Complications
Most chemotherapeutic agents used to treat breast cancer may be classified as having low to high emetogenic potential. Among those with high emetogenic potential are cisplatin, doxorubicin, epirubicin, and cyclophosphamide.[438]
The American Society of Clinical Oncology recommends the use of a 4-drug regimen consisting of a neurokinin-1 receptor antagonist (e.g., aprepitant or fosaprepitant), dexamethasone, a 5-HT3 antagonist, and olanzapine in patients receiving cisplatin or other single agents with high emetogenic potential, or receiving an anthracycline combined with cyclophosphamide.[439]
Approximately 10-14 days following administration of each chemotherapy cycle, the leukocyte count decreases to its nadir.
During the nadir, the likelihood of superimposed infection is highest. A deep decline in the leukocyte count is highly likely with dose-dense chemotherapy and TAC (docetaxel, doxorubicin, and cyclophosphamide).[440]
Some data suggest that body mass index influences toxicity, with less febrile neutropenia and fewer neutropenic events in obese patients.[441]
Giving white blood cell growth factors in this situation can help reduce the risk of hospitalization due to neutropenic fever.
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If a patient develops a neutropenic fever, a complete blood count, blood and urine cultures, and site-specific and viral diagnostics should be performed.[442]
After cultures have been obtained, antimicrobial therapy may be initiated; oral therapy is acceptable in low-risk patients, but high-risk patients may require hospitalization and intravenous antibiotic therapy.
Due to their continued suppression of estrogen levels in postmenopausal women, aromatase inhibitors enable bone resorption, increasing the risk of osteopenia and osteoporosis. Consequently, patients are encouraged to increase weight-bearing exercise and calcium supplementation while taking aromatase inhibitors.
In the ATAC (Anastrozole, Tamoxifen, Alone, or in Combination) study, after 2 years of anastrozole treatment, a median 4.1% loss of lumbar spine bone mineral density (BMD) and 3.9% loss of total hip BMD were noted.[389]
In postmenopausal women with early breast cancer taking adjuvant letrozole, lumbar spine BMD was 4.4% higher at 12 months in women who received upfront zoledronic acid compared with those who received delayed zoledronic acid (when the T-score decreased to less than -2.0 or when a nontraumatic fracture occurred).[460] The comparable figure for total hip BMD was 3.3%.[460]
Vasomotor symptoms (including hot flashes, irritability, sleep alterations, and vaginal dryness) may occur due to premature ovarian failure caused by cytotoxic therapy, hormonal blockade due to tamoxifen, or depletion in estradiol and estrone levels due to aromatase inhibitors.
Serotonin levels, which are low in menopausal women, may be related to these symptoms. Venlafaxine, a selective serotonin reuptake inhibitor (SSRI), was studied in double-blind trial of breast cancer survivors. It reduced vasomotor symptoms by 61% (compared with a 27% reduction by placebo alone).[469][470] However, SSRIs also block the 2D6 enzyme, which is responsible for the conversion of tamoxifen to its active metabolite (endoxifen). In particular, agents such as fluoxetine and paroxetine have been found to reduce levels of endoxifen.[471]
For patients who do not respond to or are unable to take SSRIs, other options include gabapentin (which reduced hot flashes by 48% in women with breast cancer, compared with a 23% reduction by placebo), clonidine (which reduced hot flashes by 2.2 per day, compared with a 1.2 per day reduction by placebo), and acupuncture.[472][473]
The progestin megestrol acetate was effective in reducing vasomotor symptoms in breast cancer patients. The potential risks associated with therapy remain unknown.[474]
Lymphedema may occur following an axillary node dissection. To reduce the risk of lymphedema, preventive exercises may be used, such as reaching with both hands behind the neck, behind the waist, overhead, and straight ahead.[461][462]
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One Cochrane review found low-certainty evidence from two studies that lymphaticovenular anastomosis is effective in preventing the development of lymphedema after breast cancer surgery.[463]
If, despite preventive measures, lymphedema occurs, the patient should be referred for occupational and/or physical therapy, where treatment may include manual lymph massage to improve lymph drainage from the affected extremity, measuring for and placing a compression sleeve to reduce fluid accumulation, teaching and performing lymphedema exercises to improve fluid flow, vasopneumatic sequential pumping, and discussing safety precautions to reduce risk of superimposed infection.
Patients should avoid medical procedures (such as blood draws, vaccinations, and BP measurements) involving the affected extremity, wear long sleeves and gloves outdoors to reduce risk of cuts, elevate the arm above the heart when lying down, and avoid lifting or moving heavy objects. Clinicians should be vigilant for the development of secondary limb angiosarcoma, which carries a high mortality.[464]
Prospective studies have shown that complex decongestive therapy is associated with volume reduction of the affected limb and improved quality of life in patients with early breast cancer-related lymphedema. Lymphatic bypass and lymph node transfer are associated with improvements in more advanced breast cancer-related edema.[465]
One 6-week randomized trial of decongestive lymphatic therapy for the treatment of lymphedema compared daily manual lymphatic drainage and bandaging followed by compression garments with compression garments alone. The study found no difference between groups in those losing 50% or greater excess arm volume.[466]
Taxanes, such as paclitaxel and docetaxel, are associated with a dose- and schedule-dependent motor and sensory peripheral neuropathy.
Agents that have been used to treat this complication include tricyclic antidepressants (such as amitriptyline), gabapentin, and venlafaxine.[467][468] Patients with significant motor or sensory neuropathy should be referred to a physical therapist, who may educate them on strengthening exercises and balance training, to reduce risk of injury.
The IBIS-I (International Breast Cancer Intervention Study-1) prevention trial found a nonstatistically significant twofold increase in the incidence of endometrial cancer in women who received tamoxifen.[109] The NSABP P-1 trial found 4 cases of uterine sarcoma in tamoxifen-treated women.
Close gynecologic monitoring is warranted before, during, and after completion of tamoxifen therapy.
The incidence of ovarian failure after chemotherapy increases with the age at which chemotherapy was given.[443] One retrospective study found that 40% of women younger than age 40 years, and 76% of women older than age 40 years, developed ovarian failure after cyclophosphamide, methotrexate, and fluorouracil (CMF).[443]
Interventions to address the potential for infertility include ovarian suppression (using gonadotropin-releasing hormone [GnRH] agonists), oophoropexy, and cryopreservation of oocytes.
In one meta-analysis, GnRH agonists given with chemotherapy were associated with increased rates of recovery of regular menses in premenopausal women undergoing treatment for early-stage breast cancer.[444]
Persistent pain after breast cancer treatment affects approximately 30% of women who have surgery, and 27% of women who receive radiation therapy.[475]
Younger age, radiation therapy, axillary lymph node dissection, and greater acute postoperative pain all increase the odds of persistent pain.[476]
Management includes physical therapy, psychological therapy, and medications for neuropathic pain.[477]
The likelihood of doxorubicin-induced cardiomyopathy rises with the cumulative dose of doxorubicin received; doses of 400, 550, and 700 mg/m² correlate to 3%, 7%, and 18% of patients developing cardiotoxicity, respectively.[445] Risk of epirubicin-related cardiotoxicity was found to occur at a significantly lower cumulative dose than previously assumed (900 mg/m²).[446]
The risk of cardiomyopathy is increased in patients who receive trastuzumab, either sequentially or concurrently.[311][447] Trastuzumab-induced cardiotoxicity may be associated with long-term impairment of cardiopulmonary function.[448] Shorter courses of trastuzumab are associated with a decreased risk of cardiomyopathy.[326]
Obesity in patients with breast cancer may further increase the risk of anthracycline- and trastuzumab-related cardiomyopathy.[449]
Patients who receive anthracyclines and/or trastuzumab should be closely monitored for symptoms and signs of cardiac failure. Infusional administration of the anthracycline may reduce risk of cardiotoxicity.[450]
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If the patient develops anthracycline-induced congestive heart failure, seek guidance from the cardiology service.
Data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) trials revealed that, following treatment with standard AC (doxorubicin and cyclophosphamide), the cumulative incidence of acute myelogenous leukemia (AML) and/or myelodysplastic syndrome was 0.21%; this increased to 1.01% in patients who had received more intense chemotherapy regimens.[451]
Data from the Surveillance, Epidemiology and End Results (SEER) database suggest an absolute risk of developing AML at 10 years after any adjuvant chemotherapy for breast cancer of 1.8% (versus 1.2% for women who had not received chemotherapy).[452]
The NSABP P-1 Breast Cancer Prevention Trial found that tamoxifen resulted in an increase in the risk of DVT, especially among women over the age of 50 years.[109]
Evidence regarding the association between aromatase inhibitors and cardiovascular disease is sparse and conflicting.[453] A scientific statement from the American Heart Association states that aromatase inhibitors increase the risk of cardiovascular disease risk factors and events, including myocardial infarction.[453] The increased risk of adverse cardiovascular outcomes associated with aromatase inhibitors is especially a concern for long-term use of aromatase inhibitors.[454]
One systematic review reported a higher risk of myocardial infarction and angina among patients treated with aromatase inhibitors compared with tamoxifen.[455] This may be driven partially by the cardioprotective effect of tamoxifen.[455][456] There was inconclusive evidence that endocrine therapy contributed significantly to risk of stroke.[455]
One subsequent meta-analysis found that patients treated with aromatase inhibitors did not have an increased risk of cardiovascular events compared with controls (not otherwise specified). Subgroup analysis identified an increased risk of cardiovascular events in patients taking exemestane, compared with controls. Risk of cardiovascular events was not significantly increased in patients taking anastrozole or letrozole compared with controls.[457]
Observational studies have variously reported that, compared with tamoxifen: the risk of the most serious cardiovascular events (cardiac ischemia or stroke) is not elevated in aromatase inhibitor-only users; or, that aromatase inhibitors are associated with increased risk of heart failure and cardiovascular mortality.[458][459]
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