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© 2003 American Society for Clinical Oncology Radiation Therapy Plus Tamoxifen Versus Tamoxifen Alone After Breast-Conserving Surgery in Postmenopausal Women With Stage I Breast Cancer: A Decision Analysis
From the Joint Center for Radiation Therapy, Harvard Medical School; Department of Health Policy and Management, Harvard School of Public Health; Department of Radiation Oncology, Brigham and Women’s Hospital; and Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA. Address reprint requests to Rinaa S. Punglia, MD, MPH, Brigham and Women’s Hospital, Department of Radiation Oncology, 75 Francis St, L2, Boston, MA 02115; email: rpunglia{at}lroc.harvard.edu.
Purpose: To compare outcomes for hypothetical cohorts of postmenopausal patients with estrogen receptor–positive tumors that are ≤ 2 cm in size, with pathologically uninvolved axillary nodes, treated with radiation therapy plus tamoxifen versus tamoxifen alone after breast-conserving surgery. Methods: A Markov model was used to simulate patients’ clinical course and estimate overall survival, recurrence-free survival, time with an intact breast, and death from breast cancer. Probabilities were derived from randomized trials and retrospective studies. Analyses were performed separately by age of diagnosis in 5-year increments from 50 to 80 years. Sensitivity analyses tested the stability of radiation benefit. Results: The modeled recurrence-free survival benefit of giving radiation therapy was 3.35 years for women who were 50 years of age at diagnosis, versus 0.61 years for women who were 80 years of age. In the 50-year-old cohort, radiation therapy resulted in additional 0.60 years survival, compared with 0.04 years among 80-year-olds. A 50-year-old woman who received radiation therapy plus tamoxifen was less likely to die from breast cancer than if she received tamoxifen alone (2.43% v 5.29%; relative-risk reduction, 54%). An 80-year-old woman had a 1.17% chance of dying from breast cancer if she received radiation therapy plus tamoxifen, versus 2.02% with tamoxifen alone (relative-risk reduction, 42%). Sensitivity analyses showed that the magnitude of benefit was strongly influenced by including unequal rates of developing distant disease after breast recurrence between the treatment arms and varying rates of local recurrence. Conclusion: The absolute and relative benefits of radiation therapy and individual patient preferences for different health states should be considered when selecting treatment.
LARGE RANDOMIZED trials have shown that the addition of radiation therapy (RT) after breast-conserving surgery reduces local recurrence rates.1 Nevertheless, RT does have associated burdens, such as loss of time from work, transportation issues, the direct costs of treatment, and potential side effects.2 The question therefore arises of whether there exists a low-benefit group of patients for whom the absolute gains from RT are so small that they may not justify its potential morbidity. Older age,3–9 positive estrogen-receptor (ER) status,9,10 negative axillary nodal status,3,10,11 and small tumor size4–6,9,12 are prognostic factors for decreased locoregional recurrence in patients after breast-conserving surgery without RT. Moreover, tamoxifen can further decrease locoregional recurrence rates in patients with ER-positive tumors treated with breast-conserving surgery and RT.13–15 Thus, postmenopausal women diagnosed with ER-positive, invasive breast cancers that are ≤ 2 cm in size with pathologically negative nodes have been considered potential candidates for omission of RT after breast-conserving surgery when tamoxifen is given. Randomized trials have studied the need for RT in women receiving tamoxifen.16–19 Each of these trials had distinct enrollment criteria, but all included patients with either T1 or T2 tumors with clinically or pathologically negative axillary nodes. Follow-up time in these trials is limited. They have demonstrated substantial reductions in local recurrence rates with the addition of radiation therapy, but no significant differences in overall survival between the treatment arms.16–19 Because RT has become the standard of care for women treated with breast-conserving surgery,20 we studied the impact of omitting RT after breast-conserving surgery in patients who are at low risk for local recurrence using a decision-analytic model. Specifically, we sought to predict the long-term results of such an omission, using data from the reported randomized studies, and to determine which clinical factors might influence these results.
Decision Model We constructed a Markov model to simulate the clinical history of a hypothetical cohort of postmenopausal women with pathologically node-negative, ER-positive breast cancers ≤ 2 cm in size (pT1N0 by tumor-node-metastasis system), after conservative surgery. Age at diagnosis varied from 50 to 80 years and was examined at 5-year increments. This Markov simulation21 allows subjects to make transitions annually among health states of being well, having recurrent local disease, having undergone treatment for recurrent disease, having metastatic disease, death from breast cancer, and death from other cause (Fig 1  ). The model compared the average amount of time spent in various health states after treatment with tamoxifen alone versus after treatment with RT plus tamoxifen, in each age cohort, and was run until all subjects had died. Outcomes studied included life expectancy, time with an intact breast, recurrence-free survival, and death from breast cancer. The impact of adding RT was studied by adjusting the local recurrence risk relative to the arm without RT. The strength of the model was tested using one-way sensitivity analyses. The model was designed using DATA 3.5 (TreeAge Software, Williamstown, MA).
Assumptions All hypothetical subjects started the model in the well health state. Subjects were able to exit this state as a result of death from non–breast-cancer causes, the diagnosis of local recurrence, or the diagnosis of distant disease. In the baseline analysis, the probabilities of distant disease at the time of an ipsilateral breast tumor recurrence (IBTR) and subsequent to local recurrence were assumed to be the same in both arms, providing the maximum benefit from radiation therapy. Under this assumption, our analysis provides a worst-case scenario for the departure from standard treatment by omitting RT after breast-conserving surgery. The risks of local and distant recurrence were assumed to be constant for 10 years after initial diagnosis or after a local recurrence and were zero thereafter. In the RT plus tamoxifen arm, women were presumed to undergo mastectomy after the diagnosis of breast recurrence, as is standard practice.22 In the tamoxifen-alone arm, women could undergo either conservative surgery with RT or mastectomy after diagnosis of an IBTR.23 All patients, regardless of surgical treatment at diagnosis of local recurrence, were assumed to be at the same risk of developing distant disease. Patients who underwent conservative surgery and RT after recurrence in the tamoxifen-alone arm were also at risk for a subsequent, second breast recurrence. This risk was assigned the same value as that assumed for the RT plus tamoxifen arm for 10 years. For considerations of simplicity, the model did not consider the risks of contralateral breast cancer because this risk is essentially the same in both arms.24 Because the excess risk of contralateral breast tumors from RT is negligible for women older than 50 years,25–27 this potential effect was ignored. The model did not include the risk of developing an isolated axillary recurrence, as this risk is quite small for patients with pathologically uninvolved nodes after axillary dissection regardless of whether RT is given.28 Because tamoxifen was given to all patients, the small risk of life-threatening side effects from tamoxifen (endometrial cancer and thromboembolic disease) is the same for both arms and was not included in the model.13,24 Because the rate of secondary cancers from radiation is substantially less than 1% over a lifetime, carcinogenesis from radiation therapy was not included.29–33 Death from other causes was assumed not to be increased after radiation in the baseline analysis, based on published data.34–36 The prior two assumptions were tested with sensitivity analyses by varying the risk of non–breast-cancer death between the arms. Recurrence rates were assumed to be constant across the age cohorts studied,3 although some evidence suggests that local recurrence rates after breast-conserving surgery without radiation therapy decrease after age 65 to 70 years.37
Sources of Probabilities and Values Used in the Sensitivity Analyses
The probability of exiting the well health state from distant relapse was derived from the initial report of the randomized NSABP B-21 trial38 by averaging the rates of distant recurrence in the two arms (because the rate of distant disease after initial diagnosis was assumed to be the same in both the tamoxifen and RT plus tamoxifen treatment arms and independent of initial local treatment). Their initial abstract (average follow-up, 73 months) was used for this purpose, because the later publication did not separate out the rate of distant disease alone as a first event.19 This average (2.1 distant recurrences per 1,000 patient-years) was near the average of the initial distant recurrence rates of the Intergroup trial arms16 but lower than those reported in the Canadian trial17 (which included patients with tumors up to 5 cm). However, sensitivity analyses included the initial distant metastatic rates reported in the Canadian study. The baseline probability of local recurrence after tamoxifen alone was derived from the Canadian trial and the subset of women with ER-positive tumors in the NSABP B-21 study, both of which reported similar rates.17,19 The range of values used in the sensitivity analysis (double and half of the rate from the Canadian and NSABP trials) included the value reported in the Intergroup study.16 Likewise, the rate of IBTR after RT plus tamoxifen in the baseline analysis was similar to that reported in the Canadian study and the ER-positive tumors in the NSABP B-21 study.17,19 This rate was doubled and halved in the sensitivity analysis. The Intergroup trial has not yet reported any local recurrences in its RT plus tamoxifen arm.16 In the baseline analysis, adding RT was assumed to decrease the rate of local recurrence by 87.5% of the risk without RT, consistent with reported values from ER-positive tumors in the NSABP study.19 Sensitivity analyses included the 90% reduction in recurrence seen with adding RT in the Canadian study.17 The minimum relative risk reduction (75%) was determined from data using wide local excision (quadrantectomy).37 In the tamoxifen-alone arm, half of the patients with IBTR were assumed to undergo mastectomy, while the other half underwent conservative surgery and RT, based on data from salvage therapy used in the NSABP B-17 trial for patients with ductal carcinoma-in-situ.23 For the sensitivity analysis, the proportion of women in the tamoxifen-alone arm who underwent mastectomy at diagnosis of a breast tumor recurrence varied from 0.25 to 0.75. This range included the percentage of women who actually underwent mastectomy at diagnosis of an IBTR after treatment with surgery alone for invasive breast cancer in two other randomized trials.3,5 On the basis of data from our institution for women who experienced local recurrences after breast-conserving surgery and RT, we assumed that 7.2% of women were found to have distant disease during the year of diagnosis of IBTR.39 The 10-year risk of developing metastatic disease after the year of an IBTR diagnosis was 20%.39 Although these estimates derive from patient groups that included premenopausal women and those with stage II disease and may therefore be higher than those expected in our study population, they were used in the baseline analysis so that the maximum benefit from RT could be determined, as described above. For the sensitivity analysis, these values were halved and doubled. The age-dependent probability of death from causes other than breast cancer was based on 1998 United States life-tables. Women diagnosed with distant disease were assumed to die from breast cancer at an annual probability of 0.326, which was derived from 5-year survival data of postmenopausal women with metastatic disease in the Surveillance, Epidemiology and End Results database.40 The presence or absence of a survival benefit from RT depends on one’s view regarding how breast cancer spreads. We originally assumed identical distant recurrence rates after IBTR in the treatment arms (Halstedian hypothesis)41,42 to see the maximum possible benefit from RT. However, the competing Fisherian hypothesis41,42 states that IBTR is not itself a harbinger of distant disease, but only a sign of inadequate initial local treatment. Therefore, the annual rate of developing distant disease after an IBTR in the tamoxifen-alone arm was reduced to one half and one-eighth of the rate in the RT plus tamoxifen arm in the sensitivity analyses; the latter fully compensated for the eight-fold excess in local recurrence risk in the tamoxifen-alone arm versus the RT plus tamoxifen arm. The possibility that RT increases non–breast-cancer mortality was modeled by increasing the proportion of subjects dying from other causes to 1.015 and 1.03 times the rate in the tamoxifen-alone arm in the sensitivity analyses. This increase was also applied to those patients in the tamoxifen-alone arm who eventually underwent RT after local recurrence.
Modeled recurrence-free survival was greater in the RT plus tamoxifen arm (Table 2 ). However, the absolute difference between the arms decreased with increasing age at diagnosis. For example, for women who were 50 of age at diagnosis, expected recurrence-free survival was 30.38 years if treated with RT plus tamoxifen, which decreased to 27.03 without RT (net benefit, 3.35 years). However, for women who were 80 years of age at diagnosis, the expected recurrence-free survival increased by 0.61 years with the addition of RT.
Table 2  also shows the expected years with an intact breast. Again, increasing age decreased the benefits of RT. A woman who was 50 years of age at diagnosis could expect 30.46 years with an intact breast with RT plus tamoxifen. This time decreased to 28.74 years (difference, 1.72 years) with tamoxifen alone. In contrast, a woman who was 80 years of age at diagnosis could expect to gain 0.25 years with an intact breast by adding RT.
With respect to overall survival, a woman diagnosed at 50 years of age could expect 30.86 years of life if treated with RT plus tamoxifen (Table 2
Changing the ratio of distant disease after an IBTR in the tamoxifen-alone arm to one half and one-eighth the rate in the RT plus tamoxifen arm decreased the simulated survival benefit of adding RT from the 0.60 years seen in the baseline analysis to 0.26 years and zero years, respectively. However, adjusting this ratio did not affect recurrence-free survival benefits. Figure 2
Table 3 shows the percentage of women who were free of recurrence and the percentage who were alive at 10 years derived by the baseline model, which does include a survival benefit from radiation. The chance of dying from breast cancer is shown for each treatment group as a function of age at diagnosis (Fig 4). The chance of dying from breast cancer among women diagnosed at age 50 years was 2.4% if they were treated with RT plus tamoxifen versus 5.3% if treated with tamoxifen alone (relative risk reduction, 54%). Among women who were 80 years of age at diagnosis, the risk of dying from breast cancer was 1.2% if treated with RT plus tamoxifen and 2.0% if treated with tamoxifen alone (relative risk reduction, 42%).
Adding 1.5% and 3.0% excess non–breast-cancer mortality for patients who were 50 years of age at initial diagnosis who received RT decreased the modeled overall survival benefits from adding RT to 0.47 and 0.35 years, respectively. These additions, however, had little effect on recurrence-free survival benefits from RT, which dropped from 3.35 years in the baseline analysis to 3.21 and 3.08 years, respectively.
The results of the remaining sensitivity analyses are shown in Fig 5A
Figure 5B shows the results of the same sensitivity analysis with respect to overall life expectancy. The survival benefit from adding RT was not influenced by the proportion undergoing mastectomy at recurrence. Life expectancy benefit also did not change greatly with varying the rate of distant metastases after initial treatment, the proportion of women presenting with distant disease at time of local recurrence, or with changing the efficacy of RT (proportional reduction in the risk of local recurrence). However, the model was sensitive to varying the overall rates of local recurrence after initial treatment and distant disease after the year of IBTR diagnosis.
Our analysis demonstrated that absolute benefits of RT decrease with increasing age at diagnosis. The relative benefits of adding RT varied only slightly with age. Overall and recurrence-free survival benefits were sensitive to the absolute risk of local recurrence. Assuming excess non–breast-cancer deaths from radiation or unequal rates of distant recurrence after an IBTR between the treatment arms affected survival benefits, but not recurrence-free survival benefits. The value assigned to the risk of distant recurrence after an IBTR in each of the treatment arms and the subsequent effect of local recurrence on mortality reflect one of two views regarding how breast cancer spreads.41,42 The Halstedian theory assumes that breast cancer cells spread in an orderly fashion away from the primary and reach distant sites through fascial planes and lymph channels. This theory posits a window of opportunity during which adequate local treatment offers a patient a chance of cure. It also predicts that improved local control will likely have a substantial impact on the chance of cure. In contrast, the Fisherian theory rigidly divides breast cancers into two groups: those that have potential to spread distantly and those that do not. Those tumors with metastatic potential are thought to spread early in their evolution, before clinical detection occurs. Therefore, this theory predicts that locoregional control has no effect on developing distant disease. The spectrum hypothesis, a combination of these theories, states that for many cancers, there is a point where they may not have spread distantly. It is impossible to determine whether this point has been passed at diagnosis for an individual patient. Therefore, this theory predicts that failure to achieve local control initially allows some tumors to disseminate and reduces the chance of cure.41,42 Our baseline model had equal rates of distant recurrence after IBTR in the treatment arms and therefore followed the Halstedian theory. These results can therefore be viewed as the simulated estimate of average maximum benefit expected from RT. We intentionally chose this position to bias our results toward favoring the RT arm, because we wanted to ensure that RT after lumpectomy (the current standard of care) is omitted only when patients do not feel that the maximum possible benefit derived from RT justifies its potential morbidities and costs. Moreover, six randomized studies analyzing the effect of adding RT to breast-conserving surgery have shown decreased rates of distant disease with the addition of RT.5,10,11,43–48 Each of these studies also showed a trend toward increased overall survival rates in the RT arm, which reached statistical significance in only one of these studies because of the limited number of patients analyzed.42 Furthermore, the view to which one subscribes (Halstedian, Fisherian, or spectrum) does not influence the recurrence-free survival estimates. Gains in recurrence-free survival time, time with an intact breast, and overall survival need to be interpreted carefully, as they apply to the average time gained across a cohort, not for an individual patient. Instead, these figures should serve as the basis for assessing the tradeoffs between the burdens and potential benefits of RT for an individual patient. We have modeled the benefits of RT using different outcomes (recurrence-free survival time, time with an intact breast, the chance of dying from breast cancer, and overall survival time) so that the outcomes most important to an individual patient may be used in making her choice. For many women, the most appropriate outcome may be recurrence-free survival because of the negative impact of a local recurrence for them.49 One analysis of patient preferences revealed that 46% of patients were unwilling to forego RT, even in the face of no stated benefit.50 However, other patients may be more concerned about potential toxicity from RT and hence be less interested in having such treatment, even if it improves local control. Our model has several limitations. The probabilities of local failure are based on early clinical data from three recent trials, two of which have only been published in abstract form, and are projected to 10 years, so that results should be interpreted with caution.16,17,19 In addition, the probabilities of distant recurrence are derived from a retrospective experience in women whose clinical characteristics and systemic treatment may be dissimilar from those of women enrolled in prospective trials. As previously stated, a number of potential effects of RT (contralateral breast cancer, secondary malignancies, cardiac toxicity) and tamoxifen were ignored in the baseline model because of their modest anticipated impact on the results. Less well described is the impact of advanced age on the risk of local failure and the rate of distant dissemination. Our model held these probabilities constant across age cohorts, which may not be accurate. Moreover, these results apply to a theoretical population in which all women are given and are able to take tamoxifen for 5 years, which may not always be achieved in reality. Our study was designed to aid in individual decision making and does not address the population impact of adding or withholding RT from selected subsets of patients. In conclusion, our analysis shows that the absolute benefits of RT plus tamoxifen, compared with tamoxifen alone, decrease substantially with increasing patient age at diagnosis and vary with respect to outcome studied (recurrence-free survival time, time with an intact breast, and overall survival time). Therefore, the absolute and relative benefits of RT and individual patient preferences for different health states should be considered for each patient in helping her select among treatment options.
Supported in part by a fellowship from the Agency for Healthcare Research and Quality, Rockville, MD (32 HS00020-16). Presented in part at the Thirty-Eighth Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18–22, 2002, and at the Forty-Fourth Annual Meeting of the American Society for Therapeutic Radiology and Oncology, New Orleans, LA, October 6–10, 2002.
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49. Hayman JA, Fairclough DL, Harris JR, et al: Patient preferences concerning the trade-off between the risks and benefits of routine radiation therapy after conservative surgery for early-stage breast cancer. J Clin Oncol 15:1252–1260, 1997 50. Palda VA, Llewellyn-Thomas HA, Mackenzie RG, et al: Breast cancer patients’ attitudes about rationing postlumpectomy radiation therapy: Applicability of trade-off methods to policy-making. J Clin Oncol 15:3192–3200, 1997[Abstract] Submitted July 12, 2002; accepted March 26, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
