Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical Sarcoma Research
Published in: Clinical Sarcoma Research 1/2015

Open Access 01-12-2015 | Review

Fifteen years of irinotecan therapy for pediatric sarcoma: where to next?

Author: Lars M. Wagner

Published in: Clinical Sarcoma Research | Issue 1/2015

Login to get access

Abstract

Over the past 15 years, irinotecan has emerged as an important agent for treating pediatric sarcoma patients. This review summarizes the activity noted in previous studies, and outlines current issues regarding scheduling, route of administration, and amelioration of side effects. Also discussed are new pegylated and nanoliposomal formulations of irinotecan and its active metabolite, SN-38, as well as future plans for how irinotecan may be used in combination with other conventional cytotoxic as well as targeted agents.
Literature
1.
Furman WL, Stewart CF, Poquette CA, Pratt CB, Santana VM, Zamboni WC, et al. Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol. 1999;17:1815–24.PubMed
2.
Houghton PJ, Cheshire PJ, Hallman JD 2nd, Lutz L, Friedman HS, Danks MK, et al. Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol. 1995;36:393–403.CrossRefPubMed
3.
Vassal G, Couanet D, Stockdale E, Geoffray A, Geoerger B, Orbach D, et al. Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children’s Cancer Study Group. J Clin Oncol. 2007;25:356–61.CrossRefPubMed
4.
Morland B, Platt K, Whelan JS. A phase II window study of irinotecan (CPT-11) in high risk Ewing sarcoma: a Euro-E.W.I.N.G. study. Pediatr Blood Cancer. 2014;61:442–5.CrossRefPubMed
5.
Bomgaars L, Kerr J, Berg S, Kuttesch J, Klenke R, Blaney SM. A phase I study of irinotecan administered on a weekly schedule in pediatric patients. Pediatr Blood Cancer. 2006;46:50–5.CrossRefPubMed
6.
Shitara T, Shimada A, Hanada R, Matsunaga T, Kawa K, Mugishima H, et al. Irinotecan for children with relapsed solid tumors. Pediatr Hematol Oncol. 2006;23:103–10.CrossRefPubMed
7.
Bomgaars LR, Bernstein M, Krailo M, Kadota R, Das S, Chen Z, et al. Phase II trial of irinotecan in children with refractory solid tumors: a Children’s Oncology Group Study. J Clin Oncol. 2007;25:4622–7.CrossRefPubMed
8.
Cosetti M, Wexler LH, Calleja E, Trippett T, LaQuaglia M, Huvos AG, et al. Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol. 2002;24:101–5.CrossRefPubMed
9.
Bisogno G, Riccardi R, Ruggiero A, Arcamone G, Prete A, Surico G, et al. Phase II study of a protracted irinotecan schedule in children with refractory or recurrent soft tissue sarcoma. Cancer. 2006;106:703–7.CrossRefPubMed
10.
Mascarenhas L, Lyden ER, Breitfeld PP, Walterhouse DO, Donaldson SS, Paidas CN, et al. Randomized phase II window trial of two schedules of irinotecan with vincristine in patients with first relapse or progression of rhabdomyosarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2010;28:4658–63.PubMedCentralCrossRefPubMed
11.
Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E, et al. Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res. 1996;56:3752–7.PubMed
12.
Wagner LM, Crews KR, Stewart CF, Rodriguez-Galindo C, McNall-Knapp RY, et al. Reducing irinotecan-associated diarrhea in children. Pediatr Blood Cancer. 2008;50:201–7.CrossRefPubMed
13.
Furman WL, Crews KR, Billups C, Wu J, Gajjar AJ, Daw NC, et al. Cefixime allows greater dose escalation of oral irinotecan: a phase I study in pediatric patients with refractory solid tumors. J Clin Oncol. 2006;24:563–70.CrossRefPubMed
14.
McGregor LM, Stewart CF, Crews KR, Tagen M, Wozniak A, Wu J, et al. Dose escalation of intravenous irinotecan using oral cefpodoxime: a phase I study in pediatric patients with refractory solid tumors. Pediatr Blood Cancer. 2012;58:372–9.PubMedCentralCrossRefPubMed
15.
Pappo AS, Lyden E, Breitfeld P, Donaldson SS, Wiener E, Parham D, et al. Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children’s Oncology Group. J Clin Oncol. 2007;25:362–9.CrossRefPubMed
16.
O’Dwyer PJ, Catalano RB. Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin Oncol. 2006;24:4534–8.CrossRefPubMed
17.
Stewart CF, Panetta JC, O’Shaughnessy MA, Throm SL, Fraga CH, Owens T, et al. UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan. J Clin Oncol. 2007;25:2594–600.CrossRefPubMed
18.
Wagner LM, Villablanca JG, Stewart CF, Crews KR, Groshen S, Reynolds CP, et al. Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study. J Clin Oncol. 2009;27:1290–6.PubMedCentralCrossRefPubMed
19.
Drengler RL, Kuhn JG, Schaaf LJ, Rodriguez GI, Villalona-Calero MA, Hammond LA, et al. Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors. J Clin Oncol. 1999;17:685–96.PubMed
20.
Wagner LM, Perentesis JP, Reid JM, Ames MM, Safgren SL, Nelson MD Jr, et al. Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children’s Oncology Group phase I consortium study. Pediatr Blood Cancer. 2010;54:538–45.PubMedCentralPubMed
21.
Bagatell R, Norris R, Ingle AM, Ahern C, Voss S, Fox E, et al. Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children’s Oncology Group Study. Pediatr Blood Cancer. 2014;61:833–9.PubMedCentralCrossRefPubMed
22.
Brennan RC, Furman W, Mao S, Wu J, Turner DC, Stewart CF, et al. Phase I dose escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors. Cancer Chemother Pharmacol. 2014;74:1191–8.CrossRefPubMed
23.
Wagner LM. Oral irinotecan for treatment of pediatric solid tumors: ready for prime time? Pediatr Blood Cancer. 2010;54:661–2.PubMed
24.
Stewart CF, Leggas M, Schuetz JD, Panetta JC, Cheshire PJ, Peterson J, et al. Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Res. 2004;64:7491–9.CrossRefPubMed
25.
Furman WL, Navid F, Daw NC, McCarville MB, McGregor LM, Spunt SL, et al. Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors. J Clin Oncol. 2009;27:4599–604.PubMedCentralCrossRefPubMed
26.
Vassal G, Terrier-Lacombe MJ, Bissery MC, Vénuat AM, Gyergyay F, Bénard J, et al. Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts. Br J Cancer. 1996;74:537–45.PubMedCentralCrossRefPubMed
27.
McNall-Knapp RY, Williams CN, Reeves EN, Heideman RL, Meyer WH. Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood Cancer. 2010;54:909–15.CrossRefPubMed
28.
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.PubMed
29.
Hawkins DS, Anderson JR, Mascarenhas L, McGowage GB, Rodeberg DA, Wolden SL, et al. Vincristine, dactinomycin, cyclophosphamide (VAC versus VAC/V plus irinotecan for intermediate-risk rhabdomyosarcoma: a report from the Children’s Oncology Group Soft Tissue sarcoma Committee. J Clin Oncol. 2014;32:suppl abstr 10004.CrossRef
30.
Houghton PJ, Stewart CF, Cheshire PJ, Richmond LB, Kirstein MN, Poquette CA, et al. Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models. Clin Cancer Res. 2000;6:4110–8.PubMed
31.
Patel VJ, Elion GB, Houghton PJ, Keir S, Pegg AE, Johnson SP, et al. Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft. Clin Cancer Res. 2000;6:4154–7.PubMed
32.
Pourquier P, Waltman JL, Urasaki Y, Loktionova NA, Pegg AE, Nitiss JL, et al. Topoisomerase I-mediated cytotoxicity of N-methyl-N′-nitro-N-nitrosoguanidine: trapping of topoisomerase I by the O6-methylguanine. Cancer Res. 2001;61:53–8.PubMed
33.
Kurucu N, Sari N, Ilhan IE. Irinotecan and temozolamide treatment for relapsed Ewing sarcoma: a single-center experience and review of the literature. Pediatr Hematol Oncol. 2015;32:50–9.CrossRefPubMed
34.
Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall-Knapp RY, McCarville MB, et al. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007;48:132–9.CrossRefPubMed
35.
Casey DA, Wexler LH, Merchant MS, Chou AJ, Merola PR, Price AP, et al. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009;53:1029–34.CrossRefPubMed
36.
Raciborska A, Bilska K, Drabko K, Chaber R, Pogorzala M, Wyrobek E, et al. Vincristine, irinotecan, and temozolomide in patients with relapsed and refractory Ewing sarcoma. Pediatr Blood Cancer. 2013;60:1621–5.CrossRefPubMed
37.
Mixon BA, Eckrich MJ, Lowas S, Engel ME. Vincristine, irinotecan, and temozolomide for treatment of relapsed alveolar rhabdomyosarcoma. J Pediatr Hematol Oncol. 2013;35:e163–6.CrossRefPubMed
38.
Dharmarajan KV, Wexler LH, Wolden SL. Concurrent radiation with irinotecan and carboplatin in intermediate- and high-risk rhabdomyosarcoma: a report on toxicity and efficacy from a prospective pilot phase II study. Pediatr Blood Cancer. 2013;60:242–7.CrossRefPubMed
39.
McGregor LM, Spunt SL, Furman WL, Stewart CF, Schaiquevich P, Krailo MD, et al. Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors: a children’s oncology group study. Cancer. 2009;115:1765–75.PubMedCentralCrossRefPubMed
40.
Hartmann C, Weinel P, Schmid H, Grigull L, Sander A, Linderkamp C, et al. Oxaliplatin, irinotecan, and gemcitabine: a novel combination in the therapy of progressed, relapsed, or refractory tumors in children. J Pediatr Hematol Oncol. 2011;33:344–9.CrossRefPubMed
41.
Zak D, Styler MJ, Rosenbluth JZ, Brodsky I. Combination of gemcitabine and irinotecan for recurrent metastatic osteogenic sarcoma. Clin Adv Hematol Oncol. 2005;3:297–9.PubMed
42.
Crews KR, Stewart CF, Liu T, Rodriguez-Galindo C, Santana VM, Daw NC. Effect of fractionated ifosfamide on the pharmacokinetics of irinotecan in pediatric patients with osteosarcoma. J Pediatr Hematol Oncol. 2004;26:764–7.CrossRefPubMed
43.
Yoon JH, Kwon MM, Park HJ, Park SY, Lim KY, Joo J, et al. A study of docetaxel and irinotecan in children and young adults with recurrent or refractory Ewing sarcoma family of tumors. BMC Cancer. 2014;14:622.PubMedCentralCrossRefPubMed
44.
Geoerger B, Kieran MW, Grupp S, Perek D, Clancy J, Krygowski M, et al. Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma, and rhabdomyosarcoma. Eur J Cancer. 2012;48:253–62.PubMedCentralCrossRefPubMed
45.
Mascarenhas L, Meyer WH, Lyden E, Rodeberg DA, Indelicato DJ, Linardic CM, et al. Randomized phase II trial of bevacizumab and temsirolimus in combination with vinorelbine and cyclophosphamide for first relapse/disease progression of rhabdomyosarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2014;32:suppl abstr 10003.
46.
Olmos D, Tan DS, Jones RL, Judson IR. Biological rationale and current clinical experience with anti-insulin-like growth factor 1 receptor monoclonal antibodies in treating sarcoma: twenty years from the bench to the bedside. Cancer J. 2010;16:183–94.CrossRefPubMed
47.
Malempati S, Weigel B, Ingle AM, Ahern CH, Carroll JM, Roberts CT, et al. Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30:256–62.PubMedCentralCrossRefPubMed
48.
Weigel B, Malempati S, Reid JM, Voss SD, Cho SY, Chen HX, et al. Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2014;61:452–6.PubMedCentralCrossRefPubMed
49.
Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570–5.PubMedCentralCrossRefPubMed
50.
Choy E, Butrynski JE, Harmon DC, Morgan JA, George S, Wagner AJ, et al. Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer. 2014;14:813.PubMedCentralCrossRefPubMed
51.
Smith MA, Reynolds CP, Kang MH, Kolb EA, Gorlick R, Carol H, et al. Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program. Clin Cancer Res. 2015;21:819–32.CrossRefPubMed
52.
Stewart E, Goshorn R, Bradley C, Griffiths LM, Benavente C, Twarog NR, et al. Targeting the DNA repair pathway in Ewing sarcoma. Cell Rep. 2014;9:829–41.PubMedCentralCrossRefPubMed
53.
Kreahling JM, Gemmer JY, Reed D, Letson D, Bui M, Altiok S. MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. Mol Cancer Ther. 2012;11:174–82.PubMedCentralCrossRefPubMed
54.
Russell MR, Levin K, Rader J, Belcastro L, Li Y, Martinez D, et al. Combination therapy targeting the Chk1 and Wee1 kinases shows therapeutic efficacy in neuroblastoma. Cancer Res. 2013;15(73):776–84.CrossRef
55.
Wagner L, Turpin B, Nagarajan R, Weiss B, Cripe T, Geller J. Pilot study of vincristine, oral irinotecan, and temozolomide (VOIT regimen) combined with bevacizumab in pediatric patients with recurrent solid tumors or brain tumors. Pediatr Blood Cancer. 2013;60:1447–51.CrossRefPubMed
56.
Okada K, Yamasaki K, Tanaka C, Fujisaki H, Osugi Y, Hara J. Phase I study of bevacizumab plus irinotecan in pediatric patients with recurrent/refractory solid tumors. Jpn J Clin Oncol. 2013;43:1073–9.CrossRefPubMed
57.
Pastorino F, Loi M, Sapra P, Becherini P, Cilli M, Emionite L, et al. Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor. Clin Cancer Res. 2010;16:4809–21.CrossRefPubMed
58.
Norris RE, Shusterman S, Gore L, Muscal JA, Macy ME, Fox E, et al. Phase 1 evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children adolescents and young adults with relapsed or refractory solid tumors. Pediatr Blood Cancer. 2014;61:1792–7.CrossRefPubMed
59.
Awada A, Garcia AA, Chan S, Jerusalem GH, Coleman RE, Huizing MT, et al. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study. Lancet Oncol. 2013;14:1216–25.CrossRefPubMed
60.
Vergote IB, Garcia A, Micha J, Pippitt C, Bendell J, Spitz D, et al. Randomized multicenter phase II trial comparing two schedules of etirinotecan pegol (NKTR-102) in women with recurrent platinum-resistant/refractory epithelial ovarian cancer. J Clin Oncol. 2013;31:4060–6.CrossRefPubMed
61.
Kalra AV, Kim J, Klinz SG, Paz N, Cain J, Drummond DC, Nielsen UB, Fitzgerald JB. Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion. Cancer Res. 2014;74:7003–13.CrossRefPubMed
62.
Drummond DC, Noble CO, Guo Z, Hong K, Park JW, Kirpotin DB. Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 2006;66:3271–7.CrossRefPubMed
63.
Kang MH, Wang J, Makena MR, Lee JS, Paz N, Hall CP, et al. Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing’s family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression. Clin Cancer Res. 2015;21:1139–50.CrossRefPubMed
Metadata
Title
Fifteen years of irinotecan therapy for pediatric sarcoma: where to next?
Author
Lars M. Wagner
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Clinical Sarcoma Research / Issue 1/2015
Electronic ISSN: 2045-3329
DOI
https://doi.org/10.1186/s13569-015-0035-x

Other articles of this Issue 1/2015

Clinical Sarcoma Research 1/2015 Go to the issue

Research

High-grade focal areas in low-grade central osteosarcoma: high-grade or still low-grade osteosarcoma?

Research

First line palliative chemotherapy in elderly patients with advanced soft tissue sarcoma

Research

Pazopanib as first line treatment for solitary fibrous tumours: the Royal Marsden Hospital experience

Case Report

Alveolar rhabdomyosarcoma confined to the bone marrow with no identifiable primary tumour using FDG-PET/CT

Case Report

Response to sunitinib of a gastrointestinal stromal tumor with a rare exon 12 PDGFRA mutation

Case Report

Response of conventional chondrosarcoma to gemcitabine alone: a case report
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits