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© 2003 American Society for Clinical Oncology
Sequential Single-Agent Chemotherapy for Metastatic Breast Cancer: Therapeutic Nihilism or Realism?Memorial Sloan-Kettering Cancer Center, New York, NY COMBINATION CYTOTOXIC chemotherapy regimens for the treatment of metastatic breast cancer have been exhaustively pursued, motivated at least in part by shining examples of curative combination chemotherapy regimens for other advanced malignancies, such as lymphoma and germ cell tumors. Results in breast cancer have unfortunately been disappointing. The Sledge study published in this issue of the Journal of Clinical Oncology1 (Eastern Cooperative Oncology Group [ECOG] 1193), shows no clear advantage for combination therapy over the use of sequential single agents and should send a loud message to clinical oncologists who have been compelled by phase II data2–6 to consider anthracycline/taxane combination chemotherapy not as a gold standard, but perhaps as a reasonable option for selected patients. Exactly who these selected patients might be falls as much within the domain of the art of clinical oncology as the science at present, as we lack high-level, evidence-based medicine to guide such choices. Many oncologists consider anthracycline/taxane combinations for patients with rapidly progressing visceral disease, whereas others believe this to be most appropriate in the adjuvant or neoadjuvant setting. For example, it is disappointing that the substitution of docetaxel for fluorouracil in the FAC regimen (fluorouracil, doxorubicin, and cyclophosphamide) to create TAC (docetaxel, doxorubicin, and cyclophosphamide) did not prolong time to progression or improve survival as first-line chemotherapy for metastatic breast cancer,7 yet the same substitution (with doxorubicin/cyclophosphamide) has improved outcomes in an adjuvant trial.8 Certainly specific combinations in specific circumstances may be beneficial, yet evidence-based guidelines for selecting such patients are lacking. When asking the question, "Is A + B together superior to A followed by B?" in the chemotherapeutic management of metastatic breast cancer, it is critical to be clear about what indeed defines superiority. Many medical oncologists rate regimens based on objective responses, but our patients tend to care more about whether or not a given treatment will prolong survival, or the time until their cancer progresses, rather than whether the treatment will cause a 50% reduction in the sum of the products of the bi-perpendicular diameters of their measurable tumor lesions (ie, a partial response). Patients do not generally ask if their tumor lesions have decreased by 60% or 40%. Perhaps we should care more about the bigger picture ourselves. Of course, response proportion could be a surrogate for quality of life or symptom relief. However, rigorous prospective evaluation of quality of life in ECOG 1193 unfortunately does not demonstrate this parallel—the higher objective response rate for the doxorubicin/paclitaxel combination did not translate into improved quality of life. This trial is but one piece of high-level, evidence-based medicine, a randomized phase III trial that informs us about the relative role of single-agent therapy versus combination therapy for metastatic breast cancer. Joensuu et al9 found no advantage in time to progression or overall survival for the use of combinations as first- and second-line therapy as opposed to single agents, with less toxicity and superior quality of life seen in the sequential monotherapy arm. Single-agent docetaxel outperformed a prior standard postanthracycline doublet, mitomycin plus vinblastine, with superior response, time to progression, and survival.10 Single-agent paclitaxel compared quite favorably to the four-drug combination regimen of cyclophosphamide, methotrexate, fluorouracil, and prednisone as first-line chemotherapy.11 Single-agent mitoxantrone likewise compared favorably to the combination of fluorouracil, epirubicin, and cyclophosphamide in another multicenter randomized trial, with prospective evaluation of quality of life favoring monotherapy.12 The National Cancer Institute of Canada found no therapeutic advantage (response rate, time to progression, or overall survival) for vinorelbine combined with doxorubicin as opposed to doxorubicin alone (again, with more toxicity for the combination arm).13 Most recently, the Journal of Clinical Oncology reported the phase III findings of Berutti et al,14 demonstrating that time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine. We have the report of a randomized trial of single-agent docetaxel compared with the combination of docetaxel plus capecitabine. O’Shaughnessy et al15 reported a higher response rate, a longer time to progression, and improved overall survival for the combination versus docetaxel alone. However, the lack of subsequent (ie, cross-over) use of capecitabine in 73% of patients who received poststudy chemotherapy makes the superiority of this doublet uncertain. Could the sequential use of docetaxel first, then capecitabine at progression, have yielded the same overall survival as the combination (perhaps with less toxicity)? This tenable hypothesis was indeed tested in ECOG 1193, where the sequential use of paclitaxel and doxorubicin offered no disadvantage compared with the combination. The lack of predesigned cross-over in the trial by O’Shaughnessy et al15 precludes one from addressing this hypothesis, although an exploratory subset analysis of the patients treated sequentially with docetaxel and then capecitabine (as opposed to other agents) is supportive. Those afficionados of high-level, evidence-based medicine will perhaps point to the ambitious meta-analysis published previously in the Journal of Clinical Oncology by Fossati et al16 as justification for the routine use of combination chemotherapy in metastatic breast cancer. To be sure, this effort combined the results of numerous, rather small randomized clinical trials of combination therapy compared with single-agent chemotherapy. No single trial was sufficiently powered to discern a statistically significant survival advantage for combinations versus monotherapy. However, collectively, there seemed to be a trend that indeed combinations could be superior to single agents. How are we to interpret this, in light of the present data from ECOG 1193? First, the trials in the meta-analysis were performed in the pretaxane era, and single-agent taxane therapy is not considered. Second, although this is technically a meta-analysis, it is quite modest compared with the Early Breast Cancer Trialists’ Collaborative Group effort.17 The number of patients in this meta-analysis (n = 996) is comparable to the number of patients in the ECOG 1193 trial alone (n = 739), and the data do not enlighten us as to the relative value of sequential single-agent therapy compared with combinations, as does this trial. The sum total of patients enrolled in the randomized trials mentioned above that have not shown significant advantages for combinations over monotherapy (vide infra)9–13 is 2,103—more than double the sum of patients subjected to meta-analysis by Fossati et al16 on this subject. Thus, there certainly seems to be a significant amount of high-level, evidence-based medicine challenging the conventional wisdom that combination chemotherapy is the gold standard for treatment of metastatic breast cancer. Should we abandon the search for additional active chemotherapeutic combinations in metastatic breast cancer? Or would this be overly nihilistic? This question seems to be beginning to answer itself. With the preclinical and clinical development of more targeted biologic agents (eg, monoclonal antibodies), many of which are expected to possess a higher therapeutic index as compared with conventional cytotoxic chemotherapy, certainly a significant amount of refocusing of energy away from combination cytotoxic chemotherapy seems in order—and is fortunately already occurring. If uncoupling chemotherapeutic agents from one another dose not adversely affect outcome in the adjuvant setting,18 (Cancer and Leukemia Group B Study 9741), why should sequential single-agent therapy be expected to be suboptimal for metastatic disease? More than three decades of innumerable combination chemotherapy trials have taught us that metastatic breast cancer does not behave as certain very chemosensitive lymphomas, nor most testicular cancers, do—unfortunately. We should look to the highest available level of evidence-based medicine to decide what is nihilistic, and what is realistic, in the management of hormone-insensitive metastatic breast cancer. The trial conducted by Sledge et al,1 taken together with other recent randomized trials that have failed to show consistent survival benefit for anthracycline-taxane combinations versus nontaxane containing combinations,19–24 do not support the notion that anthracycline/taxane combinations are a reference regimen for metastatic breast cancer, unless perhaps a major goal of treatment is to increase the response rate, which is seemingly more suited to neoadjuvant therapy. The only trial to report a survival advantage for such a combination19 (paclitaxel plus doxorubicin compared with FAC) is notable for the fact that only 25% of FAC-treated patients ever received taxane as part of subsequent therapy for their metastatic disease. Metastatic breast cancer often behaves biologically ("reads") like a novel with many chapters, fortunately, rather than a short story. It could indeed be short-sighted to expect to know how the book will end based solely on what happens in chapter one (ie, first-line therapy). Undoubtedly, meta-analysis of randomized trials of anthracycline/taxane combinations compared with anthracycline/nontaxane combinations (doxorubicin and cyclophosphamide, epirubicin and cyclophosphamide, FAC, and fluorouracil, epirubicin, and cyclophosphamide) will be performed, as one author has recently suggested.21 Absent the demonstration of a meaningful benefit in survival, time to progression, or quality of life from such an endeavor, this trial, E1193, argues strongly for monochemotherapy and realism, rather than polychemotherapy, for metastatic breast cancer. This realism should not be interpreted as therapeutic nihilism. REFERENCES
1. Sledge GW, Neuberg D, Bernardo P, et al: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An Intergroup Trial (E1193). J Clin Oncol 21:588–592, 2003 2. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13:2688–2699, 1995[Abstract]
3. Gehl J, Boesgaard M, Paasket T, et al: Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 7:687–693, 1996
4. Misset JL, Dieras V, Gruia G, et al: Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 10:553–560, 1999
5. Sparano JA, O’Neill A, Schaefer PL, et al: Phase II trial of doxorubicin and docetaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: Eastern Cooperative Oncology Group Study E1196. J Clin Oncol 18:2369–2377, 2000
6. Sparano JA, Hu P, Rao RM, et al: Phase II trial of doxorubicin and paclitaxel plus granulocyte colony stimulating factor in metastatic breast cancer: An Eastern Cooperative Oncology Group study (E4195). J Clin Oncol 17:3828–3834, 1999 7. Mackey JR, Paterson A, Dirix LY, et al: Final results of the phase III randomized trial comparing docetaxel, doxorubicin and cyclophosphamide to FAC as first line chemotherapy for patients with metastatic breast cancer. Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 137) 8. Nabholtz J-M, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer patients: Interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 21:36a, 2002 (abstr 141)
9. Joensuu H, Holli K, Heikkinen M, et al: Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer: A prospective randomized trial. J Clin Oncol 16:3720–3730, 1998
10. Nabholtz J-M, Senn HJ, Bezwoda WR, et al: Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol 17:1413–1422, 1999
11. Bishop JF, Dewar J, Toner GC, et al: Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol 17:2355–2364, 1999
12. Heidemann E, Stoeger H, Souchon R, et al: Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic breast cancer patients as effective as combination chemotherapy? No difference in survival but higher quality of life were found in a multicenter randomized trial. Ann Oncol 13:1717–1729, 2002
13. Norris B, Pritchard KI, James K, et al: Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated/metastatic recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8. J Clin Oncol 18:2385–2394, 2000
14. Berutti A, Bitossi R, Gorzegno G, et al: Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: Final results of a phase III study with a factorial design. J Clin Oncol 20:4150–4159, 2002
15. O’Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812–2823, 2002 16. 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 16:3439–3460, 1998[Abstract] 17. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 352:930–942, 1998[CrossRef][Medline] 18. Citron M, Berry D, Cirrincione C, et al: Superiority of dose-dense over conventional scheduling and equivalence of sequential versus combination adjuvant chemotherapy for node-positive breast cancer. (CALGB 9741, INT 9741). Breast Cancer Res Treat 76:S32, 2002 (abstr 15) 19. Jassem J, Pienkowski T, Pluzanska A, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol 6:1707–1715, 2001 20. Nabholtz JN, Falkson G, Campos D, et al: A Phase III trial comparing doxorubicin and docetaxel to doxorubicin and cyclophosphamide as first-line therapy for women with metastatic breast cancer. Proc Am Soc Clin Oncol 18:127a, 1999 (abstr 485)
21. Biganzoli L, Cufer T, Bruning P, et al: Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III trial. J Clin Oncol 20:3114–3121, 2002 22. Luck HJ, Thomssen C, Untch M, et al: Multicentric phase III study in first line treatment of advanced breast cancer: Epirubicin/paclitaxel vs. epirubicin/cyclophosphamide—A study of the AGO Breast Cancer Group. Proc Am Soc Clin Oncol 19:73a, 2000 (abstr 280). 23. Bonneterre J, Dieras V, Tubiana-Hulin M, et al: 6 cycles of epirubicin/docetaxel versus 6 cycles of 5FU, epirubicin/cyclophosphamide (FEC) as first line metastatic breast cancer treatment. Proc Am Soc Clin Oncol 20:42a, 2001 (abstr 163). 24. Carmichael J. UKCCCR trial of epirubicin and cyclophosphamide (EC) vs. epirubicin and Taxol (ET) in the first line treatment of women with metastatic breast cancer. Proc Am Soc Clin Oncol 20:22a, 2001 (abstr 84).
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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