This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Overmoyer, B. Search for Related Content PubMed PubMed Citation Articles by Overmoyer, B. Social Bookmarking                            What's this?

Combination Chemotherapy for Metastatic Breast Cancer: Reaching for the Cure

University Hospitals of Cleveland, Case Western Reserve University

FOR MORE than 30 years, clinicians caring for patients with breast cancer have struggled unsuccessfully to reach consensus on a contentious issue: should combination chemotherapy be used for the palliation of metastatic disease, or should sequential single-agent regimens be favored?^1,2 While the debate has raged, the treatment of breast cancer has evolved considerably. Accordingly, this may be a propitious opportunity to reassess the appropriateness of pursuing clinical trials of combination chemotherapy for metastatic breast cancer (MBC) in light of our current understanding of the disease. An important article in this issue of the Journal of Clinical Oncology makes such a reappraisal timely.³

Sledge et al³ compared combination chemotherapy for MBC with sequential single-agent chemotherapy, using the end points of response rate, disease palliation, disease-free survival, and overall survival. Unlike prior studies designed to address this issue, the current Intergroup trial (E1193) used optimal chemotherapeutic agents, doxorubicin (A) and paclitaxel (T), with the hypothesis that combination treatment (AT) would result in greater efficacy when compared with sequential single-agent treatment (A T, or T A). Their results, however, were consistent with several prior studies,^4,5 which showed that tumor response was improved with combination therapy, whereas overall survival and palliative effects were comparable.

What is the appropriate message of the Sledge study for the clinical oncologist? Do the results establish sequential single-agent chemotherapy as the standard of care in the treatment of MBC? Can we confidently abandon clinical trials that investigate combination chemotherapy in this disease setting? To begin to address these issues, one should keep in mind that it is generally accepted that metastatic breast cancer is not curable. Therefore, the clinical oncologist often uses assumptions of disease response based on the work of Smalley et al,⁵ which indicates that approximately 25% of patients are destined to rapidly succumb to their disease, regardless of intervening treatment. An equal number will thrive clinically regardless of treatment offered. The remaining 50% of patients with MBC thus have some potential to be affected by systemic therapy. This discussion pertains to the treatment of their disease.

POINT 1: APPLICATION OF COMBINATION CHEMOTHERAPY REGIMENS SHOULD BE INDIVIDUALIZED IN TERMS OF BIOLOGIC PROGNOSTIC INDICATORS

As in the adjuvant setting, we suffer from a lack of prognostic indicators that predict which patients should receive more aggressive combination chemotherapy regimens for metastatic disease. Just as it may not be clinically appropriate to treat all patients with MBC using aggressive combination regimens, it is also inappropriate to use one treatment algorithm of sequential single-agent chemotherapy for all patients. Our current scientific limitation is less in finding effective regimens than in determining which patients should receive them.

In general, patients with extensive visceral involvement (ie, hepatic metastasis, pulmonary lymphangitic spread) seem to benefit from rapid disease response and may therefore be appropriate candidates for combination chemotherapy.^6,7 Once such disease is stabilized by combination therapy, proceeding to sequential single-agent regimens may be suitable. Sledge et al³ attempted to identify prognostic features that could identify patients who achieve increased benefit from combination regimens. Unfortunately, only previously established prognostic factors, such as estrogen receptor status, disease-free interval, and number of visceral sites, were found to be significantly related to response to combination therapy in the multivariate analysis. Thus, little new information was obtained on this issue, underscoring the urgent need to detect new biologic indicators that will aid in the identification of appropriate patients for combination therapy.

POINT 2: DEVELOP NEW COMBINATION REGIMENS ON THE BASIS OF IN VITRO DATA TO IMPROVE THERAPEUTIC EFFICACY

Older clinical trials that evaluated combination regimens in MBC simply grouped available agents without sufficient preclinical evidence of efficacy.^5,6 Newer studies have evaluated combination chemotherapies in vitro and have documented synergistic efficacy that is biologically based. A recent example of this is the combination of capecitabine and docetaxel. Capecitabine was designed to target thymidine phosphorylase in tumor tissue to generate intracellular fluorouracil.⁸ Further information from xenograft and human models demonstrates that thymidine phosphorylase can be upregulated by docetaxel and that coadministration of these chemotherapeutic agents results in synergistic antitumor activity.^9,10 The natural extension of these in vitro data is to evaluate the clinical response of combination capecitabine and docetaxel in the metastatic setting, the focus of a recent clinical trial by O’Shaughnessy et al.¹¹ The goals of this study were twofold: to determine whether combination chemotherapy improved overall survival in MBC and to determine whether the disease response rate warranted further investigation in the adjuvant setting. Unlike the disappointing results reported by Sledge et al³ using combination doxorubicin and paclitaxel, treatment with combination capecitabine and docetaxel resulted in an improved overall survival, as well as time to tumor progression and objective tumor response. The superior outcomes obtained by O’Shaughnessy et al¹¹ may reflect their focus on using preclinical data to justify combination therapies, rather than merely demonstrating clinical evidence of non–cross-resistance.

POINT 3: EXAMINE NOVEL COMBINATION REGIMENS IN MBC IN ANTICIPATION OF APPLYING THEM IN THE ADJUVANT OR NEOADJUVANT SETTING

Although the goal of treating MBC is palliation, newer therapies are investigated in this setting for two additional reasons: to cure metastatic disease, and to develop more effective regimens to cure all patients with early-stage disease. Although the goal of curing MBC is a laudable one, the majority of research focuses on evaluating the efficacy of novel combination chemotherapy regimens in MBC, with the expectation of applying these therapies in the adjuvant or neoadjuvant setting. This has been an accepted approach in oncologic treatment for decades. A recent example of this process is the development of the docetaxel, doxorubicin, and cyclophosphamide regimen (TAC).

The TAC regimen is based on the same premise that led to the combination of doxorubicin and paclitaxel, two effective single-agent chemotherapies that do not exhibit cross-reactivity. Nabholtz et al^12,13 added docetaxel to doxorubicin and cyclophosphamide to compare the efficacy of this novel combination to the standard regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC). The phase II trial was performed in MBC to determine baseline efficacy and to evaluate toxicity. Because these parameters cannot ethically be evaluated de novo in early-stage breast cancer, the metastatic setting is the appropriate clinical laboratory. Once the antitumor efficacy of TAC was established, two phase III studies ensued in which TAC was compared with standard FAC in MBC and in lymph node-positive early-stage disease (Breast Cancer International Research Group [BCIRG] 001).^14,15 The phase III trial, comparing the disease response and overall survival of these two regimens in MBC, demonstrated a statistically significant overall response rate in favor of TAC, without a survival advantage.¹⁴ However, BCIRG 001 demonstrated a 33% improvement in disease-free survival (P = .0011), with a trend toward improvement in overall survival (TAC 92% v FAC 87%) among stage II/III breast cancer patients.¹⁵ This lends support to the premise that combination regimens for metastatic disease that result in improved disease response may translate into improved overall survival when applied to earlier-stage disease.

The National Cancer Institute Consensus Conference on Adjuvant Therapy for Breast Cancer 2000 concluded that "adjuvant polychemotherapy should be recommended to the majority of women with localized breast cancer," and that "ongoing studies evaluating these treatment strategies should be supported."¹⁶ The TAC regimen is now being evaluated in two phase III trials in adjuvant therapy, National Surgical Adjuvant Breast and Bowel Project Study B-30, and BCIRG 005. In essence, the investigation of combination chemotherapy in MBC enables the development of improved adjuvant therapies, which hopefully will translate into improved treatment of early disease and increased cure rates. This process supports the charge of the National Institutes of Health Consensus Conference.

POINT 4: EVALUATION OF COMBINATION CHEMOTHERAPY WITH TARGETED AGENTS TRANSFORMS THE BIOLOGY OF DISEASE

One of the pivotal therapeutic interventions in the treatment of breast cancer occurred from the translational work of Slamon et al¹⁷ in the development of trastuzumab. Preclinical studies with the murine monoclonal antibody 4D5 demonstrated antiproliferative effects against human breast cancer cell lines and xenografts.¹⁸ Clinical trials with the humanized version of murine monoclonal antibody 4D5, trastuzumab, demonstrated a modest but significant disease response of 15% in pretreated patients with MBC (H0649g).¹⁹ When this targeting agent was administered with chemotherapy, either doxorubicin and cyclophosphamide or paclitaxel, the patients receiving combination chemotherapy and trastuzumab achieved a statistically significant improvement in disease response, time to tumor progression, and 2-year survival (H0648g).¹⁷ These data prompted further investigation into the optimal use of trastuzumab in breast cancer that overexpresses HER2.

Further in vitro data demonstrated synergistic antitumor effects when trastuzumab was combined with docetaxel and platinum salts (cisplatin and carboplatin), but additive effects when combined with paclitaxel.^20–22 These preclinical data prompted two combination chemotherapy trials for MBC, which evaluated the efficacy of combination chemotherapy with either docetaxel and cisplatin (BCIRG 101) or docetaxel and carboplatin (UCLA Network) administered with trastuzumab.^23,24 Response rates ranged from 64% to 76%. The relevance of these studies is less their effect on survival in MBC than their demonstrating the effect of the targeting agent, trastuzumab, on the efficacy of conventional combination chemotherapy and its potential application to adjuvant treatment. BCIRG 006 is an ongoing phase III trial that investigates combination docetaxel/platinum salt (cisplatin or carboplatin) with trastuzumab as a novel, noncardiotoxic regimen for HER2-positive, high-risk, lymph node-negative or lymph node-positive breast cancer. Understanding the biologic impact of targeting agents, such as trastuzumab, and their interaction with combination chemotherapy in MBC further supports the multiple advantages of ongoing investigation in this setting by improving the treatment of MBC and elucidating life-saving advances in the treatment of early-stage breast cancer.

The controversy over whether patients with MBC should be treated with combination chemotherapy or sequential single-agent regimens has, perhaps, been historically framed with unnecessary and inappropriate oversimplification. Treatment of MBC should be individualized; a standard treatment algorithm cannot apply to all patients. Ongoing investigation of combination chemotherapy should continue in the metastatic setting for several reasons: (1) to facilitate investigation of biologic prognostic indicators that will identify which patients benefit from aggressive combination treatment and which patients will not; (2) to develop combination chemotherapeutic regimens based on preclinical models that improve efficacy, with the goal of applying these regimens in the treatment of early-stage disease; and (3) to understand the biologic effect of targeted therapies used in combination with chemotherapeutic regimens, with the goal of enhancing the efficacy of conventional chemotherapy and applying such regimens to earlier-stage disease. If our investigations are guided by these objectives and we are successful in attaining them, we may move closer to the ultimate therapeutic goal of cure for patients with all stages of breast cancer.

REFERENCES

1. 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]

2. Ahmann DL, Schaid DJ, Bisel HF, et al: The effect on survival of initial chemotherapy in advanced breast cancer: Polychemotherapy versus single drug. J Clin Oncol 5:1928–1932, 1987[Abstract/Free Full Text]

3. 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[Abstract/Free Full Text]

4. 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[Abstract/Free Full Text]

5. Smalley RV, Murphy S, Huguley CM, et al: Combination versus sequential five-drug chemotherapy in metastatic carcinoma of the breast. Cancer Res 36:3911–3916, 1976[Abstract/Free Full Text]

6. Swenerton KD, Legha SS, Smith T, et al: Prognostic factors in metastatic breast cancer treated with combination chemotherapy. Cancer Res 39:1552–1562, 1979[Abstract/Free Full Text]

7. Falkson G, Gelman RS, Leone L, et al: Survival of premenopausal women with metastatic breast cancer: Long-term follow-up of Eastern Cooperative Group and Cancer and Leukemia Group B studies. Cancer 66:1621–1629, 1990[CrossRef][Medline]

8. Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281, 1998[CrossRef][Medline]

9. Sawada N, Ishikawa T, Fukase Y, et al: Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by Taxol/Taxotere in human cancer xenografts. Clin Cancer Res 4:1013–1019, 1998[Abstract]

10. Kurosumi M, Tabei T, Suemasu K, et al: Enhancement of immunohistochemical reactivity for thymidine phosphorylase in breast carcinoma cells after administration of docetaxel as a neoadjuvant chemotherapy in advanced breast cancer patients. Oncol Rep 7:945–948, 2000[Medline]

11. 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[Abstract/Free Full Text]

12. Nabholtz JM, Mackey JR, Smylie M, et al: Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer. J Clin Oncol 19:314–321, 2001[Abstract/Free Full Text]

13. Greenberg PAC, Hortobagyi GN, Smith TL, et al: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14:2197–2205, 1996[Abstract]

14. Mackey JR, Paterson A, Dirix LY, et al: Final results of the phase III randomized trial comparing docetaxel (T), doxorubicin (A) and cyclophosphamide (C) to FAC as first line chemotherapy (CT) for patients (pts) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 137)

15. Nabholtz JM, 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 (BC) patients: Interim analysis of BCIRG 001 study. Proc Am Soc Clin Oncol 21:36a, 2002 (abstr 141)

16. National Institutes of Health Consensus Developmental Panel: National Institutes of Health consensus development conference statement: Adjuvant therapy for breast cancer, November 1–3, 2000. J Natl Cancer Inst 93:979–989, 2001[Abstract/Free Full Text]

17. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792, 2001[Abstract/Free Full Text]

18. Sliwkowski MX, Lofgren JA, Lewis GD, et al: Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol 26:60–70, 1999 (suppl)[Medline]

19. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648, 1999[Abstract/Free Full Text]

20. Pegram MD, Slamon DJ: Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: Evidence for receptor-enhanced chemosensitivity. Semin Oncol 26:89–95, 1999 (suppl)[Medline]

21. Pegram MD, Hsu S, Lewis G, et al: Inhibitory effects of combination of HER2 antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18:2241–2251, 1999[CrossRef][Medline]

22. Pegram M, Finn RS, Arzoo K, et al: The effect of HER2 overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15:537–547, 1997[CrossRef][Medline]

23. Pienkowski T, Fumoleau P, Eiermann W, et al: Taxotere, cisplatin and Herceptin (TCH) in first-line HER2 positive metastatic breast cancer (MBC) patients: A phase II pilot study by the Breast Cancer International Research Group (BCIRG 101). Proc Am Soc Clin Oncol 20:70b, 2001 (abstr 2030)

24. Slamon DJ, Patel R, Northfelt R, et al: Phase II pilot study of Herceptin combined with Taxotere and carboplatin (TCH) in metastatic breast cancer (MBC) patients overexpressing the HER2neu proto-oncogene: A pilot study of the UCLA Network. Proc Am Soc Clin Oncol 20:49a, 2001 (abstr 193)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Overmoyer, B. Search for Related Content PubMed PubMed Citation Articles by Overmoyer, B. Social Bookmarking                            What's this?