Abstract
Purpose. To make recommendations for the use of doxorubicin-based chemotherapy in patients with soft-tissue sarcoma.
Patients. The recommendations apply to patients with symptomatic unresectable locally advanced or metastatic soft-tissue sarcoma who are candidates for palliative chemotherapy.
Methods. A systematic review of the published literature was combined with a consensus process around the interpretation of the evidence in the context of conventional practice to develop an evidence-based practice guideline.
Results. Eight randomized trials comparing doxorubicin-based combination versus doxorubicin single-agent chemotherapy were reviewed. Response rates and overall survival were evaluated using pooled statistical analysis.The pooled response data in 2281 patients showed a slight trend favouring the combination therapy, although this did not reach statistical significance (odds ratio (OR), 0.79; 95% confidence interval (CI), 0.60–1.05; p=0.10). Survival data could only be abstracted from six studies involving 2097 patients, and showed no significant advantage for combination therapy (OR, 0.84; 95% CI, 0.67–1.06; p=0.13). Data on adverse effects could not be combined in a meta-analysis; however nausea, vomiting and myelosuppression were consistently more severe with combination chemotherapy than with single-agent chemotherapy.
Discussion. Single-agent doxorubicin is an appropriate first-line chemotherapy option for advanced or metastatic soft-tissue sarcoma. Some doxorubicin-based combination chemotherapy regimens, given in conventional doses, produce only marginal increases in response rates, at the expense of increased adverse effects, and with no improvements in overall survival. Future randomized clinical trials should compare new regimens, whose activity has been established in single-arm studies, with single-agent doxorubicin, and include quality of life as an outcome measure.
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Selected References
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- Antman K. H., Ryan L., Elias A., Sherman D., Grier H. E. Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol. 1989 Jan;7(1):126–131. doi: 10.1200/JCO.1989.7.1.126. [DOI] [PubMed] [Google Scholar]
- Antman K., Crowley J., Balcerzak S. P., Rivkin S. E., Weiss G. R., Elias A., Natale R. B., Cooper R. M., Barlogie B., Trump D. L. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993 Jul;11(7):1276–1285. doi: 10.1200/JCO.1993.11.7.1276. [DOI] [PubMed] [Google Scholar]
- Borden E. C., Amato D. A., Edmonson J. H., Ritch P. S., Shiraki M. Randomized comparison of doxorubicin and vindesine to doxorubicin for patients with metastatic soft-tissue sarcomas. Cancer. 1990 Sep 1;66(5):862–867. doi: 10.1002/1097-0142(19900901)66:5<862::aid-cncr2820660509>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
- Borden E. C., Amato D. A., Rosenbaum C., Enterline H. T., Shiraki M. J., Creech R. H., Lerner H. J., Carbone P. P. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol. 1987 Jun;5(6):840–850. doi: 10.1200/JCO.1987.5.6.840. [DOI] [PubMed] [Google Scholar]
- Bramwell V. H. Chemotherapy for metastatic soft tissue sarcomas--another full circle? Br J Cancer. 1991 Jul;64(1):7–9. doi: 10.1038/bjc.1991.230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bramwell V. H., Mouridsen H. T., Mulder J. H., Somers R., Van Oosterom A. T., Santoro A., Thomas D., Sylvester R., Markham D. Carminomycin vs adriamycin in advanced soft tissue sarcomas: an EORTC randomised phase II study. Eur J Cancer Clin Oncol. 1983 Aug;19(8):1097–1104. doi: 10.1016/0277-5379(83)90034-2. [DOI] [PubMed] [Google Scholar]
- Bramwell V. H., Mouridsen H. T., Santoro A., Blackledge G., Somers R., Verwey J., Dombernowsky P., Onsrud M., Thomas D., Sylvester R. Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol. 1987 Mar;23(3):311–321. doi: 10.1016/0277-5379(87)90075-7. [DOI] [PubMed] [Google Scholar]
- Browman G. P., Levine M. N., Mohide E. A., Hayward R. S., Pritchard K. I., Gafni A., Laupacis A. The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol. 1995 Feb;13(2):502–512. doi: 10.1200/JCO.1995.13.2.502. [DOI] [PubMed] [Google Scholar]
- Buesa J. M., Mouridsen H. T., van Oosterom A. T., Verweij J., Wagener T., Steward W., Poveda A., Vestlev P. M., Thomas D., Sylvester R. High-dose DTIC in advanced soft-tissue sarcomas in the adult. A phase II study of the E.O.R.T.C. Soft Tissue and Bone Sarcoma Group. Ann Oncol. 1991 Apr;2(4):307–309. doi: 10.1093/oxfordjournals.annonc.a057942. [DOI] [PubMed] [Google Scholar]
- Chang P., Wiernik P. H. Combination chemotherapy with adriamycin and streptozotocin. I. Clinical results in patients with advanced sarcoma. Clin Pharmacol Ther. 1976 Nov;20(5):605–610. doi: 10.1002/cpt1976205605. [DOI] [PubMed] [Google Scholar]
- Demetri G. D., Elias A. D. Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematol Oncol Clin North Am. 1995 Aug;9(4):765–785. [PubMed] [Google Scholar]
- 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]
- Edmonson J. H., Ryan L. M., Blum R. H., Brooks J. S., Shiraki M., Frytak S., Parkinson D. R. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993 Jul;11(7):1269–1275. doi: 10.1200/JCO.1993.11.7.1269. [DOI] [PubMed] [Google Scholar]
- Frost D. B. Pulmonary metastasectomy for soft tissue sarcomas: is it justified? J Surg Oncol. 1995 Jun;59(2):110–115. doi: 10.1002/jso.2930590208. [DOI] [PubMed] [Google Scholar]
- Jelić S., Kovcin V., Milanović N., Babović N., Kreacić M., Ristović Z., Vlajić M., Filipović-Ljesković I. Randomised study of high-dose epirubicin versus high-dose epirubicin-cisplatin chemotherapy for advanced soft tissue sarcoma. Eur J Cancer. 1997 Feb;33(2):220–225. doi: 10.1016/s0959-8049(96)00297-3. [DOI] [PubMed] [Google Scholar]
- Mouridsen H. T., Bastholt L., Somers R., Santoro A., Bramwell V., Mulder J. H., van Oosterom A. T., Buesa J., Pinedo H. M., Thomas D. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987 Oct;23(10):1477–1483. doi: 10.1016/0277-5379(87)90089-7. [DOI] [PubMed] [Google Scholar]
- Muss H. B., Bundy B., DiSaia P. J., Homesley H. D., Fowler W. C., Jr, Creasman W., Yordan E. Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer. 1985 Apr 15;55(8):1648–1653. doi: 10.1002/1097-0142(19850415)55:8<1648::aid-cncr2820550806>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
- Nielsen O. S., Dombernowsky P., Mouridsen H., Crowther D., Verweij J., Buesa J., Steward W., Daugaard S., van Glabbeke M., Kirkpatrick A. High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer. 1998 Dec;78(12):1634–1639. doi: 10.1038/bjc.1998.735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Omura G. A., Major F. J., Blessing J. A., Sedlacek T. V., Thigpen J. T., Creasman W. T., Zaino R. J. A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer. 1983 Aug 15;52(4):626–632. doi: 10.1002/1097-0142(19830815)52:4<626::aid-cncr2820520409>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
- Pinedo H. M., Kenis Y. Chemotherapy of advanced soft-tissue sarcomas in adults. Cancer Treat Rev. 1977 Jun;4(2):67–86. doi: 10.1016/s0305-7372(77)80006-6. [DOI] [PubMed] [Google Scholar]
- Santoro A., Tursz T., Mouridsen H., Verweij J., Steward W., Somers R., Buesa J., Casali P., Spooner D., Rankin E. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995 Jul;13(7):1537–1545. doi: 10.1200/JCO.1995.13.7.1537. [DOI] [PubMed] [Google Scholar]
- Schoenfeld D. A., Rosenbaum C., Horton J., Wolter J. M., Falkson G., DeConti R. C. A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycin-D, and cyclophosphamide for advanced sarcoma. Cancer. 1982 Dec 15;50(12):2757–2762. doi: 10.1002/1097-0142(19821215)50:12<2757::aid-cncr2820501211>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
- Stuart-Harris R. C., Harper P. G., Parsons C. A., Kaye S. B., Mooney C. A., Gowing N. F., Wiltshaw E. High-dose alkylation therapy using ifosfamide infusion with mesna in the treatment of adult advanced soft-tissue sarcoma. Cancer Chemother Pharmacol. 1983;11(2):69–72. doi: 10.1007/BF00254247. [DOI] [PubMed] [Google Scholar]
- Van Glabbeke M., van Oosterom A. T., Oosterhuis J. W., Mouridsen H., Crowther D., Somers R., Verweij J., Santoro A., Buesa J., Tursz T. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 1999 Jan;17(1):150–157. doi: 10.1200/JCO.1999.17.1.150. [DOI] [PubMed] [Google Scholar]
- Yap B. S., Benjamin R. S., Burgess M. A., Murphy W. K., Sinkovics J. G., Bodey G. P. A phase II evaluation of methyl CCNU and actinomycin D in the treatment of advanced sarcomas in adults. Cancer. 1981 Jun 15;47(12):2807–2809. doi: 10.1002/1097-0142(19810615)47:12<2807::aid-cncr2820471209>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
- van Geel A. N., Pastorino U., Jauch K. W., Judson I. R., van Coevorden F., Buesa J. M., Nielsen O. S., Boudinet A., Tursz T., Schmitz P. I. Surgical treatment of lung metastases: The European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer. 1996 Feb 15;77(4):675–682. doi: 10.1002/(sici)1097-0142(19960215)77:4<675::aid-cncr13>3.3.co;2-h. [DOI] [PubMed] [Google Scholar]