- Email: [email protected]
A Rationale for the Reinitiation of Adjuvant Tamoxifen Therapy in Women Receiving Fewer than 5 Years of Therapy
comprehensive
review
A Rationale for the Reinitiation of Adjuvant Tamoxifen Therapy in Women Receiving Fewer than 5 Years of Therapy William J. Gradishar1 and Richard Hellmund2 Abstract The overview analysis of adjuvant therapy trials in early-stage breast cancer by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) compared 1, 2, and 5 years of adjuvant therapy. The optimal benefit to patients in terms of reduced risk of recurrence and death was clearly conferred by 5 years of therapy with tamoxifen compared to shorter durations of therapy. Many women with early-stage breast cancer treated in the past received a recommendation for shorter durations of tamoxifen therapy. The obvious question is whether reinitiating tamoxifen to complete a full 5-year course would further reduce the risk of recurrence and death. In an attempt to explore this issue, we have analyzed recurrence rates in women who received different durations of tamoxifen therapy in the adjuvant setting. The data used for this analysis are directly from the EBCTCG. Our analysis suggests that women who received 1-2 years of adjuvant tamoxifen therapy may benefit from reinitiation of tamoxifen to complete a 5-year course. Clinical Breast Cancer, Vol. 2, No. 4, 282-286, 2002 Key words: Tamoxifen, Adjuvant duration, Reinitiation
Introduction The most recent overview analysis of adjuvant therapy trials in early-stage breast cancer by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) compared 1, 2, and 5 years of adjuvant tamoxifen therapy.1 The optimal benefit to patients, in terms of reduced risk of recurrence and death, was clearly conferred by 5 years of therapy with tamoxifen. Until relatively recently the optimal duration of tamoxifen therapy was not established, and as a result, many patients received durations of adjuvant tamoxifen therapy less than 5 years, including those who did not receive any tamoxifen.2,3 Although the overview analysis confirms that patients who received less than 5 years of tamoxifen are at an increased risk of recurrence and death compared to patients who received 5 years of treatment, it is unclear whether the magnitude of their increased risk justifies retreatment with
1Division
of Hematology/Oncology, Department of Medicine, Northwestern University Medical School and The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 2Biometry Section, AstraZeneca, LP, Wilmington, DE Submitted: April 10, 2001; Revised: Sept. 20, 2001; Accepted: Nov. 2, 2001 Address for correspondence: William J. Gradishar, MD, Division of Hematology and Medical Oncology, Department of Medicine, Northwestern University Medical School, 676 North St. Clair Street, Suite 850, Chicago, IL 60611-2927 Fax: 312-695-6189; e-mail: [email protected]
282 • Clinical Breast Cancer January 2002
tamoxifen to complete a full 5 years of therapy. From a pragmatic standpoint, future clinical trials are unlikely to be designed to address this question. In an attempt to explore this issue, we have analyzed recurrence rates in women who received different durations of tamoxifen therapy in the adjuvant setting. The data used for this analysis are from the EBCTCG.1
Methods Originating directly from the EBCTCG overview of randomized trials, Figure 1 shows the absolute risk reduction for recurrence among patients not receiving tamoxifen compared to those receiving 1, 2, or approximately 5 years of tamoxifen. The data are separated on the basis of nodal involvement (estrogen receptor (ER)-negative patients excluded).1 For our purposes, the EBCTCG secretariat kindly provided us with the recurrence and mortality rates used to generate the figures. Table 1 shows the percentage of patients free of recurrence in the control group or at different times after initiation of tamoxifen therapy. We calculated the percentage of patients experiencing a recurrence during various periods after initiating tamoxifen therapy (all units of time are in years). If n • t is the percentage of patients free of recurrence at time t (years), then the absolute percentage who experienced a recurrence in the next 5 years (between times t and t + 5) is [(n • t) - n(t + 5)]. The relative percentage experiencing a recurrence in this
To examine the effect of tamoxifen therapy at different times after primary tamoxifen, we sought to compare projected 5-year risk of recurrence for patients at different stages of treatment. These data are shown in Table 2. As an example, consider patients with node-positive disease who received 1 year of tamoxifen therapy and are now at a point 5 years since initiating tamoxifen treatment: 58.3% of such patients have not experienced a recurrence (Table 1). Thus, only 58.3% of the original cohort are at risk for recurrence during the next 5 years (years 5-10 after primary treatment). Following through with this example, the projected 5-year risk of recurrence among node-positive patients who received 1 year of tamoxifen is 24.2% (Table 2). Note that among women in the control group, the projected 5-year risk of recurrence is 26.9%. In contrast, 75.6% of patients with node-positive disease who received 5 full years of tamoxifen did not experience a recurrence 5 years after initiating tamoxifen therapy (Table 1). The projected 5-year risk of recurrence (years 5-10) for this group of patients is 21.0% (Table 2). Among the node-positive patients in the control group, the projected 5-year risk of recurrence is 23.7% (Table 2).
1 Year of Treatment 100 % Recurrence Free
Results
Figure 1 Absolute Risk Reduction for Recurrence Among Patients Not Receiving Tamoxifen Compared to Those Receiving 1, 2, or 5 Years of Tamoxifen
Tamoxifen
80
Control
60
N-
Tamoxifen
40
Control
N+
20
0
5
10
Years from Randomization 2 Years of Treatment 100 Tamoxifen
% Recurrence Free
time period is {[(n • t) - n(t + 5)] / (n • t)} • 100. We have defined this term as the projected 5-year risk of recurrence. This calculation is analogous to calculating the 5-year recurrence rate starting at different times after initiating therapy and including only those still at risk (ie, excluding patients who have already had a recurrence). In this regard, the projected 5-year risk of recurrence is an absolute rate with regard to those remaining at risk at time t.
80 Control
60
N-
Tamoxifen
N+
40
Control
20
0
5
10
Years from Randomization Approximately 5 Years of Treatment 100
Discussion
Tamoxifen
% Recurrence Free
These results indicate that 5 years after primary treatment, women with ER-positive or ER-unknown early-stage breast cancer who received 5 years of tamoxifen have benefited more than women who received only 1 or 2 years of tamoxifen.1 Nevertheless, 5 years after initiating primary therapy, all women remain at a high risk of recurrence during the next 5 years (Table 2). However, these comparisons are indirect, as they are derived from meta-analytic data. Therefore, these conclusions should be interpreted with caution.
80 60 40
Control
N-
Tamoxifen
N+
Control
20
0
5
10
Years from Randomization
NSABP Trial To put the ongoing risk of recurrence in perspective, we compared the data shown in Tables 1 and 2 with the levels of risk encountered in the Breast Cancer Prevention Trial (P-1) conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP).4 In the NSABP P-1 trial, women were eligible for entry if their 5-year absolute risk of developing breast cancer was ≥ 1.66%.4,5 Although women with a history of breast cancer were excluded from this trial, the data in Table 2 clearly indicate that the projected 5-year risk of recurrence among all patients included in the table would have been sufficient to make them eligible for the NSABP P-1.
Abbreviation: N = axillary node Reproduced with permission from: Early Breast Cancer Trialists’ Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351:1451-1467.
Not shown in the tables is the observation that differences in recurrence rates were associated with differences in mortality rates in the EBCTCG meta-analysis.1 Thus, among node-positive patients who received 5 years of tamoxifen, 80.1% were still alive 5 years after initiating primary treatment. In contrast, among those who received 1 year of tamoxifen, only 68.3% were alive at the same time point.
Clinical Breast Cancer January 2002 • 283
Reinitiation of Adjuvant Tamoxifen Therapy Table 1 Percentage of Recurrence-Free Patients Average Duration of Therapy (Years)
Nodal Status
1
Negative
1
2
2
About 5
About 5
Positive
Negative
Positive
Negative
Positive
Years Since Randomization Treatment (N) 1
2
3
4
5
6
7
8
9
Tamoxifen (1079)
97.4
93.5
89.4
85.6
82.7
79.6
77.8
76.7
75.9
Control
96.3
92.2
86.4
83.9
79.9
76.8
74.4
72.9
71.2
Tamoxifen (2685)
92.0
80.3
71.3
63.7
58.3
54.1
50.8
47.8
45.4
Control
88.6
74.3
63.7
56.1
50.2
46.1
43.0
40.4
37.9
Tamoxifen (3131)
98.3
95.0
92.1
89.48
87.1
85.3
83.0
81.5
79.7
Control
97.1
91.9
87.6
3.9
81.4
79.0
77.3
76.2
74.6
Tamoxifen (4180)
92.1
83.3
76.5
69.05
63.5
59.6
56.5
54.1
51.1
Control
88.0
73.3
62.6
6.1
51.4
47.4
45.3
42.7
40.7
Tamoxifen (2611)
98.0
95.0
92.1
89.4
87.4
85.5
84.0
82.3
80.5
Control
95.2
87.9
82.2
78.2
74.9
71.9
69.3
67.4
65.6
Tamoxifen (1127)
95.1
88.9
83.9
79.3
75.6
73.1
69.3
65.4
61.6
Control
90.4
76.8
69.4
63.1
58.3
54.9
52.6
49.2
46.6
These trends were statistically significant as reported in the metaanalysis. An important clinical issue related to these results involves patients who did not receive any adjuvant tamoxifen but have been disease free for some time after a diagnosis of ER-positive/unknown breast cancer. Are such patients likely to still benefit from tamoxifen therapy? These patients remain at risk for recurrence for more than 15 years after their initial diagnosis (Tables 1 and 2).1,6 Furthermore, all women with a history of breast cancer are at elevated risk for new cancers in the same or contralateral breast. The annual risk for contralateral breast cancer in women with a history of the disease is between 0.5% and 1% during each year of follow-up.7 Without tamoxifen treatment, more than 20% of women with node-negative early-stage breast cancer and about 50% with node-positive disease will experience a recurrence within 5 years of primary therapy (Table 1).1 Limited clinical trial data are available to guide decisions on whether these patients are likely to benefit from delayed tamoxifen therapy. In a multi-institutional study conducted in France, 494 women with a history of breast cancer were enrolled to evaluate the benefit of delayed tamoxifen therapy.8,9 To be eligible, a woman had to have been diagnosed with breast cancer at least 2 years before the study and had to have received local treatment (surgery and/or radiation therapy) with or without adjuvant chemotherapy. Systemic hormonal therapy was not allowed. Patients were randomized to receive tamoxifen 30 mg/day for 5 years or no treatment. At 5 years of follow-up, the women receiving delayed tamoxifen had significantly better disease-free survival (reduction in risk of reccurence 35%; P = 0.05) compared to those who did not receive tamoxifen, although there was no significant difference in survival. Among patients with ER-positive dis-
284 • Clinical Breast Cancer January 2002
ease, delayed tamoxifen treatment was associated with a significant reduction in the odds of death (P = 0.04) and recurrence (P = 0.03). Although the data are sparse, they do support the use of tamoxifen for reducing recurrence in women who did not receive the drug as adjuvant therapy, but who are still at risk for recurrence, particularly if their original breast cancer was ER positive. Results from the Wisconsin Tamoxifen Study also support these conclusions.10 This placebo-controlled randomized trial included women who were diagnosed with node-negative invasive breast cancer 10 years prior to the study. Women were randomized to receive tamoxifen 20 mg/day or placebo. The two randomized groups, each containing 70 women, had comparable demographics including a mean of 7-8 years from the diagnosis of breast cancer. After 5 years, and again after 10 years, all participating women known to be alive were recontacted. At last follow-up, there were 3 deaths in the tamoxifen group (1 death was related to breast cancer), and 11 deaths in the placebo group (4 deaths were related to breast cancer).
Duration of Adjuvant Tamoxifen Beyond 5 Years Another issue involves women who received 5 years of tamoxifen as adjuvant therapy. The clear relationship between the magnitude of risk reduction and the duration of adjuvant tamoxifen therapy raises the issue of whether durations of therapy beyond 5 years provide additional risk reduction. In the NSABP B-14 trial, node-negative patients who received 5 years of tamoxifen were rerandomized to 5 additional years of tamoxifen or no additional therapy.11 There was a statistically significant higher recurrence rate and a trend towards more deaths in patients receiving 10 years of tamoxifen compared to 5 years of treatment. However, there are some data
William J. Gradishar and Richard Hellmund Table 2 Projected 5-Year Risk of Recurrence (%) Years of Therapy
Nodal Status
1
Negative
1
Positive
2
Negative
2
Positive
5
Negative
5
Positive
Years Since Beginning Tamoxifen
Treatment 1
2
3
4
5
Tamoxifen
18.3
16.8
14.2
11.3
10.2
Control
20.2
19.3
16.0
15.1
12.9
Tamoxifen
41.2
36.7
33.0
28.7
24.2
Control
48.0
42.1
36.6
32.4
26.9
Tamoxifen
13.2
12.6
11.5
10.9
10.2
Control
18.6
15.9
13.0
11.1
10.8
Tamoxifen
35.3
32.2
29.3
25.9
22.0
Control
46.1
38.2
31.8
27.5
23.2
Tamoxifen
12.8
11.6
10.6
10.0
9.4
Control
24.5
21.2
18.0
16.1
14.2
Tamoxifen
23.1
22.0
22.1
22.3
21.0
Control
39.3
31.5
29.1
26.1
23.7
that suggest that longer durations of therapy may still be of benefit, particularly for certain populations of women, such as those who were node positive.12 The results of ongoing trials such as the Adjuvant Tamoxifen-Longer Against Shorter (ATLAS) trial and the Adjuvant Tamoxifen Treatment-Offer More? (ATTOM) trial will help to resolve these issues.13,14 Nevertheless, the most recent overview analysis from the EBCTCG has established that 5 years of adjuvant tamoxifen therapy is superior to 2 years for women with ERpositive disease.1 These results are in concordance with those of individual trials.15 Even after 10 years of follow-up, women who received 5 years of adjuvant tamoxifen experienced lower rates of recurrence and increased survival compared to their peers who received 1 or 2 years of therapy.1
Reinitiation of Adjuvant Tamoxifen In the middle of the spectrum are women who received only 1-2 years of tamoxifen as adjuvant therapy for ER-positive/unknown disease, who are no longer taking tamoxifen, and have not experienced a recurrence. There are no randomized data to answer the question of whether these women are likely to benefit from reinitiation of tamoxifen. The evidence available, although indirect, suggests that such women may benefit from the reinitiation of tamoxifen to complete a 5-year course. Future studies that examine the biologic characteristics of recurrences (eg, ER status) may add further support to this strategy. There are several factors that temper the conclusions from our calculations. First, it is unknown whether tamoxifen is as effective when reinitiated in women who received 1-2 years of the drug in the past. However, it is clear that breast cancer patients with ER-positive tumors continue to benefit from tamoxifen beyond 2 years.1 Thus, it is likely
that reinitiating tamoxifen will benefit those women who received it for only 1-2 years. Because it is unlikely that a largescale trial will be initiated to address this issue, we have approached the question indirectly.
Risk and Benefits of Adjuvant Tamoxifen The data presented and the hypothesis generated clearly apply to the minority of patients treated with tamoxifen. Our ability to calculate exactly how many patients may be affected is limited. Most patients treated in recent years have received 5 years of tamoxifen therapy, except perhaps for a brief time around 1996-1997 when concern was raised about the risk of developing endometrial carcinoma secondary to tamoxifen use, and patients may have decided to discontinue therapy short of 5 years. The clinical trials that examined shorter durations of tamoxifen therapy compared to 5 years of therapy are clearly older. Comparing cohorts of patients from one era to another may be inappropriate. Short of actually conducting a clinical trial to examine these issues, a precise estimate of risk reduction with reinitiation of tamoxifen therapy to complete 5 years of treatment would be impossible. The data we have presented suggest that it may be appropriate to consider reinitiating tamoxifen in women who had ER-positive disease but did not receive 5 years of adjuvant tamoxifen therapy. Clearly, the physician and patient need to discuss issues such as side effects and patient preference before reaching a decision. If the patient discontinued adjuvant tamoxifen because of vasomotor side effects (such as hot flashes or irregular menses), she may find it reassuring that many of the vasomotor side effects of tamoxifen are reported more frequently in perimenopausal women.16 Thus, such side effects may be less severe if more time has passed
Clinical Breast Cancer January 2002 • 285
Reinitiation of Adjuvant Tamoxifen Therapy since the patient’s last menses. Many women may have discontinued therapy in the past because of fears regarding endometrial cancer. The many studies reported recently, particularly NSABP P-1, have provided reliable estimates of the risk of endometrial cancer in women on tamoxifen.4 For example, NSABP P-1 reported 2.30 cases of endometrial cancer per 1000 women per year on tamoxifen compared to 0.91 per 1000 women per year on placebo. The risk of endometrial cancer associated with tamoxifen is age dependent; nearly all the increase in risk reported in NSABP P-1 was found in women older than 50 years. Furthermore, Bernstein and colleagues demonstrated that women at the highest risk of developing uterine cancer are those who are overweight or have a history of using unopposed estrogen.17 Women of normal body weight who had never used unopposed estrogen had a nonstatistically significant increase in the incidence of uterine cancer while on tamoxifen. Furthermore, the EBCTCG reported that the reduction in incidence of contralateral breast cancer associated with tamoxifen was about twice as large as the increased incidence of endometrial cancer, and endometrial cancer was the more curable of the two diseases.4 Other risks of tamoxifen that should be considered include thromboembolic disease (especially pulmonary embolism and deep venous thrombosis).4 A woman with a history of thromboembolism should be aware of the increased risk associated with tamoxifen. Indeed, such women were excluded from NSABP P-1 The question of how long a woman should receive tamoxifen is still being addressed by randomized trials.13 Similarly, for a woman reinitiating therapy, the optimal duration of therapy is not known. A reasonable approach may be for her to complete a total of 5 years of tamoxifen therapy. A challenge for the future is what to do at 5 years if tamoxifen is not continued. Agents such as the selective aromatase inhibitors and the ER downregulators18 deserve consideration and adjuvant clinical trials are being developed to assess them.
Conclusion Data from the EBCTCG worldwide overview published in 1998 were used to compare projected recurrence rates for women who received different durations of adjuvant tamoxifen for ER-positive breast cancer. Our analysis suggests that women who received only 1-2 years of adjuvant tamoxifen may benefit from reinitiating therapy. Furthermore, women
286 • Clinical Breast Cancer January 2002
who received 5 years of tamoxifen are still at high risk of recurrence. New trials may be necessary to determine the optimal treatment strategy for these women.
References 01. Early Breast Cancer Trialists’ Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351:1451-1467. 02. Early Breast Cancer Trialists’ Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med 1988; 319:16811692. 03. Early Breast Cancer Trialists’ Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992; 339:71-85. 04. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90:1371-1388. 05. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989; 81:1879-1886. 06. Karrison TG, Ferguson DJ, Meier P. Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 1999; 91:80-85. 07. Rosen PP, Groshen S, Kinne DW, et al. Contralateral breast carcinoma: an assessment of risk and prognosis in stage I (T1N0M0) and stage II (T1N1M0) patients with 20-year follow-up. Surgery 1989; 106:904-910. 08. Delozier T, Switsers O, Genot JY, et al. [Tamoxifen adjuvant delays early breast cancer. Results of a cooperative randomized trial]. Bull Cancer 1997; 84:25-30. 09. Delozier T, Switsers O, Genot JY, et al. Delayed adjuvant tamoxifen: tenyear results of a collaborative randomized controlled trial in early breast cancer (TAM-02 trial). Ann Oncol 2000; 11:515-519. 10. Love RR, Olsen MR, Havighurst TC. Delayed adjuvant tamoxifen in postmenopausal women with axillary node-negative breast cancer: mortality over 10 years. J Natl Cancer Inst 1999; 91:1167-1168. 11. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996; 88:1529-1542. 12. Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 1996; 88:1828-1833. 13. Baum M. Tamoxifen--the treatment of choice. Why look for alternatives? Br J Cancer 1998; 78 (suppl 4):1-4. 14. Peto R. Five years of tamoxifen--or more? J Natl Cancer Inst 1996; 88: 1791-1793. 15. Nordenskjold B, Carstensen J, Rutqvist L, et al. Prolonged follow-up of the Swedish Randomized Trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer and relationships to hormone receptor and ERBB2 levels. Proc Am Soc Clin Oncol 2000; 19:72a (Abstract #276). 16. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998; 339:1609-1618. 17. Bernstein L, Deapen D, Cerhan JR, et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999; 91:16541662. 18. Howell A, DeFriend DJ, Robertson JF, et al. Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer. Br J Cancer 1996; 74:300-308.
review
A Rationale for the Reinitiation of Adjuvant Tamoxifen Therapy in Women Receiving Fewer than 5 Years of Therapy William J. Gradishar1 and Richard Hellmund2 Abstract The overview analysis of adjuvant therapy trials in early-stage breast cancer by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) compared 1, 2, and 5 years of adjuvant therapy. The optimal benefit to patients in terms of reduced risk of recurrence and death was clearly conferred by 5 years of therapy with tamoxifen compared to shorter durations of therapy. Many women with early-stage breast cancer treated in the past received a recommendation for shorter durations of tamoxifen therapy. The obvious question is whether reinitiating tamoxifen to complete a full 5-year course would further reduce the risk of recurrence and death. In an attempt to explore this issue, we have analyzed recurrence rates in women who received different durations of tamoxifen therapy in the adjuvant setting. The data used for this analysis are directly from the EBCTCG. Our analysis suggests that women who received 1-2 years of adjuvant tamoxifen therapy may benefit from reinitiation of tamoxifen to complete a 5-year course. Clinical Breast Cancer, Vol. 2, No. 4, 282-286, 2002 Key words: Tamoxifen, Adjuvant duration, Reinitiation
Introduction The most recent overview analysis of adjuvant therapy trials in early-stage breast cancer by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) compared 1, 2, and 5 years of adjuvant tamoxifen therapy.1 The optimal benefit to patients, in terms of reduced risk of recurrence and death, was clearly conferred by 5 years of therapy with tamoxifen. Until relatively recently the optimal duration of tamoxifen therapy was not established, and as a result, many patients received durations of adjuvant tamoxifen therapy less than 5 years, including those who did not receive any tamoxifen.2,3 Although the overview analysis confirms that patients who received less than 5 years of tamoxifen are at an increased risk of recurrence and death compared to patients who received 5 years of treatment, it is unclear whether the magnitude of their increased risk justifies retreatment with
1Division
of Hematology/Oncology, Department of Medicine, Northwestern University Medical School and The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 2Biometry Section, AstraZeneca, LP, Wilmington, DE Submitted: April 10, 2001; Revised: Sept. 20, 2001; Accepted: Nov. 2, 2001 Address for correspondence: William J. Gradishar, MD, Division of Hematology and Medical Oncology, Department of Medicine, Northwestern University Medical School, 676 North St. Clair Street, Suite 850, Chicago, IL 60611-2927 Fax: 312-695-6189; e-mail: [email protected]
282 • Clinical Breast Cancer January 2002
tamoxifen to complete a full 5 years of therapy. From a pragmatic standpoint, future clinical trials are unlikely to be designed to address this question. In an attempt to explore this issue, we have analyzed recurrence rates in women who received different durations of tamoxifen therapy in the adjuvant setting. The data used for this analysis are from the EBCTCG.1
Methods Originating directly from the EBCTCG overview of randomized trials, Figure 1 shows the absolute risk reduction for recurrence among patients not receiving tamoxifen compared to those receiving 1, 2, or approximately 5 years of tamoxifen. The data are separated on the basis of nodal involvement (estrogen receptor (ER)-negative patients excluded).1 For our purposes, the EBCTCG secretariat kindly provided us with the recurrence and mortality rates used to generate the figures. Table 1 shows the percentage of patients free of recurrence in the control group or at different times after initiation of tamoxifen therapy. We calculated the percentage of patients experiencing a recurrence during various periods after initiating tamoxifen therapy (all units of time are in years). If n • t is the percentage of patients free of recurrence at time t (years), then the absolute percentage who experienced a recurrence in the next 5 years (between times t and t + 5) is [(n • t) - n(t + 5)]. The relative percentage experiencing a recurrence in this
To examine the effect of tamoxifen therapy at different times after primary tamoxifen, we sought to compare projected 5-year risk of recurrence for patients at different stages of treatment. These data are shown in Table 2. As an example, consider patients with node-positive disease who received 1 year of tamoxifen therapy and are now at a point 5 years since initiating tamoxifen treatment: 58.3% of such patients have not experienced a recurrence (Table 1). Thus, only 58.3% of the original cohort are at risk for recurrence during the next 5 years (years 5-10 after primary treatment). Following through with this example, the projected 5-year risk of recurrence among node-positive patients who received 1 year of tamoxifen is 24.2% (Table 2). Note that among women in the control group, the projected 5-year risk of recurrence is 26.9%. In contrast, 75.6% of patients with node-positive disease who received 5 full years of tamoxifen did not experience a recurrence 5 years after initiating tamoxifen therapy (Table 1). The projected 5-year risk of recurrence (years 5-10) for this group of patients is 21.0% (Table 2). Among the node-positive patients in the control group, the projected 5-year risk of recurrence is 23.7% (Table 2).
1 Year of Treatment 100 % Recurrence Free
Results
Figure 1 Absolute Risk Reduction for Recurrence Among Patients Not Receiving Tamoxifen Compared to Those Receiving 1, 2, or 5 Years of Tamoxifen
Tamoxifen
80
Control
60
N-
Tamoxifen
40
Control
N+
20
0
5
10
Years from Randomization 2 Years of Treatment 100 Tamoxifen
% Recurrence Free
time period is {[(n • t) - n(t + 5)] / (n • t)} • 100. We have defined this term as the projected 5-year risk of recurrence. This calculation is analogous to calculating the 5-year recurrence rate starting at different times after initiating therapy and including only those still at risk (ie, excluding patients who have already had a recurrence). In this regard, the projected 5-year risk of recurrence is an absolute rate with regard to those remaining at risk at time t.
80 Control
60
N-
Tamoxifen
N+
40
Control
20
0
5
10
Years from Randomization Approximately 5 Years of Treatment 100
Discussion
Tamoxifen
% Recurrence Free
These results indicate that 5 years after primary treatment, women with ER-positive or ER-unknown early-stage breast cancer who received 5 years of tamoxifen have benefited more than women who received only 1 or 2 years of tamoxifen.1 Nevertheless, 5 years after initiating primary therapy, all women remain at a high risk of recurrence during the next 5 years (Table 2). However, these comparisons are indirect, as they are derived from meta-analytic data. Therefore, these conclusions should be interpreted with caution.
80 60 40
Control
N-
Tamoxifen
N+
Control
20
0
5
10
Years from Randomization
NSABP Trial To put the ongoing risk of recurrence in perspective, we compared the data shown in Tables 1 and 2 with the levels of risk encountered in the Breast Cancer Prevention Trial (P-1) conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP).4 In the NSABP P-1 trial, women were eligible for entry if their 5-year absolute risk of developing breast cancer was ≥ 1.66%.4,5 Although women with a history of breast cancer were excluded from this trial, the data in Table 2 clearly indicate that the projected 5-year risk of recurrence among all patients included in the table would have been sufficient to make them eligible for the NSABP P-1.
Abbreviation: N = axillary node Reproduced with permission from: Early Breast Cancer Trialists’ Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351:1451-1467.
Not shown in the tables is the observation that differences in recurrence rates were associated with differences in mortality rates in the EBCTCG meta-analysis.1 Thus, among node-positive patients who received 5 years of tamoxifen, 80.1% were still alive 5 years after initiating primary treatment. In contrast, among those who received 1 year of tamoxifen, only 68.3% were alive at the same time point.
Clinical Breast Cancer January 2002 • 283
Reinitiation of Adjuvant Tamoxifen Therapy Table 1 Percentage of Recurrence-Free Patients Average Duration of Therapy (Years)
Nodal Status
1
Negative
1
2
2
About 5
About 5
Positive
Negative
Positive
Negative
Positive
Years Since Randomization Treatment (N) 1
2
3
4
5
6
7
8
9
Tamoxifen (1079)
97.4
93.5
89.4
85.6
82.7
79.6
77.8
76.7
75.9
Control
96.3
92.2
86.4
83.9
79.9
76.8
74.4
72.9
71.2
Tamoxifen (2685)
92.0
80.3
71.3
63.7
58.3
54.1
50.8
47.8
45.4
Control
88.6
74.3
63.7
56.1
50.2
46.1
43.0
40.4
37.9
Tamoxifen (3131)
98.3
95.0
92.1
89.48
87.1
85.3
83.0
81.5
79.7
Control
97.1
91.9
87.6
3.9
81.4
79.0
77.3
76.2
74.6
Tamoxifen (4180)
92.1
83.3
76.5
69.05
63.5
59.6
56.5
54.1
51.1
Control
88.0
73.3
62.6
6.1
51.4
47.4
45.3
42.7
40.7
Tamoxifen (2611)
98.0
95.0
92.1
89.4
87.4
85.5
84.0
82.3
80.5
Control
95.2
87.9
82.2
78.2
74.9
71.9
69.3
67.4
65.6
Tamoxifen (1127)
95.1
88.9
83.9
79.3
75.6
73.1
69.3
65.4
61.6
Control
90.4
76.8
69.4
63.1
58.3
54.9
52.6
49.2
46.6
These trends were statistically significant as reported in the metaanalysis. An important clinical issue related to these results involves patients who did not receive any adjuvant tamoxifen but have been disease free for some time after a diagnosis of ER-positive/unknown breast cancer. Are such patients likely to still benefit from tamoxifen therapy? These patients remain at risk for recurrence for more than 15 years after their initial diagnosis (Tables 1 and 2).1,6 Furthermore, all women with a history of breast cancer are at elevated risk for new cancers in the same or contralateral breast. The annual risk for contralateral breast cancer in women with a history of the disease is between 0.5% and 1% during each year of follow-up.7 Without tamoxifen treatment, more than 20% of women with node-negative early-stage breast cancer and about 50% with node-positive disease will experience a recurrence within 5 years of primary therapy (Table 1).1 Limited clinical trial data are available to guide decisions on whether these patients are likely to benefit from delayed tamoxifen therapy. In a multi-institutional study conducted in France, 494 women with a history of breast cancer were enrolled to evaluate the benefit of delayed tamoxifen therapy.8,9 To be eligible, a woman had to have been diagnosed with breast cancer at least 2 years before the study and had to have received local treatment (surgery and/or radiation therapy) with or without adjuvant chemotherapy. Systemic hormonal therapy was not allowed. Patients were randomized to receive tamoxifen 30 mg/day for 5 years or no treatment. At 5 years of follow-up, the women receiving delayed tamoxifen had significantly better disease-free survival (reduction in risk of reccurence 35%; P = 0.05) compared to those who did not receive tamoxifen, although there was no significant difference in survival. Among patients with ER-positive dis-
284 • Clinical Breast Cancer January 2002
ease, delayed tamoxifen treatment was associated with a significant reduction in the odds of death (P = 0.04) and recurrence (P = 0.03). Although the data are sparse, they do support the use of tamoxifen for reducing recurrence in women who did not receive the drug as adjuvant therapy, but who are still at risk for recurrence, particularly if their original breast cancer was ER positive. Results from the Wisconsin Tamoxifen Study also support these conclusions.10 This placebo-controlled randomized trial included women who were diagnosed with node-negative invasive breast cancer 10 years prior to the study. Women were randomized to receive tamoxifen 20 mg/day or placebo. The two randomized groups, each containing 70 women, had comparable demographics including a mean of 7-8 years from the diagnosis of breast cancer. After 5 years, and again after 10 years, all participating women known to be alive were recontacted. At last follow-up, there were 3 deaths in the tamoxifen group (1 death was related to breast cancer), and 11 deaths in the placebo group (4 deaths were related to breast cancer).
Duration of Adjuvant Tamoxifen Beyond 5 Years Another issue involves women who received 5 years of tamoxifen as adjuvant therapy. The clear relationship between the magnitude of risk reduction and the duration of adjuvant tamoxifen therapy raises the issue of whether durations of therapy beyond 5 years provide additional risk reduction. In the NSABP B-14 trial, node-negative patients who received 5 years of tamoxifen were rerandomized to 5 additional years of tamoxifen or no additional therapy.11 There was a statistically significant higher recurrence rate and a trend towards more deaths in patients receiving 10 years of tamoxifen compared to 5 years of treatment. However, there are some data
William J. Gradishar and Richard Hellmund Table 2 Projected 5-Year Risk of Recurrence (%) Years of Therapy
Nodal Status
1
Negative
1
Positive
2
Negative
2
Positive
5
Negative
5
Positive
Years Since Beginning Tamoxifen
Treatment 1
2
3
4
5
Tamoxifen
18.3
16.8
14.2
11.3
10.2
Control
20.2
19.3
16.0
15.1
12.9
Tamoxifen
41.2
36.7
33.0
28.7
24.2
Control
48.0
42.1
36.6
32.4
26.9
Tamoxifen
13.2
12.6
11.5
10.9
10.2
Control
18.6
15.9
13.0
11.1
10.8
Tamoxifen
35.3
32.2
29.3
25.9
22.0
Control
46.1
38.2
31.8
27.5
23.2
Tamoxifen
12.8
11.6
10.6
10.0
9.4
Control
24.5
21.2
18.0
16.1
14.2
Tamoxifen
23.1
22.0
22.1
22.3
21.0
Control
39.3
31.5
29.1
26.1
23.7
that suggest that longer durations of therapy may still be of benefit, particularly for certain populations of women, such as those who were node positive.12 The results of ongoing trials such as the Adjuvant Tamoxifen-Longer Against Shorter (ATLAS) trial and the Adjuvant Tamoxifen Treatment-Offer More? (ATTOM) trial will help to resolve these issues.13,14 Nevertheless, the most recent overview analysis from the EBCTCG has established that 5 years of adjuvant tamoxifen therapy is superior to 2 years for women with ERpositive disease.1 These results are in concordance with those of individual trials.15 Even after 10 years of follow-up, women who received 5 years of adjuvant tamoxifen experienced lower rates of recurrence and increased survival compared to their peers who received 1 or 2 years of therapy.1
Reinitiation of Adjuvant Tamoxifen In the middle of the spectrum are women who received only 1-2 years of tamoxifen as adjuvant therapy for ER-positive/unknown disease, who are no longer taking tamoxifen, and have not experienced a recurrence. There are no randomized data to answer the question of whether these women are likely to benefit from reinitiation of tamoxifen. The evidence available, although indirect, suggests that such women may benefit from the reinitiation of tamoxifen to complete a 5-year course. Future studies that examine the biologic characteristics of recurrences (eg, ER status) may add further support to this strategy. There are several factors that temper the conclusions from our calculations. First, it is unknown whether tamoxifen is as effective when reinitiated in women who received 1-2 years of the drug in the past. However, it is clear that breast cancer patients with ER-positive tumors continue to benefit from tamoxifen beyond 2 years.1 Thus, it is likely
that reinitiating tamoxifen will benefit those women who received it for only 1-2 years. Because it is unlikely that a largescale trial will be initiated to address this issue, we have approached the question indirectly.
Risk and Benefits of Adjuvant Tamoxifen The data presented and the hypothesis generated clearly apply to the minority of patients treated with tamoxifen. Our ability to calculate exactly how many patients may be affected is limited. Most patients treated in recent years have received 5 years of tamoxifen therapy, except perhaps for a brief time around 1996-1997 when concern was raised about the risk of developing endometrial carcinoma secondary to tamoxifen use, and patients may have decided to discontinue therapy short of 5 years. The clinical trials that examined shorter durations of tamoxifen therapy compared to 5 years of therapy are clearly older. Comparing cohorts of patients from one era to another may be inappropriate. Short of actually conducting a clinical trial to examine these issues, a precise estimate of risk reduction with reinitiation of tamoxifen therapy to complete 5 years of treatment would be impossible. The data we have presented suggest that it may be appropriate to consider reinitiating tamoxifen in women who had ER-positive disease but did not receive 5 years of adjuvant tamoxifen therapy. Clearly, the physician and patient need to discuss issues such as side effects and patient preference before reaching a decision. If the patient discontinued adjuvant tamoxifen because of vasomotor side effects (such as hot flashes or irregular menses), she may find it reassuring that many of the vasomotor side effects of tamoxifen are reported more frequently in perimenopausal women.16 Thus, such side effects may be less severe if more time has passed
Clinical Breast Cancer January 2002 • 285
Reinitiation of Adjuvant Tamoxifen Therapy since the patient’s last menses. Many women may have discontinued therapy in the past because of fears regarding endometrial cancer. The many studies reported recently, particularly NSABP P-1, have provided reliable estimates of the risk of endometrial cancer in women on tamoxifen.4 For example, NSABP P-1 reported 2.30 cases of endometrial cancer per 1000 women per year on tamoxifen compared to 0.91 per 1000 women per year on placebo. The risk of endometrial cancer associated with tamoxifen is age dependent; nearly all the increase in risk reported in NSABP P-1 was found in women older than 50 years. Furthermore, Bernstein and colleagues demonstrated that women at the highest risk of developing uterine cancer are those who are overweight or have a history of using unopposed estrogen.17 Women of normal body weight who had never used unopposed estrogen had a nonstatistically significant increase in the incidence of uterine cancer while on tamoxifen. Furthermore, the EBCTCG reported that the reduction in incidence of contralateral breast cancer associated with tamoxifen was about twice as large as the increased incidence of endometrial cancer, and endometrial cancer was the more curable of the two diseases.4 Other risks of tamoxifen that should be considered include thromboembolic disease (especially pulmonary embolism and deep venous thrombosis).4 A woman with a history of thromboembolism should be aware of the increased risk associated with tamoxifen. Indeed, such women were excluded from NSABP P-1 The question of how long a woman should receive tamoxifen is still being addressed by randomized trials.13 Similarly, for a woman reinitiating therapy, the optimal duration of therapy is not known. A reasonable approach may be for her to complete a total of 5 years of tamoxifen therapy. A challenge for the future is what to do at 5 years if tamoxifen is not continued. Agents such as the selective aromatase inhibitors and the ER downregulators18 deserve consideration and adjuvant clinical trials are being developed to assess them.
Conclusion Data from the EBCTCG worldwide overview published in 1998 were used to compare projected recurrence rates for women who received different durations of adjuvant tamoxifen for ER-positive breast cancer. Our analysis suggests that women who received only 1-2 years of adjuvant tamoxifen may benefit from reinitiating therapy. Furthermore, women
286 • Clinical Breast Cancer January 2002
who received 5 years of tamoxifen are still at high risk of recurrence. New trials may be necessary to determine the optimal treatment strategy for these women.
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