Search

Background: Ifosfamide with Mesna, given every other day over a 5-day period, was evaluated in 20 children with recurrent or progressive primary brain tumors., Methods: The patients were assigned to dosage cohorts separated on the basis of prior exposure to cisplatin (n = 10) or the absence of such exposure (n = 10). The initial dose in each treatment arm was 2133 mg/m2 every other day for three doses, which represented 80% of the total dose delivered in our prior study of ifosfamide given daily over 5 days. The dose was escalated by 20% in each of the two subsequent cohorts (2560 mg/m2 and 3072 mg/m2 every other day for three doses)., Results: The hematologic toxicity was dose limiting. Prior exposure to cisplatin did not seem to increase the hematologic toxicity. The most frequent and significant metabolic disturbance was hyponatremia, resulting in self-limited seizure activity in three patients. This complication was prevented in subsequent patients by changing the post-ifosfamide hydration fluids from 5% dextrose in quarter normal saline to 5% dextrose in normal saline., Conclusions: Although no child achieved a complete response, the activity of ifosfamide was demonstrated for a variety of tumors. The recommended dose of ifosfamide in a Phase II study for brain tumors is 3000 mg/m2 given with Mesna every other day for three doses.

Of 29 consecutive children treated for malignant primary tumors of the central nervous system (CNS) at this institution, postoperative examination showed radiographic or cytologic evidence of neuraxis dissemination in 10 (34%). Given the historically poor results in disseminated CNS tumors treated with surgery and radiation therapy alone, these ten patients were treated prospectively with an investigational Phase II protocol consisting of preirradiation cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 3 and 4). The diagnoses included medulloblastoma (n = 4), malignant glioma (n = 3), cerebral primitive neuroectodermal tumor (n = 1), pineoblastoma (n = 1), and mixed glioma of the brainstem (n = 1). Postoperative neuraxis scanning with computed tomography, magnetic resonance imaging, or spinal myelography showed measurable intracranial or spinal metastases in all children. The cerebrospinal fluid (CSF) cytologic examination was positive for tumor cells in five. The best responses, based on serial imaging of neuraxis metastases, included two complete responses, four partial responses, and three stable disease states. One patient had progressive disease at the primary site despite stable disease in the spine; progressive neuraxis disease was documented in only one patient during chemotherapy. Clearance of tumor cells from the CSF was documented in three patients. The adverse effects of chemotherapy, consisting of transient myelosuppression and mild ototoxicity, were minimal. Reversible neurologic deterioration occurred in two patients; one patient became acutely quadriplegic after a prolonged convulsive seizure without radiographic evidence of tumor progression.

To evaluate the anticancer agent flavone acetic acid (FAA), we conducted a Phase I trial involving 17 pediatric patients with various malignant solid tumors. Dosages investigated included 5,120 and 6,144 mg/m2 given as 3-hour intravenous infusions; and 10,000, 12,500, 15,000, and 17,500 mg/m2 delivered in a 24-hour constant infusion with alkalinization. Grade 2 or worse toxicity was minimal, with 2 patients having nausea/vomiting, 2 having diarrhea, 1 becoming hypertensive, 1 becoming hypotensive, and 2 having myalgia. Three patients who received a 17,500 mg/m2 dose had no toxicity. Disease was stabilized for a brief period in 2 patients--1 with brain stem glioma and 1 with astrocytoma. The FAA pharmacokinetics varied with an average (SD) terminal half-life of 27.9 hr (18.7), clearance of 2.04 L/hr/m2 (0.37), and steady-state volume of 19.9 L/m2 (10.6). This study was discontinued because FAA caused no significant toxicity or therapeutic responses at doses 2.5 gm/m2 greater than had been tolerated by adults.

The authors report the clinicopathologic and neuroimaging findings in ten children with primary abdominal or thoracic neuroblastoma who relapsed in the central nervous system (CNS) without evidence of concurrent intracranial extension from adjacent bone, dura, or dural sinus metastases. At diagnosis, the patients ranged in age from 0.3 to 4.5 years (median, 2 years). Their times to CNS relapse ranged from 2 to 34 months from diagnosis. In seven patients the relapse occurred from 1 to 14 months after elective discontinuation of therapy. In four patients, the CNS relapse was the primary (isolated) adverse event. Four patients could not be treated at the time of relapse, and they died within 7 days of progressive CNS disease. In the remaining group, craniospinal irradiation with or without administration of a platinum compound and an epipodophyllotoxin caused complete CNS remissions lasting 4, 5, 16, and 62+ months. Neuroimaging and autopsy findings indicated that cerebrospinal fluid is the major pathway for neuraxis dissemination by neuroblastoma cells. There was no evidence of dural penetration in any patient. The possibility of relapse in the neuraxis should be considered for any patient with neuroblastoma who had neurologic deterioration. A combination of craniospinal radiation and administration of a platinum compound and an epipodophyllotoxin will induce complete responses in some patients with neuraxis involvement by neuroblastoma, but the risk of subsequent failure outside the CNS remains high.

The incidence, clinical characteristics, and outcome of hypersensitivity reactions to teniposide (VM-26), etoposide (VP-16), or both were determined in 108 children with acute lymphoblastic leukemia (ALL) treated with a contemporary regimen of intensive multiagent chemotherapy. Fifty (46%) of the 108 patients had one or more hypersensitivity reactions. The risk of any child having an initial reaction over the cumulative dose range studied was 52% (95% confidence limits, 41% and 63%) for VM-26, compared with 34% (95% confidence limits, 24% and 44%) for VP-16. The risk of having an initial reaction to VM-26 or VP-16 was clearly related to the cumulative dose. This risk peaked at 1500 to 2000 mg/m2 for VM-26 and at 2000-3000 mg/m2 for VP-16. All reactions were Type 1 reactions according to the Gell and Coombs classification, characterized by urticaria, angioedema, flushing, rashes, or hypotension, and 86% of reactions were of Grade 1 or 2 severity according to standard criteria. There was no evidence of increasing clinical severity on repeated rechallenge with premedication, and no deaths occurred. The findings suggested that hypersensitivity reactions to epipodophyllotoxins in children with ALL are more common than previously reported, but only rarely constitute dose-limiting toxicity.

The clinicopathologic features and response to therapy of 28 patients with non-Ewing's flat bone sarcoma treated at St. Jude Children's Research Hospital, Memphis, Tennessee, over a 25-year period were reviewed. Twenty-two patients had osteosarcoma, four malignant fibrous histiocytoma, one chondrosarcoma, and one fibrosarcoma. Ages at diagnosis ranged from 3 to 24 years (median, 15 years). Primary sites were craniofacial bones in ten patients, pelvis eight, scapula four, ribs two, metatarsal bones two, clavicle one, and vertebra one. All primary tumors were associated with soft tissue extension; none of the patients had metastatic disease at presentation. Six cases represented second malignancies that arose 5 to 16 years after irradiation for an unrelated tumor. Complete excision was possible in ten patients, eight of whom received postoperative chemotherapy. Five of these patients remain free of disease 1.8+ to 13+ years (median, 8.1 years) from diagnosis. Prolonged remissions after adjuvant chemotherapy were achieved in only two of 18 patients after incomplete surgical resection or biopsy. The median survival time in this group was 1 year (range, 0.2-7.7+ years). The remaining 16 patients had progressive local disease, but only two developed concurrent metastases. Thus, complete surgical resection appears to maximize disease-free survival in patients with non-Ewing's flat bone sarcoma. For the large percentage of patients in whom total resection is not possible, because of soft tissue extension and local invasion of bulky tumors, preoperative chemotherapy may increase the likelihood of complete excision and improve long-term survival.

Medulloblastoma, pineoblastoma, and cerebral neuroblastoma are malignant embryonal tumors of the CNS that may demonstrate similar histologic features, a propensity for neuraxis dissemination and sensitivity to radiation therapy and, in certain cases, chemotherapy. To evaluate the activity of preirradiation chemotherapy in such tumors, 11 newly diagnosed children with measurable residual disease and characteristics indicative of poor prognosis were treated postoperatively with cisplatin (CDDP) and etoposide (VP-16). Responses graded on the basis of radiographic findings in areas of either macroscopic residual tumor or metastatic disease included two complete responses (CRs), eight partial responses (PRs), and one stable disease (SD). Acute and subacute toxicity consisted of high-frequency hearing loss in four patients, reversible signs and symptoms of increased intracranial pressure in two patients, and transient neutropenia. Seven of eight patients with high-risk medulloblastoma and two of two with pineoblastoma remain free of tumor progression following neuraxis irradiation at 8 to 48 months postdiagnosis (median, 18 months). CDDP and VP-16 is a highly active drug combination when given before irradiation in children with high-risk medulloblastoma and other malignant embryonal tumors of the CNS, producing objective responses in at least one site of measurable disease in 10 of 11 newly diagnosed patients, including all of five with gross neuraxis dissemination.

Hyperuricemia is an unusual presenting feature of acute lymphoblastic leukemia (ALL) and is generally associated with a large leukemic cell burden. We describe three children with T-cell ALL who presented with acute renal failure and very high serum uric acid concentrations, despite a relatively small leukemic cell burden. Two of the three patients had normal complete blood counts without circulating blasts or other physical evidence of leukemia. An isolated renal relapse in one case was associated with hyperuricemia, increased renal excretion of uric acid, and renal dysfunction. An unusually high rate of purine catabolism of the lymphoblasts may cause hyperuricemia in these cases. Unexplained hyperuricemia should prompt a search for occult malignancy.

Chloromas are solid tumours resulting from the localised proliferation of myelogenous leukemia cells, and are frequently responsible for the initial manifestations of acute myelocytic leukemia. We report a patient with a thoracic extradural chloroma whose presentation with acute paraplegia led to the diagnosis of an unsuspected myelocytic leukemia. Early recognition of the etiology of the paraplegia and the underlying systemic involvement with leukemia resulted in an excellent neurological and hematological outcome. The previously described association of the 8:21 chromosomal translocation with a good prognosis is noted in our patient.

There is still controversy regarding the relative merits of catecholamine metabolite estimations on 24 h versus untimed urine collections. The former has the advantage of taking into account diurnal variation in the rate of metabolite excretion but has the disadvantages of delaying results and of being affected by errors in collection. In this study percentile values were established for a reference population of 181 children for urinary 4-hydroxy-3-methoxyphenylacetic acid (HVA)/creatinine and 163 children for 4-hydroxy-3-methoxymandelic acid (VMA)/creatinine, using untimed urine collections. Results of similar determinations performed as part of the diagnostic work up of 23 consecutive children subsequently proven to have neural crest tumours showed that all patients had the value of at least one metabolite concentration at or above the highest reference value. In neuroblastoma all patients' VMA/creatinine exceeded the highest reference value and in neural crest tumours overall, this ratio was greater than the highest reference value in 96% of patients. These results are as good as, or better than, previously published results and demonstrate the practical value of using catecholamine metabolite determinations expressed as 'creatinine equivalents' on untimed urine specimens in the diagnosis of neuroblastoma and related tumours in children.

A review of the pathological material from 42 children with non-Hodgkin's lymphoma seen over a 44 month period revealed 10 large cell tumours. Of these, six were classified as peripheral T-cell lymphoma, an entity rarely reported in childhood. Three patients were boys and three girls (median age 9.5 years), and extranodal presentation was a feature of two patients. Five had high-grade tumours; of these, three were classified as large cell anaplastic, Ki-1 positive and two as pleomorphic large cell. The remaining patient had a low-grade tumour of angioimmunoblastic type. T-cell subsets were examined in three cases and showed the following phenotypes: CD4-, CD8-; CD4+, CD8-; CD4-, CD8+. Three of the patients with high-grade tumours died, with a mean survival of 22 weeks. The remaining patients are alive and clinically disease-free for between 10 and 24 months after treatment.

We describe, in a young boy, a case of neuroblastoma presenting only as a painless unilateral testicular mass. Clinical and laboratory evidence of disseminated neuroblastoma was first apparent nine months after high orchiectomy. As far as we are aware this is the only reported instance of testicular neuroblastoma in the absence of disseminated disease. Discussion is directed to the possible explanations for this rare testicular lesion, and in addition, underlines the potential difficulties in the diagnosis of certain small cell tumors.

Among 131 boys with advanced (stage III or IV) non-Hodgkin's lymphoma (NHL) consecutively treated at St. Jude Children's Research Hospital, testicular involvement was present at the time of diagnosis in six and as an isolated site of relapse in three. Testicular involvement was not seen in any patient with localized (stage I or II) disease. Four of the six patients with involvement at presentation are free of disease 2.9+ to 8.3+ years after diagnosis, following chemotherapy alone (three patients) or chemotherapy plus orchiectomy. Overt testicular relapse while on therapy resulted in death from progressive disease in two patients; the third relapsed after completing therapy for Burkitt's lymphoma and is in second remission after chemotherapy, orchiectomy, and scrotal irradiation. The prolonged remissions seen in children with testicular involvement at diagnosis suggest that scrotal irradiation may not be necessary in chemosensitive disease. By contrast, testicular relapse on therapy appears to indicate drug-resistant disease and a poor prognosis, despite testicular irradiation and chemotherapy.

A prospective study of the effectiveness of ifosfamide as a single agent in the management of previously untreated patients with Evans stage IV neuroblastoma was undertaken. Eighteen children aged more than 1 year were treated with ifosfamide (IFX) 3 g/m2 daily for 2 days immediately after diagnosis and 3 weeks later. Treatment was continued with combination chemotherapy using vincristine, cyclophosphamide, cisplatinum and etoposide (OPEC) or a variant. Mesna (2-mercaptoethane sulphonate) was given to all patients during IFX treatment to prevent urotoxicity. Eight of the 18 patients (44%) responded to IFX. Nine had greater than 66% reduction in baseline tumor volume. Of 15 evaluable patients with raised pre-treatment urinary catecholamine excretion, six (40%) achieved greater than 50% reduction in pretreatment levels. Two of 10 patients evaluable for bone marrow response had complete clearance. Toxicity was mild in all patients. Upon completing 'first line' therapy, only four patients (22%) achieved a good partial remission (GPR) or complete response (CR). Median survival was 11 months. There was a lower rate of attaining GPR and shortened median survival in patients receiving phase II IFX before OPEC or variant, compared to patients with similar pre-treatment characteristics treated with OPEC from diagnosis in an earlier study.

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.

A proved first relapse occurred in the anterior segment of eight children with acute leukaemia, two of whom had concurrent central nervous system or bone marrow relapse. A further child developed uveitis after remission was induced, but in this patient no causal relationship with leukaemia was established. Uveitis in children who have had acute leukaemia should be regarded as evidence of relapse, and anterior chamber aspiration and iris biopsy are essential procedures in their evaluation. The outlook for children with anterior segment relapse remains poor despite intensive local and systemic treatment.