New Strategies for Managing Metastatic Breast Cancer
For many oncologists and their patients with metastatic breast cancer, these are quite confusing times. A growing body of evidence suggests that pure dose-escalation strategies of high-dose chemotherapy with stem-cell support are unlikely to provide much additional benefit in patients with advanced breast cancer.[1] In fact, selection bias may explain much of the potential benefit seen in so many single-arm high-dose chemotherapy studies.[2]
For many oncologists and their patients with metastatic breast cancer, these are quite confusing times. A growing body of evidence suggests that pure dose-escalation strategies of high-dose chemotherapy with stem-cell support are unlikely to provide much additional benefit in patients with advanced breast cancer.[1] In fact, selection bias may explain much of the potential benefit seen in so many single-arm high-dose chemotherapy studies.[2]
Recent findings of scientific misconduct in a South African trial of high-dose chemotherapy for early-stage high-risk women[3] have also called into question the published reports of a survival benefit from high-dose chemotherapy in patients with metastatic breast cancer.[4] In fact, it is somewhat ironic that not long ago many patients and physicians skirted enrollment in randomized trials comparing high-dose chemotherapy with conventional-dose therapy because of the certainty that the answer was known and that more is better. Now, the pendulum has swung to the exact opposite extreme. Yet, we still have very little prospective, randomized data to fully address this strategy.
In their review article, Olin and Muss emphasize that the main goal in the treatment of patients with metastatic breast cancer should be palliation. The authors present a balanced discussion of several controversial topics and offer a well-reasoned framework to guide practitioners in their discussions with an ever more educated group of patients.
As Olin and Muss remind us, metastatic breast cancer is an incurable disease. Although 16.6% of women with metastatic breast cancer in the M. D. Anderson database achieved a complete response following induction chemotherapy with an anthracycline-regimen, only a very small number of these patients remained in complete response over the long term.[5]
This database suggests that a few women with such features as young age, a low tumor burden, and good performance status may enjoy long-term disease-free survival. Unfortunately, most women with metastatic breast cancer will suffer a relapse and die. Even in the taxane era, patients with metastatic breast cancer still have a median survival of only about 2 years.[6] Still, for a number of women, metastatic breast cancer can behave like a chronic disease, and associated morbidities are related to either the biology of the disease and/or the selected treatment(s). Consequently, these are important issues for both physicians and patients to take into account when considering treatment strategies.
Hormonal Therapies
Symptoms should play an important role in the selection of treatment options. Many patients with hormone receptorpositive disease, regardless of menopausal status, should be considered candidates for first-line hormonal therapy, particularly if they have minimal or no symptoms from their disease and no impending visceral crisis.
Olin and Muss discuss potential hormonal strategies for both premenopausal and postmenopausal patients. Certainly, the more prevalent use of prior adjuvant tamoxifen (Nolvadex) is likely to decrease a patients chances of responding to hormonal therapy in the metastatic setting. However, the excellent toxicity profile of many hormonal options still justifies a therapeutic trial. In this regard, physicians and patients should remember that a potential response may not be observed for several months, and that stable disease in the absence of worsening symptoms should not be considered a failure of treatment.
Chemotherapeutic Agents
The last 10 years have witnessed the rapid incorporation of the taxane compounds into the treatment of breast cancer, leading to the recent Food and Drug Administration (FDA) approval of paclitaxel (Taxol) as part of the adjuvant treatment of node-positive disease. The potential benefits of taxanes in metastatic breast cancer are well documented. Both currently available taxanespaclitaxel and docetaxel (Taxotere)offer a better toxicity profile than regimens incorporating either doxorubicin[7] or CMF (cyclophosphamide, methotrexate, and fluorouracil).[8] In addition, a survival advantage favoring taxanes was observed in randomized trials of first-line therapy in patients with metastatic breast cancer[8] and in those whose disease progressed despite previous anthracycline-containing chemotherapy.[9]
Interestingly, such survival advantage seems related to whether[10] or not[8] patients whose disease progressed during treatment with a first-line nontaxane regimen were subsequently crossed over to a taxane drug. This advantage is less apparent in the studies in which a more substantial number of patients in both arms were treated with a taxane, whether initially or at the time of progression. Eastern Cooperative Oncology Group (ECOG) trial 1193, the largest of all such randomized trials, compared an anthracycline vs a taxane vs both drugs in combination.[6] Despite a higher response rate and longer time to treatment failure, all three treatment arms demonstrated similar overall survival rates.[6]
Whereas the issues of dose density and dose intensity are still being addressed in several adjuvant trials, the above studies reinforce the notion that single-agent therapy may be the preferred option in metastatic disease. Weekly taxane regimens are more tolerable,[11,12] although any potential survival advantage in the adjuvant or metastatic setting is still a research question.
Olin and Muss also review data on a few other compounds that can be used as single agents in the palliative setting.
Trastuzumab
The initial studies of therapy with trastuzumab (Herceptin) in HER2-positive metastatic breast cancer, first presented at the 1998 American Society of Clinical Oncology (ASCO) meeting, showed activity of this monoclonal antibody whether used as salvage single-agent therapy in refractory disease[13] or in combination with chemotherapy vs chemotherapy alone as first-line therapy.[14]. More recent data from the randomized trial also indicate an overall survival advantage favoring the combination given upfront.[15]
These findings suggest that the paradigm of no survival benefit for combination chemotherapy over sequential single-agent chemotherapy may not apply to new regimens that include novel biological compounds. Unfortunately, less than one-third of patients with metastatic breast cancer have HER2-positive disease. Also, there is still much disagreement regarding the optimal method(s) to determine tumoral HER2 status; available methods include gene amplification and protein expression assays.
Unfortunately, trastuzumab therapy is associated with a risk of cardiotoxicity in patients who have had prior exposure to an anthracycline and in patients who receive both drugs in combination.[14] Several studies are evaluating potential alternatives to circumvent this problem, such as alternative sequences with trastuzumab given upfront, use of liposomal anthracyclines, and the development of combination regimens of trastuzumab with nonanthracycline compounds. These research questions should help us determine how to safely incorporate trastuzumab into adjuvant treatment strategies.
The issue of the duration of tras-tuzumab therapy (short induction or long-term therapy) must also be addressed in adjuvant trials. In patients with metastatic disease, it is still unclear whether or not trastuzumab should be discontinued upon disease progression, given its low toxicity profile and the theoretical possibility that it may slow the rate of tumor progression.
Bisphosphonates
The authors also review supportive care issues, such as the use of the bisphosphonates. The ASCO guidelines recommend the use of intravenous pamidronate (Aredia) to relieve pain in women with osteolytic metastasis, when administered concurrently with systemic chemotherapy and/or hormonal therapy.[16] The ASCO panel also emphasizes that pamidronate should not displace current standards of care for cancer pain, such as analgesics and local radiation therapy. Current practice is to continue pamidronate even in patients with progressive bone disease. However, one must keep in mind the quite substantial costs of this agent, especially when used with hormonal therapy (more than $300,000 per quality-adjusted year).[17]
Conclusions
Olin and Muss have written a comprehensive review of the treatment of metastatic breast cancer, which emphasizes realistic goals and objectives in the attempt to palliate and maximize quality of life of patients with an incurable disease. Hopefully, their article will be useful to physicians in their discussions with patients and in their decision-making process.
It is also important for all involved to focus research resources on testing novel treatment concepts, eg, biologically targeted strategies given either as a single modality or in combination with other cytotoxic compounds. Patients should be encouraged to participate in clinical trials, including those addressing the treatment of minimal residual disease in both the adjuvant and metastatic settings.
References:
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2. Rahman ZU, Frye DK, Buzdar AU, et al: Impact of selection process on response rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose doxorubicin-containing chemotherapy in patients with metastatic breast cancer. J Clin Oncol 15:3171-3177, 1997.
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16. Hillner BE, Ingle JN, Berenson JR, et al: American Society of Clinical Oncology guideline on the role of bisphosphonates on breast cancer. J Clin Oncol 18:1378-1391, 2000.
17. Hillner BE, Weeks JC, Desch CE, et al: Pamidronate in prevention of bone complications in metastatic breast cancer: A cost-effectiveness analysis. J Clin Oncol 18:72-79, 2000.
