Cancer Res Treat.  2018 Jan;50(1):148-155. 10.4143/crt.2016.511.

Topotecan-Vincristine-Doxorubicin in Stage 4 High-Risk Neuroblastoma Patients Failing to Achieve a Complete Metastatic Response to Rapid COJEC: A SIOPEN Study

Affiliations
  • 1Paediatric Oncology, Istituto Giannina Gaslini, Genova, Italy.
  • 2Epidemiology and Biostatistics Unit, Istituto Giannina Gaslini, Genova, Italy. riccardohaupt@gaslini.org
  • 3Institute of Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
  • 4Divisions of Cancer Therapeutics and Clinical Studies, Institute of Cancer Research and Children and Young People’s Unit, The Royal Marsden NHS Foundation Trust, London, UK.
  • 5Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
  • 6Paediatric Oncology, Institute Gustave Roussy, Villejuif, France.
  • 7Paediatric Oncology, Hospital Universitario La Fe, Valencia, Spain.
  • 8Department of Hematology-Oncology Hopital des Enfants, Toulouse, France.
  • 9Department of Paediatric Hematology, Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
  • 10Pediatric Intensive Care and Onco-Hematology Units, Nantes Hospital, Nantes, France.
  • 11Department of Paediatric Oncology, Istituto Nazionale Tumori, Milan, Italy.
  • 12Children’s Cancer Research Institute, St. Anna Children’s Hospital, Vienna, Austria.

Abstract

PURPOSE
Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([123I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate.
MATERIALS AND METHODS
Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m2/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m2, and doxorubicin, 45 mg/m2.
RESULTS
Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%).
CONCLUSION
TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.

Keyword

Neuroblastoma; Recurrence; Child; Neoplasm; Phase 2 clinical trial; Second line drugs

MeSH Terms

3-Iodobenzylguanidine
Bone Marrow Diseases
Child
Doxorubicin
Europe
Humans
Iodine
Neuroblastoma*
Radionuclide Imaging
Recurrence
Stomatitis
Topotecan
Vincristine
3-Iodobenzylguanidine
Doxorubicin
Iodine
Topotecan
Vincristine

Figure

  • Fig. 1. The topotecan-vincristine-doxorubicin (TVD) salvage therapy for children included in the HR-NBL-1 protocol. Patients with persistent metastatic disease after the COJEC induction therapy of the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol were eligible for TVD therapy with the aim of eradicating the metastatic disease. Children achieving complete remission (CR) or good partial response (GPR) become eligible for consolidation with high dose therapy (HDT) as planned by the original HR-NBL-1 protocol, all the other were considered failures. PPR, poor partial response; MR, mixed response; SD, stable disease; PD, progressive disease.


Reference

References

1. Haupt R, Garaventa A, Gambini C, Parodi S, Cangemi G, Casale F, et al. Improved survival of children with neuroblastoma between 1979 and 2005: a report of the Italian Neuroblastoma Registry. J Clin Oncol. 2010; 28:2331–8.
Article
2. Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, et al. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013; 14:999–1008.
Article
3. Pearson AD, Pinkerton CR, Lewis IJ, Imeson J, Ellershaw C, Machin D, et al. High-dose rapid and standard induction chemo-therapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol. 2008; 9:247–56.
Article
4. Ladenstein R, Valteau-Couanet D, Brock P, Yaniv I, Castel V, Laureys G, et al. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010; 28:3516–24.
Article
5. Ladenstein R, Potschger U, Hartman O, Pearson AD, Klingebiel T, Castel V, et al. 28 years of high-dose therapy and SCT for neuroblastoma in Europe: lessons from more than 4000 procedures. Bone Marrow Transplant. 2008; 41 Suppl 2:S118–27.
Article
6. Decarolis B, Schneider C, Hero B, Simon T, Volland R, Roels F, et al. Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. J Clin Oncol. 2013; 31:944–51.
Article
7. Yanik GA, Parisi MT, Shulkin BL, Naranjo A, Kreissman SG, London WB, et al. Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children’s oncology group. J Nucl Med. 2013; 54:541–8.
Article
8. Garaventa A, Luksch R, Biasotti S, Severi G, Pizzitola MR, Viscardi E, et al. A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. Cancer. 2003; 98:2488–94.
Article
9. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993; 11:1466–77.
Article
10. Castagnola E, Mikulska M, Viscoli C. Prophylaxis and empirical therapy of infection in cancer patients. In : Bennett JE, Dolin R, Blaser MJ, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. New York: Elsevier;2015. p. 3395–413.
11. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989; 10:1–10.
Article
12. Kim JH, Kim SH, Kolozsvary A, Khil MS. Potentiation of radiation response in human carcinoma cells in vitro and murine fibrosarcoma in vivo by topotecan, an inhibitor of DNA topoisomerase I. Int J Radiat Oncol Biol Phys. 1992; 22:515–8.
13. Rowinsky EK, Verweij J. Review of phase I clinical studies with topotecan. Semin Oncol. 1997; 24(6 Suppl 20):S20–3S20.
14. Thompson J, George EO, Poquette CA, Cheshire PJ, Richmond LB, de Graaf SS, et al. Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts. Clin Cancer Res. 1999; 5:3617–31.
15. Vassal G, Pondarre C, Cappelli C, Terrier-Lacombe MJ, Boland I, Morizet J, et al. DNA-topoisomerase I, a new target for the treatment of neuroblastoma. Eur J Cancer. 1997; 33:2011–5.
Article
16. Pratt CB, Stewart C, Santana VM, Bowman L, Furman W, Ochs J, et al. Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol. 1994; 12:539–43.
Article
17. Blaney SM, Needle MN, Gillespie A, Sato JK, Reaman GH, Berg SL, et al. Phase II trial of topotecan administered as 72-hour continuous infusion in children with refractory solid tumors: a collaborative Pediatric Branch, National Cancer Institute, and Children's Cancer Group Study. Clin Cancer Res. 1998; 4:357–60.
18. Santana VM, Furman WL, Billups CA, Hoffer F, Davidoff AM, Houghton PJ, et al. Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmacokinetically guided dosing approach. J Clin Oncol. 2005; 23:4039–47.
Article
19. London WB, Frantz CN, Campbell LA, Seeger RC, Brumback BA, Cohn SL, et al. Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children’s Oncology Group study. J Clin Oncol. 2010; 28:3808–15.
Article
20. Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001; 19:3463–9.
21. Rubie H, Geoerger B, Frappaz D, Schmitt A, Leblond P, Ndiaye A, et al. Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours. Eur J Cancer. 2010; 46:2763–70.
Article
22. Di Giannatale A, Dias-Gastellier N, Devos A, Mc Hugh K, Boubaker A, Courbon F, et al. Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: a European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study. Eur J Cancer. 2014; 50:170–7.
Article
23. Simon T, Langler A, Harnischmacher U, Fruhwald MC, Jorch N, Claviez A, et al. Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. J Cancer Res Clin Oncol. 2007; 133:653–61.
Article
24. Kretschmar CS, Kletzel M, Murray K, Thorner P, Joshi V, Marcus R, et al. Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a pediatric oncology group study. J Clin Oncol. 2004; 22:4119–26.
Article
25. Park JR, Scott JR, Stewart CF, London WB, Naranjo A, Santana VM, et al. Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study. J Clin Oncol. 2011; 29:4351–7.
Article
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