Phase II study of interleukin-2 and 13-cis-retinoic acid as maintenance therapy in metastatic colorectal cancer
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We have previously shown that low-dose interleukin-2 (IL-2) and 13-cis-retinoic acid (13-cis-RA) improved lymphocyte and natural killer (NK) cell count of patients with advanced tumors showing a clinical benefit from chemotherapy. The primary endpoint of this study was to ask whether IL-2 and 13-cis-RA improved (-0%) lymphocyte and NK cell count in patients with metastatic colorectal cancer (MCRC) that had a clinical benefit from induction chemotherapy. Secondary endpoint was the evaluation of toxicity, progression-free survival (PFS), and overall survival (OS).
Patients and methods
Forty patients with MCRC, showing a clinical benefit from chemotherapy, were treated with subcutaneous low-dose IL-2 (1.8 × 106 IU) and oral 13-cis-RA (0.5 mg/kg) in order to maintain responses and improve survival through the increase of lymphocyte and NK cells. The biological parameters and the clinical outcome of these patients were compared with those of a control group of patients (80) with a similar disease status, including clinical benefit from chemotherapy.
The most common adverse events were mild cutaneous skin rash and fever. After 4 months and 2 years of biotherapy, a statistically significant improvement was observed in lymphocyte and number of NK cells with respect to baseline values and to controls. After a median follow-up of 36 months, median PFS was 27.8 months, while median OS was 52.9 months.
These data show that maintenance immunotherapy with low-dose IL-2 and oral 13-cis-RA in patients with MCRC showing a clinical benefit from chemotherapy is feasible, has a low toxicity profile, improves lymphocyte and NK cell count. An improvement in the expected PFS and OS was also observed. A randomized trial is warranted.
KeywordsMaintenance therapy Metastatic colorectal cancer Interleukin-2 13-cis-retinoic acid Lymphocyte Natural killer cells
- 1.Aass N, De Mulder PH, Mickisch GH, Mulders P, van Oosterom AT, van Poppel H, Fossa SD, de Prijck L, Sylvester RJ (2005) Randomized phase II/III trial of interferon alfa-2a with and without 13-cis-retinoic acid in patients with progressive metastatic renal cell carcinoma: the European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951). J Clin Oncol 23:4172–4178CrossRefPubMedGoogle Scholar
- 2.Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A (2004) Multicenter international study of oxaliplatin/5-fluorouracil/leucovorin in the adjuvant treatment of colon cancer (MOSAIC) investigators. N Engl J Med 350:2343–2351CrossRefPubMedGoogle Scholar
- 5.Cascinu S, Graziano F, Valentini M, Catalano V, Giordani P, Staccioli MP, Rossi C, Baldelli AM, Grianti C, Muretto P, Catalano G (2001) Vascular endothelial growth factor expression, S-phase fraction and thymidylate synthase quantitation in node-positive colon cancer: relationships with tumor recurrence and resistance to adjuvant chemotherapy. Ann Oncol 12:239–244CrossRefPubMedGoogle Scholar
- 6.Cesana GC, Gail DeRaffele G, Cohen S, Moroziewicz D, Mitcham J, Stoutenburg J, Cheung K, Hesdorffer C, Kim-Schulze S, Kaufman HL (2006) Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol 24:1169–1177CrossRefPubMedGoogle Scholar
- 7.Correale P, Cusi MG, Tsang KY, Del Vecchio MT, Marsili S, La Placa M, Intrivici C, Equino A, Micheli L, Nencini C, Ferrari F, Giorni G, Bonmassar E, Guido Francini G (2005) Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J Clin Oncol 23:8950–8958CrossRefPubMedGoogle Scholar
- 13.Greco FA, Figlin R, York M, Einhorn L, Schilsky R, Marshall EM, Buys SS, Froimtchuk MJ, Schuller J, Schuchter L, Buyse M, Ritter L, Man A, Yap AK (1996) Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol 14:2674–2681PubMedGoogle Scholar
- 16.Hill M, Norman A, Cunningham D, Findlay M, Nicolson V, Hill A, Iveson A, Evans C, Joffe J, Nicolson M (1995) Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer J Clin Oncol 13:1287–1290Google Scholar
- 18.Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342CrossRefPubMedGoogle Scholar
- 20.Kosmidis PA, Tsavaris N, Skarlos D, Theocharis D, Samantas E, Pavlidis N, Briassoulis E, Fountzilas G (1996) Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Hellenic Cooperative Oncology Group. J Clin Oncol 14:2682–2687PubMedGoogle Scholar
- 23.Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ, British MRC Colorectal Cancer Working Party (2002) Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet 359:1555–1563CrossRefPubMedGoogle Scholar
- 26.Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666CrossRefPubMedGoogle Scholar
- 37.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (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 92:205–216CrossRefPubMedGoogle Scholar