Switching to anastrozole (ANA) vs continued tamoxifen (TAM) treatment of early breast cancer (EBC). Updated results of the Italian tamoxifen anastrozole (ITA) trial

Boccardo, Francesco; Rubagotti, A.; Puntoni, Matteo; Guglielmini, Pamela; Porpiglia, M; Mesiti, M.; Rinaldini, M.; Paladini, Giuseppe; Distante, V.; Franchi, R.

doi:10.1200/jco.2005.23.16_suppl.526

Cited by 32 publications

(16 citation statements)

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“…For studies of the use of an AI after 2 -3 years of tamoxifen, hazard rates of 0.70 have been reported for the IES study using exemestane (Coombes et al, 2004a, b), 0.60 for the ABCSG8/ ARNO95 trial (Jakesz et al, 2005a) and 0.46 for the latest update of the much smaller Italian trial using anastrozole in node-positive women only (Boccardo et al, 2005). In this model, we have given equal weight to the two large trials and assumed a hazard ratio of 0.65 beginning after 2 years of tamoxifen.…”

Section: Sequencing Trialsmentioning

confidence: 99%

Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen?

2006

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A number of trials have studied the value of aromatase inhibitors (AIs) for the adjuvant treatment of early hormone-responsive postmenopausal breast cancer. Three different AIs have been used and they have been compared as initial treatment (two trials) or after 2 -3 years of tamoxifen (four trials), in both cases against a standard arm of 5 years of tamoxifen. In addition, two trials have evaluated AIs against no treatment after 5 years of tamoxifen. In all circumstances, the AIs have demonstrated superior efficacy. However, no results are currently available for the key question, that is -is it better to start initially with an AI or use it sequentially after 2 years of tamoxifen? Here, we review the trial results and present two models, which address this issue. The models clearly show that early treatment with an AI is superior to using it after 5 years of tamoxifen. They also favour an upfront strategy to sequencing after 2 years of tamoxifen, but in this case the differences are small and model-dependent. A key question is whether AIs have substantially better efficacy than tamoxifen for ER-positive -PgR-negative tumours, where the data are currently contradictory. A mechanism explaining why greater efficacy might be so is proposed. Further results from ongoing trials will be needed to resolve this issue.

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Section: Sequencing Trialsmentioning

confidence: 99%

Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen?

2006

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“…In the MA.17 trial of letrozole or placebo after 5 years of tamoxifen, the hazard ratio for recurrence-free survival after the switch was 0.57 (6), and in the Intergroup Exemestane Study (IES) of 3 or 2 years exemestane after 2 to 3 years of tamoxifen compared with continuation to 5 years of tamoxifen, the hazard ratio was 0.64 (5). Data for the Italian Tamoxifen Anastrozole (7) and Austrian Breast and Colorectal Cancer Study Group 6a (8) trials are qualitatively similar, although follow-up is not yet mature.…”

mentioning

confidence: 99%

Is There a Role for Adjuvant Tamoxifen in Progesterone Receptor–Positive Breast Cancer? An In silico Clinical Trial

Hilsenbeck

Osborne

2006

Clinical Cancer Research

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Purpose: Subset analysis from the Arimidex, Tamoxifen, Alone or in Combination trial, a major adjuvant therapy trial, suggests that progesterone receptor^negative (PRÀ) cases may derive greater benefit from aromatase inhibitor compared with tamoxifen than PR+ cases.We postulated that estrogen receptor^positive (ER+)/PR+ patients might do as well or better by starting on tamoxifen and later switching to an aromatase inhibitor rather than by starting on an aromatase inhibitor as initial therapy. Experimental Design: We constructed a computer model using retrospective data to approximate exponential failure rates for PR+ and PRÀ in tamoxifen-treated and tamoxifen-untreated patients, adding the assumptions that about half of patients are cured at surgery and that f20% of postmenopausal ER+ early breast cancer cases are PRÀ. This model provided a very good approximation to the published overview data and to the clinical trials. We then used the failure rates to generate relapse times for a large number of cases (n = 50,000) for each treatment scenario. Results: In PRÀ cases, initial therapy with an aromatase inhibitor is superior to tamoxifen and this advantage can never be made up by switching. In PR+ cases, tamoxifen is only modestly inferior to aromatase inhibitor at the outset, and after switching to an aromatase inhibitor at 3 or 5 years the tamoxifen relapse-free survival curve catches up and then begins to surpass the aromatase inhibitor curve at 7.5 or 12 years, respectively. Discussion: Although our in silico trial is based on many assumptions, it closely approximates results of the published trials and, therefore, suggests that an in vivo comparison in ER+/PR+ patients of aromatase inhibitor versus tamoxifen followed by aromatase inhibitor may be worth considering.

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“…The switch from tamoxifen to anastrozole was associated with a signiWcant reduction in breast cancer events (event-free survival and progression-free survival) and a 43% improvement in distant-progression-free survival at either the 36-month follow-up (HR = 0.49; 95% CI 0.22-1.05; P = 0.06) or the 52-month follow-up (Table 2), with a marked reduction in locoregional recurrences at both of these follow-up points (36-month: HR = 0.15; P = 0.003; 52-month: HR = 0.13; P = 0.002) (Boccardo et al 2005b). More lipid disorders were seen with patients who switched to anastrozole (9.3% vs. 4.0%; P = 0.04), while more gynecologic changes, including endometrial carcinoma, were observed in the patients on tamoxifen compared with anastrozole (11.3% vs. 1.0%; P = 0.0002), and signiWcantly more SAEs were observed with tamoxifen (22% vs. 13.9%; P = 0.04) (Boccardo et al 2005a).…”

Section: Ita Trialmentioning

confidence: 86%

“…The results of this Wrst primary core analysis (n = 4,003 letrozole, n = 4,007 tamoxifen), at a median of 25.8 months' follow-up, have shown a signiWcant beneWt of initial adjuvant therapy with letrozole, with a 19% improvement in DFS (HR = 0.81; P = 0.003) over tamoxifen and a 27% reduction in the risk of distant metastases over tamoxifen (HR = 0.73; P = 0.001). Results of the primary core analysis showed a total of 177 distant metastases events (4.4%) in the letrozole arm compared with 232 (5.8%) in the tamoxifen arm (Thurlimann et al 2005 The safety proWle of letrozole vs. tamoxifen in this initial analysis showed a higher incidence of fractures (5.7% vs. 4.0%; P < 0.001), arthralgia (20.3% vs. 12.3%; P < 0.001), hypercholesterolemia [5.4% vs. 1.2% (in patients who had normal baseline values that then became 1.5 times higher than the upper normal limits)], and cardiac failure (0.8% vs. 0.4%; P = 0.01) in the letrozole group, while the tamoxifen Table 2 EYcacy of aromatase inhibitors (AIs) when used as upfront or switch adjuvant therapy (Howell et al 2005;Anastrozole PI 2005;Coates et al 2006;Boccardo et al 2005b;Jonat et al 2006;Jakesz et al 2005a;Coombes et al 2007 group showed signiWcantly more thromboembolic events (3.5% vs. 1.5%; P < 0.001), vaginal bleeding (6.6% vs. 3.3%; P < 0.001), hot Xashes (38.0% vs. 33.5%; P < 0.001), and night sweats (16.2% vs. 13.9%; P = 0.004) (Thurlimann et al 2005;Letrozole 2005). More recently, results from the exploratory analysis restricted to the two monotherapy arms, with a 51-month follow-up, have conWrmed those Wndings (n = 2,463 letrozole and n = 2,459 tamoxifen).…”

Section: Atac Trialmentioning

confidence: 97%

Treatment strategies that effectively reduce early recurrence risk in postmenopausal women with endocrine-sensitive breast cancer: AIs upfront vs. switching

Paepke

Jacobs

Öhlinger

et al. 2007

J Cancer Res Clin Oncol

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Several large, well-controlled clinical trials have now established that the aromatase inhibitors (AIs), including letrozole, anastrozole, and exemestane, are more effective than tamoxifen when used as adjuvant endocrine therapy in postmenopausal women with breast cancer. Yet, it is an open question as to how these drugs should be best integrated into the adjuvant treatment regimen. Both letrozole and anastrozole have shown efficacy over tamoxifen when used as initial adjuvant therapy (initiated just following surgery for breast cancer), while exemestane and anastrozole have been used as switching adjuvant therapy, i.e., following 2-3 years of initial adjuvant tamoxifen therapy, with proven efficacy over continued tamoxifen. Studies demonstrate that recurrence risk peaks in the early period after surgery, and that distant metastases in particular, accounting for most of the early recurrences, have worse survival rates when compared with other types of recurrences. Treatments that reduce recurrences, especially distant metastases, in this early period are therefore likely to improve overall survival (OS) and reduce mortality from breast cancer. In this review, we discuss early recurrence risk among postmenopausal women with successfully treated early breast cancer, the efficacy of the different AIs in reducing early recurrences and distant metastases when incorporated into adjuvant therapy, and the evidence for increased OS when AIs are used as initial or switch adjuvant therapy.

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Switching to anastrozole (ANA) vs continued tamoxifen (TAM) treatment of early breast cancer (EBC). Updated results of the Italian tamoxifen anastrozole (ITA) trial

Cited by 32 publications

References 0 publications

Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen?

Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen?

Is There a Role for Adjuvant Tamoxifen in Progesterone Receptor–Positive Breast Cancer? An In silico Clinical Trial

Treatment strategies that effectively reduce early recurrence risk in postmenopausal women with endocrine-sensitive breast cancer: AIs upfront vs. switching

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