Case Vignettes in Metastatic Breast Cancer
Case Vignette 3: Factors to consider when selecting treatments
Elizabeth is a 76-year-old widow who lives by herself. She was diagnosed with ER- and PR-positive/HER-negative MBC 3 years ago and has experienced disease progression with 3 successive endocrine therapies, including tamoxifen, letrozole, and fulvestrant. As bone metastases were discovered after progression on letrozole, she has additionally received treatment with denosumab. At the most recent progression, liver metastases were detected. Elizabeth suffers from hypertension and metabolic syndrome and has been treated with an angiotensin-converting enzyme (ACE) inhibitor for 8 years. After failure of endocrine therapy, Elizabeth moves in with her daughter’s family. Her daughter, a nurse, has investigated options for hospice care but currently considers home care feasible, which is much preferred by Elizabeth, who enjoys the company of her grandchildren. Elizabeth is willing to try CT and is placed on a weekly paclitaxel regimen, during which she needs to delay 2 cycles due to peripheral neuropathy; she also suffers from ongoing fatigue. She experiences stable disease for 7 months. A subsequent regimen with liposomal doxorubicin is interrupted after 3 cycles because Elizabeth experiences hand-foot skin reactions. She is unwilling to resume CT because she feels that therapy is starting to affect her cognition and functional status. She and her daughter discuss options with her oncologist, and Elizabeth decides to begin treatment with eribulin.
Personalizing goals of CT in MBC
At present, MBC remains incurable, and the general goals of therapy are to prolong survival, palliate symptoms, and optimize QOL. Treatment selection should therefore not be solely based on efficacy data but should also include toxicity profile, the patient’s performance status and comorbid conditions, prior therapy received, disease pace (indolent, rapidly progressive), and the patient’s preferences regarding additional therapy and anticipated AEs, as well as schedule and dosing mode.7 Endocrine therapy is preferable to CT as first-line treatment for patients with ER-positive MBC unless very rapid clinical improvement is medically necessary or endocrine resistance is present. Optimal first- or later-line therapy can therefore vary substantially between individual patients and can be influenced also by estimated survival and expected gain from treatment.
Based on a comprehensive literature review, the ASCO guidelines provide a listing of multiple randomized clinical trials in which superiority of one CT treatment arm over the other was found both in respect to efficacy outcomes such as median survival, ORR, PFS, or TTP and in respect to QOL, AEs, functioning, and specific AE.7 This listing can provide guidance in treatment selection, incorporating patient goals and preferences, and will likely be expanded with increasing incorporation of QOL assessments as an outcome measure in breast cancer clinical trials.105 A survey of 181 patients with MBC reported that effectiveness (OS) was of primary importance to patients, followed by AEs specifically alopecia, fatigue, neutropenia, neuropathy, and nausea/vomiting, and lastly, dosing regimen schedule.110 Approximately 33% of patients reported nonadherence to regimens, with forgetfulness and AEs as main reasons.110 Outcomes from a study of 226 patients with limited life expectancy for various medical reasons emphasize the importance of QOL. Almost all patients indicated that they would accept a low-burden treatment, but 74% and 89% would decline a treatment that resulted in severe functional impairment or cognitive impairment, respectively.111
Although long-term survival is possible for a small subgroup of patients with MBC, approximately 1% to 3%, usually young patients with good performance status and limited metastatic disease,112 the majority of patients face a limited life expectancy, which renders communication about disease state and possible and expected benefits from therapy of high importance. Most patients prefer to obtain information regarding survival, side effects, symptoms, and treatment options.113 Shared decision making between physicians and patients will be different for newly diagnosed patients and those whose disease has progressed on multiple previous treatment regimens. A recent study revealed that patients with breast cancer expected much greater benefits from therapy than did physicians; about 50% of patients responding to a questionnaire outlining therapy options for MBC in specific case settings expected more than a 12-month increase in OS for all therapies.114Previous experience of side effects and having young children in the family were the strongest influencing factors.114
Discussions with patients regarding treatment goals should therefore include the rationales for evidence-based therapies and provide guidance to patient resources such as Cancer.Net. Additionally, patients should be referred to psychosocial support and introduced to concepts of concurrent palliative and antitumor therapy.7 Defining the disease context with patients and families includes the consideration of specific psychosocial needs, such as job flexibility, rehabilitation, body image (including sexuality), home and child care in younger patients, and incorporating family members in consultations and decision making for older patients.115,116 Specific domains to be evaluated in geriatric assessment include functional status (such as ability to live independently), comorbidities, psychological state, social support, nutritional status, cognition, and medications and possible drug interactions.34 Particularly in older patients, a tendency exists for undertreatment because of fear of toxicity or concern about comorbidities; however, age alone should not affect treatment selection, and management needs to be customized individually.34
Tolerance of adverse effects
Adverse effects may require dose reduction and cessation of CT prior to disease progression. Both the ASCO and NCCN guidelines recognize the difficulty of balancing the benefits of CT (ie, modest improvement of OS but substantial improvement of PFS), particularly with continuous CT versus shorter-course CT, against toxicity and QOL.4,7 The ASCO guidelines suggest that short breaks, flexibility in scheduling, or a switch to endocrine therapy may be offered to selected patients; this decision will be influenced by many factors including drug used (eg, long-term use of capecitabine is generally feasible whereas docetaxel is limited by cumulative toxicity) and requires a continuing dialogue between doctor and patient.
An important consideration is to determine which, if any, comorbid condition may have an impact on treatment toxicity. Common comorbidities differ between younger and older patients (TABLE 6) and may be disproportionately present in patients of racial/ethnic minorities.7 Predicting toxicity in older patients is complex, as age-related changes in physiology, such as impaired renal clearance, decreased hepatic mass, and alterations in gastric function, can affect drug metabolism and clearance, and thus toxicity.34
TABLE 7 lists therapies in MBC and specific geriatric considerations. Outcomes from a recent phase III trial comparing pegylated liposomal doxorubicin (PLD) with capecitabine as first-line CT in older patients revealed similar effectiveness (median PFS, 5.6 months vs 7.7 months; median OS, 13.8 months vs16.8 months) and feasibility, with grade 3 toxicities consisting of fatigue (both arms: 13%), hand-foot syndrome (PLD: 10%; capecitabine: 16%), stomatitis (PLD: 10%; capecitabine: 3%), exanthema (PLD: 5%), and diarrhea (PLD: 3%; capecitabine: 5%).116
Among microtubule-targeting agents, clinical trial evidence suggest a more favorable toxicity profile of eribulin compared with other agents, with a lower incidence of peripheral neuropathy, at rates of 31% to 32.6% in phase II trials, which are lower than those observed in similar trials with paclitaxel, nab-paclitaxel, and ixabepilone (70%, 71%, and 63%, respectively).90 A recent phase III study found that QOL and cognitive functioning improved more significantly in pretreated patients with MBC who received eribulin compared with capecitabine, whereas emotional functioning improved significantly for patients receiving capecitabine. Patient-reported signs/symptoms in favor of eribulin included nausea and vomiting and diarrhea; systemic side effects and upset by hair loss favored capecitabine.105
An important consideration is to encourage accurate communication of AEs, as frequency and severity of many symptoms that impact upon an individual patient’s QOL are often not sufficiently recognized and treated.117 Instruments and measures of patient-reported outcomes that can be used to more accurately monitor the harms and benefits of patient experience include the EORTC QLQC3 (http://groups.eortc.be/qol/eortc-qlq-c30) and the FACT (http:// www.facit.org/FACITOrg/Questionnaires).115
Sequencing of therapies in the metastatic setting and QOL considerations
According to the ASCO guidelines, second- and later-line therapy may be of clinical benefit and should be offered as determined by previous treatments, toxicity, co-existing medical conditions and patient choice. As with first-line treatment, no clear evidence exists for the superiority of one specific drug or regimen; for later-line treatment, outcomes from the EMBRACE trial demonstrated survival superiority with eribulin over best standard treatment. Evidence suggests that response to second and subsequent lines of CT is strongly influenced by response to earlier treatment; patients whose disease has not responded to up to 2 initial lines of treatment are less likely to respond to a third or subsequent line.7
Palliative care should be incorporated into treatment early on and be offered throughout. This need is underlined by multiple studies documenting poor QOL among patients with MBC, caused by pain and poor symptom control but also psychological distress, with depression, anxiety, and loss of self-image.112,118,119 Psychological distress also represents a challenge for family members. Incorporating distress screening and psychosocial interventions such as nurse-delivered interventions can improve QOL.120,121
With diminishing effectiveness of later lines of CT, clinicians should also offer best supportive care without further CT as an option.7 The NCCN considers not obtaining a tumor response with any of 3 sequential CT regimens or ECOG performance status of 3 or greater an indication for supportive therapy only.4 Lack of response to a CT regimen is defined as the absence of even a marginal response to the use of a given CT regimen.4 Hospice and palliative-care interventions can substantially improve QOL, and possibly survival, in cancer patients.122 Outcomes from a trial evaluating early addition of a structured palliative-care program to CT in patients with metastatic NSCLC showed significant improvement in QOL and mood compared with standard care, as well as extended median survival.123 The importance of early referral to palliative care and hospice is underlined by findings that patients with referral are more likely to have an advanced directive and die at home; however, in many cases, hospice services are delayed.124,125 Consultations on end-of-life planning can increase the use of hospice care and reduce potentially unnecessary interventions.126