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Reduction From Seven to Five Cycles of Intensive Induction Chemotherapy in Children With High-Risk Neuroblastoma

From the Departments of Pediatrics and Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Brian H. Kushner, MD, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: kushnerb{at}mskcc.org

	ABSTRACT

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PURPOSE: We previously reported a high response rate with a dose-intensive chemotherapy regimen in 24 children with high-risk neuroblastoma (NB). We now describe similar results with changes that reduce toxicity (fewer cycles, less vincristine, use of granulocyte colony-stimulating factor).

PATIENTS AND METHODS: Eighty-seven consecutive newly diagnosed children with high-risk NB underwent induction that initially had seven cycles (57 patients) but was later limited to five (30 patients). Cycles 1, 2, 4, and 6 used cyclophosphamide (140 mg/kg)/doxorubicin (75 mg/m²)/vincristine (0.15 mg/kg in the first 27 patients, 0.067 mg/kg subsequently). Cycles 3, 5, and 7 used cisplatin (200 mg/m²)/etoposide (600 mg/m²). Tumor resection followed a minimum of three cycles. The induction was eventually modified to include anti-G_D2 immunotherapy after each of the last three cycles (38 patients).

RESULTS: Bone marrow disease resolved in 70 (91%) of 77 patients and was not detected pre- and postinduction in 10 patients. After cycle 3 or 4, 86% of primary tumors were more than 50% smaller. Postinduction metaiodobenzylguanidine scans showed normal radiotracer distribution in metastatic sites in 74 (87%) of 85 patients. Overall results were: 68 (79%) complete/very good partial responses (CR/VGPR); 14 (16%) partial responses (PR); three (3%) less than PR; one (1%) death from infection; and one patient not assessable for response. Five cycles yielded a CR/VGPR rate of 83%, compared with a 77% rate from seven cycles. Side effects were myelosuppression, mucositis, and hearing deficits; neurotoxicity was insignificant with the lower vincristine dosage. Four patients (each received seven cycles) developed myelodysplasia/leukemia.

CONCLUSION: Five cycles of this induction regimen, plus surgery, suffice to achieve CR/VGPR in 80% of children with high-risk NB.

	INTRODUCTION

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In 1994, we presented the rationale for, and described the antitumor and toxic effects of, a dose-intensive induction chemotherapy regimen used in 24 children with newly diagnosed high-risk neuroblastoma (NB) entered on the Memorial Sloan-Kettering Cancer Center (MSKCC) multimodality N6 protocol.¹ The induction included two putatively non–cross-resistant drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E); the aim, which was based on the Goldie-Coldman hypothesis,² was to achieve rapid cytoreduction in order to avert drug resistance. Dosages and methods of administration were derived from previous studies at MSKCC^3-5 and elsewhere.⁶ An emphasis on dose-intensity was adopted due to conclusions of a retrospective analysis of NB chemotherapy reports.⁷

Because of favorable effects against metastatic disease and primary tumors,^1,8 and in the absence of clearly better results with other induction regimens in use in the 1990s,^9-13 we have continued to use the same induction chemotherapy in successor MSKCC multimodality protocols (N7 and N8). Based on our study of 63 additional patients (for a total of 87), we now report that this chemotherapy regimen with two modifications—five (rather than seven) cycles and a lower vincristine dosage¹⁴—retains a high response rate and has less toxicity. Two additional changes to the overall induction program were the use of granulocyte colony-stimulating factor (G-CSF) to counter myelosuppression caused by the chemotherapy,¹⁵ and treatment with the anti-G_D2 3F8 monoclonal antibody (ie, immunotherapy)^16,17 following each of the last three cycles of chemotherapy.

	PATIENTS AND METHODS

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Eighty-seven consecutive newly diagnosed children (ie, preadolescents older than 12 months) with high-risk NB treated at MSKCC (Table 1) were the subjects of this report: 77 were formally enrolled onto the N6 (1990 through 1993; n = 27), N7 (1994 to September 1999; n = 31), or N8 (September 2000 to August 2003; n = 19) protocols, and 10 were treated according to but not formally enrolled onto the protocols (nine were diagnosed October 1999 to August 2000, ie, between completion of N7 and opening of N8, and the parents of one patient refused formal enrollment onto N8). Each protocol used the same induction,¹ with three eventual modifications: lower vincristine dosage,¹⁴ five (rather than seven) cycles of chemotherapy, and 5-day courses of immunotherapy with the anti-G_D2 3F8 monoclonal antibody following each of the last three cycles. Informed written consent for treatment was obtained in accord with institutional review board rules.

Cycles 1, 2, 4, and 6 consisted of CAV. Cyclophosphamide (70 mg/kg) was infused intravenously (IV) for 6 hours on days 1 and 2 (140 mg/kg/cycle), with hydration using D5/1/2 normal saline plus potassium chloride (KCl) 30 mEq/L and furosemide 10 mg/L at 150 mL/m²/h. Mesna was not routinely used in the first 27 patients, but in subsequent patients 24-hour IV infusions of mesna were started simultaneously with, and were dosed the same as, cyclophosphamide. Beginning on day 1, doxorubicin (75 mg/m²) and vincristine were given by 72-hour IV infusion. In the first 27 patients, vincristine was given at 0.1 mg/kg by 72-hour infusion, plus 0.05 mg/kg by bolus injection on day 9.¹ Neurotoxicity led to deletion of the bolus and use of 0.067 mg/kg in the 72-hour infusion (59 patients).

Cycles 3, 5, and 7 consisted of P/E, with 1-hour IV infusions of 50 mg/m² of cisplatin on days 1 to 4 (ie, 200 mg/m²/cycle), and 2-hour IV infusions of 200 mg/m² of etoposide on days 1 to 3 (ie, 600 mg/m²/cycle). Cisplatin was preceded by 2 hours of D5/1/2 normal saline with KCl 30 mEq/L, magnesium sulfate 500 mg/L, and Ca²⁺ gluconate 250 mg/L (hydration fluid) at 10 mL/kg/h, plus a 15-minute infusion of 20% mannitol at 8 g/m². Cisplatin was followed by hydration fluid at 7.5 mL/kg/h for 8 hours, plus 20% mannitol at 35 mL/m²/h for the first 6 hours.

3F8 was neither used during induction in the N6 protocol nor during induction in the initial version of the N7 protocol. However, N7 was amended to include immunotherapy with 3F8 after the last three cycles of chemotherapy (after cycles 5, 6, and 7, when the protocol included seven cycles of chemotherapy, and after cycles 3, 4, and 5, when the protocol was changed to include only five cycles of chemotherapy). Like the final version of N7, the N8 protocol was limited to five cycles of induction chemotherapy, with 3F8 used after cycles 3, 4, and 5. 3F8 (10 mg/m²/d) was administered for five days, by 30-to-90-minute IV infusion, as described.^16,17 The 10 patients who were not formally enrolled onto N6, N7, or N8 did not receive 3F8 during induction.

Surgery to resect the primary tumor was performed at diagnosis if the procedure would not jeopardize vital organs or entail a long delay in starting chemotherapy. Otherwise, tumor resection was attempted after a minimum of four cycles of chemotherapy in the seven-cycle group and three cycles in the five-cycle group. Radiotherapy was not part of induction.

Comprehensive evaluations to define disease status were done at diagnosis and after completion of induction. These evaluations included computed tomographic scans (CT) of the primary site and adjacent anatomic compartments, ^99mTc-bone scan, ¹³¹I- or ¹²³I-metaiodobenzylguanidine (MIBG) scan, urine catecholamine measurements, and bone marrow (BM) studies (histochemical examinations of bilateral biopsy specimens and aspirates from bilateral anterior and bilateral posterior iliac crests). During induction, CTs were repeated after cycle 3 or 4, and BM studies were repeated after cycle 1 or 2 and, if still showing NB, after each subsequent cycle until complete response (CR) was documented.

An independent team of data managers categorized response using the International Neuroblastoma Response Criteria¹⁸: CR, no evidence of disease; very good partial response (VGPR), volume of primary mass reduced by 90% to 99%, no evidence of distant disease (including normal MIBG) except for residual ^99mTc-bone changes, and catecholamines normal; partial response (PR), more than 50% decrease in measurable disease and 1 positive BM site; mixed response, more than 50% decrease of any lesion with less than 50% decrease in any other; no response, less than 50% decrease but less than 25% increase in any lesion; and progressive disease (PD), new lesion or more than 25% increase in an existing lesion.

	RESULTS

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Patient Characteristics
The 87 patients (Table 1) included 85 (98%) with stage 4 and two with MYCN-amplified stage 3 NB; patient ages ranged from 1 to 10.1 years (median, 3.3 years), including two patients 12 to 18 months old without MYCN amplification (which may be a prognostically favorable subset^19,20). Primary NB sites were abdomen in 79 patients (91%) and thorax (± abdomen) in seven patients (8%); no primary tumor was detected in one patient (1%). At diagnosis, BM metastases were histologically evident in 77 patients (89%) and skeletal metastases were present in 67 patients (77%). Amplified MYCN ( 10 copies) was documented in 33 patients (38%). The 30 patients in the five-cycle group and the 57 patients in the seven-cycle group had overlapping clinical profiles, though MYCN amplification was more common in the former (57% v 28%; Table 1). Thirty-eight patients (44%) received 3F8 during induction.

Responses
Table 2 summarizes patient responses. One patient in the five-cycle group was not assessable for response. She had multiple skeletal lytic lesions evident by CT (but not by scintigraphic studies), BM was not morphologically involved, and her primary (abdominal) tumor was resected at diagnosis; at the end of induction there was no evidence of disease, except for the skeletal abnormalities. Overall responses in the other 86 patients were: 68 (79%) CR/VGPR, 14 (16%) PR, three (3%) no response or PD, and one (1%) death from toxicity (infection), as reported.²¹ PR classifications were based on MIBG scans that were improved but still abnormal (n = 8), residual soft tissue disease (n = 2), minimal BM involvement (n = 3), or elevated urine catecholamine levels (n = 1). Five cycles of induction yielded a CR/VGPR rate of 83%, compared with 77% in the seven-cycle group.

Sixty-six of 67 patients with skeletal metastases had follow-up bone scans; these scans were normal in 47 patients (71%), improved in 17 patients (26%), falsely negative in one patient (2%) with PD in pterion (as evidenced by CT), and unchanged in one patient (2%). Bone scans in 20 patients with no skeletal metastases showed normal radiotracer uptake pre- and postinduction.

After induction, 85 patients underwent ¹³¹I-MIBG (n = 57) or ¹²³I-MIBG (n = 28) scans; radiotracer distribution in metastatic sites was normal in 74 patients (87%; Table 2). All 28 ¹²³I-MIBG scans were performed on patients in the five-cycle group; only two scans showed radiotracer uptake indicative of NB.

Primary tumors (16 adrenal, two small midline retroperitoneal) were resected at diagnosis in 18 patients (including only two of the 30 patients in the five-cycle group); one patient had no evident primary mass, one patient died before a follow-up CT could be done, and four patients had no baseline CT. In the 63 other patients, CT after cycle 3 or 4 showed no CRs, VGPR in 19 (30%), PR in 35 (56%), and less than PR in nine (14%). Among the total of 68 patients who had primary tumors present at the start of chemotherapy, one patient died as a result of infection²¹ before surgical resection could be attempted. Sixty-six (99%) of the other 67 patients had all visible tumors resected after cycles 3 (n = 24), 4 (n = 33), 5 (n = 7), 6 (n = 1), or 7 (n = 1) and had no MIBG uptake in the primary site. Complete (100%) necrosis was seen in three masses (one resected after cycle 3, two resected after cycle 4), and only ganglioneuroma was seen in one mass (resected after cycle 3). No nephrectomies occurred with the delayed surgical procedures.

Toxicity
The sole toxic death occurred after cycle 2 and resulted from fungal meningitis.²¹ This same patient experienced tumor lysis syndrome during cycle 1.

The strongly myelosuppressive effects of this induction were previously reported.¹⁵ Each cycle of CAV caused severe neutropenia (< 200/uL) by median day 8 that typically lasted at least 7 days. The incidence of severe neutropenia increased from 45% with the first cycle, to 67% with the second cycle, and to 80% with the third cycle of P/E. G-CSF hastened neutrophil recovery but had no other beneficial effects and may have contributed to prolonged thrombocytopenia in cycles 5, 6, and 7.

Mucositis and hearing deficits were the only common nonhematologic toxicities. Mucositis, to some degree, occurred with at least one cycle of CAV in most patients but was not associated with P/E. Audiograms revealed Common Toxicity Criteria grade 3 or 4 ototoxicity in 31 (63%) of 49 patients tested after seven cycles of chemotherapy, and in seven (30%) of 23 patients tested after five cycles.

With the lower vincristine dosing (see Patients and Methods), no patient had ileus, dysesthesias, or jaw pain. Significant urinary tract toxicity was limited to transient elevated serum creatinine (> 3 mg/mL) in two patients consequent to dehydration after a cycle of P/E. Liver and cardiac function remained intact.

3F8 toxicities were manageable pain and occasional hives, as previously reported.^16,17 These insignificant problems allowed outpatient treatment.

BM disorders emerged postinduction in four patients. One patient presented with leukocytosis 12 months after the start of induction, and was found to have acute lymphocytic leukemia with a chromosomal t(4;11)(q21;q23) translocation. One patient had acute myeloid leukemia with deletion of chromosome 11q23 discovered in a routine surveillance BM examination 15 months after the start of induction. Two patients presented with myelodysplasia (thrombocytopenia, chromosome 5q and 7q deletions) at 27 months and at 50 months, respectively, from diagnosis. All four of these patients received seven cycles of chemotherapy and multiple cycles of 3F8; the patient with myelodysplasia at 50 months also received targeted radiotherapy with ¹³¹I-3F8.¹⁴

	DISCUSSION

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The experience with testing our dose-intensive induction regimen in an additional 63 children with previously untreated high-risk NB confirmed the favorable antitumor activity noted in the first 24 patients.¹ The myelosuppressive effects and mucositis continued to be manageable, and the neurotoxicity seen in the initial cohort of patients was absent when the vincristine dosage was reduced.

Rapid responses were evident, regardless of whether 3F8 was included in the induction. Thus, after three to five cycles of chemotherapy in 80% of patients, BM was in CR and primary tumors were resectable. In an interim analysis, we saw no antitumor benefit from cycles 6 and 7. This finding, plus the prolonged thrombocytopenia after cycles 6 and 7 that sometimes caused delays in starting consolidative therapy,¹⁵ led us to conclude that using seven cycles might adversely affect long-term outcome. We then limited induction to five cycles, which remains our current practice (with no concomitant use of 3F8).

Toxicity concerns also favored reducing the number of induction cycles, with the obvious benefits of fewer hospitalizations related to pancytopenia and decreased risks of early or late noxious effects on key organs such as the heart and kidneys. As expected, grade 3 or 4 ototoxicity was less common with five cycles of induction. Finally, five rather than seven cycles might eventuate in a lower incidence of secondary myelodysplasia/leukemia.²²

In the 1970s and 1980s, MSKCC treatments for high-risk NB evolved with the aim of improving remission rates; the trend was toward greater dose-intensity.^3-5,7 Subsequently, the induction remained constant in its principal components because it reliably achieved a minimal disease state in 80% of patients. Reducing the number of cycles from seven to five had no adverse effect on the good response rate. Longer follow-up will show whether the change affects event-free survival, though this ultimate goal might also depend on postinduction therapy. Our findings should be considered in the context of the better long-term outcome conferred by myeloablative consolidation, as demonstrated by the Children's Cancer Group.¹² Fewer induction cycles should decrease toxicity risks with myeloablative treatments.

We do not know why the MSKCC results are better than those reported in a preliminary communication from the French Society of Pediatric Oncology (39% CR/VGPR of metastatic disease in 41 patients), which used seven cycles of this induction followed by surgery after the seventh cycle.²³ Single institutional studies often give better results than multi-institutional studies. Differences between the French and MSKCC studies include earlier surgery and the use of ¹³¹I-MIBG scintigraphy in the MSKCC cohort treated with seven cycles, though the more sensitive ¹²³I-MIBG was used in the subsequent MSKCC cohort treated with five cycles (Table 2). Six cycles of this induction are currently being tested in the Children's Oncology Group A3973 trial for high-risk NB. That trial will provide additional data on this regimen in a larger patient population that can be compared with the high response rate observed at MSKCC.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank the independent team of data managers, especially Karen Danis and Yvonne Podzikowski, for their meticulous review of the data.

	NOTES

 
Supported in part by grants from the National Cancer Institute (CA61017, CA72868), Bethesda, MD; Hope St Kids, Alexandria, VA; the Justin Zahn Fund, New York, NY; the Katie's Find A Cure Fund, New York, NY; and the Robert Steel Foundation, New York, NY.

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

	REFERENCES

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1. 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]

2. Goldie JH, Coldman AJ: The somatic mutation theory of drug resistance: The "Goldie-Coldman" hypothesis revisited, in Devita VT, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology, PPO Updates, Vol. 3, Philadelphia, PA, Lippincott, 1989, pp 1-12

3. Helson L, Helson C, Peterson RF, et al: A rationale for the treatment of metastatic neuroblastoma. J Natl Cancer Inst 57:727-729, 1976

4. Kushner BH, Helson L: Coordinated use of sequentially escalated cyclophosphamide and cell-cycle-specific chemotherapy (N4SE protocol) for advanced neuroblastoma: Experience with 100 patients. J Clin Oncol 5:1746-1751, 1987[Abstract/Free Full Text]

5. Kushner BH, O'Reilly RJ, LaQuaglia M, et al: Dose-intensive use of cyclophosphamide in ablation of neuroblastoma. Cancer 66:1095-1100, 1990[CrossRef][Medline]

6. Philip T, Ghalie R, Pinkerton R, et al: A phase II study of high-dose cisplatin and VP-16 in neuroblastoma: A report from the Societe Francaise d'Oncologie Pediatrique. J Clin Oncol 5:941-950, 1987[Abstract/Free Full Text]

7. Cheung NV, Heller G: Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. J Clin Oncol 9:1050-1058, 1991[Abstract]

8. LaQuaglia MP, Kushner BH, Heller G, et al: Stage 4 neuroblastoma diagnosed at more than 1 year of age: Gross total resection and clinical outcome. J Pediatr Surg 29:1162-1166, 1994[CrossRef][Medline]

9. Pearson ADJ, Craft AW, Pinkerton CR, et al: High-dose rapid schedule chemotherapy for disseminated neuroblastoma. Eur J Cancer 28A:1654-1659, 1992

10. 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]

11. Keneko M, Nishihira H, Mugishima H, et al: Stratification of treatment of stage 4 neuroblastoma patients based on N-myc amplification status. Med Pediatr Oncol 31:1-7, 1998[CrossRef][Medline]

12. 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[Abstract/Free Full Text]

13. De Bernardi B, Nicolas B, Boni L, et al: Disseminated neuroblastoma in children older than one year at diagnosis: Comparable results with three consecutive high-dose protocols adopted by the Italian Co-operative Group for Neuroblastoma. J Clin Oncol 21:1592-1601, 2003[Abstract/Free Full Text]

14. Cheung N-KV, 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]

15. 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]

16. Cheung N-KV, Kushner BH, Yeh SDJ, et al: 3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: A phase II study. Int J Oncol 12:1299-1306, 1998[Medline]

17. Cheung N-KV, Kushner BH, Cheung I, 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[Abstract/Free Full Text]

18. 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]

19. George R, London WB, Maris JM, et al: Age as a continuous variable in predicting outcome for neuroblastoma patients with metastatic disease: Impact of tumor biological features. Proc Am Soc Clin Oncol 22:799, 2003 (abstr 3213)

20. Schmidt ML, Lal A, Seeger R, et al: Favorable prognosis for patients ages 12-18 months with stage 4 MYCN-nonamplified neuroblastoma. Proc Am Soc Clin Oncol 22:800, 2003 (abstr 3214)

21. Kushner BH, LaQuaglia MP, Modak S, et al: Tumor lysis syndrome, neuroblastoma, and correlation between serum lactate dehydrogenase levels and MYCN amplification. Med Pediatr Oncol 41:80-82, 2003[CrossRef][Medline]

22. Kushner BH, Cheung N-KV, Kramer K, et al: Neuroblastoma and treatment-related myelodysplasia/leukemia: The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 16:3880-3889, 1998[Abstract/Free Full Text]

23. Valteau-Couanet D, Michon J, Perel Y, et al: Results of NB 97 SFOP protocol in children >1 year with a stage 4 neuroblastoma. Presented at the conference on Advances in Neuroblastoma Research, Paris, France, June 17-19, 2002

Submitted February 13, 2004; accepted September 17, 2004.

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