Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1997;76(11):1509–1517. doi: 10.1038/bjc.1997.586

Cisplatin and vinorelbine followed by ifosfamide plus epirubicin vs the opposite sequence in advanced unresectable stage III and metastatic stage IV non-small-cell lung cancer: a prospective randomized study of the Southern Italy Oncology Group (GOIM).

G Colucci 1, V Gebbia 1, D Galetta 1, F Riccardi 1, S Cariello 1, N Gebbia 1
PMCID: PMC2228170  PMID: 9400950

Abstract

A multicentric, prospective phase III study was carried out with the aim of testing the so-called 'worst drug rule' hypothesis, which suggests the use of an effective but 'less active' regimen that first eradicates tumoral cells resistant to a second effective and 'more active' regimen. With respect to this hypothesis, we considered the cisplatin plus vinorelbine regimen (CCDP/VNR) as the more active regimen compared with the non-cisplatin-containing regimen of ifosfamide plus high-dose epirubicin (IFO/EPI). Thus, a randomized study was carried out to compare the sequencial strategy of three cycles of CDDP/VNR followed by three cycles of IFO/EPI with the opposite sequence in advanced non-small-cell lung cancer. A total of 100 consecutive previously untreated patients with stage III-IV non-small-cell lung cancer were centrally randomized in two arms according to stage of disease and the performance status. Patients allocated to arm A received CDDP (100 mg m-2 on day 1) plus VNR (25 mg m-2 i.v. on days 1 and 8) every 21 days for three cycles (step 1) followed, after restaging, by three cycles of IFO (2.5 g m-2 with mesna on day 1) plus high-dose EPI (100 mg m-2 on day 1) every 21 days (step 2). Patients in arm B received the opposite sequence. Type and rates of objective response were evaluated after step 1 and step 2 in agreement with WHO criteria and an intent-to-treat analysis. Patients were also analysed for toxicity patterns, time to progression and survival. After the first three cycles (step 1), overall response rate (ORR), calculated according to an intent-to-treat analysis, was 47% and 21% for arm A and arm B respectively (P = 0.0112). ORR for stage III patients was 55% and 14% for arm A and B respectively (P = 0.0097). In stage IV patients ORR was higher in arm A than in arm B (42% vs 28%) but not statistically significant (P = 0.4). Clinical responses to the shift of chemotherapy (step 2) showed that no patient pretreated with CDDP/VNR and subsequently treated with IFO/EPI showed further response, whereas in the inverse sequence arm CDDP/VNR was able to induce 26% partial response (PR) rate in patients pretreated with IFO/EPI. This difference was statistically significant (P = 0.037). The overall median time to progression (TTP) of arm A and arm B did not significantly differ (6 vs 4 months; P = 0.665). However, median TTP of stage III patients was, respectively, 7 months for arm A and only 3 months for arm B. This difference was statistically significant (P = 0.049). Median overall survival (OS) was 9 and 7 months respectively for arm A and arm B. Despite this trend the difference was not significant (P = 0.328). Median OS of stage III patients showed a statistically significant advantage for arm A over arm B (13 vs 7 months, P = 0.03). In addition, no statistically significant difference in OS was recorded for stage IV patients (both arms 7 months, P = 0.526). Our data do not confirm Day's 'worst drug rule' hypothesis, at least in patients with advanced non-small-cell lung cancer treated with the above-mentioned regimens. The combination of CDDP and VNR seems more active, at least in terms of response rate, than the IFO/EPI, which performed poorly.

Full text

PDF
1517

Selected References

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

  1. Alberola V., Rosell R., González-Larriba J. L., Molina F., Ayala F., García-Conde J., Benito D., Pérez J. M. Single agent Taxol, 3-hour infusion, in untreated advanced non-small-cell lung cancer. Ann Oncol. 1995;6 (Suppl 3):S49–S52. doi: 10.1093/annonc/6.suppl_3.s49. [DOI] [PubMed] [Google Scholar]
  2. Brocato N., Bruno M. F., Araujo C. E., Cervellino J. C., Pirisi C., Temperley G., Sparrow C., Savulsky C., Balbiani L. R. Treatment of non-small cell lung cancer with ifosfamide (IFO)+ 4'-epiadriamycin (EPI)+platinum vs. IFO+EPI: a GETLAC Study. Grupo de Estudio y Tratamiento Latinoamericano del Cáncer Study. Oncology. 1995 Jan-Feb;52(1):24–31. doi: 10.1159/000227422. [DOI] [PubMed] [Google Scholar]
  3. Carney D. N. Chemotherapy in the management of patients with inoperable non-small cell lung cancer. Semin Oncol. 1996 Dec;23(6 Suppl 16):71–75. [PubMed] [Google Scholar]
  4. Crinò L., Clerici M., Figoli F., Carlini P., Ceci G., Cortesi E., Carpi A., Santini A., Di Costanzo F., Boni C. Chemotherapy of advanced non-small-cell lung cancer: a comparison of three active regimens. A randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.). Ann Oncol. 1995 Apr;6(4):347–353. doi: 10.1093/oxfordjournals.annonc.a059183. [DOI] [PubMed] [Google Scholar]
  5. Cullen M. H. Mitomycin, ifosfamide, and cisplatin in non-small cell lung cancer. Oncology. 1993 Apr;50 (Suppl 1):31–34. doi: 10.1159/000227245. [DOI] [PubMed] [Google Scholar]
  6. Depierre A., Chastang C., Quoix E., Lebeau B., Blanchon F., Paillot N., Lemarie E., Milleron B., Moro D., Clavier J. Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial. Ann Oncol. 1994 Jan;5(1):37–42. doi: 10.1093/oxfordjournals.annonc.a058687. [DOI] [PubMed] [Google Scholar]
  7. Ettinger D. S. Overview of paclitaxel (Taxol) in advanced lung cancer. Semin Oncol. 1993 Aug;20(4 Suppl 3):46–49. [PubMed] [Google Scholar]
  8. Feld R., Wierzbicki R., Walde P. L., Shepherd F. A., Evans W. K., Gupta S., Shannon P., Lassus M. Phase I-II study of high-dose epirubicin in advanced non-small-cell lung cancer. J Clin Oncol. 1992 Feb;10(2):297–303. doi: 10.1200/JCO.1992.10.2.297. [DOI] [PubMed] [Google Scholar]
  9. Fukuoka M., Masuda N., Furuse K., Negoro S., Takada M., Matsui K., Takifuji N., Kudoh S., Kawahara M., Ogawara M. A randomized trial in inoperable non-small-cell lung cancer: vindesine and cisplatin versus mitomycin, vindesine, and cisplatin versus etoposide and cisplatin alternating with vindesine and mitomycin. J Clin Oncol. 1991 Apr;9(4):606–613. doi: 10.1200/JCO.1991.9.4.606. [DOI] [PubMed] [Google Scholar]
  10. Gebbia V., Caruso M., Valenza R., Testa A., Cannata G., Verderame F., Cipolla C., Curto G., Oliveri D., Chiarenza M. Vinorelbine plus cisplatinum for the treatment of stage IIIB and IV non small cell lung carcinoma. Anticancer Res. 1994 May-Jun;14(3B):1247–1249. [PubMed] [Google Scholar]
  11. Gebbia V., Galetta D., Majello E., Valenza R., Colucci G., Gebbia N. Treatment of stage III-IV non-small-cell lung carcinoma with vinorelbine in combination with ifosfamide plus MESNA: a study by the Southern Italy Oncology Group (GOIM). Am J Clin Oncol. 1996 Jun;19(3):278–280. doi: 10.1097/00000421-199606000-00014. [DOI] [PubMed] [Google Scholar]
  12. Goldie J. H., Coldman A. J., Gudauskas G. A. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep. 1982 Mar;66(3):439–449. [PubMed] [Google Scholar]
  13. Gridelli C., Rossi A., Incoronato P., Bruni G. S., Scognamiglio F., Ruffolo P., Rinaldi L., Bianco A. R. Phase I study of ifosfamide plus high-dose epirubicin in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 1996;37(6):613–615. doi: 10.1007/s002800050437. [DOI] [PubMed] [Google Scholar]
  14. Grilli R., Oxman A. D., Julian J. A. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol. 1993 Oct;11(10):1866–1872. doi: 10.1200/JCO.1993.11.10.1866. [DOI] [PubMed] [Google Scholar]
  15. Grunberg S. M., Crowley J., Livingston R., Gill I., Williamson S. K., O'Rourke T., Braun T., Marshall M. E., Weick J. K., Balcerzak S. P. Extended administration of oral etoposide and oral cyclophosphamide for the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1993 Aug;11(8):1598–1601. doi: 10.1200/JCO.1993.11.8.1598. [DOI] [PubMed] [Google Scholar]
  16. Johnson D. H. Chemotherapy for unresectable non-small cell lung cancer. Semin Oncol. 1990 Aug;17(4 Suppl 7):20–29. [PubMed] [Google Scholar]
  17. Joss R. A., Bürki K., Dalquen P., Schatzmann E., Leyvraz S., Cavalli F., Ludwig C., Siegenthaler P., Alberto P., Stahel R. Combination chemotherapy with mitomycin, vindesine, and cisplatin for non-small cell lung cancer. Association of antitumor activity with initial tumor burden and treatment center. Cancer. 1990 Jun 1;65(11):2426–2434. doi: 10.1002/1097-0142(19900601)65:11<2426::aid-cncr2820651104>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  18. Joss R. A., Hansen H. H., Hansen M., Renard J., Rozencweig M. Phase II trial of epirubicin in advanced squamous, adeno- and large cell carcinoma of the lung. Eur J Cancer Clin Oncol. 1984 Apr;20(4):495–499. doi: 10.1016/0277-5379(84)90234-7. [DOI] [PubMed] [Google Scholar]
  19. Le Chevalier T., Brisgand D., Douillard J. Y., Pujol J. L., Alberola V., Monnier A., Riviere A., Lianes P., Chomy P., Cigolari S. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol. 1994 Feb;12(2):360–367. doi: 10.1200/JCO.1994.12.2.360. [DOI] [PubMed] [Google Scholar]
  20. Lilenbaum R. C., Green M. R. Novel chemotherapeutic agents in the treatment of non-small-cell lung cancer. J Clin Oncol. 1993 Jul;11(7):1391–1402. doi: 10.1200/JCO.1993.11.7.1391. [DOI] [PubMed] [Google Scholar]
  21. Martoni A., Guaraldi M., Casadio M., Busutti L., Pannuti F. A phase II study of high-dose epirubicin plus cisplatinum in advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 1992 Dec;3(10):864–866. doi: 10.1093/oxfordjournals.annonc.a058114. [DOI] [PubMed] [Google Scholar]
  22. Martoni A., Melotti B., Guaraldi M., Pannuti F. Activity of high-dose epirubicin in advanced non-small cell lung cancer. Eur J Cancer. 1991;27(10):1231–1234. doi: 10.1016/0277-5379(91)90087-t. [DOI] [PubMed] [Google Scholar]
  23. Meyers F. J., Cardiff R. D., Quadro R., Gribble M., Kohler M., Medrano V., Mitchell E. P., Shiffman R., William L. Epirubicin in non-oat cell lung cancer--response rates and the importance of immunopathology: a Northern California Oncology Group Study. Cancer Treat Rep. 1986 Jun;70(6):805–806. [PubMed] [Google Scholar]
  24. 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]
  25. Miller T. P., Chen T. T., Coltman C. A., Jr, O'Bryan R. M., Vance R. B., Weiss G. B., Fletcher W. S., Stephens R. L., Livingston R. B. Effect of alternating combination chemotherapy on survival of ambulatory patients with metastatic large-cell and adenocarcinoma of the lung. A Southwest Oncology Group Study. J Clin Oncol. 1986 Apr;4(4):502–508. doi: 10.1200/JCO.1986.4.4.502. [DOI] [PubMed] [Google Scholar]
  26. Norton L., Day R. Potential innovations in scheduling of cancer chemotherapy. Important Adv Oncol. 1991:57–72. [PubMed] [Google Scholar]
  27. Shepherd F. A., Evans W. K., Goss P. E., Latreille J., Logan D., Maroun J., Stewart D., Warner E., Paul K. Ifosfamide, cisplatin, and etoposide (ICE) in the treatment of advanced non-small cell lung cancer. Semin Oncol. 1992 Feb;19(1 Suppl 1):54–58. [PubMed] [Google Scholar]
  28. Stanley K. E. Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst. 1980 Jul;65(1):25–32. [PubMed] [Google Scholar]
  29. Weick J. K., Crowley J., Natale R. B., Hom B. L., Rivkin S., Coltman C. A., Jr, Taylor S. A., Livingston R. B. A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1991 Jul;9(7):1157–1162. doi: 10.1200/JCO.1991.9.7.1157. [DOI] [PubMed] [Google Scholar]
  30. Wils J., Utama I., Sala L., Smeets J., Riva A. Phase II study of high-dose epirubicin in non-small cell lung cancer. Eur J Cancer. 1990;26(11-12):1140–1141. doi: 10.1016/0277-5379(90)90271-t. [DOI] [PubMed] [Google Scholar]

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

RESOURCES