ABSTRACT: A key objective in the follow-up of women with a history of breast cancer is the detection of local and distant disease at a curable stage. Regular clinical examination and yearly mammography are the standard of care. No consistent evidence supports annual chest radiography, bone scans, or tests of serum tumor markers. Order laboratory or diagnostic tests only if indicated by clinical findings. Advise women to report new symptoms promptly rather than waiting for the next scheduled examination. Some evidence supports the use of venlafaxine for tamoxifen-associated hot flashes. Despite the increased incidence of endometrial carcinoma in women taking tamoxifen, routine endometrial biopsies are not recommended. Most experts advise that women with a history of breast cancer who wish to have a child wait 2 to 3 years before becoming pregnant.
Breast cancer deaths have been diminishing in recent years; the absolute annual decrease is 1.7%.1 As a result, a growing number of women-more than 2 million in 2000-have a history of breast cancer. Because many of these women are followed by primary care practitioners, a general understanding of their medical needs is essential.
The goals of evidence-based primary care follow-up of survivors include:
Diagnosis of local and systemic recurrences.
Evaluation of complications of the disease and of therapy.
Lack of standardization of follow-up leads to a wide variation in the types and numbers of tests performed. Evidence-based guidelines allow patients to avoid tests that do not decrease mortality or improve quality of life.
In this article, we review current strategies for the follow-up evaluation of survivors of breast cancer. In a future article, we will focus on survivors of colon cancer.
By the end of this year, an estimated 250,000 new cases of breast cancer will have been diagnosed in the United States. The incidence was stable in the 1990s but appears to be declining in younger women.1 After a breast cancer diagnosis, the risk of a new primary breast cancer is 3 to 5 times the risk of a first breast cancer.2,3 Metastatic disease develops in 23% of women with stage I or II breast cancer.4
Evaluation is determined by the pattern of recurrence associated with each type of primary therapy. The preferred primary therapy for breast cancer is lumpectomy with radiation. The role of radiation following mastectomy remains controversial.
The American Society of Clinical Oncology (ASCO) published guidelines for the follow-up for breast cancer patients in 1997.5 The following recommendations are based on the ASCO guidelines and additional studies as indicated; they are not intended to supersede physician judgment with respect to individual patients.
The ASCO guidelines were modified initially from criteria established by the Canadian Task Force on Periodic Health Examination.6 The ASCO classification system is outlined in Table 1.
Several studies have evaluated intensive versus symptomatic follow-up after breast cancer treatment. A recent multicenter trial of 1320 women compared intensive surveillance with a program of regular physician visits and clinically indicated tests. There was no significant difference in overall survival time, time to detection of recurrence, or health-related quality of life.7
Most recurrences are signaled by symptoms or by findings on physical examination.8 Advise patients to report any new symptoms immediately rather than waiting for their next scheduled appointment.
Recommended examinations. Regular clinical assessment and mammography are the only recommended evaluations (Table 2).5,6,9
History and physical examination.The ASCO guidelines recommend a history taking and physical examination every 3 to 6 months for 3 years after primary therapy, then every 6 to 12 months for 2 years, then annually.5 The history taking focuses on symptoms of recurrence, which include palpable or visual breast changes, bone pain, shortness of breath, and weight loss as well as neurologic changes such as headache, weakness, numbness, and incontinence. Physical examination includes an evaluation of both breasts, critical lymph node areas, and spine, as well as auscultation of the chest and palpation of the liver.
Mammography. An annual mammogram of the contralateral breast is a level IA recommendation.5,9,10 The ASCO guidelines recommend that women have their first posttreatment mammogram 6 months after the completion of radiotherapy and annually thereafter, unless signs or symptoms warrant earlier investigation.5 Mammography of the ipsilateral breast is a level IVC recommendation. However, it is prudent to obtain an annual mammogram of the ipsilateral breast in women older than 40 years.11
Other diagnostic tests. The level of evidence varies.
Breast self-examination.There is insufficient evidence to recommend for or against teaching or performing monthly bilateral breast self-examination. In one study, the authors observed that the number of recurrences detected at routine visits was about the same as the number detected at unscheduled visits.12 Monthly bilateral breast self-examination is a level IIID recommendation.10,12,13
Chest radiography.The evidence forannual chest radiography varies.4,5,8,10,14,15 The ASCO guidelines do not recommend this test and encourage the development of better means of detection of pulmonary recurrences. A number of studies have demonstrated that although intrathoracic metastases were diagnosed earlier, survival time was not improved. One study found no increase in survival time with biannual chest radiography.14 However, Loprinzi15 and the senior author of this article10 recommend annual radiography for the first 3 years after primary therapy because of improved quality of life with treatment of pulmonary metastases. Some experts recommend annual screening chest radiography.8
Other studies.Routine bone scans are not indicated for asymptomatic patients.4,5,8,14,16 Although regular bone scans may occasionally provide earlier diagnosis of bony metastases, survival time is not improved.
The ASCO guidelines do not recommend routine complete blood cell count or evaluation of electrolytes or liver enzymes.5 Routine tests of serum tumor markers (CEA and CA 15-3) are not recommended, nor are ultrasonography and abdominal CT. There is no evidence that earlier treatment of metastatic breast cancer alters prognosis.5,16
COMPLICATIONS OF THERAPY
Surgery, chemotherapy, and radiotherapy (whether primary or adjuvant) are often associated with adverse effects, some of which may be long-lasting and/or life-threatening. For example, surgical resection can result in lymphedema, infection, or seroma formation. An increased frequency of hot flashes and sweats-resulting from ovarian failure or tamoxifen use-is seen in women who undergo adjuvant chemotherapeutic treatment.17 In one study, primary radiotherapy reduced recurrence by two thirds and breast-cancer mortality by 13.2%.18 However, overall mortality was increased by 21.2%.
Lymphedema. This condition, which has been reported to affect up to 44.4% of women following an axil-lary dissection,19,20 results in pain, decreased mobility, and cosmetic damage. Since it cannot be cured, prevention is extremely important. The risk of lymphedema is directly related to the extent of axillary surgery and radiotherapy. In one study, overweight or obesity was the only significant risk factor for lymphedema after a level I or II axillary dissection.19
Neither physical therapy nor drug treatment (including coumarin21) is effective for treating lymphedema. A randomized study that compared treatment with pneumatic compression with no treatment failed to show a statistically significant response in the treatment group.22
Seroma formation after an axillary dissection occurs in a small number of patients. One study showed that 59.5% of patients required seroma aspirations after the discontinuation of postoperative drainage.19 The incision and surrounding area must be checked carefully for fluctuance.
Cardiotoxicity. Doxorubicin, a common component of both adjuvant and metastatic chemotherapeutic regimens, has been associated with 3 forms of cardiotoxicity23:
Acute or subacute injury.
Chronic anthracycline-induced cardiomyopathy.
Acute toxicity may range from nonspecific ECG changes to rare incidences of sudden death with the first administration. Elderly patients with preexisting heart disease are susceptible to congestive heart failure (CHF) after several doses of doxorubicin. Other risk factors for cardiotoxicity include age greater than 70 years, preexisting heart disease, and concomitant chest irradiation.23 Dexrazoxane can be administered before doxorubicin infusions to bind free radicals and limit cardiotoxicity.24 Echocardiographic evaluation is warranted in patients with a history of doxorubicin treatment if signs or symptoms of CHF develop.
Side effects of tamoxifen. Widely used for the adjuvant treatment of breast cancer, tamoxifen is associated with an increased risk of hot flashes, thrombophlebitis, and endometrial carcinoma.
Hot flashes. These occur in about half of women who take tamoxifen. The symptoms appear to intensify for 2 to 3 months and then plateau or decrease.25 A number of studies have evaluated medical and alternative therapies for significant hot flash symptoms.
The use of soy for hot flashes was evaluated in a double-blind, randomized, placebo-controlled multicenter trial of postmenopausal women. Soy protein, 40 g/d, was associated with a significant reduction in the number of hot flashes.26 However, in another study no alleviation of hot flashes with soy phytoestrogens was noted.27 The means to evaluate the efficacy of alternative agents for hot flashes is still evolving.28 In the meantime, the use of soy protein for symptomatic hot flashes cannot be recommended.
In a phase II trial of venlafaxine, 12.5 mg bid, a reduction of more than 50% in hot flash scores from week 1 to week 4 of treatment was reported in 58% of patients.29 A larger randomized, prospective trial confirmed the efficacy of venlafaxine.30
Clonidine was associated with a moderate reduction of tamoxifen-induced hot flashes in one study; side effects included dry mouth, constipation, and drowsiness.31 Although several studies have supported the use of clonidine for hot flashes, its side-effect profile is a significant disadvantage.
Vitamin E, 800 units daily, was associated with a statistically significant but marginal decrease in hot flashes compared with placebo.32
A trial is under way to evaluate fluoxetine for the treatment of hot flashes.
Endometrial carcinoma.Although some breast cancer survivors forgo tamoxifen therapy because of the fear of endometrial carcinoma, the incidence of this malignancy in this group is only about 2 per 1000 women (compared with 1 per 1000 in the general population).33,34 Tamoxifen use is limited to 5 years because of the 4-fold risk of endometrial carcinoma with longer exposure.35 However, the benefits of tamoxifen in terms of improving disease-free and overall survival time far outweigh the risks of endometrial carcinoma. Two recent reviews concluded that annual gynecologic examinations are indicated for women taking tamoxifen; however, routine endometrial biopsy or uterine ultrasonography is not indicated unless patients report abnormal bleeding or discharge.33,35
Thrombophlebitis. This condition has been reported in 1% to 3% of patients taking tamoxifen. Thrombophlebitis is unlikely to occur in women who are generally active.
GYNECOLOGIC AND REPRODUCTIVE ISSUES
Hormone replacement therapy (HRT). The role of HRT in postmenopausal women has been the subject of debate and controversy for many years. From the late 1980s through the early 1990s, prescriptions for HRT rose because of evidence based on observational and cohort studies that appeared to show an association between this therapy and a reduction in the risk of coronary artery disease of 30% to 70%. However, more recent studies have not demonstrated cardioprotection with HRT in women with established coronary artery disease.36,37
In women with breast cancer, adjuvant chemotherapy and tamoxifen result in premature ovarian failure and thus a lack of estrogen. Because of concern that estrogen might accelerate the development of breast cancer, HRT was traditionally discouraged in postmenopausal breast cancer survivors. Following an editorial by Cobleigh and colleagues38 that challenged this concept, a number of trials were instituted to evaluate the safety and efficacy of HRT in this group of women.
However, recent results from the Women's Health Initiative study have reopened the question of the safety of HRT.39 In this trial, more than 16,000 women were randomized to receive a combination of conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo. The trial was discontinued after an average of 5.2 years of follow-up because of the increased risk of cardiovascular disease, stroke, and breast cancer in the group taking HRT. The risk of breast cancer was 26% higher in this group. Consequently, the role of HRT in postmenopausal breast cancer survivors remains undefined.
Pregnancy. Most physicians recommend that women who have had breast cancer wait 2 to 3 years before becoming pregnant. A recent study compared women with a history of breast cancer who subsequently became pregnant with women who did not become pregnant. The results suggested that pregnancy did not adversely affect survival.40 The age-adjusted relative risk of death associated with subsequent pregnancy was 0.8. The US Army Breast Cancer Research Program is conducting a prospective study that will address the issue of pregnancy following breast cancer. n
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