Treatment of stage III neuroblastoma with emphasis on intensive induction chemotherapy: A report from the neuroblastoma group of the spanish society of pediatric oncology

From October 87 to April 92, 172 children were admitted in the N-I-87 protocol of the Spanish Society of Pediatric Oncology for the diagnosis and treatment of neuroblastoma. Forty-eight were considered Evans stage III, 33 of them being older than 1 year. All children were treated with induction chemotherapy (IC) and surgery. IC consisted of three courses of high-dose cisplatin-VM-26 alternating with three further courses of cyclophosphamide-doxorubicin (CAD). Infants less than 1 year received the same drugs at lower doses. After surgery, maintenance chemotherapy was administered to all children during 14 months. It consisted of four pairs of drugs rotated every 4 weeks. Radiotherapy was administered exclusively to patients older than 1 year with residual tumor after IC and surgery. Response was evaluated after IC and surgery. In children older than 1 year, response was obtained in 28/33 (88%). Fifteen of them (47%) achieved complete remission (CR), seven (22%) good partial response (GPR), six (19%) partial response (PR); and in three patients (9%) there was progressive disease (PD). Actuarial survival at 48 months was 0.60 ± 0.10 and EFS was 0.61 ± 0.12. Audiologic impairment was considered the worst toxicity. In children less than 1 year the response rate to IC and surgery was 93% (14/15); nine infants obtained complete response and four had GPR. Only one patient experienced PD in the first 6 months of therapy and died. The other 14 are alive and well at a mean follow-up time of 48 months. Chemotherapy toxicity was mild and reversible. © 1995 Wiley-Liss, Inc.     

Treatment combined with bone marrow transplantation for advanced neuroblastoma: An analysis of patients who were pretreated intensively with the protocol of the study group of Japan

One hundred and ten patients with advanced neuroblastoma were treated with the protocol of the Study Group of Japan between January 1985 and March 1991. Patients received six cyclic courses of regimen A₁, consisting of cyclophosphamide (1,200 mg/m²), vincristine (1.5 mg/m²), tetrahydropyranyl adriamycin (40 mg/m²), and cisplatin (90 mg/m²). Primary tumors and regional lymph node metastases were removed some time during the first six cycles of regimen A₁. After six cycles of A₁, the patients were divided into three groups. Patients in group 1 received alternating treatment with regimen B (cyclophosphamide and ACNU) and intensified A₁, and those in group 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A₁. Patients in group 3 were treated with supralethal therapy and bone marrow transplantation (BMT). Event-free survival rates at five years were 38.8% in the chemotherapy group (groups 1 and 2) and 50.0% in the transplant group (group 3). Because of the study design that was not in truly randomized fashion and because of the small number of patients in each risk group, it is indicated, though not concluded, that the transplant group had a better prognosis than the chemotherapy group in the cases with stage III disease or with amplified N-myc oncogene, based on the statistical calculations. Differences in survival rates for patients who underwent BMT when complete remission (CR) was achieved and for those who achieved CR but who did not undergo marrow transplant were statistically insignificant. BMT-related death occurred in 3 of 31 cases (9.7%) undergoing marrow transplant, and the causes of the death included hemorrhagic pneumonia, myocardial disturbance and hemorrhagic uremia. © 1995 Wi1ey-Liss Inc.     

Multiagent chemotherapy for children with metastatic neuroblastoma: A report from childrens cancer study group

During the past 10-15 years there has not been a significant improvement in the overall survival of children with metastatic neuroblastoma. From 1971 through 1975, 104 eligible patients were entered on two clinical studies for newly diagnosed cases of stage IV neuroblastoma by the Childrens Cancer Study Group (CCSG). Patient data from both studies were evaluated for activity of cyclophosphamide, imidazole carboxamide, and vincristine and of these same agents plus adriamycin. Response was evaluated by serial measurements of tumor size. Eighty-four patients experienced a complete or partial response. The life-table estimate of median survival on both studies was 11–12 months for all patients and 13-18 months for responders, unchanged from the results of previous CCSG studies. Long-term survival, however, for patients on these studies demonstrates a significant increase compared with results reported from the three previous CCSG studies. Children less than 1 year or greater than 6 years of age at diagnosis showed a significantly improved survival pattern over the intermediate age group. It is suggested that there is a need to consider the induction response pattern and age at diagnosis when planning a maintenance program so that nonresponders can be identified early and considered for treatment with new agents or aggressive multimodal therapy.     

Influence of image‐defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group

Background

The European multicenter study LNESG1 was designed to evaluate the safety and efficacy of surgical treatment alone in patients with localised neuroblastoma. In a retrospective, observational study we examined the impact of image‐defined risk factors (IDRF) on operative complications and survival (EFS and OS).

Procedure

534 patients with localised, non‐MYCN amplified neuroblastoma were recruited between 1995 and 1999. Group 1 consisted of 291 patients without IDRF (Stage L1 in the International Neuroblastoma Risk Group (INRG) staging system), all treated with primary surgery. Group 2: 118 patients with IDRF (INRG Stage L2), also treated with primary surgery. Group 3: 125 patients in whom primary surgery was not attempted, 106 receiving neo‐adjuvant chemotherapy.

Results

In L1 patients (Group 1) 5‐year EFS was 92% and OS 98%. In L2 patients (Group 2 and 3) EFS was 79% and OS 89%. The differences in both EFS and OS were significant. EFS and OS in Group 2 (86% and 95%) were significantly better than 73% and 83% in Group 3. In INSS stage 1, 2 and 3, EFS were respectively 94%, 81% and 76%. Except between stage 2 and 3 the differences were significant. OS were respectively 99%, 93% and 83%, all significantly different. The 17% operative complication rate in L2 patients was significantly higher than 5% in L1 patients.

Conclusions

In localised neuroblastoma, IDRF at diagnosis are associated with worse survival rates and higher rates of operative complications. The impact of IDRF should become an integrated part of therapy planning. Pediatr Blood Cancer 2015;62:1536–1542. © 2015 Wiley Periodicals, Inc.     

Cyclophosphamide/doxorubicin vs. Cisplatin/teniposide in the treatment of children older than 12 months of age with disseminated neuroblastoma: A pediatric oncology group randomized phase II study

This prospective study was designed to estimate the response rates and to compare two drug pairs, cyclophosphamide/doxorubicin (Cy/A) and cisplatin/teniposide (P1/VM) in previously untreated patients with disseminated neuroblastoma >12 months of age at diagnosis. Estimated complete clinical response rates after five courses of therapy were 13% (70 patients) and 22% (64 patients) for Cy/A and P1/VM, respectively (P = 0.17). After surgical removal of residual tumors in patients with partial response, the complete response rates were 27% and 34% (P = 0.50), respectively. The overall CR/PR rates after induction and surgery were 59% and 73% (P = 0.077). There was no significant difference in event free survival (P = 0.48) or survival (P = 0.40). Five year survival on the two arms were 14% (SE = 5%) and 12% (SE = 4%), respectively. Toxicity was significant but manageable. The Cy/A arm had significantly higher hematopoietic toxicity but significantly lower GI toxicity. Significant allergic reactions were seen with the P1/VM arm, none in the Cy/A arm. Given the activity of these two regimens, further therapy with a combination of these regimens is suggested. © 1995 Wiley-Liss, Inc.     

Treatment of high-risk acute lymphoblastic leukemia in children using the AL851 and ALHR88 protocols: A report from the Kyushu-Yamaguchi children cancer study group in Japan

A total of 125 children, who were diagnosed as having high-risk acute lymphoblastic leukemia (ALL), were treated with two consecutive protocols designated as AL851 (1985–1988) and ALHR88 (1988–1990). All patients received induction therapy consisting of vincristine (VCR), prednisolone (PSL), daunorubicin (DNR), and l-asparaginase (l-Asp). In the ALHR88 protocol, the patients whose blasts in the bone marrow (BM) were ≥25% on day 14 of induction therapy and who were classified into T-cell type received additional cytosine arabinoside (AraC). After consolidation with intermediate-dose methotrexate (MTX), reinduction therapy including VCR, dexamethasone, and adriamycin followed by high-dose AraC was done for all patients. Intrathecal MTX and 24Gy of cranial irradiation were used to prevent central nervous system leukemia. A maintenance therapy consisting of 6-mercaptopurine, cyclophosphamide, MTX, DNR, VCR, and AraC was administered for 3 years after achieving a complete remission (CR). CR was achieved in 51/55 (92.7%) for AL851 and 68/70 (97.1%) for ALHR88. The 5-year event-free survival rates were 49.1 ± 6.7% in AL851 and 62.5 ± 6.1% in ALHR88. The factors related to a poor prognosis were a high initial leukocyte count of greater than 50 × 10⁹/L (P < 0.001), an L2 morphology of leukemic cells by FAB classification (P = 0.009), the chromosomal abnormality (P = 0.004) and high residual leukemic cells in BM (≥25%) on day 14 of induction therapy (P < 0.001). Taking these factors into consideration, more intensive protocols were started in 1990 for the patients with high-risk ALL. © 1996 Wiley-Liss, Inc.     

Long-term survival data and prognostic factors of a complete response to chemotherapy in patients with head and neck cancer treated with platinum-based induction chemotherapy: A hellenic co-operative oncology group study

A group of 154 patients with locally advanced head and neck cancer, treated with platinum-based induction chemotherapy, were followed up for 5 years and several pretreatment characteristics were analyzed for possible correlation to a complete response (CR) to chemotherapy, time to progression (TTP) and overall survival (OS). Clinical stage (p = 0.0125) were selected as important prognostic factors for CR by step-wise logistic regression. We also identified response to chemotherapy (p = 0.0120), age (p = 0.0066), clinical stage (p = 0.0363), N stage (p = 0.0028), and tumor grade (p = 0.0101) as significant prognostic variables for TTP. Response to chemotherapy (p < 0.0001) and age (p = 0.0017) were found also significant for OS. These long-term prognostic factors which retain their prognostic significance after several years of follow-up could be helpful in the design of future trials in this patient population. Med. Pediatr. Oncol. 28:401–410, 1997. © 1997 Wiley-Liss, Inc.     

High-dose epirubicin and r-met-hu G-CSF (Filgrastim) in the treatment of patients with advanced breast cancer: A hellenic cooperative oncology group study

The delivery of high-dose epirubicin in patients with advanced breast cancer usually entails serious myelotoxicity and frequent treatment delays. Concurrent administration of G-CSF probably allows the administration of epirubicin on schedule with minimal morbidity. From August 1990 to February 1992, 42 women with advanced breast cancer were treated with six cycles of epirubicin 110 mg/m² every 4 weeks. Filgrastim 5 μg/kg per day for 14 days was administered subcutaneously starting 24 hours after chemotherapy. All patients had multiple metastatic sites, and 39 had visceral metastases. All cases were evaluable for response, toxicity, and survival. Treatment was delayed in only two cases. The actually administered average dose per unit time per patient amounted to 99.6% of the dose prescribed by the protocol. Two (4.5%; 95% confidence interval [C.I.] 0–16%) patients demonstrated a complete response and 14 (33%; 95% C.I. 19–49%) a partial response. Median time to progression was 31 weeks and median survival was 60 weeks. Severe granulocytopenia was seen in six patients; stomatitis and diarrhea in one patient each. Myoskeletal pain was noticed in 23 (55%) patients, while cardiac problems were reported in 3 cases. The present study shows that the prophylactic use of r-met-hu G-CSF allows the administration of high-dose epirubicin every 4 weeks with minimal morbidity and an improved quality of life. © 1995 Wiley-Liss, Inc.