Cardiovascular disease, the leading cause of death in both men and women, is a major contributor to morbidity and mortality in breast cancer survivors. Increasing age, alcohol consumption, excess body weight, and low levels of physical activity are common risk factors for both cardiovascular disease and breast cancer. In addition, some treatments for breast cancer, including anthracycline-based chemotherapy, trastuzumab, radiation, and endocrine treatment have been associated with cardiovascular toxicity. Treatment with anthracycline containing chemotherapy increases long-term risk of cardiomyopathy.
Risk factors for this toxicity include higher cumulative dose of anthracycline, concurrent use of trastuzumab, receipt of radiation, older age, increasing body mass index, lower baseline ejection fraction, and pre-existing hypertension, diabetes or tobacco use. Anthracycline containing regimens used most commonly in the United States to treat breast cancer typically limit the total dose of doxorubicin to 240mg/m2. At this dose, the long-term risk of cardiotoxicity should be less than 5% in the absence of pre-existing cardiac disease.
Higher cumulative doses of doxorubicin and cardiac risk factors increase this risk. Treatment with trastuzumab, which is typically administered for about 1 year in the curative intent setting, is associated with an approximate 0.4% risk of clinical congestive heart failure (CHF) when given without anthracyclines and about a 2% risk of CHF when given following anthracyclines. Reported rates of cardiotoxicity are higher when asymptomatic declines in ejection fraction are included. In contrast to what has been observed with anthracyclines, trastuzumab associated cardiotoxicity is commonly reversible after discontinuation of therapy and long-term risk of cardiotoxicity from trastuzumab appears to be relatively low.
Radiation treatment for breast cancer has also been associated with an increased risk of cardiovascular toxicity. In a meta-analysis conducted by the Early Breast Cancer Trialists Collaborative Group, receipt of adjuvant radiation was associated with an overall survival benefit but an increased risk of death from cardiovascular causes among women treated prior to 1990 in randomized clinical trials.
Since that time, a number of advances in radiation treatment have allowed for reducing the radiation dose to the heart, including modern 3 dimentional treatment planning, heart blocking, patient positioning, active breathing techniques, partial breast irradiation, as well as intensity modulated radiation treatment planning. In a population-based study of women treated in the years 2000–2010, there was no significant excess risk of late cardiotoxicity observed among women who received radiation for early stage breast cancer compared with women who did not receive radiation, supporting the relative cardiac safety of modern radiotherapy techniques.
Bone density loss is another consequence of cancer treatmentrelated premature menopause and of estrogen lowering therapies including ovarian ablation and aromatase inhibition. Among premenopausal women receiving adjuvant chemotherapy, those who retain ovarian function tend to maintain bone density while those who experience ovarian failure have significant bone density loss in the year following chemotherapy.
Compared with placebo, women using aromatase inhibitors experience greater declines in bone mineral density of hip and spine and, at least with extended use of aromatase inhibitors, there is an increased risk of fractures. Tamoxifen appears to have differential effects on bone density depending on menopausal status. While premenopausal women taking tamoxifen may experience bone density loss, tamoxifen appears to favorably affect bone density in postmenopausal women.
It is recommended that bone density be monitored with dual-energy x-ray absorptiometry every 2 years in postmenopausal women receiving aromatase inhibitors, and in premenopausal women treated with ovarian ablation or tamoxifen. A number of studies have demonstrated that upfront use of bisphosphonates, including intravenous zoledronic acid or oral clodronate, can reduce breast cancer treatment related bone density loss and fracture risk among postmenopausal women receiving aromatase inhibitors and among premenopausal women receiving ovarian ablation and either aromatase inhibitors or tamoxifen. Bisphosphonate use in some of these trials was also associated with improved disease related outcomes.
In a meta-analysis of clinical trials evaluating the adjuvant use of bisphosphonates in women with early stage breast cancer, statistically significant reductions were observed in distant recurrence of breast cancer and in breast cancer mortality; notably, however, these benefits were not observed among women who remained premenopausal and did not receive ovarian ablative treatments. The adjuvant use of denosumab every 6 months has also been associated with favorable effects on bone density, reduction in fracture risk and improvement in disease-free survival compared with placebo in postmenopausal women receiving aromatase inhibitor therapy for early breast cancer.
Menopausal symptoms, sexuality, and fertility
Other major consequences of endocrine treatment for breast cancer and treatment related ovarian failure are menopausal symptoms, sexual symptoms and loss of fertility. The risk of ovarian failure with chemotherapy is increased with older age at treatment, and with higher cumulative dose of alkylating agent exposure.
Vasomotor and sexual symptoms can occur in women receiving endocrine treatment for breast cancer regardless of menopausal status. Their management is complicated by the recommendation to avoid menopausal hormone therapy in women with a history of hormone sensitive breast cancer. For some women, environmental and dietary modifications such as dressing in layers, using fans and avoiding caffeine or alcohol are adequate for managing hot flashes.
Lymphedema and chronic pain including arthralgias and neuropathy
Lymphedema is a common complication of breast cancer and its treatment in which interruption of lymphatic drainage by axillary surgery, radiation or by cancer involved lymph nodes results in excessive accumulation of interstitial fluid and swelling of the affected extremity. Risks factors for developing lymphedema include higher body mass index, post-operative infection, receipt of radiation and axillary dissection.
Newer surgical techniques including axillary reverse lymphatic mapping and lymphaticovenous bypass may allow for preservation of important lymphatic channels in patients at high risk for lymphedema. Data do not support that lymphedema risk can be reduced by avoiding blood draws, injections or blood pressure measurements on the affected arm or by avoiding airplane travel.
Awareness of lymphedema risk can allow for early intervention with physical therapy and compression garments which may be more effective when applied before symptoms are severe. In addition, there is evidence that exercise, including weight lifting, is not only safe but actually reduces lymphedema.
Chronic pain is another highly prevalent symptom among breast cancer survivors and may be a consequence of surgery and/or radiation treatment or a result of systemic treatment including chemotherapy induced neuropathy or endocrine therapy related arthralgias. Pain concerns in breast cancer survivors often worsen rather than improve with time and appear to be more prevalent in those who are overweight or obese and in those with lower levels of physical activity.
In addition to the previously discussed treatments for managing lymphedema, and to analgesics such as acetaminophen and nonsteroidal anti-inflammatories, a number of options are available for managing various pain syndromes.
Fatigue, sleep problems, cognitive changes and psychological effects
Causes of fatigue, sleep problems, cognitive changes and psychological concerns may be multifactorial and more than one of these issues often coexist. Cognitive changes can result from fatigue which may be a consequence of sleep problems. Psychological distress may affect sleep. Breast cancer treatments can affect any of these.
In the evaluation of a breast cancer survivor with fatigue, it is important to assess for treatable causes such as anemia, thyroid disease, cardiac dysfunction, other medical issues, or medication effects. Fatigue is an expected side effect of chemotherapy which typically resolves within a year or two of treatment completion, however, some individuals may have longer-lasting fatigue.
Factors that may increase the risk of long-term fatigue in breast cancer survivors include sedentary lifestyle, obesity, aromatase inhibitor use, and certain pre-existing medical issues including migraines, arthritis, peripheral arterial disease and depression . Exercise may improve fatigue in cancer survivors, particularly within the first few years after diagnosis, as can cognitive behavioral therapy aimed at reducing insomnia.
Adherence, recurrence, and subsequent primary cancers
Financial stress and concerns about side effects may lead to non-adherence to treatment and therefore potentially increase risk of metastasis. Some of the factors associated with reduced adherence to adjuvant endocrine treatment include higher out-of-pocket medication costs, lower patient-perceived benefit from endocrine therapy, and side effects impacting quality of life. Management of treatment-related side effects, providing support resources and educating patients on the rationale for recommended treatments may help improve adherence and, as a result, breast cancer outcomes.
Author: Halle C.F. Moore