Adjuvant systemic therapies in women with breast cancer:an audit of clinical practice in Italy

Annals of Oncology 14: 843–848, 2003 DOI: 10.1093/annonc/mdg256

Original article

Adjuvant systemic therapies in women with breast cancer: an audit of clinical practice in Italy F. Roila1*, E. Ballatori2, L. Patoia3, S. Palazzo4, A. Veronesi5, A. Frassoldati6, G. Cetto7, S. Cinieri8 & A. Goldhirsch8 On behalf of the Drug Utilization Review Team in Oncology† 1

Divisione Oncologia Medica, Ospedale Policlinico, Perugia; 2Unità di Statistica Medica, Dip. Medicina Interna e Salute Pubblica, Università, L’Aquila; Dipartimento Medicina Interna e Scienze Oncologiche, Università, Perugia; 4Divisione Oncologia Medica, Cosenza; 5Oncologia Preventiva, Centro di Riferimento Oncologico, Aviano, Pordenone; 6Divisione Oncologia Medica, Policlinico, Modena; 7Divisone Oncologia Medica, Ospedale Borgo Trento, Verona; 8 Dipartimento di Medicina, Istituto Europeo di Oncologia, Milan, Italy 3

Background: Evidence-based guidelines, consensus conferences and experts’ opinion are rarely promptly transferred to patient care. We audited prescriptions of adjuvant systemic therapies for Italian breast cancer patients and compared them with recommendations of an International Consensus Panel. Patients and methods: Disease characteristics and adjuvant therapies for 768 breast cancer patients referred to 87 Italian centers from 16 to 23 March 2000 were evaluated for adherence to the published recommendations. Results: Endocrine therapy was not prescribed for 102 of 541 patients (19%) with endocrine-responsive disease and for 22 of 45 patients (49%) with unknown hormonal receptor status. Instead, endocrine therapy was prescribed for 22 of 182 patients (12%) with endocrine-unresponsive disease. Adjuvant chemotherapy was prescribed for 98% of the patients. The type of chemotherapy was the cyclophosphamide, methotrexate, 5-fluorouracil regimen for 453 of 754 (60%), while 253 of 754 (34%) received an anthracycline-based regimen. The proportion of patients with anthracyclines increased with the number of involved axillary nodes and grading, and decreased with age. Endocrine therapy was administered to 482 of 768 (63%) and was mainly represented by an antiestrogen. Conclusions: Lack of adherence to evidence-based guidelines for adjuvant treatment of Italian breast cancer patients was as high as 19%. It might be wise for national health authorities to promote education on lifesaving procedures, like adjuvant systemic treatments, in cancer medicine. Key words: adjuvant therapies, breast carcinoma, drug utilization review, guidelines adherence, practice guidelines

Introduction Analyses of the appropriateness of health interventions are an essential part of the evaluation of health needs [1, 2] and are a source of information of relevant importance, especially for diseases with a high incidence of mortality and morbidity such as cancer. Only a few studies have been conducted on daily clinical practice and its relationship to evidence derived from clinical research. Several available reports show that a gap exists between the conclusions from clinical trials, summarized in international consensus conferences, and patient care [2–5].

*Correspondence to: Dr F. Roila, Medical Oncology Division, Policlinico Hospital, 06122 Perugia, Italy. Tel: +39-075-5783968; Fax: +39-075-5720990; E-mail: [email protected] †Members of the Drug Utilization Review Team in Oncology are listed in the Acknowledgements © 2003 European Society for Medical Oncology

Breast cancer is a suitable model for study of treatment prescription patterns due to its high incidence and prevalence, the complexity of multidisciplinary approaches involved in offering adequate therapies, and the availability of results from highquality randomized clinical trials to indicate evidence for given adjuvant treatments. Adjuvant systemic therapies have significantly reduced breast cancer mortality. Thus, adherence to international guidelines has an important impact on public health. In our study, prescriptions of both adjuvant chemotherapy and endocrine therapy administered to Italian breast cancer patients were audited and compared with recommendations suggested by an International Consensus Panel [6].

Patients and methods From 16 to 23 March 2000 status and treatment of all consecutive breast cancer patients referred to 87 Italian oncology centers were audited, regard-

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Received 30 October 2002; revised 14 January 2003; accepted 24 February 2003

844 less of the type of care received. For each patient, information on personal, clinical and disease characteristics, as well as administered therapy, was recorded on a specific form by the treating oncologists of each center. Inclusion criteria were a past or current diagnosis of breast cancer, and patient’s written informed consent for use of personal data. During that week each patient was evaluated only once even if treated for several days. The study was approved by all ethics committees of the participating centers.

Table 1. Patient characteristics

Total

No.

%

768

100

31

4

Age (years) ≤35 36–49

270

35

50–69

400

52

54

7

13

2

0

709

92

1

54

7

2

5

1

Pre or peri

368

48

Post

380

49

20

3

HR+

541

70

HR–

182

24

HR?

45

6

0

290

38

1–3

228

30

4–10

130

17

>10

78

10

42

5

47

6

≥70 Not reported ECOG performance status

Results Of the 2564 patients visiting the centers during the audit week, 840 received adjuvant treatments. Of those, only 72 patients were not included in the analysis due to the following reasons: lack of nodal definition (52), male gender (10) and breast cancer in situ only (10). Thus, we report results for 768 patients, whose characteristics are shown in Table 1. Two hundred and ninety patients (38%) had N– disease, while 42 patients (5%) had some axillary nodes involved, without information on their exact number. As expected, the ECOG performance status was 0 in over 90% of patients and estrogen and/or progesterone receptor status was positive in ~70% of patients. Most were treated in a general hospital (504 patients, 66%), while 128 (17%) and 136 (18%) were treated in academic medical centers or National Scientific Institutes for Cancer Research, respectively. The geographical distribution of audited centers showed a higher prevalence for Northern Italy (365 patients, 47%), while 103 (13%) and 300 (39%) patients were treated, respectively, in Central and in Southern Italy. The patients had, as expected in a population referred for treatment to an oncological center, a high prevalence of prescribed adjuvant chemotherapy (754 of 768, 98%). The prescribed treatments were compared with the latest recommendations (at that time) of the St Gallen International Consensus Panel (Table 2) [6]. As shown in Table 3, endocrine therapy was not prescribed for 62 of 368 patients (17%) with N+ HR+ disease and for 40 of 173 (23%) patients classified as having a N– HR+ breast cancer, a total of 102 of 541 patients (19%). On the other hand, endocrine therapy was prescribed for 22 of 182 patients (12%) who had a HR– disease, of whom 12 of 83 were N+ patients (14%) and 10 of 99 were N– (10%). Noteworthy are also the 22 of 45 patients (49%) with unknown hormone receptor status (HR?), who did not receive adjuvant endocrine therapy. In summary, with respect to

Menopausal status

Not reported Receptor status

No. of metastatic nodes

Positive but number not reported Grading Well differentiated Moderately differentiated

305

40

Poorly differentiated

302

39

Unknown

74

10

Not reported

40

5

<2

371

48

2–5

307

40

>5

25

3

Inflammatory

59

8

Not reported

6

1

Pathological tumor size (cm)

ECOG, Eastern Cooperative Oncology Group.

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In the current evaluation, only patients with adjuvant therapies, either planned or administered, were included. Treatment was assessed according to nodal (N) and steroid hormone receptor (HR) status. Disease for each patient was classified as N-positive (N+) or N-negative (N–), and as HR-positive (HR+), HR-negative (HR–) or HRunknown (HR?) according to estrogen and/or progesterone receptor expression determined by each center’s pathologist. Age, Eastern Cooperative Oncology Group (ECOG) performance status, menopausal status, number of metastatic nodes, grading and pathological tumor size were considered as clinical features that might have influenced the therapeutic decision otherwise based on the HR and N status and patient’s co-morbid conditions. To compare two (or more) proportions, a two-tailed χ2-test or Fisher’s exact test (generalized by Freeman–Halton), in the case of at least one frequency less than 5, were used.

HR status, the prescribed treatment was different from that recommended in 19% of patients. Among the features usually influencing therapeutic decisions, some were found to have a significant role. Patients with HR+ N+ disease had a higher chance of receiving the recommended treatment, chemotherapy plus endocrine therapy, if they had one to three (148 of 183, 81%) or 4–10 (89 of 100, 89%) positive nodes

845 Table 2. Adjuvant therapy recommended in relationship to hormonal receptor and node statusa HR+ N+

Table 4. Type of prescribed chemotherapy with respect to the number of metastatic nodes, age and grading

Chemotherapy + endocrine therapy

HR– N+

Chemotherapy

HR+ N–

Endocrine therapy ± chemotherapy

HR– N–

Chemotherapy

No. of patients

Anthracyclines

No.

%

No.

%

87

24

11

No. of metastatic nodes

a

Goldhirsch et al. [6]. HR+, hormone receptor positive; HR–, hormone receptor negative; N+, node positive; N–, node negative.

0

210

186

1–3

218

135

62

83

38

73

181

54

30

127

70

29

8

28

21

72

36–49

258

154

60

104

40

50–69

392

260

66

132

34

51

41

80

10

20

Age (years) ≤35

≥70

No. of patients

CT + ET (%)

CT (%)

ET (%)

No therapy (%)

368

299 (81)

62 (17)

5 (1)

2 (1)

Well differentiated

46

36

78

10

22

289

187

65

102

35

281

160

57

121

43

Grading

HR– N+

83

12 (14)

71 (85)

0

0

Moderately differentiated

HR? N+

27

13 (48)

14 (52)

0

0

Poorly differentiated

HR+ N–

173

128 (74)

40 (23)

5 (3)

0

HR– N–

99

9 (9)

89 (90)

1 (1)

0

HR? N–

18

9 (50)

8 (44)

1 (6)

0

CT, chemotherapy; ET, endocrine therapy; HR+, hormone receptor positive; HR–, hormone receptor negative; N+, node positive; N–, node negative.

rather than those who had >10 positive nodes (33 of 46, 72%, P <0.034). The recommended treatment, chemotherapy alone, was more frequently prescribed to patients classified as having N+ HR– disease if they were pre- or perimenopausal (39 of 42, 93%) rather than postmenopausal (29 of 38, 76%, P <0.058). The number of metastatic nodes was also found significant for this cohort: chemotherapy alone was administered to 21 of 21 patients (100%) with 4–10, to 26 of 32 patients (81%) with one to three, and to 15 of 20 patients (75%) with >10 metastatic nodes (P <0.044). For patients with HR+ N– disease the recommended treatment was chemotherapy plus endocrine therapy or endocrine therapy alone. Instead, 23 of 77 women (30%) aged <50 years and 15 of 92 (16%) ≥50 years received chemotherapy alone (P <0.036). Moreover, the difference with respect to menopausal condition was also significant: 25 of 88 patients (28%) in pre- or perimenopausal and 12 of 82 (15%, P <0.030) in postmenopausal status were treated with chemotherapy alone. No significant difference was detected in the other patient subgroups. The most widely used adjuvant chemotherapy regimen was cyclophosphamide, methotrexate, 5-fluorouracil (CMF), administered to 453 of 754 patients receiving chemotherapy (60%), a fact that might be explained by the more frequent visits for this regimen, as compared with the every 3-week anthracycline regimens. Among these, 388 of 453 patients (86%) received a day 1 and 8 every 28 days intravenous schedule, 34 of 453 (7%) the

CMF, cyclophosphamide, methotrexate, 5-fluorouracil.

‘classic’ CMF (oral cyclophosphamide) and 31 of 453 (7%) the day 1 every 21 days intravenous schedule. Anthracyclines were used in 253 of 754 patients (34%). In 113 of 253 patients (45%) doxorubicin or epirubicin were used alone. Combination regimens were used in 253 patients (40%), 102 received doxorubicin plus cyclophosphamide or epirubicin plus cyclophosphamide and 28 (11%) either combination with the addition of 5-fluorouracil. Considering the 706 patients who were treated with either CMF or anthracyclines, the proportion of those treated with the latter increased significantly with the number of involved axillary nodes (χ2 = 141.8, P <0.0001), with higher tumor grade (χ2 = 9.123, P <0.011) and with lower age (χ2 = 25.36, P <0.0001) (Table 4). A selective estrogen receptor modulator was used as adjuvant endocrine therapy in 426 of 482 patients (88%), while its combination with a gonadotropin-releasing hormone analog was used in 35 of 482 patients (7%). No patient was submitted to adjuvant surgical oophorectomy.

Discussion Only a few studies have evaluated the degree of adherence in daily medical practice to cancer treatments identified as ‘the best available’ by clinical research. A prospectively defined audit focusing on adjuvant therapies of cancer is particularly relevant in those fields in which these therapies have been identified as most efficacious [7–9]. This study is the first to evaluate the adjuvant systemic therapies prescribed in Italy to women surgically treated for breast cancer in several Italian oncology centers. Almost all patients underwent chemotherapy (754 of 768, 98%); in many cases endocrine therapy was added (470 of 754,

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Table 3. Adjuvant therapy prescribed in relationship to hormonal receptor and nodes status: recommended therapy in bold type

HR+ N+

CMF

846

Acknowledgements We thank Glaxo Wellcome S.p.A. Italy for giving a grant covering the expenses for a organizational meeting among the participating centers and for printing and distribution of Clinical Record Forms and E. Roila and C. Lesandrelli for inputting data. Investigators and collaborating centers of the Drug Utilization Review Team in Oncology: Dipartimento di Medicina, Istituto Europeo di Oncologia, Milan (S. Cinieri, E. Verri, G. Peruzzotti, M. Mandalà, A. Dicorato, L. Orlando, F. Nolè, M. Colleoni, G. Martinelli, A. Goldhirsch); Oncologia Preventiva, Divisione di Oncologia Medica, Centro di Riferimento Oncologico, Aviano (A. Veronesi, C. Paolello, D. Lombardi, C. Scuderi, S. Spazzapan, D. Crivellari, M. D. Magri, A. Buonadonna); Dipartimento di Oncologia e Ematologia, Sezione di Oncologia, Policlinico, Modena (A. Frassoldati, R. Sabbatini, A. Zironi, M. Nicolini, L. Lombardo, A. Mode); Oncologia Medica, Ospedale Ascoli, Palermo (A. Biagio); Oncologia Medica, Ospedale S Bortolo, Vicenza (V. Fosser, L. Merlini, M. Megazù, P. Morandi, M. Gulisano, L. Biscari); Dipartimento di Medicina Clinica e Sperimentale, Ospedale Borgo Trento, Verona (G. Cetto, A. M. Molino, P. Manno, R. Pedersini, A. Dal Cin, M. Pavarana); Divisione di Oncologia Medica, Ospedale S Carlo Borromeo, Milan (S. Masseroni, R. Valsecchi); Divisione di Oncologia Medica, Policlinico, Perugia (R. Cherubini, S. Porrozzi, V. De Angelis); Unità Operativa di Oncologia Medica, Ospedale Renzetti, Lanciano (A. Nuzzo, N. D’Ostilio, S. Forciniti, A. Di Blasio); Cattedra di Oncologia Medica, Università, Cagliari (B. Massidda, M. T. Ionta, D. Vacca, I. Esposito); Dipartimento di Oncologia ed Ematologia, Ospedale S. M. Croci, Ravenna (A. Tienghi, U. De Giorgi, P. Giovanis, B. Kopf); Divisione di Oncologia, Azienda Ospedaliera, Parma (S. Salvaggi, R. Camisa, V. Franciosi, S. Cascinu); Unità Operativa di Oncologia Medica, Ospedale S Spirito, Casale Monferrato (M. Botta, A. Muzio, D. Degiovanni, B. Castagneto); Dipartimento di Oncologia, Ospedale degli Infermi, Biella (M. Clerico, M. Vincenti, G. Turrisi, C. Marinozzi); Oncologia Medica e Radioterapia, Ospedali Riuniti, Bergamo (R. Labianca, C. Tondini, N. Personeni, A. Personeni); Centro Catanese di Oncologia, Catania (M. Caruso, M Chiarenza, G. Mauceri); Unità Operativa di Oncologia Medica, Ospedale Bufalini, Cesena (M. Faedi, D. Bruschi, A. P. Rossi, R. Urbinati); Divisione di Oncologia Medica, Ospedale Civile, Castelfranco Veneto (P. Manente, G. Vicarlo, G. Sgarbossa, M. Bortolin); Unità Operativa di Oncologia Medica, Ospedale S Chiara, Trento (A. Lucenti, O. Caffo, A. Ferro, F. Valduga); Unità Operativa di Oncologia Medica, Ospedale Civile SS Annunziata, Sassari (M. Piras, G. Baldino, N. Olmeo, A. Deriu); Unità Operativa di Oncologia Medica, P. O. Mariano Santo, Cosenza (S. Palazzo, A. Rovito, A. Rea, C. M. Mastroianni); Oncologia Medica, Ospedale S. G. Addolorata, Rome (C. Megale, G. Mauri); Istituto Nazionale per la Ricerca sul Cancro di Genova, Sezione di Rome (S. Tomao, A. Romiti, L. Santuari); Oncologia Medica, Dipartimento di Medicina Sperimentale e Patologia, Policlinico Umberto I, Rome (E. Cortesi, M. Palma, A. Mancuso); Dipartimento di Oncologia Medica, Ospedale S Spirito, Pescara (M. Lombardo, D. Luisi, P. Di Stefano); Day Hospital Oncologico, Ospedale Perrino, Brindisi (M. C. Chetrì, P. Rizzo); Clinica di Oncologia Medica, Università, Ancona (N. Battelli); Unità

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62%); and only a few patients received only endocrine therapy (12 of 768, 2%), while two patients did not receive adjuvant therapy (Table 3). The distribution of the population by treatments is obviously biased by the larger proportion of patients going to an oncology ward who are thus more likely to receive therapy. The majority of the ‘well’ patients to whom adjuvant therapy was either not prescribed or was based upon endocrine agents rarely attend the clinic. The findings were striking. About one in five of the patients did not receive endocrine therapy as suggested by pragmatic international guidelines [6]. In particular, 19% of patients with endocrineresponsive disease were not scheduled to receive adjuvant endocrine therapy. On the other hand, endocrine therapy was administered to 12% of patients classified as having HR– disease. It must be recognized that several patients of the latter group are likely to have tumors expressing HR in a few cells. Recent information provides some justification for offering endocrine treatment to patients with tumors which contain as few as 2% or more immunostained cells [10]. The preference to consider chemotherapy as the sole proper treatment, even for patients with endocrine-responsive disease, might be due to the fact that for some oncologists the higher the risk of relapse the less ‘important’ is the endocrine component of the adjuvant treatment program. In fact, 13 of 46 patients with endocrine-responsive disease and >10 axillary nodes involved underwent chemotherapy alone; this indicates the common prejudice of oncologists for the exclusive role of intensive cytotoxics in controlling poor prognosis disease, even if it is highly endocrine responsive. It is noteworthy that, according to international guidelines, these patients should also have received endocrine therapy. CMF was the most used chemotherapy regimen, but anthracyclines were more frequently used in the youngest patients, in those with the highest grade and in those with a larger degree of involvement of axillary nodes. Taxanes, alone or in combination, were seldom used as adjuvant chemotherapy. During the 2001 St Gallen Conference an updated experts’ consensus was issued [11] with significant changes in some key features: risk categories were simplified; patient preferences were incorporated more clearly in the treatment choice; and no group was defined as being excluded from adjuvant systemic therapy, thus recognizing that many patients consider treatment worthwhile even for small benefit. Most importantly, selection of treatment was recommended to be primarily based on endocrine responsiveness. This latter event emphasizes the need for a substantial educational program for the medical community to increase its awareness of the rapid progress in breast cancer therapeutics, and this in turn could have a significant public-health impact. The results of this study are intended to be part of an Italian national program for transfer of information in order to favor proper patient care. It is intended that 1 year after the publication of these data a re-audit of prescription patterns in the same institutions will take place. The failure to prescribe proper programs of adjuvant therapies to one in every five breast cancer patients should be considered unacceptable.

847 Mare); Unità Operativa di Oncologia, Avezzano (F. Recchia, S. De Filippis); Unità Operativa di Oncologia, Ospedale Bellaria, Bologna (G. Benedetti, L. Scopece); Oncologia Medica, Ospedale Campo di Marte, Lucca (G. R. Barsanti, M. Battistoni); Divisione Oncologia Medica, Ospedale S Vincenzo, Taormina (F. Ferraù, P. Colina); Oncologia Medica, Ospedale Generale Provinciale, Saronno (G. Schieppati, E. Milvio); Dip. Medicina Interna e Scienze Oncologiche, Università, Perugia (L. Patoia); Dipartimento Medicina Sperimentale e Patologia, Policlinico Umberto I, Rome (S. Mezi); Divisione di Oncologia Medica, USL 12, Venice (A. Paccagnella, M. G. Ghi, R. Biason); DH Oncologico, Ospedale Umberto I, Enna (R. Carroccio); Radioterapia Oncologica, Ospedale Civile, Barletta (M. Serlenga); Oncologia Medica B, Istituto Tumori Pascale, Naples (L. Silvestro); Ambulatorio Oncologico, Ospedale S. M. Pietà, Nola (O. Marano); Divisione Oncologia Medica 3, Ospedale Oncologico, Cagliari (V. Mascia); Unità Operativa Autonoma di Oncologia, Ospedale E. Agnelli, Pinerolo (V. Sidoti); Unità di Senologia e Chemioterapia nella Patologia Mammaria, Ospedale Ascoli Tomaselli, Catania (G. Maugeri); Oncologia Medica, Casa di Cura Musumeci, Catania (A. Mangiameli); Unità Operativa di Oncologia Medica, Dipartimento Oncoematologico, Ospedale Generale, Civitanova Marche (F. Sturba); Cattedra e Unità Operativa di Oncologia Medica, Policlinico, Bari (I. Lolli); Oncologia Ginecologica, Ospedale Civile, Palermo (F. M. Romano); DH Oncologico, Ospedale Civile, Chioggia (A. Prosperi); Oncologia Medica, Azienda Ospedale S. G. Moscati, Monteforte Irpino (F. Del Gaizo); Servizio Oncologia Medica, Ospedale S. Antonio Abate, Tolmezzo (E. Vigevani); Oncologia, Ospedale Apicella, Pollena (E. Russo); Divisione Oncologia, Ospedale SS Annunziata, Antella (I. Meucci); Unità Operativa Semplice di Oncologia Medica, Azienda Sanitaria, Firenze (L. Fioretto).

References 1. Wright J, Williams DDR, Wilkinson JR. Health needs assessment: development and importance of health needs assessment. Br Med J 1998; 316: 1310–1313. 2. Williams R, Wright J. Health needs assessment: epidemiological issues in health needs assessment. Br Med J 1998; 316: 1379–1382. 3. Liberati A, Apolone G, Nicolucci A et al. The role of attitudes, beliefs and personal characteristics of Italian physicians in the surgical treatment of early breast cancer. Am J Public Health 1990; 81: 38–42. 4. Grilli R, Apolone G, Marsoni S et al. The impact of patient management guidelines on the care of breast, colorectal, and ovarian cancer patients in Italy. Med Care 1991; 29: 50–63. 5. O’Connor G, Quinton HB, Traven ND et al. Geographic variation in the treatment of acute myocardial infarction. The Cooperative Cardiovascular Project. J Am Med Assoc 1999; 281: 627–633. 6. Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: International Consensus Panel on the treatment of primary breast cancer. J Natl Cancer Inst 1998; 90: 1601–1608. 7. Early Breast Cancer Trialists’ Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996; 348: 1189–1196. 8. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451–1467.

Downloaded from http://annonc.oxfordjournals.org/ at Stockholm University Library on July 6, 2015

Operativa di Oncologia Medica, Ospedale S M Goretti, Latina (M. D’Aprile, F. Cardillo, G. Pistilucci); Unità Operativa di Oncologia Medica, Dipartimento Oncoematologico, Ospedale S Salvatore, Pesaro (A. Fedeli, D. Rossi, A. M. Baldelli); Unità Operativa di Oncologia Medica, Ospedale S Carlo, Potenza (L. Manzione, G. Rosati, A. Rossi); Medicina Sperimentale, Università, L’Aquila (P. Marchetti); U. O. Oncologia Medica-DH, Azienda Ospedaliera Umberto 1°, Siracusa (S. Spada, M. G. Bonaiuto, M. Spada); Oncologia Medica, Azienda Ospedaliera, Ragusa (C. Iacono); Oncologia Medica, Istituto Oncologico, Bari (L. Caporusso); Unità Operativa di Oncologia Medica, Ospedale Civile, Asti (F. Testore, R. Manfredi, E. De Conciliis); Oncologia Medica, Ospedale S Lazzaro, Alba (G. F. Porcile, A. Dalla Mola, F. Castiglione); Oncologia Medica, Ospedale S Cuore-Don Calabria, Negrar (M. Nicodemo, V. Picece, R. Magarotto); Servizio Oncologia, Presidio Ospedaliero, Lugo (G. Cruciani); Dipartimento Oncologico, Azienda Ospedale L. Sacco, Polo Universitario, Milan (E. Piazza, N. Tosca); Clinica Ostetrico-Ginecologica, Policlinico Umberto I, Rome (M. L. Frammarino dei Malatesta); Unità Operativa di Medicina Interna, DH Oncologico, Ospedale Civile, Sassuolo (G. Santacroce, G. Partesotti); Unità Operativa di Medicina Oncologica, Ospedale Ramazzini, Carpi (L. Scaltriti, F. Artioli); Divisione Oncologia Medica, Ospedale Civile, Ivrea (S. Bretti, S. Bombaci); Unità Operativa di Oncologia Medica, Ospedale S Croce, Fano (R. Mattioli, G. Laici); Day Hospital Oncologico-Senologia, Ospedale Civile, Lucera (R. Laricchiuta, A. Suriano); Oncologia Medica, Ospedale Miuli, Acquaviva Fonti (G. Lucarelli); Oncologia Clinica, Università G. D’Annunzio, Chieti (M. T. Scognamiglio, M. Tinari); Oncologia Medica, Ospedale Mazzoni, Ascoli Piceno (R. Trevisonne, D. Morale); Oncologia Medica, Ospedale Civile, Vittorio Veneto (L. Salvagni, V. Palmisano); Clinica Oncologica, Policlinico Universitario, Udine (F. Puglisi, M. Ramello); Dipartimento di Medicina Clinica e Scienze Cardiovascolari, Università Federico II, Naples (S. Cigolari, V. Angelini, V. Guardasole); Unità Operativa di Oncologia Medica Ospedale A. Cardarelli, Naples (T. Guida, R. D’Antonio); Radioterapia Oncologica, Ospedale Maggiore Caritò, Novara (M. Krengli); Oncologia Medica, Centro Oncologico, Trieste (G. Mustacchi, R. Ceccherini); Oncologia Medica, Ospedale G. di Maria, Avola (P. Tralongo, A. Dimari); Unità Operativa di Oncologia Medica, Presidio Ospedaliero SS Luigi e Currò, Catania (R. Bordonaro, G. Failla, D. Giuffrida, P. Salice); Oncologia Medica, Ospedale Civile, Lamezia Terme (E. Greco, C. Aiello); Servizio di Oncologia, Ospedale San Giovanni di Dio, Crotone (T. Prantera, M. Anania); Oncologia Medica, Ospedale Macchiarella, Palermo (T. Sciacchitano); Unità Operativa di Oncologia Medica, Azienda Sanitaria n. 12, S Benedetto del Tronto (G. De Signoribus, F. Giorgi); Oncologia Medica, Ospedale Cervello, Palermo (G. Solina); Unità di Senologia, Casa di Cura Oncologica La Maddalena, Palermo (A. Marrazzo, P. Taormina); Oncologia Medica, Ospedale G. Rummo, Benevento (G. P. Ianiello, V. Tinessa); Unità Operativa di Oncologia Medica, Azienda Sanitaria, Castrovillari (G. Cicero, G. Di Pinto); Oncologia Medica, Ospedale Civile, Paola (G. F. Filippelli, A. Caputo); Unità Operativa di Oncologia Medica, Olbia (S. Ortu, T. Pira); Unità Operativa di Oncologia Medica, Policlinico Universitario G. Martino, Messina (S. Munaò, M.

848 9. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–942. 10. Harvey JM, Clark GM, Osborne CK et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17: 1474–1481.

11. Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol 2001; 19: 3817–3827.

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