Theory Clin Pract Pediatr

Received: December 8, 2017; Accepted: December 23, 2017; Published: December 30, 2017

Correspondence to: Paolo Indolfi, Unit of Pediatric Oncology, Pediatric Department, Second University of Naples, via Luigi De Crecchio 280138 Naples, Italy;
1 Unit of Pediatric Oncology, Pediatric Department, Second University of Naples, via Luigi De Crecchio 280138 Naples, Italy
2 Department of Pediatrics and Adolescent Medicine, University of Regensburg, Regensburg, Germany
3 Unit of Pediatric Oncology,Department of Women-Children and General and Specialistic Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
4 Department of Pediatric Surgery, University of Campania Luigi Vanvitelli, Naples, Italy

Citation: P. Indolfi. Targeted molecular therapy (modified rist regimen) in relapsed high riskstage IV neuroblastoma: two cases report. Theory Clin Pract Pediatr, 2017, 1(2):1-4

Copyright: © 2018 Paolo Indolfi et al . This is an open access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, dis- tribution, and reproduction in any medium, provided the original author and source are credited.

1 Introduction

The prognosis for children with recurrent or refractory neuroblastoma remains a significant clinical challenge,and currently there are no known curative salvage regimens.Recently, a combination of temozolomide with the topoisomerase-I inhibitor irinotecan has been suggested.[1, 2] Therefore, in recent years the use of small molecule inhibitors, targeting aberrantly activated signaling cascades, has become a promising approach.Likewise the mTOR inhibitor rapamycin, a downstream target of P13K signaling, showed in several models growth inhibiting activity.[3, 4] In this paper we investigated the effect of imatinib with rapamycin and the chemotherapeutic agents temozolomide and irinotecan. We treated two children with recurrent neuroblastoma with this so called RIST protocol, as published by Corbacioglu.[4]The RIST protocol has a multimodal metronomic trial design consisting of consecutive courses of rapamycin (R) and dasatinib (S) followed by irinotecan (I) and temozolomide (T) which is currently investigated in a prospective randomized international Phase II trial (Eudract Number: 2011-004062-15; Identifier: NCT01467986) and which in our two cases was modified using imatinib instead of dasatinib.

2 Case Report

2.1 Case 1

A previously healthy 5-year-old male was admitted to our clinic for persistent pain to inferior legs and chest wall.A chest X-ray and CT-scan showed a posterior mediastinum swelling. MRI thoraco-lumbar confirmed this finding demonstrating a large paraspinal mass to D4-D9 vertebra.Bilateral bone marrow aspirates and trephine biopsies contains unequivocal tumor cells. Immunohistochemical studies were positive for CD56, Tirosinasi and chromogranin. 131IMIBG (the radiolabeled norepinephrine analogue iodine-131-metaiodobenzylguanidine) scintigraphy demonstrated mediastinal, bone marrow, and bone positivity, as confirmed byTC-99-diphosphonate scintigraphy. Urinary catecholamine metabolism (HVA and VMA) showed increased values. No amplification of the MYCN oncogene. Abdominal ultrasound and CT scan were negative. The global evaluation established the diagnosis of stage IV neuroblastoma MYCN not amplified. The patient began standard front-line therapy according to NB-AR-01 AIEOP-E-SIOP protocol. The revaluation of the disease, before the maintenance treatment, showed complete remission of disease (October 2010). Five months later the child complained of increasing pain in the left hip. The diagnostic approach confirmed the local relapse of neuroblastoma. Adjuvant chemotherapy, included four courses of TVD (topotecan vincristine, and doxorubicin) and five courses of ICE (ifosfamide, carboplatin, and etoposide)were performed. Restaging evaluation of disease after the 9 cycles by bone marrow aspirate, trephine biopsy, MRI, 131I-MIBG scintigraphy, urinary HVA and VMA, and DOPA-PET revealed a complete second remission. Related to the dismail long-term outcome we started a modified RIST protocol (February 2012). A complete restaging after the end of RIST (September 2013) revealed a persistent complete responseof disease. The patient has been off therapy for 31 months (April 2016), is well, and is developing normally and without any complications.

2.2 Case 2

A 7-year-old female presented to our clinic with fever and abdominal pain. Abdominal ultrasound and a CT scan showed a large mass with calcifications measuring 11 x 7.7 x 6.7 cm in the right paraspinal region. A biopsy of the mass was consistent with a ganglioneuroblastoma intermixed stroma poor. Immunohistochemical studies (CD56, chromogranin, NSE, synaptophysin) were consistent with diagnosis.Bilateral bone marrow aspirates and trephine biopsies contained unequivocal tumor cells. 131I-MIBG scintigraphy demonstrated right paravertebral region, bone marrow and bone positivity, as confirmed by TC-99-diphosphonate scintigraphy. Urinary HVA and VMAshowed increased values. The diagnosis was of stage IV neuroblastoma. The patient began standard front-line therapy according to NB-AR-01 AIEOP-E-SIOP protocol. In March 2008, the patient started therapy with imatinib for the local and bone marrow residual disease and a restaging evaluation after 1 year of therapy demonstrated a complete remission of disease. Nevertheless, at 3 months off-therapy, she developed a bone metastasis (right femur) with cytological bone marrow infiltration. A salvage regimen with TVD (3 cycles) and ICE (3 cycles) was administered for 6 months manifesting a very good partial remission: This mixed response prompted a change to temozolomide and topotecan (TT). The patient completed 12 TT cycles beforethat anew isolate bone relapse (right tibia) (May 2012) was identified. For this reason she began salvage therapy with the modified RIST protocol, in combination with local radiotherapy (30 Gy in 10 fractions of 300 cGy).A complete restaging after the end of RIST (January 2015) revealed a persistent complete response of disease. The patient has been off therapy for 15 months (April 2016), is well, and is developing normally and without any complications.

3 Treatment plain

The RIST design for our patients was essentially as described by Corbacioglu et al, modified using imatinib instead of dasatinib. The treatment is organized in phases, cycles and courses and is divided in three phases. Each phase consists of recurrent cycles containing the study drugs rapamycin (R), dasatinib (S; Sprycel®), irinotecan (I) and temozolomide (T). The treatment duration of R/S course is 4 days with a rest phase of three days: rapamycin (3 mg/m2 day 1 and 1mg/m2 on days 2-4) and in our case imatinib (300 mg/m2) were administered orally on days 1 to 4. Irinotecan (50 mg/m2 intravenously) and temozolomide (150 mg/m2 orally) were administered on the consecutive days 1 to 5.

4 Discussion

High risk stage IV neuroblastoma, >1 year of age at diagnosis, is an aggressive pediatric neoplasm marked by frequent relapses and poor overall survival. Several agents have been evaluated, but none have substantially altered long-term outcomes. Among those agents with demonstrated efficacy toward neuroblastoma the COG has demonstrated that the combination irinotecan with temozolomide has been feasible in the phase 1 setting.[5]Therefore, temozolomide is active against relapsed solid tumors as a single agent[6–8] and synergistic with irinotecan in a mouse xenograft model system and relapsed alveolar rhabdomiosarcoma[9–11] Imatinib mesylate is also being studied in neuroblastoma because some tumours express c-kit and/or PDGFR.[12, 13] Both patients by our treated abided the treatment regimen relatively well with common side effects. Notably, over a long period of time (15 and 31 months) after withdrawing of therapy no evidence of disease was noted. Taken together, our data show that in a clinical setting RIST modified protocol can be considered a promising treatment strategy in relapsed/refractory high risk neuroblastoma. The metronomic applicationof drugs, as suggested by Corbacioglu,[14]was designed to reduce toxic burden, emerge drug resistance and to synchronize the cell cycle phases of the individual cancer cells. Further, the altered drug administration may increase the chemo-sensitizing effect of the molecular targeted drugs followed by chemotherapy and may modulate the microenvironment in a more anti-tumorigenic manner[3, 15, 16] According the results of our single-institution experience, these findings suggest that a combination regimen of RIST may provide a therapeutic benefit with a favorable toxicity profile to a unfortunate subset of patients with relapsed or refractory high risk neuroblastoma. In the absence of a more efficacious alternative, and given the need to balance disease control with quality of life for patients and families, the RIST regimen, also in our modified version using imatinib, is an attractive treatment option for patients with recurrent neuroblastoma, even in the context of extensive prior chemo-radiotherapy. In conclusion, we confirm the need of a prospective randomized multicenter trial for the treatment of patients with relapsed and refractory neuroblastoma, as is currently in progress (Eudract Number: 2011-004062-15; Identifier: NCT01467986).

5 Acknowledgment

The Authors express their gratitude to the Lions of the 108YA-Italy District, for their considerable support.


[1] Pourquier P, Waltman JL, Urasaki Y, et al. Topoisomerase-I-mediated cytotoxicity of N-methyl-N- mitro-N-mitrosoguanide: trapping of topoisomerase I by the O6- methylguanine. Cancer Res, 2001, 61:53-58

[2] Reardon DA, Quinn JA, Rich JN, et al. Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma. Cancer, 2005, 104: 1478-1486

[3] Corbacioglu S, Kilic M,Westhoff MA, et al. Newly identified c-KIT receptor tyrosine kinase ITD in childhood AML induces ligand independent growth and is responsive to a synergistic effects of imatinib and rapamycin. Blood, 2006, 108: 3504-3513

[4] Corbacioglu S, Steinbach D, Lode HN, et al. The RIST design: a molecularly targeted multimodal approach for the treatment of patients with relapsed and refractory neuroblastoma. J Clin Oncol,2013, 31 (suppl; abstr 10017)

[5] Wagner LM, Crews KR, Iacono LC, et al. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res, 2004, 10: 840-848

[6] Nicholson HS, Krailo M, Ames MM, et al. Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children’s Cancer Group. J Clin Oncol, 1998, 16: 3037-3043

[7] Estlin EJ, Lashford L, Ablett S, et al. Phase I study of temozolomide in pediatric patients with advanced cancer. United Kingdom Children’s Cancer Study Group. Br J Cancer, 1998, 78: 652-661

[8] De Sio L, Milano GM, Castellano A, et al. Temozolomide in resistant or relapsed pediatric solid tumors. Pediatr Blood Cancer, 2006, 47: 30-36

[9] Middlemas DS, Stewart CF, Kirstein MN, et al. Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models. Clin Cancer Res, 2000, 6: 998-1007

[10] Houghton PJ, Stewart CF, Cheshire PJ, et al. Antitumor activity of temozolomide combined with irinotecan is partly independent of 06- methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models. Clin Cancer Res, 2000, 6:4110-4118

[11] Mixon BA, Eckirich MJ, Lowas S, et al. Vincristine, Irinotecan, and Temozolomide for treatment of relapsed alveolar rhabdomyosarcoma. J Pediatr Hematol Oncol, 2013, 35: 163-166

[12] Beppu K, Jaboine J, Merchant MS, et al. Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression. J Natl Cancer Inst, 2004, 96: 46-55

[13] Vitale R, Cesi V, Nicotra MR, et al. c-KIT is preferentially expressed in MYCN-amplified neuroblastoma and its effect on cell proliferation is inhibited in vitro by STI-571. Int J Cancer, 2003, 106: 147-152

[14] Heimberg AB, Wang E, McGary EC, et al. Mechanisms of action of rapamycin in gliomas. Neuro Oncol, 2005, 7: 1-11

[15] Qayum N, Im J, Stratford MR, et al. Modulation of the tumor microvasculature by phosphoinositide-3 kinase inhibition increases doxorubicin delivery in vivo. Clin cancer Res, 2012, 18: 161-169

[16] Saito K, Matsumoto S, Yasui H, et al. Longitudinal imaging studies of tumor microenvironment in mice treated with the mTOR inhibitor rapamycin. Plos One, 2012, 7: e49456