Tamoxifen's Impact on the Management of Breast Cancer: Patient Perspectives

ABSTRACT: Tamoxifen citrate has been prescribed to millionsof women with breast cancer and has been one of the most important advancesin breast cancer treatment over the past 25 years. Because she is a femalephysician, the author's patients tend to be particularly open about theirconcerns regarding breast cancer and its treatment. Women accept tamoxifenas a treatment because of its demonstrated efficacy in breast cancer, extendingsurvival and reducing contralateral breast cancer. They also recognizethe potential benefits of secondary effects on lipids and bone. However,patients do have concerns regarding side effects and their impact on everydaylife. [ONCOLOGY 11(Suppl 1):55-58, 1997]

Introduction

Physicians need to be acutely aware of and sensitive to those concernsand factors that affect quality of life in order to be able to communicatethe necessary information to their patients. Physicians must be able toprovide information to their patients and to place simplistic or incorrectmedia reports into perspective.

Patients need to be aware of the side effects and what can be done tominimize them. They should also realize that some side effects may be dueto other processes, including natural or induced menopause.

As a group, women are sensitive to issues that affect body image; thisis particularly true of breast cancer survivors. Therefore, weight gainwhile on tamoxifen may represent a major concern. Menopausal symptoms suchas hot flashes, sleeplessness, and urinary and vaginal changes may be debilitatingand long lasting. Sexual function in the cancer survivor is an issue thatis rarely broached by oncologists. Depression can also occur.

Other risks associated with tamoxifen, such as uterine cancer and oculartoxicity, are rare, and the role of the drug in the pathology of theseconditions needs to be further defined.

If physicians are aware of patient concerns, communication can be improved.When patients are adequately informed about the real benefits and risksof tamoxifen, they are unlikely to refuse treatment and are more compliantwith treatment recommendations.

Tamoxifen is an effective treatment for many women with advanced ormetastatic breast cancer. Recent studies of early-stage breast cancer haveconfirmed that tamoxifen, when given after initial surgery or radiationtherapy as "adjuvant systemic therapy," can prevent or delaybreast cancer recurrence.

These studies have also shown that tamoxifen decreases the chance ofbreast cancer occurring in the untreated (opposite) breast. Tamoxifen hasalso been shown to prevent breast cancer in laboratory experiments. Tamoxifenis also currently being studied as a preventive treatment for women whoare at an increased risk for breast cancer for a variety of reasons, includingfamily history, age, and previous history of lobular neoplasia (LCIS orlobular carcinoma in situ).

Tamoxifen is a hormonal medication that acts against breast cancer cellsby preventing estrogen from binding to the special estrogen receptors thatare present in many breast cancer cells. This interaction inhibits thegrowth of cancer cells. Most tumors are tested for estrogen receptors andtheir presence determines the likelihood of response to tamoxifen. Thereare other mechanisms through which tamoxifen interferes with cancer cells,some of which are not well understood.

Like all medications, tamoxifen has advantages and disadvantages toits use. However, for most women with early-stage or operable breast cancer,the risks of tamoxifen are greatly outweighed by its benefits.

My experience with tamoxifen citrate has been gathered through practiceas a physician. My patients tend to reveal personal concerns to me thatthey might not discuss with a male physician. This has put me in a positionto evaluate the benefits and drawbacks of breast cancer treatments fromthe patient perspective.

Patient Communication

When patients are well-informed, they tend to understand both the benefitsand risks of taking tamoxifen. They know what side effects to expect andfeel a sense of control over their lives. Providing educational materialssuch as handouts and videos and referring women to support groups or therapistsare particularly helpful in preparing patients for treatment.

The negative media attention tamoxifen has received lately has createdhysteria in many medical offices. We have to actively debunk negative impressionspatients have developed based on inadequate or misleading information obtainedfrom the media. We must provide our patients with accurate informationand discuss their concerns in detail in order to help the patient bettermanage both their disease and treatment.

Benefits of Tamoxifen

Patients easily recognize the benefits of tamoxifen in relation to breastcancer. I do not have problems explaining these benefits in discussingwhy breast cancer patients should take tamoxifen. Clinical trials haverevealed an increase in overall survival as well as disease-free survivalin both premenopausal and postmenopausal patients, particularly those withestrogen receptor (ER)-positive disease.[1] Data from adjuvant trials havealso demonstrated a 39% reduction in the incidence of contralateral primarybreast cancer with tamoxifen.[2]

Predictors of tamoxifen response include the presence of ER-positivedisease, soft tissue rather than osseous or visceral metastases, olderage, longer time to recurrence, indolent course of disease, and prior responseto hormonal therapy.

Tamoxifen also has favorable secondary effects on bone mineral densityin postmenopausal women and on the cardiovascular system that may not beas well recognized. The cardiovascular effects are possibly related tothe observed 12% reduction in non-cancer-related mortality. These benefitsmay be significant to some women.

Duration of Tamoxifen

The scientific question of how long to give tamoxifen remains unresolved,but for the patient, it is often a more personal question. Many patientsfeel that continuing therapy makes them feel proactive and secure--"thetamoxifen security blanket."

For patients with node-negative breast cancer, it is relatively clearthat there may be no further benefit in continuing tamoxifen beyond fiveyears; however, for patients with node-positive disease--and within itsvarious subgroups--the answer is less clear. Patients with node-positivebreast cancer need to be handled on a case-by- case basis. To formulatethe best plan for the individual patient, we use all the prognostic informationthat we have available including pathologic findings, tumor size, numberand level of lymph node involvement, hormonal receptor status, patientage, and menopausal status. Of course, the patient's preferences must alsobe considered.

Because of the media's inaccurate reporting, the public doesn't understandthe full story about duration and doesn't make the distinction betweennode-positive and node-negative disease. Media reports often give the impressionthat five years of therapy is standard for all patients, when this is notthe case. Such reports often raise unnecessary concern among patients.

Quality of Life

Side effects of any drug are important to patients in relation to qualityof life, especially when the drug is taken for extended periods. Beingaware of side effects and minimizing their impact are important factorsin continued compliance, which is necessary for maximum effectiveness.

A preliminary investigation was made into the quality of life of tamoxifenpatients participating in the National Surgical Adjuvant Breast and BowelProject (NSABP) B-14 protocol (Table 1).[3]The results demonstrated that there was no major difference between tamoxifenand placebo in the quality of life: no negative impact on social activitiesor work habits, including housework and volunteer work.

More patients receiving tamoxifen experienced hot flashes than thosereceiving placebo. Contrary to what I would expect, more placebo patientsreported that they felt less feminine and had reduced sexual desire thantamoxifen patients. Clearly more quality of life studies with detailedanalyses need to be conducted in breast cancer patients on tamoxifen.

Patients who realize that certain side effects can occur tend to dealwith the side effects better than those who have not been informed priorto their occurrence. Uninformed patients may not recognize side effectsor seek help. Some patients report that they feel like they are "losingtheir mind" and that the side effects are imaginary. Patients mustrecognize that the side effects are real.

Side Effects of Tamoxifen

Types of side effects of tamoxifen vary significantly as does theirreported incidences. As is the norm, patients tend to talk about theirnegative experiences rather than their positive ones, so we are more likelyto hear from patients having significant side effects. Discussions on theInternet and in patient groups also tend to focus on negative experiences,although occasionally patients report after discontinuing tamoxifen thatthey had felt better while on the drug.

Menopausal Symptoms

Many of the symptoms reported by tamoxifen patients are similar to thoseexperienced by women going through natural or chemotherapy-induced menopause,since these symptoms are due to loss of estrogen. Some younger women experienceabrupt, premature menopause on tamoxifen or as a result of chemotherapyand are very distressed by their symptoms. However, older women seem tohave just as much difficulty.

As do women undergoing menopause, many women on tamoxifen struggle withhot flashes as well as sleeplessness. Bloating, constipation, irregularmenses, vaginal complaints (dryness, itching, and/or discharge), nonmenstrualbleeding, depression, memory loss, and hair thinning are also reported.In many cases it is hard to separate the etiology of the symptoms; theimportant thing is to listen and to alleviate symptoms if possible.

Vasomotor symptoms may be remedied by taking vitamin E, B6, or selenium.Prescription drugs include progesta- tional agents, Bellargal, and clonidine,the latter two causing major side effects. Using a divided schedule oftamoxifen or taking it at different times of the day may help to decreasehot flashes. Incorporation of soy products into the diet several timesa week may be helpful.

Although estrogens are generally contraindicated in breast cancer patients,some physicians prescribe them to treat estrogen deprivation-related symptoms.This use of estrogens needs further investigation in controlled clinicaltrials.

A wide variety of herbal and natural remedies have been used, many withoutsignificant clinical studies on their safety and efficacy (Table2). Products such as primrose oil, dong quai, cat's claw, blue cohash,false unicorn root, fennel, thistle, anise, and shark cartilage have beenreported as being used. With some herbs, we do not know why or if theyreally help, or if there is a placebo effect. The bioavailability amongpreparations may be different. Many of these types of remedies are reportedfrom patient to patient. When you ask patients what medicines they aretaking, they often do not report all of the additional agents; such remedieshave to be queried about specifically.

Weight Gain

Physicians treating breast cancer patients need to be especially sensitiveabout the issue of weight gain. Interestingly, weight gain has been correlatedwith both menopause and hormone replacement therapy, as well as tamoxifen.Women in general are concerned about body image, and patients with breastcancer have just experienced relatively deforming surgery, regardless ofconservation and/or reconstruction, that makes them even more sensitiveto body image.

Weight gain is common in healthy postmenopausal women[4] and is prevalentin breast cancer patients as a group, regardless of their particular treatment.My best approach is to tell women that they may gain weight, and I stressthe importance of optimizing their overall health through maintaining goodbody weight and exercise, which may prevent osteoporosis and heart disease.

Sexual Dysfunction

New interest has been generated in a historically neglected issue: sexualfunction in the cancer survivor. The lack of estrogen with tamoxifen treatmentcauses vaginal dryness, and dyspareunia may result. Painful intercourseis likely to produce reduced desire and hence sexual avoidance in thesewomen.[5] In a 1994 abstract,[6] 53% of tamoxifen patients in partneredrelationships reported dyspareunia and 29% reported decreased sexual desire.A loss of ability to achieve orgasm was suggested by the study. Treatmentwith topical estrogens and the use of systemic hormone replacement therapyin this population is controversial. We recommend the use of a varietyof nonhormonal lubricants (ie, Replens, Astroglide) for this condition.Vaginal dilators may also prevent or delay vaginal atrophy.

Treatment for reduced sexual desire is less straightforward. The lateDr. Helen Singer Kaplan attributed reduced libido and sexual responsivenessin breast cancer survivors, as well as postmenopausal women as a whole,to reduced circulating testosterone levels.[7,8] She was able to reversethis condition with low, nonvirilizing doses of testosterone. In addition,many women are emotionally vulnerable and depressed after breast cancerdiagnosis and surgery, and this has a major impact on sexual life. Antidepressantsand counseling should be considered for these women.

Other Effects

Some reported side effects of tamoxifen are very infrequent, includingdizziness, headache, thromboembolism, and visual changes. Recently, concernin the media has focused on risks of tamoxifen with respect to the developmentof other cancers in breast cancer patients treated with tamoxifen. Thesereports have raised concern and need to be discussed openly. It shouldbe noted that a higher proportion of colon and endometrial cancers havebeen reported in breast cancer patients than among the general population.The actual risks need to be communicated to patients. When patients areinformed about the real risk of developing uterine cancer, they are unlikelyto refuse tamoxifen. Indeed, tamoxifen patients are now monitored moreclosely for gynecological symptoms. However, evaluation beyond annual Papsmears and investigation of nonmenstrual bleeding appear unwarranted.

In postmenopausal women, the benefits of tamoxifen in preserving bonemineral density is known, although some data imply that there may be boneloss in premenopausal patients.[9] We should determine whether our patientshave adequate calcium intake with vitamin D and if they are performingweight-bearing exercise on a regular basis. Bone density evaluation mightbe considered in some patients to determine whether further implementationwould be beneficial.

Another rare concern is tamoxifen- associated ocular toxicity.[10] Thepathology of eye findings in tamoxifen patients is very unclear and itsinvestigation is complicated by age-related eye disease and other medicalillnesses. I recommend baseline eye exams in all my patients.

Conclusion

For women with breast cancer, the benefits of tamoxifen, in terms ofthe reduction in contralateral breast cancer and increased survival, clearlyoutweigh the risks and toxicity associated with the drug. Despite tamoxifen'sdemonstrated efficacy in breast cancer treatment, physicians need to beconcerned about issues that have an impact on a patient's quality of life.

Breast cancer patients are particularly sensitive about body image,and weight gain on tamoxifen may be a major issue. Menopausal symptomssuch as hot flashes, sleeplessness, and vaginal changes may be prolonged.Physicians need to broach the subject of sexual function with breast cancerpatients receiving tamoxifen and offer appropriate counsel and/or referral.

In my experience, informing patients about what they can expect fromtamoxifen has made a great deal of difference in their acceptance of treatment.

References:

1. Jaiyesimi IA, Buzdar AU, Decker DA, et al: Use of tamoxifen for breastcancer: Twenty-eight years later. J Clin Oncol 13(2):513-529, 1995.

2. Early Breast Cancer Trialists' Collaborative Group: Systemic treatmentof early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet339(8784):1-15, 71-85, 1992.

3. NSABP Protocol P-1 (Breast Cancer Prevention Trial) May 20, 1992.Pittsburgh, NSABP Central Headquarters, 1992.

4. Wing R, Matthews KA, Kuller LH, et al: Weight gain at the time ofmenopause. Arch Intern Med 151:97-102, 1991.

5. Auchincloss S: Sexual dysfunction after cancer treatment. J PsychosocialOncol 9:23-42, 1991.

6. Mortimer JE, Knapp DL, Fracasso PM, et al: Assessment of sexual functionin women treated with tamoxifen (abstract). Proc Am Soc Clin Oncol 13:A1554,1994.

7. Kaplan HS: A neglected issue: The sexual side effects of currenttreatments for breast cancer. J Sex Marital Ther 18:3-19, 1992.

8. Kaplan HS: The female androgen deficiency syndrome. J Sex MaritalTher 19:3-24, 1993.

9. Powles TJ, Hickish T, Kanis JA, et al: Effect of tamoxifen on bonemineral density measured by dual-energy x-ray absorptiometry in healthypremenopausal and postmenopausal women. J Clin Oncol 14:78-84, 1996.

10. Nayfield SG and Gorin MB: Tamoxifen-associated eye disease: A review.J Clin Oncol 14:1018-1026, 1996.