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
Received 30 October 2002; revised 14 January 2003; accepted 24 February 2003
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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Background: Evidence-based guidelines, consensus conferences and experts’ opinion are rarely promptly
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
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
Table 3. Adjuvant therapy prescribed in relationship to hormonal receptor and nodes status: recommended therapy in bold type
≥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
