Skip to main content
SpringerLink
Log in

Escalating doses of interferon alpha-2A with cisplatin and concomitant radiotherapy: a phase I study

  • Original Articles
  • Interferon, Cisplatin, Radiotherapy
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

In this phase I study, we added escalating doses of interferon-alpha2A (IFN) to cisplatin and twice-daily radiotherapy based on the following rationale. Radiation enhancement has been shown for both interferon and cisplatin; in addition, potentiation of the cytotoxic activity of cisplatin by interferon has been demonstrated. A total of 48 patients with advanced solid tumors were treated with radiotherapy in 2 daily fractions of 125 cGy plus cisplatin at 8–10 mg/m2 per day delivered on 3 different schedules (continuous infusion, daily short-term infusion, and single short-term infusion of 50 mg/m2). IFN was injected s.c. 2h preceding the first daily fraction of radiation. IFN doses ranged from 0 to 5.0×106 U/m2 per day. All therapy was given over 5 days of every other week until completion of the radiotherapy. Treatment at all dose levels was well tolerated during cycles 1 and 2, with no instance of acute grade 3 or 4 toxicity being noted. However, cumulative myelosuppression in patients receiving more than two treatment cycles was seen at all dose levels and was attributed to the repeated administration of cisplatin. Alteration of the cisplatin schedule did not allow for further dose escalation of cisplatin. Our recommended doses are cisplatin given at 8 mg/m2 per day as a continuous infusion with IFN at 5.0×106 U/m2 per day. Among 24 patients with non-small-cell lung cancer, 2 had a complete response, 9 had a partial response, and 7 had stable disease. We conclude that this concomitant cisplatin-IFN-radiotherapy regimen is feasible. Activity was seen in non-small-cell lung cancer, and further studies of this regimen in that disease appear indicated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ardizzoni A, Rosso R, Salvati F, Scagliotti G, Soresi E, Ferrara G, Pennucci C, Baldini E, Cruciani AR, Antilli A, Tonachella R, Rinaldi M, Genovese G, Crippa M, Gatti E, Fortini C (1991) Combination chemoradiotherapy and interferon alpha-2b in the treatment of advanced non-small-cell lung cancer. The Italian Lung Cancer Task Force. Am J Clin Oncol 14: 120–123

    Google Scholar 

  2. Begg AC (1990) Cisplatin and radiation: interaction probabilities and therapeutic possibilities. Int J Radiat Oncol Biol Phys 19: 1183–1189

    Google Scholar 

  3. Borden EC (1979) Interferons: rationale for clinical trials in neoplastic disease. Ann Intern Med 91: 472–479

    Google Scholar 

  4. Bowman A, Fergusson RJ, Allan SG, Stewart ME, Gregor A, Cornbleet MA, Greening AP, Crompton GK, Leonard RCF, Smyth JF (1990) Potentiation of cisplatin by alpha-interferon in advanced non-small-cell lung cancer (NSCLC): a phase II study. Ann Oncol 1: 351–353

    Google Scholar 

  5. Carmichael J, Fergusson RJ, Wolf CR, Balkwill FR, Smyth JF (1986) Augmentation of cytotoxicity of chemotherapy by human α-interferons in human non-small-cell lung cancer xenografts. Cancer Res 46: 4916–4920

    Google Scholar 

  6. Chang AYC, Keng PC (1987) Potentiation of radiation cytotoxicity by recombinant interferons, or phenomenon associated with increased blockage at the G2-M phase of the cell cycle. Cancer Res 47: 4338–4341

    Google Scholar 

  7. Cockeroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16: 31–41

    Google Scholar 

  8. Devine S, Vokes EE, Weichselbaum RR (1991) Chemotherapeutic and biologic radiation enhancement. Current Opin Oncol 3: 1087–1095

    Google Scholar 

  9. Deyton LR, Walker RE, Kovacs JA, Herpin B Parker M, Masur H, Fauci AS, Clifford Lane H (1989) Reversible cardiac dysfunction associated with interferon alfa therapy in AIDS patients with Kaposi's sarcoma. N Engl J Med 321: 1246–1249

    Google Scholar 

  10. Dritschilo A, Mossman K, Gary M, Sreevalsan T (1982) Potentiation of radiation injury by interferon. Am J Clin Oncol 5: 79–82

    Google Scholar 

  11. Fu KK, Phillips TL, Silverbeg IY, Jacobs C, Goffinet DR, Chun C, Friedman MA, Kohler M, McWhirter K, Carter SK (1987) Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial. J Clin Oncol 5: 1410–1418

    Google Scholar 

  12. Fu KK, Phillips TL (1991) Biologic rationale of combined radiotherapy and chemotherapy. Hematol Oncol Clin North Am 5: 737–751

    Google Scholar 

  13. Gould MN, Kakria RC, Olson S, Bordon EC (1984) Radiosensitization of human bronchogenic carcinoma cells by interferon beta. J Interferon Res 4: 123–128

    Google Scholar 

  14. Gutterman JD, Fine S, Quesada J, Horning SJ, Levine JF, Alexanian R, Bernhardt L, Kramer M, Spiegel H, Colburn W, Trown P, Merigan T, Dziewanowski Z (1982) Recombinant leukocyte A interferon: pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Ann Intern Med 96: 549–556

    Google Scholar 

  15. Herskovic A, Martz K, Al-Sarraf M, Leichman, L, Brindle J, Vaitkevicius V, Cooper J, Byhard R, Davis L, Emami B (1992) Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 32: 1593–1598

    Google Scholar 

  16. Hoffman P, Drinkard L, Haraf D, Golomb H, Ferguson M, Vogelzang NJ, Vokes E (1993) Intensive concomitant chemoradiotherapy with cisplatin dose escalation in advanced chest malignancies: a phase I study (abstract). Proc Am Soc Clin Oncol 12: 357

    Google Scholar 

  17. Holsti LR, Mattson K, Niiranen A, Standertskiold-Nordenstam CG, Stenman S, Sovijarvi A, Cantell K (1987) Enhancement of radiation effects by alpha interferon in the treatment of small-cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 13: 1161–1166

    Google Scholar 

  18. Hong WS, Lee JO, Kang TW, Kim YW, Song JK, Yun TK (1989) Enhancement of cytotoxicity of cisplatin in vitro by recombinant human tumor necrosis factor and/or recombinant human interferonalpha, beta, and-gamma. Jpn J Cancer Res 80: 904–909

    Google Scholar 

  19. Horiot JC, LeFur R, N'Guyen T, Chenal C, Schraub S, Alfonsi S, Gardani G, Van Den Bogaert W, Danczak S, Bolla M, Van Glabbeke M, DePauw M (1992) Hyperfractionated versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC Cooperative Group on Radiotherapy. Radiother Oncol 25: 231–241

    Google Scholar 

  20. Hreshchyshyn MM, Aron BS, Boronow RC, Franklin EW, Shingleton HM, Blessing JA (1979) Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys 5: 317–322

    Google Scholar 

  21. Kallman RF, Rapacchietta D, Zaghloul MS (1991) Schedule-dependent therapeutic gain from the combination of fractionated irradiation plus c-DDP and 5-FU or plus c-DDP and cyclophosphamide in C3H/Km mouse model systems. Int J Radiat Oncol Biol Phys 20: 227–232

    Google Scholar 

  22. Kanazawa H, Rapacchietta D, Kallman RF (1988) Schedule-dependent therapeutic gain from the combination of fractionated irradiation andcis-diamminedichloroplatinum(II) in C3H/Km mouse model systems. Cancer Res 48: 3158–3164

    Google Scholar 

  23. Kardamakis D, Gillies NE, Souhami RL, Bewerley PCL (1989) Recombinant human interferon alpha-2b enhances the radiosensitivity of small cell lung cancer in vitro. Anticancer Res 9: 1041–1044

    Google Scholar 

  24. Kirkwood JM, Ernstoff MS (1984) Interferons in the treatment of human cancer. J Clin Oncol 2: 336–352

    Google Scholar 

  25. Kyle G, Woolley P, Kumar S, Mossman K (1985) Antiproliferative effect of human recombinant interferon in combination with radiation and chemotherapeutic drugs in five human cell lines. Proc Am Assoc Cancer Res 26: 2327

    Google Scholar 

  26. Laaksonen R, Niiranen A, Iivanainen M, Mattson K, Holsti L, Färkkilä M Cantell K (1988) Dementia-like, largely reversible syndrome after cranial irradiation and prolonged interferon treatment. Ann Clin Res 20: 201–203

    Google Scholar 

  27. Lelieveld P, Scoles MA, Brown JM, Kallman RF (1985) The effect of treatment in fractionated schedules with the combination of X-irradiation and six cytotoxic drugs on the RIF-1 tumor and normal mouse skin. Int J Radiat Oncol Biol Phys 11: 111–121

    Google Scholar 

  28. Lo TC, Wiley AL Jr, Ansfield FJ, Brandenburg JH, Davis Jr HL, Gollin FF, Johnson RO, Ramirez G, Vermund H (1976) Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: a randomized study. AJR 126: 229–235

    Google Scholar 

  29. Lvovsky EA, Mossman KL, Levy HB, Dritschilo A (1985) Response of mouse tumor to interferon inducer and radiation. Int J Radiat Oncol Biol Phys 11: 1721–1725

    Google Scholar 

  30. Maasilta P, Holsti LR, Halme M, Kivisaari L, Cantel K, Mattson K (1992) Natural alpha-interferon in combination with hyperfractionated radiotherapy in the treatment of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 23: 863–868

    Google Scholar 

  31. Merlano M, Vitale V, Rosso R, Benasso M, Corvo R, Cavallari M, Sanguineti G, Bacigalupo A, Badellino F, Margarino G, Brema F, Pastorino G, Marziano C, Grimaldi A, Scasso F, Sperati G, Pallestrini E, Garaventa G, Accomando E, Cordone G, Comella G, Daponte A, Rubagotti A, Bruzzi P, Santi L (1992) Treatment of advanced squmous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 327: 1115–1121

    Google Scholar 

  32. Namba M, Yamamoto S, Tanaka H, Kanamori T, Nobuhara M, Kimoto T (1984) In vitro and in vivo studies on potentiation of cytotoxic effects of anticancer drugs or cobalt 60 gamma ray by interferon on human neoplastic cells. Cancer 54: 2262–2267

    Google Scholar 

  33. Rosell R, Carles J, Ariza A, Moreno I, Ribelles N, Solano V, Pellicer I, Barnadas A, Abad A (1991) A phase II study of days 1 and 8 cisplatin and recombinant alpha-2B interferon in advanced non-small-cell lung cancer. Cancer 67: 2448–2453

    Google Scholar 

  34. Rosso R, Ardizzoni A, Salvati F, Rinaldi M, Rubagotti A, Pennucci C, Tonachella R, De Marinis F, Rinaldi M, Mantellini E, Soresi E, Ferrara G, Romano F, Bandera M, Martini M, Fortini C, for the Italian Lung Cancer Task Ford (FONICAP) (1990) Combination chemotherapy and recombinant (R) alfa interferon (IFN) for metastatic non-small cell lung cancer (NSCLC): a randomized FONICAP trial (abstract). Proc Am Soc Clin Oncol 9: 227

    Google Scholar 

  35. Schaake-Koning C, Van Den Bogaert W, Dalesio O, Festen J, Hoogenhout J, Van Houtte P, Kirkpatrick A, Koolen M, Maat B, Nijs A, Renaud A, Rodrigus P, Schuster-Uitterhoeve L, Sculier J-P, Van Zandwijk N, Bartelink H (1992) Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326: 524–530

    Google Scholar 

  36. Schwachöfer JH, Crooijmans MA, Hoogenhout J, Kal HB, Theeuwes GM (1991) Effectiveness in inhibition of recovery of cell survival by cisplatin and carboplatin: influence of treatment sequence. Int J Radiat Oncol Biol Phys 20: 1235–1241

    Google Scholar 

  37. Sklarin NT, Chahinian AP, Feuer EJ, Lahman LA, Szrajer L, Holland JF (1988) Augmentation of activity ofcis-diammine-dichloroplatinum(II) and mitomycin-C by interferon in human malignant mesothelioma xenografts in nude mice. Cancer Res 48: 64–67

    Google Scholar 

  38. Sonnenblick M, Rosin A (1991) Cardiotoxicity of interferon: a review of 44 cases. Chest 99: 557

    Google Scholar 

  39. Tanabe M, Godat D, Kallman RF (1987) Effects of fractionated schedules of irradiation combined withcis-diamminedichloroplatinum(II) on the SCCVII/ST tumor and normal tissues of the C3H/KM mouse. Int J Radiat Oncol Biol Phys 13: 1523–1532

    Google Scholar 

  40. Terheggen PM, Emondt JY, Floot BG, Dijkman R, Schrier PI, Engelse L den, Begg AC (1990) Correlation between cell killing bycis-diamminedichloroplatinum(II) in six mammalian cell lines and binding of acis-diamminedichloroplatinum(II)-DNA antiserum. Cancer Res 50: 3556–3561

    Google Scholar 

  41. Third International Conference on the Interaction of Radiation Therapy and Systemic Therapy (1991) Int J Radiat Oncol Biol Phys 20: 195–386

    Google Scholar 

  42. Torrisi J, Berg C, Bonnem E, Dritschilo A (1986) The combined use of interferon and radiotherapy in cancer management. Semin Oncol 13 [Suppl 2]: 78–83

    Google Scholar 

  43. Vokes EE, Weichselbaum RR (1990) Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol 8: 911–934

    Google Scholar 

  44. Vokes EE, Ackland SP, Vogelzang NJ (1990) Cisplatin, carboplatin, and gallium nitrate. In: Lokich JJ (ed) Cancer chemotherapy by infusion, 2nd edn. Precept, Chicago, pp 176–196

    Google Scholar 

  45. Vokes EE (1992) Concomitant chemoradiotherapy for solid tumors: rationale and clinical experience. Proceedings of a symposium. Semin Oncol 19 [Suppl 11]: 1–102

    Google Scholar 

  46. Vokes EE (1993) The interaction of chemotherapy and radiation. Semin Oncol 20: 70–79

    Google Scholar 

  47. Vokes EE, Weichselbaum RR, Lippman S, Hong WK (1993) Head and neck cancer. N Engl J Med 328: 184–194

    Google Scholar 

  48. Vokes EE, Ratain MJ, Mick R, McEvilly J-M, Haraf D, Hamasaki V, Kozloff M, Weichselbaum RR, Panje WR, Wenig B, Berezin F (1993) Cisplatin, fluorouracil and leucovorin augmented by interferon alfa-2B in head and neck cancer: a clinical and pharmacologic analysis. J Clin Oncol 11: 360–368

    Google Scholar 

  49. Wadler S, Schwartz EL, Goldman M, Lyver A, Rader M, Zimmerman M, Itri L, Weinberg V, Wiernik PH (1989) Fluorouracil and recombinant alfa-2a-interferon: an active regimen against advanced colorectal carcinoma. J Clin Oncol 7: 1769

    Google Scholar 

  50. Wadler S, Schwartz EL (1990) Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res 50: 3474–3486

    Google Scholar 

  51. Weissberg JB, Son YH, Papac RJ, Sasaki C, Fischer DB, Lawrence R, Rockwell S, Sartorelli AC, Fischer JJ (1989) Randomized clinical trial of mitomycin-C as an adjunct to radiotherapy in head and neck cancer. Int J Radiat Oncol Biol Phys 17: 3–9

    Google Scholar 

  52. Zak M, Drobnik J (1971) Effects ofcis-dichlorodiammineplatinum(II) on the post-irradiation lethality in mice after irradiation with X-rays. Strahlentherapie 142: 112–115

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Hematology/Oncology, University of Chicago, 60637, Chicago, IL, USA

    Everett E. Vokes & Philip C. Hoffman

  2. Department of Radiation and Cellular Oncology, University of Chicago, 60637, Chicago, IL, USA

    Everett E. Vokes & Daniel J. Haraf

Authors
  1. Everett E. Vokes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel J. Haraf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip C. Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vokes, E.E., Haraf, D.J. & Hoffman, P.C. Escalating doses of interferon alpha-2A with cisplatin and concomitant radiotherapy: a phase I study. Cancer Chemother. Pharmacol. 33, 203–209 (1993). https://doi.org/10.1007/BF00686217

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00686217

Keywords

Search

Navigation