1 Divisione Oncologia Medica, Ospedale Policlinico, Perugia; 2 Unità di Statistica Medica, Dip. Medicina Interna e Salute Pubblica, Università, LAquila; 3 Dipartimento Medicina Interna e Scienze Oncologiche, Università, Perugia; 4 Divisione Oncologia Medica, Cosenza; 5 Oncologia Preventiva, Centro di Riferimento Oncologico, Aviano, Pordenone; 6 Divisione Oncologia Medica, Policlinico, Modena; 7 Divisone Oncologia Medica, Ospedale Borgo Trento, Verona; 8 Dipartimento di Medicina, Istituto Europeo di Oncologia, Milan, Italy
Received 30 October 2002; revised 14 January 2003; accepted 24 February 2003
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Abstract |
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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 life-saving procedures, like adjuvant systemic treatments, in cancer medicine.
Key words: adjuvant therapies, breast carcinoma, drug utilization review, guidelines adherence, practice guidelines
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Introduction |
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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 [25].
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 high-quality 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].
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Patients and methods |
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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 HR-unknown (HR?) according to estrogen and/or progesterone receptor expression determined by each centers 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 patients co-morbid conditions.
To compare two (or more) proportions, a two-tailed 2-test or Fishers exact test (generalized by FreemanHalton), in the case of at least one frequency less than 5, were used.
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Results |
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The prescribed treatments were compared with the latest recommendations (at that time) of the St Gallen International Consensus Panel (Table 2) [6].
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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 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 (2 = 141.8, P <0.0001), with higher tumor grade (
2 = 9.123, P <0.011) and with lower age (
2 = 25.36, P <0.0001) (Table 4).
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Discussion |
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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, 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 endocrine-responsive 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.
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Acknowledgements |
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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. DOstilio, 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 Operativa di Oncologia Medica, Ospedale S M Goretti, Latina (M. DAprile, 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, LAquila (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. DAnnunzio, 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. DAntonio); 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. 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).
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Footnotes |
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Members of the Drug Utilization Review Team in Oncology are listed in the Acknowledgements
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References |
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