Faith Kung

POG 8625: A randomized trial comparing chemotherapy with chemoradiotherapy for children and adolescents with stages I, IIA, IIIA 1 Hodgkin disease: A report from the children's oncology group

To determine if 6 courses of chemotherapy alone could achieve the same or better outcome than 4 courses of chemotherapy followed by radiation therapy (chemoradiotherapy) in pediatric and adolescent patients with Hodgkin disease. Children ≤21 years old with biopsy-proven, pathologically staged I, IIA, or IIIA1 Hodgkin disease were randomly assigned 6 courses of alternating nitrogen mustard, oncovin, prednisone, and procarbazine/doxorubicin, bleomycin, vinblastine, and dacarbazine (treatment 1) or 4 courses of alternating nitrogen mustard, oncovin, prednisone, and procarbazine/doxorubicin, bleomycin, vinblastine, and dacarbazine +2550 cGy involved-field radiotherapy (treatment 2). The complete response rate was 89%, with a complete response and partial response rate of 99.4%. There was no statistically significant difference in event-free survival (EFS) or overall survival between arms. The EFS for those who achieved an early complete response was significantly higher than for those who did not. For pediatric patients with asymptomatic low-stage and intermediate-stage Hodgkin disease, chemotherapy and chemoradiotherapy both resulted in 3-year EFS of approximately 90% and statistically indistinguishable 8-year EFS and overall survival, without significant long-term toxicity. Early response to therapy was associated with higher EFS, a concept that has led to the Childrens Oncology Group paradigm of response-based risk-adapted therapy for pediatric Hodgkin disease.

Clinical trial of VP 16–213 (NSC 141540) I.V. Twice weekly in advanced neoplastic disease a study by the cancer and leukemia group B

The epipodophyllotoxin derivative VP 16–213 (NSC 141540) was studied by the Cancer and Leukemia Group B in a broad phase II trial at three dose levels: 60 mg/m2, 90 mg/m2, and 135 mg/m2 I.V. twice weekly. No correlation between dose of VP 16–213 and response frequency in a particular disease category could be demonstrated. Of the 382 patients, 8% obtained a complete (CR) or partial remission (PR), 8% showed improvement, and 14% had stable disease. By tumor type the best responses were obtained in lymphomas (8/31 CR + PR), uterus (2/9), prostate (1/5), rhabdomyosarcoma (2/6), neuroblastoma (2/4), colon/rectum (5/81), other gastrointestinal (4/32). In lung tumors, 4/80 patients obtained CR or PR. VP 16–213 has definite antineoplastic activity but the response frequency with the twice weekly schedule may be lower than that reported with other schedules.

Chemotherapy of reticuloendotheliosis: Comparison of methotrexate plus prednisone vs. vincristine plus prednisone

Twenty‐eight children, ages 2 months to 13 years, with a diagnosis of reticuloendotheliosis were treated on a random basis with either vincristine (VCR) 2 mg/m2/week or methotrexate (MTX) 30 mg/m2 twice a week. Both groups received prednisone 40 mg/m2/day. The responders received randomly either MTX 30 mg/m2 twice weekly or no maintenance therapy. Of the 11 patients receiving VCR, 2 achieved complete and 5 partial remissions. Among 17 treated with MTX there were 8 complete and 1 partial remissions. The complete plus partial remission rate is 64% for VCR and 53% for MTX. The duration of response was superior in the MTX‐treated group, with a median remission duration of 315 days; the 4 patients above the median are still in remission. With VCR therapy, the median was 96 days, and all patients have relapsed. Maintenance therapy also improved the duration of remission, with a median of 20 months, compared to 79 days with no maintenance. Thus, in this clinical trial the best results were obtained when methotrexate plus prednisone were used for induction, followed by methotrexate maintenance therapy.

Protracted Intermittent Schedule of Topotecan in Children With Refractory Acute Leukemia: A Pediatric Oncology Group Study

PURPOSE To determine dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of a protracted, intermittent schedule of daily 30-minute infusions of topotecan (TPT) for up to 12 consecutive days, every 3 weeks, in children with refractory leukemia. PATIENTS AND METHODS Forty-nine children were enrolled onto this phase I trial (24 with acute nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m(2)/d for 5 days and 2.4 mg/m(2)/d from 7 days to the same dose for 9 and 12 days in cohorts of three to six patients when no DLT was identified. TPT pharmacokinetics were studied in 33 children once or twice (first and last doses in patients who received TPT for > 7 days). RESULTS Seventy assessable courses of TPT were administered to 49 children who had refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and the MTD was 2.4 mg/m(2)/d for 9 days in this group of heavily pretreated children. In 33 patients, the median TPT lactone clearance after the first dose was 19.2 L/h/m(2) (range, 9.4 to 45.9 L/h/m(2)) and did not change during the course. There were significant responses (one complete response [CR] and four partial responses [PR] in patients with ANLL and one CR and two PRs in patients with ALL), and all but one were at dosages of TPT given for at least 9 days. CONCLUSION The MTD was 2.4 mg/m(2)/d for 9 days. Further testing is warranted of TPTs schedule dependence in children with leukemia.

Vincristine, prednisone and L-asparaginase in the induction of remission in children with acute lymphoblastic leukemia following relapse.

Two hundred and twenty‐seven children with recurrent acute lymphoblastic leukemia were treated with various combinations of vincristine, prednisone, cyclophosphamide and L‐asparaginase in an approach to the induction of remission. The combination of L‐asparaginase 1,000 μ/kg iv q.d. X 10, vincristine 2.0 mg/m2iv q.w. X 4 and prednisone 40 mg/m2 p.o.q.d. X 28 days was found to be highly effective. The incidence of remission was 73%. No significant improvement was achieved when cyclophosphamide was added to this regimen. Various combinations of cytosine arabinoside, cyclophosphamide, vincristine, prednisone, BCNU or CCNU failed to maintain remission duration for more than two to three months. Neither BCNU nor CCNU prevented the development of CNS leukemia.

With modern imaging techniques, is staging laparotomy necessary in pediatric Hodgkin's disease? A Pediatric Oncology Group study.

PURPOSE To determine whether the information gained from staging laparotomy can be predicted by imaging and/or clinical factors in children with Hodgkins disease. PATIENTS AND METHODS Between 1986 and 1991, 216 consecutive pediatric patients with Hodgkins disease underwent laparotomy and were treated on two concurrent protocols in a multiinstitutional cooperative group. All patients had computed tomography (CT) of the chest, abdomen, and pelvis. Clinical factors studied included sedimentation rate, B symptoms, histology, number and location of involved sites, sex, mediastinal involvement, and age. Pretreatment CTs were centrally reviewed in 88 cases for the presence and size of both supradiaphragmatic and infradiaphragmatic lymph nodes, intrinsic spleen lesions, and splenic size. Models were generated that were predictive of any abdominal disease, splenic involvement, extensive splenic involvement, and upstaging at the laparotomy. False-positive and false-negative rates were calculated. RESULTS For the end point of any abdominal disease, a model based on B symptoms, histology, sedimentation rate, and number and location of involved sites was highly significant (P < .0001). However, the success in predicting abdominal disease in an individual patient was limited: false-negative rate, 26%; false-positive rate, 32%. Highly significant models based on clinical factors and/or radiographic findings were also generated to predict splenic involvement, extensive splenic involvement, and upstaging with laparotomy, but they also had high false-positive and false-negative rates. CONCLUSION Laparotomy findings cannot be predicted accurately in the majority of patients based on knowledge of CT findings and clinical factors.

Clinical trial of etoposide (VP-16) in children with recurrent malignant solid tumors

SummaryEtoposide (VP-16), 150 mg/M2, given intravenously daily for 3 days every 3 weeks resulted in 3 complete responses and 6 partial responses in 154 patients with a spectrum of recurrent malignant solid tumors. There was evidence of disease control in an additional 37 patients (27 mixed responses and 10 stable disease). These responses occurred primarily in patients with Ewings sarcoma, Hodgkins disease, neuroblastoma and rhabdomyosarcoma. Most of the patients had every extensive prior therapy; however prior therapy with teniposide (VM-26), the congener of VP-16, did not seem to preclude responses to the latter drug. Myelosuppression was the principal form of toxicity. Neutropenia characterized by absolute neutrophil counts of 0.5 to 0.9 × 109/L occurred in one-half of the patients, and thrombopenia with platelet counts of < 25 to 49 × 109/L in one-fourth. These results demonstrate a favorable therapeutic index for VP-16 in several recurrent childhood solid tumors, supporting its use as a component of primary therapy for these diseases.

Hodgkin's disease in children 4 years of age or younger

The natural history of Hodgkins disease in children younger than 4 years of age is unknown. Thirty‐eight patients younger than 4 years of age at the time of diagnosis of Hodgkins disease were treated at the member institutions of the Pediatric Oncology Group. They were found to be predominantly white and male with early‐stage disease. Mixed cellularity and nodular sclerosing histologies were most commonly seen and occurred in equal frequency. They responded to therapy extremely well attaining a complete remission rate of 92% to 94%. Even after relapse, they can be successfully retrieved with salvaging therapy.

Temozolomide and radiation for aggressive pediatric central nervous system malignancies.

This study describes the outcomes of children treated with combinations of temozolomide and radiation therapy for various aggressive central nervous system malignancies. Their age at diagnosis ranged from 1 to 15 years. Patients with focal disease were treated with concomitant temozolomide (daily 75 mg/m2) and three-dimensional conformal radiotherapy in a dose that ranged from 50 to 54 Gy, followed by temozolomide (200 mg/m2/d × 5 days/month in three patients, 150 mg/m2 × 5 days/ month in one patient). Patients with disseminated disease were treated with craniospinal radiation (39.6 Gy) before conformal boost. One patient received temozolomide (200 mg/m2 × 5 days/month) before craniospinal radiation, and one patient received temozolomide (daily 95 mg/m2) concomitant with craniospinal radiation and a radiosurgical boost, followed by temozolomide (200 mg/m2 × 5 days/month). Three patients achieved a partial response during treatment, with two of these patients dying of progressive disease after treatment. One patient has no evidence of disease. Three patients achieved stable disease, with one of these patients dying of progressive disease after treatment. Toxicities observed included low-grade neutropenia, thrombocytopenia, and lymphopenia. The combination of temozolomide and radiotherapy appears to be well tolerated in a variety of treatment schemas for aggressive pediatric central nervous system malignancies. This information is of particular use in designing future studies, given the recent positive results in a randomized study examining the use of temozolomide concomitant with radiation in the treatment of adult glioblastoma.

Antibody responses in normal infants and in infants receiving chemotherapy for congenital neuroblastoma

Three infants with congenital neuroblastoma received a primary series of diptheria‐pertassis‐tetanus (DPT) immunizations during and after courses of chemotherapy with immunosuppressive medications. Serum IgG, IgA and IgM levels and antidiphtheria and antitetanus antibody responses were measured and compared with those of normal infants of similar age. Protective levels of antibody were achieved by the study patients as well as by the control group. These results support the view that children with malignancies who are receiving chemotherapy should not be denied immunization with inactivated vaccines.