Results of the Cooperative Protocol (N-III-95) for Metastatic Relapses andRefractory Neuroblastoma

V. Castel, A. Canete,* C. Melero, T. Acha, A. Navajas, P. Garcıa-Miguel,T. Contra, J. Molina, P. Galaron, and O. Cruz, on behalf of the Group for

Neuroblastoma of the Spanish Society of Pediatric Oncology (SEOP)

Background. Prognosis of relapsed and re-fractory neuroblastoma is uniformely fatal; newtherapeutic approaches are needed. Procedure.Relapsed and refractory neuroblastoma patientswere treated with continuous infusion chemo-therapy combined with MIBG. Results. Over 4years, 35 heavily pretreated patients were reg-istered, 29 with bone or/and bone marrow me-tastases. Grade 3 or 4 hematologic toxicity was

frequent, without toxic deaths. Sixteen patientsresponded. The probability of 5-year overallsurvival was 0.19. Conclusions. This approachis feasible and toxicity manageable; it rescuedsome patients and prolonged their survival. Itmerits assay in newly diagnosed high-risk neu-roblastoma patients. Med. Pediatr. Oncol. 35:724–726, 2000. © 2000 Wiley-Liss, Inc.

Key words: neuroblastoma; relapse; continuous-infusion chemotherapy; MIBG

INTRODUCTION

Patients with neuroblastoma who do not respond toinitial chemotherapy or relapse after intensive treatmenthave an almost fatal prognosis presently. Continuous in-fusion of chemotherapeutic agents permits a more pro-longed exposure of tumor cells to antimitotic drugs. Be-cause not all the tumoral cells are at the same time pointin the cellular cycle, this type of drug delivery increasestime exposure to the drug and, consequently, efficacy.Previous studies in neuroblastoma were conducted in theearly 1990s by French [1] and American [2,3] groups andshowed some response in this cohort of patients. Metaio-dobencylguanidine (MIBG) is a well-known noradrena-line analog that has a well-described therapeutic effectwhen coupled with131I at high dose [3–5]. In 1995, theSpanish Neuroblastoma Study Group decided to design astudy, combining those elements, in order to offer asecond-line therapy for those patients who failed first-line treatment.

PATIENTS AND METHODS

Neuroblastoma patients who could be included in thestudy were: 1) those with metastatic relapses, 2) thosewith stage 4 for over 1 year who did not respond or hada mixed response to induction chemotherapy or had pro-gressive disease, and 3) exceptionally patients with localrelapses could also be included after discussion with thecoordinator. Normal renal, hepatic, and cardiac functionwere required, along with a life expectancy over 3 weeks,a central venous line, and informed consent. The secre-tary of the study was at the Pediatric Oncology Unit, in

La Fe Children’s Hospital, as for other Spanish studies.Biological studies of tumoral tissue at inclusion in theprotocol were not mandatory. After evaluation accordingto INSS [7] [NSE, LDH, catecholamines, imaging stud-ies, 123I-MIBG (at the center where MIBG treatmentwould be delivered), bone marrow aspirations, and biop-sies], treatment was begun. It consisted of alternatingcourses of continuous-infusion chemotherapy, calledABA, followed by evaluation and therapeutic MIBG, un-til a total of three ABA and three MIBG courses werecompleted. A course consisted of continuous-infusion ofEpiadryamicin (10 mg/m2/day), cisplatinum (40 mg/m2/day), and etoposide (100 mg/m2/day) plus ifosfamide (2gm/m2/day) over 30 min, repeated for 3 days. Course Bconsisted of continuous-infusion vincristine (1.5 mg/m2)on day 1, followed by etoposide (1 gm/m2) on day 2.Supportive care included hyperhydration, mannitol,Mesna, antiemetics, and G-CSF. Courses A and B wererepeated every 4 weeks until completion of a cycle(ABA). Those patients who were not progressing and hadpositive diagnostic uptake could proceed to therapeuticMIBG, with thyroid blockade as usual. In patients withdiffuse bone marrow infiltration, MIBG treatment waspostponed until the degree of bone marrow infiltrationdiminished.

Unidad de Oncologı´a Pedia´trica, Hospital Infantil La Fe, Valencia,Spain

*Correspondence to: A. Can˜ete, MD, PhD, Unidad de Oncologı´a Pe-diatrica, Hospital Infantil La Fe, Avda Campanar 21, 46009 Valencia,Spain. E-mail: canyete_ade@gva.es

Medical and Pediatric Oncology 35:724–726 (2000)

© 2000 Wiley-Liss, Inc.

Data were collected regularly from participating cen-ters by the secretary of the study. Toxicity was gradedaccording to WHO. The SPSS statistical package wasused for analysis (Survival curves by Kaplan-Meier, log-rank for comparisons, etc.).

RESULTS

From April, 1995, to May, 1999, 35 patients wereincluded, with a median age of 1.9 years (range 0.9–14years); 20 were male and 15 female. At diagnosis ofneuroblastoma, 27 were in stage 4, 7 in stage 3, and 1 instage 2. All of them except one had been previouslytreated with the N-II-92 protocol for high-risk patients[8], which is based on dose intensity. Nineteen patientshad abdominal tumors at recurrence (11 adrenal); 11 of21 tumors infiltrated the midline, and 17 of 30 patientshad general symptoms. Median values of LDH, NSE, andferritin were increased (647 IU/liter, 32 ng/ml, and 501ng/ml, respectively). Twenty-five patients underwentMycN studies (either at diagnosis or recurrence): Threehad more than 10 copies of the oncogene and one patienthad between 3 and 10 copies. Nineteen patients had un-dergone megatherapy before as part of their first-linetreatment. Twenty-five patients were included as re-lapsed cases (14 metastatic, 5 local and metastatic, and 4isolated local relapses), and 10 were refractory patients.Among the 35 patients, 29 had disease at metastatic sites,with bone metastases being predominant (74%), fol-lowed by bone marrow metastases (51%). Twenty-twohad multiple metastases, and 15 had combined bone and

bone marrow disease. All patients except for three wereMIBG-positive.

One hundred nine A courses and 55 B courses wereadministered to all patients. Toxicity was mainly hema-tologic, as shown in Tables I and II. When A and Bcourses were compared, the percentages of grade 4 he-matologic toxicity were similar, but there were only 27%hospitalizations for toxicity after B courses vs. 66% afterA courses. There were no toxic deaths nor major organtoxicities.

Eleven patients received 20 doses of MIBG, with amedian dose of 200 mCi (range 100–500). It was verywell-tolerated, with only hematologic toxicity, mostlythrombocytopenia. Five patients had local radiotherapy,because of craneospinal irradiation for CNS disease (n42) or orbital disease (n4 1) or MIBG negativity (n4 1)or very young age.

Response was evaluated at different time points: 1)after first ABA, 2) after MIBG + second ABA, 3) aftersecond MIBG + third ABA, and 4) after finishingtherapy. As is shown in Figure 1, initial response wasobserved in more than 50% of the patients, but it couldnot be maintained very long. Only 15 patients could com-

TABLE I. Toxicity After Course A (n = 109). Number ofCourses A With Grade I–IV Toxicities

Grade LeukocyteRedcells Platelet Infection

GItoxicity

I 2 3 2 1 4II 6 21 4 13 10III 9 28 34 12 13IV 61 24 63 6 0Percentage of

grade IVtoxicity 56 22 58 6 0

TABLE II. Toxicity After Course B (n = 55). Number of BCourses With Grade I–IV Toxicities

Grade LeukocyteRedcells Platelet Infection

GItoxicity

I 1 0 0 0 4II 8 18 7 8 3III 14 13 10 8 2IV 31 16 35 3 1Percentage of

grade IVtoxicity 56 29 63 5 2

Fig. 1. Number of patients and their types of response after chemo-therapy and MIBG at three time points: 1) after first ABA, 2) after firstMIBG + second ABA, and 3) after second MIBG + third ABA.

Fig. 2. Overall survival curve.

Cooperative Protocol N-III-95 725

plete 3 ABA and 3 MIBG, as planned, and were evalu-ated at that point (see Fig. 1). Twenty-seven patients havedied, mostly from disease, and eight are alive (at 9, 12,15, 37, 38, 43, 57, and 60 months from relapse) . Medianfollow-up for the whole cohort is 9 months (range 1–60).Five of the eight living patients could receive continu-ous-infusion chemotherapy and MIBG as planned in thestudy. Three isolated local relapse patients are alive (2alive free of disease, 1 with tumor) and 5 of the 29metastatic patients are alive (1 free of disease, 4 withpositive MIBG uptake in bone). Overall survival rate is0.19 (Fig. 2). There was no statistical difference in sur-vival according to the presence of bone metastases (P 40.21), refractory disease vs. relapse (P 4 0.52), local vs.metastatic disease (P 4 0.33), or bone marrow disease(P 4 0.28).

DISCUSSION

Despite the extremely bad prognosis in our cohort ofpatients, we have observed responses after MIBGtherapy combined in an alternating manner with continu-ous infusion of drugs. It was difficult to evaluate theeffect of each component (continuous-infusion chemo-therapy,131I-MIBG) independently. Despite these diffi-culties and the intensity of the protocol, in very heavilypretreated patients it was well-tolerated, manageable in amulticentric study, and continuing responses were ob-served in a group of patients, leading to a prolongedsurvival. In summary, this protocol is feasible, and tox-icity is manageable. It has been shown to rescue deeplypretreated patients and to prolong their survival; there-fore, it should be assayed in newly diagnosed high-riskneuroblastoma patients.

ACKNOWLEDGMENTS

We thank all collaborating hospitals: Hospital InfantilLa Fe (Valencia), Hospital Clı´nico Universitario (Valen-cia), Hospital Infantil La Paz (Madrid), Hospital Infantil12 de Octubre (Madrid), Hospital Infantil Nin˜o Jesus(Madrid), Hospital Infantil Gregorio Maran˜n (Madrid),Hospital Carlos Haya (Malaga), Hospital Virgen DelCamino (Navarra), Hospital Central de Asturias(Oviedo), Hospital General de Galicia (Santiago), Hos-pital Sant Joan de Deu (Barcelona), Hospital San Juan(Alicante), Hospital Cruces (Vizkaia), and Hospital Uni-versitario (Salamanca).

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