Endocrine Therapy and Chemotherapy
The challenge in making treatment decisions in older vs younger patients is how to estimate the benefits of treatment after factoring in life expectancy, functional status, and potential side effects. The majority of breast cancers in women 70 years and older are HR+ and HER2-negative (HER2−). The major issue in these patients, most of whom are candidates for endocrine therapy, is the potential added value of chemotherapy. HR+, HER2− breast cancers have significantly different clinical courses compared with triple-negative (estrogen receptor [ER]-negative, progesterone(Drug information on progesterone) receptor [PR]-negative, and HER2-negative) breast cancer (TNBC) and with HR−, HER2+ cancers. For HR+, HER2− tumors, the majority of relapses for patients given adjuvant endocrine therapy are seen 5 years after diagnosis, with a continued hazard for relapse of 1% to 2% per year after 5 years; the majority of deaths in this group are seen after 5 years as well. Conversely, the majority of patients with TNBC or HR−, HER2+ breast cancers relapse within 5 years. This difference in natural history based on HR phenotype has profound treatment implications for older patients with short estimated survival times. Endocrine therapy is usually well tolerated by older patients with only modest risks for toxicity. Older patients with a life expectancy less than 10 years who have HR+, node-negative disease, or only one to three positive nodes, are excellent candidates for endocrine therapy. Few will benefit from chemotherapy. Furthermore, chemotherapy can cause substantial toxicity, leading to loss of function and diminished quality of life.
TNBC and HER2+ breast cancers are each seen in about 15% of older patients. For TNBC, chemotherapy is the only systemic therapy of benefit and should be considered for most patients. HER2+ cancers that are HR− are the worst breast phenotype when untreated, and consideration of chemotherapy and trastuzumab(Drug information on trastuzumab) is appropriate for most of these patients. Those with small HR+, HER2+ tumors (triple positive) have a better short-term prognosis, and the decision regarding chemotherapy/trastuzumab is more complex; those with larger tumors with this phenotype should be considered for chemotherapy and trastuzumab.
There is no question that the addition of chemotherapy to endocrine therapy improves survival in women with HR+ early-stage breast cancer. However, data are sparse for patients 70 years and older; moreover, it is likely that the benefits of chemotherapy vary greatly depending on the biologic characteristics of the tumor. For patients 70 years and older with T1 and T2 node-negative, HR+ tumors (and probably for those with one to three positive lymph nodes ) who are recommended for adjuvant endocrine therapy, the added value of chemotherapy can be estimated by the Oncotype DX assay (Genomic Health, Redwood City, California). Current data from this assay suggest that the major benefit of chemotherapy in this patient group is in those with high recurrence scores, and that chemotherapy is of no added value among patients with low recurrence scores. The value of chemotherapy in those with an intermediate score is uncertain and is being addressed in a randomized clinical trial, TAILORx (Trial Assigning IndividuaLized Options for Treatment [Rx]; clinialtrials.gov identifier NCT00310180); this trial is closed to accrual, and results are expected in 2015. At present we suggest that patients with intermediate recurrence scores also be evaluated using Adjuvant! Online (www.adjuvantonline.com; also see Table) to estimate the added value of chemotherapy in lowering breast cancer mortality. The potential value of chemotherapy using the estimates from both Oncotype DX and Adjuvant! Online can help in making the decision of whether or not to recommend chemotherapy. Adjuvant! Online also integrates patient age into its survival calculations and can be adjusted to account for comorbidity—extremely helpful information when discussing the risks and benefits of treatment with older patients.
Selection and pitfalls of endocrine therapy
Randomized trials have clearly shown that tamoxifen(Drug information on tamoxifen) in women 70 years and older dramatically lowers the annual risk of recurrence of breast cancer by 51% and the annual odds of dying of breast cancer by 37%. These risk reductions are similar for node-negative and node-positive patients; however, the absolute value benefits can vary greatly and be quite small for patients with cancers that have a low risk of recurrence. Conversely, these results may represent a “worst-case scenario,” as many older patients are noncompliant with tamoxifen (and AIs). Tamoxifen is generally well tolerated in older patients and is extremely low in cost and readily available. There is a small risk of endometrial cancer, about 1%, associated with 5 years of use, and a similar small risk of venous thrombosis. In postmenopausal women, tamoxifen can also maintain or improve bone density and lower cholesterol levels. In older patients who have not had a hysterectomy, the requirement for a pelvic examination and Papanicolaou (Pap) smear yearly can be an obstacle to use but is essential for appropriate management.
Numerous randomized trials involving thousands of patients have now compared tamoxifen to AIs, and updated American Society of Clinical Oncology (ASCO) guidelines for use of endocrine therapy are available. In almost all of these trials, a small improvement in relapse-free survival of a few percentage points has been shown for use of AIs, but without any convincing improvement in overall survival. A strategy of initiating endocrine therapy with tamoxifen and then changing to an AI 2 to 3 years later has been shown to improve survival and may represent the best strategy. Until now, AIs have been extremely expensive, but since coming off patent, costs have dropped dramatically. ASCO guidelines have recommended that AIs be considered for use in all postmenopausal patients at some time during their endocrine treatment. Unlike tamoxifen, AIs are not associated with an increased risk of endometrial cancer or thromboembolism, but even in older patients they can be associated with severe arthralgia and myalgia that can impede function. The symptoms, when severe, are hard to ameliorate. Changing to another AI can be helpful in some patients. If symptoms persist after changing AIs, switching to tamoxifen is probably the best strategy.
The other major toxicity associated with AI use is accelerated bone loss and an increased risk of fracture. Many older patients already have osteopenia or osteoporosis when breast cancer is diagnosed. Older patients on AIs should be encouraged to exercise and use recommended doses of vitamin D and calcium. For those with severe osteopenia (T-score less than −2.0) or osteoporosis, either bisphosphonates or other bone-protecting agents such as denosumab (Prolia) should be considered. These agents, although generally safe, can add to the costs of treatment. The World Health Organization fracture risk assessment tool, “FRAX,” can be used to estimate fracture risk from clinical and bone densitometry data (www.shef.ac.uk/FRAX).
Older adults are more susceptible to medication nonadherence for a variety of reasons, but common associations with adherence problems include cognitive, visual, and physical impairments that impact the treatment plan. Polypharmacy is common among older adults because of their prescribed medications for treatment of comorbidities. Because of the large number of medications taken by older patients, drug interactions and side effects are more common than in younger age groups, and patients must be closely monitored. In one study, 49% of patients over 65 years of age discontinued adjuvant tamoxifen before 5 years; being 75 to 80 years old, having increased comorbidity, having increased cardiopulmonary comorbidity, and having received breast-conserving therapy without breast radiation were all related to nonadherence. Poor adherence to AIs has also been found in older women. The best way to improve adherence is uncertain, but educating older patients and their families about the value of treatment and possible side effects of treatment is certainly important as family members and other caregivers play a key role in having patients take their medications as prescribed. In addition, providers should query patients on each visit concerning compliance with treatment and should encourage adherence to therapy.
The decision to recommend chemotherapy to an older patient is a complicated one and includes consideration of the effect of chemotherapy on improving survival, the potential for toxicity and resulting functional loss, and both the social (logistics and increased need for family support), and financial costs of treatment. Like endocrine therapy, chemotherapy regimens result in similar proportional reductions in recurrence and survival for both node-negative and node-positive patients. The major decision for the medical oncologist is which chemotherapy regimen to recommend. Historically, cyclophosphamide(Drug information on cyclophosphamide), methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil) (CMF); and doxorubicin(Drug information on doxorubicin) and cyclophosphamide (AC) were among the most frequently used regimens. These regimens resulted in significant improvements in breast cancer survival, but newer regimens have substantially enhanced these results. In addition, recent data suggest that 4 cycles of docetaxel(Drug information on docetaxel) and cyclophosphamide (TC) are superior to 4 cycles of AC, even in older women. Our bias is to select chemotherapy regimens based on their absolute reduction in breast cancer mortality (which is related to risk of recurrence), potential toxicity, and the patient's life-expectancy. Adjuvant! Online is a useful tool to use when making these decisions; it compares survival outcomes of first-generation chemotherapy regimens (such as CMF or 4 cycles of AC) with second-generation regimens (such as TC or 6 cycles of an anthracycline-containing regimen) and with third-generation regimens (such as dose-dense AC and paclitaxel(Drug information on paclitaxel); and docetaxel, doxorubicin, and cyclophosphamide [TAC]). For fit patients at high risk of recurrence, survival is improved by a few percentage points with more aggressive third-generation regimens compared with first- or second-generation regimens. For other patients, we suggest consideration of second-generation regimens such as TC, as they avoid the potential higher risks of cardiac damage and leukemia associated with anthracyclines. Unlike the more aggressive and more toxic third-generation regimens, which have not been extensively studied in older patients, the TC regimen has been well tolerated in older patients in the adjuvant setting, with minimal effect on functional status, but is associated with a 20% to 30% risk of neutropenic fever unless prophylactic growth factors are used. An example of the potential benefits of first-, second-, and third-generation regimens in improving survival in older patients is shown in Figure 3. A large retrospective study of node-positive patients in randomized trials comparing less-intense vs more-intense chemotherapy showed that the more-intensive regimens were associated with a similar proportion of benefits in terms of improvement in relapse and survival rates for older vs younger patients. It should be noted, however, that the effectiveness of second- and third-generation chemotherapy regimens in older patients, as estimated by Adjuvant! Online, has not been validated in clinical trials, and it is possible that the value of such regimens is overestimated in this patient group.
Chemotherapy toxicity is a major concern in older patients, and there is a paucity of clinical trial data on how such toxicity affects function in older women. In one recent trial focused on elderly patients with breast cancer, both CMF and AC were found superior to capecitabine(Drug information on capecitabine) (Xeloda) in improving survival. Surprisingly, AC was better tolerated than CMF, with 92% of patients completing the 4 planned cycles of AC but only 62% completing the 6 planned cycles of CMF. Third-generation regimens such as “dose-dense” AC and paclitaxel, AC followed by docetaxel, and TAC are all associated with substantial toxicity. Such regimens should be reserved for patients who are at very high risk of recurrence and highly functional, without major organ dysfunction. The recent EBCTCG study comparing long-term outcomes of combination chemotherapy (polychemotherapy) regimens showed that longer durations of chemotherapy, such as 6 cycles of an anthracycline-containing regimen (with either doxorubicin or epirubicin(Drug information on epirubicin)), were superior to 4 cycles of AC or CMF. Concerns about toxicity should not preclude providing adequate dosing, and doses should be those shown to be effective in published trials. Arbitrary dose modifications of trial-defined dosage can be associated with poorer outcomes and should be avoided; when necessary, granulocyte-stimulating growth factors should be used for initial and subsequent dosing, following published guidelines.[42,43]
Patients with HER2+ tumors derive the best survival improvements from the combination of chemotherapy and trastuzumab. Trastuzumab, like anthracyclines, is associated with a higher risk of cardiac toxicity in older adults. The regimen of docetaxel, carboplatin(Drug information on carboplatin), and trastuzumab is similar in efficacy to trastuzumab-and-anthracyline–containing chemotherapy and is associated with less cardiac toxicity; it should be considered for older patients with HER2+ high-risk tumors. Other potentially less toxic chemotherapy regimens such as TC can also be given with trastuzumab. Although not tested in the clinical setting, trastuzumab alone might be considered for older, more frail patients with high-risk HER2+ tumors. At present, calculating the added value of including trastuzumab with chemotherapy in patients with HER2+ tumors cannot be done directly using Adjuvant! Online, but it can probably be fairly estimated by multiplying the chemotherapy percentage in the “Adjuvant Therapy Effectiveness” box by 1.5 (based on a hazard ratio of about 0.5 for chemotherapy plus trastuzumab compared with chemotherapy alone).
Caring for women 70 years of age and older with early-stage breast cancer is challenging. A general approach to caring for such patients is presented in Figure 4. In addition to the challenges posed by multiple comorbidities and loss of function for many of these patients at the time of diagnosis, there are scant data from clinical trials that can be used to guide treatment decisions. More widespread use of CGA can certainly help to determine the suitability of treatment, and using CGA as part of clinical trials to determine therapy has been shown to be of benefit and should be more widely used. In addition, addressing the barriers to clinical trial participation by elders, developing methods to ensure that adequate numbers of elders participate in major trials, and increasing funding for research in geriatric oncology are all essential if we are to increase our knowledge and provide optimal care for this ever-expanding group of patients.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
This work was supported by funding from the National Cancer Institute's Cancer Care Quality Training Post-Doctoral Fellowship (5R25CA116339).