Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Dec 8;82(1):104–111. doi: 10.1054/bjoc.1999.0885

A phase II study of cisplatin and 5-fluorouracil with concurrent hyperfractionated thoracic radiation for locally advanced non-small-cell lung cancer: a preliminary report from the Okayama Lung Cancer Study Group

Y Segawa 1, H Ueoka 2, K Kiura 2, H Kamei 2, M Tabata 2, K Sakae 3, Y Hiraki 3, S Kawahara 4, K Eguchi 1, S Hiraki 5, Mine Harada for the Okayama Lung Cancer Study Group 2
PMCID: PMC2363201  PMID: 10638975

Abstract

A recent meta-analysis and randomized studies have demonstrated that combined chemoradiotherapy is associated with a survival advantage for selected patients with locally advanced unresectable non-small-cell lung cancer (NSCLC). We conducted a phase II study of combined chemoradiotherapy to find a more effective combination of drugs and radiation than those previously reported for such patients. Between January 1994 and November 1996, 50 previously untreated patients with locally advanced unresectable NSCLC (stage IIIA with N2 or IIIB disease) were entered in this study. Patients were required to have Eastern Cooperative Oncology Group performance status ≤ 2, age ≤ 75 years and adequate organ function. Treatment consisted of three cycles of cisplatin (20 mg m−2, days 1–5) and 5-fluorouracil (5-FU) (500 mg m−2, days 1–5) every 4 weeks, and concurrent hyperfractionated thoracic radiation (1.25 Gy twice daily, with a 6-h interfraction interval; total radiation dose, 62.5–70 Gy). Of the 50 patients entered, 37 (74%) responded to this chemoradiotherapy, including two (4%) with complete response. By a median follow-up time of 41.0 months, 35 patiennts had died and 15 were stil alive. The median time to progression for responding patients was 14.1 months (range, 2.6–51.3+ months). The median survival time was 18.7 months, with a survival rate of 66.0% at 1 year, 46.0% at 2 years and 27.6% at 3 years. Survival outcome was strongly affected by the extent of nodal involvement (median survival time, 27.4 months for N0–2 disease (n = 37) vs 10.7 months for N3 disease (n = 13);P = 0.007). The major toxicities of treatment were leukopenia and neutropenia (≥ Grade 3, 58% and 60% respectively). Other toxicities of ≥ Grade 3 included thrombocytopenia (26%), anaemia (26%), nausea/vomiting (16%) and radiation oesophagitis (6%). Treatment-related death occurred for one patient. Our findings suggest that cisplatin and 5-FU in combination with concurrent hyperfractionated thoracic radiation is effective and feasible for the treatment of locally advanced unresectable NSCLC. The short-term survival in this study appeared to be more encouraging than those of similar chemoradiation trials. A randomized trial will be needed to compare the combination of cisplatin and 5-FU with other platinum-based regimens together with concurrent hyperfractionated thoracic radiation. In addition, in future studies, inclusion criteria for N3 disease with or without supraclavicular involvement should be reconsidered to correctly evaluate the effect of combined chemoradiotherapy for locally advanced unresectable NSCLC. © 2000 Cancer Research Campaign

Keywords: combined chemoradiotherapy, hyperfractionated thoracic radiation, cisplatin, 5-fluorouracil, non-small-cell lung cancer

Full Text

The Full Text of this article is available as a PDF (103.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albain K. S., Rusch V. W., Crowley J. J., Rice T. W., Turrisi A. T., 3rd, Weick J. K., Lonchyna V. A., Presant C. A., McKenna R. J., Gandara D. R. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol. 1995 Aug;13(8):1880–1892. doi: 10.1200/JCO.1995.13.8.1880. [DOI] [PubMed] [Google Scholar]
  2. Blanke C., Ansari R., Mantravadi R., Gonin R., Tokars R., Fisher W., Pennington K., O'Connor T., Rynard S., Miller M. Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol. J Clin Oncol. 1995 Jun;13(6):1425–1429. doi: 10.1200/JCO.1995.13.6.1425. [DOI] [PubMed] [Google Scholar]
  3. Blanke C., DeVore R., Shyr Y., Epstein B., Murray M., Hande K., Stewart S., Johnson D. A pilot study of protracted low dose cisplatin and etoposide with concurrent thoracic radiotherapy in unresectable stage III nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys. 1997 Jan 1;37(1):111–116. doi: 10.1016/s0360-3016(96)00478-6. [DOI] [PubMed] [Google Scholar]
  4. Bonner J. A., McGinnis W. L., Stella P. J., Marschke R. F., Jr, Sloan J. A., Shaw E. G., Mailliard J. A., Creagan E. T., Ahuja R. K., Johnson P. A. The possible advantage of hyperfractionated thoracic radiotherapy in the treatment of locally advanced nonsmall cell lung carcinoma: results of a North Central Cancer Treatment Group Phase III Study. Cancer. 1998 Mar 15;82(6):1037–1048. [PubMed] [Google Scholar]
  5. Choy H., Akerley W., Safran H., Graziano S., Chung C., Williams T., Cole B., Kennedy T. Multiinstitutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer. J Clin Oncol. 1998 Oct;16(10):3316–3322. doi: 10.1200/JCO.1998.16.10.3316. [DOI] [PubMed] [Google Scholar]
  6. Citron M. L., Modeas C., Propert K., Goutsou M., Green M. R. Phase II trial of high-dose 24-hour continuous intravenous 5-fluorouracil for advanced non-small cell lung cancer: a Cancer and Leukemia Group B study. Cancer Invest. 1992;10(3):215–219. doi: 10.3109/07357909209032763. [DOI] [PubMed] [Google Scholar]
  7. Clamon G., Herndon J., Cooper R., Chang A. Y., Rosenman J., Green M. R. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol. 1999 Jan;17(1):4–11. doi: 10.1200/JCO.1999.17.1.4. [DOI] [PubMed] [Google Scholar]
  8. Cox J. D., Azarnia N., Byhardt R. W., Shin K. H., Emami B., Pajak T. F. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11. J Clin Oncol. 1990 Sep;8(9):1543–1555. doi: 10.1200/JCO.1990.8.9.1543. [DOI] [PubMed] [Google Scholar]
  9. Dillman R. O., Herndon J., Seagren S. L., Eaton W. L., Jr, Green M. R. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996 Sep 4;88(17):1210–1215. doi: 10.1093/jnci/88.17.1210. [DOI] [PubMed] [Google Scholar]
  10. Eberhardt W., Wilke H., Stamatis G., Stuschke M., Harstrick A., Menker H., Krause B., Müeller M. R., Stahl M., Flasshove M. Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer: mature results of a phase II trial. J Clin Oncol. 1998 Feb;16(2):622–634. doi: 10.1200/JCO.1998.16.2.622. [DOI] [PubMed] [Google Scholar]
  11. Esaki T., Nakano S., Tatsumoto T., Kuroki-Migita M., Mitsugi K., Nakamura M., Niho Y. Inhibition by 5-fluorouracil of cis-diamminedichloroplatinum(II)-induced DNA interstrand cross-link removal in a HST-1 human squamous carcinoma cell line. Cancer Res. 1992 Dec 1;52(23):6501–6506. [PubMed] [Google Scholar]
  12. Furuse K., Kubota K., Kawahara M., Kodama N., Ogawara M., Akira M., Nakajima S., Takada M., Kusunoki Y., Negoro S. Phase II study of concurrent radiotherapy and chemotherapy for unresectable stage III non-small-cell lung cancer. Southern Osaka Lung Cancer Study Group. J Clin Oncol. 1995 Apr;13(4):869–875. doi: 10.1200/JCO.1995.13.4.869. [DOI] [PubMed] [Google Scholar]
  13. Gemma A., Kudoh S., Yoshimura A., Ono Y., Takenaka K., Hayashihara K., Hino M., Shibuya M., Niitani H. Pilot trial of a combination comprising of consecutive oral administration of UFT, and two-divided administration of CDDP in non-small cell lung cancer. Anticancer Res. 1995 Nov-Dec;15(6B):2691–2695. [PubMed] [Google Scholar]
  14. Jeremic B., Shibamoto Y., Acimovic L., Djuric L. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol. 1995 Feb;13(2):452–458. doi: 10.1200/JCO.1995.13.2.452. [DOI] [PubMed] [Google Scholar]
  15. Jeremic B., Shibamoto Y., Acimovic L., Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. J Clin Oncol. 1996 Apr;14(4):1065–1070. doi: 10.1200/JCO.1996.14.4.1065. [DOI] [PubMed] [Google Scholar]
  16. Jeremic B., Shibamoto Y., Milicic B., Nikolic N., Dagovic A., Milisavljevic S. Concurrent radiochemotherapy for patients with stage III non-small-cell lung cancer (NSCLC): long-term results of a phase II study. Int J Radiat Oncol Biol Phys. 1998 Dec 1;42(5):1091–1096. doi: 10.1016/s0360-3016(98)00283-1. [DOI] [PubMed] [Google Scholar]
  17. Kemeny N., Israel K., Niedzwiecki D., Chapman D., Botet J., Minsky B., Vinciguerra V., Rosenbluth R., Bosselli B., Cochran C. Randomized study of continuous infusion fluorouracil versus fluorouracil plus cisplatin in patients with metastatic colorectal cancer. J Clin Oncol. 1990 Feb;8(2):313–318. doi: 10.1200/JCO.1990.8.2.313. [DOI] [PubMed] [Google Scholar]
  18. Lau D. H., Crowley J. J., Gandara D. R., Hazuka M. B., Albain K. S., Leigh B., Fletcher W. S., Lanier K. S., Keiser W. L., Livingston R. B. Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer. J Clin Oncol. 1998 Sep;16(9):3078–3081. doi: 10.1200/JCO.1998.16.9.3078. [DOI] [PubMed] [Google Scholar]
  19. Le Chevalier T., Arriagada R., Quoix E., Ruffie P., Martin M., Tarayre M., Lacombe-Terrier M. J., Douillard J. Y., Laplanche A. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst. 1991 Mar 20;83(6):417–423. doi: 10.1093/jnci/83.6.417. [DOI] [PubMed] [Google Scholar]
  20. Lee J. S., Scott C., Komaki R., Fossella F. V., Dundas G. S., McDonald S., Byhardt R. W., Curran W. J., Jr Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: radiation therapy oncology group protocol 91-06. J Clin Oncol. 1996 Apr;14(4):1055–1064. doi: 10.1200/JCO.1996.14.4.1055. [DOI] [PubMed] [Google Scholar]
  21. Lynch T. J., Jr, Kalish L. A., Kass F., Strauss G., Elias A., Skarin A., Shulman L., Sugarbaker D., Frei E. Continuous-infusion cisplatin, 5-fluorouracil, and leucovorin for advanced non-small cell lung cancer. Cancer. 1994 Feb 15;73(4):1171–1176. doi: 10.1002/1097-0142(19940215)73:4<1171::aid-cncr2820730408>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  22. Miller A. B., Hoogstraten B., Staquet M., Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207–214. doi: 10.1002/1097-0142(19810101)47:1<207::aid-cncr2820470134>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  23. Mountain C. F. A new international staging system for lung cancer. Chest. 1986 Apr;89(4 Suppl):225S–233S. doi: 10.1378/chest.89.4_supplement.225s. [DOI] [PubMed] [Google Scholar]
  24. Paesmans M., Sculier J. P., Libert P., Bureau G., Dabouis G., Thiriaux J., Michel J., Van Cutsem O., Sergysels R., Mommen P. Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients. The European Lung Cancer Working Party. J Clin Oncol. 1995 May;13(5):1221–1230. doi: 10.1200/JCO.1995.13.5.1221. [DOI] [PubMed] [Google Scholar]
  25. Roach M., 3rd, Gandara D. R., Yuo H. S., Swift P. S., Kroll S., Shrieve D. C., Wara W. M., Margolis L., Phillips T. L. Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors. J Clin Oncol. 1995 Oct;13(10):2606–2612. doi: 10.1200/JCO.1995.13.10.2606. [DOI] [PubMed] [Google Scholar]
  26. Rooney M., Kish J., Jacobs J., Kinzie J., Weaver A., Crissman J., Al-Sarraf M. Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer. 1985 Mar 1;55(5):1123–1128. doi: 10.1002/1097-0142(19850301)55:5<1123::aid-cncr2820550530>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  27. Saunders M. I., Dische S., Barrett A., Parmar M. K., Harvey A., Gibson D. Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small-cell lung cancer: an interim report. CHART Steering Committee. Br J Cancer. 1996 Jun;73(12):1455–1462. doi: 10.1038/bjc.1996.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sause W. T., Scott C., Taylor S., Johnson D., Livingston R., Komaki R., Emami B., Curran W. J., Byhardt R. W., Turrisi A. T. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995 Feb 1;87(3):198–205. doi: 10.1093/jnci/87.3.198. [DOI] [PubMed] [Google Scholar]
  29. Scanlon K. J., Newman E. M., Lu Y., Priest D. G. Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci U S A. 1986 Dec;83(23):8923–8925. doi: 10.1073/pnas.83.23.8923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Segawa Y., Takigawa N., Kataoka M., Takata I., Fujimoto N., Ueoka H. Risk factors for development of radiation pneumonitis following radiation therapy with or without chemotherapy for lung cancer. Int J Radiat Oncol Biol Phys. 1997 Aug 1;39(1):91–98. doi: 10.1016/s0360-3016(97)00297-6. [DOI] [PubMed] [Google Scholar]
  31. Strauss G. M., Herndon J. E., Sherman D. D., Mathisen D. J., Carey R. W., Choi N. C., Rege V. B., Modeas C., Green M. R. Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIA non-small-cell carcinoma of the lung: report of a Cancer and Leukemia Group B phase II study. J Clin Oncol. 1992 Aug;10(8):1237–1244. doi: 10.1200/JCO.1992.10.8.1237. [DOI] [PubMed] [Google Scholar]
  32. Tsuchiya S., Minato K., Nakano H., Takise A., Ezawa K., Fueki N., Hoshino H., Naruse I., Takei Y., Makimoto T. A phase II study of 72-hour continuous infusion consisting of cisplatin and 5-fluorouracil for treatment of non-small cell lung cancer. Oncology. 1995 May-Jun;52(3):246–250. doi: 10.1159/000227466. [DOI] [PubMed] [Google Scholar]
  33. Vokes E. E., Weichselbaum R. R. Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol. 1990 May;8(5):911–934. doi: 10.1200/JCO.1990.8.5.911. [DOI] [PubMed] [Google Scholar]
  34. Weiden P. L., Piantadosi S. Preoperative chemotherapy (cisplatin and fluorouracil) and radiation therapy in stage III non-small-cell lung cancer: a phase II study of the Lung Cancer Study Group. J Natl Cancer Inst. 1991 Feb 20;83(4):266–273. doi: 10.1093/jnci/83.4.266. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES