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Results of Induction Chemotherapy in Children Older Than 1 Year With a Stage 4 Neuroblastoma Treated With the NB 97 French Society of Pediatric Oncology (SFOP) Protocol

From the Pediatrics Department, Statistics Department, Institut Gustave Roussy, Villejuif Cedex; Pediatrics Department, Institut Curie, Paris; Nuclear Medicine Department, Institut Claudius Regaud; Onco-hematology Unit, CHU Purpan, Toulouse; Onco-hematology Department, CHU Pellegrin, Bordeaux; Pediatrics Department, Centre Léon Bérard, Lyon; Pediatric Oncology Unit, CHU La Timone, Marseille; Pediatric Oncology Unit, CHU, Grenoble; Pediatric Oncology Unit, Hopital St Charles, Montpellier; Pediatric Oncology Unit, CHR, Hopital d'Enfants Brabois, Vandoeuvre, France

Address reprint requests to Dominique Valteau-Couanet, MD, PhD, Département de Pédiatrie, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: valteau{at}igr.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To test the metastatic response rate in stage 4 neuroblastoma, using dose-intensive induction chemotherapy in a multi-institutional setting.

PATIENTS AND METHODS: From 1998 to 1999, 47 consecutive children were treated according to N7 protocol. Children received cyclophosphamide 140 mg/kg, doxorubicin 75 mg/m², and vincristine 0.066 mg/kg (CAV) in cycles 1, 2, 4, and 6, and cisplatinum 200 mg/m² and etoposide 600 mg/m² (P/VP) in cycles 3, 5, and 7. The International Neuroblastoma Staging system was used with an emphasis on skeletal evaluation by 123-iodine-metaiodobenzylguanidine (MIBG) scintigraphy. A phase II study evaluating the metastasis complete response rate after induction chemotherapy was conducted in patients who had positive metastatic sites on MIBG scans at diagnosis.

RESULTS: Forty-six patients were assessable for toxicity. Hematologic toxicity was the main toxicity observed. Neutropenia was more frequent after CAV than after P/VP (P < .001). A higher rate of thrombocytopenia was observed after P/VP (P = .03). Forty patients with positive MIBG were assessable for metastatic response, and complete regression of metastases was achieved in 17 patients (ie, 43%; 95% CI, 27% to 59%). Of all 47 patients, 21 achieved complete metastatic response.

CONCLUSION: The N7 induction chemotherapy protocol was feasible in a multicentric setting. The observed metastasis complete response rate was similar to that obtained in our previous studies and significantly lower than that published in a previous series using the same regimen. In our hands, escalating doses of cyclophosphamide and prolonging conventional chemotherapy with the same drugs failed to improve the metastasis complete response rate.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The prognosis of stage 4 neuroblastoma in children older than 1 year remains poor despite strategies involving conventional chemotherapy, surgical resection of the primary tumor, and consolidation with myeloablative therapy followed by autologous stem-cell transplantation. A randomized study recently demonstrated an improvement in survival with myeloablative therapy followed by autologous bone marrow transplantation.¹ We previously reported that the combination of busulfan and melphalan is an efficient conditioning regimen that has a significant impact on disease-free survival. Several studies have underscored the prognostic significance of the metastasis status at the time of consolidation.^2-4 Kushner et al⁵ reported a very high complete response (CR) rate for metastases after the N6 induction protocol. Indeed, in a cohort of 24 patients, the rate of CR plus very good partial remissions was as high as 85%. A similar response rate was reported with the N7 protocol, though vincristine doses were decreased to reduce digestive toxicity.⁶

The French Society of Pediatric Oncology (SFOP) Neuroblastoma Study Group designed the NB 97 protocol aimed at improving the survival of children with stage 4 neuroblastoma. The primary goal of the study was to reproduce the excellent results published by the investigators at the Memorial Sloan-Kettering Cancer Center. This protocol combines the induction chemotherapy regimen in the N7 protocol followed by surgical excision of the primary tumor and consolidation with busulfan-melphalan with stem-cell transplantation (SCT) in patients who achieve a complete response of metastases or a partial response with fewer than three metastatic sites on metaiodobenzylguanidine scan of metastases. We report here the response of metastatic disease and the toxicity of the N7 induction regimen in 47 consecutive, previously untreated patients with stage 4 neuroblastoma who were older than 1 year.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Patients
From March 1998 to April 1999, 20 SFOP institutions participated in this study. Forty-seven unselected newly diagnosed stage 4 neuroblastoma cases, as defined by international criteria,⁷ were included in this study. This protocol was approved by the Kremlin-Bicêtre ethical committee. Patient characteristics are described in Table 1. All parents signed an informed consent form before the initiation of treatment.

Disease extension was assessed by 123-iodine-metaiodobenzylguanidine (MIBG) scintigraphy. Technetium-99m bone scans were performed in all patients with no MIBG uptake in the primary tumor. Biologic markers (vanillylmandelic acid, homovanillic acid, dopamine) were determined in all patients. Two biopsy specimens and at least four aspirates, performed in iliac bones, were obtained for morphologic evaluation of bone marrow. Diagnosis and staging were performed according to the revised International Neuroblastoma Diagnosis and Staging Criteria.⁷ NMYC amplification was evaluated according to published criteria.⁸

Treatment
The NB 97 protocol comprised seven courses of chemotherapy according to the N7 protocol (Table 2), with 21-day intervals between courses that were dependent on hematologic recovery as evidenced by a neutrophil count exceeding 0.5 x 10⁹/L and a platelet count of 100 x 10⁹/L. Courses 1, 2, 4, and 6 consisted of cyclophosphamide, doxorubicin, and vincristine (CAV). Cyclophosphamide (70 mg/kg/d) was infused over 6 hours in 250 mL of normal saline on days 1 and 2 (ie, 140 mg/kg per course), in conjunction with hydration (2,500 mL/m²/d) using D5 normal saline (1/3) with potassium chloride 2 g/L, magnesium sulfate 2 g/L, and calcium gluconate 2 g/L. Mesna was routinely used at a dose of 85 mg/kg/d in a continuous intravenous (IV) infusion. Furosemide was only administered if diuresis was inadequate. Doxorubicin (75 mg/m²) and vincristine (0.066 mg/kg with a maximal 2-mg dose per course) were administered in a continuous IV infusion for 72 hours, as of day 1. Courses 3, 5, and 7 consisted of cisplatin and etoposide (P/VP) with 2-hour IV infusions of etoposide (200 mg/m²/d) on days 1 to 3 (ie, 600 mg/m² per course), and 1-hour IV infusions of cisplatinum (50 mg/m²/d) on days 1 to 4 (ie, 200 mg/m²/course).

Consolidation with high-dose chemotherapy followed by peripheral SCT was performed in patients achieving a CR of metastases or with a partial remission of MIBG spots with not more than three persisting spots. The conditioning regimen was a combination of busulfan (600 mg/m²) and melphalan (140 mg/m²).³ Radiation therapy was delivered to the primary tumor site when MYCN amplification had been identified in the tumor cells. The results of this consolidation treatment will be reported elsewhere.

Supportive Care
Granulocyte colony-stimulating factor (G-CSF; Filgrastim; Amgen, Neuilly sur Seine Cedex, France) at a dose of 5 µg/kg/d was recommended after each course. When performed, it was started the day after the end of chemotherapy, and stopped when the neutrophil count was greater than 500/mm³. It was administered subcutaneously in outpatients, and IV when patients were hospitalized.

Platelets were transfused to maintain a platelet count above 20 x 10⁹/L or to control bleeding. RBCs were transfused when the hemoglobin level was below 7 g/dL. All blood products were irradiated. All patients received trimethoprim-sulfamethoxazole as prophylaxis against Pneumocystis carinii.

Evaluation of Tumor Response
Tumor response of primary tumor and metastases was evaluated after the third and seventh courses of the induction therapy with the tools used at diagnosis.

As response of metastatic lesions evaluated by MIBG scintigraphy was the main end point of the phase II study, the quality of these images and their interpretation were critical. MIBG scintigraphy had to be performed according to the published recommendation. A blind review of all MIBG scans was performed by a panel of six experts, in order to evaluate the quality of the scans and tumor response. The scoring system used in this study had been previously validated to evaluate response in multicentric studies.⁹ Briefly, the body was divided into seven sectors for osteomedullary lesions (skull, face, chest, spine, pelvis, legs, and arms). In each region, the lesions were scored as follows for extension of metastases: the segmental score was graded as 0, no site per segment; 1, one site per segment; 2, more than one site per segment. Intensity of the uptake was not taken into account. Soft tissues metastases were not evaluated with this scoring system.

A CR of metastases was defined as the disappearance of all metastatic spots on MIBG scans associated with the disappearance of cytologic and histologic bone marrow involvement. Technetium-99m bone scans were obtained in all patients who had negative MIBG scans.

Evaluation of Toxicity
The evaluation of toxicity included a physical examination; CBCs; and serum creatinine, liver enzyme, and bilirubin determinations. Complete clinical and biologic analyses were required before each course. Echocardiography and glomerular filtration rate determination were performed periodically. Audiometry was used to evaluate hearing loss according to Brock's grading.¹⁰ Toxicity was graded according to WHO criteria.¹¹

Statistical Methods
This protocol was designed as a phase II study since the main objective was to reproduce the metastasis response rate obtained after the N6 induction therapy.⁵ All study patients were treated with the same protocol and evaluated with the same tools, particularly the MIBG scan for the evaluation of response of metastases. Thus, only patients with a positive MIBG scan at diagnosis were included in this study.

According to the previously defined criteria, the expected metastases CR rate after the N6 induction chemotherapy regimen was 21 of 24 (82.5%; 95% CI, 68% to 95%).

A multistage procedure was used for this phase II study (three stages). The lowest stage below which treatment had to be considered insufficiently effective was the lowest limit of the 95% CI for the N6 data (ie, 70%). The highest success rate beyond which the study was to be stopped and the treatment considered effective was fixed at 80%. Forty-five patients (15 patients for each stage) had to be included in the phase II study to answer the question, with and ß errors of 5% and 10%, respectively.

	RESULTS

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Treatment Administration and Toxicity
Of the 47 children enrolled in the study, 46 were assessable for toxicity, since one patient received the courses in a different order. Of these 46 patients, 42 completed the seven courses of conventional chemotherapy. Three patients were withdrawn from the study after the fifth course because of progressive disease in one, severe hemorrhagic cystitis in one, and severe hematological toxicity in one, with repeated prolonged aplastic episodes. Protocol violations occurred in two patients, with replacement of cisplatin by carboplatin in the last P/VP course because of grade 1 and 2 hearing loss, respectively (one of these patients had received courses in a different order). Doses were adapted in only three courses in two patients. Half-doses of vincristine were administered during the second CAV course in a patient who had a paralytic ileus after the first one. Full vincristine doses were subsequently infused after the third and fourth CAV courses without unusual gastrointestinal toxicity. In a malnourished girl, the last two courses of CAV (courses 4 and 6) were administered in two-thirds doses because of severe hematologic and infectious complications.

The median duration of induction chemotherapy from day 1 of the first course to day 1 of the seventh course was 140 days (range, 121 to 188 days). The median interval between day 1 of the first course and day 1 of the fifth course was 90 days (range, 77 to 130 days), when the theoretical interval was 84 days. Nineteen patients received their fifth course with a delay greater than 10%. As presented in Table 3, hematologic toxicity was severe.

Extrahematologic toxicity was mainly gastrointestinal. Severe vomiting was more frequent after the P/VP courses, whereas mucositis occurred more often after the CAV courses and was severe (> grade 3) in 8%. Thirty-four patients (74%) received parenteral nutrition at least once for a median duration of 17 days (range, 3 to 104 days) because of anorexia or vomiting. Grade 1 hematuria was observed five times (3.7%), always after the fifth course, and resolved easily. The unique case of hemorrhagic cystitis required bladder catheterization and irrigation, and the severity of the condition led to the cessation of induction chemotherapy. One child developed a lysis syndrome with severe metabolite disorders and acute respiratory distress syndrome after the first course of CAV. He was admitted to the intensive care unit for a few days, during which symptoms resolved with symptomatic treatment, and chemotherapy was resumed as planned by the protocol. Hearing loss was evaluated in 21 patients. Grade 1, 2, and 3 toxicity was documented in six, one, and one patient, respectively. This evaluation was performed early, however, and hearing could worsen with time. The only case of neurologic toxicity was a paralytic ileus observed after the first course of CAV and resolved with symptomatic treatment. No toxicity-related deaths occurred during induction chemotherapy.

Tumor Response
After the central review by experts, 40 of 47 patients were considered to have metastatic spots on initial MIBG scan and to be assessable in the phase II study. Six patients had a negative MIBG scintigraphy; among them, two had been previously considered as positive, and one patient had poor-quality MIBG scans. Thirty-eight of these 40 patients had initial bone marrow involvement. Progression of metastatic disease was documented in one patient. During the time of evaluation, 17 of 40 patients had a complete remission of metastases, 15 had persistent metastases on MIBG scan with a negative bone marrow evaluation, and eight had metastases both on MIBG scan and on bone marrow evaluation. Bone marrow status and MIBG osteomedullary scores of these 40 patients at diagnosis and at the end of induction therapy are presented in Table 4. Patient 15's skull and face MIBG images are shown in Figure 1. It emphasizes the sensitivity of the MIBG scans in evaluating the status of the disease, which was particularly difficult to define in this patient.

View larger version (83K): [in this window] [in a new window]   Fig 1. The face and skull metaiodobenzylguanidine scans of patient 15 display an extensive metastatic disease at diagnosis (A), and the persistence of a less intense but significant spot of the skull after induction chemotherapy (B).

	DISCUSSION

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In a single-institution study of stage 4 neuroblastoma patients older than 1 year, Kushner et al reported a very high response rate with the N6 induction chemotherapy regimen.⁵ Indeed, 21 of 24 patients achieved a complete remission of metastatic lesions (87%; 95% CI, 68% to 95%), as evaluated by MIBG scintigraphy and extensive bone marrow evaluation after seven courses of conventional chemotherapy. However, the repeated use of vincristine-induced severe digestive toxicity that led the investigators to omit the D9 vincristine injection and to decrease the vincristine doses (0.022 mg/m²/d for 3 days instead of 0.033) in the CAV courses in their subsequent induction regimen (N7 protocol). A similar tumor response rate was reported with the N7 protocol.¹² The EBMT registry analysis emphasized that complete remission of metastases at the time of consolidation and SCT was of critical prognostic significance.² In that study, persistent skeletal lesions on technetium-99m scans and/or MIBG scans, and persistent bone marrow involvement before consolidation and SCT, were two independent adverse factors influencing event-free survival, with P values at .004 and .03, respectively. Similarly, in a cohort of 99 patients treated with the Lyon-Marseille-Curie East of France (LMCE3) strategy,⁴ patients who achieved a CR or very good partial remission after the four courses of the NB 87 SFOP protocol¹³ had significantly improved progression-free survival compared with those who had not (50% v 23%; P = .02). Moreover, a trend in favor of a better prognosis was observed in children in whom metastases were eradicated with a second or third line of conventional chemotherapy before consolidation (38% v 22%; P = .11). A similar trend was found in the Institut Gustave Roussy series of patients consolidated with high-dose chemotherapy and SCT, in which prognostic factors were analyzed.¹⁴

This prompted the SFOP Neuroblastoma Study Group to evaluate the metastasis response rate after the seven courses of the N7 protocol. A metastasis CR rate evaluated on MIBG scans was the main end point of this phase II study in patients with a positive MIBG scan at diagnosis, since MIBG is the most sensitive tool for the evaluation of response of metastases.¹⁵ Concomitant extensive bone marrow assessment was performed to confirm CR of metastases. Extensive bone marrow evaluation and MIBG scintigraphy have recently been reported as "prerequisites for accurate determination of disease status."¹⁵ The scoring system used in this study had been previously validated to evaluate response in multicentric studies.⁹ It is very close to that used in the study published by Matthay et al,¹⁶ correlating the early metastatic response on MIBG scintigraphy with overall response and event-free survival in metastatic neuroblastoma. The only difference was the inclusion of soft tissues metastases in the scoring system used by Matthay et al. The central review of the MIBG scans by a panel of six experts guarantees the quality of interpretation. The metastasis CR rate of 43%, (95% CI, 27% to 59%) is significantly lower than that published with the N6 protocol. Indeed, the upper limit of the CI is lower than the 68% lower limit of the N6 response CI. Patient characteristics in our study were similar to those in the N6 protocol and did not account for such a difference in the metastasis response rate. In the present study, MIBG scan was performed with MIBG, whereas iodine-131-metaiodobenzylguanidine was used to evaluate the 24 patients treated according to the N6 protocol. The greater sensitivity of MIBG may account for the different response rate observed in the present study.^15-17 Furthermore, we have also demonstrated that the N7 induction regimen was feasible in a multicentric study, since protocol violations were observed in only two patients, and dose-intensity was respected, with a median time from day 1 of course 1 to day 1 of course 7, of 140 days (range, 121 to 188 days) in our patients, compared with 152 days (range, 130 to 188 days) in the study of Kushner et al, which means that dose intensity was respected in these patients. Surgical excision of the primary tumor was performed after the fourth course in patients of the N6 protocol, whereas it was performed after the end of the induction chemotherapy in the NB 97 protocol. Thus, initial dose intensity may have been greater in N6 cohort. However, the response rate was not statistically different according to the induction chemotherapy duration, even taking into account only the first five courses (P = .76).

Finally, in our hands, the results obtained with this induction regimen were similar to those previously observed after the four courses in NB 87,¹³ using the same work-up for the evaluation of metastases. In that large series of 192 unselected patients, with shorter (four courses), less intensive chemotherapy, a 39% CR rate was observed for metastases. Whereas bone marrow CR was significantly better under NB 97 protocol (82%) than under NB 87 (66%; P = .04), skeletal MIBG response was not different: 43% and 38% in NB 97 and NB 87, respectively (P = .73). Alkylating agents, including cyclophosphamide, are effective against neuroblastoma.¹⁸ Moreover, a log-linear dose response has been demonstrated in tumor cells in vitro.¹⁹ In a retrospective analysis on the treatment of stage 4 neuroblastoma, Cheung et al demonstrated that the dose intensity was a strong predictor of clinical response, median survival and PFS.²⁰ We previously reported that high-dose cyclophosphamide (6 g/m²/course) combined with standard-dose etoposide (250 mg/m² per course) could be effective in 36% of patients with refractory neuroblastoma who had previously received lower doses of the same drugs.²¹ However, the early administration of high-dose cyclophosphamide (6 g/m²; CADE) instead of alternating cyclophosphamide-adriamycin-vincristine (CADO) with etoposide or cisplatinum failed to improve the metastasis response rate (34%) in the NB 92 protocol (Hartmann, personal communication, 1996). Thus, neither increased cyclophosphamide doses like those administered in NB 92 nor both higher cyclophosphamide doses and prolonging induction chemotherapy with the same drugs were found to improve the rate of response of metastatic lesions. However, prolonging induction with different drugs may help improve the CR rate. Indeed, we observed a 43% response rate in patients with refractory stage 4 neuroblastoma by adding carboplatin-etoposide even after induction therapy including cisplatinum.²² New drugs such CPT 11 have been proven effective against neuroblastoma in vitro and in animal models.^23-26 If their efficacy is confirmed by ongoing phase I/II studies, these drugs should be introduced in first-line regimens for high-risk neuroblastoma patients and could potentially improve the response rate via a different cytotoxic mechanism. The other way to increase survival of these patients is to improve the efficacy of drugs contained in high-dose chemotherapy regimen and to improve minimal residual disease treatment. Retinoic acid has been demonstrated to improve survival of high-risk patients¹ and various strategies combining retinoïc acid and monoclonal antibodies are currently evaluated in Europe and the United States. Complications due to toxicity caused by this induction regimen were manageable, and no toxicity-related death occurred. As described in the N6 and N7 protocols, grade 4 myelosuppression occurred very frequently with substantial blood product transfusion requirements.⁵ As previously observed with the NB 87 protocol¹³ and in other studies,²⁷ a strikingly high incidence of infectious and extra-hematological complications were observed after the first course of chemotherapy. These complications may be due to the poor clinical status of these children at diagnosis and the heavy tumor burden. In our experience, a significant decrease was observed in the duration of neutropenia after each course of CAV when G-CSF was administered, whereas such benefits were not so clear cut after CADO.²⁸ Similar findings were demonstrated by the analysis of 58 patients treated according to N6 and N7 protocols.¹² The use of G-CSF accelerated absolute neutrophil count recovery but did not reduce the incidence of febrile episodes and had a minimal impact on infection rates. However, the prolonged thrombocytopenia previously observed with the use of G-CSF was not observed in the present study. Most patients received parenteral nutrition because of erratic food consumption and a poor clinical status. Although doses were higher in the N7 protocol, extra-hematological toxicity was similar to that observed in NB 87. Although only one patient experienced severe hearing loss, a longer follow-up is warranted to better evaluate the incidence and severity of ototoxicity.

In conclusion, the acute toxicity induced by this intensive and prolonged induction regimen in the N7 protocol was manageable in this multicentric study. However, this protocol failed to improve the metastasis complete response rate in patients over one year of age with stage 4 neuroblastoma. Nevertheless, a longer follow-up is needed to evaluate the survival of these patients who subsequently received high-dose chemotherapy with busulfan-melphalan and SCT. This study highlights the need for common tools and standard terminology to evaluate the response of metastases in order to compare the efficacy of different therapeutic approaches.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank P. Boutard, A. Deville, V. Gandemer, O. Lejars, G. Leverger, P. Lutz, F. Méchinaud, M. Munzer, B. Pautard, E. Plouvier, N. Sirvent, V. Edeline, F. Giammarile, J. Lumbroso, S. Siles, and M. Wioland; Lorna Saint Ange, and Severine Faure.

	NOTES

 
Supported by a grant from Amgen, Neuilly sur Seine Cedex, France.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. 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: Children's Cancer Group. N Engl J Med 341:1165–1173, 1999[Abstract/Free Full Text]

2. Ladenstein R, Philip T, Lasset C, et al: Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: A report from the European Bone Marrow Transplantation Solid Tumor Registry. J Clin Oncol 16:953–965, 1998[Abstract]

3. Hartmann O, Valteau-Couanet D, Vassal G, et al: Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: A multivariate analysis in 218 patients treated in a single institution. Bone Marrow Transplant 23:789–795, 1999[CrossRef][Medline]

4. Frappaz D, Michon J, Coze C, et al: LMCE3 treatment strategy: Results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis. J Clin Oncol 18:468–476, 2000[Abstract/Free Full Text]

5. Kushner BH, LaQuaglia MP, Bonilla MA, et al: Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. J Clin Oncol 12:2607–2613, 1994[Abstract/Free Full Text]

6. Cheung NK, Kushner BH, LaQuaglia M, et al: N7: A novel multi-modality therapy of high risk neuroblastoma (NB) in children diagnosed over 1 year of age. Med Pediatr Oncol 36:227–230, 2001[CrossRef][Medline]

7. Brodeur GM, Pritchard 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[Abstract/Free Full Text]

8. Ambros IM, Benard J, Boavida M, et al: Quality assessment of genetic markers used for therapy stratification. J Clin Oncol 21:2077–2084, 2003[Abstract/Free Full Text]

9. Frappaz D, Bonneu A, Chauvot P, et al: Metaiodobenzylguanidine assessment of metastatic neuroblastoma: Observer dependency and chemosensitivity evaluation—The SFOP Group. Med Pediatr Oncol 34:237–241, 2000[CrossRef][Medline]

10. Brock PR, Bellman SC, Yeomans EC, et al: Cisplatin ototoxicity in children: A practical grading system. Med Pediatr Oncol 19:295–300, 1991[Medline]

11. World Health Organization.WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, 1979

12. Kushner BH, Heller G, Kramer K, et al: Granulocyte-colony stimulating factor and multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy in children with neuroblastoma. Cancer 89:2122–2130, 2000[CrossRef][Medline]

13. Coze C, Hartmann O, Michon J, et al: NB87 induction protocol for stage 4 neuroblastoma in children over 1 year of age: A report from the French Society of Pediatric Oncology. J Clin Oncol 15:3433–3440, 1997[Abstract/Free Full Text]

14. Hartmann O, Valteau-Couanet D, Benhamou E, et al: Stage IV neuroblastoma in patients over 1 year of age at diagnosis: Consolidation of poor responders with combined busulfan, cyclophosphamide and melphalan followed by in vitro mafosfamide-purged autologous bone marrow transplantation. Eur J Cancer 33:2126–2129, 1997

15. Kushner BH, Yeh SD, Kramer K, et al: Impact of metaiodobenzylguanidine scintigraphy on assessing response of high-risk neuroblastoma to dose-intensive induction chemotherapy. J Clin Oncol 21:1082–1086, 2003[Abstract/Free Full Text]

16. Matthay KK, Edeline V, Lumbroso J, et al: Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol 21:2486–2491, 2003[Abstract/Free Full Text]

17. Shapiro B, Gross MD: Radiochemistry, biochemistry, and kinetics of 131I-metaiodobenzylguanidine (MIBG) and 123I-MIBG: Clinical implications of the use of 123I-MIBG. Med Pediatr Oncol 15:170–177, 1987[Medline]

18. Carli M, Green AA, Hayes FA, et al: Therapeutic efficacy of single drugs for childhood neuroblastoma. Amsterdam, the Netherlands, Ecerpta Medica, 1982

19. Frei E III, Teicher BA, Holden SA, et al: Preclinical studies and clinical correlation of the effect of alkylating dose. Cancer Res 48:6417–6423, 1988[Abstract/Free Full Text]

20. Cheung NK, Heller G, Kushner BH, et al: Stage IV neuroblastoma more than 1 year of age at diagnosis: Major response to chemotherapy and survival durations correlated strongly with dose intensity. Prog Clin Biol Res 366:567–573, 1991[Medline]

21. Meresse V, Vassal G, Michon J, et al: Combined continuous infusion etoposide with high-dose cyclophosphamide for refractory neuroblastoma: A phase II study from the Societe Francaise d'Oncologie Pediatrique. J Clin Oncol 11:630–637, 1993[Abstract]

22. Frappaz D, Michon J, Hartmann O, et al: Etoposide and carboplatin in neuroblastoma: A French Society of Pediatric Oncology phase II study. J Clin Oncol 10:1592–1601, 1992[Abstract/Free Full Text]

23. Furman WL, Stewart CF, Poquette CA, et al: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17:1815–1824, 1999[Abstract/Free Full Text]

24. Vassal G, Terrier-Lacombe MJ, Bissery MC, et al: Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts. Br J Cancer 74:537–545, 1996[Medline]

25. Vassal G, Pondarre C, Cappelli C, et al: DNA-topoisomerase I: A new target for the treatment of neuroblastoma. Eur J Cancer 33:2011–2015, 1997

26. Vassal G, Pondarre C, Boland I, et al: Preclinical development of camptothecin derivatives and clinical trials in pediatric oncology. Biochimie 80:271–280, 1998[Medline]

27. De Bernardi B, Carli M, Casale F, et al: Standard-dose and high-dose peptichemio and cisplatin in children with disseminated poor-risk neuroblastoma: Two studies by the Italian Cooperative Group for Neuroblastoma. J Clin Oncol 10:1870–1878, 1992[Abstract]

28. Michon JM, Hartmann O, Bouffet E, et al: An open-label, multicentre, randomised phase 2 study of recombinant human granulocyte colony-stimulating factor (filgrastim) as an adjunct to combination chemotherapy in paediatric patients with metastatic neuroblastoma. Eur J Cancer 34:1063–1069, 1998

Submitted March 10, 2003; accepted October 15, 2004.

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				B. Tanno, C. Mancini, R. Vitali, M. Mancuso, H. P. McDowell, C. Dominici, and G. Raschella Down-Regulation of Insulin-Like Growth Factor I Receptor Activity by NVP-AEW541 Has an Antitumor Effect on Neuroblastoma Cells In vitro and In vivo. Clin. Cancer Res., November 15, 2006; 12(22): 6772 - 6780. [Abstract] [Full Text] [PDF]

				K. J. Yoon, J. Qi, J. S. Remack, K. G. Virga, M. J. Hatfield, P. M. Potter, R. E. Lee, and M. K. Danks Development of an etoposide prodrug for dual prodrug-enzyme antitumor therapy. Mol. Cancer Ther., June 1, 2006; 5(6): 1577 - 1584. [Abstract] [Full Text] [PDF]

				B. H. Kushner, K. Kramer, M. P. Laquaglia, S. Modak, K. Yataghene, and N.-K. V. Cheung In Reply: J. Clin. Oncol., September 1, 2005; 23(25): 6263 - 6263. [Full Text] [PDF]

				D. Valteau-Couanet Event-Free Survival of Patients With High-Risk Neuroblastoma Treated With an N6-Like Induction Treatment J. Clin. Oncol., September 1, 2005; 23(25): 6262 - 6263. [Full Text] [PDF]

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