Biomedical subjects
Publications and source records attributed to C B Pratt.
Ongoing studies using ifosfamide with mesna for primary or recurrent pediatric malignancies are reviewed. These studies include evaluations of ifosfamide given before conventional agents, in combination with other agents, with other effective agents and radiation therapy, and in alternative schedules.
To characterize the excretion of 2-mercaptoethanesulfonate sodium (mesna) administered by intermittent infusion, urinary concentrations of mesna and its corresponding inactive disulfide were measured during 50 courses of ifosfamide (1.6 g/m2 for 5 days) and mesna (400 mg/m2 at 0.25, 4, and 6 h after each ifosfamide dose) administered i.v. to 19 patients. Some patients had previously received nephrotoxic therapy that might influence the excretion of mesna and its associated uroprotective effects. The median urinary free thiol concentration increased to 3 mM by 1 h after mesna infusion, declining to background levels by 4 h. The rate of mesna excretion correlated with the creatinine clearance rate in a subset of six patients. The proportion of mesna recovered in urine within 4 h after infusion was lower (P less than 0.05) in children who had evidence of preexisting renal tubular damage. Ifosfamide-induced tubular proteinuria was associated with lower urinary mesna recovery. Low urinary mesna concentrations indicated potentially subtherapeutic renal tubular levels. However, ifosfamide nephrotoxicity was subclinical and is not necessarily linked to differences in mesna excretion.
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From January 1962 to July 1988, 34 infants less than 29 days of age who had cancer were seen at St. Jude Children's Research Hospital (SJCRH). The malignancies in this group consisted of 19 neuroblastomas, 6 leukemias, 3 retinoblastomas, 2 Wilms' tumors, 2 melanomas, and 2 teratomas. Twenty-three patients (68%) are alive and free of disease 2 months to 24 years after diagnosis. We reviewed the presentation and initial symptoms, pathology reports, patient population, associated anomalies, potential genetic influences, and possible perinatal factors. The most common initial symptom was an enlarging abdomen or abdominal mass. Pathological findings were occasionally difficult to interpret; five additional infants who were referred to us did not have malignancies. There was no increased incidence of associated anomalies or perinatal insults. The only genetic factor was retinoblastoma in one parent of each infant diagnosed as having retinoblastoma. The possible etiology of neonatal tumors is discussed.
Bone sarcomas are the most common second malignant neoplasms in survivors of a malignant solid tumor in childhood. In contrast to de novo tumors, secondary bone cancers are typically associated with a poor prognosis, reflecting both a preponderance of primary sites that preclude complete resection in the flat bones of the axial skeleton, and the tendency for local invasiveness or distant metastasis. We describe a patient who developed malignant extradural osteosarcoma of the temporal bone 6 years after successful treatment for a malignant cerebellar astrocytoma with surgical resection and local irradiation. A complete resection of the sarcoma was not possible; however, she achieved a biopsy-proven complete response after intensive chemotherapy with ifosfamide, followed by cisplatin and doxorubicin. At age 13, she remains free of recurrence 3 years after completing all therapy. In view of the rarity of prolonged disease control after incomplete resection for osteosarcoma, this report suggests the value of intensive combination chemotherapy in achieving a durable unmaintained remission in our patient.
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4'-Deoxydoxorubicin was given to 15 patients with drug-resistant pediatric malignant solid tumors with the objectives of determining the maximum tolerated dosage and dose-limiting toxicity. Maximum tolerated dosage was 36 mg/m2 given IV once every 3 weeks. Dose limiting toxicity was myelosuppression, which was severe and prolonged. Therapeutic benefits were not observed for these patients.
Ifosfamide/mesna was given to 97 patients who had malignant solid tumors diagnosed before they were 21 years of age. Patients received 1.6 g/m2 ifosfamide daily x 5, given i.v. over 15 min, followed by 400 mg/m2 i.v. mesna at 15 min and 4 and 6 h after ifosfamide. Responses were noted in patients with osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma and other soft-tissue sarcomas, rhabdoid tumor, neuroblastoma, Wilms' tumor, primitive neuroectodermal tumor, retinoblastoma, germ-cell tumors, and B-cell lymphoma. Toxicity included mild to moderate nausea and vomiting, transient, reversible myelosuppression, transient elevations of serum blood urea nitrogen (BUN) and creatinine and liver enzymes, infections, and self-limiting neurotoxicity characterized by changes in mental status, motor dysfunction, cranial nerve palsy, cerebellar dysfunction, and seizures. Neurotoxic symptoms were generally seen in patients who had previously received cisplatin. Ifosfamide is an important alkylating agent that should be combined with other agents in phase II and III trials. Alternate dose schedules should also be investigated.
The nephrotoxic effects of ifosfamide were assessed in 18 children and adolescents given cumulative doses of 32-112 g/m2 (1.6 g/m2 per day in sequential 5-day courses) with the uroprotectant mesna (1.2 g/m2 per day). Tubular nephrotoxicity was evaluated by measuring the urinary concentrations of N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), and total protein before and during sequential courses of therapy. Of 15 patients who had normal levels of tubular markers before ifosfamide therapy, only 1 developed a persistent increase in baseline values of the three tubular markers with the sixth course of ifosfamide. Although transient increases in the excretion of these markers were observed during each 5-day course of ifosfamide, the magnitude did not increase over sequential courses in these 15 patients. Of the remaining three patients who had increased NAG levels before ifosfamide therapy, two showed a progressive increase in enzymuria and proteinuria, and serum creatinine concentrations increased in a single patient who had obstructive uropathy. Our data suggest that children with normal renal function can be given large cumulative amounts of ifosfamide in fractionated doses with little risk of progressive clinical nephrotoxicity.
Between 1962 and 1988, a total of 104 patients with head and neck rhabdomyosarcoma (RMS) and 17 patients with nonrhabdomyosarcoma (NRMS) were evaluated and treated at St. Jude Children's Research Hospital. All parameningeal sites (middle ear, orbit, or nasopharynx) were excluded from further analysis; thus, 50 patients represent the cohort of head and neck sarcomas for this review. Survival was good in this group of patients, 28 of 50 being alive and disease-free at last follow-up. Twenty of the 38 patients with RMS were alive and disease-free. Similarly, 8 of the 12 patients with NRMS were disease-free at a median follow-up of 5 years. However, the site and size of the primary tumor impacted on the extent of the initial resection and further treatment in addition to surgery. Although the treatment policy evolved over time to a stage-specific strategy for treatment modalities, the data suggest that surgery alone may be sufficient initial therapy for a subset of patients. For patients in whom complete resection is not achieved, the addition of radiotherapy and chemotherapy may result in improved survival.
Lumbar punctures (n = 115) and bone marrow aspirations (n = 114) were performed as part of the routine initial diagnostic evaluation of 115 children with retinoblastoma. Three spinal fluid examinations were positive for tumor cells, and bone marrow smears of three children demonstrated clumps of tumor cells. Five of the six positive studies were in patients with stage IV (extraglobar) disease. These results show that demonstrable CSF or bone marrow involvement is so infrequent an event at diagnosis in patients without symptoms, signs, or histologic evidence of tumor dissemination (stages I-II) as to support a recommendation that these studies need not be performed routinely in such patients. If, after enucleation, there is evidence of extraglobar extension, or if patients have symptoms or signs of CNS or systemic spread (stages III or IV), both procedures should be performed to accurately stage disease and provide baseline measurements of tumor involvement for monitoring of response to chemotherapy and/or irradiation. These results have importance in terms of justification of invasive work-up of most (greater than 85%) affected children, and cost containment.
A phase-II study of ifosfamide with mesna, given intravenously daily for five days by bolus injection, has demonstrated the activity of ifosfamide against a spectrum of childhood malignant solid tumors. Ifosfamide presently is being investigated in alternative phase-I schedules, daily times three or every other day times three with the aim of delivering comparable amounts of ifosfamide without increasing toxicity--specifically, neurotoxicity. Additionally, response following ifosfamide treatment is being evaluated for previously untreated children with osteosarcoma and rhabdomyosarcoma after 6 weeks of treatment, and for previously untreated patients with Ewing's sarcoma after 9 weeks of treatment with ifosfamide/VP-16 (etoposide) given in combination.
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Carcinomas occur rarely in children and adolescents. Despite their rarity, these tumors present a unique opportunity to assess theories of origin because the interval from birth to tumor onset is relatively short compared with that seen in adults. We describe the clinical and demographic characteristics of 151 patients younger than 20 years of age with carcinomas who were treated at a pediatric cancer center having a large referral area. Incidence data for the major types of carcinomas in children, based on unpublished data provided by the National Cancer Institute's Surveillance, Epidemiology and End Results Program (SEER), also are reported.
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We investigated the relationship between prior therapy and three distinct forms of toxicity that developed during ifosfamide administration (1.6 g/m2/day for 5 days) in 36 children with malignant solid tumors. Of ten therapies that were studied by multiple regression techniques, only the number of doses of cisplatin that patients had received was significantly related to neurotoxicity, hematotoxicity, and tubular nephrotoxicity, with the more severe cases occurring after three or more doses (P less than 0.05). Increased urinary concentrations of the renal tubular enzyme N-acetyl-beta-D-glucosaminidase, measured before each course of ifosfamide, were predictive of neurotoxicity (P = 0.02) and hematotoxicity (P = 0.01). We suggest that cisplatin-induced renal tubular damage, leading to the impaired clearance of ifosfamide metabolites, may account for this added toxicity.
From July 1972 through September 1984, 8 of 44 children diagnosed as having primary malignant hepatic tumors, who were treated at St. Jude Children's Research Hospital, had undifferentiated (embryonal) sarcoma (five patients) or rhabdomyosarcoma (three patients). The natural history and response to multimodal therapy of these rare tumors are described. The pathologic material was reviewed and evidence for the differentiating potential of undifferentiated (embryonal) sarcoma is presented. At diagnosis, disease was restricted to the right lobe of the liver in three patients, was bilobar in four patients, and extended from the left lobe into the diaphragm in one patient. Lung metastases were present in two patients at diagnosis. All three patients with rhabdomyosarcoma had intrahepatic lesions without involvement of the biliary tree. Survival ranged from 6 to 73 months from diagnosis (median, 19.5 months); two patients are surviving disease-free for 55+ and 73+ months, and one patient recently underwent resection of a recurrent pulmonary nodule 22 months from initial diagnosis. Three patients died of progressive intrahepatic and extrahepatic abdominal tumors, and two patients, who died of progressive pulmonary tumor, also had bone or brain metastasis but no recurrence of intra-abdominal tumor. Six patients had objective evidence of response to chemotherapy. The authors suggest an aggressive multimodal approach to the treatment of these rare tumors in children.