Indications and results of diagnostic biopsy in pediatric renal tumors: A retrospective analysis of 317 patients with critical review of SIOP guidelines.

OBJECTIVES: According to the Renal Tumor Study Group (RTSG) of the International Society of Paediatric Oncology (SIOP), diagnostic biopsy of renal tumors prior to neoadjuvant chemotherapy is not mandatory unless the presentation is atypical for a Wilms tumor (WT). This study addresses the relevance of this strategy as well as the accuracy and safety of image-guided needle biopsy. METHODS: Clinical, radiological, and pathological data from 317 children (141 males/176 females, mean age: 4 years, range, 0-17.6) consecutively treated in one SIOP-affiliated institution were retrospectively analyzed. RESULTS: Presumptive chemotherapy for WT was decided for 182 patients (57% of the cohort), 24 (8%) were operated upfront, and 111 (35%) were biopsied at diagnosis. A non-WT was confirmed after surgery in 5/182 (3%), 11/24 (46%), and 28/111 (25%), respectively. Age at diagnosis was the most commonly (46%) used criterion to go for biopsy but a nine-year threshold should be retrospectively considered more relevant. Tumor volumes of clear cell sarcoma of the kidney and WT were significantly higher than those of other tumors (P = 0.002). The agreement between core-needle biopsy (CNB) and final histology was 99%. No significant morbidity was associated with CNB. CONCLUSION: The use of SIOP criteria to identify patients eligible for presumptive WT neoadjuvant chemotherapy or upfront surgery avoided biopsy in 65% of children and led to a 97% rate of appropriate preoperative chemotherapy. Image-guided CNB is a safe and accurate diagnostic procedure. The relevance of SIOP biopsy criteria might be improved by using an older age threshold (9 years instead of 6 years) and by adding initial tumor volume.

From childhood to adulthood: long-term outcome of medulloblastoma patients. The Institut Curie experience (1980-2000).

Medulloblastoma patients treated at the Institute Curie between 1980 and 2000 were reviewed. Only patients whose primary treatment included craniospinal radiation were considered. Surviving patients were identified and evaluated by means of self-report questionnaires using the Health Utility Index (HUI). Psychosocial functioning, employment, and other health-related indicators were recorded. Seventy-three patients were treated during the study period. At a median follow-up from diagnosis of 14.4 years, 49 patients were alive and 45 surviving patients could be contacted. Late sequelae were frequent, particularly neurological deficits (71%) and endocrine complications (52%). Impairments of psychosocial functioning, including employment, driving capacity, independent living, and marital status, were identified in most patients. Most long-term medulloblastoma survivors suffer persistent deficits in several domains, with a significant impact on their psychosocial functioning. These findings reinforce the importance of early intervention programs for all survivors in order to reduce the psychosocial impacts of their disease.

Catecholamine metabolism in neuroblastoma.

Previous studies indicating the importance of catecholamine metabolism in neuroblastoma were briefly reviewed. Metabolic pathways were presented showing how the major urinary metabolites 3-methoxy-4-hydroxymandelic acid (VMA) and 3-methoxy-4-hydroxy-phenylacetic acid (HVA) are formed from norepinephrine and from dopamine plus 3,4-dihydroxyphenylalanine (DOPA), respectively. For 289 neuroblastoma patients at the time of diagnosis, the urinary excretion of VMA was significantly elevated in 75%, and HVA was elevated in 80%. Periodic assay of these metabolites during the course of the disease revealed that the excretion trends were of prognostic value with 80-90% reliability. By contrast, when the excretion in only the initial urine specimens was considered, the survival rate was the same for patients with normal, and with significantly elevated, excretion. Review of the results of tracer studies aimed at elucidating the in vivo metabolic origins of the urinary metabolites suggested that a) in neuroblastoma, the catecholamines were largely inactivated by intracellular metabolism in the tumor cells; b) there was excess production and excretion of the norepinephrine precursors, DOPA and dopamine; and c) in the tumors of most neuroblastoma patients, the initial enzyme in catecholamine synthesis, tyrosine hydroxylase, had an activity comparable with that in normal adrenal glands. The importance of the metabolism of catecholamines in patients with neuroblastoma was stressed: a) The excretion of elevated levels of urinary catecholamine metabolites were useful in diagnosis and in following the course of the disease, and b) study of the catecholamine metabolism in these patients permitted examination of possible relationships between the activity of the enzymes involved in catecholamine synthesis and the malignancy of this tumor.

Very-high-dose cisplatin and etoposide in children with untreated advanced neuroblastoma.

Between January and December 1985, 17 children with advanced neuroblastoma who were greater than 1 year old (16 stage IV, one stage III) were administered cisplatin (CPDD, 200 mg/m2) and etoposide (VP-16, 500 mg/m2) as a pilot study of toxicity and response rates for the European Neuroblastoma Study Group (ENSG). The study was designed to assess toxicity of two courses of treatment, and evaluate response rates after this short therapy. The creatinine clearance declined in seven of 15 patients. No patient experienced clinically significant hearing loss, but formal audiometric assessment of nine children revealed characteristic high tone loss in seven patients. Peripheral neuropathy was not seen. Asymptomatic hypomagnesemia (less than 0.7 microEq/L) was frequent, despite routine supplementation. Asymptomatic electrolyte imbalances occurred frequently, but were generally transient. Myelosuppression was severe, but brief. Seven patients required platelet transfusions and seven were readmitted between courses due to febrile episodes while neutropenic. There were no treatment-related deaths. According to strictly defined criteria, 12 of 17 patients showed a partial response (PR), and extensive marrow evaluation showed complete clearing of disease in six of 15 patients. This high-dose regimen, if carefully supervised, is associated with acceptable toxicity, comparable to that seen when the dose of CPDD is spread over several months. The rapidity and degree of response was encouraging and merits further evaluation.

Wilm's tumor with pulmonary metastases at diagnosis: the significance of primary chemotherapy. International Society of Pediatric Oncology Nephroblastoma Trial and Study Committee.

Data from patients with pulmonary metastases (PM) from Wilms' tumor at diagnosis (stage IV) were collected from six European centers. All patients were pretreated with a chemotherapy (CT) regimen consisting of vincristine (VCR), dactinomycin (AD), and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH). After nephrectomy, local therapy for residual pulmonary disease was considered to avoid whole-lung irradiation. Only four of 36 patients still had multiple inoperable metastases after preoperative CT. Thirty patients survived. Four of them were irradiated. Of the six patients who died, four died of PM, one died of abdominal recurrence, and one of therapy-related disease. Disease-free survival and actuarial survival rates are 83% with a mean follow-up of 4 years postnephrectomy.

A phase II study of high-dose cisplatin and VP-16 in neuroblastoma: a report from the Société Française d'Oncologie Pédiatrique.

Forty-seven children or adolescents with initial stage IV (42 patients) or stage III (five) advanced neuroblastoma (12 were progressing after relapse and 35 had never reached complete remission [CR] after conventional therapy) were included in a phase II study of the combination of high-dose VP-16 (100 mg/m2/d X 5) and high-dose cisplatin (CDDP) (40 mg/m2/d X 5). Twenty patients had received prior CDDP therapy (total dose, 100 to 640 mg/m2; median, 320 mg/m2) and 38 of 47 had bone marrow involvement when included in the study. The overall response rate was 55%, with 22% CR. Duration of response was 5 to 18 months, with a median of 10 months. Eight patients are still disease free, with a median observation time of 13 months, but all had received additional therapy after two courses of this regimen. Gastrointestinal toxicity was frequent but tolerable. Myelosuppression was severe but of brief duration, ie, nadir of neutrophils was observed at day 15 with 95% of the patients recovering a normal count before day 28, and nadir of platelet count was at day 17 with only two severe and reversible episodes of bleeding. The overall incidence of sepsis was 8% (seven of 92 courses), with no death related to infection. No acute renal failure was observed after two courses, and only three of 47 children experienced a clear reduction of renal function. After two courses, only two children showed a hearing loss in the 1,000 to 2,000 Hz range, although hearing loss above the 2,000 Hz level was frequently encountered. It is concluded that high-dose VP-16 and CDDP is an effective regimen in advanced neuroblastoma with acceptable toxicity. Phase III studies are needed in previously untreated patients. J Clin Oncol 5:941-950.

Presence of tumor cells in bone marrow but not in blood is associated with adverse prognosis in patients with Ewing's tumor. Société Française d'Oncologie Pédiatrique.

PURPOSE: Gene fusions that result from the chromosome translocations observed in Ewing's tumor (ET) provide tumor-specific markers that can be used to detect the presence of tumor cells in peripheral blood (PB), bone marrow (BM), and stem cell collection (SCC). These markers were used to evaluate, at diagnosis, a series of 67 ET patients. PATIENTS AND METHODS: RNA was extracted from nucleated cells from PB and BM and a nested reverse-transcriptase polymerase chain reaction (RT-PCR) was performed to search for EWS-FLI-1 or EWS-ERG fusion transcripts that resulted from the t(11;22) or t(21;22) translocations, respectively. RESULTS: At diagnosis, 16 of 62 (26%) patients had circulating tumor cells. This was not correlated with any clinical parameter. In contrast, Ewing's cells were detected by RT-PCR in BM in 14 of 43 (33%) patients and were associated with the presence of clinically detectable metastases and a statistically significant unfavorable outcome in univariate analysis. There was no correlation between the RT-PCR results in PB and in BM. CONCLUSION: These results suggested that the monitoring of BM but not of PB by RT-PCR might constitute an important criterion for the staging, at diagnosis, of patients with ET. Further studies should appreciate the relationship or independence of this marker toward other classical prognostic factors in ET, particularly to the presence of clinically detectable metastases.

Sequential cisplatin/VM-26 and vincristine/cyclophosphamide/doxorubicin in metastatic neuroblastoma: an effective alternating non-cross-resistant regimen?

We report the results of a French multicentric pilot study of remission induction therapy in metastatic neuroblastoma. Thirty-five successive unselected patients entered the study over 1 year and were treated by alternating sequences of cisplatin/VM-26 (PE) and vincristine/cyclophosphamide/doxorubicin (CADO). Three courses of each sequence were delivered. Disease reevaluation was extensive, with special focus on bone marrow status. Using strict criteria, 24 patients (68%) achieved a good partial response (GPR), which comprised normalization of bone marrow, and ten (28%) achieved a partial response (PR), and one progressed. The overall response rate was 96%. Thirty-two patients underwent surgery, and complete macroscopic removal of the primary was achieved in 21 (65%). After completion of induction and surgery, six patients (17%) were in complete remission (CRm), without evidence of any residual disease; nine (26%) were in very good partial remission (VGPRm; same as CRm except persistence of nonpathologically evaluable improved bone scan), and 19 (51%) were in partial remission (PRm). Toxicity was acceptable, and no treatment-related deaths occurred. These results show no substantial improvement compared with those previously reported with similar but nonalternating regimens. We advocate a two-category concept (response, remission) to describe initial therapy results in metastatic neuroblastoma and emphasize the need to assess bone marrow by an extensive evaluation.

Impact of megatherapy on survival after relapse from stage 4 neuroblastoma in patients over 1 year of age at diagnosis: a report from the European Group for Bone Marrow Transplantation.

PURPOSE: Relapse from stage 4 neuroblastoma usually carries a poor prognosis. A retrospective study using the European Bone Marrow Transplant (EBMT) Solid Tumor Registry was undertaken to define the role of megatherapy (MGT) in relapsed patients. PATIENTS AND METHODS: After relapse, 33 boys and 15 girls with previous stage 4 neuroblastoma received intensification by MGT followed by either autologous (n = 42) or allogeneic (n = 6) bone marrow rescue in 11 European institutions. The median age at diagnosis was 47 months (range, 14 to 134) and the median interval from diagnosis to relapse was 16 months (range, 4 to 94). Thirty patients had received only conventional-dose primary treatments (group A), whereas 18 patients had previously received intensification with MGT (group B). The median follow-up time of the total group is 95 months (range, 25 to 185). RESULTS: The actuarial overall survival rate at 2 years after MGT for relapse is 27% for group A and 0% for group B (P = .02). Three adverse, independent prognostic factors were confirmed by multivariate analysis using the Cox proportional hazards regression model: an interval of less than 12 months between diagnosis and relapse (P < .0001), nonresponding or untreated relapse (P = .0002), and previous MGT during primary treatments (P = .055). None of the other variables analyzed, such as sex, age, bone or bone marrow involvement at diagnosis or at relapse, and type of MGT at relapse, influenced outcome in this patient cohort. CONCLUSION: Responding patients who relapse more than 12 months from diagnosis who had not received previous MGT appear to benefit from consolidation MGT. Relapse patients who do not fulfill these criteria gain no advantage from this cost-intensive procedure and should be treated differently.

Etoposide in relapsed or refractory Wilms' tumor: a phase II study by the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group.

PURPOSE: Despite a high cure rate of approximately 85% in Wilms' tumor by multimodality therapy, to date only four drugs are known to be active against such tumors. There is a clear need for new active drugs. PATIENTS AND METHODS: Thirty-one patients with relapsed or refractory Wilms' tumor from three British and 14 French centers were treated with intravenous (IV) etoposide 200 mg/m2 daily for 5 days. Original stage was I (n = 3), II (n = 7), III (n = 9), IV (n = 10), and V (n = 2). Prior chemotherapy, administered initially or at relapse, included vincristine and dactinomycin in all cases, doxorubicin or epirubicin in 30, and ifosfamide in 20. Sites of relapse or resistant disease were lung in 13, abdomen or pelvis in six, liver in one, and multiple in 11. When entered onto the study, 12 patients were in first relapse, 10 in second relapse, and four in third or more relapse. Five had never obtained a complete remission. All but two (progressing) patients received two courses of etoposide, the second course being administered at day 21. RESULTS: A complete response (CR) was documented in two patients, partial response (PR) in 11, stable disease in 10, and progressive disease (PD) in eight. The duration of response could not be evaluated, because all responding patients were subsequently treated with multimodality therapy. The major toxicities observed were neutropenia and thrombocytopenia, but most patients had been heavily pretreated. No toxic death clearly associated with etoposide was noted. CONCLUSION: It is concluded that etoposide in this schedule is an active agent in Wilms' tumor and should be considered for inclusion in regimens for high-risk patients, such as those with metastatic disease at diagnosis and those who relapse after multiagent chemotherapy.

High-dose chemoradiotherapy with bone marrow transplantation as consolidation treatment in neuroblastoma: an unselected group of stage IV patients over 1 year of age.

Since January 1983, 56 consecutive children over 1 year of age with stage IV neuroblastoma entered an aggressive protocol, including chemotherapy, radiation therapy, and bone marrow transplantation. The induction protocol included platinum and epipodophyllotoxin (VM-26), alternating with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and vincristine (PE/CADO). Surgery was performed after 2 to 4 months, and consolidation with intensive chemoradiotherapy and bone marrow transplantation (BMT) was performed within 12 months of diagnosis. The combination of vincristine, melphalan and total body irradiation (TBI) was used before BMT, and no further treatment was administered before progression. With the exception of two allografts, autologous BMT (ABMT) was given in all cases and was purged using an immunomagnetic procedure (Kemshead technique) in 32 of 35 cases, and a chemical procedure in three of 35. Of the 56 patients, 45 were evaluable. Of those, 23 were grafted in partial remission (PR), and 14 were grafted in either complete remission (CR) or very good partial remission (VGPR). The acute toxic death rate was 19%, the relapse rate was 32%, and the progressive disease rate was 19%. The progression-free survival in the CR/VGPR group (ie, 44% at 32 months post-diagnosis) and in the PR group (13% at 32 months) was not significantly different (P greater than .05). At 24 months, the overall survival of the 56 unselected patients was 39% compared with 12% for comparable patients previously treated by our group (P less than .005).

Improved survival rate in children with stage III and IV B cell non-Hodgkin's lymphoma and leukemia using multi-agent chemotherapy: results of a study of 114 children from the French Pediatric Oncology Society.

Children with B cell non-Hodgkin's lymphoma who have not relapsed 1 year after diagnosis and treatment are generally cured. We report here the results of treatment in 114 children who all had a minimum follow-up of 20 months. The protocol LMB 0281 from the French Pediatric Oncology Society was used. This nine-drug intensive-pulsed chemotherapy was based on high-dose cyclophosphamide, high-dose methotrexate (HD MTX), and cytosine arabinoside (ara-C) in continuous infusion. CNS prophylaxis was with chemotherapy only. No local irradiation was performed. No debulking surgery was recommended. There were 72 patients with stage III lymphoma and 42 patients with stage IV lymphoma or B cell acute lymphocytic leukemia (B-ALL). Among those 42 patients, seven had CNS involvement alone, 21 had bone marrow alone, and 14 had both; 26 had greater than 25% blast cells in bone marrow, 14 of whom had blast cells in blood. The primary site of involvement was the abdomen in 90 patients, the Waldeyer Ring in nine, and various sites in eight; seven patients presented without tumor. Seventy-seven patients are alive with a median follow-up of 2 years and 8 months. Seven patients died due to initial treatment failure, 11 died from toxicity, and 19 died after relapse. Among the 93 patients without initial CNS involvement, only one isolated relapse in CNS occurred. Survival and disease-free survival rates reached 67% and 64%, respectively, for all patients, 75% and 73% for stage III patients and 54% and 48% for stage IV and B-ALL patients. Bone marrow involvement was not an adverse prognostic factor. Contrary initial CNS involvement indicated a bad prognosis with a disease-free survival rate of 19% compared with 76% without CNS disease. This study showed that CNS prophylaxis and local control of the primary tumor can be achieved by intensive chemotherapy alone, without radiotherapy or debulking surgery.

No benefit of ifosfamide in Ewing's sarcoma: a nonrandomized study of the French Society of Pediatric Oncology.

PURPOSE: To undertake a new protocol with the goals of improving the chemotherapeutic treatment of pediatric Ewing's sarcoma by introducing ifosfamide, and to widen the indications for surgical resection of Ewing's tumor to obtain better local control and to reduce radiation doses. PATIENTS AND METHODS: The French Society of Pediatric Oncology initiated its first cooperative Ewing's sarcoma study in 1978, using a four-drug regimen (cyclophosphamide, dactinomycin, Adriamycin [doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France], and vincristine). Ninety-five patients were included, and, at 5 years, the disease-free survival reached a plateau of 51%. After encouraging responses of recurrent soft tissue or bone sarcomas to ifosfamide, a second study began in 1984 using a new chemotherapy regimen in which cyclophosphamide was replaced by ifosfamide. Sixty-five patients were treated. RESULTS: By February 1992, the median follow-up was 5.8 years. The estimated 5-year disease-free survival was 52%. We observed unexpected cardiac toxicity. Three patients experienced acute cardiac failure that was lethal in two cases. The acute toxicity of ifosfamide prompted us to stop the protocol. Retrospectively, the lack of efficacy reinforced our decision. CONCLUSION: We conclude that ifosfamide did not improve the outcome of the patients despite the fact that these two treatment regimens were not randomized.

Optimal duration of preoperative therapy in unilateral and nonmetastatic Wilms' tumor in children older than 6 months: results of the Ninth International Society of Pediatric Oncology Wilms' Tumor Trial and Study.

PURPOSE: To determine the optimal duration of preoperative chemotherapy to further increase the proportion of stage I tumors by comparison of two regimens in the treatment of patients older than 6 months who have unilateral Wilms' tumor. PATIENTS AND METHODS: Eligible patients (n = 382) initially received four weekly doses of vincristine (VCR) and two courses of actinomycin D (AMD) and were randomized either to be operated on (4-week group [n = 193]) or to receive 4 more weeks of the same chemotherapy regimen (8-week group [n = 189]). The assessment criterion was the observed percentage of stage I tumors. After surgery, patients were assigned according to tumor stage and histology to four different treatment groups: stage I and favorable histology (n = 5) were to have no further treatment (NFT); stage I and standard histology or anaplasia (n = 244), VCR and AMD for 17 weeks (AV); stages II and III and favorable or standard histology, VCR, AMD, and an anthracycline for 27 weeks (AVE) with no abdominal radiotherapy for stage II N0 disease (n = 75) or with a 15-Gy dose of abdominal irradiation (RTH) in case of stages IIN1 and III (n = 56). Anaplastic tumors staged higher than I or clear-cell sarcoma of the kidney (14), AMD, VCR, an anthracycline, and ifosfamide for 36 weeks (DEVI). RESULTS: No advantage was found in favor of prolonged preoperative treatment. The percentages obtained for the 4-week and the 8-week groups, respectively, were as follows: stage I, 64% versus 62%; intraoperative tumor rupture rate, 1% versus 3%; 2-year EFS, 84% versus 83%; and 5-year OS, 92% versus 87%. Two-year EFS and 5-year OS rates, respectively, of the different treatment groups were as follows: NFT, 100% for both EFS and OS; AV, 88% and 93%; AVE, 84% and 88%; AVE RTH, 71% and 85%; and DEVI, 71% and 71%. The rate of abdominal recurrences in stage II N0 nonirradiated patients was 6.6%. CONCLUSION: The 4-week schedule pre-nephrectomy chemotherapy regimen should be considered the standard treatment. Clinical trials should continue to improve the cure rate of high-risk patients and the quality of life of children with a more favorable prognosis.

High survival rate in advanced-stage B-cell lymphomas and leukemias without CNS involvement with a short intensive polychemotherapy: results from the French Pediatric Oncology Society of a randomized trial of 216 children.

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.

Improved survival at 2 and 5 years in the LMCE1 unselected group of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: is cure possible in a small subgroup?

The objectives of this study were to determine (1) the role of selection before bone marrow transplantation (BMT), (2) the role of vincristine, melphalan, and total body irradiation (TBI) as consolidation of induction therapy for stage IV over 12 months at diagnosis, and (3) the role of immunomagnetic purging in metastatic neuroblastoma. Among 72 consecutive unselected patients, 10 were not grafted (four died at induction: two in complete remission [CR], two in partial remission [PR]); three had bone marrow progression before harvest; one had uncontrolled progression; and two had parental refusal). Sixty-two patients were grafted (23 in CR/very good PR [VGPR] and 39 in PR). Among the 62, 33 were consolidated with at least 90% excision of their initial tumor excised (53.2%), 15 with catecholamine secretions (24.2%), 22 with minor bone marrow involvement (35.5%), and 31 with positive bone scan (50%). Median observation time is 59 months. Progression-free survival (PFS) for the 10 excluded patients was 20% at 2 years and 0% at 4 years. PFS for the grafted population (n = 62) is 40% at 2 years, 20% at 4 years, and 13% at 7 years. No difference was observed between patients grafted in CR/VGPR or in PR. However, a group of 19 children was grafted resulting in complete normalization of metastasis (regardless of primary-site tumor status). In this group, PFS at 59 months was 38% with no relapses up to 7 years post-BMT. A group of 31 patients with no bone involvement at BMT was also identified. PFS at 5 years is 30% compared with 12% for bone-positive patients at BMT. Moreover, the 11 children presenting at diagnosis with no bone involvement (Evans stage IVS or stage C Memphis) and consolidated with BMT had PFS at 5 years of 50% with no late relapses. A subgroup of stage IV neuroblastoma patients older than 1 year of age at diagnosis may be curable with this therapeutic approach, and the use of multivariate analyses to search for prognostic factors is warranted in currently existing international registries.

Etoposide and carboplatin: a highly effective combination in relapsed or refractory Wilms' tumor--a phase II study by the French Society of Pediatric Oncology.

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.

LMCE3 treatment strategy: results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis.

PURPOSE: To tailor postinduction therapy for stage 4 neuroblastoma in children who are older than 1 year at diagnosis according to status after induction. PATIENTS AND METHODS: From March 1987 to December 1992, 99 patients who were consecutively admitted were included in the Lyon-Marseille-Curie East of France (LMCE)3 strategy. After induction with the French Society of Pediatric Oncology NB87 regimen and surgery, patients who were in complete remission immediately proceeded to consolidation therapy with vincristine, melphalan, and fractionated total-body irradiation (VMT). All other patients underwent a postinduction strategy before VMT, either an additional megatherapy regimen or further chemotherapy with etoposide/carboplatin. RESULTS: The progression-free survival (PFS) is 29% at 7 years from diagnosis, which compares favorably with that of a similar cohort of 72 patients previously reported by our group (LMCE1; PFS of 20% at 5 years and 8% at 14 years, P =.004). In the multivariate analysis, only age younger than 3 years at diagnosis (P =.0085) and achievement of complete or very good partial remission after NB87 and surgery (P =.00024) remained significant. The PFS of the 87 patients who were included in the postinduction strategy was significantly better than that of the comparable 62 patients on the LMCE1 study (32% v 11% at 7 years; P =.005). CONCLUSION: The progressive improvements in the LMCE results over the last 10 years suggest that improvements in supportive care measures and increases in each component of this strategy (induction, postinduction, consolidation) may all contribute to increased survival rates.

NB87 induction protocol for stage 4 neuroblastoma in children over 1 year of age: a report from the French Society of Pediatric Oncology.

PURPOSE: NB87 was designed to test the efficacy of a short, non cross-resistant, induction protocol for unselected patients over 1 year of age with stage 4 neuroblastoma. A secondary objective was to compare in a randomized study the toxicity of two modalities of cisplatin administration. PATIENTS AND METHODS: A total of 183 patients received two cycles of alternating sequences: cyclophosphamide 300 mg/m2/d on days 1 to 5, vincristine 1.5 mg/m2/d on days 1 and 5, and doxorubicin 60 mg/m2/d on day 5 (CADO); and cisplatin 40 mg/m2/d and etoposide 100 mg/m2/d on days 1 to 5 (CVP), followed by surgery of the primary tumor (126 patients). Ninety-one were randomized to receive cisplatin either as bolus (BO; n = 48) or continuous infusion (CI; n = 43). International Neuroblastoma Staging System (INSS) and Response Criteria (INRC) were used with emphasis on skeletal evaluation by meta-iodobenzylguanidine (MIBG). RESULTS: Hematotoxicity was predominant, with a higher incidence of neutropenia (P = .01) for CADO and of thrombocytopenia for CVP (P < .001). Severe infections, as well as nonhematologic toxicities, occurred more often after the first sequence. Gastrointestinal complications were predominant during both courses of CVP. The toxic death rate, including surgery, was 3%. Complete remissions (CRs) were less frequent on MIBG (45%) compared with marrow (66%) or other metastases (61%). Combining all metastatic sites resulted in a 39% CR rate. After surgery, the final CR rate was 42%. Nephrotoxicity was minimal in both arms (92% normal clearance for CI v 82% for BO). Hearing loss greater than 40 dB at 6,000 to 8,000 Hz was reported equally in both arms (n = 6 for CI v n = 5 for BO). CONCLUSION: Intensified chemotherapy using CADO/CVP increases CR rates despite a shorter induction duration. However, the rate of MIBG normalization remains unsatisfactory and could be raised through the dose-intensive use of agents such as cyclophosphamide.