Catherine Patte

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 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-Hodgkins 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.

Relapses of childhood anaplastic large-cell lymphoma: Treatment results in a series of 41 children - a report from the French Society of Pediatric Oncology

PURPOSE To study response to chemotherapy and the outcome of children treated for a relapsed anaplastic large-cell lymphoma (ALCL) and to evaluate the role of bone marrow transplantation (BMT) in these patients. PATIENTS AND METHODS Clinical data concerning the 41 relapses that occurred in 119 patients with ALCL enrolled in 3 consecutive studies since 1975 were analysed. First-line treatment consisted of intensive chemotherapy according to the COPAD protocol for the first series of 12 patients treated between 1975 and 1989 and to the SFOP (French Society of Pediatric Oncology) HM protocols for the 30 patients treated between 1989 and 1997. Twenty-eight patients were treated with CV(B)A (CCNU, vinblastine, ara-C with or without bleomycin), and the others with miscellaneous protocols for recurrent disease. Fifteen patients underwent autologous BMT and 1 allogeneic BMT while in CR2. RESULTS Thirty-six of forty-one (88%) patients achieved CR2. With a median follow-up of 5 years, 12 patients died, 9 of their disease and 29 patients are alive in CR2 (20 patients), CR3 (5 patients), CR4 (2 patients), CR5 (1 patient) or CR6 (1 patient). Overall and disease-free survival are respectively 69% (53%-82%) and 44% (29%-61%) at three years. In univariate analysis, patients treated with ABMT while in CR2 did not appear to have a better outcome than the other. Remarkably, a long-lasting remission was obtained in 8 of 13 patients treated with weekly vinblastine for a relapse including 6 relapses occurring after ABMT. CONCLUSIONS Relapsed ALCL are highly chemosensitive but over 40% of the patients experience several relapses. Prolonged conventional chemotherapy based on vinblastine might, in some cases, be as efficient as short intensive treatment with ABMT.

The response to initial chemotherapy as a prognostic factor in localized Ewing's sarcoma

Ninety-five children with localized Ewings sarcoma were included in a prospective cooperative study. All patients received initial chemotherapy with the purpose of early prevention of metastases and improvement of the conditions of the subsequent local therapy, radiotherapy in all cases, surgical resection in selected cases. Clinical response to initial chemotherapy was evaluated in 67 patients who had measurable soft tissue mass or functional symptoms. This response appeared highly correlated with outcome as the disease-free survival was 57.3% for the 41 good responders and 9% for the 26 bad responders (P less than 0.00001), though 23 of these bad responders reached complete remission with radiotherapy. This study also confirms the prognostic significance for survival of the site of the primary tumor on axial skeleton or on limbs. Nevertheless, this factor had no predictive value for response to chemotherapy, which thus appears to be an independent factor.

Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study

High cure rates are possible in children with localized mature B‐cell lymphoma (B NHL) using a variety of chemotherapeutic strategies. To reduce late sequelae, the duration and intensity of chemotherapy has been progressively reduced. The Lymphome Malins de Burkitt (LMB) 89 study reported long‐term survival in almost all children with localized resected disease treated with two courses of COPAD (cyclophosphamide, vincristine, prednisolone and doxorubicin). This study was designed to confirm the effectiveness of this approach in a larger number of patients in a multinational co‐operative study. The patient cohort was part of an international study (French‐American‐British LMB 96), which included all disease stages and involved three national groups. Patients in this part of the study had resected stage I or completely resected abdominal stage II disease. Following surgery, two courses of COPAD were given, without intrathecal (IT) chemotherapy. One hundred and thirty‐two children were evaluable. Two of 264 (0·9%) courses were associated with grade IV toxicity (one stomatitis and one infection). With a median follow up of 50·5 months, the 4 year event‐free survival is 98·3% and overall survival is 99·2%. Children with resected localized B‐NHL can be cured with minimal toxicity following two courses of low intensity treatment without IT chemotherapy.

SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease

BACKGROUND We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). METHODS Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. RESULTS Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival. CONCLUSIONS Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.

Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study

Clinical studies showed that advanced stage, high LDH, poor response to reduction therapy and combined bone marrow and central nervous system disease are significantly associated with a decreased event-free survival (EFS) in pediatric mature B-cell non-Hodgkins lymphoma (B-NHL) treated on FAB/LMB96. Although rearranged MYC/8q24 (R8q24) is characteristic of Burkitt lymphoma (BL), little information is available on other cytogenetic abnormalities and their prognostic importance. We performed an international review of 238 abnormal karyotypes in childhood mature B-NHL treated on FAB/LMB96: 76% BL, 8% Burkitt-like lymphoma, 13% diffuse large B-cell lymphoma (DLBCL). The main BL R8q24-associated chromosomal aberrations were +1q (29%), +7q and del(13q) (14% each). The DLBCL appeared heterogeneous and more complex. Incidence of R8q24 (34%) was higher than reported in adult DLBCL. The prognostic value of cytogenetic abnormalities on EFS was studied by Cox model controlling for the known risk factors: R8q24, +7q and del(13q) were independently associated with a significant inferior EFS (hazard ratio: 6.1 (P=0.030), 2.5 (P=0.015) and 4.0 (P=0.0003), respectively). The adverse prognosis of R8q24 was observed only in DLBCL, whereas del(13q) and +7q had a similar effect in DLBCL and BL. These results emphasize the significant biological heterogeneity and the development of cytogenetic risk-adapted therapy in childhood mature B-NHL.

Single-Drug Vinblastine As Salvage Treatment for Refractory or Relapsed Anaplastic Large-Cell Lymphoma: A Report From the French Society of Pediatric Oncology

PURPOSE To evaluate the efficacy of vinblastine for relapsed/refractory anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS Data were reviewed on all 36 patients included prospectively in the French database for pediatric ALCL who were treated with vinblastine (6 mg/m(2)/wk) for resistant primary disease (one), a first relapse (15), or subsequent relapses (20). Fifteen patients had undergone hematopoietic stem-cell transplantation (HSCT) for a previous relapse. RESULTS Six patients were not evaluable for response, 25 (83%) of 30 evaluable patients achieved a complete remission (CR), and five experienced progressive disease. Among the 31 patients who achieved a CR with vinblastine or before its initiation, six patients were treated with HSCT and 25 with vinblastine alone (median duration, 14 months). Overall, nine of 25 patients treated with vinblastine alone have remained in CR (median, 7 years since the end of treatment), and 16 patients have relapsed. Vinblastine was still efficient for subsequent relapses. With a median follow-up of 9.2 years, 12 patients have died (four as a result of toxicity after HSCT and eight as a result of disease), and 24 patients are alive (15 following treatment with single-agent vinblastine for the last event). Five-year overall survival is 65% (95% CI, 48% to 79%), and 5-year event-free survival is 30% (95% CI, 17% to 47%). CONCLUSION Vinblastine is highly efficient in relapsed ALCL and may produce durable remissions. The optimal treatment duration still has to be assessed. These results should be borne in mind when designing future phase II studies with the targeted therapies directed against anaplastic lymphoma kinase.

Hemorrhagic cystitis following high-dose chemotherapy and bone marrow transplantation in children with malignancies: incidence, clinical course, and outcome.

Two hundred ninety-one courses of high-dose chemotherapy (HDC) with bone marrow transplantation (BMT) in children with malignancies were reviewed in order to assess the incidence, clinical course, outcome, and predisposing factors of hemorrhagic cystitis. Hemorrhagic cystitis occurred in 19 HDC courses (6.5%). Three patients had grade I hematuria linked to thrombopenia, nine had grade II hematuria despite platelet levels greater than 50 x 10(9)/L, and seven had grade III hematuria with clots and bladder obstruction. Severe complications occurred in grade III patients, but no deaths were directly linked to the cystitis. Fourteen patients recovered within two to 120 days of onset. The other patients died before the cystitis resolved, either of a relapse of the malignancy or of infection. Predisposing factors were age (increased incidence in older children), conditioning regimen containing cyclophosphamide, previous vesical irradiation, association with prolonged aplasia, and hepatic complications. The role of busulfan was also probable. No viral agent was found.

Prognostic Factors in Children With Localized Malignant Nonseminomatous Germ Cell Tumors

PURPOSE Prognostic factors were studied in children older than 1 year who were treated with chemotherapy for extracranial localized malignant non seminomatous germ cell tumors. PATIENTS AND METHODS Data from two consecutive protocols were pooled. The TGM 85 (1985-1989) protocol consisted of alternating courses of cyclophosphamide, dactinomycin and vinblastine, bleomycin, and cisplatin at a dose of 100 mg/m(2) per course. The TGM 90 (1990-1994) protocol was initiated with carboplatin 400 mg/m(2) substituted for cisplatin as the only modification to the previous protocol. RESULTS We examined alpha-fetoprotein (AFP) levels, disease stage, and primary site and identified three prognostic groups. Patients with a poor prognosis had either an AFP level >/= 10,000 ng/mL or stage III disease and a sacrococcygeal or mediastinal primary site; such patients represented 46% of the patient population and experienced a 43% 3-year failure-free survival rate and a 77% overall survival rate. Patients with a good prognosis had an AFP level less than 10,000 ng/mL, stage I or II disease, and a testicular, ovarian, perineal, or retroperitoneal primary site; such patients represented 22% of the patient population and experienced no treatment failures. The other patients were classified in the intermediate prognosis group and represented 37% of the patient population, with an 81% 3-year failure-free survival rate and a 92% overall survival rate. CONCLUSION Initial AFP level, disease stage, and primary site are the most important prognostic factors in this analysis. Prognostic models for pediatric germ cell tumors should allow the stratification of patients for a risk-adapted approach to treatment.