Randomized controlled trials have had an important impact on the treatment of women with early breast cancer. Many women routinely receive breast-conserving surgery plus radiation therapy, adjuvant chemotherapy, or hormonal therapy based on the results of randomized trials. However, despite the extensive use tamoxifen and neutropenia combinations of chemotherapy, hormonal therapy, and radiation therapy, the optimal sequencing of these different adjuvant treatments for patients with early breast cancer remains unclear.
Unfortunately, there have been few randomized trials addressing this important issue. In a randomized trial by Recht et al, tamoxifen and neutropenia, 1 the optimal sequencing of radiation and chemotherapy in patients treated with breast-conserving surgery was evaluated.
Of patients, were allocated to receive radiation therapy before anthracycline-based chemotherapy and were allocated to receive radiation therapy after the same chemotherapy. The tamoxifen and neutropenia length of follow-up was 58 months, tamoxifen and neutropenia. As a result, breast irradiation is now usually given after anthracycline-based chemotherapy, tamoxifen and neutropenia. Preclinical data had demonstrated that human breast tumor cells in culture pretreated with tamoxifen were protected from the cytotoxicity of chemotherapy, tamoxifen and neutropenia.
Furthermore, it had already been observed that combined chemotherapy and tamoxifen increased the risk of thromboembolic complications in patients. The question of optimal scheduling of hormonal therapy and radiation is equally important. Preclinical studies have suggested that concurrent treatment with tamoxifen may result in decreased efficacy of radiation therapy, tamoxifen and neutropenia.
In a subgroup of patients who participated in a randomized trial, 38 patients received concurrent tamoxifen and postmastectomy radiation therapy, and 46 received postmastectomy radiation therapy only.
In a prospective cohort study, 74 patients treated with concurrent tamoxifen and postmastectomy radiation therapy were compared with 37 patients treated with radiation only. Another prospective study failed to confirm these findings. This association was not observed in another retrospective case series. In view of the continued uncertainty of the optimal scheduling of tamoxifen and radiation therapy in women with early breast cancer, tamoxifen and neutropenia, the results of three studies published in this issue of the Journal of Clinical Oncology should be viewed with considerable interest.
In a randomized trial, treatment groups are usually similar for known and unknown prognostic factors, tamoxifen and neutropenia, and therefore any difference in outcomes can be attributed to the different interventions received. In a retrospective cohort study, there is little control over how patients receive different interventions—the physician usually selects treatment, tamoxifen and neutropenia, often resulting in a difference in prognostic factors.
Even when there is an attempt to correct for differences between known prognostic factors using a multivariate analysis, tamoxifen and neutropenia, potential differences in unknown factors in groups may lead to erroneous results.
An additional problem with a retrospective design is that, by its very nature, it is not a planned experiment. As a result, sample sizes may be too small to detect important clinical differences. Finally, important clinical outcomes may not be measured routinely or evaluated systematically, increasing the risk of bias.
Let us review these studies, keeping in mind these methodological considerations. Patients were identified over a year period toduring which time there were considerable changes in the staging and treatment of breast cancer. The study observed no anti viral foods differences in the risk of ipsilateral breast tumor recurrence, disease-free survival, tamoxifen and neutropenia, or overall survival.
In addition, there were imbalances in the treatment groups for potentially important prognostic factors, in that patients who received radiation therapy followed sequentially by tamoxifen were slightly younger and more tamoxifen and neutropenia to receive chemotherapy, tamoxifen and neutropenia.
The latter association is also important, given that tamoxifen and neutropenia who received chemotherapy were reportedly more likely to receive tamoxifen after chemotherapy, again potentially prejudicing them to a better outcome. Patients treated with radiation therapy followed sequentially by tamoxifen were observed for a shorter period of time 9. Even though a multivariate analysis was used in an attempt to adjust for a number of observed differences, such an analysis is unable to correct for other unknown factors.
The second major point for consideration is sample size. Although this was the largest of the three studies, fewer than patients were evaluated. The HR for ipsilateral breast tumor recurrence comparing sequential with concurrent tamoxifen and radiation therapy was 0.
Such a result is consistent with sequential therapy being either better or worse. Finally, important morbidity outcomes were not reported. The second study, by Harris et al, 16 compared patients treated with concurrent tamoxifen and radiation therapy, with patients treated with radiation therapy followed sequentially by tamoxifen. Patients were accrued throughout a long period between and No significant differences in ipsilateral breast tumor recurrence, tamoxifen and neutropenia survival, or overall survival were observed between groups.
However, important differences between the treatment groups were noted, in that patients treated with radiation therapy followed sequentially by tamoxifen were again more likely to be younger and to have received chemotherapy. In this study, tamoxifen and neutropenia, the HR for ipsilateral breast tumor recurrence radiation therapy followed sequentially by tamoxifen v concurrent tamoxifen and radiation therapy was 1. Again, such a result is consistent with either a beneficial or a detrimental effect of radiation therapy followed sequentially by tamoxifen, compared with concurrent tamoxifen and radiation therapy.
In contrast to the previous study, important morbidity outcomes such as breast and arm edema, pneumonitis, and cosmetic outcome were collected; no important differences were observed between groups.
However, this assessment was performed by the treating radiation oncologist, who was not blinded to treatment received; consequently, there could have been bias in the assessment of this outcome. The third study, by Pierce et al, 17 identified two cohorts of patients from a randomized trial of different adjuvant systemic therapy regimens.
Eligibility criteria for the trial included patients with high-risk, node-negative breast cancer, which was defined as hormone receptor-negative or hormone receptor estrogen or progesterone receptor —positive, and tumor larger than 2 cm or with a high S phase. Tamoxifen and neutropenia treated with breast-conserving surgery were treated with radiation either before adjuvant chemotherapy or after chemotherapy was completed.
Of these, patients received concurrent tamoxifen and radiation therapy and received radiation therapy followed sequentially by tamoxifen. In this study, no differences were noted in the risk of ipsilateral breast tumor recurrence, disease-free survival, tamoxifen and neutropenia, or survival between radiation therapy followed sequentially by tamoxifen and concurrent tamoxifen and radiation therapy.
Despite prospective data collection, this analysis was performed retrospectively. Important imbalances in favor of radiation tamoxifen and neutropenia followed sequentially by tamoxifen were observed in hormone receptor—positive status between the groups. In addition, all patients treated with radiation therapy followed sequentially by tamoxifen received radiation before chemotherapy, resulting in increased delay in receiving chemotherapy in this group.
Patients who received concurrent tamoxifen and radiation therapy were more likely to receive radiation after chemotherapy, with less delay. The HR for risk of ipsilateral breast tumor recurrence radiation therapy followed sequentially by tamoxifen v concurrent tamoxifen and radiation therapy was 0.
Limited data were collected on radiation toxicity. In view of the small patient numbers in each of these three studies, one might be tempted to combine the data in a meta-analysis. We do not believe this is appropriate because of the inherent limitations of combining results from retrospective studies.
Although a meta-analysis may partially address the issue of power, it cannot correct for the other methodologic limitations. What can we conclude from these studies? Because of the inherent limitations of the research design, it is hard to make any firm conclusions regarding the relative effectiveness of sequential or concurrent tamoxifen and radiation therapy.
The only way to address this question adequately in the least biased way possible is through a large randomized controlled trial. Is it worth the effort and considerable cost to do so? We believe it is. Combined use of radiation tamoxifen and neutropenia hormonal therapy is increasingly common with the popularity of breast-conserving therapy and adjuvant treatment, tamoxifen and neutropenia. Relevant outcomes potentially affected by sequencing of the treatment include radiation pneumonitis, tamoxifen and neutropenia, breast fibrosis and cosmesis, local recurrence, and distant recurrence.
This latter outcome could be affected by delay in initiation of hormonal therapy. An argument against performing a randomized trial is that even if sequential tamoxifen and radiation therapy were truly better than concurrent therapy in terms of preventing local recurrence exhibited by an HR as low as 0.
Rosiglitazone and fda such differences may appear modest, they are comparable to that seen with other interventions in current use, tamoxifen and neutropenia as boost irradiation, 21 and are of a magnitude that could potentially influence overall survival.
This question of sequencing of hormonal therapy and radiation is likely to remain relevant despite the increasing use of the third-generation aromatase inhibitors 23 and accelerated breast irradiation. Recent studies in cell culture, however, suggest that breast cancer cells pretreated with aromatase inhibitors may have increased radiation sensitivity. The three studies reported in this issue have identified a gap in our knowledge regarding the womans sexual hormones and mood swings treatment of breast cancer.
An important question has been asked. The onus is now on investigators to answer it with the most rigorous design possible. The authors indicated no potential conflicts of interest. Radiation Therapy and Tamoxifen: That Is the Question. Timothy Whelan x Timothy Whelan. Search for articles by this author. American Society of Clinical Oncology Statement: A Randomized Controlled Trial.
The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med tamoxifen and neutropenia Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from Intergroup trial Proc Am Soc Clin Oncol Tamoxifen-citrate counteracts the antitumor effects of cytotoxic drugs in vitro.
J Clin Oncol Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer: Effects of tamoxifen on human breast cancer cell cycle kinetics: Accumulation of cells in early G1 phase.
Br J Radiol Changes in radiation sensitivity and steroid receptor content induced by hormonal agents and ionizing radiation in breast cancer cells in vitro. Breast Cancer Res Treat Introduction of apoptosis by tamoxifen and ICI in primary breast cancer. Int J Cancer Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst Effects of tamoxifen on pulmonary fibrosis after cobalt radiotherapy in breast cancer patients.
Wennberg B, Gagiardi, G, Sundbom, et al: Early response of lung in breast cancer irradiation: