Summary
Anastrozole (Arimidex®) is better than tamoxifen (Nolvadex®) at preventing a recurrence of breast cancer in postmenopausal women with early-stage hormone receptor-positive tumors, according to 10-year follow-up results from ATAC, a large international clinical trial. However, it does not improve overall survival compared with tamoxifen.
Source
The Lancet Oncology, November 17, 2010 (see the journal abstract: see below).
Background
Postmenopausal women who have been treated for early breast cancer and whose tumors are hormone receptor positive (that is, their tumors grow in response to the hormone estrogen) have been advised to take 5 years of adjuvant treatment with hormone therapy. For years the standard option was the antiestrogen drug tamoxifen. Tamoxifen treatment had been shown to help prevent a relapse and was considered the standard of care for this group of patients.
However, tamoxifen increases the risk of endometrial cancer and blood clotting disorders. It has been suggested that drugs called aromatase inhibitors (AIs), which are a different type of antiestrogen, might be a better alternative.
Like tamoxifen, AIs interfere with cancer cells’ use of hormones. But whereas tamoxifen interferes directly with the cancer cells’ ability to use estrogen to fuel growth, AIs block the action of an enzyme called aromatase, which helps the body to produce estrogen. Another difference is that tamoxifen can be used by both premenopausal and postmenopausal women, whereas AIs block estrogen production only in postmenopausal women.
The Study
The Arimidex, Tamoxifen Alone or in Combination (ATAC) study was a double-blinded phase III clinical trial that was designed to compare the ability of the AI anastrozole, tamoxifen, and the two drugs in combination to prevent breast cancer recurrence in postmenopausal women with hormone receptor-positive tumors.
The study enrolled 9,366 postmenopausal women with localized breast cancer (that is, cancer that hadn’t spread, or metastasized). The women were randomly assigned to receive 5 years of adjuvant treatment with anastrozole alone, tamoxifen alone, or a combination of the two. (The combination treatment group was subsequently discontinued because outcomes for patients in this group were essentially the same as those in the group receiving tamoxifen alone.) Most of the participants (84 percent) had hormone receptor-positive disease.
Results after a median follow-up of 68 months (5.7 years), published in 2005 (see the journal abstract), showed that, compared with tamoxifen, anastrozole prolonged disease-free survival by 13 percent, increased time to relapse by 21 percent, reduced the occurrence of cancer spreading to other organs (distant metastases) by 14 percent, and reduced the occurrence of cancer in the other breast by more than 40 percent. The differences were even greater when the analysis was restricted to women with hormone receptor-positive cancer.
In addition, anastrozole was associated with fewer serious side effects (endometrial cancer, blood clots, vaginal bleeding, and hot flashes) than tamoxifen, although bone fractures and joint pain were more common among patients in the anastrozole group. However, overall survival was similar in the two groups.
In 2006, researchers with the ATAC trial reported data showing that anastrozole was better tolerated than tamoxifen and resulted in fewer serious complications (see the journal abstract). Furthermore, anastrozole had a more favorable overall risk–benefit profile than tamoxifen, and women taking anastrozole had a lower recurrence rate than those taking tamoxifen.
Mainly on the basis of the results published in 2005, treatment with an AI became the standard adjuvant therapy for hormone receptor-positive breast cancer, although tamoxifen is still considered a reasonable alternative. Other trials, involving a total of more than 30,000 women, confirmed that treatment with an AI alone or after tamoxifen was beneficial for patients with hormone-sensitive breast cancer.
The current study reports findings after participants in ATAC had been followed for median of 10 years.
Results
This analysis continued to show a benefit of anastrozole compared with tamoxifen. Among women with hormone receptor-positive tumors, those randomly assigned to receive treatment with anastrozole had a 4.3 percent lower absolute rate of breast cancer recurrence after 10 years, and a 2.6 percent lower absolute rate of distant metastasis, than those randomly assigned to receive treatment with tamoxifen.
The differences between anastrozole and tamoxifen in time to relapse, cancer in the other breast, and disease-free survival were greatest in the first two years of treatment but were maintained throughout the follow-up period, including the period after treatment was completed. However, the authors found that this so-called “carryover effect” – in which benefits extend beyond the treatment period – began to wane after about 8 years.
During treatment, women in the anastrozole group had fewer serious adverse events related to treatment than women in the tamoxifen group. After treatment was completed, however, rates of serious adverse events evened out between the two groups. Patients taking anastrozole reported more fractures during treatment than those taking tamoxifen, but after the completion of treatment fracture rates again became similar in both groups.
Patients taking tamoxifen had higher rates of endometrial cancer and melanoma than those taking anastrozole. There was a slight trend toward more colorectal and lung cancers in patients taking anastrozole compared with those taking tamoxifen. Overall, however, cancers other than breast cancer occurred at similar rates in both groups.
The number of patient deaths, with or without breast cancer recurrence, was similar in the two groups after 10 years of follow-up. Thus, treatment with anastrozole did not improve overall survival compared with tamoxifen.
Comments
In an accompanying editorial, Michael Gnant, M.D., of the Medical University of Vienna in Austria, wrote that he is encouraged by the finding that “the benefit of 5 years’ treatment with anastrozole persists and even seems to increase over time. This so-called carryover effect gives reason for hope because it essentially means that we can intervene early in the course of the disease and affect the rate of recurrence and overall survival.”
It is reassuring, Dr. Gnant added, that “the clinically most important side-effect of aromatase inhibition – an increase in fractures because of reduced serum [estrogen] concentrations – subsides soon after intake of the active drug is stopped.”
Jo Anne Zujewski, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program, said: “The 10-year results from ATAC provide strong evidence that anastrozole is both safe and effective in the treatment of postmenopausal women with early-stage breast cancer.”
Dr. Zujewski added, however, that “whether an individual patient should start therapy with an AI or begin therapy with tamoxifen and then change to an AI remains a subject of medical judgment and clinical research. Patients should talk with their doctors about which drug would be best for them given their particular medical condition.”
In August 2010, an ASCO expert committee released an updated Clinical Practice Guideline that recommends that postmenopausal women with hormone receptor-positive breast cancer consider using an AI during adjuvant treatment, either initially or after a course of adjuvant tamoxifen. The committee noted, however, that patients and their physicians should carefully consider side effect profiles when deciding on whether and when to use AI therapy.
full-text:
Anastrozole Reduces Reurrence in Breast Cancer: ATAC - National Cancer Institute
Lancet Oncol. 2010 Dec;11(12):1135-41. Epub 2010 Nov 17.
Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial.
Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators.
Source
Cancer Research UK, Centre for Epidemiology, Mathematics, and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary School of Medicine and Dentistry, University of London, London, UK. j.cuzick@qmul.ac.uk
Abstract
BACKGROUND: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months.
METHODS: We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230.
FINDINGS: Patients were followed up for a median of 120 months (range 0-145); there were 24,522 woman-years of follow-up in the anastrozole group and 23,950 woman-years in the tamoxifen group. In the full study population, there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival (hazard ratio [HR] 0·91, 95% CI 0·83-0·99; p=0·04), time to recurrence (0·84, 0·75-0·93; p=0·001), and time to distant recurrence (0·87, 0·77-0·99; p=0·03). For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0·86, 95% CI 0·78-0·95; p=0·003), time to recurrence (0·79, 0·70-0·89; p=0·0002), and time to distant recurrence (0·85, 0·73-0·98; p=0·02). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2·7% at 5 years and 4·3% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0·81, 95% CI 0·67-0·98; p=0·03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0·87, 95% CI 0·74-1·02; p=0·09), but there was little difference in overall mortality (0·95, 95% CI 0·84-1·06; p=0·4). Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1·33, 95% CI 1·15-1·55; p<0·0001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0·98, 95% CI 0·74-1·30; p=0·9). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0·57, 95% CI 0·48-0·69; p<0·0001), but were similar after treatment completion (66 vs 78; OR 0·84, 95% CI 0·60-1·19; p=0·3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported. INTERPRETATION: These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer. Copyright © 2010 Elsevier Ltd. All rights reserved. Comment in Lancet Oncol. 2010 Dec;11(12):1109-10. Nat Rev Clin Oncol. 2011 Feb;8(2):64. Lancet Oncol. 2011 Mar;12(3):216-7; author reply 217. PMID:21087898[PubMed - indexed for MEDLINE] Effect of anastrozole and tamoxifen as adjuvant tr... [Lancet Oncol. 2010] - PubMed result
Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial.
Arimidex, Tamoxifen, Alone or in Combination Trialists' Group, Buzdar A, Howell A, Cuzick J, Wale C, Distler W, Hoctin-Boes G, Houghton J, Locker GY, Nabholtz JM.
Source
University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Abstract
BACKGROUND: The Arimidex (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with early-stage breast cancer. After an extended follow-up beyond the 5 years of treatment, we aimed to assess the safety, tolerability, and risk-benefit indices of these compounds.
METHODS: We analysed postmenopausal women (mean age 64 years [SD 9]) with localised breast cancer randomly assigned to anastrozole (n=3125) or tamoxifen (n=3116). Efficacy measures, including death and risk-benefit indices, were analysed by intention to treat. Safety analyses were based on treatment first received (n=3092 for anastrozole and n=3094 tamoxifen). We calculated a risk-benefit analysis using the two global indices for the Women's Health Initiative and for Disease-Free Survival and Serious Adverse Events. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230.
FINDINGS: At median follow-up of 68 months (range 1-93), treatment-related adverse events occurred significantly less often with anastrozole than with tamoxifen (1884 [61%] vs 2117 [68%]; p<0.0001), as did treatment-related serious adverse events (146 [5%] vs 277 [9%]; p<0.0001) and adverse events leading to withdrawal (344 [11%] vs 442 [14%]; p=0.0002). Patients given anastrozole had significantly fewer overall events for the Global Index of the Women's Health Initiative (744 [24%] vs 851 [27%]; hazard ratio 0.85 [95% CI 0.77-0.94], p=0.001) and the Global Index of Disease-Free Survival and Serious Adverse Events (1453 [46%] vs 1594 [51%]; 0.88 [0.82-0.94]; p=0.0004). INTERPRETATION: Anastrozole is tolerated better than tamoxifen by postmenopausal women with early-stage breast cancer, and results in fewer serious adverse events. Furthermore, it has a more favourable overall risk-benefit profile and lower recurrence rate than tamoxifen. Comment in ACP J Club. 2007 Jan-Feb;146(1):4. PMID:16887480[PubMed - indexed for MEDLINE] Comprehensive side-effect profile of anastrozole a... [Lancet Oncol. 2006] - PubMed result
American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer.
Burstein HJ, Prestrud AA, Seidenfeld J, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Malin J, Mamounas EP, Rowden D, Solky AJ, Sowers MR, Stearns V, Winer EP, Somerfield MR, Griggs JJ; American Society of Clinical Oncology.
Source
Dana-Farber Cancer Institute, Boston, MA, USA.
Abstract
PURPOSE: To develop evidence-based guidelines, based on a systematic review, for endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer.
METHODS: A literature search identified relevant randomized trials. Databases searched included MEDLINE, PREMEDLINE, the Cochrane Collaboration Library, and those for the Annual Meetings of the American Society of Clinical Oncology (ASCO) and the San Antonio Breast Cancer Symposium (SABCS). The primary outcomes of interest were disease-free survival, overall survival, and time to contralateral breast cancer. Secondary outcomes included adverse events and quality of life. An expert panel reviewed the literature, especially 12 major trials, and developed updated recommendations.
RESULTS: An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI after 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5 years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or as sequential treatment after 2 to 3 years of tamoxifen yields similar outcomes. Tamoxifen and AIs differ in their adverse effect profiles, and these differences may inform treatment preferences.
CONCLUSION: The Update Committee recommends that postmenopausal women with hormone receptor-positive breast cancer consider incorporating AI therapy at some point during adjuvant treatment, either as up-front therapy or as sequential treatment after tamoxifen. The optimal timing and duration of endocrine treatment remain unresolved. The Update Committee supports careful consideration of adverse effect profiles and patient preferences in deciding whether and when to incorporate AI therapy.
PMID:20625130[PubMed - indexed for MEDLINE]
American Society of Clinical Oncology clinical pra... [J Clin Oncol. 2010] - PubMed result
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