Given the lack of prospective data showing an improvement in OS among patients with mBC who are treated with combination rather than single-agent chemotherapy10 and the lack of a well-validated, consensus-derived surrogate endpoint,11 the choice between chemotherapy strategies is typically dependent upon many factors, including the degree of tumor burden, rate of disease progression, site of metastasis, organ involvement and function, cancer-related symptoms, and residual toxicities from prior therapies.12Taking these variables into account, clinicians often use combination chemotherapy in mBC only when it has been determined that the patient is in need of significant treatment response or stabilization in a relatively short amount of time.13 While minimizing the burden of disease outside the CNS reduces the risk of CNS metastases, systemic chemotherapy is relatively ineffective at treating CNS disease.
Perhaps the most critical variable to consider in making a treatment decision in mBC involves the assessment of the patient’s Eastern Cooperative Oncology Group performance status (ECOG PS) or Karnofsky performance status, especially if the clinician determines that the treatment is likely to cause more harm than benefit or significantly decreases QOL. Preexisting treatment-related toxicities also play a role in the treatment selection, as side effect profiles and cumulative toxicities (ie, anthracyclines in patients with cardiac disease, microtubule inhibitors or platinums in patients with neuropathy, and platinum compounds in patients with chronic kidney disease or high frequency hearing loss) vary. Patients with progression of their disease within several months of treatment with a chemotherapeutic agent are often deemed to have resistance to that agent or class of agents. With this in mind, these patients are often sequentially treated with a chemotherapeutic agent, which has a different mechanism of action. As with any chronic disease requiring long-term follow-up and treatment, an approach in mBC incorporating patient preferences into the shared decision-making process is critical for patient compliance and QOL. For example, some patients may be willing to accept more risk in return for a greater response, whereas others desire a specific route of chemotherapy (orally vs intravenously) and a limited number of infusions or duration of infusions and frequency of phlebotomy, or a desire to avoid specific side effects, such as alopecia.
As opposed to the limited and fixed treatment duration that occurs in the curative intent setting, treatment duration for mBC is more individualized and potentially indefinite. Patients are typically continued on therapy until best response, disease progression, or significant toxicity. With regard to the concept of maintenance (continual) treatment, a 2011 meta-analysis analyzed 11 trials of 2,300 treatment-naive patients with mBC, some of which were mTNBC. Maintenance therapy when compared to intermittent treatment found that the former was associated with both an improved PFS and OS.14 Another trial with 324 patients with mBC (<25% of which were mTNBC) who achieved at least stable disease on paclitaxel and gemcitabine (PG) were randomized to observation or maintenance PG chemotherapy until disease progression.15 Maintenance chemotherapy resulted in a higher PFS rate at six months (60% vs 36%) and an improved OS (32 vs 24 months) but was associated with a higher incidence of grades 3–4 neutropenia (61% vs 0.9%) and grades 2–3 neuropathy (0.9% vs 0%). In an unplanned subset analysis, the improved survival was primarily seen among those women who were <50 years of age, had ER/PR-negative tumors, had previously responded to chemotherapy, and had predominantly visceral disease. Additionally, although >70% of the patients had ER/PR-positive tumors, >20% of the patients were endocrine naive. Based on this trial, it is generally recommended that young patients who are responding to treatment continue beyond best response, especially if they experienced limited associated treatment toxicity.
The decision to switch therapies in mBC may be due to serial changes in tumor markers, evidence of progressive disease on imaging (new metastasis or increasing size of previously documented metastatic lesions), and/or clinical deterioration during treatment (due to increasing disease-related symptoms, intolerable treatment toxicities, or declining performance status). Although response evaluation criteria in solid tumors (RECIST) is required by most clinical trials to assess for disease progression, clinicians could reasonably use similar thresholds before abandoning a given line of treatment. The RECIST defines PD as a 20% or more increase in the sum of measurable target lesions compared with the smallest sum previously recorded, the appearance of any new lesions, or the worsening of existing nontarget lesions, such as bone metastases.16