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Background: To evaluate the efficacy of BCNU, cisplatin, and vincristine (BCV regimen) in a prospective nonrandomized study among newly diagnosed children with high-grade glioma., Procedure: Following surgery, patients received a combination of BCNU + cisplatin + VP16 (BCV), over 3 consecutive days. Patients with residual tumor continued this regimen unless no further improvement was observed on MRI, for a maximum of six courses. Patients who underwent complete surgical resection received six courses of adjuvant BCV., Results: Seventy-three patients were enrolled. Out of 66 eligible patients with central pathology review, the diagnosis of high-grade glioma was confirmed in 53 cases. The response rate was 20%. With a median follow-up of 128 months, 5- and 10-year event free survival rates are 16 +/- 9 and 13.3 +/- 9.4%. In univariate analysis, two prognostic factors were statistically significant: extent of resection and tumor location, while macroscopic total resection was the only significant prognostic factor in the multivariate analysis. The response to BCV did not translate into improved event free survival. Interstitial pneumonitis occurred in seven patients, leading to six deaths., Conclusion: This BCV regimen could not be recommended in the treatment of high-grade gliomas in children, according to its lack of efficacy and its unacceptable pulmonary toxicity., ((c) 2006 Wiley-Liss, Inc.)

Aim: Improvement of EFS of children older than 3 years with high risk medulloblastoma., Methods: Between 1993 and 1999, 115 patients (3-18 years, mean 8 years) with high risk medulloblastoma were included. After surgery treatment consisted of chemotherapy ('8in1' and etoposide/carboplatin) before and after craniospinal radiotherapy., Results: Patients were staged using Chang-criteria (PF residue only, M1 and M2/M3) by local investigator as well as by central review panel (82.4% concordance). Chemotherapy was well tolerated without major delays in radiotherapy. With a mean follow up of 81 months (9-119), 5-year EFS was 49.8% and OS 60.1%. In detail according to subgroups EFS was 68.8% for PF residue only, 58.8% for M1 disease and 43.1% for M2/M3., Conclusion: M1 patients are legitimate high risk patients. Survival rates are still very low for high risk medulloblastoma patients and future trials should therefore focus on more intensive (chemotherapy/radiotherapy) treatment.

The aim of this study was to evaluate a chemotherapy strategy that avoids radiotherapy in first-line treatment of young children with high-grade glioma. A total of 21 children under 5 years of age received the BBSFOP protocol, comprising seven cycles of three drug pairs (carboplatin/procarbazine, cisplatin/etoposide and vincristine/cyclophosphamide) administered over a 16 month period. Radiotherapy was performed in case of recurrence/progression. Median age at diagnosis was 23 months. Histology was classified as World Health Organisation (WHO) grade III in 13 and grade IV in 8. Of the 13 children with a residual tumour, chemotherapy induced 2 partial responses (PR), 1 minor response (MR) and 1 stable disease (SD) with no recurrent disease. Five-year progression-free survival was 35% and 5-year overall survival was 59%, with a median follow-up of 5.2 years. At the last update, 12 children were alive (10 without radiotherapy). In conclusion, this study shows that an adjuvant chemotherapy first approach is safe and allows radiotherapy to be avoided in selected children.

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.

Purpose: To evaluate a strategy that avoids radiotherapy in first-line treatment in children under 5 years of age with brain or posterior fossa ependymoma, by exclusively administering 16 months of adjuvant multiagent chemotherapy after surgery., Patients and Methods: Between June 1990 and October 1998, 73 children with ependymoma (82% with high-grade tumors) were enrolled onto this multicenter trial. Children received adjuvant conventional chemotherapy after surgery consisting of seven cycles of three courses alternating two drugs at each course (procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) over a year and a half. Systematic irradiation was not envisaged at the end of chemotherapy. In the event of relapse or progression, salvage treatment consisted of a second surgical procedure followed by local irradiation with or without second-line chemotherapy., Results: Conventional chemotherapy was well tolerated and could be administered in outpatient clinics. No radiologically documented response to chemotherapy more than 50% was observed. With a median follow-up of 4.7 years (range, 5 months to 8 years), the 4-year progression-free survival rate in this series was 22% (95% confidence interval [CI], 13% to 43%) and the overall survival rate was 59% (95% CI, 47% to 71%). Overall, 40% (95% CI, 29% to 51%) of the patients were alive having never received radiotherapy 2 years after the initiation of chemotherapy and 23% (95% CI, 14% to 35%) were still alive at 4 years without recourse to this modality. In the multivariate analysis, the two factors associated with a favorable outcome were a supratentorial tumor location (P =.0004) and complete surgery (P =.0009). Overall survival at 4 years was 74% (95% CI, 59% to 86%) for the patients in whom resection was radiologically complete and 35% (95% CI, 18% to 56%) for the patients with incomplete resection., Conclusion: A significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy. Deferring irradiation at the time of relapse did not compromise overall survival of the entire patient population.

Background: The role of high dose chemotherapy (HDC) in patients with pediatric brain tumors currently is ill-defined. The purpose of this pilot study was to assess the feasibility and the benefit of HDC after radiotherapy in a group of children with newly diagnosed diffuse pontine gliomas., Methods: Patients eligible for study were ages 3-18 years with diffuse intrinsic tumors arising in the pons, who were not treated previously with radiotherapy or chemotherapy. Histologic confirmation was not mandatory, provided clinical findings and magnetic resonance imaging were typical. Patients were given focal radiotherapy followed 2-3 months later by HDC. Busulfan (150 mg/m(2) on Days 8, 7, 6, and 5) and thiotepa (300 mg/m(2) on Days 4, 3, and 2) were administered prior to autologous bone marrow transplantation. Survival was the endpoint, and the statistical procedure was based on sequential subgroup analysis., Results: Thirty-six patients were entered on to the study, 12 of whom underwent stereotactic biopsy or open surgery at the time of diagnosis. One patient eventually was excluded due to inappropriate eligibility criteria. All 35 eligible patients received irradiation. Early progression (9 patients) and parental refusal (2 patients) precluded the use of HDC in 11 patients. Three patients died of HDC-related complications. All 21 patients who survived HDC eventually died of disease progression. The median survival time was 10 months for the study group. The median survival time in the subgroup of patients who received HDC was 10 months (range, 3-26 months). Statistical analysis did not suggest any evidence of survival benefit., Conclusions: For patients with diffuse pontine gliomas, survival using this aggressive treatment modality does not appear to be any better than that reported for conventional radiotherapy., (Copyright 2000 American Cancer Society.)

Unlabelled: This study evaluates histological response, long-term outcome, and toxicity in an intensive chemotherapy program given before surgery., Patients and Methods: Sixty-two patients (39 males, 23 females: median age 14) with biopsy, chest computerised-tomography, technetium bone-scan and magnetic resonance imaging, were enrolled. Primary localisations were femur (44%) and tibia (26%). Induction chemotherapy involved seven courses of high-dose methotrexate and two courses of HELP (ifosfamide, eldesine (vindesine), cisplatin (platinum)-doxorubicin. After surgery, patients received six courses of high-dose methotrexate and two courses of HELP-doxorubicin., Results: Pre- and postoperative toxicities were similar. Fifty-nine patients underwent surgery; histological response was good in thirty-eight patients (64%) and poor in twenty-one (36%). Median follow-up is 57 months (range 30-80), with 77% overall survival and 59% progression-free survival. In a multivariate analysis, age under 10 years is the only prognostic factor that significantly correlates with outcome., Conclusions: This regimen appears to increase histological necrosis, but associates with severe toxicity. Results for patients with less necrosis at surgery are encouraging. Future trials should determine the minimum effective doses to reduce toxicity. New drugs should be added.

Purpose: The three-drug combination of melphalan (M), etoposide (E), and carboplatin (C) followed by autologous stem-cell (ASC) rescue has been evaluated prospectively by the French Society of Pediatric Oncology (SFOP) in pediatric high-risk recurrent (HRR) Wilms' tumor (WT) patients with chemotherapy-responsive disease., Patients and Methods: From October 1988 to October 1994, 29 patients with HRR WT were treated in nine SFOP centers. Two additional patients with stage IV anaplastic WT were consolidated in first complete response (CR) with the same regimen and have been studied separately. The regimen consisted of M 180 mg/m2 for 1 day, E 200 mg/m2/d for 5 days, and C at a daily targeted area under the concentration-time curve (AUC) of 4 mg x min/mL for 5 days. ASCs were reinfused 48 hours after M., Results: Twelve of 28 assessable patients with HRR WT are still in continuous CR at a median of 48.5 months (range, 36 to 96) after consolidation. Disease-free survival (DFS) and overall survival (OS) estimated by the Kaplan-Meier method at 3 years were 50%+/-17% and 60%+/-18%, respectively. Sixteen patients relapsed at a median of 8.5 months (range, 3 to 53) after consolidation. Toxicity data are available in 31 grafted patients. Grade III and IV toxicities included hematologic side effects (n=31), hemorrhage (n=8), mucositis (n=24), diarrhea (n=12), renal disorders (n=8), and pneumonitis (n=3)., Conclusion: The adverse prognostic factors (APF) used to select patients for this dose-intensive chemotherapy define children with very-poor-risk recurrent WT. Despite high treatment-related toxicity, about half of these patients remain disease-free at 3 years. Patient outcome is statistically better when high-dose chemotherapy (HDCT) is performed as early as the second CR or partial response (PR). Novel therapeutic approaches with innovative preparative regimens are warranted for the remaining high-risk patients.

This study investigates the role of high-dose chemotherapy with haematopoietic stem cell rescue as consolidation treatment in high-risk retinoblastoma (extraocular disease at diagnosis or relapse or invasion of cut end of optic nerve). 25 patients received high-dose chemotherapy including carboplatin (250 mg/m2/day from day 1 to day 5 for the 6 first patients and 350 mg/m2/day from day 1 to day 5 for the other patients), etoposide (350 mg/m2/day from day 1 to day 5) and cyclophosphamide (1.6 g/m2/day from day 2 to day 5) (CARBOPEC) followed by autologous haematopoietic stem cell rescue. 19 patients received this drug combination for chemosensitive extraocular relapse. The other 6 patients with histological high-risk factors were given this treatment as consolidation after enucleation and conventional chemotherapy. The three year disease-free survival was 67.1%. In 7 of the 9 relapsing patients, the first site of relapse was the central nervous system. All patients with central nervous system disease died except one. The main toxicity was haematological and digestive (mucositis and diarrhoea). 2 of the 13 evaluable patients had grade III and IV ototoxicity. One patient experienced an acute grade I reversible cardiotoxicity. The CARBOPEC regimen seems to be a promising therapeutic strategy in patients with high-risk retinoblastoma, especially those with bone and/or bone marrow involvement. This treatment did not improve the outcome of patients with central nervous system disease.

The aim of this phase II study was to determine the efficacy of high-dose ifosfamide with moderate dose etoposide in childhood osteosarcoma. From January 1992 to January 1995, 27 children (15 male, 12 female) with relapsed or refractory evaluable osteosarcoma were included in a phase II study of two courses of ifosfamide 3g/m2/day and etoposide 75 mg/m2/day for 4 days. Median age was 14 years (7-19 years). All but one had received high-dose methotrexate and doxorubicin as first-line treatment. 22 patients had previously received ifosfamide. This regimen was given as first-line in 1 patient, second-line in 23 and third-line in 3. Evaluable disease was lung metastases in 21 patients, local relapse in 5 and adenopathy in 1. There were six complete responses, seven partial responses, three minor responses, six stable disease and five progressive disease (including one mixed response). Response rate was 48% (95% confidence interval, 29-67%). Duration of response was not available (10 responding patients had other treatments). Response rate was equivalent in the subgroup of 22 patients who had previously received ifosfamide (4 CR, 6 PR). Among 3 patients who received the phase II regimen as third-line chemotherapy, there was 1 PR. All but 4 patients had a well tolerated grade 4 neutropenia. Transient mild confusion or seizures were each observed once. 5 patients are alive 15-31 months after the beginning of chemotherapy. This combination of drugs at this dosage has tolerable toxicity, is efficient and deserves evaluation in phase III studies.

Purpose: A phase II study of etoposide (VP-16) and carboplatin was performed in patients with extraocular retinoblastoma to evaluate the response rate with this drug combination., Patients and Methods: Twenty patients with extraocular retinoblastoma, age 9 to 120 months, were included in a cooperative multicenter phase II study of the Société Francçaise d'Oncologie Pédiatrique (SFOP). The schedule consisted of consecutive 5-day treatment with VP-16 100 mg/m2/d and carboplatin 160 mg/m2/d., Results: The response rate for the 20 patients was 85%; there were nine complete responses and eight partial responses. Hematologic toxicity was the only serious observed toxicity and was always manageable., Conclusion: This combination of VP-16 and carboplatin is highly effective in extraocular retinoblastoma. The high response rate is encouraging for further evaluation of this drug combination in adjuvant chemotherapy when necessary after enucleation or in neoadjuvant chemotherapy for intraocular tumors.

The aim of this study was to evaluate the feasibility and efficacy of a protocol that includes "sandwich" chemotherapy, that is, chemotherapy alternated with radiotherapy, and reduced doses of supratentorial irradiation in children with medulloblastoma. Between March 1985 and September 1988, 70 successive children with newly diagnosed medulloblastoma from eight centers were treated in this prospective nonrandomized study. Patients were assigned to two risk groups. Group A included patients with macroscopically complete or subtotal excision, no brainstem involvement, no atypical cells in the cerebrospinal fluid, normal myelography, and who were more than 2 years of age. Group B patients encompassed those who did not fit the criteria for Group A. Two children were excluded from analysis after histological review confirmed ependymoma. Thus, a population of 68 children was selected, with 31 in Group A and 37 in Group B. Treatment consisted of two courses of the "eight drugs in 1 day" ("8/1") regimen followed by two courses of high-dose methotrexate (12 g/m2). Radiotherapy was begun during the 7th week after surgery in Group A and during the 5th week in Group B. In patients older than 2 years, the median radiation dose to the posterior fossa, the spinal axis, and the brain was 54 Gy, 36 Gy, and 27 Gy, respectively. Group B patients received postirradiation chemotherapy with four 8/1 courses monthly. The median time from surgery to radiation therapy was 50 days (range 21 to 141 days). One fatality due to chicken pox on Day 102 and one World Health Organization Grade IV infection occurred. The estimated 5- and 7-year disease-free survival (DFS) rates were 62% and 59%, respectively. These were 74% and 62% in Group A and 57% and 57% in Group B. Patient age, extent of resection, and radiation dose to the whole brain had no prognostic value. Patients with metastasis had a nonsignificant trend for a worse prognosis than patients with nonmetastatic disease (7-year DFS 45% vs. 68%, p = 0.11). In Group B, the 7-year DFS rates for children who received more or less than 30 Gy to the brain were 69% and 52% respectively (p = 0.15). There were recurrences in the posterior fossa (37%), spine (20%), and brain (20%). After a review of radiotherapeutic treatments, only one supratentorial failure could be blamed on reduction of the supratentorial radiation dose. This "sandwich" chemotherapy appeared to be feasible and did not show adverse survival data when compared to other series.

Purpose: Since we had previously demonstrated encouraging efficacy of etoposide in patients with relapsed or refractory Wilms' tumor (WT), the likely synergism between etoposide and platinum compounds prompted us to conduct a phase II study of a combination with carboplatin., Patients and Methods: Twenty-six relapsed or refractory WT patients were included in a phase II study of two courses of combination etoposide 100 mg/m2/d for 5 days and carboplatin 160 mg/m2/d for 5 days, with a 21-day interval between the two courses. Initial stages were I (n = 2), II (n = 8), III (n = 6), IV (n = 6), V (n = 3), and unknown (n = 1). Sites of diseases were lung(s) (11 patients), abdomen-pelvis or liver or primary tumor (six patients), and multiple (eight patients). Histology was unfavorable in three of 26 patients., Results: Complete response (CR) was documented in eight patients and partial remission (PR) in 11 (overall response rate, 73%). Stable disease (SD) was observed in five patients and progressive disease (PD) in two. Thrombocytopenia (grade IV) was the major toxicity, and platelet transfusions were required in all but two patients. Grade III anemia and grade III to IV neutropenia were seen in 19 and 23, respectively, of 25 assessable first courses. Venoocclusive disease of the liver was fatal in one child who had undergone irradiation to the whole abdomen, 8 weeks before study., Conclusion: Combination etoposide and carboplatin has impressive activity in refractory or relapsed WT at the cost of high-grade hematologic toxicity, especially thrombocytopenia. It is of great interest in second-line therapy, since eight of 26 patients are still alive in continuous CR (median follow-up duration, 40 months; range, 24 to 56). This combination deserves further investigation as first-line or consolidation treatment.

Purpose: The MMT 84 multicentric prospective trial of the International Society of Pediatric Oncology (SIOP) was designed to (1) test the effectiveness of ifosfamide 3 g/m2 on days 1 and 2, vincristine 1.5 mg/m2 on days 1 and 14, and dactinomycin 0.9 mg/m2 on days 1 and 2 (IVA) repeated every 21 days; and (2) reduce late effects of treatment by reserving radiation therapy to the primary site for patients not achieving a complete response (CR) to primary chemotherapy., Materials and Methods: Between 1984 and 1989, the MMT 84 study registered 34 children with nonmetastatic rhabdomyosarcomas (RMSs) and other malignant mesenchymal tumors (MMTs) of the orbit in this trial., Results: The 4-year event-free survival rate is 62% +/- 9% (SD) and the 4-year survival rate 86% +/- 7% (SD). A total of 11 local recurrences occurred, 10 among 22 patients treated without initial radiation. Salvage of local failure was achieved in nine of 11 patients with the use of radiation and additional chemotherapy, but three later developed distant metastases and two have died. One isolated regional lymph node failure has occurred, while no patient relapsed with isolated distant metastases. Six of 12 patients who failed are alive with no evidence of disease from 16 to 50 months after relapse. The treatment was well tolerated in all patients, except for one with renal tubular acidosis and one who died of cardiotoxicity. Twelve patients remain in first remission without the use of radiation to the primary tumor from 27 to 84 months., Conclusion: Despite a higher incidence of local recurrence when treated by primary chemotherapy, early survival rates were not compromised and a significant number of patients avoided the late effects of radiation. However, longer follow-up is required to assess the ultimate outcome of patients treated in this manner.

The purpose of this study is to evaluate the antitumor activity of combination carboplatin and etoposide in measurable medulloblastoma. From January '89 to January '92, 26 patients with medulloblastoma were included in a multicentric phase II study of 2 courses of carboplatin 160 mg/m2/d day 1 to day 5 and VP16 100 mg/m2/d day 1 to day 5. Median age was 10 years (19 months-14.5 years). First treatment was surgery alone in 1 patient, surgery + radiotherapy in 4 patients, surgery + chemotherapy in 2 patients less than 3 years old, surgery + radiotherapy + chemotherapy in 19 patients ("8 drugs in 1 day" based:17, SIOP I:1, SIOP II:1). Previous treatment included cisplatin (20 cases), carboplatin (1 case), and VP16 (7 cases). Measurable disease was evaluated by CT scan, MRI or myelogram and CSF. Response rate (RR) was 72 +/- 10%:8 complete responses (CR), 10 partial responses (PR), 1 objective effect (OE), 6 progressive disease (PD), 1 non-evaluable. Thirty-six courses were evaluated for toxicity. Median duration of WHO grade 4 neutropenia was 8 days (0-23). One patient died at day 18 after the first course because of diffuse haemorrhage during septic aplasia. Five other non-life-threatening septicemias were recorded. Median number of platelet transfusions was 1 (0-4). One child who had achieved a PR after two courses died from CNS bleeding after the third course. This drug combination achieves a high response rate in childhood medulloblastoma. Severe toxicity has been mainly encountered in previously heavily treated patients. Tolerance may be acceptable in newly diagnosed children, but careful hematological follow-up and platelet transfusional support are definitely mandatory.

Purpose: A phase II study of etoposide (VP 16) and carboplatin (CBDCA) was performed in patients with metastatic neuroblastoma (NB). The aim of the study was to find an alternative treatment for induction with different toxicities than the VP 16/cisplatin (CDDP) combination., Patients and Methods: Forty-seven patients who were from 6 months to 16 years of age, with either relapsed (29) or primary resistant (18) NB, were included in a cooperative multicenter phase II study of the French Society of Pediatric Oncology (SFOP). The schedule consisted of 5 consecutive days of VP 16 100 mg/m2/d and CBDCA 160 mg/m2/d., Results: The response rate for the 39 assessable patients was 43%; there were four complete remissions and 13 partial remissions. Neither the status of the patients nor the total dose of CDDP that was received previously influenced response. Hematologic toxicity was marked and caused considerable delay between courses (median interval, 39 days). In these heavily pretreated patients, 16% had a more than 50% decrease in creatinine clearance and a 22% World Health Organization (WHO) grade 2 ototoxicity., Conclusion: This VP 16/CBDCA combination deserves further evaluation for efficacy and toxicity in newly diagnosed patients, and the combination of both drugs should be considered for high-dose therapy with bone marrow transplantation.

From April 1984 to December 1987, the French Pediatric Oncology Society (SFOP) organized a randomized trial for advanced-stage B-cell lymphoma without CNS involvement to study the possibility of reducing the length of treatment to 4 months. After receiving the same three intensive six-drug induction courses based on high-dose fractionated cyclophosphamide, high-dose methotrexate (HD MTX), and cytarabine in continuous infusion, patients were evaluated for remission. Those who achieved complete remission (CR) were randomized between a long arm (five additional courses with two additional drugs; 16 weeks of treatment) and a short arm (two additional courses; 5 weeks). For patients in partial remission (PR), intensification of treatment was indicated. Two hundred sixteen patients were registered: 15 stage II nasopharyngeal and extensive facial tumors, 167 stage III, and 34 stage IV, 20 of the latter having more than 25% blast cells in bone marrow. The primary sites of involvement were abdomen in 172, head and neck in 30, thorax in two, and other sites in 12. One hundred sixty-seven patients are alive in first CR with a minimum follow-up of 18 months; four are lost to follow-up. Eight patients died from initial treatment failure, 14 died from toxicity or deaths unrelated to tumor or treatment, and 27 relapsed. The event-free survival (EFS), with a median follow-up of 38 months, is 78% (SE 3) for all the patients, 73% (SE 11) for the stage II patients, 80% (SE 3) for the stage III patients, and 68% (SE 8) for the stage IV and acute lymphoblastic leukemia (ALL) patients. One hundred sixty-six patients were randomized: 82 in the short arm and 84 in the long arm. EFS is, respectively, 89% and 87%. Statistical analysis confirms equivalence of both treatment arms with regard to EFS. Moreover, morbidity was lower in the short arm. This study confirms the high survival rate obtained in the previous LMB 0281 study without radiotherapy or debulking surgery and demonstrates the effectiveness of short treatment.

Twenty-five children or adolescents with relapsed or refractory non-Hodgkin's lymphoma (NHL) were included in this phase II study of the combination of cytarabine (ARA-C) 50 mg/m2/d by 12 hours continuous infusion day 1 to day 5, ARA-C 3 g/m2/d in 3 hours day 1 to day 4, and etoposide (VP 16) 200 mg/m2 daily from day 1 to day 4. Twelve patients had B-cell, 12 T-cell, and one non-T, non-B-cell lymphoma; according to Murphy's staging system, 15 had stage III and nine stage IV disease with bone marrow involvement at diagnosis. All had previously received ARA-C by push or continuous infusion. Two patients had received epipodophyllotoxins. At the time of the study, three children had initial refractory disease, 18 were in first relapse (14 on therapy), two in first refractory relapse, and two in second relapse (on therapy). The overall response rate (RR) was 60%: eight complete responses (CRs), seven partial responses (PRs) (two became CRs after a second course). The RR was 66% (four CRs plus four PRs) in B-cell and 54% (four CRs, three PRs) in non-B-cell NHL. It was 20% (one PR per five patients) in initial or relapsed refractory disease. In four patients with measurable CNS disease, there were three CRs. Duration of response was nonassessable since all the responding patients received high-dose polychemotherapy followed by autologous bone marrow transplantation (ABMT) (five are alive with long follow-up [FU]). Toxicity was marked mostly by pancytopenia for 2 weeks, and half the patients encountered a grade-3 infection. One severe diarrhea was observed. In conclusion, high-dose ARA-C (HD-ARA-C) and VP 16 are an effective regimen in relapsed NHL, especially with CNS disease, and its toxicity is acceptable with regards to the prognosis of the disease.

The authors treated 188 patients with osteosarcoma by chemotherapy followed by surgery and additional chemotherapy (Rosen's T regimen). In 14% of cases, infectious, neurologic or cardiac complications were observed, which resulted in death in 2% of the patients. Forty-six per cent responded well to the primary chemotherapy, 76% of which are alive and disease-free, as opposed to merely 42% of the bad responders.

Since 1981 in the French Pediatric Oncology Society, a multidrug intensive-pulsed chemotherapy was proposed for bad prognosis B-cell lymphomas (stage II ORL, III and IV) and for B acute lymphocytic leukemias (B-ALL). Between 1981 and 1984, the nine-drug regimen was based on high-dose cyclophosphamide, high-dose methotrexate and cytosine arabinoside in continuous infusion (regimen LMB-81). No irradiation was performed. CNS prophylaxis was made by high-dose methotrexate and by intrathecal injections. No debulking surgery was recommended. Since 1984, considering the high rate of continuous remission, some modifications were made for reducing the duration and toxicity of the treatment of most B-cell lymphomas without CNS involvement (regimen LMB-84). For B-cell lymphomas with CNS involvement and B-ALL, an intensive high-dose multidrug combination was proposed (regimen LMB-86). Between 1981 and 1984, 153 children (stage II ORL: 6%, III: 63%, IV: 31%) were treated with the LMB-81 regimen. The overall disease-free survival rate is 69%. No relapse occurred after 12 months. Only two CNS relapses were observed. Among stage IV, a worse prognosis was associated with initial CNS involvement (disease free survival: 19%). On the contrary, bone marrow involvement was not an adverse prognostic factor. With the LMB-84, the overall disease free survival rate is 74%. A noteworthy reduction of toxicity is observed.

Phase II studies using ifosfamide both alone and combined with vindesine and cisplatin have shown the effectiveness of this drug in patients with Ewing's sarcoma (ES) who had relapsed during VAC (vincristine, actinomycin, cyclosphosphamide)/VAd (vincristine, Adriamycin) therapy. In November 1984, these results led the SFOP to adopt a protocol consisting of (1) initial chemotherapy with three cycles of IVA (ifosfamide, 3 g/m2 on days 1 and 2; actinomycin D, 750 mg/m2 on days 1-3; vincristine, 1.5 mg/m2 on day 1) alternating every 3 weeks with IVAd (vincristine on day 22; ifosfamide on days 21-23; Adriamycin, 60 mg/m2 on day 22); (2) radical surgery if possible; (3) local radiotherapy (RT); and (4) maintenance chemotherapy with alternating IVA and VAd (vincristine, Adriamycin) for up to 9 months. In May 1987, 87 patients with previously untreated ES entered the study; 61 had localized ES. To date, 54 patients with localized disease and 22 with metastatic disease have finished initial chemotherapy; 40 patients with localized disease have been evaluated. In all, 28 patients (70%) were in complete remission (17 patients) or had a tumor regression of greater than 50% 11 patients) and were considered to be good responders; 12 patients were considered to be poor responders. After local radiotherapy in all but 7 patients and surgical resection in 29, 52 of 54 were considered to be in clinical remission. A total of 13 patients with metastatic disease were good responders at the completion of the initial chemotherapy. These results confirm the efficacy of primary chemotherapy using ifosfamide for the treatment of ES.