Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study (original) (raw)
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Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1998
Although a high rate of spontaneous regression is observed in infants with stage D(S) neuroblastoma (NB), survival is not uniform. To determine the prognostic relevance of age at diagnosis, therapy, and tumor biology in infants with stage D(S) NB, we reviewed the Pediatric Oncology Group (POG) experience. A review of patients diagnosed with stage D(S) NB registered on POG protocols was performed. Survival according to age at diagnosis, treatment, and tumor biology was determined. Between 1987 and 1996, 110 infants with stage D(S) NB had an estimated 3-year survival rate of 85% +/- 4%; survival rate was 71% +/- 8% for infants 2 months of age or younger, and 68% +/- 12%, 44% +/- 33%, and 33% +/- 19% for patients with diploid, MYCN-amplified, and unfavorable histology tumors, respectively. Survival rates were similar for patients who received adjuvant chemotherapy versus those who did not (82% +/- 5% v 93% +/- 6%, respectively; P = .187). Furthermore, there was no statistical differenc...
Journal of Clinical Oncology, 2018
Purpose Infants with stage 4S neuroblastoma usually have favorable outcomes with observation or minimal chemotherapy. However, young infants with symptoms secondary to massive hepatomegaly or with unfavorable tumor biology are at high risk of death. Our aim was to improve outcomes for patients with symptomatic and/or unfavorable biology 4S neuroblastoma with a uniform treatment approach using a biology- and response-based algorithm. Patients and Methods The subset of patients with 4S disease with MYCN-not amplified tumors with impaired or impending organ dysfunction, or with unfavorable histology and/or diploid DNA index, were eligible. Patients were assigned to receive two, four, or eight cycles of chemotherapy on the basis of histology, diploid DNA index, chromosome arm 1p or 11q loss of heterozygosity (LOH) status, and symptoms. Results Forty-nine eligible patients were enrolled: 41 were symptomatic and 28 had unfavorable biology. Seventeen patients (symptomatic, favorable biolog...
British Journal of Cancer, 2000
Neuroblastoma (NB) is one of the most common solid tumours usually affecting children in the first years of life. Approximately 30% of patients are under 1 year at the time of diagnosis (Bernstein et al, 1992). In infants, the most frequent stages are stage 1 (35%) followed by stage 4-s (20%) and stage 4 (14%) (Castel Sanchez et al, 1997). When Evans et al (1971) proposed a staging system for neuroblastoma, they gave a clear definition of stage 4-s disease. Essentially observed in infants under 1 year-ofage, this special stage was defined as disease that would otherwise be stage 1 or 2, but with dissemination confined to one or more of the following sites: liver, skin or bone marrow (without radiological evidence of bone metastases at complete skeletal survey). The revised International Neuroblastoma Staging System (Brodeur et al, 1993) stipulated an upper limit at 10% of bone marrow involvement for stage 4-s disease. Thus, infants with stage 4 disease are patients with metastatic disease which does not correspond to the 4-s definition. Recently described genetic markers are being analysed extensively in children over 1 year with stage 4 neuroblastoma, but their prognostic significance remains unclear. The overriding objectives of the present study were to undertake an analysis of prognostic factors in an unselected cohort of infants with stage 4 neuroblastoma, and especially to assess the prognostic significance of MYCN amplification (MNA) and bone lesions in this population. In 1990, a national prospective study (NBL 90) was initiated that was to include all consecutive infants with metastatic NB diagnosed in the member institutions of the French Society of Pediatric Oncology (SFOP). We report herein the results of the SFOP-NBL 90 study. PATIENTS AND METHODS Patient population Between February 1990 and February 98, 21 member institutions of the SFOP participated in this study. All infants under 1 year-ofage with newly diagnosed stage 4 neuroblastoma were eligible for entry. Previous chemotherapy was an exclusion criterion, but primary surgery was not. Data concerning all infants were reviewed to verify their consistency with the revised International Neuroblastoma Staging System (INSS) and Response Criteria (INRC) for diagnosis, staging and assessment of response (Brodeur et al, 1993). A total of 55 infants were enrolled in the study. Four were ineligible, due to uncertainty regarding compliance and follow-up evaluation (n = 3), or to insufficient available data (n = 1). The present analysis therefore concerns 51 infants. It reports the outcome of infants as of November 1998, 9 months after inclusion of the last case.
Journal of Clinical Oncology, 2005
Purpose The goal of Pediatric Oncology Group 9243 was to improve outcomes for children with intermediate-risk neuroblastoma (NB). Patients and Methods Patients were assigned to treatments on the basis of age, tumor MYCN status, and tumor cell ploidy. Children in the less intensive arm A received cyclophosphamide/doxorubicin and surgery. Patients not in complete remission postoperatively were treated with cisplatin/etoposide, cyclophosphamide/doxorubicin, and additional surgery. Patients with less favorable features were assigned to arm B, which consisted of carboplatin, etoposide, ifosfamide, and surgery. Survival rates were determined using an intent-to-treat approach. Results For arm-A patients, the 6-year event-free survival (EFS) was 86% with an SE of 3%. For arm-B patients, the 6-year EFS was 46% with an SE of 7%. MYCN status was the only statistically significant prognostic variable. Among patients whose tumors were MYCN nonamplified, a trend toward improved EFS was seen in ch...
Localised and unresectable neuroblastoma in infants: Excellent outcome with primary chemotherapy
Medical and Pediatric Oncology, 2001
, 8 for the Neuroblastoma Study Group, Société Française d' Oncologie Pédiatrique Procedure. Infants with neuroblastoma (NB) were assessed according to INSS recommendations, including MIBG scan and extensive bone marrow staging to eliminate metastatic spread. Patients with unresectable tumour received chemotherapy, including two courses of carboplatin-etoposide (CE) and two of vincristinecyclophosphamide-doxorubicin (CAdO). Postoperative treatment was to be given only in infants with MYCN amplification. Between 1990 and 1994, 52 consecutive children were registered. Results. Among the 44 patients who received CE as a first course, the response rate was 66% and the primary could be removed in all children but one, who was in remission. The toxicity was mainly haematological and was always manageable. The 5 year overall survival (OS) and event-free survival (EFS) were 94 and 90 ± 8%, respectively, with a median follow-up of 48 months. The outcome of infants with no MYCN amplification was excellent; OS and EFS were, respectively, 97 and 94%.Conclusions. Chemotherapy allows surgical excision and excellent outcome in infants with localised and unresectable NB. Less intensive Chemotherapy should be investigated in such patients. Med.
1997
Background: Current staging systems for unresectable or metastatic neuroblastoma do not reliably predict responses to chemotherapy in infants under 1 year of age. Previous studies have indicated that the DNA content, or ploidy, of malignant neuroblasts can discriminate between good and poor responders in this group of patients, but the clinical utility of ploidy assessment has remained in question. Purpose: We tested, in a prospective nonrandomized study, the hypothesis that neuroblast ploidy could be used as the sole guide for treatment selection in infants with unresectable or metastatic tumors and could differentiate between those who would respond to our previous standard regimen and those who would benefit from an immediate switch to another therapy. Methods: One hundred seventy-seven infants were enrolled in this trial. Five of these infants were subsequently excluded (two ineligible, two lacking ploidy information, and one protocol violation); therefore, 172 patients were included in the study. One hundred thirty infants with hyperdiploid tumors (DNA index >1.0; better prognosis in retrospective studies) were treated with a well-tolerated regimen of cyclophosphamide (150 mg/m 2 per day orally or intravenously on days 1-7) and doxorubicin (35 mg/m 2 intravenously on day 8). Forty-two infants with diploid tumors (DNA index =1.0; worse prognosis in retrospective studies) received cisplatin (90 mg/m 2 intravenously on day 1) and teniposide (100 mg/ m 2 intravenously on day 3) after an initial course of cyclophosphamide plus doxorubicin. Statistical end points were response and long-term survival. In addition, we assessed within each ploidy group (i.e., patients with hyperdiploid tumors and those with diploid tumors) the prognostic significance of NMYC gene copy number, tumor stage, and other variables commonly measured in this disease. Results: Of the 127 assessable infants with hyperdiploid tumors, 115 (91%) had complete responses-85 after receiving five courses of cyclophosphamide plus doxorubicin and 30 after receiving further therapy including cisplatin plus teniposide. The 3-year survival estimate for the entire hyperdiploid group was 94% (95% confidence interval [CI] = 89%-98%). Nineteen (46%) of 41 assessable infants with diploid tumors were complete responders. The overall 3-year survival estimate for this group was 55% (95% CI = 39%-70%). Prognostic factor analysis indicated that NMYC gene amplification and an elevated serum lactate dehydrogenase level were statistically significant markers of higher risk disease within the diploid group (two-sided P values of .005 and .003, respectively). Only NMYC was predictive in the hyperdiploid group (P = .003). Conclusion: Use of a prognostic staging system based on tumor cell ploidy, augmented with the NMYC gene copy number and serum level of lactate dehydrogenase, would very likely improve the treatment of infants with unresectable or metastatic neuroblastoma. Patients with diploid tumors characterized by an amplified NMYC locus represent a particularly unfavorable risk group that may benefit from innovative new therapies
Journal of Clinical Oncology
PURPOSE The primary objective of the Children's Oncology Group study ANBL0531 (ClinicalTrials.gov identifier: NCT00499616) was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma using a biology-and response-based algorithm to assign treatment duration while maintaining a 3-year overall survival (OS) of 95% or more for the entire cohort. PATIENTS AND METHODS Children younger than age 12 years with intermediate-risk stage 2A/2B or stage 3 tumors with favorable histology; infants younger than age 365 days with stage 3, 4 or 4S disease; and toddlers from 365 to younger than 547 days with favorable histology, hyperdiploid stage 4, or unfavorable histology stage 3 tumors were eligible. Patients with MYCN-amplified tumors were excluded. Patients were assigned to initially receive two (group 2), four (group 3), or eight (group 4) cycles of chemotherapy with or without surgery on the basis of prognostic markers, including allelic status of chromosomes 1p and 11q; ultimate duration of therapy was determined by overall response. RESULTS Between 2007 and 2011, 404 evaluable patients were enrolled. Compared with legacy Children's Oncology Group studies, subsets of patients had a reduction in treatment. The 3-year event-free survival and OS rates were 83.2% (95% CI, 79.4% to 87.0%) and 94.9% (95% CI, 92.7% to 97.2%), respectively. Infants with stage 4 tumors with favorable biology (n = 61) had superior 3-year event-free survival compared with patients with one or more unfavorable biologic features (n = 47; 86.9% [95% CI, 78.3% to 95.4%] v 66.8% [95% CI, 53.1% to 80.6%]; P = .02), with a trend toward OS advantage (95.0% [95% CI, 89.5% to 100%] v 86.7% [95% CI, 76.6% to 96.7%], respectively; P = .08). OS for patients with localized disease was 100%. CONCLUSION Excellent survival was achieved with this treatment algorithm, with reduction of therapy for subsets of patients. More-effective treatment strategies still are needed for infants with unfavorable biology stage 4 disease.
Journal of Clinical Oncology, 2011
Purpose To evaluate the efficacy of low-dose chemotherapy in infants with nonmetastatic and unresectable neuroblastoma (NB) without MYCN amplification. Patients and Methods Infants with localized NB and no MYCN amplification were eligible in the SIOPEN Infant Neuroblastoma European Study 99.1 study. Primary tumor was deemed unresectable according to imaging defined risk factors. Diagnostic procedures and staging were carried out according to International Staging System recommendations. Children without threatening symptoms received low-dose cyclophosphamide (5 mg/kg/d × 5 days) and vincristine (0.05 mg/kg at day 1; CyV), repeated once to three times every 2 weeks until surgical excision could be safely performed. Children with either one threatening symptom or insufficient response to CyV were given carboplatin and etoposide (CaE), sometimes followed by vincristine, cyclophosphamide, and doxorubicin. No postoperative treatment was to be administered. Results Between December 1999 a...
Journal of Clinical Oncology, 2019
10051 Background: Infants with neuroblastoma typically have low-risk disease with excellent survival. Therapy has been de-intensified over time to minimize late effects, however the impact on survivors’ risk of late mortality, subsequent malignant neoplasms (SMN), and chronic health conditions (CHC) is unclear. Methods: We evaluated late mortality, SMNs and CHCs (graded according to CTCAE v4.03), overall and by diagnosis era, among 990 5-year neuroblastoma survivors diagnosed at < 1 year of age between 1970-1999. Cumulative mortality, standardized mortality ratios (SMR), and standardized incidence ratios (SIR) of SMNs were estimated using the National Death Index and SEER rates, respectively. Cox proportional hazards estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC, compared to 5,051 CCSS siblings. Results: Among survivors (48% female; median attained age: 24 years, range 6-46), there was increased treatment with surgery alone across the 1970s, 1980s and 199...