Randomised double-blind trial in postmenopausal women with primary breast cancer who have received adjuvant tamoxifen for 2-3 years, comparing subsequent adjuvant exemestane treatment with further tamoxifen

Nel marzo 1998 é stato avviato uno studio sul tumore della mammella.

Lo studio (Protocollo 1/98), multicentrico internazionale, ha l’obiettivo di confrontare l’attività e la tollerabilità dell’exemestane, inibitore dell’aromatasi, rispetto al tamoxifen, in fase adiuvante, in donne con carcinoma mammario operato radicalmente, in postmenopausa.

Sono state arruolate 179 pazienti dal Gruppo I.T.M.O.; 4726 nella totalità.

Lo studio, chiuso al reclutamento nel febbraio 2003,  ha finora dimostrato che  la terapia ormonale adiuvante con tamoxifen, somministrato per 2-3 anni seguito da exemestane fino al completamento di 5 anni di terapia, risulta più efficace in termini di sopravvivenza libera da malattia rispetto alla terapia con solo tamoxifen per 5 anni in termini di riduzione delle recidive, con beneficio anche in termini di sopravvivenza globale. I primi risultati relativamente alla tollerabilità sono più che confortanti.

Centri partecipanti :                     Ospedale Fatebenefratelli, MILANO

Policlinico Universitario, PALERMO

Az. Ospedaliera Carlo Poma, MANTOVA

Az. Ospedaliera di TREVIGLIO (BG)

Ospedale Civile, TRESCORE BALNEARIO (BG)

Ospedale di Circolo Fondazione Macchi, VARESE

Ospedale ASL 20, TORTONA

Ospedale Cardarelli, NAPOLI

Ospedale Regina Elena, ROMA

Istituto Nazionale Tumori, MILANO

Istituti Ospitalieri, CREMONA

Ospedale S. Carlo, MILANO

Ospedale Maggiore, LODI

Ospedale S. Gerardo, MONZA

Ospedale Businco, CAGLIARI

Ospedale Civile, LECCO

Riferimenti Bibliografici:

  • A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.
    (Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study).
    N Engl J Med. 2004 Mar 11;350(11):1081-92.     

    Erratum in
    N Engl J Med. 2004 Dec 2;351(23):2461.
    N Engl J Med. 2006 Oct 19;355(16):1746. van de Velde, Cornelius [added].Abstract

    BACKGROUND:
    Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse.

    METHODS:
    We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival.

    RESULTS:
    Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported–183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04).

    CONCLUSIONS:
    Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.
    Comment in
    New stars in the sky of treatment for early breast cancer. [N Engl J Med. 2004]
    Adjuvant treatment of breast cancer with exemestane. [N Engl J Med. 2004]
    Adjuvant treatment of breast cancer with exemestane. [N Engl J Med. 2004]
    Adjuvant treatment of breast cancer with exemestane. [N Engl J Med. 2004]

    Download articolo: N Engl J Med. 2004 Mar 11;350(11):1081-92.


 

  • Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial.
    (Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study).
    Lancet. 2007 Feb 17;369(9561):559-70. 

    Erratum in
    Lancet. 2007 Mar 17;369(9565):906.Abstract

    BACKGROUND:
    Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival.

    METHODS:
    4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920.

    RESULTS:
    After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded.

    CONCLUSIONS:
    Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

    Comment in
    To switch or not to switch: implications of sequencing adjuvant endocrine therapy in patients with breast cancer. [Nat Clin Pract Oncol. 2007]
    Switching to aromatase inhibitors in early breast cancer. [Lancet. 2007]
    Exemestane or tamoxifen? [Lancet. 2007]
    Exemestane or tamoxifen? [Lancet. 2007]
    Exemestane or tamoxifen? [Lancet. 2007]

    PMID: 17307102   [PubMed – indexed for MEDLINE]

    Download articolo: Lancet 2007