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Phase II Study of Temozolomide in Relapsed or Refractory High-Risk Neuroblastoma: A Joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study

Hervé Rubie, Julia Chisholm, Anne Sophie Defachelles, Bruce Morland, Caroline Munzer, Dominique Valteau-Couanet, Véronique Mosseri, Christophe Bergeron, Clare Weston, Carole Coze, Anne Auvrignon, Latifa Djafari, Rachel Hobson, Christiane Baunin, Fiona Dickinson, Hervé Brisse, Kieran McHugh, Lorenzo Biassoni, Francesco Giammarile, Gilles Vassal

From the Unités d’Hémato-Oncologie et de Radiologie, Hôpital des Enfants, Toulouse; Département d’Oncologie Pédiatrique, Centre Oscar Lambret, Lille; Départements de Statistiques, d’Oncologie Pédiatrique et de Radiologie, Institut Curie, Paris; Départements d’Oncologie Pédiatrique et de Médecine Nucléaire, Centre Léon Bérard, Lyon; Service d’Oncologie Pédiatrique, Hôpital d’Enfants de la Timone, Marseille; Service d’Hémato-Oncologie, Hôpital Trousseau, Paris; Département d’Oncologie Pédiatrique, Institut Gustave Roussy, Villejuif; Schering Plough, Levallois, France; Departments of Paediatric Oncology and Radiology, Great Ormond St Hospital; Leicester Royal Infirmary, London; Oncology Department, Children’s Hospital, Birmingham; Royal Marsden Hospital, Sutton; and the United Kingdom Children’s Cancer Study Group Data Centre, Leicester, United Kingdom

Address reprint requests to Hervé Rubie, MD, Unité d’Hémato-Oncologie - Hôpital des Enfants - 330 avenue de Grande Bretagne, BP 3119 - TSA 70034 - 31059 Toulouse cedex 9 - France; e-mail: rubie.h{at}chu-toulouse.fr

	ABSTRACT

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

 
Purpose To determine the response rate (RR) of neuroblastoma (NB) in children to temozolomide (TMZ), and evaluate the duration of response and tolerance of the drug in this patient population.

Patients and Methods A multicenter, phase II evaluation of an oral, daily schedule of TMZ (200 mg/m²/d x 5 days every 28 days) was undertaken in children with refractory or relapsed high-risk NB (metastatic or localized with Myc-N amplification). Response assessment was based on imaging with two-dimentional measurement of disease and meta-iodobenzylguanidine (MIBG) score. Activity was defined by a reduction in lesion size or isotope uptake at anytime. Methodology included a two-step design using Fleming’s method with a first step of 15 patients and a second of 10 additional patients if two to four responses had been observed in the first cohort. All data was centrally reviewed by a panel.

Results Twenty-five assessable patients were recruited over a 14-month period in 14 centers and received 94 cycles of chemotherapy. Twenty-three patients had metastatic NB either refractory (n = 9) or in relapse (n = 14). Grade 3 or 4 thrombocytopenia was the most frequent toxicity (16% of cycles). Myelosuppression resulted in treatment delays and dose reductions (24% and 21% of cycles, respectively). Response (complete response, very good partial response, or partial response) was observed in five patients (RR = 20% ± 8%) with a median duration of 6 months and an objective or mixed response in five additional patients.

Conclusion Temozolomide shows activity in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug.

	INTRODUCTION

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

 
Neuroblastoma (NB) accounts for 8% to 10% of childhood cancers.¹ The two main prognostic factors are age and stage.^2,3 Localized NB and those arising in infants have a 90% survival rate except in cases of Myc-N amplification, where survival is below 30%.^3-5 Approximately 50% of NB occurring in children older than 1 year are metastatic at diagnosis. NB is a chemosensitive tumor. Chemotherapy is indicated in localized NB with large primary tumors in order to attempt a safe surgical excision^6,7 as well as in metastatic NB to achieve a complete remission of metastases. The most effective drugs are alkylating agents, platinum compounds, anthracyclines and epipodophyllotoxins.⁸ High-dose chemotherapy (HDC) followed by hematopoietic stem cell transplantation (HSCT) and maintenance therapy with retinoic acid improves survival by 35% in children presenting with metastatic NB,^9,10 but the 5-year event-free survival remains below 50%. Consequently, the evaluation of new drugs is strongly needed in this disease.

Temozolomide (TMZ) is an imidazotetrazazine prodrug that undergoes spontaneous degradation to a cytotoxic methyl derivative, monomethyl 5-triazeno imidazole carboxyamide.¹¹ The principal cytotoxic mechanisms involve the 0⁶ alkylation of guanine with subsequent aberrant repair of the methyl adduct.^12,13 Consequently, after DNA replication, the action of the mismatch repair pathway (MMR) ¹⁴ 0⁶-methylguanine is repaired by the action of the nuclear protein O⁶alkyl-guanine-DNA-alkyltransferase (Alk-transferase or MGMT). Resistance to TMZ correlates with a high activity of MGMT and absence of MMR in vitro.^12-15 In vitro studies have indicated that TMZ is effective in tumor cell lines resistant to other agents.¹⁶ A preclinical study reported activity of TMZ in four xenograft models of human NB, which correlated with MGMT activity.¹⁷ Moreover, in 13 of 17 specimens, MGMT expression was lower than in responsive xenograft tumors, suggesting the activity of TMZ in vivo.

TMZ is rapidly and completely absorbed after oral administration.¹³ Phase I studies in adults^18,19 and children^20,21 have determined the maximum tolerated dose as 200 mg/m²/d for 5 days. The dose-limiting toxicity was myelosuppression, which occurred at a total dose of 1.25 g/m² and was reversible and noncumulative. Marrow recovery normally occurs within 28 days, allowing a 28-day dosing schedule. Recent studies have demonstrated that continuous TMZ administration allows dose escalation from 1,000 to 2,100 mg/m² over 28 days and causes prolonged MGMT depletion,^22-25 but such schedules have not yet been used in children.

Phase II studies in adults have demonstrated efficacy in malignant gliomas^26-31 but this was not confirmed in children with brainstem glioma.³² There are no convincing data on the use of TMZ in pediatric extracranial tumors except some children with NB having stable disease.³³

From the aforementioned data, TMZ may be a promising drug in NB, and a phase II study was undertaken in these patients.

	PATIENTS AND METHODS

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

 
Patients
All patients had refractory or relapsed high-risk NB, either metastatic or localized with Myc-N amplification. Refractory NB was defined as disease showing no significant response of metastases after induction chemotherapy and skeletal MIBG showing at least three foci. Patients were required to fulfill the following criteria: age 12 months to 20 years; histologically proven NB; life expectancy of more than 3 months; measurable disease defined as residual abnormal tissue at a primary or metastatic site measuring more than 1 cm in any dimension, or at least three persisting skeletal foci on meta-iodobenzylguanidine (MIBG) follow-up scans; no more than two lines of treatment before inclusion; Lansky Play Score more than 30 or WHO performance status 0 to 2; adequate blood cell count (polymorphonuclear cells > 0.5 x 10⁹/L and platelets 100 x 10⁹/L or 50 for patients with bone marrow involvement or prior HSCT); and a serum concentration of aspartate, ALT, or bilirubin lower than 1.5x the upper limit of the normal range and no significant organ toxicity (< grade 2 National Cancer Institute Common Toxicity Criteria [NCI-CTC], version 2.0). Patients were excluded if chemotherapy had been administered within the last 21 days or radiotherapy within the last 30 days except for palliative purposes (ie, pain control). Signed informed consent from the parents or the guardians was mandatory before entering the study, in accordance with the Declaration of Helsinki. Patients were registered on line by local investigators and case report forms were reviewed by the principal investigators (C.M., H.R.). Ethical approval was obtained from the UK Trent Multicenter Research Ethics Committee and the institutional review board at each of the participating centers.

Methods
Study design and treatment. Inclusion work-up included full blood count, measurement of standard hepatic and renal biologic parameters, cross-sectional imaging of the primary (computed tomography [CT]scan or magnetic resonance imaging [MRI]) in at least two dimensions, a whole body I¹²³-MIBG scan, 24-hour urinary catecholamine measurements and bone marrow staging (at least two smears and two trephine biopsies) within 14 days before start of therapy. Measurable disease was defined as residual abnormal tissue at a primary or metastatic site measuring more than 1 cm in any dimension. The MIBG score was calculated according to European standards.³⁴ In brief, seven skeletal areas were defined and each of them was scored from 1 to 3 according to the intensity of the uptake. Thus, the overall MIBG score could range from 0 up to a maximum of 21.

TMZ was given orally in the morning, after overnight fasting and a 5HT3 receptor antagonist as an antiemetic. The recommended dose was 200 mg/m²/d (or 150 mg/m²/d for children with prior HSCT or in the case of bone marrow involvement and thrombocytopenia between 50 and 100 x 10⁹/L) over 5 consecutive days. The second course was to be started at day 28 after the beginning of course 1. Doses of TMZ could be decreased to 160 or 120 mg/m²/d depending on the initial dosage in case of either a grade 4 hematologic toxicity lasting more than one week or grade 3 nonhematologic toxicity after the first course. Dosing was continued until disease progression or completion of 12 months of treatment, according to the patient and investigator’s decision.

Assessment of Efficacy
The primary aim of the study was to determine the response rate (RR) to TMZ. Consequently, important eligibility criteria included the presence of radiologically assessable disease by cross-sectional imaging and MIBG scans. Response was determined by a reduction in size of measurable lesions or disappearance of abnormal MIBG foci and by the duration of that response on serial scans. MIBG activity was also assessed. However, serial results of bone marrow aspirates, trephine biopsies and urinary catecholamines were reviewed only for responding patients to confirm response or lack of progression. Hence, complete response (CR) consisted of complete disappearance of all detectable disease. Very good partial (VGPR) or partial response (PR) were determined respectively by a decrease of at least 90% or between 50% and 90% of the sum of the products of the largest perpendicular diameters or the number and intensity of MIBG spots over the same time span. Mixed response (MR) was defined as a VGPR/PR in one site of the disease and no response (NR) in another one. Objective response (OR) was defined as a response (VGPR/PR) not confirmed 1 month later or improvement in clinical status (ie, disappearance of bone pains). Stable disease (SD) was defined as less than 50% decrease in tumor size or less than 25% increase. The assessment of response included the initial measurable targets and was to be performed after two courses. A patient was defined as a responder if CR/VGPR/PR was observed at anytime of the treatment and confirmed 1 month later according to international criteria. Progressive disease (PD) was defined by at least a 25% increase in tumor size or the appearance of a new lesion. The time to the first response or progression was defined as the time from the initial administration of TMZ to the first evidence of a confirmed response or disease progression. The duration of a response was defined as the time from the achievement of a response to progression. All data were centrally reviewed by the panel (C.B., H.B., F.D. and K.M.H. for radiology; J.C. and H.R. for clinical data). Each MIBG scan was evaluated by two independent and experienced observers (L.B. and F.G.). Two meetings were organized, one after registration of the 15 first patients, and the second after inclusion of the whole cohort. CRFs were all reviewed, as well as MIBG scans and imaging (CT scans and/or MRI).

Assessment of Safety and Other Secondary End Points
Adverse events were assessed at each visit and graded according to the NCI-CTC (version 2.0) from the first dose until 30 days after the last dose of TMZ.

Statistical Analysis
The trial was an open, multicenter, nonrandomized phase II study. The analysis was performed according to the Fleming’s one-sample multiple testing procedure.³⁵ Two steps were planned with an alpha risk of 5% of falsely accepting the treatment as effective and a beta risk of 20% of falsely discarding the treatment as ineffective. We aimed at a 30% RR and considered a 10% RR as the minimum below which the drug would not appear to us as efficacious. Consequently, we planned to include a minimum of 15 and a maximum of 25 assessable patients. After the inclusion and the evaluation of the 15 first patients, the trial was to be stopped for ineffectiveness if fewer than two responses were observed. If five or more responses were observed, the trial was to be stopped and the drug would be considered effective. If two to four responses were observed, the trial was to be ongoing with the inclusion of 10 additional patients. After inclusion and evaluation of 25 patients, the drug was to be considered effective if six or more responses were observed.

The planned duration of the study was 24 months.

	RESULTS

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Study Population
Between March 2003 and June 2004, 14 centers (11 in Société Française des Cancers de l’Enfant [SFCE], three in United Kingdom Children Cancer Study Group–New Agents Group [UKCCSG]) enrolled 34 patients. Nine patients were excluded at final analysis for the following reasons: more than two lines of prior treatment (n = 4); inappropriate initial work-up (n = 3); no measurable targets (n = 2); or unassessable data (n = 1). They were all initially registered by the local investigators and were finally excluded either after review of the completed CRFs or during the central review at the panel’s meetings. Thus, this study deals with 25 assessable patients. As shown in Table 1, these patients all had advanced-stage disease (23 metastatic patients, of whom nine were refractory) and had been heavily pretreated (16 received HDC and 10 a second-line treatment).

A total number of 94 courses of TMZ were administered to 25 patients. Forty NCI-CTC grade 3 or 4 toxic events were reported as being possibly or probably related to TMZ. The most frequent toxic events were grade 3 or 4 hematologic toxicities: thrombocytopenia occurred in 15 cycles (16%), anemia in 9% and neutropenia in 12% of cycles. A grade 3 infection was observed in two patients. These adverse effects were observed at a median delay of 8 days after the beginning of the course for thrombocytopenia (range, 0 to 42 days), 6 days for anemia (range, 0 to 13 days) and 15 days for neutropenia (range, 5 to 25 days) and all resolved within 2 weeks. All were easily manageable. Most patients received their treatment on an outpatient-based regimen. The median time between courses was 31 days (range, 21 to 85 days; ie, 3 days more than recommended by the protocol). Despite the relatively low incidence of severe hematologic toxicity, prolonged thrombocytopenia resulted in both delays to treatment (7 days or more in 24% of cycles) and dose reductions (21% of cycles). These toxicities were observed in 10 patients, all of whom had metastatic relapse (n = 7) or refractory (n = 3) NB.

Efficacy
As shown in Table 2, among these 25 patients with assessable disease, five patients (20% ± 8%) had a VGPR (n = 1) or PR (n = 4) to TMZ, all confirmed 1 month later. None of them had bone marrow progression or elevation of catecholamines. The best response was observed after two (n = 4) or six courses (n = 1) of TMZ, and the median duration of this response was 6.1 months (range, 2 to 8.6 months). In addition, MR was observed in three patients (one patient with PR on the primary and a decrease of MIBG score from 19 to 10 and disappearance of marrow involvement, one with VGPR on the primary and NR for metastasis, and one with a tumor shrinkage of 40% and marrow normalization) and OR in two (one patient with VGPR which was not confirmed by appropriate investigations 1 month later, and one experiencing a clinical relief of bone pain and disappearance of bone marrow involvement without significant response on imaging data). In total, improvement of the clinical status and/or imaging was observed in 10 patients (40%). SD was observed in another patient and was almost a PR (one primary tumor shrinkage of 47%, that patient achieving CR after subsequent surgical excision of the residue). NR or SD was observed in six patients and PD in eight, four of these after the first course. Consequently, the overall response after two courses was assessable in 21 patients. One patient with a VGPR underwent HDC followed by HSCT. We had hoped to evaluate MGMT tumor status, but no assay was available at the time of the study, so no correlation could be established between clinical response and biochemical profile of the tumor so far. All responders subsequently experienced disease progression within a median time of 8 months (range, 3.7 to 14.7 months) and ultimately died as a result of the disease.

	DISCUSSION

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

 
This study included patients with high-risk NB who were heavily pretreated. To our knowledge, this is the first trial determining the efficacy of TMZ in children with extracranial tumors.

The results confirm hematologic toxicity as the principal complication of TMZ administration. Indeed, 21% of the cycles needed dose reductions and 24% were delayed by 7 days beyond the 28 days specified by the protocol. Hematopoietic growth factors such as granulocyte colony-stimulating factor are not indicated, because thrombocytopenia was the most frequent toxicity. However, for routine use of this agent in such patients, a reduced dose or a longer delay between two courses may be beneficial. The dose and schedule were otherwise well tolerated. These findings differ from toxicity observed in adults, and three factors may explain this difference. First, adult patients commonly begin therapy with a lower starting dose if they have had any previous treatment. Second, they have usually been less heavily pretreated. Third, the pharmacokinetic study undertaken in the phase I study indicated significantly greater drug exposure after oral dosing in childhood, with a higher-risk peak plasma levels of the drug and approximately 40% greater systemic drug exposure as determined by estimates of the area under the curve when compared with adults.²⁰ Thus, greater experience with the compound indicates that a lower starting dose may be necessary for some children, particularly if TMZ is to be used with other myelosuppressive drugs.

In metastatic NB, the achievement of CR of the metastases is one of the strongest prognostic factors.³⁶ Disappearance of all metastatic foci on MIBG scanning is commonly regarded as CR in NB staging and follow-up. However the CR rate after induction regimens does not exceed 50%,^2,9,37 and it does not improve with time.³⁸ Furthermore, many studies do not include MIBG scanning for evaluation of response, which may lead to an overestimation of the RR. There is one published study reporting an 80% CR rate after induction therapy in 24 patients, using International Neuroblastoma Response Criteria (INRC) and MIBG,³⁹ but these results were not confirmed by the French group, who reported a 42% CR rate in 40 patients treated with the same protocol.⁴⁰ Thus, new drugs or combinations are strongly needed in high-risk NB, particularly in disseminated NB.

Some studies reported encouraging results with several drug-containing regimens, such as topotecan/vincristine/doxorubicin with a 60% RR,⁴¹ or up-front paclitaxel/topotecan with a 37% RR.⁴² However, single-drug trials have usually been disappointing with a RR usually below 10%.⁴³

In this phase II trial, we evaluated the efficacy of TMZ in patients with relapsed/refractory high-risk NB, and the overall RR was 20% ± 8%. Although this was below the threshold that we had set of at least six responses out of 25 assessable patients, such RR is noteworthy as all patients were heavily pretreated. In addition, MR and OR were observed in five patients (three MR, two OR). Thus, if we include OR and MR, as many studies do, the observed RR is 40% ± 10%. The median duration of response was 6 months, and one patient was able to undergo subsequently HDC followed by HSCT.

The novel mechanism of action of TMZ may explain its efficacy, because the drugs conventionally considered as effective in NB act differently. The expression of MGMT is generally lower in gliomas than in other brain tumors, and it may be the explanation of the higher sensitivity of these tumors to TMZ and related drugs in adults.⁴⁴ Indeed, epigenetic silencing of the MGMT DNA-repair gene by promoter methylation compromises DNA repair. A recent study showed that adult patients with glioblastoma containing a methylated MGMT promoter benefited significantly from TMZ administration.⁴⁵ A similar observation has been made for pediatric tumors,⁴⁶ although in one large study of 110 pediatric brain tumors, alkyl guanine transferase activity could vary markedly, ranging between 0.34 and 498 fmol/10⁶ cells.⁴⁷

In summary, TMZ has been investigated in patients with relapsing or refractory high-risk NB. Toxicity was moderate. In terms of efficacy, our encouraging results in such heavily pretreated patients deserve further evaluation, possibly with a lower dose, in combination with another drug in order to evaluate the potential role of a new regimen in the first-line treatment of metastatic NBs.

	Authors’ Disclosures of Potential Conflicts of Interest

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

 
The authors indicated no potential conflicts of interest.

	Author Contributions

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

 

Conception and design: Hervé Rubie, Véronique Mosseri, Gilles Vassal Financial support: Latifa Djafari Administrative support: Latifa Djafari Provision of study materials or patients: Hervé Rubie, Julia Chisholm, Anne Sophie Defachelles, Bruce Morland, Dominique Valteau-Couanet, Christophe Bergeron, Carole Coze, Anne Auvrignon Collection and assembly of data: Caroline Munzer, Clare Weston, Rachel Hobson Data analysis and interpretation: Caroline Munzer, Christiane Baunin, Fiona Dickinson, Hervé Brisse, Kieran McHugh, Lorenzo Biassoni, Francesco Giammarile Manuscript writing: Hervé Rubie, Julia Chisholm Final approval of manuscript: Hervé Rubie, Julia Chisholm, Bruce Morland, Gilles Vassal

 

	ACKNOWLEDGMENTS

 
The SFCE and UKCCSG gratefully acknowledge the contribution of clinical investigators and patients at the Hôpital des Enfants, Toulouse (Dr Hervé Rubie), Great Ormond Street Hospital, London (Dr Julia Chisholm), Royal Marsden Hospital, London (Prof Andy DJ Pearson), Centre Oscar Lambret, Lille (Dr Anne Sophie Defachelles), Children’s Hospital, Bristol (Dr Bruce Morland), Institut Gustave Roussy, Villejuif (Dr Dominique Valteau-Couanet, Prof Gilles Vassal), Institut Curie, Paris (Mrs Véronique Mosseri, Dr Jean Michon), Royal Marsden Hospital, London (Dr Darren Hargrave), Centre Léon Bérard, Lyon (Dr Christophe Bergeron), Hôpital de la Timone-Enfants, Marseille (Dr Carole Coze), Hôpital Armand Trousseau, Paris (Dr Anne Auvrignon), Caen (Dr Patrick Boutard), Clermont-Ferrand (Dr Justyna Kanold), Dijon (Dr Gérard Couillault), and Limoges (Dr Christophe Piguet). Further radiologic and isotopic review was provided by Dr Christiane Baunin, Hôpital des Enfants, Toulouse; and Dr Hervé Brisse, Institut Curie, Paris; and Dr Fiona Dickinson, Leicester Royal Infirmary, London; Dr Kieran McHugh, Dr Lorenzo Biassoni, Great Ormond Street Hospital, London; and Francesco Giammarile, Centre Léon Bérard, Lyon. Data management and statistical support was provided through the UKCCSG Data Centre (Ann Elsworth, Rachel Hobson and Clare Weston) and Hôpital des Enfants, Toulouse (Mrs Caroline Munzer).

	NOTES

 
Supported by a grant from Schering Plough, Cent pour Sang la Vie, Agence Française de Sécurité Sanitaire des Produits de Santé, Voeux d’Artistes, and the Direction Régionale à la Recherche Clinique des Hôpitaux de Toulouse.

Presented in part at the 36th Annual Meeting of the International Society of Pediatric Oncology, September 16-19, 2004, Oslo, Norway; and the 42nd Annual Meeting of the American Society of Clinical Oncology June 2-6, 2006, Atlanta, GA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 15, 2006; accepted September 7, 2006.

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