Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Jun 2;83(1):8–15. doi: 10.1054/bjoc.2000.1164

Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent

J-L Pujol 1,2, Carestia 1,2, J-P Daurès 1
PMCID: PMC2374541  PMID: 10883661

Abstract

Chemotherapy is the backbone of small-cell lung cancer therapy. However, optimal drug combinations and schedules remain to be defined and there is hitherto no world-wide accepted standard regimen. Cisplatin, an alkylating agent with high putative toxicity is currently widely used although its effectiveness in this disease has not been established firmly. We conducted a meta-analysis of published data reporting trials randomizing a cisplatin-containing regimen versus a regimen without this alkylating agent in order to determine possible differences in survival response and toxicity. Nineteen trials have been identified in medical literature (4054 evaluable patients). Ten trials randomized patients to receive a cisplatin-etoposide regimen versus a regimen without any of these two drugs. A subgroup analysis was, therefore, carried out in the nine remaining trials that randomly allocated patients between two regimens differing in the absence or presence of cisplatin, whereas etoposide was given (or not given) in both arms (1579 evaluable patients). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death and the increase in probability of being responders to chemotherapy. There was no significant difference between the cisplatin-containing regimen and the regimen without this drug when the risk of toxic-death was taken into account with respective probabilities of 3.1 and 2.7% (NS). Patients randomized in a cisplatin-containing regimen had an increase in probability of being responders with an OR of 1.35, 95% confidence interval (CI) of 1.18–1.55;P< 10–5corresponding to an increase of objective (partial plus complete) response rate from 0.62 to 0.69 (a result taking into account a significant heterogeneity). Patients treated with a cisplatin-containing regimen benefited from a significant reduction of risk of death at 6 months and 1 year with respective OR 0.87, 95% CI 0.75–0.98, P = 0.03, and or 0.80, 95% CI 0.69–0.93, P = 0.002 (no statistical heterogeneity). This corresponded to a significant increase in the probability of survival of 2.6% and 4.4% at 6 months and 1 year respectively. The meta-analysis restricted to the subset of nine trials without etoposide treatment imbalance reached similar conclusions. A cisplatin-containing regimen yields a higher response rate and probability of survival than does a chemotherapy containing others alkylating agents without a perceptible increase in risk of toxic-death. © 2000 Cancer Research Campaign

Keywords: SCLC, chemotherapy, cisplatin, meta-analysis

Full Text

The Full Text of this article is available as a PDF (80.2 KB).

Footnotes

Present address: Cliniques Universitaires UCL de Mont-Godinne, B 5530 Yvoir, Belgium

Selected References

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

  1. Cerny T., Blair V., Anderson H., Bramwell V., Thatcher N. Pretreatment prognostic factors and scoring system in 407 small-cell lung cancer patients. Int J Cancer. 1987 Feb 15;39(2):146–149. doi: 10.1002/ijc.2910390204. [DOI] [PubMed] [Google Scholar]
  2. Chahinian A. P., Propert K. J., Ware J. H., Zimmer B., Perry M. C., Hirsh V., Skarin A., Kopel S., Holland J. F., Comis R. L. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol. 1989 Aug;7(8):993–1002. doi: 10.1200/JCO.1989.7.8.993. [DOI] [PubMed] [Google Scholar]
  3. DerSimonian R., Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986 Sep;7(3):177–188. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
  4. Eagan R. T., Lee R. E., Frytak S., Fleming T. R., Ingle J. N., Creagan E. T., Nichols W. C., Kvols L. K., Coles D. T. An evaluation of low-dose cisplatin as part of combined modality therapy of limited small cell lung cancer. Cancer Clin Trials. 1981 Fall;4(3):267–271. [PubMed] [Google Scholar]
  5. Einhorn L. H., Donohue J. Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med. 1977 Sep;87(3):293–298. doi: 10.7326/0003-4819-87-3-293. [DOI] [PubMed] [Google Scholar]
  6. Evans W. K., Feld R., Murray N., Willan A., Coy P., Osoba D., Shepherd F. A., Clark D. A., Levitt M., MacDonald A. Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer. A multicenter, randomized clinical trial by the National Cancer Institute of Canada. Ann Intern Med. 1987 Oct;107(4):451–458. doi: 10.7326/0003-4819-107-4-451. [DOI] [PubMed] [Google Scholar]
  7. Evans W. K., Osoba D., Feld R., Shepherd F. A., Bazos M. J., DeBoer G. Etoposide (VP-16) and cisplatin: an effective treatment for relapse in small-cell lung cancer. J Clin Oncol. 1985 Jan;3(1):65–71. doi: 10.1200/JCO.1985.3.1.65. [DOI] [PubMed] [Google Scholar]
  8. Evans W. K., Shepherd F. A., Feld R., Osoba D., Dang P., Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985 Nov;3(11):1471–1477. doi: 10.1200/JCO.1985.3.11.1471. [DOI] [PubMed] [Google Scholar]
  9. Farris A., Bisail M., Sarobba M. G., Sanna G., Scotto T., Valzelli S., Intini C. Cisplatin-VP16 alternating with cyclophosphamide-epirubicin versus cyclophosphamide-epirubicin-vincristine in small cell lung cancer. J Chemother. 1993 Oct;5(5):344–347. doi: 10.1080/1120009x.1993.11741080. [DOI] [PubMed] [Google Scholar]
  10. Feld R., Evans W. K., DeBoer G., Quirt I. C., Shepherd F. A., Yeoh J. L., Pringle J. F., Payne D. G., Herman J. G., Chamberlain D. Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung. J Clin Oncol. 1984 Apr;2(4):294–304. doi: 10.1200/JCO.1984.2.4.294. [DOI] [PubMed] [Google Scholar]
  11. Fukuoka M., Furuse K., Saijo N., Nishiwaki Y., Ikegami H., Tamura T., Shimoyama M., Suemasu K. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst. 1991 Jun 19;83(12):855–861. doi: 10.1093/jnci/83.12.855. [DOI] [PubMed] [Google Scholar]
  12. Fukuoka M., Takada M., Negoro S., Kusunoki Y., Matsui K., Ryu S., Sakai N., Takifuji N., Kudoh S., Tamai S. Alternating non-cross resistant chemotherapy for small cell lung cancer. Jpn J Clin Oncol. 1986 Sep;16(3):261–270. [PubMed] [Google Scholar]
  13. Goodman G. E., Crowley J. J., Blasko J. C., Livingston R. B., Beck T. M., Demattia M. D., Bukowski R. M. Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study. J Clin Oncol. 1990 Jan;8(1):39–47. doi: 10.1200/JCO.1990.8.1.39. [DOI] [PubMed] [Google Scholar]
  14. Hansen H. H., Kristjansen P. E. Chemotherapy of small cell lung cancer. Eur J Cancer. 1991;27(3):342–349. doi: 10.1016/0277-5379(91)90543-m. [DOI] [PubMed] [Google Scholar]
  15. Havemann K., Wolf M., Holle R., Gropp C., Drings P., Manke H. G., Hans K., Schroeder M., Heim M., Victor N. Alternating versus sequential chemotherapy in small cell lung cancer. A randomized German multicenter trial. Cancer. 1987 Mar 15;59(6):1072–1082. doi: 10.1002/1097-0142(19870315)59:6<1072::aid-cncr2820590605>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  16. Ihde D. C., Mulshine J. L., Kramer B. S., Steinberg S. M., Linnoila R. I., Gazdar A. F., Edison M., Phelps R. M., Lesar M., Phares J. C. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol. 1994 Oct;12(10):2022–2034. doi: 10.1200/JCO.1994.12.10.2022. [DOI] [PubMed] [Google Scholar]
  17. Joss R. A., Alberto P., Bleher E. A., Ludwig C., Siegenthaler P., Martinelli G., Sauter C., Schatzmann E., Senn H. J. Combined-modality treatment of small-cell lung cancer: randomized comparison of three induction chemotherapies followed by maintenance chemotherapy with or without radiotherapy to the chest. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol. 1994 Dec;5(10):921–928. doi: 10.1093/oxfordjournals.annonc.a058731. [DOI] [PubMed] [Google Scholar]
  18. Kánitz E., Kolaric K., Jassem J., Mechl Z., Pawlicki M., Ringwald G., Rolski J., Schoket Z., Vukas D., Kaplan E. Randomized phase II trial of high-dose 4'-epi-doxorubicin + cyclophosphamide versus high-dose 4'-epi-doxorubicin + cisplatin in previously untreated patients with extensive small cell lung cancer. Oncology. 1992;49(5):327–332. doi: 10.1159/000227066. [DOI] [PubMed] [Google Scholar]
  19. Maksymiuk A. W., Jett J. R., Earle J. D., Su J. Q., Diegert F. A., Mailliard J. A., Kardinal C. G., Krook J. E., Veeder M. H., Wiesenfeld M. Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial. J Clin Oncol. 1994 Jan;12(1):70–76. doi: 10.1200/JCO.1994.12.1.70. [DOI] [PubMed] [Google Scholar]
  20. O'Bryan R. M., Crowley J. J., Kim P. N., Epstein R. B., Neilan B., Coltman C. A., Jr, Stuckey W. J., Pazdur R. Comparison of etoposide and cisplatin with bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide for salvage treatment in small cell lung cancer. A Southwest Oncology Group Study. Cancer. 1990 Feb 15;65(4):856–860. doi: 10.1002/1097-0142(19900215)65:4<856::aid-cncr2820650404>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  21. Osterlind K., Hansen H. H., Hansen M., Dombernowsky P., Andersen P. K. Long-term disease-free survival in small-cell carcinoma of the lung: a study of clinical determinants. J Clin Oncol. 1986 Sep;4(9):1307–1313. doi: 10.1200/JCO.1986.4.9.1307. [DOI] [PubMed] [Google Scholar]
  22. Porter L. L., 3rd, Johnson D. H., Hainsworth J. D., Hande K. R., Greco F. A. Cisplatin and etoposide combination chemotherapy for refractory small cell carcinoma of the lung. Cancer Treat Rep. 1985 May;69(5):479–481. [PubMed] [Google Scholar]
  23. ROSENBERG B., VANCAMP L., KRIGAS T. INHIBITION OF CELL DIVISION IN ESCHERICHIA COLI BY ELECTROLYSIS PRODUCTS FROM A PLATINUM ELECTRODE. Nature. 1965 Feb 13;205:698–699. doi: 10.1038/205698a0. [DOI] [PubMed] [Google Scholar]
  24. Roth B. J., Johnson D. H., Einhorn L. H., Schacter L. P., Cherng N. C., Cohen H. J., Crawford J., Randolph J. A., Goodlow J. L., Broun G. O. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol. 1992 Feb;10(2):282–291. doi: 10.1200/JCO.1992.10.2.282. [DOI] [PubMed] [Google Scholar]
  25. Sculier J. P., Klastersky J., Libert P., Ravez P., Thiriaux J., Lecomte J., Bureau G., Vandermoten G., Dabouis G., Michel J. A randomized study comparing etoposide and vindesine with or without cisplatin as induction therapy for small cell lung cancer. EORTC Lung Cancer Working Party. Ann Oncol. 1990;1(2):128–133. doi: 10.1093/oxfordjournals.annonc.a057690. [DOI] [PubMed] [Google Scholar]
  26. Sculier J. P., Paesmans M., Bureau G., Dabouis G., Libert P., Vandermoten G., Van Cutsem O., Berchier M. C., Ries F., Michel J. Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol. 1993 Oct;11(10):1858–1865. doi: 10.1200/JCO.1993.11.10.1858. [DOI] [PubMed] [Google Scholar]
  27. Smith A. P., Anderson G., Chappell G., Bowen D. R. Does the substitution of cisplatin in a standard four drug regimen improve survival in small cell carcinoma of the lung? A comparison of two chemotherapy regimens. Thorax. 1991 Mar;46(3):172–174. doi: 10.1136/thx.46.3.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Smith M. C., Sephel G. C. Long-term in vitro stability of cyclosporine in whole-blood samples. Clin Chem. 1990 Nov;36(11):1991–1992. [PubMed] [Google Scholar]
  29. Souhami R. L., Spiro S. G., Rudd R. M., Ruiz de Elvira M. C., James L. E., Gower N. H., Lamont A., Harper P. G. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst. 1997 Apr 16;89(8):577–580. doi: 10.1093/jnci/89.8.577. [DOI] [PubMed] [Google Scholar]
  30. Stewart L. A., Parmar M. K. Meta-analysis of the literature or of individual patient data: is there a difference? Lancet. 1993 Feb 13;341(8842):418–422. doi: 10.1016/0140-6736(93)93004-k. [DOI] [PubMed] [Google Scholar]
  31. Urban T., Baleyte T., Chastang C. L., Jeannin L., Delaval P., Zaegel M., Mornet M., Coetmeur D., Lebeau B. Standard combination versus alternating chemotherapy in small cell lung cancer: a randomised clinical trial including 394 patients. 'Petites Cellules' Group. Lung Cancer. 1999 Aug;25(2):105–113. doi: 10.1016/s0169-5002(99)00050-1. [DOI] [PubMed] [Google Scholar]
  32. Veronesi A., Cartei G., Crivellari D., Magri M. D., Della Valentina M., Foladore S., Trovò M. G., Nascimben O., Sibau A., Talamini R. Cisplatin and etoposide versus cyclophosphamide, epirubicin and vincristine in small cell lung cancer: a randomised study. Eur J Cancer. 1994;30A(10):1474–1478. doi: 10.1016/0959-8049(94)00253-2. [DOI] [PubMed] [Google Scholar]
  33. Wampler G. L., Heim W. J., Ellison N. M., Ahlgren J. D., Fryer J. G. Comparison of cyclophosphamide, doxorubicin, and vincristine with an alternating regimen of methotrexate, etoposide, and cisplatin/cyclophosphamide, doxorubicin, and vincristine in the treatment of extensive-disease small-cell lung carcinoma: a Mid-Atlantic Oncology Program study. J Clin Oncol. 1991 Aug;9(8):1438–1445. doi: 10.1200/JCO.1991.9.8.1438. [DOI] [PubMed] [Google Scholar]
  34. Wiltshaw E., Kroner T. Phase II study of cis-dichlorodiammineplatinum(II) (NSC-119875) in advanced adenocarcinoma of the ovary. Cancer Treat Rep. 1976 Jan;60(1):55–60. [PubMed] [Google Scholar]
  35. Wolf M., Havemann K., Holle R., Gropp C., Drings P., Hans K., Schroeder M., Heim M., Dommes M., Mende S. Cisplatin/etoposide versus ifosfamide/etoposide combination chemotherapy in small-cell lung cancer: a multicenter German randomized trial. J Clin Oncol. 1987 Dec;5(12):1880–1889. doi: 10.1200/JCO.1987.5.12.1880. [DOI] [PubMed] [Google Scholar]
  36. Yusuf S., Collins R., Peto R., Furberg C., Stampfer M. J., Goldhaber S. Z., Hennekens C. H. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials. Eur Heart J. 1985 Jul;6(7):556–585. doi: 10.1093/oxfordjournals.eurheartj.a061905. [DOI] [PubMed] [Google Scholar]

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

RESOURCES