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COMPLICATIONS OF SURGERY, RADIOTHERAPY, CHEMOTHERAPY AND HORMONAL TREATMENT IN PATIENTS WITH BREAST CANCER
Patients with breast cancer may have long-lasting complications of local therapy (surgery and radiotherapy) and of systemic treatments (chemotherapy and hormonal therapy). This review will concentrate on early and late side effects of treatments in women in whom invasive or noninvasive breast carcinoma has been diagnosed.
SIDE EFFECTS OF SURGICAL TREATMENT
The most important post- surgical complication is certainly represented by swelling of the omolateral superior limb (lymphedema). Following axillary dissection, lymphedema presents with incidences varying from 1 to 10%. Incidence increases significantly if axillary radiotherapy is performed after surgery. The removal of the axillary lymph nodes involves the local stagnation of lymphatic fluid (lymph stasis), with progressive sclerosis of the lymphatic vessels and swelling of the arm. Early rehabilitation, with exercises to be started on the first post-operative day and to be continued at home, and a low lipid and low protein diet (especially in obese women), may protect against lymphedema. A pleasant and effective technique for the treatment of lymphedema is represented by manual lymphatic drainage, that consists in the stimulation of lymphatic flow and reabsorption by massage, manipulation, and compressive manoeuvers, to be performed by a rehabilitation therapist with experience in this type of treatment. Manual lymphatic drainage requires sessions of the duration of about one hour, at least 3 times a week for 4-6 weeks.
Restricted arm and shoulder mobility or weakness occur in 70% of patients treated with breast surgery and axillary dissection. Restricted arm sensitivity and presence of local paresthesias are also frequent in women after mastectomy. Specific physioterapeutic sessions are very important in order to restore arm mobility and to reduce the incidence of lymphedema. The rehabilitation programme (image A and image B) starts on the first postsurgical day and continue subsequently until mobility is entirely restored.
SIDE EFFECTS OF RADIOTHERAPY
Radiation-related pneumonitis, with fever, cough and dyspnea, occurs two to nine months after radiotherapy in less than 1% of patients. The incidence of pneumonitis is higher in older women, with higher dose of radiation or larger radiation field and when radiotherapy is performed contemporaneously with chemotherapic treatment. Radiation pneumonitis generally recovers without therapy in a few weeks or months. Pulmonary fibrosis rarely develops in women treated with radiotherapy.
Rib fractures occur in 1 to 2% of patients treated with modern radiation techniques. Risk factors are higher dose of radiations or larger field.
Increased risk of of heart disease is described in women treated with left-sided radiation therapy, especially with older techniques. Pericarditis, cardiac failure and coronary artery disease increase mortality from cardiac causes in these patients. Recent clinical studies, however, have not found higher incidence of cardiac disease in women treated with modern techniques with limited radiation fields. The risk of cardiac toxicity is increased in patients who received radiation therapy in combination with anthracycline-based chemotherapy.
Among patients who received radiotherapy after mastectomy, the risk of controlateral mammary carcinoma is slightly increased (especially in younger women and in patients treated with higher dose of radiation or larger field), because of "scatter" radiation. Angiosarcoma of the skin occurs in 0,1-0,5% of women with chest wall irradiation after mastectomy. The excess risk of ipsilateral lung cancer and esophageal cancer is very small in irradiated patients. The incidence of acute myeloid leukemia is slightly increased after chest wall radiotherapy.
The risk of brachial plexopathy (with pain, paresthesia, ipoesthesia and muscolar weakness) depends on total and daily dose of radiation. Higher doses of radiation or larger field increase risk. In patients treated with modern techniques the risk of brachial plexopathy is 1 to 2 %.
Breast irradiation (as surgical resection of centrally located nodules) impair lactation. The majority (70-75%) of women treated with radiotherapy have difficult and inadequate lactation in the irradiated breast. Breast irradiation causes fibrosis of the lobules of the mammary gland.
SIDE EFFECTS OF CHEMOTHERAPY
Chemotherapy causes mild nausea and vomiting in the majority of patients treated with chemotherapy. Severe symtoms (>10 episodes/24 h) are present in less than 5% of patients. Administration of serotonin-receptor antagonists (ondasetron, granisetron), metoclopramide or glucocorticoids represents an effective treatment.
Chemotherapy causes mild or severe fatigue in the majority of patients during treatment. The possible use of erythropoietin to reduce the incidence and severity of fatigue is currently studied in clinical trials. Fatigue usually resolves after treatment.
Chemotherapy reduces white-cell and platelet count; myelosuppression usually occurs 10 to 14 days after each treatment. An absolute neutrophil count below 500 per cubic millimeter, with life-threatening systemic infections requiring hospitalization, occurs in 2% of patients. When myelosuppression is severe, the administration of hematopoietic growth factors usually increases white-cell and platelet count.
CMF (Cyclophosphamide, Methotrexate and Fluorouracil) chemotherapic regimen causes weight gain (2-6 Kg) in the majority of patients, especially in premenopausal women. Other chemotherapic regimens are associated with less weight gain. Ovarian failure, reduced rates of metabolism and reduced physical activity contribute to weight change in patients treated with chemotherapy.
The administration of taxanes often induces sensor and motor peripheral neuropathy, with sensory loss, paresthesias and muscolar weakness. Usually these neurologic symptoms improve or resolve without therapy after chemotherapic treatment with taxanes.
Chemotherapic treatment causes pronounced or total hair loss in the majority of women, especially with anthracyclines-containing regimens. Hair loss (alopecia) resulting from chemotherapic treatment often involves also pubic and axillary hairs and eyebrows. Alopecia is temporary and always reverses after the suspension of chemotherapy. Alopecia may be partially prevented with the application - for about thirty minutes before and after the intravenous administration of chemotherapeutic drugs - of a plastic helmet containing ice.
Anthracyclines damage myocardium and often cause cardiomyopathy in treated women. Congestive heart failure develops in 0.5 to 1.0 percent of patients treated with standard doses of doxorubicin or other anthracyclines. Cardiac symptoms, with echocardiographic evidence of systolic disfunction, generally develop within several months after chemotherapic treatment, but they may develop later. Older age, preexisting cardiac failure and irradiation of the heart increase the risk of cardiac toxicity in patients treated with anthracyclines. The coadministration of paclitaxel or trastuzumab also increases the incidence of anthracyclines-related cardiomyopathy. In women treated with anthracyclines, the presence of symptoms suggestive of cardiac failure should be evaluated with echocardiographic and electrocardiographic examination.
Chemotherapic treatment induces ovarian failure, with diminished circulating levels of estrogen and progesterone, and is often associated with menopausal symptoms and temporary or permanent amenorrhea. The incidence of permanent amenorrhea is lower with regimens of doxorubicin and cyclophosphamide than with regimens of cyclophosphamide, methotrexate and fluorouracil. Amenorrhea is less likely to be permanent in younger women (40% of permanent ovarian failure). If these patients become pregnant, previous chemotherapy does not appear to determine teratogenic effects. In patients over 40 years of age, treatment with CMF for six months causes permanent amenorrhea in 70% of cases. Ovarian failure increases the risk of osteoporosis in women treated with chemotherapy for breast cancer.
Chemotherapy induces myelodisplastic syndromes or secondary leukemias (acute myeloid leukemias) in 0.2 to 1.0 percent of patients treated with CMF. Leukemias arise five to seven years after chemotherapic treatment. Less informations are present in oncologic literature on the risk of second cancers associated with regimens containing anthracyclines or taxanes
SIDE EFFECTS OF HORMONAL THERAPY
Tamoxifen is a mixed estrogen agonist and antagonist that is used for hormonal therapy in patients with estrogen-receptor positive breast cancers. Tamoxifen has an antiestrogenic effect on breast and on central nervous system Tamoxifen has estrogen-like effects on bone (it preserves bone mineral density in post-menopausal patients), on lipid metabolism (in postmenopausal patients treated with tamoxifen, plasmatic concentrations of total cholesterol and of LDL are riduced of about 10%), on coagulation system and on endometrium.
Patients treated with tamoxifen, especially postmenopausal women, have a small increase in the incidence of deep vein thrombosis, pulmonary embolism and stroke. Tamoxifen has an estrogenic effect on coagulation system and decreases plasmatic concentrations of antithrombin III and protein S.
Tamoxifen increases the risk of endometrial cancer, especially in postmenopausal patients, because of its proestrogenic effect on the endometrium. Endometrial cancer develops in 0.5 to 1.0 percent of patients treated with tamoxifen for five years. Obesity and previous hormone-replacement therapy increase the risk. Most of endometrial cancers related to tamoxifen therapy are early-stage and low-grade neoplasias. Women treated with tamoxifen should undergo an annual pelvic examination; patients whith uterine bleeding have to be evaluated with transvaginal ultrasonography and endometrial biopsy.
Tamoxifen can cause menopausal symptoms both in younger and older patients. Hot flashes, night sweats, irregular menses, vaginal discharge or dryness, diminished sexual interest and satisfaction are reported in half of all patients treated with tamoxifen.
Tamoxifen causes urogenital abnormalities during fetal development. Patients who become pregnant have therefore to discontinue tamoxifen therapy because of its teratogenic effects.
Tamoxifen treatment is associated in rare cases with ocular toxicity. Women treated with tamoxifen for the presence of breast cancer have a slight increase of reversible retinopathy, catarcts and cataract surgery.
BIBLIOGRAPHY
Gian Paolo Andreoletti M.D., Oncologist, Scientific Journalist, Bergamo, Italy. Editor-in-Chief
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