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Gynecologic Surveillance of Women on Tamoxifen: First Do No Harm

Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY

TAMOXIFEN IS WIDELY used in the treatment and more recently in the prevention of breast cancer. In therapeutic dosages, tamoxifen causes benign histologic derangements of the endometrium, ranging from polyps to proliferative changes. Uterine cancer is a potentially life-threatening complication associated with tamoxifen therapy. According to the randomized, placebo-controlled National Surgical Adjuvant Breast and Bowel Project (NSABP) breast cancer prevention trial (P1), the increased annual risk of developing an endometrial cancer is approximately two in 1,000.¹ In that trial, the risk was predominantly in women 50 years of age or older. Furthermore, of the 36 patients with invasive endometrial cancer, 32 had vaginal bleeding (NSABP, personal communication, September 2000). All of the endometrial cancers diagnosed among women on the tamoxifen arm of this trial were stage I. Despite the low incidence of endometrial cancer, patients are concerned about the possibility of developing an endometrial cancer. Gynecologic surveillance of patients receiving tamoxifen remains an area of concern for practicing clinicians, despite the fact that governing bodies have issued statements or committee opinions denouncing their effectiveness.² Since the early 1990s, numerous case reports and studies have evaluated endometrial sampling and transvaginal ultrasound as methods of screening for endometrial pathology in an attempt to reduce the incidence of endometrial cancer.^3-7

In this issue of the Journal of Clinical Oncology, two reports prospectively evaluate the role of endometrial biopsy and transvaginal sonography in largely asymptomatic patients with breast cancer receiving tamoxifen. These confirmatory studies conclude that screening by endometrial biopsy or transvaginal sonography is not warranted in patients taking tamoxifen. The importance of these prospective studies is that they document the adverse consequences of screening this population of patients. In the article by Barakat et al,⁸ 111 breast cancer patients receiving tamoxifen underwent a total of 635 endometrial biopsies, with a mean number of endometrial samplings per patient of 5.8. The study included pre- and postmenopausal women, with a median age of 50 years (range, 33 to 75 years). No other demographic characteristics are noted. Five hundred forty-four endometrial biopsy samples (86%) revealed benign endometrium. Eighty-two (12.9%) of the samples were insufficient for diagnosis. The authors erroneously assume these biopsy samples were consistent with atrophic endometrium. Without a hysteroscopy, or saline-infusion ultrahysterosonography, the authors have not ruled out the presence of endometrial polyps.⁹ Nine biopsy specimens were abnormal. The abnormalities detected by endometrial biopsy were not further characterized. The authors do not state their rate of uterine perforation at the time of endometrial sampling. Fourteen patients (12.6%) underwent a dilation and curettage (D&C), with or without a hysteroscopy. Only one patient had complex hyperplasia detected by D&C, which led to a hysterectomy. The authors do not discuss the complications associated with the D&C or the hysterectomies. Although the authors were successful in monitoring the endometrium in the majority of patients, the screening led to an increase in operative procedures in this asymptomatic group of patients. This confirmatory study once again documents the futility of routine endometrial screening biopsies in asymptomatic patients receiving tamoxifen.

The study by Gerber et al¹⁰ addressed the role of transvaginal ultrasound in 247 postmenopausal women with breast cancer and compared them with 98 women with breast cancer who were not eligible for tamoxifen. The mean age at first ultrasonographic assessment was approximately 60 years in both groups. The body mass index was comparable for both groups. Fifty-two asymptomatic patients with thickened (10 mm) or morphologically suspect endometrium underwent hysteroscopy and D&C, which resulted in four uterine perforations. The mean endometrial thickness of the controls was unchanged during the study period. The majority of the patients with abnormal endometrium displayed atrophic changes. As the authors note, this may have been due to the fact that they excluded patients with suspect endometrium from the study. Nine patients had polyps, four patients had hyperplasia, and one patient had an endometrial cancer. To detect only one asymptomatic cancer, they performed 1,265 transvaginal ultrasounds. In contrast to these asymptomatic patients, among patients with vaginal bleeding, only five (25%) had atrophic changes while five had polyps, four had hyperplasia, and two had endometrial cancer. Invasive diagnostic procedures were significantly more frequent in younger and obese patients. In an attempt to reduce false-positive results, the authors chose a fairly high endometrial thickness cutoff point (10 mm) and followed up with serial ultrasounds. However, even with these criteria, they could not demonstrate that transvaginal sonography was a useful screening tool in asymptomatic patients. This study confirms previously published studies, including that recently published from the NSABP P1 trial.¹² In that trial, a subset of patients underwent endometrial sampling and transvaginal sonography. A cross-classification of the findings from the biopsy among the 210 women who underwent ultrasound revealed that ultrasound had a sensitivity of approximately 43% and a specificity of 41% for the entire population. In evaluating the postmenopausal women with an endometrial thickness greater than 10 mm, the sensitivity was 50% and the specificity was 70%. Only four of 14 participants with a positive biopsy specimen had an endometrial stripe greater than 10 mm in thickness. This study did not support the substitution of ultrasound for endometrial biopsy.

The ultimate goal of any cancer-screening program is to detect disease at a preinvasive or early stage, in order to reduce morbidity and mortality and create cost savings. To date, there is still no evidence that any form of screening for endometrial cancer in tamoxifen-treated patients will accomplish these goals. Given these two reports and the considerable volume of already published data, screening for endometrial cancer in this group of patients is associated with serious pitfalls. The complications from the screening procedures, the resulting unnecessary surgeries, and the costs associated with these procedures are not justified based on the incidence and prognosis of endometrial cancer associated with the administration of tamoxifen.¹²

The NSABP P2 study of tamoxifen and raloxifene (the STAR trial) will further evaluate the role of endometrial biopsy, transvaginal sonography, and saline-infusion hysterosonography in a subgroup of patients in this trial. The evaluation of screening modalities should be confined to prospective randomized clinical trials designed to have sufficient power to address these issues. It is hoped that these studies will identify intermediate biomarkers and epidemiologic characteristics that herald the onset of endometrial pathology. Further confirmatory studies are not needed.

Woman receiving tamoxifen should undergo an annual gynecologic examination. Given the available information, endometrial biopsy, with or without transvaginal ultrasound, should be reserved for patients with abnormal vaginal bleeding or discharge. There is no role for screening endometrial biopsy or transvaginal ultrasound in asymptomatic women outside of a clinical trial. While well-intentioned, the ordering of a battery of screening tests with unproven efficacy results in invasive procedures that feed rather than alleviate anxieties and can be associated with significant morbidity.

REFERENCES

1. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90: 1371-1388, 1988[Abstract/Free Full Text]

2. The American College of Obstetricians and Gynecologists Committee Opinion: Tamoxifen and endometrial cancer. Washington, DC, February 1996, Number 169

3. Love CDB, Muir BB, Scringeour JB, et al: Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening. J Clin Oncol 17: 2050-2054, 1999[Abstract/Free Full Text]

4. Lahti E, Blanco G, Kauppila A, et al: Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 81: 660-664, 1993[Medline]

5. Cohen I, Altaras MM, Shapiro J, et al: Postmenopausal tamoxifen treatment and endometrial pathology. Obstet Gynecol Surv 49: 823-829, 1994[Medline]

6. Kedar RP, Bourne TH, Powles TJ, et al: Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomized breast cancer prevention trial. Lancet 343: 1318-1321, 1994[Medline]

7. Suh-Burgman EJ, Goodman A: Surveillance for endometrial cancer in women receiving tamoxifen. Ann Intern Med 131: 127-135, 1999[Abstract/Free Full Text]

8. Barakat RR, Gilewski TA, Almadrones L, et al: Effect of adjuvant tamoxifen on the endometrium in women with breast cancer: A prospective study using office endometrial biopsy. J Clin Oncol 18: 3459-3463, 2000[Abstract/Free Full Text]

9. Kamel HS, Darwish AM, Mohamed SA: Comparison of transvaginal ultrasonography and vaginal sonohysterography in the detection of endometrial polyps. Acta Obstet Gynecol Scand 79: 60-64, 2000[Medline]

10. Gerber B, Krause A, Müller H, et al: Effects of adjuvant tamoxifen on the endometrium in postmenopausal women with breast cancer: A prospective long-term study using transvaginal ultrasound. J Clin Oncol 18: 3464-3470, 2000[Abstract/Free Full Text]

11. Runowicz, CD Costantino J, Kavanah MT, et al: National Surgical Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) summary analysis of transvaginal sonography and endometrial biopsy in detecting endometrial pathology. Proc Am Soc Clin Oncol 18:358A, 1999 (abstr 1380)

12. Assikis VJ, Jordan VC: Gynecologic effects of tamoxifen and the association with endometrial carcinoma. Int J Gynaecol Obstet 49: 241-257, 1995[Medline]

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