Clinical evaluation of women previously treated for breast cancer: an algorithm for the primary care physician

HONORABLE MENTION

CLINICAL EVALUATION OF WOMEN PREVIOUSLY TREATED FOR BREAST CANCER: AN ALGORITHM FOR THE PRIMARY CARE PHYSICIAN Jennifer S. Choe, MD, Nicole S. Nevadunsky, BA, Irina Burd, BA, and Gloria Bachmann, MD

Breast cancer is an extremely prevalent disease that is estimated to affect one of every nine women, as predicted by lifetime risk in the year 2002. Diagnostic efforts to detect early disease and therapeutic advances including adjuvant therapies have contributed to an increased 5-year survival rate. Therefore, a gynecologist must be prepared for the diagnosis and treatment of typical sequelae after the treatment of breast cancer, as well as aware of health maintenance guidelines particular to this patient group. There are both intrinsic sequelae of breast cancer and side effects of breast cancer treatment, including depression, decrease of libido, vasomotor complaints, vaginal symptoms, and mechanical issues secondary to surgery. Additionally, the primary care physician must consider longterm health consequences of low estrogen states in women who experience menopause as a result of chemotherapy and adjuvant therapies such as aromatase inhibitors. There is need for an algorithm to direct continuing care by the primary care physician, including the gynecologist.

From the Department of Obstetrics, Gynecology, and Reproductive Medicine and the Women’s Health Institute, UMDNJ—Robert Wood Johnson Medical School, New Brunswick, New Jersey.

Volume 10, Number 1, 2003

(Prim Care Update Ob/Gyns 2003;10:1– 8. © 2003 Elsevier Science Inc. All rights reserved.)

In the year 2002, it is estimated that one of nine women will develop breast cancer in her lifetime. Although the incidence of breast cancer is high, in recent years, mortality rates have declined.1 Indeed, there are millions of breast cancer survivors.2 Therefore, a gynecologist must be prepared for the diagnosis and treatment of typical sequelae after the treatment of breast cancer, as well as aware of health maintenance guidelines particular to this patient group. Although the oncologist and breast surgeon often perform clinical evaluation for several years after initial treatment, patients continue nononcologic health maintenance. There is a need for an algorithm to direct continuing care by the primary care physician, including the gynecologist. We propose an algorithm incorporating guidelines suggested by the American Society of Clinical Oncology (ASCO) targeted to assist primary care doctors in treating this patient group (Figures 1– 4). The premise of this algorithm is to include management of physical symptoms and signs related to breast cancer treatment that often present to a gynecologist, such as

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vaginal dryness, loss of libido, and menstrual irregularities. It is important that a gynecologist be aware that these symptoms may result from chemotherapy or hormonal therapy, and be prepared to offer treatments that are both safe and effective for a woman who has experienced a malignancy that is likely to be estrogen reactive.

Menopause and Breast Cancer There exists a relationship between breast cancer and menopause. Criterion for the diagnosis of menopause includes amenorrhea for a period of 12 months in a woman with a uterus. There is an increased incidence of breast cancer at the time of menopause, which occurs at the average age of 51 years in the North American woman.3 However, the majority of women will be diagnosed with breast cancer 20 to 30 years after the onset of menopause because the incidence of breast cancer occurs at bimodal peaks, with the larger occurring during the 7th and the 8th decade.4 In addition to women undergoing a natural menopause near or after the diagnosis of breast cancer, there is a subgroup of women who experience a secondary menopause induced by cancer PII S1068-607X(02)00137-3

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Figure 1. Pertinent historical information.

treatment, including chemo- and hormonal therapy. Current standard of care after

lumpectomy or mastectomy for estrogen-sensitive tumors includes adjuvant therapy with tamoxifen for

Figure 2. Algorithm for physical examination in patients treated for breast cancer. 2

5 years.5,6 Tamoxifen, an estrogen receptor antagonist in selective tissues of the body, is a cause of secondary menopause and is associated with typical symptoms including vasomotor instability, vaginal dryness, and loss of libido.7 Additionally, aromatase inhibitors have recently been shown to be superior to tamoxifen as adjuvant therapy in postmenopausal women.8 Aromatase is a cytochrome P-450 enzyme that converts adrenal androgens to estrogens.9 This process is the sole source of endogenous estrogens in postmenopausal women.8 Common side effects of aromatase inhibitors include hot flushes, vaginal dryness, vaginal bleeding, depression, and thromboembolic disease. Given current duration of treatment and speculation that adjuvant therapy with hormonal agents may be lengthened in the future, there is a growing prevalence of women who will be prePrim Care Update Ob/Gyns

EVALUATION OF WOMEN TREATED FOR BREAST CANCER

Figure 3. Algorithm for the treatment of menopausal symptoms.

senting to the primary care physician while taking these pharmacotherapies.

Clinical Evaluation The majority of breast cancer recurrences are within 5 years of primary treatment, and are most commonly found by history and physical exam. As suggested by ASCO guidelines, clinical examination includes a visit with the medical oncologist every 3– 6 months within the first 3 years, every 6 –12 months for the next 2 years, and once a year after 5 years. In addition to these visits, every woman is recommended to have a regular pelvic examination by her primary care provider. After total abdominal hysterectomy and oophorectomy, a pelvic exam may be performed less often. Volume 10, Number 1, 2003

HISTORY Evaluation of risk factors for breast cancer may be useful in predicting the potential for the development of a new primary tumor. These risk factors include age of menarche, age of menopause, use of hormonal pharmacotherapies, oral contraceptive use, past personal or family history of breast, ovarian, or colon cancer, and presence of BRCA genotype. Predictive information for recurrence includes stage and type of cancer, time since surgery, and type of treatment received. Specific questions pertinent to detection of recurrence include chronic bone pain/tenderness, skin rash redness or swelling, new lumps, changes in breast, chest pain, shortness of breath, abdominal pain, and decrease in weight.

Menopausal symptoms should also be queried, including amenorrhea, hot flushes, and vaginal dryness or discharge. Psychosocial issues associated with cancer and menopause include decreased libido and depression.10 Increased vaginal bleeding or discharge may also be significant for endometrial malignancy, which is slightly increased by tamoxifen therapy.11 Determination of the type of treatment received may also indicate possible sequelae. For example, patients who have received chest radiation may be more prone to development of hypothyroidism. Furthermore, patients who have undergone extensive axillary dissection may also experience lymphedema. Inquiry of herbal medication use and vitamin supplementation should not be ignored (Table 1). Many patients resort to herbal and homeopathic therapeutics for relief of menopausal symptoms. Considerable controversy exists regarding the relationship of herbal and natural supplements including phytoestrogens and breast cancer. As osteoporotic changes are associated with decreased estrogen levels, screening of patients for use of calcium supplementation, participation in weight-bearing exercise, and in some cases bone density measurements may help assess the risk for bone damage and further direct preventive action.

PHYSICAL Specific recommendations for physical examination include breast exam of remaining breast tissue and the contralateral breast. Women undergoing radiation treatment may exhibit a typical skin reaction, especially in the inframammary fold. Additionally, breast tissue after radiation may be firmer by tactile and smaller by visual observation. Other areas to be examined for metastasis include the heart, lungs, abdomen, and lymph 3

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also cause deep muscle aches and pains and even neuropathies. Costochondritis after radiation therapy is also not uncommon. Additionally, mammography continues to be an important diagnostic modality for detection of cancer recurrence. After lumpectomy, a mammogram is recommended at 6 months. Subsequent mammograms should be scheduled yearly for remaining breast tissue or the contralateral breast.

Therapeutics MENOPAUSAL SYNDROMES

Figure 4. Algorithm for the treatment of vaginal symptoms.

nodes of axillae and neck. Yearly pelvic examination including the Papanicolau test and rectal and vaginal examination are recommended. Although tamoxifen has been associated with increased incidence of endometrial cancer, routine endometrial biopsy is not recommended. Because of the occurrence of secondary menoTable 1. Common Alternative Remedies used by Women for Estrogen-Deficient Symptoms Dong quai Ginseng Evening primrose oil Licorice root Red raspberry leaves Sarsaparilla Spearmint Damaina Motherwort Chateberry (also known as Vitex) Black cohosh Wild yams Soy milk

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pause and decreased estrogen levels, possible atrophic changes of the genitourinary tract should be sought. Grossly atrophic changes include sparcity of pubic hair, shiny friable epithelium, and introital stenosis. Microscopically, these changes are manifest by immature squamous epithelial cells (Figures 5 and 6). There also exist mechanical sequelae of surgical intervention in the upper extremities. Attention to range of motion of the shoulder is important for women who have experienced axillary dissection, as well as examination for lymphedema.12 Signs of lymphedema include swelling of arm or fingers and decreased mobility of digits. Additionally, tamoxifen increases the risk for deep venous thromboembolism (DVT), and a high degree of suspicion for DVT is warranted by pain or swelling of an extremity.13 Certain chemotherapeutics may

Hormone replacement therapy is proven effective for management of menopausal symptoms including hot flushes, urogenital atrophy, and mood changes for women who have never had breast cancer. What safe and effective recommendations can the gynecologist make to patients who have had breast cancer? There are several subgroups of patients to consider who may present with menopausal symptoms. There are postmenopausal women who already have menopausal symptoms when diagnosed with breast cancer, postmenopausal women who have no symptoms and prolonged exposure to hormone replacement therapy, premenopausal women who experience premature ovarian failure secondary to chemotherapy, and both pre- and postmenopausal women taking adjuvant therapy with anti-estrogenic effects, including tamoxifen. Because hormone replacement therapy is often stopped at the time of breast cancer diagnosis, estrogenized postmenopausal women often experience severe menopausal syndromes. Frequency and severity of hot flushes have been demonstrated to be increased in women taking tamoxifen.7,14 Women taking tamoxifen have also been shown to experience more frequent hot Prim Care Update Ob/Gyns

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Figure 5. Normal Papanicolaou smear demonstrating squamous cells from the superficial and intermediate layers of the epithelium.

flushes, night sweats, and vaginal discharge than women taking placebo.14 Of note, tamoxifen in postmenopausal women has been reported to cause both vaginal dryness and secretions. Premenopausal women may experience menstrual irregularities, hot flashes, and vaginal symptoms while taking tamoxifen therapy. Women treated with alkylating agents such as cyclophosphamide are at risk for premature ovarian dysfunction. Rates of amenorrhea reported by women receiving adjuvant therapy are 53%, 84%, and 94%, for women aged ⬍35 years,

aged 35– 42 years, and aged ⬎45 years, respectively.15 Permanent ovarian failure is experienced by 96% of women over the age of 40 years.16 Menstrual irregularities typically appear within the first few cycles of chemotherapy, and regular menses may never return. Menopausal symptoms often accompany ovarian dysfunction. There remains much to be investigated regarding the relationship of sexual dysfunction to menopause and breast cancer. Aging is associated with a normal decline in libido and vaginal dryness. Moreover, dyspareunia is a logical sequela of atro-

Figure 6. Immature squamous epithelial cells with enlarged nuclei in a background of basophilic granular debris and inflammatory exudate, typical of atrophic epithelium. Volume 10, Number 1, 2003

phic degeneration of vaginal epithelium and vaginal dryness. Despite increased reports of hot flushes and vaginal dryness, Ganz et al.10 reported that sexual functioning in women after breast cancer was similar to that of healthy women. Predictive factors for development of sexual dysfunction in breast cancer survivors include vaginal dryness and use of chemotherapy.17 Further investigation of adjuvant and chemotherapeutic treatments on menopausal symptoms, sexual dysfunction, and quality of life are currently ongoing.18 Because of concerns regarding metastasis and new primary breast cancers, estrogen use has been routinely discouraged in women with a history of breast cancer. It is recognized that avoidance of estrogen in this group is based on risk minimization rather than on evidencebased medicine. Current efforts to generate data regarding estrogen use by breast cancer survivors is being undertaken by the National Cancer Institute and Eastern Cooperative Group, which is testing hormone replacement therapy in symptomatic survivors taking tamoxifen.4

NONESTROGEN THERAPEUTICS FOR VASOMOTOR SYMPTOMS There are several nonestrogen alternatives that have been used for uncontrolled menopausal symptoms. The first line of treatment should be encouragement of behavioral adaptations, including dressing in removable layers and maintaining a cool environmental climate with air conditioning whenever possible. Diary recording of times of exacerbation of vasomotor symptoms may indicate triggers such as stressful work situations. Preparation for anticipated stress and organization may reduce exposure to triggers that may lead to vasomotor symptoms. A patient complaining of discomfort mainly at night may want to consider getting a larger bed so that she 5

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can maintain a comfortable temperature and close proximity to her bedmate. It is recognized that behavioral modifications will not eliminate symptoms; however, they are nonpharmacologic attempts to maintain quality of life.

NONESTROGEN PHARMACOLOGIC THERAPEUTICS There are several nonestrogen pharmacologic alternatives. The clonidine patch has been proven by double-blind placebo-controlled cross-over design to reduce severity and frequency of hot flushes. However, because of side effects including mouth dryness, constipation, itching, drowsiness, and clinically moderate reduction of menopausal symptoms, clonidine is considered suboptimal treatment.19 Megestrol acetate, in doses ranging from 20 to 80 mg/d, has also proven to reduce hot flushes.20 The impact of lowdose progestational agents on the effectiveness of tamoxifen, development of new primary cancers, and encouragement of micrometastasis is unknown. Vitamin E in doses of 400 to 800 IU daily has been recommended for treatment of hot flashes. However, although statistically significant results are apparent, the clinical benefits are marginal.21,22 Venlafaxine, an antidepressant that inhibits serotonin and norepinephrine re-uptake, has been shown to be well tolerated and efficacious in relieving fatigue, sweating, and trouble sleeping at dosages of 12.5 mg twice daily.23

THERAPEUTICS FOR VAGINAL SYMPTOMS Vaginal symptoms may persist beyond hot flushes. Suggested nonestrogen therapeutics include several nonhormonal vaginal moisturizers.24 Topical vaginal estrogen cream, tablets, or rings may be alternatives for women with mainly vaginal complaints. These offer lo6

calized estrogen without elevating systemic levels.25

ALTERNATIVE AND COMPLEMENTARY THERAPEUTICS Alternative and complementary therapies often used by patients include soy protein, oil of evening primrose, phytoestrogens, and yam creams (source of natural progesterone). There is substantial evidence for the effectiveness of placebo in relieving symptoms that may partially explain the effectiveness of these therapeutics. However, there have been few if any randomized, controlled trials of efficacy and safety of these substances. Theoretical mechanisms of some agents include mimic of the effects of estrogen on the central nervous system and suppression of folliclestimulating hormone and symptoms.

ESTROGEN REPLACEMENT? Is estrogen use ever safe for breast cancer survivors? Prerequisite conditions for the use of estrogen in breast cancer survivors often include uncontrolled vasomotor symptoms, vaginal dryness, serious mood disturbance, trial of nonestrogen approaches, and withdrawal of tamoxifen.4 Additionally, women using estrogen are often survivors of many years. Although there are reports of estrogen replacement use by women taking tamoxifen as adjuvant therapy, there are not any carefully controlled studies.

Preventive Medicine Strategies to combat later effects of menopause in breast cancer patients also consist of many nonhormonal therapeutics. Cardiovascular disease is the most common nonneoplastic cause of death among node-negative breast cancer survivors.26 Exercise, diet, and calcium supplementation are advised for

avoidance of osteoporosis and heart disease. Cholesterol-lowering agents and osteoporosis treatments including bisphosphonates are also available as alternative approaches for women who do not wish to take hormone replacement therapy. The agonistic effects of tamoxifen have been shown to maintain bone mass and reduce death from heart attack by 20% in premenopausal women.27,28

Lymphedema Lymphedema, arm edema in a breast cancer patient caused by disruption of the axillary lymphatic system, results in accumulation of fluid in the subcutaneous tissues.29 Difference in circumferential measurement of ⬎2 cm between normal and affected arms is considered diagnostic.30 This swelling is caused by decreased distensibility of tissue around the joint and increased weight of the extremity. Chronic inflammatory changes of lymphatics and subcutaneous tissue may follow persistent lymphedema. Lymphedema is associated with decreased quality of life and psychological stress. The incidence of lymphedema is estimated to be 26%, or approximately 400,000 women who have received surgical treatment for breast cancer.31 Of note, the incidence of lymphedema greatly varies depending on the invasiveness of surgery, and almost all occurs within the first 5 years after primary therapy.

THERAPEUTICS

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LYMPHEDEMA

Strategies for the prevention of lymphedema include 1) avoidance of trauma/injury, 2) prevention of infection, 3) avoidance of arm constriction, and 4) use and exercise of the limbs. Practical application of these preventive methods includes use of protective gloves for household work and gardening; timely first aid; avoidance of heat and Prim Care Update Ob/Gyns

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excessive sun; not carrying heavy objects; avoidance of repetitive motion; and, avoidance of venipuncture, blood pressure measurement, and injection in the affected arm. Common interventions are elevation, massage, exercise, application of external pressure with compression garments, and physical therapy. Nonpharmacologic interventions have been associated with decreases in volume and circumference of 15–75%.32 Pharmacological interventions are benzopyrones, flavonoids, antibiotics, and diuretics. The length of time of onset from treatment correlates with the ability to achieve optimal results.

BRCA Testing The question of BRCA1 (located on chromosome 17q1) and BRCA2 (located on chromosome 13q12-13) testing and the potential for identification of a possible transmittable etiology of breast, ovarian, and colon cancer may be addressed by a gynecologist.33,34 BRCA testing is contraindicated in persons ⬍18 years of age, in those unable to provide informed consent, or for prenatal diagnosis. There are several social, psychological, and economical ramifications to be considered related to BRCA testing, and consultation with a geneticist may prove beneficial.35

Conclusion A gynecologist is likely to care for patients who are being treated for or have been treated for a breast malignancy. Because of the prevalence and increasingly positive prognosis for women diagnosed with breast cancer, preparedness and familiarity with important issues related to health maintenance and quality of life are essential. Breast cancer treatment is often approached by a multidisciplinary team. Because of the close association of breast canVolume 10, Number 1, 2003

cer to estrogen and adjuvant therapies that use the responsiveness of tumors to hormones with the consequence of menopausal symptoms, the obstetrician/gynecologist is an important part of this effort. As a conclusion, we offer algorithms as possible resources for the primary care physician (Figures 2 through 4). References 1. Chu KC, Tarone RE, Kessler LG, et al. Recent trends in US breast cancer incidence, survival and mortality rates. J Natl Cancer Inst 1996;88: 1571–9. 2. The Consensus Conference on Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer. Obstet Gynecol Surv 1998;53:S1–83. 3. McKinlay SM. The normal menopause transition: an overview. Maturitas 1996;23:137–45. 4. Ganz P. Menopause and breast cancer: symptoms, late effects, and their management. Semin Oncol 2001;28:274 –83. 5. Mansour EG, Gray R, Shatila AH, et al. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer. N Engl J Med 1989; 320:485–90. 6. Fisher B, Brown A, Wolmark N, et al. Prolonging tamoxifen therapy for primary breast cancer. Ann Intern Med 1987;106:649 –54. 7. Love RR, Cameron L, Connel BL, Leventhal H. Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 1991;151:1842–7. 8. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000;18:3758 –67. 9. Miller WR. Aromatase inhibitors. Endocr Relat Cancer 1996;3:65–79. 10. Ganz PA, Rowland JH, Desmond K, et al. Life after breast cancer: understanding women’s health-related quality of life and sexual functioning. J Clin Oncol 1998;16:501–14. 11. Fisher B, Constantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1. J Natl Cancer Inst 1998;90:1371–88.

12. Erickson VS, Pearson ML, Ganz PA, Adams J, Kahn KL. Arm edema in breast cancer patients. J Natl Cancer Inst 2001;93:96 –111. 13. Jaiyesimi IA, Busdar AU, Decker DA, et al. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol 1995;13:513–29. 14. Day R, Ganz PA, Costantino JP, et al. Health related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Clin Oncol 1999;17:2659 –69. 15. Mehta RR, Beattie CW, Das Gupta T. Endocrine profile in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat 1991;20: 125–32. 16. Bonadonna G, Valagussa P, Rossi A, et al. CMF adjuvant chemotherapy in operable breast cancer. In: Jones SE, Salmon SS, eds. Adjuvant therapy of cancer II. New York: Grune and Stratton, 1979:227–35. 17. Meyerowitz BE, Rowland JH, Ganz PA, et al. Sexuality following breast cancer. J Sex Marital Ther 1999;25: 237–50. 18. Ganz PA, Desmond KA, Belin TR, et al. Predictors of sexual health in women after a breast cancer diagnosis. J Clin Oncol 1999;17:2614 – 22. 19. Goldberg RM, Loprinzi CL, O’Fallon JR, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 1994;12:155–8. 20. Quella SK, Loprinzi CL, Sloan JA, et al. Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes. Cancer 1998;82:1784 –8. 21. Barton DL, Loprinzi CL, Quella SK, et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 1998; 16:495–500. 22. Cutick R. Special needs of perimenopausal and menopausal women. J Geriatr Nurs 1984;13:68s–73s. 23. Loprinzi CL, Pisansky TM, Fonseca R, et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 1998;16:2377–81. 24. Nachtigall LE. Comparative study: Replens versus local estrogen in menopausal women. Fertil Steril 1994;61:178 –80. 25. Holmgren PA, Lindskog M, von Schoulz B. Vaginal rings for continuous low-dose release of oestradiol 7

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in the treatment of urogenital atrophy. Maturitas 1989;11:55–63. Cobleigh MA, Berris RF, Bush T, et al. Estrogen replacement therapy in breast cancer survivors. JAMA 1994;272:540 –5. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992;326:852–6. McDonald CC, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial: the Scottish Breast Cancer Committee. BMJ 1991;303:435–7. Brennan MJ, DePomolo RW, Garden FH. Focused review: postmastectomy lymphedema. Arch Phys Med Rehabil 1996;77:S74 –80.

30. Knobf MK. Primary breast cancer: physical consequences and rehabilitation. Semin Oncol Nurs 1985;1: 214 –24. 31. Werner RS, McCormick B, Petrek J, Cox L, Cirrinicione C, Gray JR, et al. Arm edema in conservatively managed breast cancer: obesity is a major predictive factor. Radiology 1991;180:177–84. 32. Brennan MJ, Miller LT. Overview of treatment options and review of the current role and use of compression garments, intermittent pumps and exercise in the management of lymphedema. Cancer 1998;83: 2821–7. 33. Jensen RA, Thompson ME, Jetton TL, et al. BRCA1 is secreted and

exhibits properties of granin. Nat Genet 1996;5:1515–8. 34. Tavtigian SV, Simard J, Rummens J, et al. The complete BRCA2 gene and mutations in chromosome 13qlinked kindred. Nat Genet 1996;12: 333–7. 35. Fasoulitis SJ, Schenker J. BRCA1 and BRCA2 gene mutations: decision-making dilemmas concerning testing and management. Obstet Gynecol Surv 2000;55:373–84. Address correspondence and reprint requests to Gloria Bachmann, MD, Women’s Health Institute, UMDNJ—Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, NJ 08901.

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