Investigational New Drugs

, Volume 27, Issue 4, pp 366–373 | Cite as

Phase I trial of weekly cisplatin, irinotecan and paclitaxel in patients with advanced gastrointestinal cancer

  • William P. TewEmail author
  • Delia Radovich
  • Eileen O’Reilly
  • Gary Schwartz
  • Deborah Schrag
  • Leonard B. Saltz
  • David P. Kelsen
  • Stacey Kepler
  • David H. Ilson


Objectives: To determine the maximum tolerated dose (MTD), toxicities, and suitable dose for weekly 1-h paclitaxel combined with weekly cisplatin and irinotecan to treat advanced gastrointestinal malignancies. Methods: Thirty patients with metastatic or locally advanced (unresectable or recurrent) gastrointestinal solid tumors were enrolled on this single-center, phase I study. Patients were treated with paclitaxel given over 1h at 1 of 4 dose levels (40, 50, 65, or 80 mg/m2). Paclitaxel was followed by fixed doses of cisplatin (30 mg/m2) and irinotecan (50 mg/m2). All treatment was administered sequentially, once a week, in 6-week cycles (4 weeks on, 2 weeks off). Dose-limiting toxicity (DLT) was defined as a 2-week delay in treatment for grade 3 or 4 non-hematologic toxicity, neutropenic fever, a 1-week delay for grade 4 hematologic toxicity, or a 2-week delay for grade 3 hematologic toxicity. Results: Thirty patients were recruited; 28 patients were assessable for safety. Most of the patients (70%) had no prior chemotherapy. The primary first-cycle DLTs were neutropenia, diarrhea, and nausea. Paclitaxel at 65 mg/m2 was defined as the MTD. The most common grade 3–4 toxicities observed during all cycles were neutropenia (57%), febrile neutropenia (11%), diarrhea (29%), fatigue (29%), and nausea (18%). No patients had G-CSF (Neupogen, Amgen Inc., Thousand Oaks, CA) support. Responses were observed in gastric, esophageal, and pancreatic cancers. Conclusion: Paclitaxel at 65 mg/m2, cisplatin (30 mg/m2), and irinotecan (50 mg/m2) given weekly can be safely administered to patients with solid tumor malignancies. To improve cumulative toxicities, a schedule modification was required (3-week cycle; 2-on, 1-off) Neutropenia was the most common DLT. This combination showed substantial activity, particularly in patients with gastric and esophageal adenocarcinoma, and phase II evaluation could be considered.


Cisplatin Irinotecan Paclitaxel Phase I Gastrointestinal cancer 


  1. 1.
    Jemal A, Siegel R, Ward E et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96. doi: 10.3322/CA.2007.0010 PubMedCrossRefGoogle Scholar
  2. 2.
    Enzinger PC, Mayer RJ (2003) Esophageal cancer. N Engl J Med 349:2241–2252. doi: 10.1056/NEJMra035010 PubMedCrossRefGoogle Scholar
  3. 3.
    Shah MA, Schwartz GK (2004) Treatment of metastatic esophagus and gastric cancer. Semin Oncol 31:574–587. doi: 10.1053/j.seminoncol.2004.04.013 PubMedCrossRefGoogle Scholar
  4. 4.
    Bleiberg H, Conroy T, Paillot B et al (1997) Randomised phase II study of cisplatin and 5-fluorouracil (5-FU) versus cisplatin alone in advanced squamous cell oesophageal cancer. Eur J Cancer 33:1216–1220. doi: 10.1016/S0959-8049(97)00088-9 PubMedCrossRefGoogle Scholar
  5. 5.
    Barone C, Cassano A, Landriscina M et al (2000) Bolus and infusional 5-fluorouracil combined with cisplatin in advanced gastric cancer. Oncol Rep 7:1305–1309PubMedGoogle Scholar
  6. 6.
    Van Custem E, Moiseyenko V, Tjulandin S et al (2006) Phase 3 study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991–4997. doi: 10.1200/JCO.2006.06.8429 CrossRefGoogle Scholar
  7. 7.
    Fukuda M, Nishio K, Kanzawa F et al (1996) Synergism between cisplatin and topoisomerase I inhibitors, NB-506 and SN-38, in human small cell lung cancer cells. Cancer Res 56:789–793PubMedGoogle Scholar
  8. 8.
    Masumoto N, Nakano S, Esaki T et al (1995) Sequence-dependent modulation of anticancer drug activities by 7-ethyl-10-hydroxycamptothecin in an HST-1 human squamous carcinoma cell line. Anticancer Res 15:405–409PubMedGoogle Scholar
  9. 9.
    Kano Y, Suzuki K, Akutsu M (1992) Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer 50:604–610. doi: 10.1002/ijc.2910500420 PubMedCrossRefGoogle Scholar
  10. 10.
    Noda K, Nishiwaki Y, Kawahara M, Japan Clinical Oncology Group et al (2002) Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85–91. doi: 10.1056/NEJMoa003034 PubMedCrossRefGoogle Scholar
  11. 11.
    Hanna N, Bunn PA, Langer C et al (2006) Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:2038–2043. doi: 10.1200/JCO.2005.04.8595 PubMedCrossRefGoogle Scholar
  12. 12.
    Boku N, Ohtsu A, Shimada Y et al (1999) Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer. J Clin Oncol 17:319–323PubMedGoogle Scholar
  13. 13.
    Shirao K, Shimada Y, Kondo H et al (1997) Phase I-II study of irinotecan hydrochloride combined with cisplatin in patients with advanced gastric cancer. J Clin Oncol 15:921–927PubMedGoogle Scholar
  14. 14.
    Saltz LB, Spriggs D, Schaaf LJ et al (1998) Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors. J Clin Oncol 16:3858–3865PubMedGoogle Scholar
  15. 15.
    Ilson DH, Saltz L, Enzinger P et al (1999) Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 17:3270–3275PubMedGoogle Scholar
  16. 16.
    Ajani JA, Baker J, Pisters PW et al (2002) Irinotecan/cisplatin in advanced, treated gastric or gastroesophageal junction carcinoma. Oncology (Williston Park) 16:16–18Google Scholar
  17. 17.
    Ajani JA, Baker J, Pisters PW et al (2002) CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma: results of a phase II study. Cancer 94:641–646. doi: 10.1002/cncr.10279 PubMedCrossRefGoogle Scholar
  18. 18.
    Ilson DH, Bains M, Kelsen DP et al (2003) Phase I trial of escalating-dose irinotecan given weekly with cisplatin and concurrent radiotherapy in locally advanced esophageal cancer. J Clin Oncol 21:2926–2932. doi: 10.1200/JCO.2003.02.147 PubMedCrossRefGoogle Scholar
  19. 19.
    Ajani JA, Walsh G, Komaki R et al (2004) Preoperative induction of CPT-11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction. Cancer 100:2347–2354. doi: 10.1002/cncr.20284 PubMedCrossRefGoogle Scholar
  20. 20.
    Tew W, Minsky B, Bains M et al (2005) Phase II trial of preoperative combined modality therapy for esophageal carcinoma: induction cisplatin–irinotecan followed by concurrent cisplatin–irinotecan and radiotherapy. Proc Am Soc Clin Oncol 23:4017 abstGoogle Scholar
  21. 21.
    Ajani JA, Ilson DH, Daugherty K et al (1994) Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst 86:1086–1091. doi: 10.1093/jnci/86.14.1086 PubMedCrossRefGoogle Scholar
  22. 22.
    Ilson DH, Forastiere A, Arquette M et al (2000) A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer J 6:316–323PubMedGoogle Scholar
  23. 23.
    Ilson D, Wadleigh S, Leichman L et al (2007) Paclitaxel given by weekly one hour infusion in advanced esophageal cancer. Ann Oncol 18:898–902. doi: 10.1093/annonc/mdm004 PubMedCrossRefGoogle Scholar
  24. 24.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216. doi: 10.1093/jnci/92.3.205 PubMedCrossRefGoogle Scholar
  25. 25.
    Ross P, Nicolson M, Cunningham D et al (2002) Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20:1996–2004. doi: 10.1200/JCO.2002.08.105 PubMedCrossRefGoogle Scholar
  26. 26.
    Lin L, Hecht J (2000) A Phase II trial of irinotecan in patients with advanced adenocarcinoma of the GE junction. Proc Am Soc Clin Oncol 19:1130 abstrGoogle Scholar
  27. 27.
    Petrasch S, Welt A, Reinacher A et al (1998) Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer. Br J Cancer 78:511–514PubMedGoogle Scholar
  28. 28.
    Gordon AN, Stringer CA, Matthews CM et al (1997) Phase I dose escalation of paclitaxel in patients with advanced ovarian cancer receiving cisplatin: rapid development of neurotoxicity is dose-limiting. J Clin Oncol 15:1965–1973PubMedGoogle Scholar
  29. 29.
    Wasserheit C, Frazein A, Oratz R et al (1996) Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity. J Clin Oncol 14:1993–1999 Erratum in: J Clin Oncol 14:3175PubMedGoogle Scholar
  30. 30.
    Enzinger PC, Clark J, Ryan D et al (2004) Phase II study of docetaxel, cisplatin, and irinotecan in advanced esophageal and gastric cancer. Proc Am Soc Clin Oncol 22:4040 abstrGoogle Scholar
  31. 31.
    Socinski MA, Sandler AB, Miller LL et al (2001) Phase I trial of the combination of irinotecan, paclitaxel, and carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 19:1078–1087PubMedGoogle Scholar
  32. 32.
    Socinski MA, Sandler AB, Israel VK et al (2002) Phase II trial of irinotecan, paclitaxel and carboplatin in patients with previously untreated Stage IIIB/IV nonsmall cell lung carcinoma. Cancer 95:1520–1527. doi: 10.1002/cncr.10852 PubMedCrossRefGoogle Scholar
  33. 33.
    Frasci G, Nicolella G, Comella P et al (2001) A weekly regimen of cisplatin, paclitaxel and topotecan with granulocyte-colony stimulating factor support for patients with extensive disease small cell lung cancer: a phase II study. Br J Cancer 84:1166–1171. doi: 10.1054/bjoc.2001.1741 PubMedCrossRefGoogle Scholar
  34. 34.
    Frasci G, Panza N, Comella P et al (1999) Cisplatin–topotecan–paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: a dose-finding study. Ann Oncol 10:355–358. doi: 10.1023/A:1008301222560 PubMedCrossRefGoogle Scholar
  35. 35.
    Gonzalez MS, Calvo E, Gassent JM et al (2003) Treatment of advanced non-small cell lung cancer (NSCLC) with a bi-weekly schedule of irinotecan (I), paclitaxel (T) and cisplatinum (P). A feasibility study. Proc Am Soc Clin Oncol 22:2816 abstrGoogle Scholar
  36. 36.
    Herben VM, Panday VR, Richel DJ et al (1999) Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21days as first-line therapy in patients with advanced ovarian cancer. J Clin Oncol 17:747–755PubMedGoogle Scholar
  37. 37.
    D'Adamo DR, Bains M, Minsky B et al (2003) A phase I trial of paclitaxel, cisplatin, irinotecan and concurrent radiation therapy in locally advanced esophageal cancer. Proc Am Soc Clin Oncol 22:1401 abstrGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • William P. Tew
    • 1
    Email author
  • Delia Radovich
    • 2
  • Eileen O’Reilly
    • 2
  • Gary Schwartz
    • 2
  • Deborah Schrag
    • 2
  • Leonard B. Saltz
    • 2
  • David P. Kelsen
    • 2
  • Stacey Kepler
    • 2
  • David H. Ilson
    • 2
  1. 1.Gynecologic Medical Oncology, Medical Oncology Division, Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Gastrointestinal Oncology Services, Medical Oncology Division, Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA

Personalised recommendations