Alexander A. Green

Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation.

One hundred seventy-seven children and young adults with various malignant neoplasms were prospectively tested for hearing loss after they had received cisplatin (n = 146), cranial irradiation (n = 18), or both (n = 13). Adequate renal function, no history of treatment with ototoxic drugs other than cisplatin, and availability for repeated audiometric testing were requirements for enrollment. Substantial hearing loss, defined as a hearing threshold of 50 dB or greater, was noted in only 11% of the cohort on tests conducted at the common speech frequencies (500 to 3,000 Hz). About half the patients had substantial deficits at higher frequencies (4,000 to 8,000 Hz). The probability of substantial hearing loss was directly related to the cumulative dose of cisplatin. In nonirradiated patients tested at the speech frequencies, there was a negligible risk of substantial deficits over the dose range of 90 to 360 mg/m2. As the dose increased to 720 mg/m2, the risk increased to 22%. In irradiated patients who later received cisplatin, cumulative drug doses as low as 270 mg/m2 were associated with a high probability of substantial hearing loss, suggesting potentiation of ototoxicity when these therapies are used together. Hearing acuity was either not affected or only minimally decreased in the irradiation-only group. Younger age, prior irradiation, and the presence of a CNS tumor each contributed significantly to the severity of hearing deficits at given cisplatin dose levels. We conclude that early increases in hearing threshold at a stimulus frequency of 4,000 Hz indicate probable subsequent deficits at lower frequencies, especially in young children with CNS tumors who have received cranial irradiation. The probability charts derived from this analysis should provide a useful tool for predicting hearing loss in the speech frequencies.

Peripheral primitive neuroectodermal tumor (peripheral neuroepithelioma) in children. A review of the St. Jude experience and controversies in diagnosis and management

All patients diagnosed with primitive neuroectodermal tumor (PNET) and extraosseous Ewings sarcoma in one institution between 1962 and 1987 were reviewed. Of the 26 cases studied, 16 had been diagnosed originally as PNETs, seven tumors were rediagnosed as PNET or EOE by histologic review, and three tumors had an original diagnosis of extraosseous Ewings sarcoma. To determine whether these diagnoses determine a group of tumors with unique biologic behavior and identifiable pathologic characteristics, clinical and treatment response data were compiled, and electron microscopic and immunohistochemical studies were done for those patients with adequate samples. With combined modality therapy, this group achieved a substantially shorter disease control interval than patients with disseminated osseous Ewings sarcoma or disseminated neuroblastoma—10.8 months versus 17 months and 16 months, respectively. The pattern of relapse and distant spread also differed among these tumor types. Immunohistochemical studies (for example, neuron‐specific enolase and β2 microglobulin) were helpful in confirming the diagnosis but were not definitive in themselves. Tentative diagnostic criteria are proposed for use in studies designed to provide further information on the nature and treatment of PNET. Some of the controversies regarding diagnosis are discussed. The authors propose a uniform approach to treatment of extraosseous Ewings sarcoma and PNET in order to try to clarify their relation.

Central nervous system toxicity following the treatment of pediatric patients with ifosfamide/mesna.

Ifosfamide/mesna treatment of 50 patients with pediatric malignant solid tumors was associated with the development of neurotoxic signs and symptoms in 11 of these individuals who received 29 courses of treatment. Neurologic toxicity included changes in mental status, cerebellar function, cranial nerve, and cerebellar and motor system function, including seizures. All symptoms, signs, and EEG abnormalities were transient. Some of the affected individuals failed to develop acute neurotoxic signs of symptoms when retreated with ifosfamide. A grading system for scoring these neurologic abnormalities is presented for comparison of acute neurotoxic effects of other agents. Recommendations are made regarding early termination or delay of ifosfamide/mesna treatments in the presence of significant neurotoxicity.

Expression of the multidrug resistance, MDR1, gene in neuroblastomas.

Metastatic neuroblastoma is a childhood malignancy that is frequently responsive to chemotherapy with doxorubicin, vincristine, and teniposide (VM26), among other drugs, but in the majority of treated patients, the tumor recurs during or after chemotherapy. In this work, we have examined the hypothesis that the development of resistance to chemotherapy in neuroblastoma might be related to the expression of the human MDR1 gene, which encodes a multidrug transporter that functions as an energy-dependent drug efflux pump. RNA samples from 49 neuroblastomas were analyzed, including 31 from untreated and 18 from treated patients. MDR1 RNA was detectable in the majority of treated and untreated tumors using a sensitive, semiquantitative slot blot assay. Of the samples from treated patients, five of 18 were found to have high MDR1 RNA levels, whereas only three of 31 from untreated patients had high MDR1 levels, a statistically significant difference (P less than .01). These results show that high levels of MDR1 RNA are often associated with resistance to chemotherapy in neuroblastoma and suggest that they may contribute to this resistance. Many of the neuroblastoma samples were also evaluated for N-myc amplification but there was no correlation between N-myc copy number and the level of MDR1 mRNA expression.

Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development.

We describe events that led to successful testing of melphalan, one of the nitrogen mustard compounds, in children with newly diagnosed, poor-risk rhabdomyosarcoma (RMS). Preclinical studies with xenografts of human RMS, growing in the flanks of immune-deprived mice, had indicated superior oncolytic activity by melphalan compared with other agents commonly used to treat this tumor. However, in a conventional phase II trial, melphalan failed to produce partial responses in 12 of 13 heavily pretreated patients with recurrent tumors. Subsequent comparison of the drugs pharmacokinetics in mice and patients indicated that its poor clinical performance was not the result of interspecies differences in drug disposition. Therefore, we elected to retest melphalan in untreated patients, before they were enrolled in a phase III study. Of 13 children who received the drug for 6 weeks, ten had partial responses, confirming the significant antitumor activity seen in the xenograft system. These findings illustrate the inherent limitations of phase II drug trials in previously treated patients and suggest a useful paradigm for the development of antineoplastic drugs.

Thoracotomy for pulmonary metastatic osteosarcoma. An analysis of prognostic indicators of survival

Removal of pulmonary metastases of osteosarcoma by thoracotomy is an accepted treatment; however, few investigators have analyzed the value of various prognostic factors in estimating survival. A review of all patients undergoing thoracotomy for recurrent osteosarcoma with pulmonary metastases treated at St. Jude Childrens Research Hospital is reported. Since 1968, two thirds (39/59) of all patients who developed pulmonary metastases have had a total of 66 thoracotomies. Nine patients are alive with no evidence of disease, and six additional patients are alive with disease. Analyzed in 39 evaluable patients, the prognostic factors that correlate with survival by univariate analysis are: sex, number of nodules detected radiographically and resected, completeness of resection, and tumor location (bilateral versus unilateral). By Cox regression analysis, only sex and the number of nodules detected either radiographically or during surgery, and resected, had statistically significant correlation with survival. Thoracotomy is curative for some patients with pulmonary metastatic osteosarcoma and Prognostic factors predictive for survival are defined. Cancer 59:374–379, 1987.

Sequential cyclophosphamide and doxorubicin for induction of complete remission in children with disseminated neuroblastoma

When 70 children with disseminated neuroblastoma were treated for 4 months with a course of cyclophosphamide and doxorubicin (Adriamycin) 35 (52%) of 68 assessable patients achieved complete remissions, 13 had partial responses, and 20 had either less than a 50% regression of tumor or evidence of tumor progression. Of the 35 children with complete responses, three received local irradiation, but for the remainder, chemotherapy alone provided rapid control of tumor growth. Drug‐induced toxicity caused the hospitalization of four of 17 infants and five of 52 older children, but was related to only two of the eight deaths that occurred during treatment. Infants less than 1 year of age were more likely to achieve a complete remission than were older children. That 52% of these patients achieved complete remissions represents a marked improvement over the 22% response rate for patients seen between 1962 and 1974. Of 35 patients with complete responses, 15 have survived, contrasted with only four of 33 patients achieving less than a complete response. Median survival for patients achieving a partial response was 14.4 months, compared to 8.4 months for patients not achieving a response. A kinetically based sequence of chemotherapy seems to produce a high rate of complete remissions in children with disseminated neuroblastoma. To consolidate this gain into curative treatment will require a continuation therapy to prevent the emergence of drug‐resistant disease.

Chemotherapy as an alternative to laminectomy and radiation in the management of epidural tumor

Nine children with neuroblastoma and five with Ewing sarcoma were found at diagnosis to have epidural extension of tumor. Five children underwent laminectomy prior to referral, with good neurologic recovery in only one. Management in the other nine children did not include laminectomy. All 14 patients were given chemotherapy without radiotherapy. Rapid regression of tumor with neurologic recovery occurred in response to chemotherapy in all patients with neurologic deficits. The responses observed in these children indicate that for chemotherapy-sensitive tumors, effective chemotherapy is a feasible alternative to laminectomy and radiation therapy in the management of epidural disease.

Clinical evaluation of sequentially scheduled cisplatin and vm26 in neuroblastoma: Response and toxicity

Cis‐dichlorodiammineplatinum (CDDP) and VM26, both of which have been proven efficient in treating neuroblastoma, were combined in a sequential schedule and administered to 22 children with disseminated neuroblastomas resistant to treatment with cyclophosphamide and doxorubicin (Adriamycin). During this same study, 14 children were prospectively evaluated for the effect of CDDP on magnesium metabolism and the effect of the induced hypomagnesemia on parathyroid function. Complete or partial tumor responses were achieved in six and nine cases, respectively and were of prolonged duration (longer than six months) in eight of the 15 responding. It was also shown that CDDP‐induced hypomagnesemia is the result of excessive renal loss and is severe enough to interfere with the normal parathormone response to hypocalcemia.

Surgicopathologic staging of neuroblastoma." Prognostic significance of regional lymph node metastases

Of 254 children with neuroblastoma treated at St. Jude Childrens Research Hospital, 102 (40%) had clinically localized tumors. Using a surgicopathologic staging system, 66 of these 102 children had localized tumor and 36 had tumor dissemination to regional lymph nodes. Survival of these two groups has been markedly different; 57 of 66 (87%) with localized tumor survive, compared with 11 of 35 (33%) with node dissemination, five of whom are less than two years from diagnosis. Our data indicate that the prognosis for children with neuroblastoma metastatic only to regional lymph nodes is no different from that of patients of similar age with widely disseminated tumor.