Excellent outcome of children/adolescents with primary mediastinal large B-cell lymphoma treated with FAB/LMB-based chemotherapy regimen with rituximab.

Not available.

Predictive factors of long-term follow-up attendance in very long-term childhood cancer survivors.

BACKGROUND: Long-term follow-up (LTFU) clinics have been developed but only some childhood cancer survivors (CCS) attend long-term follow-up (LTFU). OBJECTIVE: To identify factors that influence LTFU attendance. METHODS: Five-year CCS treated for a solid tumor or lymphoma in Gustave Roussy before 2000, included in the FCCSS cohort (French Childhood Cancer Survivor Study), aged >18 years and alive at the date of the LTFU Clinic opening (January 2012) were invited to a LTFU visit. Factors associated with attendance at the LTFU clinic between 2012 and 2020 were estimated using logistic regression analyses. Analyses included different types of factors: clinical (tumor characteristics, cancer treatments, late effects), medical (medical expenses were used as a proxy of survivor's health status), social (deprivation index based on census-tract data relating to income, educational level, proportion of blue-collar workers, and unemployed people living in the area of residence), and spatial (distance to the LTFU clinic). RESULTS: Among 2341 CCS contacted (55% males, mean age at study, 45 years; SD ± 10 years; mean age at diagnosis, 6 years; SD ± 5 years), 779 (33%) attended at least one LTFU visit. Initial cancer-related factors associated with LTFU visit attendance were: treatment with both radiotherapy and chemotherapy (odds ratio [OR], 4.02; 95% CI, 2.11-7.70), bone sarcoma (OR, 2.43; 95% CI, 1.56-3.78), central nervous system primitive tumor (OR, 1.65; 95% CI, 1.02-2.67), and autologous hematopoietic cell transplant (OR, 2.07; 95% CI, 1.34-3.20). Late effects (OR, 1.70; 95% CI, 1.31-2.20), highest medical expenses (OR, 1.65; 95% CI, 1.22-2.22), living in the most advantaged area (OR vs. the most deprived area = 1.60; 95% CI, 1.15-2.22), and shorter distance from LTFU care center (<12 miles) also increased attendance. CONCLUSIONS: Patients who are apparently healthy as well as socially disadvantaged and living far away from the center are less likely to attend LTFU care. PLAIN LANGUAGE SUMMARY: Among 2341 adult childhood cancer survivors contacted between 2012 and 2020, 33% attended at least one long-term follow-up visit. Clinical factors related to attendance were multimodal treatment of first cancer (combining chemotherapy and radiotherapy), stem cell transplant, type of diagnosis (bone tumor and central nervous system primitive tumor), late effects (at least one disease among second malignancy, heart disease, or stroke), and highest medical expenses. In addition, the study identified social and spatial inequalities related to attendance, with independent negative effects of distance and social deprivation on attendance, even though the medical costs related to the long-term follow-up examinations are covered by the French social security system.

Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children.

BACKGROUND: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited. METHODS: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed. RESULTS: Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion. CONCLUSIONS: Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).

The feasibility of implementing Toronto childhood cancer stage guidelines and estimating the impact on outcome for childhood cancers in seven pediatric oncology units in sub-Saharan Africa. A study from the Franco-African Pediatric Oncology Group.

BACKGROUND: The improvement of childhood cancer outcome is determined by early diagnosis, effective treatment, supportive care, and adequate medical follow-up. Stage at diagnosis may reflect timeliness of diagnosis, therefore standardized registration of stage is essential for interpretation of regional differences and time trends in survival. Here, we describe the feasibility of implementing the Toronto Childhood Cancer Stage Guidelines (hereafter Toronto Guidelines [TG]) in the hospital-based cancer registry of the Franco-African Pediatric Oncology Group (GFAOP), and assess the impact of TG stage on outcome in pediatric oncology units (POUs) in seven low- and middle-income countries in sub-Saharan Africa (SSA). METHODS: All cancer patients diagnosed before 15 years of age with one of the 15 cancer types defined in TG, resident in one of the participating countries, and attending one of the selected POUs in 2017-2019 were included. Stage was assigned according to TG. Patients were followed-up for vital status for at least 12 months post diagnosis. Survival at 3, 6, and 12 months was calculated using Kaplan-Meier method and compared between POUs and tumor groups using log-rank test. RESULTS: TG stage was assigned to 1772 of 2446 (89%) cases diagnosed with one of 11 cancer types. It was not possible to assign TG stage to acute lymphoblastic leukemia (ALL) and the three types of the central nervous system tumors included in the TG. One-year overall survival (OS) was 58% [95% confidence interval: 55-60] and varied between POUs. Survival declined with increasing stage for four tumor types and was statistically significant for two. CONCLUSION: Except for ALL and brain tumors, we demonstrated feasibility of TG implementation for childhood solid cancers in participating POUs in SSA, and provided a baseline assessment of childhood cancer outcomes against which future stage distribution and survival can be measured as timelines of diagnosis improve over time within the GFAOP network.

Outcome and late effects of patients treated for childhood vaginal malignant germ cell tumors.

PURPOSE: Vaginal malignant germ cell tumors (MGCT) are rare, occurring in children less than 2 years old and raise the question of the optimal local treatment. METHODS: We included children treated for vaginal MGCT according to the French TGM-95/2013 regimen. Patients were classified as standard risk (SR: localized disease and alpha-fetoprotein (AFP) < 10,000 ng/mL) or high risk (HiR: metastatic and/or AFP > 10,000 ng/mL) and were treated, respectively, with three to five VBP (vinblastine-bleomycin-cisplatin) or four to six VIP (etoposide-ifosfamide-cisplatin), followed by conservative surgery and/or brachytherapy in case of post-chemotherapy residuum. RESULTS: Fourteen patients were included (median age = 12 months), of which six (43%) were classified as HiR. AFP levels were normalized after first-line chemotherapy in all cases but one. A vaginal post-chemotherapy residuum (median size = 8 mm, range: 1-24 mm) was observed in 13/14 patients, treated by complete resection in seven of 13 (viable cells in three of seven), incomplete resection in four of 13 (viable cells in two of four), with adjuvant brachytherapy in two of 13, and exclusive brachytherapy in two of 13 (viable cells in one of six). Among the six patients with viable disease, four patients received adjuvant chemotherapy. One patient (SR) experienced immediate postoperative relapse despite presenting no viable residual cells and was treated with four VIP cycles and brachytherapy. At last follow-up (median = 4.6 years, range: 0.5-16), all patients were alive in complete remission. Five patients suffered from vaginal sequelae with synechiae and/or stenosis (of whom four had undergone brachytherapy). CONCLUSION: Childhood vaginal MGCTs show a highly favorable prognosis with risk-adapted chemotherapy and local treatment of post-chemotherapy residuum (preferably by conservative surgery with partial vaginectomy). Brachytherapy could be an alternative when conservative surgery is not deemed possible or in cases of incomplete resection with residual viable cells.

Rituximab in addition to LMB-based chemotherapy regimen in children and adolescents with primary mediastinal large B-cell lymphoma: results of the French LMB2001 prospective study.

Primary mediastinal large B-cell lymphoma (PMLBL) is a rare entity predominantly affecting adolescents and young adults. Recently, an international phase II trial in pediatric patients using dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) failed to reproduce excellent survival reported in some adult studies. The optimal therapy regimen needs to be determined in this disease. The French prospective LMB2001 trial included all patients ≤18 years with mature B-cell lymphoma treated in French centers. For patients with PMLBL, treatment included four to eight courses of Lymphomes Malins B (LMB)-based chemotherapy without radiotherapy. From 2008, rituximab was added before each chemotherapy course. From 09/2001 to 03/2012, 42 patients with PMLBL were registered. The median age was 15 years (range, 8-18). Twenty-one patients were treated with chemotherapy plus rituximab. The median follow-up was 7.1 years (interquartile range, 5.8-11.1). Five-year event-free and overall survival were 88.1% (95% confidence interval (CI): 75.0-94.8) and 95.2% (95% CI: 84.0-98.7) for the whole population. The 5-year EFS was 81.0% (95% CI: 60.0-92.3) and 95.2% (95% CI: 77.3-99.2) (hazard ratio =0.24; 95% CI: 0.03- 2.2) and 5-year overall survival was 90.5% (95% CI: 71.1-97.3) and 100% for patients treated without and with rituximab, respectively. Only one of 21 patients treated with rituximab and LMB-based chemotherapy had local early treatment failure but achieved prolonged complete remission with second-line chemotherapy and radiotherapy. Intensive LMBbased chemotherapy with rituximab achieved excellent survival in children/adolescents with PMLBL. Further international prospective studies are required to confirm these results in this population.

The development of an international childhood cancer hospital register database in 13 African countries. A project of the French African Pediatric Oncology Group (GFAOP).

BACKGROUND AND AIM: The establishment of an international hospital-based register (HBR) for the French African Pediatric Oncology Group (GFAOP) was a necessary step in the group's clinical research program. With help from the Sanofi Espoir Foundation's "My Child Matters" program, the GFAOP resolved to develop an international HBR network to collect quality data on children attending the Pediatric Oncology Units (POUs). METHODS: All children entering POUs from January 2016 to December 2018 were registered using an online questionnaire. Data collection included information on diagnosis, disease stage, demographics, socioeconomic status, and outcome. An intensive training program was developed to improve both data quality and quantity. RESULTS: Among the 3348 children registered, 3230 had a suspected cancer, 681 were not confirmed. A diagnosis was confirmed on radiological, clinical, or histological examination for 2549 children including Burkitt lymphoma (516: 20%)-the most frequent diagnosis, Wilms' tumor (459: 18%), retinoblastoma (357: 14%), and acute lymphoblastic leukemia (345: 13%). Of these, 2187 children were treated. Early deaths, abandonment, economic difficulties, and lack of equipment were some of the reasons offered to explain the numbers of undiagnosed and untreated children. Vital status is known for 1994 children: 1187 died and 807 were alive, 551 of these with a follow-up > 12 months. CONCLUSION: This work has provided reliable data on children attending the POUs, especially clarifying reasons and occasions for care rupture. The data will help to identify material, human resources, and staff training needs, to evaluate progress, and to encourage consideration of pediatric cancer in national cancer plans.

Implementing the WHO Global Initiative for Childhood Cancer in Morocco: Survival study for the six indexed childhood cancers.

BACKGROUND: In 2018, the World Health Organization (WHO) launched the Global Initiative for Childhood Cancer (GICC). The goal is to achieve a global survival rate of at least 60% for all children with cancer by 2030. Morocco was designated as a pilot country for this initiative. PROCEDURE: This retrospective study included a cohort of children aged 0-15 years, with one of the six indexed cancers (acute lymphoblastic leukemia [ALL], Burkitt lymphoma [BL], Hodgkin lymphoma, retinoblastoma [RB], Wilms tumor or nephroblastoma, low-grade glioma), diagnosed between January 1, 2017 and December 31, 2019 at the six Moroccan Pediatric Hematology and Oncology units. Patients were followed-up until August 31, 2020. The Kaplan-Meier method was used to estimate survival rates, the log-rank test for comparing survival curves, and the Cox model for identifying prognostic factors. RESULTS: Data on 878 patients were included in the study. The most frequently reported cancer type was ALL (n = 383, 43.6%), followed by Wilms tumor (n = 139, 15.8%) and BL (n = 133, 15%). Most patients were less than 5 years of age (n = 446, 50.9%) and the male/female ratio was 1.46. The 1, 2, and 3-year overall survival rates were 80.1%, 73.6%, and 68.2%, respectively. In a multivariable Cox regression model, care center, cancer type, age group, and distance to the care center were statistically significantly associated to survival. Patients aged 10 years and older and patients living more than 100 km from the care center were more likely to die (respectively, HR = 1.39, p = .045 and HR = 1.44, p = .010). CONCLUSION: The reported results represent the baseline for measuring the impact of GICC implementation in Morocco.

Childhood ovarian nonseminomatous germ cell tumors: A highly curable disease with few long-term treatment-related toxicities-Results of the French TGM95 study.

We report survival and late effects analysis of TGM95 study for childhood (≤18 years) ovarian nonseminomatous germ cell tumors (NS-GCT). Patients with localized tumors (FIGO-stage IA) had no adjuvant treatment (low-risk, LR). Patients with advanced-stage received 3-5 VBP (vinblastin-bleomycin-cisplatin) in intermediate-risk group (IR: FIGO-stage IC-II-III and AFP < 15 000 ng/mL) or 4-6 VIP (etoposide-ifosfamide-cisplatin) in high-risk group (HiR: metastatic or AFP ≥ 15 000 ng/mL). Seventy-seven patients were included (median age = 12 years): 14 LR (13 FIGO-stage IA, 1 retrospectively IC), 26 IR (12 IC, 12 II-III, 2 not-available) and 37 HiR (2 IA with AFP ≥ 15 000 ng/mL, 27 II-III, 8 IV). After a median follow-up of 13.4 years, 12 events (eight relapses) and six deaths (two GCT-related, two due to acute myeloid leukemia and two noncancer related) occurred. All relapses (6 LR, 1 IR) occurred within 2 years. Four contralateral mature teratomas were observed within 8 years. Five-year EFS and OS were 88.2% (95%CI = 79-94%) and 94.6% (95%CI = 87-98%). Seven patients (9%) had bilateral gonadectomy. Among 51 survivors at 2 years aged >15 years (median = 26 years) with remaining ovarian tissue, all had developed spontaneous puberty and 21 (41%) had at least one pregnancy (including two with infertility treatment). Among 69 patients treated with platinum-based chemotherapy, chronic-kidney-disease was diagnosed in four patients (three after VIP) and significant ototoxicity occurred in three (all grade-2). Childhood ovarian NS-GCTs have an excellent prognosis with few late effects. The low-intensive etoposide-free VBP regimen could be an alternative in children with IR disease especially in cases of tumor rupture. The risk of contralateral mature teratoma needs regular monitoring of the remaining ovary.

Outcome of relapse in children and adolescents with B-cell non-Hodgkin lymphoma and mature acute leukemia: A report from the French LMB study.

INTRODUCTION: In order to describe relapsed B-cell non-Hodgkin lymphoma and mature acute leukemia in children/adolescents treated with the Lymphomes Malins B (LMB) regimen and their outcome in the rituximab era, relapses in the French LMB2001 study were reviewed. METHODS: Between February 2001 and December 2011, 33 patients out of 773 (4.3%) relapsed; 27 had Burkitt lymphoma and six large B-cell histology. Median age at diagnosis was 10.1 years. One patient was initially treated in risk group A, 21 in group B, and 11 in group C. RESULTS: Median time to relapse after diagnosis was 4.5 months (range 2.4-13.6). Thirty-two patients received salvage therapy. Twenty-seven received rituximab mainly in addition to high-dose cytarabine and etoposide (n = 18) and/or ifosfamide, carboplatin, and etoposide (n = 7). First-line salvage chemotherapy response rate was 66% with 47% being complete remission (CR). Twenty-one patients received high-dose chemotherapy (HDC) followed by autologous (n = 13) or allogeneic (n = 8) transplant. With a median follow-up of 6.8 years, the 5-year survival rate after relapse was 36.4% (95% confidence interval [CI] 22-53%). Twelve patients were still alive; all but one (group A) received consolidation treatment. Achieving CR before consolidation was significantly associated with better survival, with a 5-year survival rate of 75% (95% CI 46.8-91.1%) for patients in CR before HDC, 33% (95% CI 9.7-70%) for patients in partial remission, and 0% for nonresponders (P = .033). CONCLUSION: Survival of children/adolescents with mature B-cell lymphoma/leukemia remains poor after relapse with no apparent improvement with rituximab. Response rates to salvage chemo-immunotherapies are insufficient and new drugs are urgently needed to improve disease control.

The My Child Matters programme: effect of public-private partnerships on paediatric cancer care in low-income and middle-income countries.

In low-income and middle-income countries, an excess in treatment failure for children with cancer usually results from misdiagnosis, inadequate access to treatment, death from toxicity, treatment abandonment, and relapse. The My Child Matters programme of the Sanofi Espoir Foundation has funded 55 paediatric cancer projects in low-income and middle-income countries over 10 years. We assessed the impact of the projects in these regions by using baseline assessments that were done in 2006. Based on these data, estimated 5-year survival in 2016 increased by a median of 5·1%, ranging from -1·5% in Venezuela to 17·5% in Ukraine. Of the 26 861 children per year who develop cancer in the ten index countries with My Child Matters projects that were evaluated in 2006, an estimated additional 1343 children can now expect an increase in survival outcome. For example, in Paraguay, a network of paediatric oncology satellite clinics was established and scaled up to a national level and has managed 884 patients since initiation in 2006. Additionally, the African Retinoblastoma Network was scaled up from a demonstration project in Mali to a network of retinoblastoma referral centres in five sub-Saharan African countries, and the African School of Paediatric Oncology has trained 42 physicians and 100 nurses from 16 countries. The My Child Matters programme has catalysed improvements in cancer care and has complemented the efforts of government, civil society, and the private sector to sustain and scale improvements in health care to a national level. Key elements of successful interventions include strong and sustained local leadership, community engagement, international engagement, and capacity building and support from government.

Overall survival of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: A report from the FAB/LMB 96 study group.

We determined the risk factors associated with poor survival in children and adolescents with de novo mature B cell non-Hodgkin lymphoma (B-NHL) who had refractory or relapsed disease during or after the French-American-British mature lymphoma B (FAB/LMB) 96 multi-agent chemotherapy. Among the 1 111 registered on study, 104 patients (9·4%) had refractory disease or disease relapse after first complete remission. Among these 104 patients, 28 (27%) patients had refractory disease and 76 (73%) had relapsed disease. The estimated 1- and 2-year overall survival (OS) (95% confidence interval) was 31·5% (23·3-41·0%) and 22·3% (15·3-31·4%), respectively. Prognostic analysis of OS using a Cox multivariate model showed that factors independently associated with OS included lactate dehydrogenase ≥2 upper normal limit [hazard ratio (HR) = 2·86 (1·57-5·2), P = 0·0006]; time to failure (>6 months) [HR = 0·59 (0·36-0·97), P = 0·038]; and failure in bone marrow [HR = 2·78 (1·65-4·68), P = 0·0001]. New therapeutic strategies are required to significantly reduce refractory disease and disease relapse in patients with newly diagnosed mature B-NHL and, more importantly, there is a critical need to develop novel retrieval approaches in patients with chemotherapy-resistant disease.

Ovarian Yolk Sac Tumors; Does Age Matter?

BACKGROUND: Whereas among pediatric oncologists, ovarian yolk sac tumor (O-YST) is considered a chemosensitive tumor, it is often cited as an adverse prognostic factor in adult women with ovarian germ cell tumors. METHODS: The Malignant Germ Cell International Consortium data set included 6 pediatric clinical trials (United States, United Kingdom, and France) and 2 adult gynecology clinical trials (United States). Any patient with an O-YST that was International Federation of Gynecology and Obstetrics stage IC or higher and treated with a platinum-based chemotherapy was eligible. Age was modeled as a continuous and a categorical variable (children, 0-10 years; adolescents, 11-17 years; and adults, ≥18 years). In addition, analyses to establish the optimal cut point for age were conducted. Tumors were coded as pure YST (YST +/- teratoma), mixed YST (YST + other malignant germ cell component), or putative YST ("mixed" germ cell tumor + alpha-fetoprotein >1000 ng/mL). Histology, stage (II/III vs IV), preoperative alpha-fetoprotein levels (<1000; 1000-10,000, or >10,000 ng/mL), and chemotherapeutic regimen (carboplatin vs cisplatin) were analyzed as covariates. RESULTS: Two hundred fifty-one patients (median age, 13 years; range, 0-38 years) were identified (78 children, 139 adolescents, and 34 adults). Histology was pure, mixed, and putative in 129, 56, and 66 cases, respectively. Twenty-six patients had stage IV disease, similarly distributed in the 3 age groups. Median follow-up was 5.8 years. The overall 5-year event-free survival and overall survival was 91% (95% confidence interval, 87%-94%) and 96% (92%-98%), respectively. Age did not affect risk of event or death, modeled either as a categorical or continuous variable. Analysis failed to identify an age cut point that affected risk. None of the other covariates investigated had a prognostic impact on event-free survival or overall survival. CONCLUSIONS: Ovarian yolk sac tumors have an excellent outcome across all age-groups. Age has no apparent impact on the probability of event or death, allowing pediatric and gynecologic oncologists to enroll patients onto joint pediatric and adult trials.

Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma.

In the European Intergroup EURO-LB02 trial, children and adolescents with lymphoblastic lymphoma underwent the non-Hodgkin lymphoma Berlin-Frankfurt-Münster protocol without prophylactic cranial radiotherapy. The primary aims of this trial were to test whether replacing prednisone with dexamethasone during induction increases event-free survival in the subgroups with T-cell lymphoblastic lymphoma and whether therapy duration could be reduced from 24 to 18 months (factorial design, randomizations). These questions could not be answered due to premature closure of the trial. Here we report on the secondary aims of the trial: whether the results of the NHL-BFM90 study could be reproduced and evaluation of disease features and prognostic factors. Three hundred and nineteen patients (66 with precursor B-cell lymphoblastic lymphoma, 233 with T-cell lymphoblastic lymphoma, 12 with mixed phenotype, 8 not classifiable) were enrolled. In induction, 215 patients received prednisone and 104 patients received dexamethasone. The median follow-up was 6.8 years (range, 3.0-10.3). The 5-year event-free survival was 82±2% [12 toxic deaths, 5 secondary malignancies, 43 non-response/relapse (central nervous system n=9; all received prednisone during induction)]. The event-free survival rate was 80±5% for patients with precursor B-cell lymphoblastic lymphoma, 82±3% for those with T-cell lymphoblastic lymphoma, and 100% for patients with a mixed phenotype. During induction, significantly more grade III/IV toxicities were observed in patients receiving dexamethasone, resulting in significant treatment delays. The number of toxic deaths did not differ significantly. The only variable associated with outcome was performance status at diagnosis. The 90% event-free survival rate for patients with T-cell lymphoblastic lymphoma shown in study NHL-BFM90 was not replicated, mainly due to more toxic deaths and central nervous system relapses. Dexamethasone in induction may prevent central nervous system relapse more effectively than prednisone but produces a higher burden of toxicity. (#NCT00275106).

Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy.

Mediastinal large B-cell lymphoma (MLBL) represents 2% of mature B-cell non-Hodgkin lymphoma in patients ≤ 18 years of age. We analyzed data from childhood and adolescent patients with stage III MLBL (n = 42) and non-MLBL DLBCL (n = 69) treated with Group B therapy in the French-American-British/Lymphome Malins de Burkitt (FAB/LMB) 96 study. MLBL patients had a male/female 26/16; median age, 15.7 years (range, 12.5-19.7); and LDH < 2 versus ≥ 2 × the upper limit of normal, 23:19. Six MLBL patients (14%) had < a 20% response to initial COP (cyclophosphamide, vincristine, and prednisone) therapy. Central pathology revealed approximately 50% with classical features of primary MLBL. Five-year event-free survival for the stage III MLBL and non-MLBL DLBCL groups was 66% (95% confidence interval [CI], 49%-78%) and 85% (95% CI, 71%-92%), respectively (P < .001; 14%). The 5-year overall survival in the 42 MLBL patients was 73% (95% CI, 56%-84%). We conclude that MLBL in adolescent patients is associated with significantly inferior event-free survival compared with stage III non-MLBL DLBCL and can be of multiple histologies. Alternate treatment strategies should be investigated in the future taking into account both adult MLBL approaches and more recent biologic findings in adult MLBL.

Outcome of and prognostic factors for relapse in children and adolescents with mature B-cell lymphoma and leukemia treated in three consecutive prospective "Lymphomes Malins B" protocols. A Société Française des Cancers de l'Enfant study.

To describe relapsed B-cell lymphoma or leukemia in children/adolescents treated with a "Lymphomes Malins B" regimen and their outcome and to identify prognostic factors for survival, we studied relapses in the LMB89, 96 and 2001 studies of the Société Française d'Oncologie Pédiatrique (Société Française des Cancers de l'Enfant). Therapeutic guidelines at relapse were to obtain a second complete remission and to consolidate the remission with high-dose chemotherapy followed by autologous stem-cell transplantation. Between July 1989 and March 2007, 67 patients of 1322 (5%) relapsed: 57 had Burkitt lymphoma and 10 had large-cell histology. Three patients were initially treated in risk group A, 41 in group B and 23 in group C. Thirty-three patients had a relapse in one site (15 in the central nervous system) and 34 at multiple sites. Sixty-five patients received salvage chemotherapy and 33 achieved complete remission. Forty-one patients also received high-dose chemotherapy followed by autologous (n=33) or allogeneic (n=8) transplantation. With a median follow-up of 6.4 years, the 5-year survival rate was 29.9%. Nineteen patients were still alive, all but one (group A) received consolidation treatment. Multivariate analysis showed the following factors to be significantly associated with better survival: relapse at one site (P=0.0006), large-cell histology (P=0.012), initial prognostic group A or B with lactate dehydrogenase level below twice the normal value (P=0.005), and time to relapse more than 6 months (P=0.04).

Sex-Cord Stromal Tumors in Children and Teenagers: Results of the TGM-95 Study.

BACKGROUND: We present the results of the TGM-95 study for gonadal sex-cord stromal tumors (SCT). METHODS: Between 1995 and 2005, children (<18 years) with gonadal SCT were prospectively registered. Primary gonadal resection was recommended whenever feasible. Patients with disseminated disease or an incomplete resection received neoadjuvant or adjuvant VIP chemotherapy (etoposide, ifosfamide, cisplatinum). RESULTS: Thirty-eight children with ovarian SCT were registered. Median age was 10.7y. Endocrine symptoms were present in 21 cases. The histological diagnoses were as follows: juvenile (23) and adult (3) granulosa cell tumors, Sertoli-Leydig cell tumors (11), and mixed germ cell SCT (1). An initial oophorectomy ± salpingectomy led to complete resection in 23 patients who did not receive adjuvant treatment; two of them relapsed: one achieved second complete remission whereas the other one died of disease. Fifteen patients had tumor rupture and/or malignant ascites: 11 received chemotherapy and did not relapse, four did not receive chemotherapy and relapsed with a fatal outcome in two cases. With a median follow-up of 5.9y, the 5-y EFS and OS rates were respectively 85% and 94%. Eleven patients had localized testicular tumors (median age 0.83y): juvenile granulosa cell tumors (4), Sertoli or Leydig cell tumors (5) and not otherwise specified SCT (2). Treatment was surgery alone with an inguinal orchiectomy. None have relapsed (median follow-up: 5.4y). CONCLUSIONS: Childhood SCT carry favorable prognosis. In ovarian SCT, surgery should be complete and non-mutilating. Adjuvant chemotherapy efficiently prevents recurrences in cases of tumor rupture. In childhood testicular SCT, the prognosis is excellent with an inguinal orchiectomy, prompting the debate on testis-sparing surgery.

Treatment of Childhood T-Cell Lymphoblastic Lymphoma-Long-Term Results of the SFOP LMT96 Trial.

PURPOSE: Outcome of T-cell lymphoblastic lymphoma (T-LBL) in children is around 75-85% of event-free survival. The role of early intensification to improve outcome while using short infusions of high dose methotrexate (HDMTX) and shorter maintenance treatment was addressed by the French Society of Pediatric Oncology (SFOP) group. METHODS: From 1997 through 2003, 79 children (52 males; median age 10.5 years) were prospectively registered into the SFOP LMT 96 trial. The LMT96 protocol, with elements from the protocol of the Berlin-Frankfurt-Münster (BFM) Group included four main modifications: (a) 10 courses of HD-MTX (3 g/m(2) ) delivered over the first 44 weeks; (b) early intensification with cyclophosphamide together with the first course of HD-MTX; (c) a maintenance phase that included 6 monthly intensified chemotherapy pulses; and (d) treatment duration of 18 months for stages I-III. RESULTS: Eighty-nine percent of patients had an initial mediastinal involvement. With a median follow-up of 87 months, the 5-year event-free survival was 85% and overall survival 89%. Nine patients relapsed, eight during treatment. The early intensification did not change the pattern of relapses. Only 58% of patients experienced grade 3-4 neutropenia during the induction phase, 13% patients experienced grade 3 and 4 mucositis, and 5% patients experienced diabetes. The early intensification did not delay phases of chemotherapy. CONCLUSIONS: Early intensification in treatment for T-LBL in children is manageable. Three-hour infusion of HD-MTX did not jeopardize patient outcome. Our results are comparable with those of other international protocols in spite of shorter maintenance treatment for stages I-III.

Patients in pediatric phase I and early phase II clinical oncology trials at Gustave Roussy: a 13-year center experience.

In the European Union, the pediatric medicines regulation in 2007 modified significantly the access to new agents in pediatric oncology. Early oncology trials are still thought to be associated with limited benefit and substantial risk. We report the characteristics and outcome of patients below 21 years enrolled in investigational trials in the Pediatric and Adolescent Department at Gustave Roussy between January 2000 and December 2012. A total of 235 patients (median age, 10.4 [0.8 to 20.7] y) were included in 26 trials (16 cytotoxic and 10 targeted agents) for a total of 260 inclusions. A total of 117 patients (50%) had brain tumors and 68 (29%) had various soft tissue and bone sarcoma. Thirteen of the 106 patients in a phase I trial experienced dose-limiting toxicity. Main severe toxicity was hematologic; none had toxic death. Grade 3 to 4 toxicities were associated with combination trials, cytotoxic agent, and at least 1 previous line of therapy. Thirty patients (12%) had objective response and 42 (16%) had stable disease for >4 months. Median overall survival was 9.0 months (95% CI, 7.5-10.5) and 73% of patients received further anticancer treatment. Phase I to II pediatric oncology trials are safe, associated with clinical benefit, and can be successfully integrated in current relapse strategies.

Dose-Effect Relationship of Alkylating Agents on Testicular Function in Male Survivors of Childhood Lymphoma.

The purpose of our study was to assess the gonadal function in male survivors of childhood lymphoma. We studied 171 male survivors of childhood lymphoma (83 with B-cell non-Hodgkin lymphoma [B-NHL], 32 with T-cell non-Hodgkin lymphoma [T-NHL], 50 with Hodgkin lymphoma [HL], and 6 with anaplastic large-cell lymphoma [ALCL]), measuring follicle-stimulating hormone [FSH] and luteinizing hormone [LH] levels at a median age of 21.1 (17-30.4) years after a median delay of 9.3 (2-22.4) years from treatment. FSH levels were above normal range (≥10 IU/L) in 42.1% and LH levels ≥8 IU/L in only 8.9% of survivors. In multivariate analysis, only the following chemotherapeutic agents were associated with higher FSH or LH levels: cyclophosphamide (P < .0001, .04), lomustine (CCNU; P = .002, 0.04), and procarbazine (P < .0001, .07). No significant correlation was found between FSH or LH levels and age or pubertal status at diagnosis. Mean FSH level was significantly lower in NHL survivors treated more recently: 6 ± 5.1 IU/L in B-NHL survivors treated since 1986 versus 12.3 ± 5.4 IU/L for those treated before 1981 (P = .0001), and 6.8 ± 9.6 IU/L in T-NHL survivors treated since 1989 versus 9.4 ± 5.7 IU/L for those treated before 1989 (P = .035). In HL, mean FSH level was 12.4 ± 9.9 IU/L following procarbazine containing chemotherapy versus 3.4 ± 1.9 IU/L in the absence of procarbazine and increased significantly with the number of MOPP/OPPA (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone/Oncovin, procarbazine, and prednisone, and Adriamycin [doxorubicin]) courses received, from 6.8 ± 5.7 IU/L for 1-2 MOPP/OPPA to 12.6 ± 7.5 for 3-4 MOPP/OPPA and 19.6 ± 13.3 for more than 4 MOPP/OPPA (P for trend = .006). Testicular toxicity of alkylating agents on childhood lymphoma survivors is dose dependent and not correlated to diagnosis, age, or pubertal status at diagnosis.