Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group study.

The Pediatric Oncology Group (POG) evaluated in a prospective study the hypothesis that patients who had localized, visible residual neuroblastoma without regional lymph node involvement after surgery (POG stage B) have a favorable prognosis when treated with moderate intensive chemotherapy. Eligible patients were initially treated with five courses of Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co., Evansville, IN) and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) followed by surgery (CY/AD +/- surgery). Those patients not achieving a complete remission (CR) crossed over to five courses of cisplatin and teniposide (PL/VM) +/- surgery. Radiation therapy (XRT) was given to selected patients who still were not in CR after the crossover therapy. Of the 61 eligible patients, 38 (62%) patients achieved CR after CY/AD proven by clinical (31) or surgical (seven) evaluation. One (2%) patient in clinical partial remission (PR-C) entered CR without further therapy. Nineteen (31%) patients achieved CR with the following salvage therapies: surgery (five), PL/VM +/- surgery (five) followed by XRT (three) or autologous bone marrow transplant (ABMT) (one) and further courses of CY/AD +/- PL/VM instead of courses of PL/VM (five). The overall CR rate was 95% (58 of 61). Four patients had recurrence of the disease. The probability of being disease-free at 3 years after initial or salvage therapy was estimated at 84% (SE, 5%). The overall prognosis of children older than 1 year and younger than 1 year was similar (P = .26). If, however, the three remission deaths (all younger than 1 year) were censored, there was only one other failure in 32 children younger than one versus seven of 29 children older than 1 year (P = .018). These results confirm the excellent prognosis for patients with POG stage B neuroblastoma and indicate that most patients are curable with CY/AD +/- surgery, and those not achieving CR with this therapy are curable with alternate therapy.

Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study.

PURPOSE: The Pediatric Oncology Group (POG) designed a randomized two-arm protocol (8304) to improve the survival of children with acute lymphoblastic leukemia (ALL) who experience an isolated testicular relapse and to evaluate the efficacy of teniposide (VM-26) and doxorubicin as intensification agents during second remission. The outcome and toxicity observed in 80 patients with isolated testicular leukemia treated on POG 8304 are presented. PATIENTS AND METHODS: The following are common features of POG 8304: (1) remission reinduction therapy with vincristine, prednisone, and doxorubicin; (2) bilateral testicular irradiation (2,600 cGy) during reinduction therapy; (3) CNS prophylaxis with intrathecal hydrocortisone, methotrexate (MTX), and cytarabine (Ara-C); and (4) continuation therapy (for 80 weeks) with alternating 6-week cycles of oral mercaptopurine (6-MP)/MTX and intravenous vincristine and cyclophosphamide. Treatment differences consisted of pulses (administered every 7 weeks) of either prednisone and doxorubicin (arm 1) or VM-26 and Ara-C (arm 2) during continuation therapy and a 4-week late intensification phase with either vincristine, prednisone, and doxorubicin (arm 1) or VM-26 and Ara-C (arm 2). RESULTS: Fifty-five boys with ALL had isolated microscopic testicular leukemia detected by an elective biopsy at completion of initial treatment, and 25 had a late (greater than or equal to 6 months off-therapy) isolated overt testicular relapse. All patients with overt testicular leukemia attained a second clinical remission, and no patient with microscopic testicular leukemia progressed during reinduction. Of 42 patients on arm 1, 11 have relapsed compared with 18 of 38 patients on arm 2 (log-rank analysis, P = .22), indicating no significant difference between an anthracycline and an epipodophyllotoxin-Ara-C combination in the treatment of testicular leukemia. The overall 4-year event-free survival (EFS) among boys with occult testicular relapse was 53% +/- 8%. Age greater than 10 years at initial diagnosis, a WBC count greater than 50,000/microL at diagnosis, and black race were associated with a worse outcome. The 4-year EFS for boys with a late overt testicular relapse was 84% +/- 10%, and these patients fared significantly better than patients with occult disease (P = .007). CONCLUSION: The treatment approach reported here can secure a prolonged second remission in many patients with occult or late overt testicular leukemia.

Antithymocyte globulin, cyclosporine, and prednisone for the treatment of severe aplastic anemia in children. A pilot study.

PURPOSE: The aim of the therapeutic trial was to try to optimize the treatment of severe and moderate aplastic anemia in children who lack a suitable bone marrow donor using the most successful available drugs, with the least amount of side effects. PATIENTS AND METHODS: A pilot study for the treatment of severe aplastic anemia in children was conducted by four institutions. The treatment protocol included antithymocyte globulin (ATG), prednisone, and cyclosporine A. Twelve patients were enrolled, and 11 were evaluable. All patients had severe aplastic anemia (SAA); three had hepatitis-induced severe aplastic anemia (HI-SAA). RESULTS: Of 11 evaluable patients, eight have responded with normalization of their blood counts. Two of the three patients with HI-SAA responded to the therapy. CONCLUSION: The results of our pilot study compare favorably with previous therapeutic trials. All the patients who responded achieved complete response, i.e., restoration of blood counts to within the normal range.

Localized bone marrow relapse in acute lymphoblastic leukemia.

Localized bone marrow relapse is rare in acute lymphoblastic leukemia. Discordant bone marrow specimens were found in an 11-year-old asymptomatic girl who had been in remission for six years and off chemotherapy for 2 1/2 years. One bone marrow sample showed marked leukemic infiltration, whereas marrow from another site was normal. Three months later, with normal peripheral blood counts, she developed severe back pain and x-ray evidence of vertebral collapse and periosteal changes in the pubic bone. At that time three of the four areas of bone marrow sampled showed leukemic involvement. Reinduction therapy was begun, and she is now in remission on maintenance chemotherapy. At this time, it is unclear whether routine performance of marrow aspirations and biopsies from multiple sites, in periodic follow-up examinations of patients with acute leukemia would allow earlier detection of relapse frequently enough to justify the procedure. The issue of localized bone marrow involvement, if more common than previously reported, should be addressed at the time a decision is being made to discontinue therapy.

Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood. A Pediatric Oncology Group Phase II study.

BACKGROUND: The prognosis for children with recurrent or resistant malignant solid tumors remains dismal. More effective rescue therapy is needed for these children. METHODS: Between August 1987 and November 1990, 311 children with recurrent or resistant malignant solid tumors were treated by investigators in the Pediatric Oncology Group with intravenous infusions of 2.0 g/m2 of ifosfamide and 100 mg/m2 of etoposide (VP-16) plus mesna as uroprotection three times daily, with courses being repeated every 14-21 days for as long as the patients responded to therapy. RESULTS: Seventy-four percent of the 294 assessable patients entered in the study had metastatic disease and previously had been treated heavily. The complete response/partial response rate was 30%, and the overall response rate was 39.5%. Toxic effects included nephrotoxicity, mild liver dysfunction, neurotoxicity, and myelosuppression. Sixty-eight percent had an absolute neutrophil count (ANC) of less than 500/microliters. In 1606 courses of therapy administered, only 3.6% of patients developed a bacterial infection. Only two patients died of gram-negative sepsis. Four percent of the patients had gross hematuria (> 50 erythrocytes/high-power field), and 18.5% had microscopic hematuria (< 20 erythrocytes/high-power field). Fanconi syndrome developed in eight children. CONCLUSIONS: Ifosfamide/VP-16 is an active combination in children with recurrent malignant solid tumors. Although it was myelosuppressive, the incidence of infection was quite low (3.6%). Mesna was very effective in preventing the development of hematuria.

Successful treatment of childhood pilocytic astrocytomas metastatic to the leptomeninges with high-dose cyclophosphamide.

Leptomeningeal dissemination of childhood pilocytic astrocytoma (PA) is a rare event with little information available regarding therapy. We report here four children with disseminated PA whom we treated with high doses of cyclophosphamide with clinical benefit. The patients were aged 2.5 to 8 years. Three patients presented with PA localized in the posterior fossa, initially treated with surgical resection (n = 3) and radiotherapy (n = 1). Leptomeningeal dissemination occurred at 32, 44, and 8 months from diagnosis, respectively. The fourth patient presented with an optic pathway tumor with leptomeningeal dissemination at diagnosis. At commencement of cyclophosphamide therapy, disease was present in the subarachnoid space (intracranial, n = 2; spinal, n = 4), cerebral ventricles (n = 2), and primary site (n = 3). Histology was identical at diagnosis and recurrence in the two biopsied cases and cerebrospinal fluid was negative in all cases. Treatment was with cyclophosphamide 4-5 g/m2/cycle given every 4 weeks for a total of two cycles (n = 1) and four cycles (n = 3). One patient achieved disease stabilization (duration 27 months at the time of publication) and three patients experienced significant reductions in tumor burden. Subsequent intrathecal therapy was administered to two patients. Two patients developed disease progression at 10 and 9 months from cessation of chemotherapy. The one re-treated patient responded to further, lower dose, cyclophosphamide. This is the first report of the use of high dose cyclophosphamide for disseminated PA. The recurrence of disease in two cases with a further response to lower dose cyclophosphamide has implications for the optimal duration of therapy for these low grade, aggressive tumors.