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Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3549-3557 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.143 Consolidation Treatment With Chimeric Anti-GD2-Antibody ch14.18 in Children Older Than 1 Year With Metastatic NeuroblastomaFrom the Children's Hospital, University of Cologne, Cologne; Institute for Medical Biostatistics, Epidemiology, and Informatics, University of Mainz, Mainz; Children's Hospital, Medical School of Hanover, Hanover; Children's Hospital, University of Tübingen, Tübingen, Germany; St Jude Children's Research Hospital, Memphis, TN Address reprint requests to Thorsten Simon, MD, Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Joseph-Stelzmann-Straße 9, 50924 Köln, Germany; e-mail: thorsten.simon{at}uk-koeln.de
PURPOSE: Antibody treatment is considered tolerable and potentially effective in the therapy of neuroblastoma. We have analyzed stage 4 neuroblastoma patients older than 1 year who underwent consolidation treatment with the chimeric monoclonal anti-GD2-antibody ch14.18. PATIENTS AND METHODS: Stage 4 patients older than 1 year who completed initial treatment without event were eligible. ch14.18 was scheduled in a dose of 20 mg/m2/d during 5 days in six cycles every 2 months. Patients who did not receive ch14.18 served as controls. RESULTS: Of 334 assessable patients, 166 received ch14.18, 99 received a 12-month low-dose maintenance chemotherapy (MT) instead, and 69 had no additional treatment. During 695 ch14.18 cycles, fever (55% of cycles), abnormal C-reactive protein without infection (35%), cough (24%), rash (22%), and pain (16%) were the main side effects. Univariate analysis found similar event-free survival (EFS) for the three groups (3-year EFS, 46.5% ± 4.1%, 44.4% ± 4.9%, 37.1% ± 5.9% for patients treated with antibody ch14.18, MT, and no additional therapy, respectively; log-rank test, P = .314). For overall survival (OS), ch14.18 treatment (3-year OS, 68.5% ± 3.9%) was superior to MT (3-year OS, 56.6% ± 5.0%) or no additional therapy (3-year OS, 46.8% ± 6.2%; log-rank test, P = .018). Separate univariate analysis of patients with autologous stem-cell transplantation revealed no difference between patients with ch14.18 treatment and no additional consolidation. Multivariate analysis failed to demonstrate an advantage of antibody treatment for EFS and OS. CONCLUSION: Consolidation treatment of stage 4 neuroblastoma with ch14.18 was associated with considerable but manageable side effects. Compared with oral maintenance chemotherapy and no consolidation treatment, ch14.18 had no clear impact on the outcome of patients.
Despite progress during the last decades, the prognosis of metastatic neuroblastoma is still poor.1 Therefore, new treatment approaches for these children are welcome. Because monoclonal antibodies (MABs) directed against GD2 have become available, their use in neuroblastoma was considered a potentially effective addition to chemotherapy, surgery, and radiotherapy. The ganglioside GD2 is a glycosphingolipid that is highly expressed on neuroblastoma cells as well as on solid tumor cells (eg, melanoma, brain tumors, small-cell lung carcinoma), brain cells, and peripheral nerves.2-5 First clinical results with the murine anti-GD2-antibodies 3F8, 14.G2a, and the chimeric human/mouse antibody ch14.18 in neuroblastoma were encouraging.6-12 Therefore, the chimeric human/mouse antibody ch14.18 was used in the consolidation treatment of high-risk neuroblastoma in a nonrandomized trial including pilot patients in trial NB90 and all high-risk patients in trial NB97. For this report, we retrospectively analyzed the MAB ch14.18 cycles given during the trials NB90 and NB97 for toxicity and concomitant drug use. For outcome analysis, we compared the event-free survival (EFS) and overall survival (OS) rates of patients who received MAB ch14.18 with those of patients who underwent a 12-month maintenance therapy under the NB90 regimen instead, or who had no additional treatment after initial chemotherapy.
A total of 334 patients of the Cooperative German Neuroblastoma Trials NB90 and NB97 met the following inclusion criteria: stage 4 neuroblastoma diagnosed according to the International Neuroblastoma Staging System criteria13; age at diagnosis older than 364 days; diagnosis between September 1, 1989, and January 1, 2002; treatment according to the NB90/NB97 neuroblastoma trials; no event (relapse, progression, death, secondary malignant disease) during induction chemotherapy; no combination of NB90 maintenance treatment and ch14.18 antibody; no additional treatment with 13 cis-retinoic acid; and informed parents' consent for treatment according to trial NB90 or NB97, for the antibody treatment, and for the collection of data. Induction chemotherapy consisted of four N1 and four N2 cycles (NB90) or of three N5 and three N6 cycles (NB97; Fig 1; for details see references 14,15). Radiotherapy was administered for bone metastases and nonprogressing residual primary tumors in NB90. In the NB97 trial, radiotherapy was reserved for patients with residual metaiodobenzylguanidine-positive primary tumors only. After induction chemotherapy, patients received either maintenance chemotherapy or myeloablative high-dose chemotherapy with autologous stem-cell transplantation (ASCT) designated by the local oncologist (NB90) or by random assignment (NB97). Patients not treated with ASCT received maintenance therapy consisting of alternating D1 and D2 cycles each month for 1 year in the NB90 trial, or four N7 cycles within 3 months after induction chemotherapy in the NB97 trial.
After initial treatment, all NB97 trial patients and some NB90 ASCT pilot patients were chosen for treatment with the anti-GD2 antibody ch14.18. MAB ch14.18 was produced by BioInvent International AB (Lund, Sweden), placed in vials by the Rentschler pharmaceutical company (Langheim, Germany), and certified by the Paul-Ehrlich-Institute (Langen, Germany) for investigational use within a national trial. The Paul-Ehrlich-Institute is the German equivalent to the US Food and Drug Administration and is responsible for plasma and protein products. The status of an investigational new drug was not approached for MAB ch14.18. All hospitals collaborating in the German neuroblastoma trials were qualified to provide antibody treatment when their local ethics committee had approved the antibody treatment. MAB ch14.18 was stored in two centers (Tubingen and Cologne, Germany). It was made available to the trial centers after induction chemotherapy documentation of the individual patient was complete. The MAB ch14.18 treatment regimen consisted of an infusion of 20 mg/m2/d during 8 to 12 hours on 5 subsequent days. This cycle was repeated every 2 months for a total of six cycles. Concomitant intravenous morphine starting at a dose of 1.0 mg/kg/d was strongly recommended for pain control. Other analgesic drugs (tramadol, paracetamol, dipyrone) were allowed. The as-treated outcome analysis was based on the hypothesis that immunotherapy with ch14.18 and oral maintenance chemotherapy in NB90 share the concept of a prolonged consolidation treatment of potential minimal residual disease. Therefore, we compared the survival data of the group treated with MAB ch14.18 with those of the group receiving the maintenance therapy in the NB90 trial instead, and with the group receiving no additional treatment after initial therapy. Three groups were defined: (1) +AB –MT, which included patients with MAB ch14.18 antibody treatment but no D1/D2 maintenance treatment according to NB90. This group included patients pretreated with ASCT (NB90 or NB97) or four N7 maintenance chemotherapy cycles (NB97); (2) –AB +MT, which included patients with no ch14.18 antibody treatment but D1/D2 maintenance treatment according to the NB90 trial; and (3) –AB –MT, which included patients with no antibody ch14.18 and no NB90 D1/D2 maintenance treatment. This last group included NB90-97 ASCT patients and NB97 N7 maintenance patients. Survival curves were calculated according to Kaplan-Meier. EFS was calculated as the time from diagnosis to event or last examination if the patient had no event. Relapse, progression, death, and secondary malignant disease were regarded as events. OS was calculated as the time from diagnosis to death or last examination, if the patient survived. In the latter case, the survival time was assigned as censored. A closed test procedure according to Marcus et al16 was used for confirmatory analysis of the EFS and OS time of the three treatment groups (+AB –MT, –AB +MT, and –AB –MT). A 5% multiple significance level was chosen. Comparison of either EFS or OS among two or three groups simultaneously was done using the log-rank test. The evaluation of all other partition hypotheses (eg, OS among three groups and simultaneously EFS between +AB –MT and –AB –MT) was performed using the global Bonferroni test. All other analyses are regarded as explorative, particularly all analyses of subgroups.
Multivariate Cox regression was applied to analyze the prognostic value of these risk factors with respect to EFS and OS. The following potential explanatory prognostic factors were considered: lactate dehydrogenase (LDH) at diagnosis (abnormal v normal as reference), MYCN (amplified v not amplified as reference), age at diagnosis (continuous), protocol (NB90 v NB97 as reference), treatment group (–AB +MT, –AB –MT v +AB –MT as reference), and ASCT (yes v no as reference). Models were built using a stepwise variable selection procedure recommended by Collett.17 In the first step, all parameters were tested in a univariate Cox regression calculation one at a time. In the second step, all parameters that appeared to be important in step 1 were fitted together in a multivariate Cox regression model. In the third step, all parameters that were not important in step 1 were added to the parameters that were important in step 2, one at a time. The likelihood-ratio test P value for inclusion was P
Patient Characteristics and Treatment The characteristics of the 334 patients are listed in Table 1. The median age at initial diagnosis was 3.2 years (range, 1.0 to 20.6 years). There was no significant age difference among the treatment groups (Kruskal-Wallis test, +AB –MT v –AB +MT v –AB –MT; P = .260).
Fifty-seven patients were given the NB90 ASCT initial treatment, 120 patients were given the NB90 chemotherapy without ASCT, 88 patients were given the NB97 ASCT treatment, and 69 patients were given the NB97 chemotherapy without ASCT. After this initial treatment, 267 patients achieved complete remission (CR) or very good partial remission (VGPR), 60 patients achieved partial remission (PR), and seven patients had mixed remission or stable disease. There was no significant difference in remission status after initial treatment among the three treatment groups (  2 test, +AB –MT v –AB +MT v –AB –MT; P = .560) A total of 164 patients received the MAB ch14.18 and 168 did not; 25 of the patients with MAB ch14.18 therapy were enrolled onto the NB90 trial and 141 patients with MAB ch14.18 therapy were enrolled onto the NB97 trial. Two additional patients were included in the +AB –MT group for outcome analysis but were never treated with MAB ch14.18 because they experienced a relapse before the delayed start of the first antibody cycle. Sixteen patients received one cycle, 15 patients received two cycles, 26 patients received three cycles, seven patients received four cycles, 17 patients received five cycles, 82 patients received six cycles, and one patient received more than six cycles. MAB ch14.18 treatment was discontinued in six children because their parents believed the side effects were unacceptable, although the consulting physician recommended continuation of MAB ch14.18 treatment. Antibody treatment was stopped for medical reasons because of capillary leak syndrome in two patients and infectious hepatitis not related to antibody treatment in one patient. The median dose of antibody ch14.18 was 20 mg/m2/d (range, 12 to 40 mg/m2/d). Because of tolerance during preparation, two patients had less than 18 mg/m2/d (< 90% of the scheduled dose). No patient had a dose reduction because of adverse effects. Two patients received more than 22 mg/m2/d (> 110% of the scheduled dose). The median time interval between antibody cycles or the preceding chemotherapy to first antibody cycle was 65.5 days (range, 39.5 to 343 days; 60 days planned). From a total of 738 antibody cycles, data from 695 (94.2%) administered to 151 patients could be evaluated for use of concomitant drugs. Analgesic drugs (morphine, tramadol, paracetamol, dipyrone, or combinations of these drugs) were given during 605 antibody cycles in 138 patients. Antihistamine drugs (clemastine or dimethindene) were given during 547 cycles in 129 patients. Glucocorticoids (prednisolone, methylprednisolone, or dexamethasone) were given during 175 cycles in 62 patients.
Toxicities
Five patients needed oxygen supply during antibody therapy but did not develop other symptoms of capillary leakage. We observed capillary leak syndromes defined by ascites, pulmonary symptoms, oxygen requirement, and weight gain in two children who developed infection during antibody infusion. One child had a febrile convulsion induced by antibody-related high fever. Ocular symptoms were observed in eight patients. These data are included in an article on MAB ch14.18-related ocular symptoms.18
Outcome
By univariate analysis of EFS, we found similar rates for patients treated with MAB ch14.18 (+AB –MT 3-year EFS, 46.5% ± 4.1%) compared with the other two groups (–AB +MT 3-year EFS, 44.4% ± 4.9%; –AB –MT 3-year EFS, 37.1% ± 5.9%; Fig 2A). The log-rank test for EFS resulted in the following P values: +AB –MT versus –AB +MT, P = .464; +AB –MT versus –AB –MT, P = .108; –AB +MT versus –AB –MT, P = .514; and +AB –MT versus –AB +MT versus –AB –MT, P = .314. Censoring of toxic deaths and secondary malignant diseases gave similar results (+AB –MT v –AB +MT v –AB –MT, P = .461).
The antibody-treated group had an advantage when OS was considered (+AB –MT 3-year OS, 68.5% ± 3.9%) compared with the other patients (–AB +MT 3-year OS, 56.6% ± 5.0% and –AB –MT 3-year OS, 46.8% ± 6.2%; Fig 2B). The log-rank test for OS resulted in the following P values: +AB –MT versus –AB +MT, P = .029; +AB –MT versus –AB –MT, P = .009; –AB +MT versus –AB –MT, P = .823; and +AB –MT versus –AB +MT versus –AB –MT, P = .018. Exclusion of death as a result of toxicity or secondary malignant disease gave similar results (+AB –MT v –AB +MT v –AB –MT, P = .032). To exclude the influence of different relapse management over the years, we compared patients diagnosed in the first, second, third, or fourth time quarter separately for each treatment group. We found no difference in the effect of the date of diagnosis within the groups for EFS (+AB –MT, P = .112; –AB +MT, P = .799; –AB –MT, P = .169 [all are log-rank test]) or for OS (+AB –MT, P = .157, –AB +MT, P = .850; –AB –MT, P = .352 [all are log-rank test]). EFS analysis of patient subgroups defined by MYCN or LDH at diagnosis comparing the +AB –MT, –AB +MT, and –AB –MT groups could not demonstrate an advantage for patients treated with MAB ch14.18 (Table 4). By restricting the analysis to patients achieving either CR or VGPR, or those achieving PR after initial treatment, we could not demonstrate a better EFS after MAB ch14.18 antibody treatment. In a separate analysis of patients who underwent ASCT during initial treatment, we found no difference in EFS between +AB –MT patients (n = 103) and –AB –MT patients (n = 42; P = .317). By definition, there were no patients undergoing ASCT in the –AB +MT group. For patients who did not undergo ASCT during initial treatment, there was no EFS difference between the three treatment groups (n = 189; log-rank test, P = .161).
OS analysis of subgroups demonstrated an advantage of antibody treatment for patients with either elevated LDH at diagnosis or patients in CR or VGPR after induction therapy (Table 4). No differences in EFS (P = .146) or OS (P = .142) were found between patients receiving glucocorticoids for the control of adverse effects during one or more ch14.18 cycle and patients who were not treated with glucocorticoids during any ch14.18 cycle. Confirmatory analysis by a closed test procedure according to Marcus et al16 echoed the results of the univariate analysis. No benefit of MAB ch14.18 antibody treatment was seen regarding EFS. MAB ch14.18 treatment (+AB –MT) was significantly superior to –AB –MT in overall survival. The comparison between antibody treatment (+AB –MT) and the 12-month maintenance therapy (–AB +MT) regarding OS failed to prove significance in the closed test procedure. Stepwise multivariate Cox regression analysis was applied. For EFS, step 1 resulted in the following P values: LDH, P = .011; MYCN, P = .010; age, P = .023; ASCT, P = .023; protocol, P = .870; and treatment group, P = .315. In step 2, the factors LDH, MYCN, age, and ASCT remained in the model as important factors (P values are listed in Table 5). Addition of either protocol (P = .214) or treatment (P = .424) to the four factors of step 2 did not change the model. For OS, step 1 resulted in the following P values: LDH, P = .003; MYCN, P = .000; age, P = .041; ASCT, P = .161; protocol, P = .065; and treatment group, P = .017. In step 2, the factors LDH (P = .017), MYCN (P = .000), age (P = .002), and treatment group (P = .069) remained in the model. Addition of protocol (P = .153) did not change the model, but addition of ASCT (P = .073) resulted in exclusion of treatment group (P = .267). Hazard ratios, 95% CIs, and P values of the likelihood ratio are listed in Table 5.
This large study reports adverse effects and outcome of neuroblastoma patients treated with the chimeric anti-GD2-antibody ch14.18 after conventional chemotherapy or ASCT. In general, toxicity was considerable but manageable. A similar pattern of adverse effects was observed during 20 cycles of MAB ch14.18 cycles by Yu et al.10 Despite analgesic prophylaxis, 33% of the patients complained of bearable pain during one or more cycles. This rate is lower than that reported by the Children's Cancer Group.19 With an increasing number of antibody cycles the pain rate decreases, suggesting a decrease of available pain receptors. Elevated C-reactive protein and fever were observed frequently and are always a challenge in the differential diagnosis of infection. Skin rash and pruritus also were common adverse effects and were considered tolerable. In none of these children were additional antibody cycles abandoned by the physicians because of these symptoms. Capillary leak syndrome has been observed previously after combination treatment with granulocyte macrophage colony-stimulating factor and ch14.18.19 In our trial without comedication of granulocyte macrophage colony-stimulating factor, five patients developed signs of capillary leakage. Two patients developed severe pulmonary symptoms as a result of a concomitant infection during antibody treatment. On the basis of the hypothesis that treatment with 12 months of immunotherapy with MAB ch14.18 is similarly effective as 12 months of oral maintenance treatment, we compared the patients' outcome of both groups. Patients who received no consolidation treatment (–AB –MT) were included in the analysis as a third group. By univariate analysis and confirmatory statistics, we found no EFS advantage of MAB ch14.18 treatment (+AB –MT) compared with the 12-month NB90 D1/D2 maintenance treatment (–AB +MT), or compared with no treatment after induction therapy (–AB –MT). For overall survival, MAB ch14.18 treatment was shown to be superior in a global analysis and for patients with either elevated LDH at diagnosis, or with CR or VGPR after initial treatment (Table 3). However, the univariate outcome analysis of this nonrandomized trial has limitations. Because of the retrospective design, there is a considerable imbalance among the three treatment groups: most +AB –MT patients had the NB97 induction treatment. A considerable number of them underwent ASCT. In the –AB +MT group, all patients received the NB90 induction treatment without ASCT. Radiation therapy policy but not surgical approach was different between the protocols NB90 and NB97. Given that most of +AB –MT patients were treated in NB97, their follow-up time is shorter compared with those of the –AB +MT and –AB –MT groups. Multivariate analysis revealed no clear benefit for patients treated with MAB ch14.18. For EFS and for OS, only the factors higher age, abnormal LDH at diagnosis, MYCN amplification, and no ASCT were found to be associated with a higher risk of event and/or death. Obviously, intensive treatment of the NB90 and NB97 trial was not able to neutralize these well-known risk factors. Of note, MYCN results were missing in 70 patients. These patients had to be excluded in all calculation steps containing MYCN as a potential prognostic factor. The difference between univariate and multivariate analysis regarding OS may indicate some long-term benefit from antibody treatment after disease recurrence. A better relapse management in patients diagnosed in the middle or late 1990s is the less likely explanation because no difference in outcome after relapse was demonstrated between patients diagnosed earlier or later during the trial within each treatment group. Of course, it cannot be excluded that the antibody group had a more stringent relapse management than the other groups. In addition, the lower incidence of bone marrow relapses in the +AB –MT group might contribute to a prolonged survival time and increased ratio. The pattern of other recurrence sites did not show significant differences among the treatment groups. Treatment with MAB ch14.18 did not increase the frequency of CNS involvement during recurrence, even though the antibody cannot pass the intact blood brain barrier. Interestingly, a similar trend for prolonged survival without improvement of the EFS time and rates was observed in a small trial for stage 4 neuroblastoma with randomized use of another immunotherapeutic agent (interferon beta).20 Our analysis did not assess other factors that might influence the clinical effect of anti-GD2-antibodies (eg, GD2 synthase mRNA levels,21 development of anti-idiotypes,22 or transient presence of human antimouse antibodies23). Other authors published data from small series of anti-GD2-antibody treatment in neuroblastoma. In 11 highly selected stage 4 patients, Klingebiel et al12 reported an EFS of 70% ± 15% after ASCT followed by ch14.18 treatment. This overlaps with the 3-year EFS of 52.4% ± 5.2% for this subgroup found in our trial. The difference is due to the small patient number in the pilot trial. Handgretinger at al9 published the results of six stage 4 neuroblastoma patients treated with ch14.18 in first partial remission. In this pilot trial, the MAB ch14.18 was given in a higher dose of 30 to 50 mg/m2/day. They observed five relapse-free survivors (83%) during a follow-up between 3 and 24 months. In contrast, the result of our analysis does not confirm a better response of patients in PR to ch14.18. The question remains whether the higher dose or shorter intervals might improve the effectiveness of MAB ch14.18. In a phase I Children's Cancer Group study, six of 14 patients (43%) survived relapse free after treatment with MAB ch14.18 in first remission during a follow-up between 25 and 50 months.19 After MAB 3F8 treatment of 19 neuroblastoma patients who responded incompletely to the initial treatment, Kushner et al24 observed eight patients (42%) surviving progression free during a follow-up of 3 to 75 months. However, these results should be interpreted with caution because five of these survivors were treated with cis-retinoic acid concomitantly, which has been shown to improve survival in stage 4 neuroblastoma25 and might interfere with a potential effect of MAB 3F8. MAB 3F8 consolidation treatment during first-line treatment of 21 stage 4 neuroblastoma patients achieved an EFS of 38%.23 Cheung at al11 reported one CR (6%) for 80+ months after MAB 3F8 treatment. Yu et al10 reported one PR and four mixed responses in a series of nine neuroblastoma patients who experienced treatment failure after at least one initial regimen of therapy. In conclusion, this retrospective analysis demonstrated a considerable but manageable toxicity of MAB ch14.18 treatment. Univariate analysis found an advantage of ch14.18 treatment for overall survival but not for EFS in stage 4 neuroblastoma. Multivariate analysis did not confirm such a benefit. Because of these results, the MAB ch14.18 treatment is not continued in the current German neuroblastoma trial.
The authors indicated no potential conflicts of interest.
We thank M. Schwab, H. Christiansen, and R. Spitz for molecular genetic analysis.
The neuroblastoma trials were supported by Deutsche Krebshilfe. The antibody production was sponsored by Deutsche Leukämieforschungshilfe and Merck. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Spix C, Aareleid T, Stiller C, et al: Survival of children with neuroblastoma: Time trends and regional differences in Europe, 1987-1992. Eur J Cancer 37:722-729, 2001
2. Mujoo K, Cheresh DA, Yang HM, et al: Disialoganglioside GD2 on human neuroblastoma cells: Target antigen for monoclonal antibody-mediated cytolysis and suppression of tumor growth. Cancer Res 47:1098-1104, 1987 3. Schulz G, Cheresh DA, Varki NM, et al: Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Res 44:5914-5920, 1984[Medline]
4. Mujoo K, Kipps TJ, Yang HM, et al: Functional properties and effect on growth suppression of human neuroblastoma tumors by isotype switch variants of monoclonal antiganglioside GD2 antibody 14.18. Cancer Res 49:2857-2861, 1989 5. Kramer K, Gerald WL, Kushner BH, et al: Disaloganglioside GD2 loss following monoclonal antibody therapy is rare in neuroblastoma. Med Pediatr Oncol 36:194-196, 2001[CrossRef][Medline]
6. Cheung NK, Lazarus H, Miraldi FD, et al: Ganglioside GD2 specific monoclonal antibody 3F8: A phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol 5:1430-1440, 1987 7. Handgretinger R, Baader P, Dopfer R, et al: A phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2a. Cancer Immunol Immunother 35:199-204, 1992[CrossRef][Medline] 8. Murray JL, Cunningham JE, Brewer H, et al: Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors. J Clin Oncol 12:184-193, 1994[Abstract] 9. Handgretinger R, Anderson K, Lang P, et al: A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma. Eur J Cancer 31A:261-267, 1995 10. Yu AL, Uttenreuther-Fischer MM, Huang CS, et al: Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol 16:2169-2180, 1998[Abstract] 11. Cheung NK, Kushner BH, Yeh SD, et al: 3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: A phase II study. Int J Oncol 12:1299-1306, 1998[Medline] 12. Klingebiel T, Bader P, Bares R, et al: Treatment of neuroblastoma stage 4 with 131I-meta-iodo-benzylguanidine, high-dose chemotherapy and immunotherapy: A pilot study. Eur J Cancer 34:1398-1402, 1998
13. Brodeur GM, Prichard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466-1477, 1993 14. Berthold F, Hero B: Neuroblastoma: Current drug therapy recommendations as part of the total treatment approach. Drugs 59:1261-1277, 2000[CrossRef][Medline] 15. Berthold F, Hero B, Kremens B, et al: Long-term results and risk profiles of patients in five consecutive trials (1979-1997) in stage 4 neuroblastoma over 1 year of age. Cancer Lett 197:11-17, 2003[CrossRef][Medline]
16. Marcus R, Peritz E, Gabriel K: On closed testing procedures with special reference to ordered analysis of variance. Biometrika 63:655-660, 1976 17. Collett D: Strategy for Model Selection, Modelling Survival Data in Medical Research. London, United Kingdom, Chapman and Hall, 1994, pp 78-83 18. Kremens B, Hero B, Esser J, et al: Ocular symptoms in children treated with human-mouse chimeric anti-GD2 mAb ch14.18 for neuroblastoma. Cancer Immunol Immunother 51:107-110, 2002[CrossRef][Medline]
19. Ozkaynak MF, Sondel PM, Krailo MD, et al: Phase I study of chimeric human/murine anti-ganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: A Children's Cancer Group Study. J Clin Oncol 18:4077-4085, 2000 20. Berthold F, Burdach S, Kremens B, et al: The role of chemotherapy in the treatment of children with neuroblastoma stage IV: The GPO (German Pediatric Oncology Society) experience. Klin Padiatr 202:262-269, 1990[Medline]
21. Cheung IY, Lo Piccolo MS, Kushner BH, et al: Early molecular response of marrow disease to biologic therapy is highly prognostic in neuroblastoma. J Clin Oncol 21:3853-3858, 2003
22. Cheung NK, Guo HF, Heller G, et al: Induction of Ab3 and Ab3' antibody was associated with long-term survival after anti-G(D2) antibody therapy of stage 4 neuroblastoma. Clin Cancer Res 6:2653-2660, 2000
23. Cheung NK, Kushner BH, Cheung IY, et al: Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 16:3053-3060, 1998
24. Kushner BH, Kramer K, Cheung NK: Phase II trial of the anti-G(D2) monoclonal antibody 3F8 and granulocyte-macrophage colony-stimulating factor for neuroblastoma. J Clin Oncol 19:4189-4194, 2001
25. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341:1165-1173, 1999 Submitted September 21, 2003; accepted June 7, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.05; for exclusion, the value was P > .10. 
