Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial

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Annals of Oncology 17 (Supplement 7): vii10–vii14, 2006 doi:10.1093/annonc/mdl941

Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial

The National Cancer Research Institute and the 2University of Genoa, Genoa; 3S. Orsola-Malpighi Hospital, Bologna; 4Institute of Oncology, University of Messina, Messina; 5San Donato Hospital, Arezzo; 6S. Anna Hospital and University of Turin, Turin; 7Institute of Oncology S. Luigi- S. Curro`, Catania; 8S. Maria Hospital, Terni; 9 Civic Hospital, Casalpusterlengo; 10University of Cagliari; 11University of Florence, Florence; 12Pierantoni Hospital, Forll`; 13University and Mauriziano Hospital, Turin

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Background: Tamoxifen, for many years the ‘gold standard’ in the adjuvant setting for the management of endocrine sensitive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy due to the development of resistance. This provided the rationale for a switching trial with anastrozole, the updated results of which are reported here. Patients and methods: This trial investigated the efficacy of switching to anastrozole for women already receiving tamoxifen. After 2–3 years of tamoxifen treatment, postmenopausal, node-positive, ER-positive patients were randomized to receive either anastrozole 1 mg/day or to continue tamoxifen, 20 mg/day, giving a total duration of 5-years treatment. The primary end point was disease-free survival and secondary endpoints were event-free survival, overall survival and safety. Results: A total of 448 patients were enrolled. At a median follow-up time of 64 months (range 12–93), 63 events had been reported in the tamoxifen group compared with 39 in the anastrozole group [HR 0.57 (95% CI 0.38–0.85) P = 0.005]. Relapse-free and overall survival were also longer in the anastrozole group [HR 0.56 (95% CI 0.35–0.89) P = 0.01 and 0.56 (95% CI 0.28–1.15) P = 0.1]. However, the latter difference was not statistically significant. Overall more patients in the anastrozole group experienced at least one adverse event (209 versus 151: P = 0.000). However, numbers of patients experiencing serious adverse events were comparable (37 versus 40, respectively: P = 0.7). Conclusions: Switching to anastrozole after the first 2–3 years of treatment was confirmed to improve event-free and relapse-free survival of postmenopausal, node-positive, ER-positive early breast cancer patients already receiving adjuvant tamoxifen. Key words: anastrozole, switching, adjuvant therapy, breast cancer

introduction For several years, tamoxifen has represented the ‘gold standard’ for the adjuvant treatment of endocrine-responsive early breast cancer [1, 2]. However the prolonged use of this antiestrogen increases the risk of endometrial carcinoma and of other life-threatening conditions such as thromboembolic events [3, 4]. Moreover, many women are primarily resistant to tamoxifen although their tumors are ER-positive or develop resistance to this treatment after initially benefiting from it [5]. Aromatase inhibitors inhibit breast cancer growth by a different mechanism of action [6] and, therefore, can potentially also be active in women who become refractory to tamoxifen [7, 8]. *Correspondence to: Prof. F. Boccardo, National Cancer Research Institute and the University of Genoa, Italy, Largo R. Benzi 10, 16132 Genoa, Italy. Tel: +39-010-5600503; Fax: +39-010-352753; E-mail: [email protected]

ª 2006 European Society for Medical Oncology

Following the good results achieved in the treatment of advanced disease [7–9], the efficacy of aromatase inhibitors has been investigated in the adjuvant setting, either head to head, as an alternative to tamoxifen, combined with tamoxifen or as a switch after a few years of tamoxifen, or after a standard 5-year course of this anti-estrogen as postadjuvant treatment [10–15]. Switching women who currently receiving tamoxifen to an aromatase inhibitor may offer advantages over continued tamoxifen treatment as it allows women who are receiving an established treatment like tamoxifen, to receive a second, different type of drug that may pre-empt the development of tamoxifen resistance, and thus reduce relapse rates, and may also offer tolerability benefits. Patients therefore have the opportunity to receive 5 years of endocrine treatment whilst limiting the exposure to both tamoxifen and the aromatase inhibitor.

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F. Boccardo1,2*, A. Rubagotti1,2, P. Guglielmini2, A. Fini3, G. Paladini3, M. Mesiti4, M. Rinaldini5, S. Scali5, M. Porpiglia6, C. Benedetto6, N. Restuccia7, F. Buzzi8, R. Franchi9, B. Massidda10, V. Distante11, D. Amadori12 & P. Sismondi13 Other participants in the ITA trial (see acknowledgements)

Annals of Oncology

We have previously reported in detail the preliminary results of a study we have performed to investigate the efficacy of this approach using a sequence of tamoxifen and anastrozole [10]. A relapse-free survival benefit with comparable toxicities was observed at 3-year median follow-up. The updated results of this study, at a median follow-up time of more than 5 years, form the object of the present analysis.

patients and methods study design, study population, protocol evaluations and study end points

including four cancers in the controlateral breast and six endometrial cancers, and three breast cancer unrelated deaths) compared with 39 events (28 disease relapses, nine second primaries, including three cancers in the controlateral breast and one endometrial cancer, and two breast cancer unrelated deaths) in the anastrozole group. As is shown in Figures 1 and 2, the event-free (EFS) and relapse-free survival (RFS) differences were highly significant (EFS: HR 0.57, 95% CI 0.38–0.85; P = 0.005; RFS: HR 0.56, 95% CI 0.35–0.89, P = 0.01). Multivariate analysis confirmed allocated treatment to be the most significant predictor of both event-free and relapse-free survival (Table 1). Although approximately half of the deaths were in women who switched to anastrozole (12 versus 21) and an initial trend favored these women relative to overall survival (Figure 3), the difference between groups was not statistically significant (P = 0.1).

safety One hundred and fifty-one patients randomized to continue tamoxifen developed one or more adverse events compared with

statistical methods and sample size Relapse-free survival, event-free survival and overall survival were calculated from randomization. Curves were constructed using the method described by Kaplan and Meier [16] and compared using the log-rank test [17]. Multivariate models were constructed including variables known to be predictive of the risk of relapse in univariate models [18]. All P values were two-tailed. The v2 test or Fisher’s exact test were used to compare the incidence of adverse events in each group. Considerations about sample size have been discussed in detail in a previous paper [10].

Figure 1. Kaplan–Meier estimates of event free-survival (see text for hazard ratios).

results A total of 448 patients were enrolled into the trial between March 1998 and December 2002 and all of them were analysed according to intention-to-treat. At the time of the present analysis median follow-up was 64 months (range 12–93 months) and no patient was receiving the randomized treatment. Patient baseline demography was described in detail elsewhere [14]. Basically, groups were well balanced with respect to age, disease status, treatment of primary and prior chemotherapy.

efficacy At the time of this analysis, 102 events had occurred and 33 patients died. In the women continuing on tamoxifen there were 63 events (46 breast cancer relapses; 14 second primaries,

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Figure 2. Kaplan–Meier estimates of relapse (locoregional plus distant) free-survival (see text for hazard ratios).

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Details of the study design have been reported previously [10]. In summary postmenopausal women with histologically confirmed, estrogen receptor positive primary breast cancer with positive axillary nodes and no evidence of recurrent or metastatic disease who were receiving adjuvant treatment with tamoxifen for the last 2–3 years, were randomly allocated to continue tamoxifen (20 mg daily) or to be switched to anastrozole (1 mg daily). In both groups assigned treatment was continued up to the fifth year or patient relapse, death, undue toxicity or refusal. The Ethics Committee at each center approved the study protocol and written informed consent was obtained from all patients. The primary end point was disease recurrence, including both locoregional and distant recurrences (except contralateral breast cancer). Locoregional recurrences had to be cytologically and/or histologically confirmed and included tumor relapse in the ipsilateral breast, thoracic wall, axilla and supraclavicular nodes. For estimates of event-free survival, events included all of the previous ones plus second primaries (including contralateral breast cancer) and those deaths occurring in the absence of breast cancer recurrence. Secondary end points were incidence of death, whatever the cause, and adverse events. All second primaries were included among serious adverse events. These included all the lethal or life threatening events or those events causing disability or requiring hospitalization.

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Table 1. Hazard of developing any event or any breast cancer relapse Factor

P

Any breast cancer relapse HR (95% CI) P

1.0 0.39–0.87 0.008 1.0 0.58 0.57

0.35–0.91

0.02

1.0 0.96–2.21 0.08 1.46

1.0 1.49

0.91–2.43

0.1

1.0 0.76–1.70 0.5 1.14

1.0 1.16

0.73–1.86

0.5

1.0 1.03–2.39 0.03 1.57

1.0 1.62

0.99–2.65

0.053

1.0 0.75–1.91 0.4 1.19

1.0 1.51

0.84–2.68

0.2

Figure 3. Kaplan–Meier estimates of overall survival (see text for hazard ratios).

209 of those switched to anastrozole. The difference was statistically significant (P = 0.000). As is shown in Table 2, the patients with gastrointestinal complaints, fatigue, musculoskeletal disorders, bone fractures, cutaneous rash, lipid metabolism disorders and hyperglicemia were more numerous among those assigned to anastrozole, while those developing venous disorders, gynecological symptoms and gynecological changes (including endometrial cancer) were more numerous in the tamoxifen group. However, there was no difference between groups in the number of patients developing serious adverse events (40 versus 37, respectively: P = 0.7) except for those developing gynecological problems who were significantly more numerous in the tamoxifen group (12 versus 2: P = 0.006).

discussion The present analysis confirmed that switching to anastrozole provides patients already receiving tamoxifen with an additional

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Tamoxifen (%) n = 225 Gastrointestinal complaints Fatigue Venous disorders Lipid metabolism disorders Musculoskeletal disorders and bone fractures Gynecological symptoms Gynecological changes (including endometrial carcinoma) Cardiovascular diseases Skin disorders/rush Hyperglycemia Second primaries (excluding endometrial carcinoma and including controlateral breast) Others Total patients with event

15 – 10 6 15

(6.6) (4.4) (1.4) (6.7)

Anastrozole (%) n = 223 26 4 5 18 22

(11.7) (1.8) (2.2) (8.1) (9.9)

P value 0.07 0.045 0.2 0.01 0.2

9 (4.0) 19 (8.4)

16 (7.2) 3 (1.3)

0.1 0.001

14 5 3 8

17 9 10 8

0.6 0.3 0.045 0.6

(6.2) (2.2) (1.3) (3.6)

47 (20.9) 151 (67.1)

(7.6) (4.0) (4.5) (3.6)

71 (31.8) 209 (93.7)

0.009 0.000

benefit both in terms of event-free survival and in terms of relapse-free survival. The clinical benefit is comparable to the benefit previously seen in much larger switching trials with either anastrozole [15] or exemestane [13]. In addition a survival benefit was also noted in the present analysis, although differences in this regard were not statistically significant probably due to the small number of deaths that have occurred so far. Indeed a comparable survival trend did emerge from the switching trial with exemestane [13]. Moreover a statistically significant mortality gain in favor of the women who switched to anastrozole emerged from a recent metaanalysis including the results of our study and those of the ARNO and ABCSG studies [19]. It is therefore plausible to expect that a survival benefit will appear on an individual basis from all of the previously mentioned studies as soon as a sufficiently high number of deaths occur in each of them. The present analysis also confirms the safety of the approach adopted by us. In fact although more patients among those assigned to anastrozole developed at least one adverse event, it is noteworthy that there was no significant difference among groups relative to the incidence of serious adverse events, except for the women with gynecological problems, who were significantly more numerous in the tamoxifen group. Indeed there were six endometrial cancers among these women. By contrast, more women among those assigned to anastrozole developed a bone fracture. Although numbers were small, this finding confirms that even a few years of continuative treatment with an aromatase inhibitor induces a higher incidence of bone fractures. Interestingly, there were significantly no more cardiovascular events among women who switched to anastrozole, although significantly more patients in this group showed increased cholesterol levels after tamoxifen discontinuation. This finding is reassuring and is corroborated by a lack of evidence of increased breast cancer unrelated mortality among these women.

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Treatment Tamoxifen Anastrozole Tumor size, cm £2 cm >2 cm Tumor grade 1–2 3-Gx No. involved nodes £3 >3 Prior adjuvant chemotherapy No Yes

Any event HR 95% CI

Table 2. Patients with adverse events

Annals of Oncology

acknowledgements The authors are indebted to AstraZeneca (Milan, Italy) for providing the trial drugs and for funding the study. They wish also to acknowledge the support of CM PANSID (Milan, Italy) for trial monitoring and data management. Finally they are indebted to Mrs Simona Barozzi (University of Genoa) for her skilful secretarial assistance. The following centers and investigators have contributed to patient accrual: Ospedale San Donato, Arezzo (M. Rinaldini, S. Scali); Azienda Ospedaliera di Bologna – Policlinico S. Orsola Malpighi, Bologna (G. Paladini, A. Fini); Policlinico Universitario Monserrato, Cagliari (B. Massidda, MT. Ionta); Istituto Oncologico S. Luigi-S. Curro`, Catania (N. Restuccia, R. Bordonaro, D. Giuffrida); Presidio Ospedaliero di Casalpusterlengo, Casalpusterlengo (R. Franchi, G. Tansini); Universita` degli Studi ‘G. D’Annunzio’, Chieti (S. Iacobelli, L. Irtelli, MT. Martino); Arcispedale S. Anna, Ferrara (M. Indelli, C. Modenesi); Universita` degli Studi, Firenze (V. Distante, R. Simoncini); Ospedale L. Pierantoni, Forlı` (D. Amadori,

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P. Serra, D. Casadei Giunchi); Universita` degli Studi e Istituto Nazionale per la Ricerca sul Cancro, Genova (F. Boccardo, D, Amoroso); E.O. Ospedali Galliera, Genova (L. Gallo, C. Caroti); Ospedale Umberto I, Lugo (G. Cruciani, E. Montanari, A.Piancastelli); Azienda Policlinico G. Martino, Messina (M. Mesiti, D. Romeo); Istituto Scientifico San Raffaele, Milano (E. Villa, D. Aldrighetti, P. Zucchinelli); Arnas Ospedale Oncologico M. Ascoli, Palermo (B. Agostana, A. Traina, M. P. Cusimano); Fondazione Maugeri, Pavia (G. Bernardo, A. Bernardo); Universita` Cattolica del S. Cuore ‘A. Gemelli’, Roma (R. Bellantone, S. Mancuso, C. Barone, C. De Crea, E. Foti, C. Battelli, G. Di Leonardo); Azienda ULSS 18 – Presidio Ospedaliero di Rovigo, Rovigo (E. Ferrazzi, D. Menon); Ospedale Civile, USL 1 Imperiese, Sanremo (E. Campora, D. Guarneri); Presidio Ospedaliero di Saronno, Saronno (G. Schieppati, G. Di Lucca, C. Verusio); Universita` degli Studi, Sassari (A. Farris, G. Sanna, M. G. Sarobba); Azienda Ospedaliera S. Maria, Terni (F. Buzzi, S. Catanzani); Ospedale S. Anna, Torino (M. Porpiglia, C. Benedetto, P. Sozzani); Ospedale Mauriziano Umberto I, Torino (P. Sismondi, R. Ponzone, N. Biglia); Ospedale Edoardo Agnelli, Pinerolo Torino (L. Galletto, M. Sussio, L. Verra); Centro Oncologico ‘Mario Lovenati’, Trieste (G. Mustacchi, R. Ceccherini); Ospedale San Bortolo, Vicenza (V. Fosser, M. Magazu`, L. Merlini).

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Efficacy and safety data emerging from switching trials and from the meta-analysis of anastrozole trials are sufficient to recommend that switching to an aromatase inhibitor should be considered in all women receiving tamoxifen [20]. However, it is not so clear whether sequencing, i.e. prospectively planning from the switch of women to an aromatase inhibitor following 2 or 3 years of tamoxifen, might be appropriate as well. This approach is of no help in preventing disease relapses due to primary resistance to tamoxifen and it is now well known that a proportion of ER positive tumors cannot benefit from tamoxifen, perhaps those that are PgR negative or that amplify HER family oncogene [21–23]. It might be that front-line treatment with an aromatase inhibitor might be preferable in these women [24]. Unfortunately the results of trials actually comparing upfront treatment with an aromatase inhibitor with sequencing are not available yet and studies based on indirect comparisons and outcome simulations have yielded contrasting results [25, 26]. Moreover, no additional help in decision making has come from a recent cost–utility analysis of giving an aromatase inhibitor as monotherapy for 5 years versus sequential administration following 2–3 years of tamoxifen [27]. In fact, although according to this analysis, the sequencing approach provided the lowest cost/QALY (quality-adjusted life years), up-front use of an anti-aromatase might also provide acceptable cost/QALY for the patients, should it be able to guarantee a further improvement of relapse-free survival of 1%. While awaiting the results of trials comparing front-line versus sequencing approaches, both strategies should be considered as an alternative to tamoxifen monotherapy, not only for the women who are intolerant or unsuitable for prolonged treatment with this anti-estrogen [20] but also for those who are at higher risk of relapse or, irrespective of their risk, are more likely to be or become resistant to tamoxifen [24]. While there is no question that the results of switching trials cannot be used to predict for the efficacy of sequencing approaches, the mortality benefit emerging from our trial, from the IES trial [13] and from the recent meta-analysis of switching trials with anastrozole [15] appear very promising in this regard.

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