SPECIAL DEPARTMENTS
Authors: Giorgio Cocconi, Giorgio Cocconi, R. Fossati C. Confalonieri A. Tinazzi
Journal: Journal of Clinical Oncology (2000)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.6.1392 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10715311 Giorgio CocconixGiorgio CocconiSearch for articles by this author Giorgio CocconixGiorgio CocconiSearch for articles by this author R. Fossati C. Confalonieri A. TinazzixR. Fossati C. Confalonieri A. TinazziSearch for articles by this author Show More University Hospital ParmaItalyIstituto di Ricerche Farmacologiche “Mario Negri” MilanItaly https://doi.org/10.1200/JCO.2000.18.6.1392 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical Oncology13032000REFERENCES FOR FIG 113032000Response13032000To the Editor:Dr Fossati et al1 published an accurate systematic review concerning the systemic treatment of advanced breast carcinoma in the October 1998 issue of the Journal of Clinical Oncology. They found that the response rate to anthracycline-containing regimens was better than that to anthracycline-free regimens, but they did not find any difference in terms of survival—something that they attributed to the “salvage” effect of the corticosteroids added to a number of the comparator chemotherapy regimens.I must admit that I found this interpretation rather doubtful for two reasons. First, corticosteroids were sometimes also included in the doxorubicin-containing arm. Second, the administration of corticosteroids is not recognized as having any beneficial effect on the survival of advanced breast cancer patients.I am replying only now because I have since given considerable thought to the possible reasons for this unexpected lack of difference in terms of survival. In order to be able to explore one of my hypotheses, it would be useful to know the results of separate survival analyses of (a) the trials in which the patients in the experimental arm received anthracycline combined with all, or at least two, of the agents included in the comparator arm and (b) the trials in which the patients in the experimental arm received anthracycline combined with none, or only one, of the agents included in the comparator arm (not taking into account any other additional therapies that may have been added to the experimental arm). It is obvious that the first case substantially involves the “addition” of anthracycline to the other drugs present in the comparator arm, whereas the other case substantially involves this “addition” together with the simultaneous “subtraction” of one, two, or more of the original drugs.I am reasonably confident that, even in an adjuvant setting,2 this approach would help to clarify the results and their interpretation.28. Bull JM, Tormey DC, Li SH, et al: A randomized comparative trial of Adriamycin versus methotrexate in combination drug therapy. Cancer 41:1649-1657, 197830. Bezwoda WR, De Moor NG, Derman D, et al: Combination chemotherapy of metastatic breast cancer. A randomized trial comparing the use of Adriamycin to that of vinblastine. Cancer 44:392-397, 197935. Smalley RV, Lefante J, Bartolucci A, et al: A comparison of cyclophosphamide, Adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) in patients with advanced breast cancer. Breast Cancer Res Treat 3:209-220, 198337. Tormey DC, Weinberg VE, Leone LA, et al: A comparison of intermittent vs. continuous and of Adriamycin vs. methotrexate 5-drug chemotherapy for advanced breast cancer. Am J Clin Oncol 7:231-239, 198438. Cummings FJ, Gelman R, Horton J: Comparison of CAF versus CMFP in metastatic breast cancer: Analysis of prognostic factors. J Clin Oncol 3:932-940, 198540. Aisner J, Weinberg V, Perloff M, et al: Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each ± MER) for metastatic carcinoma of the breast: A CALGB study. J Clin Oncol 5:1523-1533, 198741. Leonard RCF, Cornbleet MA, Kaye SB, et al: Mitoxantrone versus doxorubicin in combination chemotherapy for advanced carcinoma of the breast. J Clin Oncol 5:1056-1063, 198742. Bennett JM, Muss HB, Doroshow JH, et al: A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma. J Clin Oncol 6:1611-1620, 198848. Falkson G, Tormey DC, Carey P, et al: Long-term survival of patients treated with combination chemotherapy for metastatic breast cancer. Eur J Cancer 27:973-977, 199152. Alonso MC, Tabernero JM, Ojeda B, et al: A phase III randomized trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide, Adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer. Breast Cancer Res Treat 34:15-24, 199554. Pavesi L, Preti P, Da Prada G, et al: Epirubicin versus mitoxantrone in combination chemotherapy for metastatic breast cancer. Anticancer Res 15:495-502, 199555. Green JA, Slater AJ, Campbell IR, et al: Advanced breast cancer: A randomized study of doxorubicin or mitoxantrone in combination with cyclophosphamide and vincristine. Breast Cancer Res Treat 39:155-163, 1996In Reply:We read with interest the hypothesis of Dr Cocconi suggesting a different survival impact of anthracycline (doxorubicin) when this drug is added to a comparator multidrug regimen or is used in combination with none of the drugs or only one drug included in the comparator regimen. To comply with his proposal, we grouped the studies included in our original comparison1 differently and analyzed the survival data of 13 studies in which doxorubicin was added to at least two drugs included in the control arm (Fig 1) and eight studies in which doxorubicin was combined with no drug or only one drug used in the comparator arm (Fig 2). Actually, the addition of doxorubicin to a polychemotherapic regimen or its use with at least two drugs of the original regimen seemed to improve survival in advanced breast cancer patients. Fig 1. Doxorubicin plus at least two drugs included in the control arm regimen compared with polychemotherapy without doxorubicin. (□) Hazard ratio (HR) for each trial with 99% confidence interval (CI). (⧫) Overall HR with their 95% CIs (Tinazzi A, Carinci F, Torri V: Graphical aspect of meta-analysis using SAS/GRAPH and its specific annotate language: A set of specific macro routines to perform and display result of meta-analysis. SEUGI ’96, SAS European User Group International, Hamburg, Germany, June 11-14, 1996 [CD-ROM version]) *HR obtained from survival curves. Abbreviations in Figs 1 and 2: A, doxorubicin; C, cyclophosphamide; E, epirubicin; F, fluorouracil; M, methotrexate; P, prednisone/prednisolone; V, vincristine; VBL, vinblastine; c, continuous; i, intermittent; Anthra, anthracycline. Fig 2. Doxorubicin plus no drug or only one drug included in the control arm regimen compared with polychemotherapy without doxorubicin.REFERENCE2. Fossati R, Confalonieri C, Torri V, et al: Cytotoxic and hormonal treatment for metastatic breast cancer: A systematic review of published randomized trials involving 31,510 women. J Clin Oncol 16::3439,1998-3460, Link, Google Scholar