Ambulatory High-dose Methotrexate Administration in Pediatric Osteosarcoma Patients at a Single Institution in Argentina.

BACKGROUND: The purpose of this study was to evaluate the feasibility and safety of ambulatory high-dose methotrexate (HDMTX) administration with oral hydration, alkalinization, and leucovorin rescue. HDMTX (12 g/m) was given intravenously over 4 hours after urine alkalinization. Families and patients were instructed to continue ambulatory oral hydration and alkalinization to monitor urine pH and to adjust bicarbonate according to our institution's treatment algorithm. Clinical status and MTX levels were controlled every 24 hours, and oral leucovorin dose was adjusted accordingly. RESULTS: From April 2007 to December 2010, 150 of 447 courses of HDMTX (31.4%) were given on an outpatient basis, and 91.2% were successfully completed. The main causes of failure were poor oral tolerance (n=6) and fever (n=4). Most patients (81%) had MTX levels of <10 µmol/L 24 hours post-HDMTX; only in 1 course the levels were >50 µmol/L (50.96 µmol/L). Neutropenia grade III/IV was observed in 18.3% of the courses, grade III/IV leukopenia in 2.7%, and grade III/IV thrombocytopenia and anemia in 4.7%. Around 39% were associated with grade III/IV hepatic toxicity (asymptomatic hypertransaminasemia), grade III-IV gastrointestinal toxicity (vomiting and diarrhea) (5%), grade III-IV mucositis (4%), and none of the patients developed renal toxicity. CONCLUSIONS: Ambulatory HDMTX administration is feasible and safe in a population with poor resources in a developing country.

Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high-grade, operable osteosarcomas of the extremities: A report from the Latin American Group of Osteosarcoma Treatment.

BACKGROUND: Metronomic chemotherapy (MC) consists of the administration of a low dose of chemotherapy on a daily or weekly basis without a long break to achieve an antitumoral effect through an antiangiogenic effect or stimulation of the immune system. The potential effect of MC with continuous oral cyclophosphamide and methotrexate in patients with high-grade operable osteosarcomas (OSTs) of the extremities was investigated. METHODS: Patients with high-grade OSTs who were 30 years old or younger were eligible for registration at diagnosis. Eligibility for randomization included 1) nonmetastatic disease and 2) complete resection of the primary tumor. The study design included a backbone of 10 weeks of preoperative therapy with methotrexate, adriamycin, and platinum (MAP). After surgery, patients were randomized between 2 arms to complete 31 weeks of MAP or receive 73 weeks of MC after MAP. The primary endpoint was event-free survival (EFS) from randomization. RESULTS: There were 422 nonmetastatic patients registered (May 2006 to July 2013) from 27 sites in 3 countries (Brazil, Argentina and Uruguay), and 296 were randomized to MAP plus MC (n = 139) or MAP alone (n = 157). At 5 years, the EFS cumulative proportions surviving in the MAP-MC group and the MAP-alone group were 61% (standard error [SE], 0.5%) and 64% (SE, 0.5%), respectively, and they were not statistically different (Wilcoxon [Gehan] statistic = 0.724; P =.395). The multivariate analysis showed that necrosis grades 1 and 2, tumor size, and amputation were associated with shorter EFS. CONCLUSIONS: According to the current follow-up, EFS with MAP plus MC is not statistically superior to EFS with MAP alone in patients with high-grade, resectable OSTs of the extremities. Cancer 2017;123:1003-10. © 2016 American Cancer Society.

Hepatocellular Carcinoma in Children: Does Modified Platinum- and Doxorubicin-Based Chemotherapy Increase Tumor Resectability and Change Outcome? Lessons Learned From the SIOPEL 2 and 3 Studies.

INTRODUCTION: The aim of this article is to present an experience of two prospective studies from the International Childhood Liver Tumor Strategy Group (SIOPEL 2 [S2] and SIOPEL [S3]) trials and to evaluate whether modified platinum- and doxorubicin-based chemotherapy is capable of increasing tumor resectability and changing patient outcomes. METHODS: Between 1995 and 2006, 20 patients with hepatocellular carcinoma (HCC) were included in the S2 trial and 70 were included in the S3 trial. Eighty-five patients remained evaluable. RESULTS: Response to preoperative chemotherapy was observed in 29 of 72 patients (40%) who did not have primary surgery, whereas 13 patients underwent upfront surgery. Thirty-three patients had a delayed resection. Thirty-nine tumors never became resectable. Complete tumor resection was achieved in 34 patients (40%), including seven of those treated with liver transplantation (LTX). After a median follow-up period of 75 months, 63 patients (74%) had an event (a progression during treatment, a relapse after treatment, or death from any cause). Sixty patients died. Twenty-three of 46 patients (50%) who underwent tumor resection died. Eighteen of 27 patients (63%) with complete tumor resection (without LTX) and 20 of 34 patients (59%) with LTX survived. Only one of seven patients (14%) with microscopically involved margins survived. Overall survival at 5 years was 22%. CONCLUSION: Survival in pediatric HCC is more likely when complete tumor resection can be achieved. Intensification of platinum agents in the S2 and S3 trials has not resulted in improved survival. New treatment approaches in pediatric HCC should be postulated.

Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study.

PURPOSE: MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial. PATIENTS AND METHODS: From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery. RESULTS: Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens. CONCLUSION: Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.

Prognostic stratification for children with hepatoblastoma: the SIOPEL experience.

PURPOSE: To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. PATIENTS AND METHODS: Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP < 100 ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease (V+/P+/E+) and/or metastases) and standard-risk (all others). The hierarchy of these factors plus multifocality, PRETEXT III, AFP > 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS). RESULTS: In 541 patients, reduced EFS correlated significantly with AFP < 100 ng/ml (hazard ratio [HR] 4.09, 95% confidence interval 2.16-7.75), AFP ≥ 1.2 × 10(6)ng/mL (2.48, 1.47-4.17), metastatic disease (3.02, 2.05-4.44), PRETEXT IV (2.15, 1.19-3.87), multifocality (1.59, 1.01-2.50), age > 5 years (2.76, 1.68-4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91-5.77); but not with PRETEXT III, age 30-60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age> 5 years and/or AFP > 1.2 × 10(6) have 3 year EFS of 71% and SCU and/or AFP < 100 ng/mL and/or metastatic have a 3year EFS of 49%. CONCLUSION: Prognostic stratification for clinical research on newly diagnosed hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology.

Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy.

PURPOSE: Previous studies suggest poor outcome in children with relapsed rhabdomyosarcoma (RMS). A better understanding is needed of which patients can be salvaged after first relapse. PATIENTS AND METHODS: The analysis included children with nonmetastatic RMS and embryonal sarcoma enrolled onto the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumor (MMT) 84, 89, and 95 studies who relapsed after achieving complete local control with primary therapy. All patients included in the analysis had follow-up for ≥ 3.0 years after the last event. The clinical features, initial treatment characteristics, and features of the relapse were correlated with survival in univariate and multivariate analyses. RESULTS: In all, 474 eligible patients were identified for the study. At ≥ 3.0 years from the last event, 176 (37%) were alive ("cured"). In a full-model multivariate analysis, the factors identified at first relapse that most strongly associated with poor outcome were metastatic relapse (odds ratio [OR], 4.19; 95% CI, 2.0 to 8.5), prior radiotherapy treatment (OR, 3.64; 95% CI, 2.1 to 6.4), initial tumor size > 5 cm (OR, 2.53; 95% CI, 1.5 to 4.1), and time of relapse < 18 months from diagnosis (OR, 2.20; 95% CI, 1.3 to 3.6). Unfavorable primary disease site, nodal involvement at diagnosis, alveolar histology, and previous three- or six-drug chemotherapy were also independently associated with poor outcome. To estimate chance of cure for individual patients, a nomogram was developed, which allowed for weighting of these significant factors. CONCLUSION: Some children with relapsed RMS remain curable. It is now possible to estimate the chance of salvage for individual children to direct therapy appropriately toward cure, use of experimental therapies, and/or palliation.

No advantage of a rotational continuation phase in acute lymphoblastic leukemia in childhood treated with a BFM back-bone therapy.

BACKGROUND: Our aim was to compare two different schedules of maintenance in pediatric acute lymphoblastic leukemia (ALL) treated with a BFM-based therapy, in a randomized study: an Arm with 6-MP + MTX (with or without vincristine and dexamethasone pulses) versus a more intensive continuation phase. PROCEDURE: From January 1996 to November 2002, 429 eligible children with ALL were enrolled in a protocol with BFM-based back-bone, followed by a randomized continuation phase in standard (SRG) and intermediate (IRG) risk groups. Patients were randomized between Arms A and B for SRG and B or C for IRG. Arms A and C consisted of 6-MP and MTX and in Arm C, six pulses of VCR and dexamethasone were added. Arm B combined four pairs of drugs rotated weekly. All risk-groups received maintenance until completing 2 years of therapy from diagnosis. RESULTS: With a median follow-up of 138 (range: 96-178) months, the overall pEFS (SE) was 72 (6)% for all patients and the different risk groups showed: SRG: 85 (3)%, IRG: 71 (1)%, and HRG: 42 (7)% (P-value ≤ 0.0001). The pDFS (SE) according to the assigned arm of maintenance was, for Arm A: 89 (3)% and for Arm B: 85 (4)% in SRG, and, for Arm B: 77 (4)% and for Arm C: 75 (4)% in IRG, at 10 years follow-up. There were no statistically significant differences in outcome between arms of maintenance for both risk groups. CONCLUSIONS: In protocols with initial BFM-based strategy, a more intensive continuation phase did not benefit any risk group of patients.

Diagnóstico y tratamiento de la neutropenia febril en niños con cáncer: Consenso de la Sociedad Latinoamericana de Infectología Pediátrica / Diagnosis and treatment of febrile neutropenia in pediatric cancer patients: Consensus of the Sociedad Latinoamericana de Infectología Pediátrica

La Sociedad Latinoamericana de Infectología Pediátrica, a través de su Comité de Infecciones en Niños Inmunocomprometidos, propone un documento de consenso sobre "Diagnóstico y tratamiento de la neutropenia febril en niños con cáncer". Este documento-guía aborda el manejo de la neutrope-nia febril orientado a la atención de niños con cáncer en América Latina. Se realizó una búsqueda exhaustiva de la literatura, y se consideró particularmente la experiencia publicada proveniente de centros de nuestro continente, que aporta una mirada regional y adecuada a la realidad de nuestros países. El manuscrito contiene un panorama epidemiológico de la Región y recomendaciones para la evaluación clínica y de laboratorio necesarios para el manejo de estos pacientes, establece criterios de categorización de riesgo de infecciones bacterianas invasoras, analiza las medidas de cuidado general de los pacientes en el ambiente hospitalario y extra-hospitalario, propone diferentes enfoques terapéuticos de acuerdo a las realidades epidemiológicas institucionales, parámetros clínicos y de categorización de riesgo, establece diferentes algoritmos de seguimiento según la evolución de cada paciente, especifica las situaciones en que está indicada algún tipo de profilaxis y da los lineamientos generales sobre el tipo y oportunidad de terapia antifúngica a utilizar en ellos. Se ha puesto especial énfasis en entregar, de forma práctica, y con la mayor evidencia posible, las recomendaciones para el mejor manejo de los niños con cáncer, fiebre y neutropenia, buscando la equidad y la excelencia en todos los centros oncológicos latinoamericanos.

This document is a consensus guideline on the "Diagnosis and treatment of febrile neutropenia in children with cancer" developed by the Committee for Infectious Diseases in Immunocompromised Children of the Sociedad Latinoamericana de Infectología Pediátrica. This guideline discusses the management of febrile neutropenia focused on Latin American children with cancer. It is based on a thorough review of the literature, with particular attention to experiences reported by centers within the continent in order to provide recommendations applicable to the region. The manuscript includes a description of the regional epidemiology of cancer and infections in children, recommendations for clinical and laboratory studies required for patient management, description of a classification method to identify patients at different risk for invasive bacterial infections, outpatient and inpatient general care strategies and differential treatment strategies adjusted to local epidemiological realities, different algorithms for patient follow-up according to clinical course, a discussion of the rationale for prophylaxis strategies in specific situations including general guidelines for antifungal treatment. The Guidelines intend to provide practical, evidence-based recommendations in order to promote the best possible management for children with cancer, fever and neutropenia, throughout oncology centers of Latin America.

Results of a prospective study for the treatment of unilateral retinoblastoma.

BACKGROUND: Few prospective studies about the management of unilateral retinoblastoma with pathology risk factors (PRFs) have been published. METHODS: Patients (n = 114) were divided into four groups: Group 1 (initial chemoreduction) (n = 17). Groups 2 and 3, included patients initially enucleated with no, or lower risk PRFs: (n = 65) and with higher risk PRFs (n = 30), respectively. The later included postlaminar optic nerve involvement (PLONI) (n = 23), tumor at resection margin of optic nerve (n = 5) or isolated scleral invasion (n = 2). Group 3 received adjuvant chemotherapy including a total eight cycles of carboplatin and etoposide, alternating with cyclophosphamide, idarubicin, and vincristine. Orbital radiotherapy (45 Gy) was given to patients with invasion to the resection margin. Group 4 included patients with metastatic disease (n = 2). They were given neoadjuvant therapy followed by surgery and high-dose chemotherapy and autologous stem cell rescue. RESULTS: Five-year event-free survival is 0.94 (1 for Group 1, 0.94 for Group 2, 0.96 for Group 3, and 0 for Group 4). Events included. Group 2: Systemic relapse (n = 2) and combined orbital and CNS relapse (n = 1). Relapsing patients had PLONI (n = 2) and isolated focal choroidal invasion (n = 1). Group 3: CNS relapse (n = 1) in a patient with tumor at the resection margin of optic nerve. Group 4: CNS relapse (n = 2). Only one relapsed patient survived. Eight of 17 eyes treated conservatively were preserved. CONCLUSIONS: The survival of patients with unilateral retinoblastoma was excellent and 60% were spared from adjuvant treatment. Our intensive regimen was likely to be effective for prevention of metastasis in patients with higher risk PRFs.

Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study.

PURPOSE: The primary objective was to determine the efficacy of a newly designed preoperative chemotherapy regimen in an attempt to improve the cure rate of children with high-risk hepatoblastoma. PATIENTS AND METHODS: High risk was defined as follows: tumor in all liver sections (ie, Pretreatment Extension IV [PRETEXT-IV]), or vascular invasion (portal vein [P+], three hepatic veins [V+]), or intra-abdominal extrahepatic extension (E+), or metastatic disease, or alpha-fetoprotein less than 100 ng/mL at diagnosis. Patients were treated with alternating cycles of cisplatin and carboplatin plus doxorubicin (preoperatively, n = 7; postoperatively, n = 3) and delayed tumor resection. RESULTS: Of the 151 patients (150 evaluable for response) 118 (78.7%) achieved a partial response to chemotherapy. Complete resection of the liver tumor could be achieved in 115 patients (76.2%) either by partial hepatectomy (55.6%) or by liver transplantation (20.6%). In 106 children (70.2%), complete resection of all tumor lesions (including metastases) was achieved. Among the patients with initial lung metastases, 52.2% achieved complete remission of the lung lesions with chemotherapy alone. In half of the patients with initial PRETEXT-IV tumor as the only high-risk feature, the tumor could be completely resected with partial hepatectomy. Event-free (EFS) and overall survival (OS) estimates at 3 years were 65% (95% CI, 57% to 73%) and 69% (95% CI, 62% to 77%) for the whole group. EFS and OS for all patients with PRETEXT-IV tumor were 68% and 69%, respectively, and they were 56% and 62%, respectively, for patients with metastasis. CONCLUSION: The applied treatment rendered a great proportion of tumors resectable, and, in comparison with previously published results, led to an improved survival in patients with high-risk hepatoblastoma.

Importance of multi-lineage hematologic involvement and hypoalbuminemia at diagnosis in patients with "risk-organ" multi-system Langerhans cell histiocytosis.

AIM: To perform a risk factor analysis in patients with "risk organ" multi-system Langerhans cell histiocytosis at diagnosis. METHODS: From 1987 to 2007, 77 patients were analyzed. A univariate analysis of the variables, age <2 years, lungs, spleen and hepatic involvement, presence of >or=2 risk involved organs, hypoalbuminemia and the presence of isolated anemia, anemia with thrombocytopenia with or without leukopenia at diagnosis was performed. Statistically significant variables were combined and entered into a multivariate analysis. RESULTS: Fifty-six and 66 evaluable patients had hematologic and hepatic involvement at diagnosis, respectively. Among the hematologic patients, the subgroup of anemia with thrombocytopenia with or without leukopenia showed a significantly lower 5-year survival than the subgroup of isolated anemia (0.19 vs. 0.87, respectively; P=0.0001). Of all the patients, those with hypoalbuminemia had a 5-year survival of 0.16 compared with those with normal albumin levels, who had a 5-year survival of 0.65 (P<0.0001). In multivariate analysis, only anemia with thrombocytopenia with or without leukopenia and hypoalbuminemia were the independent risk factors (relative risk 3.77; confidence interval, 1.7-8.4; P<0.0011 and relative risk 2.59; confidence interval, 1.24-5.4; P<0.0112). CONCLUSIONS: Anemia with thrombocytopenia with or without leukopenia and hypoalbuminemia, were associated with worse prognosis in multi-system Langerhans cell histiocytosis. Other therapeutic strategies should be considered at diagnosis or early during the initial treatment for this high risk subgroup of patients.

Infantile fibrosarcoma: management based on the European experience.

PURPOSE: To retrospectively analyze the clinical features and results of treatment in 56 infants with fibrosarcoma enrolled onto cooperative European protocols between 1979 and 2005 and treated with a combination of surgery and chemotherapy. PATIENTS AND METHODS: We performed a retrospective case review of infants under the age of 2 years with fibrosarcoma treated between 1979 and 2005 in six European studies. Patients were staged according to the Intergroup Rhabdomyosarcoma Staging System international classification as a function of the type of initial surgery and the extent of disease and were treated with surgery and chemotherapy. Survival was calculated using the Kaplan-Meier method. RESULTS: Primary tumor site was the limbs in 66% of patients; median tumor diameter was more than 5 cm in 63% of patients; and postoperative staging was as follows: group I, 22%; group II, 27%; group III, 47%; and group IV, 4%. Response rate to chemotherapy was 75%, and the specific response rate to vincristine-dactinomycin was 71%. Local control was obtained in 84% of patients. At the end of follow-up, 45% of survivors had been treated by surgery alone, 6% by chemotherapy alone, 46% by surgery and chemotherapy, and 2% by surgery, chemotherapy, and radiotherapy. The 5-year overall survival (OS) rate was 89%. The 5-year OS and event-free survival rates for localized patients were 89% and 81%, respectively. CONCLUSION: Although complete resection is rarely feasible at diagnosis, conservative surgery remains the mainstay treatment for infantile fibrosarcoma. An alkylating agent-free and anthracycline-free regimen is usually effective and should be chosen as first-line chemotherapy for inoperable tumors. Overall prognosis is good, but progression or relapse, mainly local, remains possible.

Some clinical findings at presentation can predict high-risk pathology features in unilateral retinoblastoma.

AIMS: To identify clinical features at presentation to help in detecting patients with retinoblastoma and pathology risk factors (PRFs) preoperatively, and therefore selecting a high-risk population that could benefit from preoperative treatment. METHODS: A retrospective analysis of a prospectively filled form of 182 consecutive patients with unilateral retinoblastoma treated with initial enucleation from 1988 to 2006. Univariate and multivariate analyses were carried out. Major choroidal invasion and postlaminar optic nerve and scleral extension were considered PRFs. Within this subgroup, a higher-risk cohort (microscopical residual disease caused by trans-scleral invasion or invasion to the resection margin of the optic nerve) was analyzed separately. RESULTS: One hundred sixty-four patients had completely resected and 18 had microscopical residual disease. Seventy three had at least 1 PRF (massive invasion to the choroid in 25, to the postlaminar optic nerve in 41, intrascleral in 10, to the resection margin of the optic nerve in 12, and trans-scleral in 6). Seventy-one patients had glaucoma and 19 had buphthalmia. Intraocular pressure, glaucoma, and buphthalmia correlated significantly with the occurrence of both PRF and microscopical residual disease in multivariate analysis. Buphthalmia was the most specific factor but the sensitivity was lower. Glaucoma and buphthalmia had a high negative predictive value. CONCLUSIONS: Patients presenting with glaucoma and/or buphthalmia have a significantly higher risk for the occurrence of PRF, including those resulting in microscopically residual disease.

Treatment results in patients with retinoblastoma and invasion to the cut end of the optic nerve.

BACKGROUND: There is little information on the outcome of patients with retinoblastoma and tumor at the resection margin of the optic nerve. PROCEDURE: Retrospective evaluation of three successive prospective protocols. Twenty-six consecutive patients were analyzed (International Staging System-IRSS-stage 2 = 21, stage 3 = 5) from three successive prospective protocols (1988-2006). Patients with stage 2 were enucleated upfront and those with stage 3 had neoadjuvant chemotherapy followed by enucleation and adjuvant therapy. Both groups received adjuvant chemotherapy and orbital radiotherapy after enucleation. Patients in protocol 1 received 1 year of the lower-dose chemotherapy regimen including cyclophosphamide, vincristine and doxorubicin along with intrathecal chemotherapy. Patients of protocols 2 and 3 received a more intense and shorter intravenous regimen including carboplatin and etoposide alternating with cyclophosphamide, idarubicin and vincristine with no intrathecal treatment. The components of protocol 2 and 3 were similar except for the dose of carboplatin which was 10% lower in protocol 3. RESULTS: Thirteen were treated in protocol 1 and 13 in protocols 2 and 3. The probability of event-free survival was 0.70 at 5 years. Events included: CNS relapse = 3, second malignancies = 3, death in complete remission = 2. There were no significant differences in outcome between protocols or stages. Endocrinological disturbances related to the hypothalamus-hypophysis axis were evident in 6/8 patients evaluated. Severe orbital sequelae occurred in 12 cases. CONCLUSIONS: A substantial number of patients with tumor at the resection margin of the optic nerve can be cured with current therapy; however, therapy related sequelae are frequent.

Revisiting the role of doxorubicin in the treatment of rhabdomyosarcoma: an up-front window study in newly diagnosed children with high-risk metastatic disease.

PURPOSE: Many cooperative groups have reported on the chemo-sensitivity of rhabdomyosarcoma (RMS). Doxorubicin has been tested but remains a controversial treatment option. We report here the results of the up-front evaluation of the efficacy of doxorubicin in children and adolescents with high-risk metastatic RMS. PATIENTS AND METHODS: Patients younger than 18 years of age (>6 months) with newly diagnosed, histologically confirmed high-risk metastatic RMS were required to have measurable disease, to have undergone no prior chemotherapy or radiation therapy and to have normal liver, renal and cardiac function before treatment. Doxorubicin was administered intravenously over 48h to a total dose of 60mg/m2. Two courses were given separated by a 21day interval. Response to therapy was assessed by diagnostic imaging after the second course. The study was designed as a two-stage procedure according to the multistep plan described by Fleming. RESULTS: Twenty patients were eligible for analysis. Median age at diagnosis was 9.8 years (range from 2 to 16). Thirteen of the 20 patients treated in the first step responded to treatment, corresponding to an overall response to doxorubicin of 65% [95% confidence interval (CI), 44-85%]. The rates of CR and PR were 5% [95% CI, 0-14%] and 60% [95% CI, 39-81%], respectively. Four (20%) patients had progressive disease, corresponding to a progression rate of 20% [95% CI, 2-38%]. CONCLUSION: This window study provides the definitive demonstration of the efficacy of doxorubicin in untreated RMS. Given the inconclusive results obtained from previous studies using differing schedules chemotherapy incorporating doxorubicin, the next step should be a randomised study testing dose intensity in high-risk localised RMS. This issue is being addressed in a current European study (EpSSG RMS 2005).

Outcome of patients with retinoblastoma and postlaminar optic nerve invasion.

PURPOSE: To evaluate the outcome of patients with retinoblastoma and postlaminar optic nerve invasion (PLONI). DESIGN: Retrospective interventional case series. PARTICIPANTS: Sixty-one consecutive patients included in 3 successive protocols were analyzed. METHODS: Pathologic review was done in each case. Patients were stratified into 2 risk groups: the high-risk group included those with concomitant full choroidal and/or scleral invasion and were given adjuvant chemotherapy. Those without these features were considered low risk and chemotherapy was withheld after 1994. MAIN OUTCOME MEASURES: Extraocular relapse and survival according to stratification. RESULTS: The probability of event-free survival (pEFS) was 0.91 and the probability of overall survival (pOS) was 0.94 at 5 years. Patients in the high-risk group (n = 22) had pEFS of 0.86. Three had extraocular relapse (involving the central nervous system; all died of disease). Microscopic scleral invasion was associated to extraocular relapse (P = 0.05). Lower risk patients (n = 39) had a pEFS of 0.94 and pOS of 1. Eighteen received postenucleation chemotherapy and none relapsed. Twenty-one received no adjuvant therapy and 2 had a systemic relapse but were successfully retrieved. Relapsing patients had a higher ratio of affected optic nerve (>25% of it overall length; P = 0.02). CONCLUSIONS: Patients with PLONI have an excellent outcome with current therapy. Risk stratification according to the presence of concomitant choroidal and/or scleral invasion may help in the decision of giving adjuvant therapy.

An aggressive bone marrow evaluation including immunocytology with GD2 for advanced retinoblastoma.

There is general agreement that bone marrow (BM) examination for staging in patients with retinoblastoma should be limited to cases with advanced disease. However, there are limited data about the yield of sampling multiple sites with aspirations and biopsies and immunocytology. Our policy for BM examination included: 2 aspirates and 2 biopsies at the posterior iliac crest scheduled only for cases with postlaminar optic nerve extension (n=56), scleral invasion (n=10) or orbital (n=5) or metastatic disease at diagnosis (n=7) or at extraocular relapse (n=18). Immunocytology with the antibodies 3A7 or 3F8 for the ganglioside GD2 was performed. From 1/1994 to 3/2005, 277 newly diagnosed patients and 5 at extraocular relapse were included. BM invasion was not found in any of the 66 patients enucleated with disease confined to the globe, but was found in 11/27 of those with overt extraocular disease. There were 2/11 cases with at least 1 negative aspirate with positive biopsy and/or immunocytology for GD2. GD2 positivity was found in 9/9 cases. A more aggressive BM evaluation has a low yield in enucleated patients with high-risk features but disease limited to the globe. However, in cases with overt extraocular dissemination, the use of BM biopsy and immunocytology for GD2 allowed for the detection of cases that would have been missed by aspirations alone. GD2 was intensively expressed and it may also be used to monitor disease response and the presence of minimal residual disease.