By the year 2030 most patients with breast cancer will be aged 65 years or more and many will be frail. Frailty implies diminished physiologic reserve; contributors include diminished organ function, comorbidities, impaired physical function, and geriatric syndromes. Time-efficient tools for assessing frailty are being developed and, once validated, can be used to identify frail cancer patients and help direct therapy. Screening mammography in frail patients is questionable, and a clinical breast exam is likely to identify breast cancers that warrant intervention. Hormonal therapy may be a reasonable primary therapy in older frail women with hormone receptor–positive lesions. For estrogen receptor– and progesterone receptor–negative lesions, excision of the primary tumor may be adequate. Adjuvant hormonal therapy may be appropriate in frail elders with high-risk hormone receptor–positive breast cancer; chemotherapy is rarely indicated regardless of tumor status. The majority of frail elders with metastases will have hormone receptor–positive breast cancers, and endocrine therapy should be considered; those with receptor-negative tumors may be treated with single-agent chemotherapy or supportive care measures. Oncologists need to acquire the skills to appropriately identify frail elders so they select appropriate therapies that will minimize toxicity and maintain quality of life.
Drs. Dittus and Muss have extensively discussed the concept of frailty, illustrated the role of geriatric assessments to better define the "status" of the older patient, and proposed appropriate therapeutic interventions for frail women with breast cancer. In particular, the authors recommend a minimalist approach for patients with early breast cancer.
We would like to remark on three specific issues:
1. The identification of frail patients in clinical practice and implications for treatment decisions
Elderly cancer patients are in many cases suboptimally treated due to the assumption that treatments would be too toxic for them to tolerate. It would therefore be extremely important, as clearly stated by Dittus and Muss, to differentiate patients who are fit from those who are currently functioning but at risk of treatment complications, and from those who are too frail to receive aggressive treatments.
At a recent consensus meeting, scientists failed to agree upon a definition of frailty. They also did not find a consensus on which criteria should be used for the recognition of frailty and its relationship with aging, disability, and chronic disease. Nonetheless, it was agreed that the distinctive trait in frail patients is an increased vulnerability to stress factors due to impairments in multiple systems that lead to a decline in homeostatic reserve and resiliency. The key point then becomes how to differentiate patients who present with reduced functional reserve and could be proposed for tailored treatments from those who have exhausted functional reserve and should be proposed only for supportive treatment.
According to an algorithm for the management of the older cancer patient based on a comprehensive geriatric assessment (CGA), patients with dependence in one or more activities of daily living (ADLs), with severe comorbidity, and with one or more geriatric syndromes are considered candidates for symptom management only, whereas patients with nonreversible dependency in instrumental ADLs and some comorbidity should be considered for personalized treatments. Since a CGA is time-consuming and possibly redundant, screening tests for vulnerability-ie, the Vulnerable Elders Survey (VES-13)-could be used to better identify patients who should undergo a complete CGA.
Unfortunately, to the best of our knowledge, no studies have been conducted that validate CGA as a tool for treatment decision-making in elderly patients with breast cancer. In the Breast International Group (BIG) 4-04 trial, women aged 65 years and older are being evaluated before being randomized to ibandronate alone or capecitabine (Xeloda) plus ibandronate (Boniva), by the means of the Charlson score and VES-13. This study, coordinated by the German Breast Group, will evaluate the role of these two geriatric assessments in predicting treatment-associated adverse events and limited life expectancy in this cohort of early breast cancer patients.
2. The role of surgery in frail patients with estrogen receptor–positive breast cancer
As stated by the authors, endocrine therapy alone is an attractive alternative to surgery in frail patients with endocrine-sensitive breast cancer. However, since lumpectomy can be easily achieved under local anesthesia, outside of clinical trials, the two approaches should be discussed with the patient. In particular, surgery might be considered the preferred treatment option in patients with low levels of hormonal receptors and some features of biologically aggressive disease (ie, high nuclear grade, high proliferative index, or HER2-positive disease). In the ESTEeM trial (Endocrine or Surgical Therapy for Elderly women with Mammary cancer), patients (including the frail ones) aged 75 years and older with estrogen receptor-positive tumors are being randomized to surgery or therapy with an aromatase inhibitor. Surgery is planned in the case of local relapse. This study will definitively clarify the role of surgery in frail patients with endocrine-sensitive early breast cancer.
3. The role of adjuvant chemotherapy in frail patients with endocrine-resistant tumors
We completely agree with the authors' statement that "frail elders with hormone receptor–negative breast cancer and with an expected survival of less than 5 years are not candidates for current adjuvant chemotherapy regimens, even if they have extensive nodal involvement." However, since patients with endocrine-resistant, node-positive tumors are at high risk of early relapse, there is a strong rationale for conducting clinical trials evaluating the role of tailored regimens in women who are not considered suitable for standard therapy. The BIG 1-05 trial, coordinated by the International Breast Cancer Study Group, was aimed at evaluating the role of a tailored dose-schedule of pegylated liposomal doxorubicin (Doxil in the US, Caelyx in Europe) as adjuvant chemotherapy for elderly women with endocrine-resistant breast cancer in whom chemotherapy regimens (derived from trials in younger women) were assumed to be too toxic or inconvenient. Unfortunately, this study will be prematurely closed due to a poor accrual rate; hence, we will miss an opportunity to answer this extremely important question.
Efforts are needed to promote research in the field of geriatric oncology. We understand the inherent difficulties in the conduct of clinical trials targeting frail elderly patients with cancer. However, a joint effort by all specialists involved in the care of these patients is needed to develop easy and reproducible tools that would permit the proper selection and treatment of this growing population.
-Laura Biganzoli, MD
-Giuseppe Mottino, MD
Dr. Biganzoli has spoken at symposia for Schering-Plough.
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