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Goals and Objectives in the Management of Metastatic Breast Cancer

^a Division of Oncology, Stanford University, Stanford, California, USA; ^b Division of Oncology, Stanford University, Palo Alto, California, USA

Correspondence: Robert W. Carlson, M.D., Division of Oncology, Stanford University, 1000 Welch Road #202, Palo Alto, California 94304, USA. Telephone: 650-725-6457; Fax: 650-725-8222; e-mail: rcarlson{at}stanford.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

 
After completing this course, the reader will be able to:

1. Describe the natural history of untreated breast cancer.
   
2. Identify the characteristics of women with metastatic breast cancer who may have especially favorable prognoses.
   
3. Balance physician and patient perspectives in the selection of treatments for metastatic breast cancer.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

 
Patients with metastatic breast cancer consist of a heterogeneous group of patients whose prognoses and clinical courses can vary depending on host factors, such as comorbidity and age, and on tumor factors, such as hormone-receptor status, grade, and anatomical site of disease. Although the median survival time for patients with metastatic breast cancer is 2–4 years, subsets of patients with either indolent or limited metastatic disease may have prolonged survival times. Further, expectations of treatment, both in terms of efficacy and of toxicity, vary greatly based upon the specific treatment, patient characteristics, and tumor characteristics. Thus, the goals of treatment for patients with metastatic breast cancer are influenced by estimates of prognoses as well as a balance between physician and patient preferences regarding efficacy and toxicity considerations. Traditionally, objective measures of response and survival have been the targeted end points in clinical trial design and in physician selection of therapy for metastatic breast cancer. More recently, issues of quality of life have surfaced as important end points, especially from the perspective of the patient. The decision-making process in selecting the optimal treatment for patients with metastatic breast cancer is, therefore, a multidimensional process involving subjective as well as objective goals of treatment. Ultimately, the benefits of treatment must justify the risks and toxicities of the treatment, and the impact of treatment should be measured in relation to specified goals. Both physician and patient perspectives are important in establishing the objectives of treatment, and this process is optimally an interactive and ongoing process throughout the course of disease.

Key Words. Goals of treatment • Metastatic breast cancer

	INTRODUCTION

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

 
In the year 2002, breast cancer was projected to account for 31% of all new cancers among women in the U.S., with 203,500 new cases and 39,600 deaths [1]. Although a greater percentage of women are being diagnosed with breast cancer when treatment with curative intent is possible, 24%–30% of women with node-negative disease and at least 50%–60% of those with node-positive disease at diagnosis will relapse [2]. Additionally, approximately 6%–10% of patients will present with metastatic disease at diagnosis [2, 3]. For women with metastatic breast cancer (MBC) at diagnosis, median survival is generally 2–4 years [2, 4], although prolonged survival is observed in a small percentage of patients [5].

There are many options for the treatment of MBC, including multiple new chemotherapies, hormonal therapies, and immunotherapies. However, breast cancer mortality rates showed only small declines from 1930–1998 (1.6% annually from 1989–1995 and 3.4% more recently) [1]. These statistics suggest that, despite our newer strategies and treatments for MBC, their impact on survival is small. In the face of toxicities of treatment, we must, therefore, evaluate the goals of treatment of MBC from both patient and physician perspectives. Moreover, we should evaluate how we may better measure the effects of treatment in relation to those defined goals.

To assist in defining the objectives of treatment of MBC, it is helpful to first examine the natural history of untreated breast cancer and patterns of relapse. Since patients with MBC display variability with respect to the course of their disease, it is also helpful to determine whether identifiable subsets of patients have specific expectations and goals of treatment.

	NATURAL HISTORY OF UNTREATED ADVANCED BREAST CANCER

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

 
The natural history of untreated advanced breast cancer has been described based upon the records of 250 women with inoperable advanced breast cancer who were admitted to Middlesex Hospital from 1805–1933 and observed from the onset of symptoms until death [6]. Within that series, 44%, 18%, and 4% of patients were alive at 3, 5, and 10 years, respectively. For patients who survived beyond 10 years, none survived beyond the nineteenth year of onset of symptoms. The median survival time was 2.7 years, which is within the range (30.2–39.8 months) confirmed by other studies involving over 1,000 cases of untreated breast cancer dating from 1926–1962 [6]. Median survival correlated with histologic grade, with median survival times of 47.3, 39.2, and 22.0 months for grades 1, 2, and 3 breast cancers, respectively. At 5 years, 22% of patients with grades 1 and 2 breast cancers were alive, whereas all patients with grade 3 breast cancer had died. It was observed, however, that the periods of survival of these patients were associated with discomfort and suffering due to metastatic disease.

These historical data provide a basis against which the impact of current treatments should be compared. From these data, it is apparent that there are subpopulations of patients with MBC who will have prolonged survival with or without treatment due to the biology of their disease [7]. For those patients, MBC may be considered a chronic disease. In such instances of indolent disease, the effects of newer treatment regimens must be assessed over long periods to quantify the impact of treatment on survival. The historical data also provide support for the value of current treatments for MBC in terms of improving quality of life. Treatments that may not provide a survival advantage, but provide palliation of symptoms, may be clinically beneficial, prompting reevaluation of the primary objectives that are set in the design of most clinical trials for MBC.

	PATTERNS OF RELAPSE

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

 
Relapse rates were retrospectively reviewed in a cohort of 716 patients with primary operable breast cancer after radical mastectomy [8]. Within that series, patients with no axillary lymph node involvement had fewer relapses and a better 10-year survival rate than patients with axillary lymph-node-positive disease (Table 1). Regardless of nodal status, the majority of relapses occurred within the first 3 years after surgery and arose at distant sites, most commonly in bone (Table 2). These data suggest that, at initial presentation, a number of patients have undetectable micrometastatic disease. For this reason, the use of systemic adjuvant therapy was adopted.

	OBJECTIVE GOALS OF TREATMENT OF MBC

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

Recent options for treatment of patients with MBC are expanding and include the potential use of single-agent or combination chemotherapy, hormonal therapy, and immunotherapy. The decision-making process as to which agents to choose is complex and requires tailoring based upon the degree of tumor-related symptoms, tumor burden, competing medical comorbidities, age, and acceptable treatment-induced toxicities. Moreover, initial estimates of durations of survival and expected gains from treatment must be balanced in choosing optimal therapies. For a select group of patients with MBC (1%–3%), for example, long-term survival is possible [14, 15]. Those patients are usually young with good performance statuses and limited metastatic disease [5]. Another small (9%–25%) subset of patients with MBC who have relatively favorable prognoses includes those patients with isolated single lesions (e.g., skin, lung, lymph nodes) amenable to local surgery and/or radiation [16]. Those patients have stage IV breast cancer with no evidence of disease (stage IV-no evidence of disease) [17, 18], and studies at the University of Texas M.D. Anderson Cancer Center have shown that combined-modality treatment including chemotherapy and/or hormonal therapy after local therapy, improved overall and disease-free survival rates. While the majority of the 134 patients in that study had chest wall recurrences, patients with visceral and bone metastases were also included, and the 5-, 10- and 15-year survival rates were 36%, 26%, and 24%, respectively [19]. Thus, there appears to be a small subpopulation of patients with MBC for whom more intense multimodality therapy may be beneficial and potentially "curative." Under those circumstances, treatments associated with greater toxicities are more acceptable because of relative gains in survival. The elucidation of additional predictive factors will allow better identification of those patients with MBC for whom treatments may be given with "curative" intent.

For the majority of patients with MBC, however, "cure" is not the goal of treatment, and in those instances, more conservative treatments, with respect to associated toxicities, are preferred. Algorithms to assist physicians in choosing appropriate therapies have been established and are available from the National Comprehensive Cancer Network [20]. Generally, patients with hormone-receptor positive disease and bone/soft tissue only or asymptomatic visceral metastases, should be given hormonal therapy as an initial treatment. For patients with hormone-receptor-negative disease or those with symptomatic visceral metastases or hormone-refractory disease, chemotherapy should be initiated. With the advent of trastuzumab (antibody against HER-2/neu), immunotherapy alone or in conjunction with chemotherapy is an option for patients whose breast cancers overexpress the HER-2/neu oncogene [20].

Ultimately, equal to the importance of choosing the most appropriate therapy is the decision of when to withhold or terminate active treatment of patients with MBC. In contrast to lung cancer, there have been no randomized studies of chemotherapy versus best supportive care for patients with MBC. Yet, meta-analyses of randomized studies comparing shorter with longer durations of chemotherapy in women with advanced-stage breast cancer show a statistically significant survival advantage and improved quality of life for patients who received longer courses of chemotherapy [21]. Moreover, when quality of life was measured, subjective ratings of toxicity from chemotherapy were outweighed by a reduction in disease-related symptoms and a gain in survival. Thus, evidence suggests that therapy for MBC should be continued until disease progression, cessation of clinical benefit, or development of unacceptable toxicities [20, 21].

	QUALITY OF LIFE

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

 
While survival is considered to be the most important outcome of cancer treatment [22], gains in survival from treatments for MBC are modest. Thus, the choice of treatments for MBC must weigh toxicities of treatment against the absolute improvement in survival and the quality of life during and following treatment. The importance of quality of life in the treatment of MBC is reflected by the increasing number of recent clinical trials that incorporate measures of quality of life as end points of study [11, 23, 24]. However, compared with end points of survival (whether measured as overall, disease-free, or progression-free survival) or surrogate measurements such as objective response [25], measurements of quality of life have been difficult to study [26, 27] because of their subjective nature. Moreover, instruments developed to assess quality of life among patients with MBC have mostly involved questionnaires that are often not clinically practical in routine practice due to limited time, lack of resources, and the nonreimbursable nature of the process [28, 29]. For these reasons, none of the instruments have been universally accepted [28]. Further complicating the utilization of quality-of-life measures is the uncertainty of what is being measured. In a study comparing two instruments, known as the Functional Assessment of Cancer Therapy and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30, measurements of different aspects of quality of life were observed even though both questionnaires overlapped in content [30]. In corroboration, a review of health-related quality-of-life measurements among randomized clinical trials involved in the treatment of patients with MBC found that such measures did not add to the clinical decision-making process beyond traditional outcomes such as toxicity, response rate, and time to disease progression [31]. For example, there was no consistent pattern to the quality-of-life variables (e.g., pain, physical, psychological, social, interpersonal) affected by treatment. This lack of effect was contributed to by inconsistent ratings of specific health-related quality-of-life parameters dependent upon the individual rating scale, insensitivity of rating instruments, and instruments that did not include domains likely to be influenced by the intervention being studied, making interpretation difficult. Nevertheless, among treatments with equivalent tumor-related outcomes but different toxicities, quality-of-life parameters can be useful to influence the clinical decision-making process in favor of one treatment over another.

Accurate and reliable methods of measuring quality of life are difficult to achieve because cancer-related quality of life is a multidimensional concept encompassing physical (e.g., symptoms caused by cancer and toxicities of treatment), psychological (e.g., effects of cancer on mood, anxiety, and cognitive function), and social (e.g., effects of cancer on interpersonal relationships with family, friends, and coworkers) domains [22, 28]. These components are, for the most part, subjective in nature, but they may assist clinicians and patients in the mutual decision-making process with respect to preferences of treatment. Issues of quality of life, therefore, complement the more objective measures, such as prolongation of survival or response rates, that are commonly used to select among the options of treatment.

Whether patients experience improvements in quality of life is influenced by the extent of symptoms present before the onset of treatment, the degree of response to treatment, and the toxicity of treatment. It was shown, for instance, that palliative chemotherapy improved frequently reported quality-of-life parameters such as cancer pain, shortness of breath, abnormal mood, anorexia, constipation, and nausea and that these improvements were usually associated with objective tumor response. Moreover, improvement in these symptoms was greatest in those patients who experienced complete or partial responses, followed by those who developed stable disease, and those in whom disease had progressed [32]. Similarly, in another study of over 2,000 pre- and postmenopausal women with node-positive breast cancer who received adjuvant chemotherapy and/or hormonal therapy, quality of life was measured at time points after the completion of adjuvant treatment and at the time of relapse [33]. At a median follow-up of 7 years, those patients who relapsed and had better quality-of-life scores at 1 and 6 months postrelapse were determined to have better overall survival rates. Taken as a group, patients with recurrent breast cancer were found to have significant impairment of physical, functional, and emotional well-being [34], which was affected by tumor-related factors such as the extent of disease, mental and physical health, and family/social support. Multiple measures of outcome, therefore, should be used to assess the efficacy of treatments with respect to intended goals of treatment.

	PHYSICIAN AND PATIENT PREFERENCES FOR TREATMENT OF MBC

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

 
Treatment preferences for MBC may vary between physicians and patients due to differing value systems, personal judgments on acceptable risk-benefit ratios, and differing goals of treatment interventions (Table 5). The question of what amount of benefit justifies what amount of toxicity for the individual patient is a particularly difficult issue for patients and physicians. In a study where clinical vignettes were presented to oncologists to determine preferences for palliative chemotherapy versus watchful waiting, patient age was the strongest predictor of preference for treatment (palliative chemotherapy was preferred for younger patients), followed by patient desire for treatment and expected survival gain. A gain of 3 months survival was strongly associated with a preference for chemotherapy [35]. Preferences for treatment from the patient perspective were addressed in a study involving 115 patients with stage I-IIIA breast cancers who had undergone primary surgery [36]. Fifty-eight percent had also received adjuvant chemotherapy. Patients were presented with different clinical scenarios regarding a woman with MBC and a life expectancy of 18 months, and were asked to choose among treatments with differing toxicities and associated with a 50% chance of prolongation of life expectancy by either 5 years, 18 months, 1 year, 6 months, 1 month, or 1 week. As expected, patients were less likely to accept treatments that were more toxic (e.g., high-dose experimental chemotherapy), although about 15% of patients reported that they would choose such treatments for as little as 1 month of added life expectancy. On the other end of the spectrum, almost all patients responded that they would accept treatment for a 5-year gain in survival. In general, younger patients were more willing to assume risks for even small increases in life expectancy, and 54%–78% of patients reported that they would start treatment even in the absence of symptoms or accept treatment in the absence of prolongation of survival as long as symptoms were palliated. Patient preferences for treatment, however, are influenced by prior experience in a particular health state [37], such that patients with MBC who have experienced prior therapy may value treatments higher than those who have not experienced treatment. Moreover, justifications for treatment are affected by the value of outcome. For example, treatments that offer only a small probability of cure may still be justified even though they may be associated with higher cost [22]. Thus, goals of treatment for patients with MBC should be placed within realistic clinical contexts determined by prior clinical experience and scientific knowledge. These goals must then be discussed in relation to individual patient preference and values, which can differ from those of physicians or family members but must be incorporated into the decision-making process.

	SUMMARY

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

	REFERENCES

Top Learning Objectives Abstract Introduction Natural History of Untreated... Patterns of Relapse Objective Goals of Treatment... Quality of Life Physician and Patient... Summary References

 

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This Article Abstract Full Text (PDF) CME: Take the course for this article: Goals and Objectives in the Management of Metastatic Breast Cancer eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chung, C. T. Articles by Carlson, R. W. Search for Related Content PubMed PubMed Citation Articles by Chung, C. T. Articles by Carlson, R. W.