-dimensional echocardiography. Congestive heart failure developed in only one patient in this series, an 8-year-old girl who ultimately died of her cardiac complication. This incidence of doxorubicin-induced cardiotoxicity was compared with that seen in a control group of pediatric patients previously treated with doxorubicin at similar dosages but with a rapid infusion. The result compared favorably to the 13% incidence of cardiotoxicity (p = 0.03) and 7% mortality (p < 0.01) in the control group. No changes in the levels of tumor response were noted in children treated by continuous infusion when compared with historical controls. Continuous-infusion schedules of doxorubicin thus result in fewer incidences of cardiotoxicity in children and should be considered for wider application in pediatric cancer patients receiving doxorubicin.

The clavicle: a vulnerable bone in pediatric oncology.

The clavicle is frequently incorporated into the radiation field in the treatment of malignant tumors located in the head and neck. From 1954 to 1995, 499 pediatric patients were treated with moderate to high-dose radiation therapy to the head and neck at the University of Texas M.D. Anderson Cancer Center. The medical records of 312 of these patients were available and were reviewed. The period of observation ranged from 5 to 30 years. Five late radiation-induced abnormalities of the clavicle were encountered: osteosarcoma; osteochondroma; malignant fibrous histiocytoma; radionecrosis and impaired healing following trauma and radionecrosis and lysis. The doses of radiation therapy which induced the abnormalities varied from 35 to 60.5 Gy (median 34.75 Gy). The interval from radiation therapy to discovery of the complications varied from 6 to 11 years. Two patients died: one from malignant fibrous histiocytoma and another from a radiation-induced meningioma of the brain (which accompanied radionecrosis of the clavicle). We conclude that the incidence of radiation-induced abnormalities of the clavicle in pediatric long-term survivors is low (1.5%). However, some of the late sequela are potentially fatal. The clavicle should be considered a vulnerable bone to radiation therapy and should be monitored in long-term survivors of childhood cancer. The experience is compared to radiation-induced abnormalities recorded in the literature.

Doxorubicin cardiotoxicity in children: comparison of a consecutive divided daily dose administration schedule with single dose (rapid) infusion administration.

BACKGROUND: Doxorubicin cardiotoxicity remains a serious problem in children with malignancy. The present study was undertaken to determine if the administration of consecutive divided daily doses of doxorubicin would significantly reduce the likelihood of cardiotoxicity in children compared with a single dose administration regimen. PROCEDURE: One hundred thirteen children (60 boys and 53 girls) received doxorubicin either by single dose infusion or by a consecutive divided daily dose schedule. The divided dose patients received one third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single dose schedule received the cycle dose as a 20-minute infusion. The mean doxorubicin dose was 341 mg/m2. Patients were followed up for 4-180 months. There were 60 boys and 53 girls in the series. RESULTS: Fifteen patients developed cardiacdysfunction, eight of whom died of progressive cardiac failure. There was no significant difference in the incidence of cardiac dysfunction between the divided and single dose infusion groups. More girls than boys developed cardiac dysfunction and more girls died of progressive cardiac failure; this difference was not statistically significant. The median time to the development of cardiac failure was 2 months. CONCLUSIONS: The divided dose regimen did not alter the incidence of cardiotoxicity. Other schedules should therefore be investigated. Our data suggest that, at similar cumulative doses, girls are more likely to develop cardiac dysfunction than are boys. If the sex-related difference is proved in larger series of patients, it may be prudent to lower the recommended cumulative doses for girls.

Melanoma as a second malignant neoplasm after childhood cancer.

BACKGROUND: As more children survive childhood cancers, the population at risk for second malignant tumors increases. The development of melanoma as a second malignant tumor is not well described. METHODS: The M.D. Anderson Cancer Center's 50-year experience with patients who developed melanoma after treatment of a childhood cancer was retrospectively reviewed. RESULTS: One hundred seventy-two patients with a second malignancy were identified; 11 patients had melanoma as a second malignancy. The most common first malignancies were Hodgkin's disease, brain tumors, and retinoblastomas. Melanoma developed in an irradiated field in 4 patients. Six patients had lymphatic or distant metastasis at diagnosis. Five of 11 patients died of melanoma. CONCLUSIONS: Factors contributing to melanoma as a second malignancy may include genetic factors and the effects of chemotherapy and radiation. Survivors of childhood malignancy should be considered at risk for developing melanoma, and suspicious pigmented lesions should be carefully evaluated.

Long-term effects of radiotherapy administered in childhood for the treatment of malignant diseases.

BACKGROUND: The use of radiotherapy for the treatment of childhood malignancy has improved long-term survival significantly, and many treated children now survive well into adulthood. As a consequence, long-term effects of childhood irradiation are being seen with increasing frequency. METHODS: The medical records of 236 patients who had been treated for malignant disease with radiotherapy during childhood were examined to determine the long-term effect of the radiation on their growth and development. RESULTS: Mean treatment dose was 35.5 Gy; mean age at treatment was 7.2 years; and mean follow-up was 14.5 years. Adjuvant chemotherapy was given to 82%. Some degree of bone deformity (usually with overlying soft-tissue hypoplasia) was seen in 40%; 21% developed some type of endocrine deficiency; 30% developed atrophic skin changes; and 7% developed second malignancies. The incidence of bone deformity and hormonal deficiency increased with the radiation dose; the incidence of second malignancy was independent of dose. Bone deformities were more common when radiation was administered before the age of 2 years. CONCLUSIONS: The consequences of radiotherapy in childhood are significant and must be considered when planning treatment. Even when treatment is essential, families should be informed of the possibility of growth disturbance to prevent subsequent misunderstanding.

Radiation-induced changes in long-term survivors of childhood cancer after treatment with radiation therapy.

This article has provided an account of the delayed effects after successful treatment for childhood cancer. Particular emphasis has been placed on sequelae induced by radiation therapy. Chemotherapy-related complications that may simulate or aggravate these sequelae also are recorded. The alterations induced by radiation therapy and chemotherapy are not limited to the organs and tissues described in this article. Subtle, and at times psychologically devastating, sequelae also may be encountered (eg, sterility due to radiation and chemotherapeutic effects on the gonads). However, an attempt has been made only to identify those complications that may be more readily detected by means of radiographic studies. It is recommended that ongoing surveillance of the long-term successfully treated childhood cancer survivor be conducted in order to detect such complications. Early detection will assist in implementing appropriate treatment, minimizing delayed effects, and maximizing the quality of life. Periodic radiographic studies of previously radiated areas at regular intervals therefore appears appropriate.

Forty-year experience with second malignancies after treatment of childhood cancer: analysis of outcome following the development of the second malignancy.

As the cure rate for childhood malignancies increases, the number of patients at risk for development of second malignancies also increases. Due to the potentially long remaining life span, long-term follow-up is difficult and patients are often at risk after presumptive cures. Some authors believe that cure rates for second malignancies are similar to cure rates for primary malignancies. We reviewed the records of 162 patients seen at our institution who had developed a second malignancy after treatment for childhood cancer. Presentation, age at diagnosis, tumor histology, extent of tumor, treatment (including radiotherapy with dosage when available, and chemotherapy) plus outcome were recorded. Mean age at diagnosis of the primary malignancy was 10.3 years. The most common primary malignancy was Hodgkin's disease (33) followed by soft tissue sarcoma (28), retinoblastoma (20), bone tumor (17), central nervous system (CNS) tumor (13), leukemia (8), Wilms' tumor (7), non-Hodgkin's lymphoma (6), neuroblastoma (5), thyroid neoplasm (5), and others (20). The average interval between diagnosis of the first and second malignancy was 10.8 years. These second tumors carried a high mortality. Only 56 patients have no evidence of disease. Five patients are known to be alive with disease and 92 patients have expired due to their second malignancy. Disease status in 8 patients is unknown. The most common second malignancy was osteosarcoma (35) followed by soft tissue sarcoma (24), breast cancer (15), leukemia (14), thyroid carcinoma (14), CNS tumors (12), melanoma (8), nonmelanomatous skin cancer (8), lymphoma (5), and others (27).(ABSTRACT TRUNCATED AT 250 WORDS)

Neurophysiological basis of cognitive deficits in long-term survivors of childhood cancer.

Thirty-three survivors of childhood cancer were tested with event-related potentials (P300), motor reaction time tests, and neuropsychological tests to assess the underlying physiological basis of treatment-related cognitive sequelae. Thirteen patients had received intrathecal chemotherapy, 11 had received intrathecal chemotherapy plus cranial radiotherapy, and nine had been treated without any form of central nervous system therapy. Neuropsychological performance of the groups treated without cranial radiotherapy was normal, but the group given cranial radiotherapy was significantly impaired. Mean reaction time and P300 latency were somewhat slower in the group given intrathecal chemotherapy relative to the group given no central nervous system treatment, but were significantly delayed in the group given cranial radiotherapy. Correlations of reaction time and P300 latency with neuropsychological test scores were also obtained. Results suggest that slowing of cortical activity secondary to white-matter damage may underlie cognitive decline in children treated with intensive central nervous system therapies, especially cranial radiotherapy.

Thyroid gland: US in patients with Hodgkin disease treated with radiation therapy in childhood.

The authors retrospectively assessed with sonography the prevalence of thyroid gland abnormalities in 30 patients who underwent radiation therapy for Hodgkin disease between 1962 and 1984. Doses ranged from 3,000 to 4,500 rad (3,000-4,500 cGy). Abnormalities were found in the sonograms of 24 patients and included unilateral (n = 6) or bilateral (n = 2) atrophy; multiple hypoechoic lesions smaller than 0.75 cm (n = 18); and dominant cystic (n = 2), solid (n = 3), or complex lesions (n = 4) larger than 0.75 cm. The risk of development of an abnormality increased as the time from irradiation increased and was comparable between patients who did and did not receive chemotherapy as part of the treatment regimen. Although the pathologic correlates of the various abnormalities seen on sonograms may differ, the findings indicate a need for long-term follow-up of patients who underwent cervical irradiation for Hodgkin disease.

Male reproductive function in long-term survivors of childhood cancer.

We evaluated reproductive function in 27 male long-term survivors of childhood cancer treated during the prepubertal and pubertal period. Sperm samples were obtained from 23 patients; four who refused to provide specimens indicated that they had fathered normal healthy children. Thirteen patients were 12 years old or younger at the time of diagnosis and initiation of therapy. Chemotherapy was calculated according to the cumulative amount of drug administered and correlated with the surface area. Sterility was associated with large doses of single alkylating agents or reduced doses administered with other agents in combination regimens. It was noted in boys treated in both the prepubertal and pubertal period. Sterility was also observed in patients who received testicular radiation alone or in combination with chemotherapy. However, it was not an inevitable consequence in all patients, despite treatment with similar or identical regimens. Fertility potential could not be predicted by clinical examination (testicular size) or gonadotrophin and testosterone values. The results were compared to published reports of treatment-induced sterility in adult males. Additional investigations are required to establish more accurate correlations of dosage with reproductive potential.

Neuropsychological effects of childhood cancer treatment.

The potential neuropsychological effects of treatment were investigated in 124 childhood cancer patients. Children were classified into groups on the basis of treatment modality and treatment status. All patients received systemic chemotherapy. Other treatment modalities included intrathecal chemotherapy and intrathecal chemotherapy plus central nervous system radiation therapy. Treatment status was determined by whether children were newly diagnosed patients in active treatment or long-term survivors of cancer. This classification resulted in five groups; group 1 (n = 29)--children with newly diagnosed disease who were receiving intrathecal chemotherapy; group 2 (n = 21)--children with newly diagnosed disease who were receiving systemic chemotherapy without central nervous system treatment; group 3 (n = 24)--long-term survivors who had received intrathecal chemotherapy; group 4 (n = 25)--long-term survivors who had received intrathecal chemotherapy plus cranial radiotherapy; and group 5 (n = 25)--long-term survivors who had received systemic chemotherapy only (no specific central nervous system treatment). Groups were compared by using multivariate analysis of variance on sets of neuropsychological test variables that represent major cognitive domains. Results of comparisons indicated significant group differences for most dependent-variable sets. Follow-up pairwise comparisons showed that the group of long-term survivors who had received intrathecal chemotherapy plus cranial radiotherapy consistently obtained lower test scores than the other four groups. These findings are consistent with results of previous studies, thus indicating that intrathecal chemotherapy plus cranial radiotherapy is associated with significant effects on neuropsychological performance. Comparisons among newly diagnosed and long-term groups of patients who did not receive cranial radiotherapy yielded null results on measures of higher-order cognitive functions. However, significant group differences were observed on measures of fine-motor and visual-motor skills; newly diagnosed groups obtained lower scores than the nonirradiated long-term survivor groups. Findings were attributed to chemotherapy-induced peripheral neuropathy that differentially affected the newly diagnosed groups.

Neuropsychological sequelae of childhood cancer in long-term survivors.

In order to assess the effects of various cancer treatments on neuropsychological functioning, 74 long-term survivors of childhood cancer were examined. A comprehensive battery of tests was administered to two CNS treatment groups (irradiated and nonirradiated leukemia and lymphoma patients) and a control group (solid tumor and Hodgkin disease patients receiving no CNS treatment). The CNS-irradiated group obtained lower scores than the other two groups, with significant differences in visual-motor and fine motor skills, spatial memory, and arithmetic achievement resulting in significant differences in IQ scores (VIQ, PIQ, FSIQ). The results are discussed in relation to: (1) the effects of CNS irradiation on cognitive development; (2) the specificity of these effects; and (3) the relationship of age at diagnosis to treatment effects. It is concluded that although there is a general lowering of scores after CNS irradiation, the effect is most pronounced for nonlanguage skills. Age at diagnosis was less important than the type of treatment, with CNS irradiation reducing performance regardless of when cancer was diagnosed. There were indications that children with any type of cancer diagnosed before age 5 years are more likely to have some cognitive difficulties.

Dental and maxillofacial abnormalities in long-term survivors of childhood cancer: effects of treatment with chemotherapy and radiation to the head and neck.

Sixty-eight long-term survivors of childhood cancer were evaluated for dental and maxillofacial abnormalities. Forty-five patients had received maxillofacial radiation for lymphoma, leukemia, rhabdomyosarcoma, and miscellaneous tumors. Forty-three of the 45 patients and the remaining 23 who had not received maxillofacial radiation also received chemotherapy. Dental and maxillofacial abnormalities were detected in 37 of the 45 (82%) radiated patients. Dental abnormalities comprised foreshortening and blunting of roots, incomplete calcification, premature closure of apices, delayed or arrested tooth development, and caries. Maxillofacial abnormalities comprised trismus, abnormal occlusal relationships, and facial deformities. The abnormalities were more severe in those patients who received radiation at an earlier age and at higher dosages. Possible chemotherapeutic effects in five of 23 patients who received treatment for tumors located outside the head and neck region comprised acquired amelogenesis imperfecta, microdontia of bicuspid teeth, and a tendency toward thinning of roots with an enlarged pulp chamber. Dental and maxillofacial abnormalities should be recognized as a major consequence of maxillofacial radiation in long-term survivors of childhood cancer, and attempts to minimize or eliminate such sequelae should involve an effective interaction between radiation therapists, and medical and dental oncologists.

Neuropsychologic assessment of long-term survivors of childhood leukemia.

Thirty-two long-term survivors of childhood leukemia who were followed up at the University of Texas M. D. Anderson Hospital were evaluated with a battery of 17 neuropsychologic tests. These tests were selected to assess the development of cognitive skills and functions associated with brain impairment in children. Statistically significant differences were found between the group of children given CNS irradiation and the nonirradiated group on full-scale IQ and verbal IQ scores, mathematics skills, constructional skills, and memory for spatial material. Of particular interest was the absence of differences in language-based measures of verbal memory and the presence of group differences on measures of memory for spatial material. While the sample size was small, the findings delineate specific areas likely to be affected. These results indicate the need for caution when including cranial irradiation in CNS prophylaxis. When any CNS treatment is given, it seems appropriate that provisions be made for assessment and remediation of affected skills.

Active sperm production after cancer chemotherapy with doxorubicin.

The sperm production of 14 cancer patients who received doxorubicin was examined after cessation of therapy. Doxorubicin was used in several multiple-drug protocols for the treatment of various malignancies. Seven patients also received radiotherapy to different sites. Total cumulative doses of doxorubicin ranged from 145 to 625 mg./m.2. Sperm concentration, motility, morphology and the frequency of quinacrine-stained sperm with 2 fluorescent bodies (2F sperm) were measured 7 to 79 months after discontinuation of doxorubicin. Of the patients 6 remained azoospermic, 3 were oligospermic and 5 were normospermic. Sperm motility among the 8 patients with sperm ranged from 20 to 80 per cent. Morphology and 2F sperm distributions were not significantly different from controls. We conclude that, in contrast with the mechlorethamine, vincristine, procarbazine and prednisone protocol, active sperm production within relatively short recovery times is possible after treatment with protocols that include doxorubicin.

Radiation induced osteochondroma in long-term survivors of childhood cancer.

The records of 200 long term survivors of childhood cancer where reviewed. Radiation induced osteochondromata were detected in 12 patients (6%). Radiation had been administered in doses ranging from 1250 R (approximately 1500 rad) to 5500 rad between the ages of 8 months and 11 1/2 years. Radiation-induced osteochrondromata were detected 3 to 13 1/2 years later, with a median of 5 years. The osteochrondomata were single in 7 patients and multiple (2-4) in 5. Two occurred at sites of previous thoracotomy. Factors related to radiation induced osteochondromata are discussed.

Hypothalamic, pituitary and thyroid dysfunction after radiotherapy to the head and neck.

One hundred-ten patients who had nasopharyngeal cancer and paranasal sinus tumors and were free of the primary disease were studied one to 26 years following radiotherapy. There were 70 males and 40 females ranging in age from 4 to 75 years, with a mean age of 36.5 years. During therapy both the hypothalamus and the anterior pituitary gland were in the field of irradiation. The radiation dose to the hypothalamus and the anterior pituitary gland was estimated to be 400 to 7500 rad with a median dose of 5618 rad to the anterior pituitary gland and a median dose of 5000 rad to the hypothalamus. We found evidence of endocrine deficiencies in 91 of the 110 patients studied. Seventy-six patients showed evidence of one or more hypothalamic lesions and 43 patients showed evidence of primary pituitary deficiency. Forty of the 66 patients who received radiotherapy to the neck for treatment or prevention of lymph node metastasis showed evidence of primary hypothyroidism. The range of the dose to the thyroid area was 3000 to 8800 rad with a median of 5000 rad. One young adult woman who developed galactorrhea and amenorrhea 2 years following radiotherapy showed a high serum prolactin level, but had normal anterior pituitary function and sella turcica. She regained her menses and had a normal pregnancy and delivery following bromocriptine therapy. These results indicate that endocrine deficiencies after radiotherapy for tumors of the head and neck are common and should be detected early and treated. Long-term follow-up of these patients is indicated since complications may appear after the completion of radiotherapy.

Long-term survival in childhood acute leukemia: "late" relapses.

The "late" relapse patterns of childhood acute leukemia were studied in 83 children in their first continuous complete remission for more than three years prior to randomization for stopping therapy (40 patients) or continuing therapy (43 patients) for a total of six years. Twenty of 83 (22.9%) have relapsed: Ten in the bone marrow, one in the central nervous system, and nine in the testes. The testes relapse rate of 41.1% (7/17) in males discontinuing therapy at three years was much higher than that of 8.7% (2/23) in males continuing therapy. This difference is significant at P = 0.01 (Wilcoxon test).