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Second cancers after adjuvant tamoxifen therapy for breast cancer in Japan
Annals of Oncology 11: 1537-1543.2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Second cancers after adjuvant tamoxifen therapy for breast cancer in Japan Y. Matsuyama,1 T. Tominaga,2 Y. Nomura, 3 H. Koyama,4 M. Kimura, 5 M. Sano,6 S. Miura, 7 S. Takashima,8 S. Mitsuyama,9 H. Ueo 10 & Y Ohashi1 1
Bioslatistics/'Epidemiology and Preventive Health Sciences, School of Health Sciences and Nursing, University of Tokyo, 2Department of Surgery, Tokyo Metropolitan Komagome Hospital; 3Department of Breast Surgery, National Kyushu Cancer Center, 4Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases; 5 Division of Surgery, Gunma Cancer Center Hospital; 6Division of Surgery, Niigata Cancer Center Hospital; "'Department of Breast Surgery, Aicht Cancer Center Hospital; s Department of Surgery, Shikoku Cancer Center Hospital; Department of Surgery, Kitakyushu Municipal Medical Center; 10Department of Surgery, Oita Prefectural Hospital
and 4.09% among tamoxifen-treated and non-tamoxifen-treated patients (P = 0.62), respectively, and the incidence rate ratio Background: Women treated with tamoxifen for breast cancer (IRR) for all second cancers was 1.06 (95% confidence interval are at increased risk of endometrial cancer. We conducted a (CI): 0.77-1.47) after adjustment of several covariates. The retrospective cohort study to evaluate the risk of second primary numbers of endometrial cancers was 9 and 3 among tamoxcancers after adjuvant tamoxifen therapy for breast cancer in ifen-treated and non-tamoxifen-treated patients, respectively, and the IRR was 2.37 (95% CI: 0.64-8.77, P = 0.20). Of the 12 Japan. Patients and methods: The subjects of the study were 6148 patients who developed endometrial cancer, 4 died of cancer women who had been diagnosed with stage I, II, or IIIA (for 3 of them, the cause of death was breast cancer), and the unilateral primary breast cancer and had received surgical treat- other 8 patients were alive as of March 1996. Stomach cancer ment during the period from January 1982 through December was the most frequent second cancer and the IRR was 1.34 1990 at nine institutions in Japan. The information on each (95% CI: 0.76-2.38, P = 0.31). There was no substantial patient was obtained from medical records or a prospectively increase in any other type of gastrointestinal cancer such as colorectal and liver cancers among tamoxifen-treated patients. compiled computer database at each institution. Conclusions: The incidence and risk of second primary Results: Of the 6148 women, 3588 (58.4%) were adminiscancers associated with tamoxifen therapy is low. The potential tered tamoxifen as an adjuvant treatment and 2560 (41.6%) were not administered. Median follow-up periods were 7.64 years for benefit of adjuvant tamoxifen therapy in breast cancer patients tamoxifen-treated patients and 8.10 years for non-tamoxifen- outweighs the risk of second primary cancers for Japanese treated patients, respectively. The duration of tamoxifen treat- breast cancer patients. ment was mostly two years or less (80.7%), and few patients received tamoxifen for more than five years. The cumulative Key words: adjuvant therapy, breast cancer, second cancer, incidence rates of all second cancers at 10 years were 4.61% tamoxifen Summary
Tamoxifen is the drug most widely prescribed as adjuvant therapy for breast cancer. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of worldwide evidence has demonstrated that a few years of adjuvant tamoxifen produces a moderate but definite benefit in reducing the incidence of contralateral breast cancer, as well as in prolonging survival and recurrencefree survival [1, 2]. The National Surgical Breast and Bowel Project (NSABP) P-l study group published the first report that tamoxifen reduced breast cancer incidence by 49% among women at high-risk for developing the disease [3]. Based on this evidence, tamoxifen was recently approved for breast cancer prevention in healthy women at high risk of developing the disease. Concerns regarding the optimal duration of tamoxifen treatment have also been raised [4-6], particularly as to whether,
after a few years on tamoxifen, most women should stop or should continue for several more years [7]. However, several studies have provided evidence indicating that tamoxifen can cause second cancers. Among women, the main carcinogenic risk of tamoxifen is for endometrium. Several randomized trials of breast cancer treatment have found an increased risk of endometrial cancer among women treated with tamoxifen [8-12]. One nonrandomized cohort study [13] and two case-control studies [14-16] have shown findings similar to those from the randomized studies. In these studies, the effect of tamoxifen on endometrial cancer has been reported to increase the incidence rate from two-fold to seven-fold. An increasing trend in the risk of endometrial cancer with the duration of tamoxifen use and with cumulative dose has also been suggested [8, 13, 16]. MacMahon [17] and Morgan [18] have provided a critical review of these and other studies that have been pub-
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Introduction
1538
Patients and methods Patients The subjects of the study were women who had been diagnosed with stage I, II, or IIIA unilateral primary breast cancer and had received surgical treatment during the period from January 1982 through December 1990. Non-invasive breast cancer patients were excluded from the study. Nine institutions in Japan were asked to cooperate in this retrospective cohort study. All women in the nine institutions who had met the eligibility requirements were the subjects of the study.
The data were computerized and checked for internal consistency by the contract research organization, and were amended or updated if necessary through correspondence with the responsible physicians at each institution. Statistical analyses In each treatment group (tamoxifen-treated and non-tamoxifentreated group), the incidence rates for each type of second primary cancer were computed as the observed number of events divided by the total number person-years at risk. The incidence rate ratio (IRR) associated with tamoxifen was estimated as the ratio between these rates; the non-tamoxifen-treated group was taken as the reference group. In these calculations, the patients were considered to be at risk from the date of surgery until the date of occurrence of each type of second cancer, the date of death, or the last date by which she was known to be alive. The cumulative incidence of all second cancers was estimated by the Kaplan-Meier method [19], and the resulting two curves were compared using the log-rank test. The effect of tamoxifen adjusted for covariates on all second cancers and the prognostic significance of individual covariates were examined by using the Cox proportional hazards model [20]. We considered several variables as potential covariates, including the age at surgery, stage of initial breast cancer, menopausal status, estrogen receptor status, lymph node metastasis, and adjuvant chemotherapy. For endometrial and stomach cancer, standardized incidence ratios (SIR) were computed as the ratio of observed to expected numbers. Expected numbers were computed by using the five-year age band-specific population-based incidence rates [21]. In the calculation of the person-years at risk, the age of each patient, both at surgery and as it changes through the period of followup, was taken into account [22]. Standard errors of SIR were based on the Poisson distribution, and the exact P-value for SIR was calculated. All statistical analyses were performed using SAS 6.12 [23].
Results
Data collection
Background characteristics ofpatients
The following information on each patient was retrospectively obtained from medical records or a prospectively compiled computer database at each institution1 date of surgery, age at surgery, type of surgery, weight, height, stage of initial breast cancer, menopausal status, estrogen receptor status, number of histological lymph node metastases, and adjuvant treatments (chemotherapy, hormonal therapy and radiotherapy). Relevant information was collected for each type of medical adjuvant treatment including the name of drugs, dosage of them and dates when the prescription was started and stopped. For tamoxifen. we gathered the data on daily dose and duration of treatment as well as a cumulative dose. The duration of tamoxifen treatment was calculated as the time from the first to the last prescription. For patients with multiple, distinct series of tamoxifen treatment, the total duration was calculated by summing up the days contributed by each continuous period of prescription. The cumulative dose of tamoxifen was calculated by multiplying the daily dose by the period (days) and summing up the total weight (grams) of each contribution if there were distinct series of prescription and/or changes in the prescribed dose. Information was also sought on the type and date of subsequent occurrence of second primary cancer, the type and date of recurrence, and the cause and date of death, with follow-up to March 1996. The patients were followed-up systematically irrespective of the nodal status of the patients, although there were a slight difference among the participating institutions. The methods of detecting the second cancers as well as recurrence of breast cancer were essentially based on the physical examination, mammography, if necessary, X-rays of chest, and bones, liver echography and CT X-rays, and tumor markers (CEA, CA15-3), and variable examinations according to the complaints of patients (e.g.. gynecological examinations for vaginal spotting, etc).
A total of 6148 patients were identified from medical records or a computer database at each institution. The selected background characteristics of the study subjects are shown in Table 1. Of the 6148 study subjects, 3588 (58.4%) were tamoxifen-treated patients and 2560 (41.6%) were non-tamoxifen-treated patients. The distributions of age at surgery, stage, and menopausal status were similar in the two treatment groups. An imbalance between the two groups was seen in terms of lymph node metastasis, estrogen receptor status, and chemotherapy. 46.4% of tamoxifen-treated patients were lymph node-positive compared with 32.4% in non-tamoxifentreated patients (Mantel-Haenszel trend test, P < 0.001), and the percentage of estrogen receptor-positive excluding unknown cases was 71.3% in tamoxifen-treated patients compared with 55.0% in non-tamoxifen-treated patients (Chi-square test, P < 0.001). 67.0% of tamoxifen-treated patients received chemotherapy compared with 58.4% in non-tamoxifen-treated patients (chisquare test, P < 0.001). Table 2 shows the distributions of the duration and cumulative dose of tamoxifen treatment. The most commonly used daily dose was 20 mg per day, ranging from 10 mg to 40 mg. The duration of tamoxifen treatment
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lished concerning the possible relationship of tamoxifen to endometrial cancer. Recently, an elevated risk of gastrointestinal cancer, particularly stomach and colorectal cancers, was reported to be associated with tamoxifen therapy [12]. In Japan, stomach cancer is still one of the leading causes of cancer death and remains as an important public health issue, despite the decline in the incidence and mortality of this disease in recent decades. Because the presence of second cancers, particularly gastrointestinal cancer, in either low-risk patients or healthy women at high risk of breast cancer could significantly reduce the net benefit from tamoxifen therapy, knowledge about the incidence of second primary cancers and the long-term effects of tamoxifen is important. We conducted a retrospective cohort study to evaluate the effect of tamoxifen on the risk of second primary cancers among women with breast cancer in Japan. This is the first large-scale study investigating the incidence and risk of second primary cancers after adjuvant tamoxifen therapy for Japanese breast cancer patients.
1539 Table 3. Frequency of second primary cancers and IRR associated
Table I. Selected characteristics of the study subjects.
1171 t h
1 il n i fW
1 1 f*n
t FC3 t T
Wllll lalllUAlICIl irt.dlliii.iiv.
Characteristics
Total
Non-tamoxifentreated group Number of subjects (%)
470(13.1) 1288(35.9) 1054(29.4) 584(16.3) 192 (5.3) (51.0 ± 10.5)
409(16.0) 810(31.6) 629 (24.6) 437(17.1) 275(10 7) (52.0 ± 12.3)
924 (25.8) 2196(61.2) 468(13.0)
823(32.1) 1359(53.1) 378(14.8)
1919(53.5) 995 (27.7) 672(18.7) 3(0.1)
1726(67.4) 536(20.9) 295(11 5) 3(0.1)
1756(49.2) 706(19.7) 1117(31.1)
1072(41.9) 878 (34.3) 610(23.8)
2049(57.1) 1532 (42.7) 7 (0.2)
1299(50.7) 1247 (48 7) 14(0.6)
2403 (67.0) 1008 1395 1185(33.0)
1494(58.4) 604 890 1066(41.6)
3588(100)
2560(100)
Table 2. Duration and cumulative dose of tamoxifen treatment. Tamoxifen treatment
Number of subjects (%)
Duration $ 1 years 1 - $ 2 years 2 - $ 3 years 3 - $ 4 years 4 - $ 5 years > 5 years Unknown Cumulative dose $7.3ga 7.3-$7.3 x 2 g 7.3 x 2-7.3 x 3 g 7.3 x 3-7.3 x 4 g 7.3 x 4-7.3 x 5 g >7.3x5g Unknown
1204(33.6) 1541 (42.9) 465(13.0) 132(3.7) 68(1.9) 113(3.1) 65(1.8)
Total
3588 (100)
1
1145(31.9) 1750(48.8) 427(11.9) 85 (2.4) 49(1.3) 72 (2.0) 60(1.7)
7.3 g corresponds to 20 mg/day 365.
was mostly two years or less (80.7%), and the greater part of the cumulative dose of tamoxifen was 7.3 x 2 g or less (71.4%).
Site of second cancers
Contralateral breast Esophagus Stomach Colon Rectum Colorectal b Liver Pancreas Lung Ovary Endometrial Cervix uteri Kidney Thyroid gland Hematological malignancy Other unknown Total Incidence rate/ 1000 women
Tamoxifen treatedgroup (n = 3497)a Number of events
Nontamoxifentreated group (n = 2529)° Number of events
IRR
95% CI
Pvalue
20 1 32 9 5 7 4 2 8 5 9 9 1 10
10 1 19 5 6 7 2 6 6 3 3 7 3 5
1 52 0 73 1 34 1.37 0.66 0.80 1.55 0.25 1.05 1.51 2 37 1.05 0.25 1 50
0.71-3.25 0.05-11.7 0.76-2.38 0.46-4.08 0.20-2 17 0.28-2.28 0 28-8 46 0 05-1 24 0.36-3.05 0 35-6 61 0.64-8 77 0.39-2.82 0.03-2.39 0.51-4 39
0.28 0.83 0.31 0.58 0.49 0.68 0 61 0 09 0.92 0 58 0 20 0.93 0 23 0 46
1 13
2 16
0.39 0 62
0.04-4.28 0.30-1 28
0 44 0 20
1
A
1.03
0.80-1.33 0.67
I
137 5 09
u 101 4 93
a
One hundred twenty-two patients were excluded1, because information on whether or not they had developed second cancers was not available (tamoxifen-treated: 91, non-tamoxifen-treated: 31). b These 14 colorectal cases were not distinguished as to colon and rectum cases.
Second primary cancers Table 3 shows the frequency of second primary cancers and the incidence rate ratio (IRR) associated with tamoxifen treatment. The total numbers of second primary cancers were 137 in tamoxifen-treated patients and 101 in non-tamoxifen-treated patients, respectively. The annual incidence rates per 1000 women of all second cancers was 5.09 and 4.93 among tamoxifen-treated and nontamoxifen-treated patients, respectively; thus the IRR was 1.03 (95% confidence interval (CI): 0.80-1.33, P - 0.67). Compared with non-tamoxifen-treated patients, tamoxifen-treated patients had numerical increases in many types of second cancers (contralateral breast, stomach, colon, liver, lung, ovary, endometrial, cervix uteri, and thyroid gland), although the IRR for all types of second cancer was not statistically significant. The IRR for endometrial cancer was 2.37 (95% CI: 0.64-8.77, P - 0.20). Stomach cancer was the most frequent second cancer and the IRR for stomach cancer was 1.34 (95% CI: 0.76-2.38, P - 0.31). The numbers of colon and rectum (or colorectal) cancers were 21 and 18, respectively. The IRR for these cases was 0.91 (95% CI: 0.49-1.72, P = 0.78). It appears that tamoxifen did not protect against breast cancer in the opposite breast (IRR = 1.52, 95% CI: 0.71-3.25). For these 30 contralateral breast cancer cases, we reinvestigated metastases to other sites and recurrence status before and after six month around the occurrence of contralateral breast
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Age at surgery <40 40-49 50-59 60-69 5=70 (Mean ± SD) Stage I II IIIA Lymph node metastasis None 1-3 5=4 Unknown Estrogen receptor status ER+ ERUnknown Menopausal status Premenopausal Postmenopausal Unknown Chemotherapy Yes Mono Combination No
Tamoxifentreatedgroup Number of subjects (%)
1540 0.12
All second cancers
0.09
Log-rank test: p-value=0.62 0.06
nna
*-
Endometrial cancer —•
0.00 6
•
-
8
10
12
14
Time (year)
Figure I. Cumulative incidence of all second primary cancers and endometrial cancer during follow-up according to treatment group; — tamoxifen-treated patients; — non-tamoxifen-treated patients.
Cumulative incidence of endometrial cancer and all second primary cancers Figure 1 shows the cumulative incidence of endometrial cancer as well as all second primary cancers by the Kaplan-Meier method. Median follow-up time was 7.64 years (range 0.003-14.0) for tamoxifen-treated patients and 8.1 years (range 0.04-13.9) for non-tamoxifentreated patients, respectively. There were no differences in time pattern for endometrial cancer between two treatment groups, although the incidence times for all endometrial cancer cases among non-tamoxifen-treated
Multivariate analysis The effect of tamoxifen effects adjusted for covariates on all second primary cancers and the prognostic significance of individual covariates are shown in Table 5. IRR associated with tamoxifen treatment was 1.06 (95% CI: 0.77-1.47, P = 0.72) after adjustment of the potential covariates. Statistically significant prognostic covariates for all second cancers were age at surgery (IRR per decade increase = 1.48, 95% CI: 1.19-1.84, P < 0.001) and lymph node metastasis (IRR compared to none = 1.59, 95% CI: 1.14-2.22, P = 0.007). Similar results (not shown) were obtained even if contralateral breast cancers (30 cases) were excluded from the multivariate analysis. Furthermore, there was no trend of increasing risk of all second cancers with duration of tamoxifen use, or with cumulative dose. Standardized incidence ratio Table 6 shows standardized incidence ratios (SIR) for endometrial and stomach cancer. The expected numbers were obtained by adding the accumulated risk over all patients in the group, where the accumulated risk was calculated by multiplying the years at risk in each period since age at surgery by each period-specific population-
Table 4. Censoring proportion in each treatment group. Treatment group
Tamoxifen Number of at risk Number of death Number of censoring Proportion of censoring (%) Non-tamoxifen Number of at risk Number of death Number of censoring Proportion of censoring (%) a
c
Calendar year 1982-1990
1991
1992
1993
1994
1995
1996/Mar
3543 a 360 85 2.4
3098 69 58 1.9
2971 77 196 6.6
2698 61 124 4.6
2513 62 314 12.5
2137 32 716C 33.5
1389 13 1376 -
2543" 246 66 2.6
2231 57 11 0.5
2163 44 65 3.0
2054 45 53 2.6
1956 43 164 8.4
1749 22 852C 48.7
875 10 865 -
t
Forty-five patients have no information on date of occurrence of outcomes. Seventeen patients have no information on date of occurrence of outcomes. These numbers include censoring due to study end in some institutions where follow-ups of the patients were terminated at the end of 1995.
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cancer. Of the 30 women, no metastases and recurrence were found in 29 patients, and only one patient had metastasis to local lymph node. There was a possibility of this patient being a recurrent case. We conducted a landmark analysis [24] to evaluate the effect of tamoxifen treatment on contralateral breast risk after three or five years. The IRRs were 1.23 (95% CI: 0.48-3.17, P = 0.67) and 0.97 (95% CI: 0.30-3.19, P = 0.96), respectively.
group were within seven years. The cumulative incidence rates of all second cancers at 10 years were 4.61% and 4.09% among tamoxifen-treated and non-tamoxifentreated patients, respectively. There was no statistically significant difference between the overall curves for all second cancers (log-rank test, P - 0.62). Table 4 shows the proportion of censoring in each year. The number of censorings in 1995 included the censoring due to study end at some institutions where follow-ups of the patients were terminated at the end of 1995. The cumulative censoring proportions through the end of 1994 were 21.9% and 14.1% among tamoxifen-treated and non-tamoxifen-treated patients, respectively.
1541 Table 5. Prognostic factor analyses for the incidence of all second cancers (proportional hazards model). Variable
Parameter estimate
Standard error
/'-value
IRR
95% CI
Tamoxifen (yes vs. no) Age (per decade) Stage (II vs. I) Stage (IIIA vs. I) Lymph node metastasis (yes vs. no) Menopausal status (post vs. pre) Estrogen receptor status (+ vs. -) Chemotherapy (yes vs. no)
0.0592 0.3885 -0.2191 -0.4970 0.4630 -0.4259 0.0542 -0.2119
0.166 0.112 0.192 0.297 0.171 0.251 0.177 0.183
0.72 0.001 0.25 0.09 0.007 0.09 0.76 0.25
1.06 1.48 0.80 0.61 1.59 0.65 1.06 0.91
0.77-1.47 1.19-1.84 0.55-1.17 0.34-1.09 1.14-2.22 0.40-1.07 0.75-1.49 0.57-1.16
Table 6 SIR for endometrial and stomach cancer. Treatment group
Endometrial
Tamoxifen Non-tamoxifen
9 3
Stomach
Tamoxifen Non-tamoxifen
32 19
1
Number of observed
Number of expected
SIR
F-value
2.50 1.82
3.60 (0.632) a 1.65(0.742)
0.0003 0.11
21.45 18.40
1.49(0.216) 1.03(0.233)
0.01 0.38
Standard error of SIR was given in parentheses.
based incidence rates and summing up each number. Compared with the general population, significant excesses of both endometrial and stomach cancer were seen in tamoxifen-treated patients. The SIR's for endometrial cancer were 3.60 (SE 0.632, P - 0.0003) and 1.65 (SE 0.742, P - 0.11), in tamoxifen-treated and nontamoxifen-treated patients, respectively, and those for stomach cancer were 1.49 (SE 0.216, P - 0.01) and 1.03 (SE 0.233, P = 0.38), respectively.
Discussion We conducted the first large-scale retrospective cohort study investigating the risk of second primary cancers after adjuvant tamoxifen therapy for Japanese breast cancer patients. In designing this study, we planned to collect data on 5000 women, and this goal was achieved (6148 cases). In the Japanese general population, the annual incidence rate of endometrial cancer during 1987-1989 at age 50-70 was about 0.1 per 1000 women [21], so we needed to collect a total of 4599 women to detect the 5-fold relative risk for endometrial cancer after 10 years of follow-up and to have a power of 80% at type I error (one-sided) of 5%. We collected data from nine institutions, which are representative cancer therapy centers in Japan, and the number of surgeries per year was one hundred or more in each institution. Several randomized controlled trials of tamoxifen as adjuvant therapy were conducted in the past ten years and all of nine institutions took part in these trials [25], which explains the reason that tamoxifen-treated and non-tamoxifen-treated groups were not remarkably imbalanced. We followed the patients for a relatively long time. Because there exists no cancer registry covering the whole of Japan, it is difficult to ascertain outcomes or
check against it for all patients. The censoring proportion through the end of 1994 was relatively small and similar across treatment groups. So, we do not believe that there would be a large bias due to the incompleteness of follow-up. However, further follow-ups of breast cancer survivors might be needed to monitor site-specific risks of second cancer over time precisely, particularly, in relation to the duration and cumulative dose of tamoxifen treatment. The results of this study showed no significant difference in the incidence rate of all second primary cancers between tamoxifen-treated and non-tamoxifen-treated patients. The results of multivariate analysis show that age and lymph node metastasis are significant risk factors of secondary cancer. It is obvious that age was picked up and lymph node metastasis might be a surrogate of susceptibility to cancer and/or immune response. Thirty contralateral breast cancer cases were observed as a second primary cancer. A landmark analysis at five years revealed a slightly favorable effect of tamoxifen treatment on contralateral breast risk (IRR = 0.97). However, if the possible reduction of contralateral breast cancer by adjuvant tamoxifen reported earlier [1, 2] is taken into account, the observed IRR (1.52 in Table 3) seems to be too large. As described earlier, the patients were followed up systematically irrespective of the nodal status of the patients, although there were slight differences among the participating institutions. So, we do not believe that the difference of incidence of contralateral breast cancer by the nodal status would be due to the detection bias in the node-positive and node-negative patients by the frequency or method of follow-up examination. The exact reasons for higher incidence of contralateral breast cancer among tamoxifen-treated group remain to be elucidated, although deterioration of the immune system might accelerate carcinogenesis in the contralateral breast.
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Site of second cancer
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For stomach cancer, a statistically significant relative Acknowledgements risk was obtained in tamoxifen-treated patients, compared with the general population (SIR = 1.49, P = 0.01). The authors thank K. Sawa, Y. Fujiki, and EPS Co., Ltd. This estimate of relative risk, however, was not so large for their assistance in data collection and management. compared with the previously reported ones [10, 12]. The authors are also grateful to the two referees for their Furthermore, statistically significant IRR was not ob- helpful comments. tained (IRR = 1.34, P - 0.31), compared with nontamoxifen-treated patients that appeared to have the same risk for stomach cancer as that of the general population (SIR in non-tamoxifen-treated patients = References 1.03). The numbers of endometrial cancers were 9 and 3 1. Early Breast Cancer Tnalists' Collaborative Group. Systemic among tamoxifen-treated and non-tamoxifen-treated treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurpatients, respectively. The IRR associated with tamoxrences and 24,000 deaths among 75,000 women. Lancet 1992; ifen use and SIR in the tamoxifen treated group were 339: 1-15,71-85 2.37 (95% CI: 0.64-8.77, P = 0.20) and 3.60 (SE 0.632; 2. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen P = 0.0003), respectively. These relative risks of two-fold for early breast cancer: An overview of the randomised trials. or three-fold support the link between tamoxifen treatLancet 1998; 351: 1451-67. 3. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for ment and subsequent development of endometrial cancer prevention of breast cancer: Report of the National Surgical that has been described in previous investigations [2, 3, Adjuvant Breast and Bowel Project P-l study. J Natl Cancer Inst 10, 13]. Of the 12 patients who developed endometrial 1998; 90. 1371-88. cancer, 4 died of cancer (three patients were tamoxifen4. Swedish Breast Cancer Cooperative Group. Randomized trial of treated and one was non-tamoxifen-treated), and the two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. J Natl Cancer Inst 1996; 88: 1543-9. other 8 patients were alive as of March 1996. For three 5. Fisher B, Dignam J, Bryant J et al. Five versus more than five of the four patients who had died, the cause of death was years of tamoxifen therapy for breast cancer patients with negbreast cancer. ative lymph nodes and estrogen receptor-positive tumors. J Natl In our data, recurrence-free survival rates for node Cancer Inst 1996; 88. 1529-42. negative patients at 10 years was 91.5% and 88.1% 6. Stewart HJ, Forrest AP, Everington D et al. Randomised comparison of five years of adjuvant tamoxifen with continuous therapy among tamoxifen-treated and non-tamoxifen-treated for operable breast cancer. Br J Cancer 1996; 74: 297-9. patients, respectively, and that for node positive patients 7. Davies C, Nomura Y, Ohashi Y. Adjuvant tamoxifen duration: was 66.1% and 63.1%, respectively. The relative hazard More large scale randomized evidence is needed. Jpn J Cancer for recurrence was significantly lower in the tamoxifenChemother 1997; 24: 1203-9. treated group compared with the non-tamoxifen-treated 8. Fornander T, Rutqvist LE, Cedermark B et al. Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. group. The IRR's for the recurrence, adjusted stage and Lancet 1989; 1: 117-20. lymph node metastasis were 0.89 (95% CI: 0.74-1.07) 9. Fornander T, Hellstrom A-C, Moberger B. Descriptive clinicoand 0.76 (95% CI: 0.63-0.93) among pre-menopausal pathologic study of 17 patients with endometrial cancer during or and post-menopausal patients, respectively. Similar benafter adjuvant tamoxifen in early breast cancer. J Natl Cancer eficial results of tamoxifen use were obtained for overall Inst 1993; 85: 1850-5. survival. These results for effectiveness of tamoxifen on 10. Anderson M, Strom HH, Mouridsen HT. Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy recurrence-free or overall survival should be interpreted early breast cancer. J Natl Cancer Inst 1991; 83: 1013-7. with great care in retrospective study. However, consid- 11. for Fisher B, Costantino JP, Redmond CK et al. Endometrial cancer ering the survival benefits of tamoxifen which have been in tamoxifen-treated breast cancer patients: Findings from the shown in the EBCTCG overview [1, 2] or several National Surgical Adjuvant Breast Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86: 527-37. randomized clinical trials [25], the total number of 12. Rutqvist LE, Johansson H, SignomklaoTet al. Adjuvant tamoxwomen with second primary cancers, particularly endoifen therapy for early stage breast cancer and second primary metrial cancer, is very small compared with the millions malignancies. J Natl Cancer Inst 1995; 87: 645-51. of women who have been exposed to tamoxifen and have 13. Curtis RE, Boice JD, Shriner DA et al. Second cancers after benefited from the drug. These findings were in accordadjuvant tamoxifen therapy for breast cancer. J Natl Cancer Inst 1996; 88: 832-4. ance with other previous studies [11, 26] and, taking 14. Hardell L. Tamoxifen as risk factor for carcinoma of corpus uteri. account of low incidence of endometrial cancer in Lancet 1988; 1:563. Japanese women (less than 1/3 of Western population), 15. Hardell L. Tamoxifen as a risk factor for endometrial cancer. the benefit-risk ratio of tamoxifen in Japanese breast Cancer 1990; 66: 1661. cancer patients is at least as good as in Western popula- 16. Van Leeuwen FE. Benraadt J. Coebergh JW et al. Risk of endometrial cancer after tamoxifen treatment of breast cancer. tions. Lancet 1994; 343: 448-52. In conclusion, the incidence and risk of second pri17. MacMahon B. Overview of studies on endometrial cancer and mary cancers associated with adjuvant tamoxifen therapy other types of cancer in humans: Perspectives of an epidemiolois low, and the potential benefit of tamoxifen therapy in gist. Semin Oncol 1997; 24: S1-122-S1-139. breast cancer patients outweighs the risk of second 18. Morgan R\V. Risk of endometrial cancer after tamoxifen treatment. Oncology' 1997; 11: 25-33. primary cancers.
1543 19. Kaplan EL. Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958: 53: 457-81. 20. Cox DR. Regression models and life tables. J R Stat Soc B 1972; 34: 187-220. 21. Osaka Foundation for Prevention of Cancer and Circulatory Diseases. Cancer Incidence and Mortality in Osaka 1963-1989. The Shinohara Publishers Inc 1993. 22. Armitage P, Berry G. Statistical Methods in Medical Research. Oxford. Blackwell Scientific Publications 1987. 23. SAS Institute, Inc. SAS/STAT Software: Changes and Enhancements through Release 6.12. Cary. North Carolina: SAS Institute Inc 1997. 24. Anderson JR, Cain ICC. Gelber RD. Analysis of survival by tumor response. J Clin Oncol 1983; 1 (11): 710-9. 25. Abe O. The role of chemoendocrine agents in postoperative adjuvant therapy for breast cancer: Meta-analysis of the first
collaborative studies of postoperative adjuvant chemoendocrine therapy for breast cancer (ACETBC). Breast Cancer 1994; 1: 1-9. 26. Jordan VC. Tamoxifen and tumorigenicity: A predictable concern. J Natl Cancer Inst 1995; 87: 623-6. Received 31 March 2000; accepted 18 August 2000. Correspondence to: Y. Matsuyama, PhD Department of Biostatistics Kyoto University School of Public Health Yoshida Konoe-cho, Sakyo-Ku Kyoto 606-8501 Japan E-mail: [email protected]
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Original article Second cancers after adjuvant tamoxifen therapy for breast cancer in Japan Y. Matsuyama,1 T. Tominaga,2 Y. Nomura, 3 H. Koyama,4 M. Kimura, 5 M. Sano,6 S. Miura, 7 S. Takashima,8 S. Mitsuyama,9 H. Ueo 10 & Y Ohashi1 1
Bioslatistics/'Epidemiology and Preventive Health Sciences, School of Health Sciences and Nursing, University of Tokyo, 2Department of Surgery, Tokyo Metropolitan Komagome Hospital; 3Department of Breast Surgery, National Kyushu Cancer Center, 4Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases; 5 Division of Surgery, Gunma Cancer Center Hospital; 6Division of Surgery, Niigata Cancer Center Hospital; "'Department of Breast Surgery, Aicht Cancer Center Hospital; s Department of Surgery, Shikoku Cancer Center Hospital; Department of Surgery, Kitakyushu Municipal Medical Center; 10Department of Surgery, Oita Prefectural Hospital
and 4.09% among tamoxifen-treated and non-tamoxifen-treated patients (P = 0.62), respectively, and the incidence rate ratio Background: Women treated with tamoxifen for breast cancer (IRR) for all second cancers was 1.06 (95% confidence interval are at increased risk of endometrial cancer. We conducted a (CI): 0.77-1.47) after adjustment of several covariates. The retrospective cohort study to evaluate the risk of second primary numbers of endometrial cancers was 9 and 3 among tamoxcancers after adjuvant tamoxifen therapy for breast cancer in ifen-treated and non-tamoxifen-treated patients, respectively, and the IRR was 2.37 (95% CI: 0.64-8.77, P = 0.20). Of the 12 Japan. Patients and methods: The subjects of the study were 6148 patients who developed endometrial cancer, 4 died of cancer women who had been diagnosed with stage I, II, or IIIA (for 3 of them, the cause of death was breast cancer), and the unilateral primary breast cancer and had received surgical treat- other 8 patients were alive as of March 1996. Stomach cancer ment during the period from January 1982 through December was the most frequent second cancer and the IRR was 1.34 1990 at nine institutions in Japan. The information on each (95% CI: 0.76-2.38, P = 0.31). There was no substantial patient was obtained from medical records or a prospectively increase in any other type of gastrointestinal cancer such as colorectal and liver cancers among tamoxifen-treated patients. compiled computer database at each institution. Conclusions: The incidence and risk of second primary Results: Of the 6148 women, 3588 (58.4%) were adminiscancers associated with tamoxifen therapy is low. The potential tered tamoxifen as an adjuvant treatment and 2560 (41.6%) were not administered. Median follow-up periods were 7.64 years for benefit of adjuvant tamoxifen therapy in breast cancer patients tamoxifen-treated patients and 8.10 years for non-tamoxifen- outweighs the risk of second primary cancers for Japanese treated patients, respectively. The duration of tamoxifen treat- breast cancer patients. ment was mostly two years or less (80.7%), and few patients received tamoxifen for more than five years. The cumulative Key words: adjuvant therapy, breast cancer, second cancer, incidence rates of all second cancers at 10 years were 4.61% tamoxifen Summary
Tamoxifen is the drug most widely prescribed as adjuvant therapy for breast cancer. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of worldwide evidence has demonstrated that a few years of adjuvant tamoxifen produces a moderate but definite benefit in reducing the incidence of contralateral breast cancer, as well as in prolonging survival and recurrencefree survival [1, 2]. The National Surgical Breast and Bowel Project (NSABP) P-l study group published the first report that tamoxifen reduced breast cancer incidence by 49% among women at high-risk for developing the disease [3]. Based on this evidence, tamoxifen was recently approved for breast cancer prevention in healthy women at high risk of developing the disease. Concerns regarding the optimal duration of tamoxifen treatment have also been raised [4-6], particularly as to whether,
after a few years on tamoxifen, most women should stop or should continue for several more years [7]. However, several studies have provided evidence indicating that tamoxifen can cause second cancers. Among women, the main carcinogenic risk of tamoxifen is for endometrium. Several randomized trials of breast cancer treatment have found an increased risk of endometrial cancer among women treated with tamoxifen [8-12]. One nonrandomized cohort study [13] and two case-control studies [14-16] have shown findings similar to those from the randomized studies. In these studies, the effect of tamoxifen on endometrial cancer has been reported to increase the incidence rate from two-fold to seven-fold. An increasing trend in the risk of endometrial cancer with the duration of tamoxifen use and with cumulative dose has also been suggested [8, 13, 16]. MacMahon [17] and Morgan [18] have provided a critical review of these and other studies that have been pub-
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Introduction
1538
Patients and methods Patients The subjects of the study were women who had been diagnosed with stage I, II, or IIIA unilateral primary breast cancer and had received surgical treatment during the period from January 1982 through December 1990. Non-invasive breast cancer patients were excluded from the study. Nine institutions in Japan were asked to cooperate in this retrospective cohort study. All women in the nine institutions who had met the eligibility requirements were the subjects of the study.
The data were computerized and checked for internal consistency by the contract research organization, and were amended or updated if necessary through correspondence with the responsible physicians at each institution. Statistical analyses In each treatment group (tamoxifen-treated and non-tamoxifentreated group), the incidence rates for each type of second primary cancer were computed as the observed number of events divided by the total number person-years at risk. The incidence rate ratio (IRR) associated with tamoxifen was estimated as the ratio between these rates; the non-tamoxifen-treated group was taken as the reference group. In these calculations, the patients were considered to be at risk from the date of surgery until the date of occurrence of each type of second cancer, the date of death, or the last date by which she was known to be alive. The cumulative incidence of all second cancers was estimated by the Kaplan-Meier method [19], and the resulting two curves were compared using the log-rank test. The effect of tamoxifen adjusted for covariates on all second cancers and the prognostic significance of individual covariates were examined by using the Cox proportional hazards model [20]. We considered several variables as potential covariates, including the age at surgery, stage of initial breast cancer, menopausal status, estrogen receptor status, lymph node metastasis, and adjuvant chemotherapy. For endometrial and stomach cancer, standardized incidence ratios (SIR) were computed as the ratio of observed to expected numbers. Expected numbers were computed by using the five-year age band-specific population-based incidence rates [21]. In the calculation of the person-years at risk, the age of each patient, both at surgery and as it changes through the period of followup, was taken into account [22]. Standard errors of SIR were based on the Poisson distribution, and the exact P-value for SIR was calculated. All statistical analyses were performed using SAS 6.12 [23].
Results
Data collection
Background characteristics ofpatients
The following information on each patient was retrospectively obtained from medical records or a prospectively compiled computer database at each institution1 date of surgery, age at surgery, type of surgery, weight, height, stage of initial breast cancer, menopausal status, estrogen receptor status, number of histological lymph node metastases, and adjuvant treatments (chemotherapy, hormonal therapy and radiotherapy). Relevant information was collected for each type of medical adjuvant treatment including the name of drugs, dosage of them and dates when the prescription was started and stopped. For tamoxifen. we gathered the data on daily dose and duration of treatment as well as a cumulative dose. The duration of tamoxifen treatment was calculated as the time from the first to the last prescription. For patients with multiple, distinct series of tamoxifen treatment, the total duration was calculated by summing up the days contributed by each continuous period of prescription. The cumulative dose of tamoxifen was calculated by multiplying the daily dose by the period (days) and summing up the total weight (grams) of each contribution if there were distinct series of prescription and/or changes in the prescribed dose. Information was also sought on the type and date of subsequent occurrence of second primary cancer, the type and date of recurrence, and the cause and date of death, with follow-up to March 1996. The patients were followed-up systematically irrespective of the nodal status of the patients, although there were a slight difference among the participating institutions. The methods of detecting the second cancers as well as recurrence of breast cancer were essentially based on the physical examination, mammography, if necessary, X-rays of chest, and bones, liver echography and CT X-rays, and tumor markers (CEA, CA15-3), and variable examinations according to the complaints of patients (e.g.. gynecological examinations for vaginal spotting, etc).
A total of 6148 patients were identified from medical records or a computer database at each institution. The selected background characteristics of the study subjects are shown in Table 1. Of the 6148 study subjects, 3588 (58.4%) were tamoxifen-treated patients and 2560 (41.6%) were non-tamoxifen-treated patients. The distributions of age at surgery, stage, and menopausal status were similar in the two treatment groups. An imbalance between the two groups was seen in terms of lymph node metastasis, estrogen receptor status, and chemotherapy. 46.4% of tamoxifen-treated patients were lymph node-positive compared with 32.4% in non-tamoxifentreated patients (Mantel-Haenszel trend test, P < 0.001), and the percentage of estrogen receptor-positive excluding unknown cases was 71.3% in tamoxifen-treated patients compared with 55.0% in non-tamoxifen-treated patients (Chi-square test, P < 0.001). 67.0% of tamoxifen-treated patients received chemotherapy compared with 58.4% in non-tamoxifen-treated patients (chisquare test, P < 0.001). Table 2 shows the distributions of the duration and cumulative dose of tamoxifen treatment. The most commonly used daily dose was 20 mg per day, ranging from 10 mg to 40 mg. The duration of tamoxifen treatment
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lished concerning the possible relationship of tamoxifen to endometrial cancer. Recently, an elevated risk of gastrointestinal cancer, particularly stomach and colorectal cancers, was reported to be associated with tamoxifen therapy [12]. In Japan, stomach cancer is still one of the leading causes of cancer death and remains as an important public health issue, despite the decline in the incidence and mortality of this disease in recent decades. Because the presence of second cancers, particularly gastrointestinal cancer, in either low-risk patients or healthy women at high risk of breast cancer could significantly reduce the net benefit from tamoxifen therapy, knowledge about the incidence of second primary cancers and the long-term effects of tamoxifen is important. We conducted a retrospective cohort study to evaluate the effect of tamoxifen on the risk of second primary cancers among women with breast cancer in Japan. This is the first large-scale study investigating the incidence and risk of second primary cancers after adjuvant tamoxifen therapy for Japanese breast cancer patients.
1539 Table 3. Frequency of second primary cancers and IRR associated
Table I. Selected characteristics of the study subjects.
1171 t h
1 il n i fW
1 1 f*n
t FC3 t T
Wllll lalllUAlICIl irt.dlliii.iiv.
Characteristics
Total
Non-tamoxifentreated group Number of subjects (%)
470(13.1) 1288(35.9) 1054(29.4) 584(16.3) 192 (5.3) (51.0 ± 10.5)
409(16.0) 810(31.6) 629 (24.6) 437(17.1) 275(10 7) (52.0 ± 12.3)
924 (25.8) 2196(61.2) 468(13.0)
823(32.1) 1359(53.1) 378(14.8)
1919(53.5) 995 (27.7) 672(18.7) 3(0.1)
1726(67.4) 536(20.9) 295(11 5) 3(0.1)
1756(49.2) 706(19.7) 1117(31.1)
1072(41.9) 878 (34.3) 610(23.8)
2049(57.1) 1532 (42.7) 7 (0.2)
1299(50.7) 1247 (48 7) 14(0.6)
2403 (67.0) 1008 1395 1185(33.0)
1494(58.4) 604 890 1066(41.6)
3588(100)
2560(100)
Table 2. Duration and cumulative dose of tamoxifen treatment. Tamoxifen treatment
Number of subjects (%)
Duration $ 1 years 1 - $ 2 years 2 - $ 3 years 3 - $ 4 years 4 - $ 5 years > 5 years Unknown Cumulative dose $7.3ga 7.3-$7.3 x 2 g 7.3 x 2-7.3 x 3 g 7.3 x 3-7.3 x 4 g 7.3 x 4-7.3 x 5 g >7.3x5g Unknown
1204(33.6) 1541 (42.9) 465(13.0) 132(3.7) 68(1.9) 113(3.1) 65(1.8)
Total
3588 (100)
1
1145(31.9) 1750(48.8) 427(11.9) 85 (2.4) 49(1.3) 72 (2.0) 60(1.7)
7.3 g corresponds to 20 mg/day 365.
was mostly two years or less (80.7%), and the greater part of the cumulative dose of tamoxifen was 7.3 x 2 g or less (71.4%).
Site of second cancers
Contralateral breast Esophagus Stomach Colon Rectum Colorectal b Liver Pancreas Lung Ovary Endometrial Cervix uteri Kidney Thyroid gland Hematological malignancy Other unknown Total Incidence rate/ 1000 women
Tamoxifen treatedgroup (n = 3497)a Number of events
Nontamoxifentreated group (n = 2529)° Number of events
IRR
95% CI
Pvalue
20 1 32 9 5 7 4 2 8 5 9 9 1 10
10 1 19 5 6 7 2 6 6 3 3 7 3 5
1 52 0 73 1 34 1.37 0.66 0.80 1.55 0.25 1.05 1.51 2 37 1.05 0.25 1 50
0.71-3.25 0.05-11.7 0.76-2.38 0.46-4.08 0.20-2 17 0.28-2.28 0 28-8 46 0 05-1 24 0.36-3.05 0 35-6 61 0.64-8 77 0.39-2.82 0.03-2.39 0.51-4 39
0.28 0.83 0.31 0.58 0.49 0.68 0 61 0 09 0.92 0 58 0 20 0.93 0 23 0 46
1 13
2 16
0.39 0 62
0.04-4.28 0.30-1 28
0 44 0 20
1
A
1.03
0.80-1.33 0.67
I
137 5 09
u 101 4 93
a
One hundred twenty-two patients were excluded1, because information on whether or not they had developed second cancers was not available (tamoxifen-treated: 91, non-tamoxifen-treated: 31). b These 14 colorectal cases were not distinguished as to colon and rectum cases.
Second primary cancers Table 3 shows the frequency of second primary cancers and the incidence rate ratio (IRR) associated with tamoxifen treatment. The total numbers of second primary cancers were 137 in tamoxifen-treated patients and 101 in non-tamoxifen-treated patients, respectively. The annual incidence rates per 1000 women of all second cancers was 5.09 and 4.93 among tamoxifen-treated and nontamoxifen-treated patients, respectively; thus the IRR was 1.03 (95% confidence interval (CI): 0.80-1.33, P - 0.67). Compared with non-tamoxifen-treated patients, tamoxifen-treated patients had numerical increases in many types of second cancers (contralateral breast, stomach, colon, liver, lung, ovary, endometrial, cervix uteri, and thyroid gland), although the IRR for all types of second cancer was not statistically significant. The IRR for endometrial cancer was 2.37 (95% CI: 0.64-8.77, P - 0.20). Stomach cancer was the most frequent second cancer and the IRR for stomach cancer was 1.34 (95% CI: 0.76-2.38, P - 0.31). The numbers of colon and rectum (or colorectal) cancers were 21 and 18, respectively. The IRR for these cases was 0.91 (95% CI: 0.49-1.72, P = 0.78). It appears that tamoxifen did not protect against breast cancer in the opposite breast (IRR = 1.52, 95% CI: 0.71-3.25). For these 30 contralateral breast cancer cases, we reinvestigated metastases to other sites and recurrence status before and after six month around the occurrence of contralateral breast
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Age at surgery <40 40-49 50-59 60-69 5=70 (Mean ± SD) Stage I II IIIA Lymph node metastasis None 1-3 5=4 Unknown Estrogen receptor status ER+ ERUnknown Menopausal status Premenopausal Postmenopausal Unknown Chemotherapy Yes Mono Combination No
Tamoxifentreatedgroup Number of subjects (%)
1540 0.12
All second cancers
0.09
Log-rank test: p-value=0.62 0.06
nna
*-
Endometrial cancer —•
0.00 6
•
-
8
10
12
14
Time (year)
Figure I. Cumulative incidence of all second primary cancers and endometrial cancer during follow-up according to treatment group; — tamoxifen-treated patients; — non-tamoxifen-treated patients.
Cumulative incidence of endometrial cancer and all second primary cancers Figure 1 shows the cumulative incidence of endometrial cancer as well as all second primary cancers by the Kaplan-Meier method. Median follow-up time was 7.64 years (range 0.003-14.0) for tamoxifen-treated patients and 8.1 years (range 0.04-13.9) for non-tamoxifentreated patients, respectively. There were no differences in time pattern for endometrial cancer between two treatment groups, although the incidence times for all endometrial cancer cases among non-tamoxifen-treated
Multivariate analysis The effect of tamoxifen effects adjusted for covariates on all second primary cancers and the prognostic significance of individual covariates are shown in Table 5. IRR associated with tamoxifen treatment was 1.06 (95% CI: 0.77-1.47, P = 0.72) after adjustment of the potential covariates. Statistically significant prognostic covariates for all second cancers were age at surgery (IRR per decade increase = 1.48, 95% CI: 1.19-1.84, P < 0.001) and lymph node metastasis (IRR compared to none = 1.59, 95% CI: 1.14-2.22, P = 0.007). Similar results (not shown) were obtained even if contralateral breast cancers (30 cases) were excluded from the multivariate analysis. Furthermore, there was no trend of increasing risk of all second cancers with duration of tamoxifen use, or with cumulative dose. Standardized incidence ratio Table 6 shows standardized incidence ratios (SIR) for endometrial and stomach cancer. The expected numbers were obtained by adding the accumulated risk over all patients in the group, where the accumulated risk was calculated by multiplying the years at risk in each period since age at surgery by each period-specific population-
Table 4. Censoring proportion in each treatment group. Treatment group
Tamoxifen Number of at risk Number of death Number of censoring Proportion of censoring (%) Non-tamoxifen Number of at risk Number of death Number of censoring Proportion of censoring (%) a
c
Calendar year 1982-1990
1991
1992
1993
1994
1995
1996/Mar
3543 a 360 85 2.4
3098 69 58 1.9
2971 77 196 6.6
2698 61 124 4.6
2513 62 314 12.5
2137 32 716C 33.5
1389 13 1376 -
2543" 246 66 2.6
2231 57 11 0.5
2163 44 65 3.0
2054 45 53 2.6
1956 43 164 8.4
1749 22 852C 48.7
875 10 865 -
t
Forty-five patients have no information on date of occurrence of outcomes. Seventeen patients have no information on date of occurrence of outcomes. These numbers include censoring due to study end in some institutions where follow-ups of the patients were terminated at the end of 1995.
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cancer. Of the 30 women, no metastases and recurrence were found in 29 patients, and only one patient had metastasis to local lymph node. There was a possibility of this patient being a recurrent case. We conducted a landmark analysis [24] to evaluate the effect of tamoxifen treatment on contralateral breast risk after three or five years. The IRRs were 1.23 (95% CI: 0.48-3.17, P = 0.67) and 0.97 (95% CI: 0.30-3.19, P = 0.96), respectively.
group were within seven years. The cumulative incidence rates of all second cancers at 10 years were 4.61% and 4.09% among tamoxifen-treated and non-tamoxifentreated patients, respectively. There was no statistically significant difference between the overall curves for all second cancers (log-rank test, P - 0.62). Table 4 shows the proportion of censoring in each year. The number of censorings in 1995 included the censoring due to study end at some institutions where follow-ups of the patients were terminated at the end of 1995. The cumulative censoring proportions through the end of 1994 were 21.9% and 14.1% among tamoxifen-treated and non-tamoxifen-treated patients, respectively.
1541 Table 5. Prognostic factor analyses for the incidence of all second cancers (proportional hazards model). Variable
Parameter estimate
Standard error
/'-value
IRR
95% CI
Tamoxifen (yes vs. no) Age (per decade) Stage (II vs. I) Stage (IIIA vs. I) Lymph node metastasis (yes vs. no) Menopausal status (post vs. pre) Estrogen receptor status (+ vs. -) Chemotherapy (yes vs. no)
0.0592 0.3885 -0.2191 -0.4970 0.4630 -0.4259 0.0542 -0.2119
0.166 0.112 0.192 0.297 0.171 0.251 0.177 0.183
0.72 0.001 0.25 0.09 0.007 0.09 0.76 0.25
1.06 1.48 0.80 0.61 1.59 0.65 1.06 0.91
0.77-1.47 1.19-1.84 0.55-1.17 0.34-1.09 1.14-2.22 0.40-1.07 0.75-1.49 0.57-1.16
Table 6 SIR for endometrial and stomach cancer. Treatment group
Endometrial
Tamoxifen Non-tamoxifen
9 3
Stomach
Tamoxifen Non-tamoxifen
32 19
1
Number of observed
Number of expected
SIR
F-value
2.50 1.82
3.60 (0.632) a 1.65(0.742)
0.0003 0.11
21.45 18.40
1.49(0.216) 1.03(0.233)
0.01 0.38
Standard error of SIR was given in parentheses.
based incidence rates and summing up each number. Compared with the general population, significant excesses of both endometrial and stomach cancer were seen in tamoxifen-treated patients. The SIR's for endometrial cancer were 3.60 (SE 0.632, P - 0.0003) and 1.65 (SE 0.742, P - 0.11), in tamoxifen-treated and nontamoxifen-treated patients, respectively, and those for stomach cancer were 1.49 (SE 0.216, P - 0.01) and 1.03 (SE 0.233, P = 0.38), respectively.
Discussion We conducted the first large-scale retrospective cohort study investigating the risk of second primary cancers after adjuvant tamoxifen therapy for Japanese breast cancer patients. In designing this study, we planned to collect data on 5000 women, and this goal was achieved (6148 cases). In the Japanese general population, the annual incidence rate of endometrial cancer during 1987-1989 at age 50-70 was about 0.1 per 1000 women [21], so we needed to collect a total of 4599 women to detect the 5-fold relative risk for endometrial cancer after 10 years of follow-up and to have a power of 80% at type I error (one-sided) of 5%. We collected data from nine institutions, which are representative cancer therapy centers in Japan, and the number of surgeries per year was one hundred or more in each institution. Several randomized controlled trials of tamoxifen as adjuvant therapy were conducted in the past ten years and all of nine institutions took part in these trials [25], which explains the reason that tamoxifen-treated and non-tamoxifen-treated groups were not remarkably imbalanced. We followed the patients for a relatively long time. Because there exists no cancer registry covering the whole of Japan, it is difficult to ascertain outcomes or
check against it for all patients. The censoring proportion through the end of 1994 was relatively small and similar across treatment groups. So, we do not believe that there would be a large bias due to the incompleteness of follow-up. However, further follow-ups of breast cancer survivors might be needed to monitor site-specific risks of second cancer over time precisely, particularly, in relation to the duration and cumulative dose of tamoxifen treatment. The results of this study showed no significant difference in the incidence rate of all second primary cancers between tamoxifen-treated and non-tamoxifen-treated patients. The results of multivariate analysis show that age and lymph node metastasis are significant risk factors of secondary cancer. It is obvious that age was picked up and lymph node metastasis might be a surrogate of susceptibility to cancer and/or immune response. Thirty contralateral breast cancer cases were observed as a second primary cancer. A landmark analysis at five years revealed a slightly favorable effect of tamoxifen treatment on contralateral breast risk (IRR = 0.97). However, if the possible reduction of contralateral breast cancer by adjuvant tamoxifen reported earlier [1, 2] is taken into account, the observed IRR (1.52 in Table 3) seems to be too large. As described earlier, the patients were followed up systematically irrespective of the nodal status of the patients, although there were slight differences among the participating institutions. So, we do not believe that the difference of incidence of contralateral breast cancer by the nodal status would be due to the detection bias in the node-positive and node-negative patients by the frequency or method of follow-up examination. The exact reasons for higher incidence of contralateral breast cancer among tamoxifen-treated group remain to be elucidated, although deterioration of the immune system might accelerate carcinogenesis in the contralateral breast.
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Site of second cancer
1542
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For stomach cancer, a statistically significant relative Acknowledgements risk was obtained in tamoxifen-treated patients, compared with the general population (SIR = 1.49, P = 0.01). The authors thank K. Sawa, Y. Fujiki, and EPS Co., Ltd. This estimate of relative risk, however, was not so large for their assistance in data collection and management. compared with the previously reported ones [10, 12]. The authors are also grateful to the two referees for their Furthermore, statistically significant IRR was not ob- helpful comments. tained (IRR = 1.34, P - 0.31), compared with nontamoxifen-treated patients that appeared to have the same risk for stomach cancer as that of the general population (SIR in non-tamoxifen-treated patients = References 1.03). The numbers of endometrial cancers were 9 and 3 1. Early Breast Cancer Tnalists' Collaborative Group. Systemic among tamoxifen-treated and non-tamoxifen-treated treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurpatients, respectively. The IRR associated with tamoxrences and 24,000 deaths among 75,000 women. Lancet 1992; ifen use and SIR in the tamoxifen treated group were 339: 1-15,71-85 2.37 (95% CI: 0.64-8.77, P = 0.20) and 3.60 (SE 0.632; 2. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen P = 0.0003), respectively. These relative risks of two-fold for early breast cancer: An overview of the randomised trials. or three-fold support the link between tamoxifen treatLancet 1998; 351: 1451-67. 3. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for ment and subsequent development of endometrial cancer prevention of breast cancer: Report of the National Surgical that has been described in previous investigations [2, 3, Adjuvant Breast and Bowel Project P-l study. J Natl Cancer Inst 10, 13]. Of the 12 patients who developed endometrial 1998; 90. 1371-88. cancer, 4 died of cancer (three patients were tamoxifen4. Swedish Breast Cancer Cooperative Group. Randomized trial of treated and one was non-tamoxifen-treated), and the two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. J Natl Cancer Inst 1996; 88: 1543-9. other 8 patients were alive as of March 1996. For three 5. Fisher B, Dignam J, Bryant J et al. Five versus more than five of the four patients who had died, the cause of death was years of tamoxifen therapy for breast cancer patients with negbreast cancer. ative lymph nodes and estrogen receptor-positive tumors. J Natl In our data, recurrence-free survival rates for node Cancer Inst 1996; 88. 1529-42. negative patients at 10 years was 91.5% and 88.1% 6. Stewart HJ, Forrest AP, Everington D et al. Randomised comparison of five years of adjuvant tamoxifen with continuous therapy among tamoxifen-treated and non-tamoxifen-treated for operable breast cancer. Br J Cancer 1996; 74: 297-9. patients, respectively, and that for node positive patients 7. Davies C, Nomura Y, Ohashi Y. Adjuvant tamoxifen duration: was 66.1% and 63.1%, respectively. The relative hazard More large scale randomized evidence is needed. Jpn J Cancer for recurrence was significantly lower in the tamoxifenChemother 1997; 24: 1203-9. treated group compared with the non-tamoxifen-treated 8. Fornander T, Rutqvist LE, Cedermark B et al. Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. group. The IRR's for the recurrence, adjusted stage and Lancet 1989; 1: 117-20. lymph node metastasis were 0.89 (95% CI: 0.74-1.07) 9. Fornander T, Hellstrom A-C, Moberger B. Descriptive clinicoand 0.76 (95% CI: 0.63-0.93) among pre-menopausal pathologic study of 17 patients with endometrial cancer during or and post-menopausal patients, respectively. Similar benafter adjuvant tamoxifen in early breast cancer. J Natl Cancer eficial results of tamoxifen use were obtained for overall Inst 1993; 85: 1850-5. survival. These results for effectiveness of tamoxifen on 10. Anderson M, Strom HH, Mouridsen HT. Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy recurrence-free or overall survival should be interpreted early breast cancer. J Natl Cancer Inst 1991; 83: 1013-7. with great care in retrospective study. However, consid- 11. for Fisher B, Costantino JP, Redmond CK et al. Endometrial cancer ering the survival benefits of tamoxifen which have been in tamoxifen-treated breast cancer patients: Findings from the shown in the EBCTCG overview [1, 2] or several National Surgical Adjuvant Breast Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86: 527-37. randomized clinical trials [25], the total number of 12. Rutqvist LE, Johansson H, SignomklaoTet al. Adjuvant tamoxwomen with second primary cancers, particularly endoifen therapy for early stage breast cancer and second primary metrial cancer, is very small compared with the millions malignancies. J Natl Cancer Inst 1995; 87: 645-51. of women who have been exposed to tamoxifen and have 13. Curtis RE, Boice JD, Shriner DA et al. Second cancers after benefited from the drug. These findings were in accordadjuvant tamoxifen therapy for breast cancer. J Natl Cancer Inst 1996; 88: 832-4. ance with other previous studies [11, 26] and, taking 14. Hardell L. Tamoxifen as risk factor for carcinoma of corpus uteri. account of low incidence of endometrial cancer in Lancet 1988; 1:563. Japanese women (less than 1/3 of Western population), 15. Hardell L. Tamoxifen as a risk factor for endometrial cancer. the benefit-risk ratio of tamoxifen in Japanese breast Cancer 1990; 66: 1661. cancer patients is at least as good as in Western popula- 16. Van Leeuwen FE. Benraadt J. Coebergh JW et al. Risk of endometrial cancer after tamoxifen treatment of breast cancer. tions. Lancet 1994; 343: 448-52. In conclusion, the incidence and risk of second pri17. MacMahon B. Overview of studies on endometrial cancer and mary cancers associated with adjuvant tamoxifen therapy other types of cancer in humans: Perspectives of an epidemiolois low, and the potential benefit of tamoxifen therapy in gist. Semin Oncol 1997; 24: S1-122-S1-139. breast cancer patients outweighs the risk of second 18. Morgan R\V. Risk of endometrial cancer after tamoxifen treatment. Oncology' 1997; 11: 25-33. primary cancers.
1543 19. Kaplan EL. Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958: 53: 457-81. 20. Cox DR. Regression models and life tables. J R Stat Soc B 1972; 34: 187-220. 21. Osaka Foundation for Prevention of Cancer and Circulatory Diseases. Cancer Incidence and Mortality in Osaka 1963-1989. The Shinohara Publishers Inc 1993. 22. Armitage P, Berry G. Statistical Methods in Medical Research. Oxford. Blackwell Scientific Publications 1987. 23. SAS Institute, Inc. SAS/STAT Software: Changes and Enhancements through Release 6.12. Cary. North Carolina: SAS Institute Inc 1997. 24. Anderson JR, Cain ICC. Gelber RD. Analysis of survival by tumor response. J Clin Oncol 1983; 1 (11): 710-9. 25. Abe O. The role of chemoendocrine agents in postoperative adjuvant therapy for breast cancer: Meta-analysis of the first
collaborative studies of postoperative adjuvant chemoendocrine therapy for breast cancer (ACETBC). Breast Cancer 1994; 1: 1-9. 26. Jordan VC. Tamoxifen and tumorigenicity: A predictable concern. J Natl Cancer Inst 1995; 87: 623-6. Received 31 March 2000; accepted 18 August 2000. Correspondence to: Y. Matsuyama, PhD Department of Biostatistics Kyoto University School of Public Health Yoshida Konoe-cho, Sakyo-Ku Kyoto 606-8501 Japan E-mail: [email protected]
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