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Oral Etoposide for Refractory and Relapsed Neuroblastoma

From the Department of Pediatrics, 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; email kushnerb{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To describe the efficacy of oral etoposide against resistant stage 4 neuroblastoma.

PATIENTS AND METHODS: Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide 50 mg/m² taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Extent-of-disease studies included imaging with 131-iodine-metaiodobenzylguanidine and extensive bone marrow (BM) sampling.

RESULTS: Oral etoposide was used in 20 children between the ages of 2 and 11 years (median, 6 years). Prior treatment included high doses of alkylating agents and a median of 4.5 cycles of etoposide-containing chemotherapy, with cumulative etoposide doses of 1,800 mg/m² to 3,935 mg/m² (median, 2,300 mg/m²). Oral etoposide produced antineuroblastoma effects in four of four children with disease refractory to intensive induction treatment; sampling variability could account for resolution (n = 3) or reduction (n = 1) of BM involvement, but improvement in other markers also occurred. Antineuroblastoma effects were also evident in five of five children with asymptomatic relapses after a long chemotherapy-free interval: BM disease resolved and all other disease markers significantly improved in two patients, and disease markers improved or stabilized in three patients on treatment for more than 6 months. In these nine patients, extramedullary toxicity was absent, neutropenia did not occur, transfusional support was not needed, and preliminary data suggested little immunosuppression (phytohemagglutinin responses). Oral etoposide was ineffective in all (11 of 11) patients with rapidly growing tumor masses.

CONCLUSION: Given the absence of toxicity to major organs, the minimal myelosuppression or immunosuppression, and the antineoplastic activity in patients with low tumor burdens after high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
STANDARD TREATMENT for poor-risk neuroblastoma includes induction with five or more cycles of chemotherapy, followed by consolidation using myeloablative therapy.¹ The induction regimens involve pulses of alkylating agents (cyclophosphamide or ifosfamide), platinum compounds (cisplatin or carboplatin), and/or topoisomerase II inhibitors (doxorubicin or etoposide). Treatment with high doses of these agents has become widely accepted because increased dose-intensity correlates with improved response rates² and because advances in supportive care have reduced the risks of strongly myelosuppressive treatments. For disease that is resistant to intensive induction, further use of high-dose therapy is unlikely to be beneficial. For disease that recurs after myeloablative consolidation, high-dose salvage therapy may not be feasible because of poor bone marrow (BM) reserve and may not be justified in view of its morbidity in the absence of a realistic chance for cure.^1,3

One treatment option in these difficult clinical settings is chronic oral administration of low-dose etoposide. In phase I and II studies in adults, this use of etoposide entailed modest toxicity and occasionally produced regressions of resistant malignancies.⁴ The reported experience with this treatment in children is limited.^5-11 The sole detailed report of a pediatric phase II study presented "disappointing" results, except for brain tumors.¹¹ Other reports also noted promising results in small numbers of children with brain tumors,^6,9,10 and one preliminary communication described antineuroblastoma effects.⁸ We now present results supporting a possible role for low-dose oral etoposide after high-dose chemotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide (VePesid; Bristol-Meyers Squibb Co, Princeton, NJ) 50 mg/m² taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Quality-of-life issues were major considerations in the choice of therapy. Informed consent for treatment was obtained in accordance with hospital policy.

Extent-of-disease studies included computed tomography, ⁹⁹Tc bone scan, ¹³¹I-metaiodo-benzylguanidine (MIBG) scan, and quantitation of urine catecholamines (vanillylmandelic acid and homovanillic acid). BM (posterior and anterior iliac crests) was evaluated by histochemical examinations of two to four biopsy specimens and smears from four aspirates, and by immunostaining of aspirates using anti-G_D2 monoclonal antibodies.¹²

Tumor response after one to three cycles of treatment was categorized using international criteria¹³: complete response, no evidence of disease; very good partial response, primary tumor decreased by 90% to 99%, no metastatic disease (except for residual bone changes), and catecholamines normal; partial response, all measurable disease decreased by more than 50% and no more than one positive BM site; mixed response, more than 50% reduction of any measurable lesion with less than 50% reduction in any other; stable disease, less than 50% reduction but less than 25% increase in any existing lesion; progressive disease, any new lesion or increase of any measurable lesion by more than 25%.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Twenty children 2 to 11 years of age (median, 6 years) were treated with oral etoposide. They had stage 4 neuroblastoma in relapse after, or refractory to, treatment with high doses of the major antineuroblastoma agents, including cyclophosphamide 4,200 mg/m², ifosfamide 10 gm/m², cisplatin 200 mg/m², and/or carboplatin 1,000 mg/m² per cycle. Before starting oral etoposide, the patients had received three to eight cycles (median, 4.5 cycles) of chemotherapy that included etoposide dosed at 150 mg/m² to 600 mg/m²; the cumulative etoposide dosages were 1,800 mg/m² to 3,935 mg/m² (median, 2,300 mg/m²).

Responses
Oral etoposide produced antineuroblastoma effects in four of four children whose disease was refractory to intensive induction treatment (but was no longer causing clinical symptoms) and who had never entered a complete remission (Table 1). All four had histologic evidence of neuroblastoma in BM, although less than 10 of 10⁶ BM cells were G_D2-positive. In patient no. 1, BM studies before treatment with oral etoposide showed neuroblastoma in aspirates from three of four sites and in biopsy specimens from two of four sites; posttreatment studies showed a single focus of neuroblastoma in one (anterior iliac crest) of four biopsies and a single clump of suspicious cells in one of four aspirates. Catecholamines were minimally elevated before treatment and were in the normal range after treatment, while MIBG scans were normal before and after treatment. Before treatment with oral etoposide, patients no. 2, 3, and 4 had long-standing BM involvement as demonstrated by repeated testing since diagnosis. At the start of treatment with oral etoposide, all three had neuroblastoma in only one biopsy specimen. Posttreatment studies in all three patients showed no neuroblastoma. Sampling variability may account for the findings, but improvement in catecholamine levels and in scintigraphic findings in patients no. 2 and 4 and the absence of neuroblastoma in two consecutive extensive BM evaluations (after the second and third cycles of oral etoposide, with four aspirates and four biopsies) in patient no. 3 provide evidence supporting an antineuroblastoma effect.

Oral etoposide also produced antineuroblastoma effects in five of five children with disease that recurred asymptomatically after a long chemotherapy-free interval (Table 1). The best responses were in patients no. 6 and 7 who had normalization or near-normalization of all disease markers (note: pre- and posttreatment bone scans were normal in patient no. 6), including reductions from 814 and 15,550 G_D2-positive cells per 10⁶ BM cells, respectively, to less than 10 G_D2-positive cells. In patient no. 5, catecholamines decreased steadily, but MIBG scans remained abnormal. Patient no. 8 was started on oral etoposide for progressive disease, as shown by BM tests, new lesions in bone and MIBG scans, and a rise in urine catecholamine levels. She was monitored by monthly measurement of urine catecholamines; the levels remained high but stable through 9 months. BM findings in this patient were also consistent with stable disease as evidenced by detection of, respectively, 2,750 and 2,250 G_D2-positive cells per 10⁶ BM cells before and after treatment with multiple cycles of oral etoposide. Patient no. 9 had near-normalization of scintigraphic findings and a decrease in catecholamines (but neuroblastoma was still present in one of six BM specimens).

Progressive disease continued in 11 of 11 patients treated palliatively with oral etoposide for far-advanced, rapidly growing disease. These patients had all previously undergone an autologous BM transplant for consolidation of remission (and four had undergone a second BM transplant). The sites of bulky tumors included the retroperitoneum, liver, chest wall, cranial bones, lungs, and posterior mediastinum. Follow-up BM tests were carried out in only one of these 11 patients (in view of unequivocal disease progression by physical examination). In the one patient, BM tests at the start of oral etoposide showed that one of six specimens had extensive involvement, whereas posttreatment specimens showed no neuroblastoma; this change could be attributed to sampling variability.

Side Effects
Treatment entailed no significant myelosuppression except in one patient treated palliatively for relapsed, rapidly progressing disease after a second BM transplant. Otherwise, neutropenia did not occur and transfusional support was not needed. There was no evident toxicity to major organs, such as the liver, heart, lungs, or kidneys. Two patients had mild alopecia. One patient had intermittent mild mucositis. No patient had nausea or emesis. In five of five patients studied (including three who had recently received two or more cycles of high-dose cyclophosphamide), immune function was not significantly impaired as measured by responses to phytohemagglutinin (Table 2); hence, there was no need for prophylaxis against Pneumocystis carinii.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Etoposide is a podophyllotoxin derivative with markedly schedule-dependent cytotoxic activity. Preclinical and clinical studies show greater efficacy with prolonged exposure.⁴ This finding is attributable to etoposide's principal mechanism of cytotoxic action: etoposide interferes with DNA function by binding to topoisomerase II, but the act is reversed and DNA repair and cell survival ensue if ambient concentrations of the drug decrease below a certain threshold level. Pharmacokinetic studies confirm the feasibility of achieving cytotoxic plasma levels of etoposide for prolonged periods of time through the oral route.^7,11,14 With a 14- to 21-day cycle, a 50- to 60-mg/m² daily dose is well tolerated, but a 75- to 80-mg/m² daily dose may entail excessive diarrhea, mucositis, or myelosuppression.^5,7 Using divided daily doses may reduce peak plasma levels and thereby limit myelosuppression and other potential toxicities.^7,14

We documented antineuroblastoma effects of low-dose oral etoposide in patients with early relapses after a long chemotherapy-free interval and in patients with disease that was refractory to intensive induction therapy. In the latter patients, the persistence of disease 9 to 13 months from diagnosis and the long interval between prior chemotherapy and the start of oral etoposide made it unlikely that improvements in disease parameters after oral etoposide were the result of a delayed response to the earlier therapy. Toxicity was negligible, allowing patients to engage in normal age-appropriate activities such as school (a welcome change from the frequent hospitalizations for febrile neutropenia and other common side effects of intensive induction chemotherapy). Oral etoposide did not alleviate disease-related symptoms in patients with rapidly growing tumor masses, but neither did it exacerbate the clinical problems. Oral etoposide may be a reasonable treatment option for an asymptomatic, unresectable, relatively stable bulky tumor mass resistant to high-dose chemotherapy, but we cannot cite our experience to support that possibility because none of our patients had that specific clinical problem.

A recent trend in the treatment of stage 4 neuroblastoma has been to augment chemotherapy dosing.¹ Indeed, dose-intensive chemotherapy has improved remission rates of stage 4 neuroblastoma,¹⁵ and myeloablative chemoradiotherapy has prolonged the survival of stage 4 patients.^16,17 However, minimal residual disease resistant to these high-dose, short-term treatments remains an obstacle to major increases in cure rates. Our experience points to a potential role for oral etoposide in helping to overcome this problem. Support for this possibility comes from a preliminary report on the use of oral etoposide for the treatment of posttransplant neuroblastoma recurrences, with responses in 12 (40%) of 30 patients who received 150 to 200 mg/m²/d on 3 consecutive days in 3 consecutive weeks each month.⁸ The only other published results of low-dose oral etoposide for neuroblastoma are from three phase I and II studies, each of which used oral etoposide at 50 to 75 mg/m²/d for 21 days.^5,7,11 These three studies included 6, 10, and 15 assessable neuroblastoma patients, respectively, and responses were noted. However, a breakdown of results by patient subgroup, ie, primary refractory disease, late relapse, and rapidly growing bulky disease, was not provided.

Promising approaches to achieve the elimination of metastatic neuroblastoma that has survived high-dose chemotherapy include induction of terminal differentiation with the vitamin A derivative cis-retinoic acid¹⁸ and immunotherapy with monoclonal antibodies.¹⁹ The optimal setting for the use of these treatments is microscopic disease. For patients who still have evidence of BM involvement by neuroblastoma at the end of induction, oral etoposide offers a treatment option that may further reduce tumor burden. This effect would enhance the likelihood of success with subsequent use of cis-retinoic acid and/or monoclonal antibodies. For patients who achieve a complete remission but who likely harbor occult disease, oral etoposide could be readily incorporated into a treatment program with cis-retinoic acid and monoclonal antibodies.

These three treatments are relatively innocuous and could be used in tandem or in combination for a long period of time. Low-dose oral etoposide has limited myelosuppressive effects and, in preliminary findings, limited immunosuppressive effects. These features suggest that low-dose oral etoposide would not undermine the efficacy of immune-based treatments. In addition, its lack of extramedullary toxicity makes it well suited for use after intensive chemoradiotherapy. One caveat is the leukemogenicity of etoposide, a particular concern after high-dose chemotherapy regimens that may carry combined alkylator-related and topoisomerase II–related leukemic risks of more than 5%.²⁰ Despite reports of isolated cases of secondary leukemia after prolonged use of oral etoposide, with^11,21 or without²² prior exposure to other leukemogenic agents, the leukemogenic potency of oral etoposide is not known. A weak leukemogenic effect can be extrapolated from (1) the less than 1% incidence of leukemia/myelodysplasia seen with long-term use of low-dose intravenous etoposide given either as a single agent or with nonleukemogenic chemotherapeutic agents, such as vinblastine or methotrexate²³; and (2) the data from a nationwide monitoring program that suggest that factors other than cumulative epipodophyllotoxin dose may be critical in the development of topoisomerase II–related secondary leukemia.²⁴

In conclusion, given the absence of toxicity to major organs, the minimal hematologic suppression, and the antitumor activity in patients with disease resistant to high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.

	ACKNOWLEDGMENTS

 
Supported in part by National Cancer Institute grants no. CA61017 and CA72868, the Robert Steel Foundation, New York, NY, the Katie's Find A Cure Fund, New York, NY, and the Justin Zahn Fund, New York, NY

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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4. Hainsworth JD, Greco FA: Etoposide: Twenty years later. Ann Oncol6:325-341, 1995[Free Full Text]

5. Davidson A, Lewis I, Pearson ADJ, et al: 21-day schedule oral etoposide in children: A feasibility study. Eur J Cancer 29A:2223-2225, 1993

6. Chamberlain MC: Recurrent brainstem gliomas treated with oral VP-16. J Neurooncol15:133-139, 1993[Medline]

7. Mathew P, Ribeiro RC, Sonnichsen D, et al: Phase I study of oral etoposide in children with refractory solid tumors. J Clin Oncol12:1452-1457, 1994[Abstract]

8. Cappelli C, Hartmann O, Pein F, et al: Efficacy of palliative oral etoposide in metastatic neuroblastoma relapsing after high-dose chemotherapy. Med Pediatr Oncol25:319, 1995 (abstr)

9. Chamberlain MC, Grafe MR: Recurrent chiasmatic-hypothalamic glioma treated with oral etoposide. J Clin Oncol13:2072-2076, 1995[Abstract/Free Full Text]

10. Ashley DM, Meier L, Kerby T, et al: Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol14:1922-1927, 1996[Abstract/Free Full Text]

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15. 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 Oncol12:2607-2613, 1994[Abstract/Free Full Text]

16. Stram DO, Matthay KK, O'Leary M, et al: Consolidation chemoradiotherapy and autologous bone marrow transplantation vs continued chemotherapy for metastatic neuroblastoma: A report of two concurrent Children's Cancer Group studies. J Clin Oncol14:2417-2426, 1996[Abstract]

17. Matthay KK, Harris R, Reynolds CP, et al: Improved event-free survival (efs) for autologous bone marrow transplantation (abmt) vs chemotherapy in neuroblastoma: A phase III randomized Children's Cancer Group (CCG) study. Proc Am Soc Clin Oncol 17:525a, 1998 (abstr 2018)

18. Villablanca JG, Khan AA, Avramis VI, et al: Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation. J Clin Oncol134:894-901, 1995

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20. Kushner BH, Cheung NKV, Kramer K, et al: Neuroblastoma and treatment-related myelodysplasia/leukemia: The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol16:3880-3889, 1998[Abstract/Free Full Text]

21. Yagita M, Ieki Y, Onishi R, et al: Therapy-related leukemia and myelodysplasia following oral administration of etoposide for recurrent breast cancer. Int J Cancer13:91-96, 1998

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Submitted March 26, 1999; accepted June 10, 1999.

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