- Email: [email protected]
Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial
Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial
Summary Randomised, double-blind controlled trials have been started to determine whether tamoxifen can prevent or delay
development of breast cancer in healthy women with a family history of the disease. We recruited a randomised cohort of 111 postmenopausal women (aged 46-71 years) from the Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital to study the effect of tamoxifen on the uterus and ovaries. The main outcome measures were obtained by transvaginal ultrasonography with colour doppler imaging and microscopic examination of endometrial biopsies removed at the time of the scan. There was no significant difference between tamoxifen (20 mg/day) and placebo groups in the age of the women, or the time of the scan (and sampling) after randomisation. Women taking tamoxifen had a significantly larger uterus and a lower impedance to blood flow in the uterine arteries. 39% of women taking tamoxifen had histological evidence of an abnormal endometrium compared with 10% in the control group. 10 patients in the tamoxifen group (16%) had atypical hyperplasia and another 5 (8%) had a polyp. Women with a histological abnormality had a significantly thicker endometrium and a decreased impedance to blood flow in the uterine arteries. There was no correlation between the presence of uterine abnormalities and the age of the women, or the concentrations of tamoxifen or desmethyl tamoxifen in the peripheral blood. These findings confirm that tamoxifen can cause potentially malignant changes in the endometrium of postmenopausal
women.
Transvaginal ultrasonography
can
be used to identify those women who should have endometrial samples removed for microscopic analysis. Lancet 1994; 343: 1318-21
Department of Obstetrics and Gynaecology, King’s College School of Medicine and Dentistry, Denmark Hill, London SE5 8RX, UK (R Kedar MD, T H Bourne MRCOG, Prof W P Collins DSc, Prof S Campbell FRCOG); Medical Breast Unit and Departments of Computing and Ultrasound, The Royal Marsden Hospital, London and Sutton, UK (T J Powles FRCP, S Ashley PhD, D O Cosgrove FRCP)
Correspondence to: Prof William P Collins 1318
Introduction About 50% of women with metastatic breast cancer benefit from tamoxifen. Furthermore the addition of this drug to other treatments reduces the recurrence and mortality rates from early stages of disease, and reduces the risk of a new primary cancer developing in the contralateral breast by 40%.’,’ The possibility of using tamoxifen to prevent or delay development of breast cancer in women with a family history of the disease has been considered and opposing views expressed on the balance of potential benefits and risks.3,4 Nevertheless, randomised controlled double-blind trials of the preventative value of tamoxifen (20 mg/day for at least 5 years) have begun in the UK, the USA, Italy, and Australia. Concerns have arisen from the results of longitudinal,s epidemiological6 and case-controlled’ studies which suggest that tamoxifen can cause endometrial changes including cancer. These observations however, may reflect an increase in the detection rate of previously occult disease, and the actual risk can only be assessed in placebo-controlled trials.8 We studied a randomised cohort of postmenopausal women receiving either tamoxifen or placebo from the Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital London, UK.9,lO The aims were to test for compliance by measuring serum concentrations of tamoxifen and desmethyl tamoxifen; assess the effects of the drug (or its metabolites) on pituitary/ovarian function; study the effects on uterine and ovarian morphology and blood flow with transvaginal ultrasonography with colour doppler imaging; and determine histopathological changes in endometrial biopsies taken at the time of ultrasound scan.
Subjects and methods All women were healthy, had at least one first degree relative who had developed breast cancer, and were randomised to receive tamoxifen (20 mg/day) or placebo.8,9 We recruited a subgroup of 111 from 112 consecutive patients from a follow-up clinic (one refused), who were > 45 years and had not menstruated for at least 12 months. 16 were receiving hormone replacement therapy, none reported any irregular postmenopausal bleeding, but 4 recorded an abnormal vaginal discharge. Tamoxifen and its metabolite, desmethyl tamoxifen, were measured by high pressure liquid chromatography (LAB [GB] Ltd, Monmouth, Gwent, UK). The concentrations of FSH, LH, and sex-hormone binding globulin (SHBG) at the time of the scan were measured by immunometric assays (Wallac UK Ltd, Milton Keynes, Bedfordshire, UK). Time-resolved fluorescence was used to determine the endpoints. Oestradiol and progesterone were measured by radioimmunoassay after extraction with diethyl ether (tritiated antigens and polyclonal antisera to oestradiol-6carboxymethyl oxime-bovine serum albumin and progesterone11tX-succinyl-bovine serum albumin were used respectively). Ultrasound equipment with endovaginal probes for B-mode and colour doppler imaging were used (Acuson 128 XP10, Acuson Ltd, Stevenage, Hertfordshire, UK; Ultramark UM 9HDI, ATL, Letchworth, Hertfordshire, UK; Aloka SSD 2000, Aloka, Tokyo, Japan.) The maximum longitudinal diameter (length) of the uterus
Variable
Indices
Group Placebo
Tamoxifen
(n=50)
(n=61)
Range
58 50-71
56 46-70
Months after randomisation Median
24
22 3-75
Age (yr) Mean
0-74
measured in mm from the internal os to the fundus, and (D1) the largest diameters in the transverse (Dz) and anterio/posterior (D3) planes. Cavity length (mm) was measured from the internal cervical os to the surface of the endometrium at the fundus. The volume (in mL) was estimated as (D1 x D2 x D3)/2. Thickness of the endometrium (double layer including potentially abnormal tissues, but not fluid) was measured at the widest point across the cavity between the endometrial-myometrial interfaces in the longitudinal plane. The ultrasonic appearance of the endometrium was classified as normal (< 5 mm), thick ( 5 mm), or thick with cysts ( 5 mm with echo-poor spaces). Uterine arteries were located above the supravaginal portion of the cervix by colour doppler imaging. An electronic gate for pulsed spectral doppler was positioned on each artery in sequence. The settings were adjusted to detect the maximum signals, which were displayed as flow velocity waveforms. The resistance index (RI) and pulsatility index (PI) were measured as indicators of blood flow impedance distal to the point of sampling: RI = (A-B)/A and PI = (A-B)/TAMXV; where A is the peak doppler shifted frequency (the systolic peak), B is the minimum doppler shifted frequency (diastolic minimum), and TAMXV is the time-average maximum velocity over the cardiac cycle. The angle-corrected peak systolic velocity (PSV, cm/sec) was also measured." There was no significant difference between the values for the right and left arteries; accordingly the means were taken for analysis. Subendometrial tissues were examined with colour doppler imaging for blood flow. Quantitative data from areas of colour were obtained by pulsed doppler spectral analysis. Both ovaries were scanned in longitudinal and transverse planes. The maximum transverse (D1), anteroposterior (D2), and longitudinal (D3) diameters were measured and the volumes estimated as (n/6) x D1 x D2 x D3’ Any abnormalities of morphology or intra-ovarian blood flow were recorded.12 Cysts were classified as simple (unilocular) or complex. An endometrial biopsy was taken after each scan with a sterile, disposable suction curette (Z-sampler, Cory Bros, Dollis Park, London, UK). 6 women with a suspected polyp also had hysteroscopy (2) or dilatation and currettage (4). Tissue fragments were examined by light microscopy and classified as normal was
atrophic endometrium, proliferative, or hyperplasia according to Ng.l3 In addition, samples containing mitotic cells, polyps, or recorded. Continuous variables were analysed by regression analysis and analysis of variance. Groups were compared by Student’s t test. cancer were
Mean
(SD)
Placebo
Tamoxifen
(n=50)
(n=61)
Length (mm)
440 (10 9)
48 (129)*
Maximum transverse diameter (mm)
34
Volume (ml)
222(15 1)
34 0 (19 7)t
Cavity length (mm)
28 0 (6 9)
34 5(94)1
PSV (cm/sec)
(mm, mean, SD) Appearance (no)
6 (9 3)
092(013) 299(145) 34
(21)
(n = 50)
4 8 (2 8)
Thickness Normal Thick
Subendometrtal blood flow detected
Ri (mean, SD) PI (mean, SD) PSV (cm/sec; mean,
Table 1: Characteristics of study population
Mean arterial RI PI
Placebo
Thick/cystic
Range
Indices
Group
SO)
Tamoxlfen (n = 61) 9 1
(4 3)*
44 4 2 3
33 7 21t 19
059(004) 100(013) 16 (9)
069(016) 128(076) 19 (17)
*p<0 001 (t-test), tp<0 001 (for abbreviations see table 2). Table 3: Effect of tamoxifen on postmenopausal endometrium -ultrasound Indices The
Mann-Whitney U test was used to compare categoric variables; a trend test was applied when appropriate.
Results
90% (55/61) of detectable
ng/mL;
women in the tamoxifen group had concentrations of the drug (> 0-1-227-55 911 ng/mL) and its main metabolite
serum
mean
desmethyl tamoxifen (>0-1-459-4
ng/mL;
mean
165-3).
Concentrations of both were <0 1 ng/mL in 90% of patients in the placebo group; the upper limit of apparent tamoxifen in the remaining 10% was 50 ng/mL and for desmethyl tamoxifen 8-0 ng/mL. There was no significant difference between the tamoxifen and placebo groups in the age of the women or the time of the scan (and sampling) after randomisation (table 1). 3 women in the placebo group were scanned at the time of randomisation. 8 in the placebo group and 8 in the tamoxifen group were taking hormone replacement therapy (HRT) at the time of investigations. 1 taking tamoxifen and HRT had atypical endometrial hyperplasia; 3 taking placebo and HRT had a proliferative endometrium, mitotic cells, or a polyp. 3 of 4 who had a vaginal discharge had a normal endometrium; the 4th (on placebo) had proliferative changes. The values (mean [Standard Deviation]) for FSH and LH (U/L) were significantly (p < 0-001) lower in the tamoxifen group (FSH, placebo 57-3 [24-0]; tamoxifen, 29-8 [17-4]; LH, placebo, 392 [28’0]; tamoxifen, 21.9 [13-0]). Mean SHBG (nmol/L) was higher in the tamoxifen group (placebo 96-9 [46-5], tamoxifen 113-2 [48-4]), but the difference was not significant. Concentrations of oestradiol and progesterone in both groups were below the detection limits of the methods (< 50 pmol/L and < 1 nmol/L respectively). The mean value for maximum transverse diameter (Dz or D3) and volume of the uterus was significantly higher in the tamoxifen group. The mean values of RI and PI in the tamoxifen group was significantly lower (table 2). The thickness of the endometrium and the number of women in both groups with the defined appearance are shown in table 3. Values in the tamoxifen group are significantly higher. Data on sub-endometrial blood flow is based on relatively small numbers (placebo, 6% of total;
tamoxifen, 31%).
39 0 (10 4)*
0 81 (0 13)t 199 (1 08)t 38 (29)
*p
Table 4: Effect of tamoxifen
- hIstological/cytological
on
postmenopausal endometrium
appearances
1319
drug and its main metabolite, showing that compliance was good, but not complete. Women with undetectable tamoxifen had no uterine abnormalities-a finding which would tend to emphasise the significance of any differences between the two groups. The apparent detection of low concentrations of tamoxifen in the serum of 5 women in the placebo group probably reflects a problem with the specificity of the analytical procedure at low concentrations
of analyte (ie, interfering compounds are being measured). There was no significant difference between tamoxifen and placebo groups in the age of the women or the time of the scan and sampling after randomisation. Our findings on the effect of tamoxifen on the circulatory levels of FSH, LH, and SHBG are similar to those reported previously, 17,18 and are consistent with direct effects of the drug or its function and the low concentrations of oestradiol and progesterone provide additional evidence that the women metabolites liver. The
were
Histological/Cytological findings Figure: Endometrial thickness (mean, 95% CI) by histological findings in the placebo and tamoxifen groups
Histological findings are summarised in table 4. 39% of taking tamoxifen had evidence of abnormal endometrium compared with 10% in controls (p < 0-001). All cases of hyperplasia were classified as atypical. There was no evidence of hyperplasia, atypia, or neoplasia in any of the polyps. One polyp in the tamoxifen group had a thick squamous epithelium. There was one case showing clear women
evidence of mitosis in each group. There was a significant negative correlation between the length of time on treatment with tamoxifen and mean uterine arterial PSV (r= - 028, p < 005). Women with a histological abnormality had a significantly thicker endometrium (p < 0-001), and a lower RI and PI (p < 0001) in the uterine arteries. The relationship between endometrial thickness and histological classification is illustrated in the figure. There was a tendency for the mean values to be lower in all subgroups of women taking placebo. The predictive value of an endometrial thickness 8 mm for atypical hyperplasia or polyps was 100% (16/16). There was no correlation between endometrial abnormalities and age, duration of treatment, or concentration of tamoxifen or desmethyl tamoxifen in the circulation. Four cysts (2 simple, 2 complex) were detected in the tamoxifen group (1 patient had bilateral cysts) compared with 2 simple cysts in the control group. The volumes (mean [95%confidence interval]) of the apparently healthy ovaries were similar in both groups (placebo, 1-30 [090-
1-62] ml; tamoxifen,
1 19
[1-00-1-38] ml.)
Discussion Previous
1320
hypothalamic/pituitary
postmenopausal.
Both ultrasonographic and histological results suggest that tamoxifen has a stimulatory effect on the uterine body and endometrium. Significantly more women in the tamoxifen group had a thick cystic endometrium and colour doppler imaging showed that a high proportion had evidence of increased uterine arterial and subendometrial peak systolic blood velocity and a lower impedance to flow. 39% of women in the tamoxifen group had histological evidence of an abnormal endometrium compared with 10% in the control group, and 16% of women taking tamoxifen had evidence of atypical hyperplasia compared with none taking the placebo. The association between tamoxifen and the development of endometrial polyps has been reported1CJ,2O but the prevalence of this type of lesion may be underestimated because they are difficult to detect by all conventional techniques.21,22 In this context we have recently developed an improved procedure for diagnosing polyps by transvaginal ultrasonography with the instillation of intracavity saline.21 Clinical evidence from randomised trials suggests that there is an increased risk of women developing endometrial cancer if tamoxifen is taken at a dose of 20 mg/day.22,23 Our results are consistent with such a risk. A recent randomised, controlled trial showed 15 cases of endometrial cancer in 1419 node-negative, oestrogen receptor-positive women treated with 20 mg tamoxifen a day and 2 cases in 1424 women given placebo.24 A previous report indicates that it is not possible to predict which postmenopausal women will develop pathological endometrial changes after tamoxifen.25 Our study detected endometrial abnormalities at various times from the first tablet of tamoxifen. Women with primary breast cancer and healthy women in prevention programmes who are receiving tamoxifen should be regularly evaluated for evidence of endometrial
polyps, atypical hyperplasia, or cancer. of
tamoxifen in and women have been postmenopausal premenopausal reviewed.14,15 To the best of our knowledge, this is the first use of a randomised placebo-controlled trial to study the effect of tamoxifen on the uterus and ovaries of healthy postmenopausal women. Our study not only confirms but extends the findings of endometrial disease from previous uncontrolled studies involving the use of pelvic ultrasonography and endometrial sampling." Only 6 women in our study who were randomised to take tamoxifen had undetectable serum concentrations of the
studies
on
the
effects
of
We thank Dr P A Trott, Cytology Department, Royal Marsden Hospital, London for histological/cytological analysis, and Ms Elizabeth Okokon for the immunoassays. RPK was supported by a grant from Zeneca Pharmaceuticals, Macclesfield, Cheshire.
References 1
2
Bonadonna G, Valagussa P, Brambilla C, Moliterni A, Zambitti M, Ferrari LS. Adjuvant and neoadjuvant treatment of breast cancers with chemotherapy and endocrine therapy. Semin Oncol 1991; 18: 515-24. Early Breast Cancer Trials Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic and immune therapy: 133
randomized trials involving 33 000 recoveries and 24 000 deaths among 3 4
5
6
7
8
9
10
11
12
13
75 000 women. Lancet 1992; 399: 1-15. Powles TJ. The case for clinical trials of tamoxifen for prevention of breast cancer. Lancet 1992; 340: 1145-47. Fugh-Berman A, Epstein S. Tamoxifen: disease prevention or disease substitution? Lancet 1992; 340: 1143-45. Neven P, De Muylder X, Van Belle Y, et al. Hysteroscopic follow-up during tamoxifen treatment. Eur J Obstet Gynaecol Rep Biol 1990; 35: 235-38. Fornander T, Rutqvist IE, Cedermark B, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; i: 117-20. Lahti E, Guillermo B, Kauppila A, et al. Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 1993; 81: 660-64. Jordan VC. How safe is tamoxifen? Only large randomised controlled trials can decide. BMJ 1993; 307: 1371-72. Powles TJ, Hardy JR, Ashley SE, et al. A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989; 60: 126-33. Powles TJ, Tillyer CR, Jones AL, et al. Prevention of breast cancer with tamoxifen: an update on the Royal Marsden pilot programme. Eur J Cancer 1990; 26: 680-84. Bourne TH, Campbell S, Steer CV, Royston P, Whitehead MI, Collins WP. Detection of endometrial cancer by transvaginal ultrasonography with color flow imaging and blood flow analysis: a preliminary report. Gynecol Oncol 1991; 40: 253-59. Bourne TH, Campbell S, Whitehead MI, et al. Screening for early familial ovarian cancer with transvaginal ultrasonography and colour flow imaging. BMJ 1993; 306: 1025-29. Ng ABP. Endometrial hyperplasia and carcinoma and extrauterine cancer. In: Bibbo M, ed. Comprehensive cytopathology. Philadelphia: WB Saunders, 1991 : 257-84.
14 Neven P. Tamoxifen and endometrial lesions. Lancet 1993; 342: 452. 15 Neven P, Shepherd JH, Lowe DG. Tamoxifen and the gynaecologist. Br J Obstet Gynaecol 1993; 100: 893-97.
I, Rosen DJD, Tepper R, et al. Ultrasonographic evaluation of the endometrium and correlation with endometrial sampling in postmenopausal patients treated with tamoxifen. J Ultrasound Med 1993; 5: 275-80. Jordan VC, Fritz NF, Tormey DC. Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administraiton of nodepositive patients with breast cancer. Cancer Res 1987; 47: 624-30. Jordan VC, Fritz NF, Tormey DC. Long term adjuvant therapy with tamoxifen: effects on sex hormone binding globulin and antithrombin III. Cancer Res 1987; 47: 4517-19. Neven P, De Muylder X, Van Belle U, Vanderick G, De Muylder E. Tamoxifen and the uterus and endometrium. Lancet 1989; i: 375. Corley D, Rowe J, Curtis MT, Hogan WM, Noumoff JS, Livolsi VA. Postmenopausal bleeding from unusual endometrial polyps in women on chronic tamoxifen therapy. Obstet Gynecol 1992; 79: 111-16. Bourne TH, Lawton F, Leather A, Granberg S, Campbell S, Collins WP. Use of intracavity saline instillation and transvaginal ultrasonography to detect tamoxifen associated endometrial polyps. Ultrasound in Obstet Gynecol 1994; 4: 73-75. Nayfield SG, Karp JE, Ford LG, et al. Potential risk of tamoxifen in the prevention of breast cancer. JNatl Cancer Inst 1991; 83: 1450-59. Catherino WH, Jordan VC. A risk-benefit assessment of tamoxifen therapy. Drug Safety 1993; 8: 381-97. Fisher B, Constantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Adjuvant Breast and Bowel Project (NSAPB-14). JNatl Cancer Inst 1994; 86: 527-37. Cohen I, Rosen DJD, Shapira J, et al. Endometrial changes in postmenopausal women treated with tamoxifen for breast cancer. Br J Obstet Gynaecol 1993; 100: 567-70.
16 Cohen
17
18
19
20
21
22
23 24
25
Continent colonic conduit for rectal evacuation in
severe
constipation
Introduction
Summary
Surgical Unit, The Royal London Hospital, Whitechapel, London E1 1BB, UK (Prof N S Williams FRCS, S F Hughes FRCS, B Stuchfield RGN)
Severe constipation may result from slow colonic transit, an inability to evacuate rectal contents, or a combination of the two. Apart from mechanical causes such as rectal cancer, there are many patients with disordered rectal evacuation in whom the cause is obscure. Some have paradoxical contraction of the pelvic floor on straining (anismus or pelvic outlet obstruction1.2); others have rectal inertia possibly due to autonomic nerve damage.3 Laxatives may be effective, but in resistant patients, biofeedback techniques, botulinum A toxin injections, division of the puborectalis, and anorectal myectomy have been tried.4-7 Colectomy and ileorectal or caecorectal anastomosis has been helpful in patients with slow colonic transit, but not when it is combined with outlet obstruction. For all surgical procedures, the results have been unpredictable.8,9 Antegrade colonic irrigation with the appendix as a continent conduit has been tried with some success in children with faecal incotinence. Malone et apo used a modification of the Mitrofanoff principle" to irrigate the whole colon via an appendicostomy. However, in adults the appendix may be absent and in patients with pelvic outlet obstruction, irrigation of the whole colon is unnecessary. We have developed a technique using the sigmoid colon to construct a continent conduit through which the distal
Correspondence to:
colon and
We describe
a
new
operation for the
disorders:
treatment of rectal
continent
colonic conduit, evacuatory incorporating an intussuscepted valve, was constructed from the sigmoid colon. Intubation of the conduit allowed irrigation and evacuation of the distal colon and rectum. Initially all 10 patients reported a reduction in time taken and the discomfort involved in completing evacuation. The number of stools passed per week increased in 9 out of 10 patients, from a median of 1 5 (range 0·25-7) to a median of 7 (range 3-7) postoperatively. Subsequently, 3 patients developed complications, 2 of whom required conversion to an ileostomy. Overall, the colonic conduit procedure was successful in treating the rectal evacuatory disorder in 7 patients, failed in 2, and 1 patient has a temporary a
defunctioning ileostomy. The procedure is a relatively simple surgical alternative for the treatment of a condition which is often resistant to conservative measures.
Lancet 1994; 343: 1321-24
Professor N S Williams
rectum can
be
irrigated from
above.
1321
Summary Randomised, double-blind controlled trials have been started to determine whether tamoxifen can prevent or delay
development of breast cancer in healthy women with a family history of the disease. We recruited a randomised cohort of 111 postmenopausal women (aged 46-71 years) from the Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital to study the effect of tamoxifen on the uterus and ovaries. The main outcome measures were obtained by transvaginal ultrasonography with colour doppler imaging and microscopic examination of endometrial biopsies removed at the time of the scan. There was no significant difference between tamoxifen (20 mg/day) and placebo groups in the age of the women, or the time of the scan (and sampling) after randomisation. Women taking tamoxifen had a significantly larger uterus and a lower impedance to blood flow in the uterine arteries. 39% of women taking tamoxifen had histological evidence of an abnormal endometrium compared with 10% in the control group. 10 patients in the tamoxifen group (16%) had atypical hyperplasia and another 5 (8%) had a polyp. Women with a histological abnormality had a significantly thicker endometrium and a decreased impedance to blood flow in the uterine arteries. There was no correlation between the presence of uterine abnormalities and the age of the women, or the concentrations of tamoxifen or desmethyl tamoxifen in the peripheral blood. These findings confirm that tamoxifen can cause potentially malignant changes in the endometrium of postmenopausal
women.
Transvaginal ultrasonography
can
be used to identify those women who should have endometrial samples removed for microscopic analysis. Lancet 1994; 343: 1318-21
Department of Obstetrics and Gynaecology, King’s College School of Medicine and Dentistry, Denmark Hill, London SE5 8RX, UK (R Kedar MD, T H Bourne MRCOG, Prof W P Collins DSc, Prof S Campbell FRCOG); Medical Breast Unit and Departments of Computing and Ultrasound, The Royal Marsden Hospital, London and Sutton, UK (T J Powles FRCP, S Ashley PhD, D O Cosgrove FRCP)
Correspondence to: Prof William P Collins 1318
Introduction About 50% of women with metastatic breast cancer benefit from tamoxifen. Furthermore the addition of this drug to other treatments reduces the recurrence and mortality rates from early stages of disease, and reduces the risk of a new primary cancer developing in the contralateral breast by 40%.’,’ The possibility of using tamoxifen to prevent or delay development of breast cancer in women with a family history of the disease has been considered and opposing views expressed on the balance of potential benefits and risks.3,4 Nevertheless, randomised controlled double-blind trials of the preventative value of tamoxifen (20 mg/day for at least 5 years) have begun in the UK, the USA, Italy, and Australia. Concerns have arisen from the results of longitudinal,s epidemiological6 and case-controlled’ studies which suggest that tamoxifen can cause endometrial changes including cancer. These observations however, may reflect an increase in the detection rate of previously occult disease, and the actual risk can only be assessed in placebo-controlled trials.8 We studied a randomised cohort of postmenopausal women receiving either tamoxifen or placebo from the Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital London, UK.9,lO The aims were to test for compliance by measuring serum concentrations of tamoxifen and desmethyl tamoxifen; assess the effects of the drug (or its metabolites) on pituitary/ovarian function; study the effects on uterine and ovarian morphology and blood flow with transvaginal ultrasonography with colour doppler imaging; and determine histopathological changes in endometrial biopsies taken at the time of ultrasound scan.
Subjects and methods All women were healthy, had at least one first degree relative who had developed breast cancer, and were randomised to receive tamoxifen (20 mg/day) or placebo.8,9 We recruited a subgroup of 111 from 112 consecutive patients from a follow-up clinic (one refused), who were > 45 years and had not menstruated for at least 12 months. 16 were receiving hormone replacement therapy, none reported any irregular postmenopausal bleeding, but 4 recorded an abnormal vaginal discharge. Tamoxifen and its metabolite, desmethyl tamoxifen, were measured by high pressure liquid chromatography (LAB [GB] Ltd, Monmouth, Gwent, UK). The concentrations of FSH, LH, and sex-hormone binding globulin (SHBG) at the time of the scan were measured by immunometric assays (Wallac UK Ltd, Milton Keynes, Bedfordshire, UK). Time-resolved fluorescence was used to determine the endpoints. Oestradiol and progesterone were measured by radioimmunoassay after extraction with diethyl ether (tritiated antigens and polyclonal antisera to oestradiol-6carboxymethyl oxime-bovine serum albumin and progesterone11tX-succinyl-bovine serum albumin were used respectively). Ultrasound equipment with endovaginal probes for B-mode and colour doppler imaging were used (Acuson 128 XP10, Acuson Ltd, Stevenage, Hertfordshire, UK; Ultramark UM 9HDI, ATL, Letchworth, Hertfordshire, UK; Aloka SSD 2000, Aloka, Tokyo, Japan.) The maximum longitudinal diameter (length) of the uterus
Variable
Indices
Group Placebo
Tamoxifen
(n=50)
(n=61)
Range
58 50-71
56 46-70
Months after randomisation Median
24
22 3-75
Age (yr) Mean
0-74
measured in mm from the internal os to the fundus, and (D1) the largest diameters in the transverse (Dz) and anterio/posterior (D3) planes. Cavity length (mm) was measured from the internal cervical os to the surface of the endometrium at the fundus. The volume (in mL) was estimated as (D1 x D2 x D3)/2. Thickness of the endometrium (double layer including potentially abnormal tissues, but not fluid) was measured at the widest point across the cavity between the endometrial-myometrial interfaces in the longitudinal plane. The ultrasonic appearance of the endometrium was classified as normal (< 5 mm), thick ( 5 mm), or thick with cysts ( 5 mm with echo-poor spaces). Uterine arteries were located above the supravaginal portion of the cervix by colour doppler imaging. An electronic gate for pulsed spectral doppler was positioned on each artery in sequence. The settings were adjusted to detect the maximum signals, which were displayed as flow velocity waveforms. The resistance index (RI) and pulsatility index (PI) were measured as indicators of blood flow impedance distal to the point of sampling: RI = (A-B)/A and PI = (A-B)/TAMXV; where A is the peak doppler shifted frequency (the systolic peak), B is the minimum doppler shifted frequency (diastolic minimum), and TAMXV is the time-average maximum velocity over the cardiac cycle. The angle-corrected peak systolic velocity (PSV, cm/sec) was also measured." There was no significant difference between the values for the right and left arteries; accordingly the means were taken for analysis. Subendometrial tissues were examined with colour doppler imaging for blood flow. Quantitative data from areas of colour were obtained by pulsed doppler spectral analysis. Both ovaries were scanned in longitudinal and transverse planes. The maximum transverse (D1), anteroposterior (D2), and longitudinal (D3) diameters were measured and the volumes estimated as (n/6) x D1 x D2 x D3’ Any abnormalities of morphology or intra-ovarian blood flow were recorded.12 Cysts were classified as simple (unilocular) or complex. An endometrial biopsy was taken after each scan with a sterile, disposable suction curette (Z-sampler, Cory Bros, Dollis Park, London, UK). 6 women with a suspected polyp also had hysteroscopy (2) or dilatation and currettage (4). Tissue fragments were examined by light microscopy and classified as normal was
atrophic endometrium, proliferative, or hyperplasia according to Ng.l3 In addition, samples containing mitotic cells, polyps, or recorded. Continuous variables were analysed by regression analysis and analysis of variance. Groups were compared by Student’s t test. cancer were
Mean
(SD)
Placebo
Tamoxifen
(n=50)
(n=61)
Length (mm)
440 (10 9)
48 (129)*
Maximum transverse diameter (mm)
34
Volume (ml)
222(15 1)
34 0 (19 7)t
Cavity length (mm)
28 0 (6 9)
34 5(94)1
PSV (cm/sec)
(mm, mean, SD) Appearance (no)
6 (9 3)
092(013) 299(145) 34
(21)
(n = 50)
4 8 (2 8)
Thickness Normal Thick
Subendometrtal blood flow detected
Ri (mean, SD) PI (mean, SD) PSV (cm/sec; mean,
Table 1: Characteristics of study population
Mean arterial RI PI
Placebo
Thick/cystic
Range
Indices
Group
SO)
Tamoxlfen (n = 61) 9 1
(4 3)*
44 4 2 3
33 7 21t 19
059(004) 100(013) 16 (9)
069(016) 128(076) 19 (17)
*p<0 001 (t-test), tp<0 001 (for abbreviations see table 2). Table 3: Effect of tamoxifen on postmenopausal endometrium -ultrasound Indices The
Mann-Whitney U test was used to compare categoric variables; a trend test was applied when appropriate.
Results
90% (55/61) of detectable
ng/mL;
women in the tamoxifen group had concentrations of the drug (> 0-1-227-55 911 ng/mL) and its main metabolite
serum
mean
desmethyl tamoxifen (>0-1-459-4
ng/mL;
mean
165-3).
Concentrations of both were <0 1 ng/mL in 90% of patients in the placebo group; the upper limit of apparent tamoxifen in the remaining 10% was 50 ng/mL and for desmethyl tamoxifen 8-0 ng/mL. There was no significant difference between the tamoxifen and placebo groups in the age of the women or the time of the scan (and sampling) after randomisation (table 1). 3 women in the placebo group were scanned at the time of randomisation. 8 in the placebo group and 8 in the tamoxifen group were taking hormone replacement therapy (HRT) at the time of investigations. 1 taking tamoxifen and HRT had atypical endometrial hyperplasia; 3 taking placebo and HRT had a proliferative endometrium, mitotic cells, or a polyp. 3 of 4 who had a vaginal discharge had a normal endometrium; the 4th (on placebo) had proliferative changes. The values (mean [Standard Deviation]) for FSH and LH (U/L) were significantly (p < 0-001) lower in the tamoxifen group (FSH, placebo 57-3 [24-0]; tamoxifen, 29-8 [17-4]; LH, placebo, 392 [28’0]; tamoxifen, 21.9 [13-0]). Mean SHBG (nmol/L) was higher in the tamoxifen group (placebo 96-9 [46-5], tamoxifen 113-2 [48-4]), but the difference was not significant. Concentrations of oestradiol and progesterone in both groups were below the detection limits of the methods (< 50 pmol/L and < 1 nmol/L respectively). The mean value for maximum transverse diameter (Dz or D3) and volume of the uterus was significantly higher in the tamoxifen group. The mean values of RI and PI in the tamoxifen group was significantly lower (table 2). The thickness of the endometrium and the number of women in both groups with the defined appearance are shown in table 3. Values in the tamoxifen group are significantly higher. Data on sub-endometrial blood flow is based on relatively small numbers (placebo, 6% of total;
tamoxifen, 31%).
39 0 (10 4)*
0 81 (0 13)t 199 (1 08)t 38 (29)
*p
Table 4: Effect of tamoxifen
- hIstological/cytological
on
postmenopausal endometrium
appearances
1319
drug and its main metabolite, showing that compliance was good, but not complete. Women with undetectable tamoxifen had no uterine abnormalities-a finding which would tend to emphasise the significance of any differences between the two groups. The apparent detection of low concentrations of tamoxifen in the serum of 5 women in the placebo group probably reflects a problem with the specificity of the analytical procedure at low concentrations
of analyte (ie, interfering compounds are being measured). There was no significant difference between tamoxifen and placebo groups in the age of the women or the time of the scan and sampling after randomisation. Our findings on the effect of tamoxifen on the circulatory levels of FSH, LH, and SHBG are similar to those reported previously, 17,18 and are consistent with direct effects of the drug or its function and the low concentrations of oestradiol and progesterone provide additional evidence that the women metabolites liver. The
were
Histological/Cytological findings Figure: Endometrial thickness (mean, 95% CI) by histological findings in the placebo and tamoxifen groups
Histological findings are summarised in table 4. 39% of taking tamoxifen had evidence of abnormal endometrium compared with 10% in controls (p < 0-001). All cases of hyperplasia were classified as atypical. There was no evidence of hyperplasia, atypia, or neoplasia in any of the polyps. One polyp in the tamoxifen group had a thick squamous epithelium. There was one case showing clear women
evidence of mitosis in each group. There was a significant negative correlation between the length of time on treatment with tamoxifen and mean uterine arterial PSV (r= - 028, p < 005). Women with a histological abnormality had a significantly thicker endometrium (p < 0-001), and a lower RI and PI (p < 0001) in the uterine arteries. The relationship between endometrial thickness and histological classification is illustrated in the figure. There was a tendency for the mean values to be lower in all subgroups of women taking placebo. The predictive value of an endometrial thickness 8 mm for atypical hyperplasia or polyps was 100% (16/16). There was no correlation between endometrial abnormalities and age, duration of treatment, or concentration of tamoxifen or desmethyl tamoxifen in the circulation. Four cysts (2 simple, 2 complex) were detected in the tamoxifen group (1 patient had bilateral cysts) compared with 2 simple cysts in the control group. The volumes (mean [95%confidence interval]) of the apparently healthy ovaries were similar in both groups (placebo, 1-30 [090-
1-62] ml; tamoxifen,
1 19
[1-00-1-38] ml.)
Discussion Previous
1320
hypothalamic/pituitary
postmenopausal.
Both ultrasonographic and histological results suggest that tamoxifen has a stimulatory effect on the uterine body and endometrium. Significantly more women in the tamoxifen group had a thick cystic endometrium and colour doppler imaging showed that a high proportion had evidence of increased uterine arterial and subendometrial peak systolic blood velocity and a lower impedance to flow. 39% of women in the tamoxifen group had histological evidence of an abnormal endometrium compared with 10% in the control group, and 16% of women taking tamoxifen had evidence of atypical hyperplasia compared with none taking the placebo. The association between tamoxifen and the development of endometrial polyps has been reported1CJ,2O but the prevalence of this type of lesion may be underestimated because they are difficult to detect by all conventional techniques.21,22 In this context we have recently developed an improved procedure for diagnosing polyps by transvaginal ultrasonography with the instillation of intracavity saline.21 Clinical evidence from randomised trials suggests that there is an increased risk of women developing endometrial cancer if tamoxifen is taken at a dose of 20 mg/day.22,23 Our results are consistent with such a risk. A recent randomised, controlled trial showed 15 cases of endometrial cancer in 1419 node-negative, oestrogen receptor-positive women treated with 20 mg tamoxifen a day and 2 cases in 1424 women given placebo.24 A previous report indicates that it is not possible to predict which postmenopausal women will develop pathological endometrial changes after tamoxifen.25 Our study detected endometrial abnormalities at various times from the first tablet of tamoxifen. Women with primary breast cancer and healthy women in prevention programmes who are receiving tamoxifen should be regularly evaluated for evidence of endometrial
polyps, atypical hyperplasia, or cancer. of
tamoxifen in and women have been postmenopausal premenopausal reviewed.14,15 To the best of our knowledge, this is the first use of a randomised placebo-controlled trial to study the effect of tamoxifen on the uterus and ovaries of healthy postmenopausal women. Our study not only confirms but extends the findings of endometrial disease from previous uncontrolled studies involving the use of pelvic ultrasonography and endometrial sampling." Only 6 women in our study who were randomised to take tamoxifen had undetectable serum concentrations of the
studies
on
the
effects
of
We thank Dr P A Trott, Cytology Department, Royal Marsden Hospital, London for histological/cytological analysis, and Ms Elizabeth Okokon for the immunoassays. RPK was supported by a grant from Zeneca Pharmaceuticals, Macclesfield, Cheshire.
References 1
2
Bonadonna G, Valagussa P, Brambilla C, Moliterni A, Zambitti M, Ferrari LS. Adjuvant and neoadjuvant treatment of breast cancers with chemotherapy and endocrine therapy. Semin Oncol 1991; 18: 515-24. Early Breast Cancer Trials Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic and immune therapy: 133
randomized trials involving 33 000 recoveries and 24 000 deaths among 3 4
5
6
7
8
9
10
11
12
13
75 000 women. Lancet 1992; 399: 1-15. Powles TJ. The case for clinical trials of tamoxifen for prevention of breast cancer. Lancet 1992; 340: 1145-47. Fugh-Berman A, Epstein S. Tamoxifen: disease prevention or disease substitution? Lancet 1992; 340: 1143-45. Neven P, De Muylder X, Van Belle Y, et al. Hysteroscopic follow-up during tamoxifen treatment. Eur J Obstet Gynaecol Rep Biol 1990; 35: 235-38. Fornander T, Rutqvist IE, Cedermark B, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; i: 117-20. Lahti E, Guillermo B, Kauppila A, et al. Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 1993; 81: 660-64. Jordan VC. How safe is tamoxifen? Only large randomised controlled trials can decide. BMJ 1993; 307: 1371-72. Powles TJ, Hardy JR, Ashley SE, et al. A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989; 60: 126-33. Powles TJ, Tillyer CR, Jones AL, et al. Prevention of breast cancer with tamoxifen: an update on the Royal Marsden pilot programme. Eur J Cancer 1990; 26: 680-84. Bourne TH, Campbell S, Steer CV, Royston P, Whitehead MI, Collins WP. Detection of endometrial cancer by transvaginal ultrasonography with color flow imaging and blood flow analysis: a preliminary report. Gynecol Oncol 1991; 40: 253-59. Bourne TH, Campbell S, Whitehead MI, et al. Screening for early familial ovarian cancer with transvaginal ultrasonography and colour flow imaging. BMJ 1993; 306: 1025-29. Ng ABP. Endometrial hyperplasia and carcinoma and extrauterine cancer. In: Bibbo M, ed. Comprehensive cytopathology. Philadelphia: WB Saunders, 1991 : 257-84.
14 Neven P. Tamoxifen and endometrial lesions. Lancet 1993; 342: 452. 15 Neven P, Shepherd JH, Lowe DG. Tamoxifen and the gynaecologist. Br J Obstet Gynaecol 1993; 100: 893-97.
I, Rosen DJD, Tepper R, et al. Ultrasonographic evaluation of the endometrium and correlation with endometrial sampling in postmenopausal patients treated with tamoxifen. J Ultrasound Med 1993; 5: 275-80. Jordan VC, Fritz NF, Tormey DC. Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administraiton of nodepositive patients with breast cancer. Cancer Res 1987; 47: 624-30. Jordan VC, Fritz NF, Tormey DC. Long term adjuvant therapy with tamoxifen: effects on sex hormone binding globulin and antithrombin III. Cancer Res 1987; 47: 4517-19. Neven P, De Muylder X, Van Belle U, Vanderick G, De Muylder E. Tamoxifen and the uterus and endometrium. Lancet 1989; i: 375. Corley D, Rowe J, Curtis MT, Hogan WM, Noumoff JS, Livolsi VA. Postmenopausal bleeding from unusual endometrial polyps in women on chronic tamoxifen therapy. Obstet Gynecol 1992; 79: 111-16. Bourne TH, Lawton F, Leather A, Granberg S, Campbell S, Collins WP. Use of intracavity saline instillation and transvaginal ultrasonography to detect tamoxifen associated endometrial polyps. Ultrasound in Obstet Gynecol 1994; 4: 73-75. Nayfield SG, Karp JE, Ford LG, et al. Potential risk of tamoxifen in the prevention of breast cancer. JNatl Cancer Inst 1991; 83: 1450-59. Catherino WH, Jordan VC. A risk-benefit assessment of tamoxifen therapy. Drug Safety 1993; 8: 381-97. Fisher B, Constantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Adjuvant Breast and Bowel Project (NSAPB-14). JNatl Cancer Inst 1994; 86: 527-37. Cohen I, Rosen DJD, Shapira J, et al. Endometrial changes in postmenopausal women treated with tamoxifen for breast cancer. Br J Obstet Gynaecol 1993; 100: 567-70.
16 Cohen
17
18
19
20
21
22
23 24
25
Continent colonic conduit for rectal evacuation in
severe
constipation
Introduction
Summary
Surgical Unit, The Royal London Hospital, Whitechapel, London E1 1BB, UK (Prof N S Williams FRCS, S F Hughes FRCS, B Stuchfield RGN)
Severe constipation may result from slow colonic transit, an inability to evacuate rectal contents, or a combination of the two. Apart from mechanical causes such as rectal cancer, there are many patients with disordered rectal evacuation in whom the cause is obscure. Some have paradoxical contraction of the pelvic floor on straining (anismus or pelvic outlet obstruction1.2); others have rectal inertia possibly due to autonomic nerve damage.3 Laxatives may be effective, but in resistant patients, biofeedback techniques, botulinum A toxin injections, division of the puborectalis, and anorectal myectomy have been tried.4-7 Colectomy and ileorectal or caecorectal anastomosis has been helpful in patients with slow colonic transit, but not when it is combined with outlet obstruction. For all surgical procedures, the results have been unpredictable.8,9 Antegrade colonic irrigation with the appendix as a continent conduit has been tried with some success in children with faecal incotinence. Malone et apo used a modification of the Mitrofanoff principle" to irrigate the whole colon via an appendicostomy. However, in adults the appendix may be absent and in patients with pelvic outlet obstruction, irrigation of the whole colon is unnecessary. We have developed a technique using the sigmoid colon to construct a continent conduit through which the distal
Correspondence to:
colon and
We describe
a
new
operation for the
disorders:
treatment of rectal
continent
colonic conduit, evacuatory incorporating an intussuscepted valve, was constructed from the sigmoid colon. Intubation of the conduit allowed irrigation and evacuation of the distal colon and rectum. Initially all 10 patients reported a reduction in time taken and the discomfort involved in completing evacuation. The number of stools passed per week increased in 9 out of 10 patients, from a median of 1 5 (range 0·25-7) to a median of 7 (range 3-7) postoperatively. Subsequently, 3 patients developed complications, 2 of whom required conversion to an ileostomy. Overall, the colonic conduit procedure was successful in treating the rectal evacuatory disorder in 7 patients, failed in 2, and 1 patient has a temporary a
defunctioning ileostomy. The procedure is a relatively simple surgical alternative for the treatment of a condition which is often resistant to conservative measures.
Lancet 1994; 343: 1321-24
Professor N S Williams
rectum can
be
irrigated from
above.
1321