Annals of Oncology Advance Access originally published online on June 21, 2006
Annals of Oncology 2006 17(9):1386-1392; doi:10.1093/annonc/mdl132
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© 2006 European Society for Medical Oncology
breast cancer |
Adjuvant systemic treatment of early breast cancer: the NORA study
1 Medical Oncology, Treviglio Hospital, Treviglio
2 Medical Oncology, University of Trieste, Trieste
3 Medical Oncology, La Spezia Hospital, La Spezia
4 Medical Oncology, Pascale Institute, Napoli
5 Medical Oncology, Careggi Hospital, Firenze
6 Oncology Department, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milano, Italy
*Correspondence to: Dr M. E. Cazzaniga, Medical Oncology, Treviglio Hospital, Treviglio (BG), Italy. Tel: +39-0363424303; Fax: +39-0363424380; E-mail: oncologia{at}tin.it
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionconclusionsAcknowledgementsReferences |
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Background: Despite recommendations contained in international guidelines, factors such as the type of oncology centre, geographic distribution and the introduction of scientific advances into clinical practice can influence the choice of recommended treatment for early breast cancer. The NORA study is a prospective, longitudinal cohort study aimed at investigating tumour characteristics, treatment modalities, and other factors that influence therapeutic choices in early breast cancer patients who have undergone mastectomy or breast-conserving surgery (BCS).
Patients and methods: From January 2000 to early 2004, we collected data on methods of cancer diagnosis, type of surgery and adjuvant medical treatment administered to the first 10 consecutive patients treated in 2000–2002 and the first 20 consecutive patients in 2003 and 2004 at 71 oncology centres in Italy, with the approval of the ethical committee at each centre.
Results: Approximately one-quarter of the cases (26.5%) were detected through screening programmes. BCS was performed in 63.7% and sentinel node biopsy (SNB) occurred in 11.1% of the patients. Of the 3515 total cases, 56.5% were node-negative. Grade 2 cancers comprised 51.3%, and 66.2% were hormone-receptor positive (ER+/PgR+). Chemotherapy (CHT) followed by hormone therapy (HT) was the most prescribed treatment (48.5%). CHT was mainly anthracycline-based (52.9%) and most patients received tamoxifen alone (77.7%) or after CHT (85.2%). For node-negative patients, HR+ and menopause status are the factors influencing the choice to add HT after CHT; patients with HR+ and pT4 tumours are more likely to receive HT instead of CHT. In node-positive patients, the addition of HT is influenced by HR+ status, the opportunity to have HT instead of CHT, and menopause.
Conclusions: NORA is the first large cohort study to describe the factors that influence therapeutic choices in early breast cancer. Understanding these findings can help physicians in daily clinical practice.
Key words: adjuvant therapy, breast cancer, cohort study
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsAcknowledgementsReferences |
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Breast cancer is the most common cancer in women in Western countries, accounting for approximately 20% of all malignant tumours. In Italy, breast cancer incidence increased by 1.7% in the last decade, and the estimated number of new cases reached 130 000 in 2001 [1].
Adjuvant treatments for operable breast cancer are well defined both by the St. Gallen guidelines [2, 3] and by the American Consensus Conference held in Bethesda, Maryland in 2000 [4]. International guidelines state that hormone therapy (HT) must be limited to patients with positive hormone-receptor (HR+) status. Tamoxifen remained the standard hormone treatment at least until the 2003 St. Gallen Consensus Conference. They also recommend that regardless of age, menopausal status, nodal involvement and tumour (T) stage, chemotherapy (CHT) must be offered to all patients, except those at low risk of relapse [3].
Although adjuvant medical treatment is well defined by these various guidelines, other factors may influence the choice of a particular therapy in clinical practice. These factors may be related to the type of the oncology centre (i.e. academic versus general hospitals), their geographical distribution or the application of scientific advances in clinical practice.
On the basis of these observations, we designed the National Oncological Research survey on adjuvant therapy in breast cancer (NORA) study to obtain information regarding adjuvant treatment strategies selected for early breast cancer patients who had undergone surgery; the study primarily focused on identifying the factors that play a leading role in therapeutic choice. Secondary aims included describing the choices available for adjuvant treatments, assessing the extent to which treatment patterns observed in clinical practice conform to international breast cancer treatment guidelines, and monitoring patient outcomes in terms of disease-free survival, site of relapse and overall survival.
In this article, which will serve as a reference for future publications about the NORA study, we describe the study design, the baseline characteristics of study participants and the results in regard to the primary focus of the study.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsAcknowledgementsReferences |
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The NORA survey is a multicentre, longitudinal, observational cohort study. Participating oncological centres were a mix of academic and non-academic institutions, distributed throughout Italy, in order to be representative of the national situation.
Each centre was asked to record data for the first 10 consecutive patients with early breast cancer treated in 2000, 2001 and 2002 (the retrospective cohort) and for the first 20 consecutive patients with early breast cancer who reached their oncology units in 2003 and 2004 (the prospective cohort), for a total of at least 50 patients at each centre. These criteria were chosen to maximise enrolment and, at the same time, to provide an adequate follow-up period and suitable coverage for enrolled patients. Patients with a first diagnosis of invasive breast cancer and absence of metastatic disease were included. Women with in situ carcinoma as the sole diagnosis and those who had undergone surgery with palliative intent (macroscopic residual disease) were considered ineligible. Concurrent participation in a clinical study was not a criterion for exclusion; however, the numbers of patients enrolled in clinical studies were to be limited to less than 20% in the retrospective cohort and less than 40% in the prospective cohort. Data concerning demographic characteristics, family and pathological history, and diagnostic methods, as well as information on surgery, pathological features and adjuvant treatments were collected. The plan also called for data collection on changes in adjuvant treatment, toxicity and cancer-related events, thus, all patients were to be followed for a minimum of 4 to a maximum of 8 years, at 6-month intervals.
The study complied with the requirements of Italian law regarding observational studies. The nature and purpose of the survey were explained in detail to each participant and consent to data handling according to Italian regulations on privacy was obtained.
Assuming that 70 centres would enrol a minimum of 50 patients each, the total planned enrolment was about 3500 women. This number would allow us to obtain an estimate of the distribution of adjuvant strategies, with a 95% confidence interval (CI) of 3% or less. Because no significant differences between the prospective and retrospective cohorts were expected, the two groups were considered as a whole in the analysis.
An independent coordinating centre was responsible for controlling and validating collected data by means of checks on missing or inconsistent values.
A multivariate regression analysis model for categorical data was used to estimate the independent and concomitant extent of association between the choices of adjuvant treatment (CHT + HT versus CHT followed by HT versus CHT) and potential determinants such as pT stage, nodal status, HR status and menopausal status. In the model, the first-level interaction terms, such as T0–1 were also included. Results are reported as odds ratios (ORs) with 95% CIs. Analyses were performed using SAS (Statistical Analysis System, SAS Institute Inc., Cary, NC, USA, Version 8.20) software; a value of P <0.05 was used to determine statistical significance. All tests were two-sided.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsAcknowledgementsReferences |
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A total of 3532 breast cancer patients were enrolled by 71 Italian centres. Seventeen patients (0.5%) were subsequently excluded due to synchronous tumours and 3515 patients remained valuable for the analysis. Academic institutions comprised 21.2% of the centres; 42.3% are located in northern Italy, 28.2% in central Italy and 29.6% in southern Italy and the islands. Therefore, both the type and geographical distribution of the institutions are well distributed and representative of the national situation.
The retrospective cohort included 2075 women (59%); 669 (32.2%) were enrolled in 2000, 697 (33.6%) in 2001 and 709 (34.2%) in 2002. Most patients in the prospective cohort (1335, 92.7%) were enrolled in 2003, while 105 (7.2%) were enrolled in 2004. Patients enrolled in clinical trials accounted for 4.9% of the total population.
The median age of patients was 58 years (range 25–92 years) and 40.3% of patients were in the group aged 50–64 years. Almost all patients presented a good Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0–1: 98.1%) and were postmenopausal when breast cancer was diagnosed (72.3%). Approximately one-third of the patients had a positive history of cardiovascular (24.1%) or gynaecological (13.2%) co-morbidities. The demographic characteristics of the patients are listed in Table 1.
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Table 2 describes principal data concerning diagnostic procedures, histology, biological characteristics and surgery. Approximately one-quarter of the breast cancers (791 out of 2989 available data, 26.5%) were detected through screening programmes; most of the breast cancers (48.2%) were discovered as a result of self-examination. The most frequently performed diagnostic procedures were mammography alone (44.5%) or with ultrasonography (49.5%). In 930 cases (36.9%) the diagnosis was done via biopsy performed during the surgical procedure.
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BCS was performed in 2238 cases (63.7%), with the highest percentage of BCS (79.4%) performed on women with tumours up to 2 cm. Sentinel node biopsy (SNB) was performed in 390 cases (11.1%), reaching 15.2% in patients suitable for a conservative approach in comparison to those who underwent mastectomy (4.0%)
Ductal carcinoma was the most frequent histological subtype (78.0%), followed by lobular (11.8%) and mixed histotype (5.7%). In 26.9% of the cases, in situ cancer was detected in association with the invasive form.
Most of the tumours were grade 2 (51.3%) and the Ki-67 labelling index was positive (cut-off 10%) in 68.8% of cases. The human epidermal growth factor receptor 2 (HER2) determination was available in 1621 cases (46.1%); HER2 was overexpressed (3+) in 18.7% of cases. HRs were both oestrogen-receptor positive (ER+) and progesterone-receptor positive (PgR+) in 2238 patients (66.2%); 592 patients (17.5%) had unresponsive endocrine disease (ER-/PgR-).
Approximately one-half of the patients (1922, 56.5%) were node-negative, while 17.1% of patients had more than four positive axillary nodes. As expected, massive axillary involvement was more frequently associated with large tumours although 19.5% of the patients with T1 tumours presented node-positive status. On the other hand, node status was negative in 0.7% and 0.8% of T3 and T4 cancers, respectively. The median number of resected nodes was 16 (range 0–77).
Adjuvant medical treatment was administered in 97.8% of the cases. Approximately one-half of patients (48.5%) received CHT followed by HT; HT alone was prescribed in 31.0% of cases. Tamoxifen was the most widely used drug, both when administered as HT monotherapy (843/1087, 77.7%) and in combination with CHT (85.2%). Aromatase inhibitors (AIs) were prescribed for 14.3% of the patients suitable for HT alone, and for 201 out of 1702 (11.8%) of those who also received CHT.
Anthracycline-based regimens, two- or three-drugs combinations, were administered to more than half of the patients as sole therapy (342 of 646, 52.9%) or before HT (884 of 1702, 51.9%). Taxanes were used in approximately 5% of the cases (CHT 4.4%; CHT + HT 4.5%). Details concerning adjuvant medical treatment are listed in Table 3.
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No difference has been observed in terms of treatment choice, according to the typology of the centres (academic versus general hospital): CHT followed by HT was the most frequent treatment in both cases. Concerning the geographical distribution, in the northern regions, HT alone was more frequently administered (16.7%) than in the south of the country (4.5%), even if in all cases, CHT followed by HT was the preferred treatment. This could be explained by the higher number of scientific events taking place in the north, which could lead to a better knowledge of the literature results.
We analysed the influence of pT stage, nodal status, HR status and menopausal status on the choice of adjuvant medical treatment using a multivariate regression analysis model; results are reported in Table 4.
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Because a statistically significant interaction was found between pT and nodal status (
2 = 39.27; 6 df; P < 0.0001), we conducted two separate analyses, one using data from node-negative patients and the other using data from node-positive patients. For node-negative patients, all variables included in the model affected the addition of HT to CHT treatment. Using pT0–1 patients as a reference, the only pT category with a statistically significant difference was pT3 in which HT was almost never added to CHT (OR 0, 95% CI 0–0.2, P = 0.0032). With respect to HR status, the positivity of both receptors (ER+/PgR+) significantly increased the likelihood of receiving CHT+HT (OR 362.3, 95% CI 136.6–961.3, P < 0.0001) in comparison to CHT alone, and this probability remains high in ER+/PgR- patients (OR 81.7, 95% CI 22.0–303.2, P < 0.0001). Postmenopausal women received CHT+HT more frequently than premenopausal ones, instead of CHT alone (OR 4.8, 95% CI 2.7–8.6, P < 0.0001).
The probability of receiving HT instead of CHT was strongly influenced by the presence of a pT4 tumour (OR 16.0, 95% CI 3.2–79.8, P = 0.0007), while the other categories of pT did not seem to influence therapeutic choice. The effect of receptor status showed a trend similar to that of the previous analysis: an increased probability of receiving HT for ER+/PgR+ patients (OR 105.3, 95% CI 43.9–252.5, P < 0.0001) and for ER+PgR- patients (OR36.6, 95% CI 10.5–128.1, P < 0.0001). Menopausal status did not affect the choice of therapy.
In node-positive patients, after adjusting for the other variables, tumours larger than T0–1 did not seem to increase the probability of receiving any particular therapy. The choice of adding HT to CHT was influenced by the presence of both positive receptors (OR 76.9, 95% CI 34.4–171.9, P < 0.0001) or at least ER positivity (OR 645.7, 95% CI 12.8–336.9, P < 0.0001), as observed in the node-negative group. The probability of receiving HT instead of CHT seemed to be influenced by HR status to an extent comparable with that observed in node-negative patients. Menopausal status did not seem to have any statistically significant influence in the choice to add HT to CHT (OR 0.7, 95% CI 0.4–1.3); on the contrary, it was one of the factors increasing the administration of HT in lieu of CHT (OR 7.0, 95% CI 2.8–17.1, P < 0.0001).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsAcknowledgementsReferences |
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The principal purpose of the NORA study was to describe tumour characteristics and adjuvant treatment modalities in a population of 3515 early breast cancer patients thought to be representative of the national situation in Italy. Only one prior audit survey was conducted in Italy by Roila and colleagues [5] in 2000 during a one-week observation period in which data on 768 breast cancer patients were collected. They found the highest incidence of breast cancers in women aged 50–69 years (52%), and our study confirms that woman in this age group are at higher risk of developing breast cancer. In the prior survey, 49% of patients were postmenopausal, 70% were HR+, 62% were node-positive and 48% had tumours sized <2 cm. In our study, the majority of patients (72.3%) were postmenopausal at diagnosis, 80.0% were HR+, 56.5% were node-negative and 59.5% had tumours <2 cm.
Compared with the prior survey, we observed an increase of nearly 50% in the proportion of postmenopausal women diagnosed with breast cancer; this could be explained by the fact that age at menopause is reportedly increasing in many Western countries [6, 7].
We also observed a slight decrease in axillary node involvement and an increase in the percentage of tumours <2 cm, which may result from widespread use of screening programmes throughout Italy. We are doing a further analysis to compare the characteristics of tumour detected via screening programmes with those discovered through self-examination.
Recently, Cutuli and colleagues [8] published a French survey conducted from September 2001 to April 2002, involving 1159 breast cancer patients. They reported T1 tumours in 49.5% of the cases and no nodal involvement in 76.7%; tumours were ER+ in 79.7% and PgR+ in 69.7% of cases. As in the French study, our results confirm the predominant finding of small tumours, although in our series, 32.7% of the T1 cases had positive axillary nodal status.
In our study, HER-2 status was determined in more patients (1621 out of 3515) compared with the French study (30.7%). In fact, HER2 was determined in 46.1% of our patients and was positive (3+) in 18.7% of them. The determination of HER2 overexpression has increased during the last few years, probably due to the increasing number of reports signalling its value as an independent prognostic factor and a predictive factor for CHT and HT response or resistance.
In our study, the BCS rate is lower than that reported in the French survey (77.5%), although the percentages are comparable for small (<2 cm) tumours.
SNB without axillary dissection was performed in a higher percentage of our cases in comparison with the French survey (7.1% versus 2%, respectively), demonstrating the widespread use and increasing accuracy of this technique in the last few years due to positive results from randomised studies [9, 10].
In our study, CHT was delivered in 66.9% of the cases, either alone (18.4%) or followed by HT (48.5%). This finding is quite different from that observed in the previous Italian audit [5], where 98% of the patients received CHT, but it is comparable with that reported by Cutuli et al. in the French survey (58.7%). This finding might be explained by the availability of robust data concerning the efficacy of HT in selected women, especially those with high expression of HR [11–13] and the new hormonal agents such as the AIs [14]. The use of AIs, in fact, is threefold higher in our patients compared with patients in the French survey (14.3% versus 5.4%, respectively); the use of AIs was not reported in the prior Italian survey. The use of AIs is expected to increase even more following the recent guidelines' recommendations.
Although the first preliminary results on the use of AIs in the adjuvant setting became available in the late 1990s, it was not until the 2003 St. Gallen Consensus Conference that anastrozole was recognised as an alternative to tamoxifen in patients for whom tamoxifen is contraindicated. The encouraging results coming from randomised trials of AIs in the metastatic setting [15, 16], as well as first results of randomised trials in the adjuvant context, and the presence of gynaecological and vascular co-morbidities in postmenopausal women have led clinicians to use AIs both as upfront therapy or sequenced after tamoxifen [17]. In our study, the use of AIs doubled in 2003 compared with the 2000–2002 period, from 8.8% to 17.9%, as reported in one of our previous communications [18]. It is likely that this increase occurred as a result of the St. Gallen Consensus Conference that occurred in early 2003, which recommended the use of AIs in women who cannot be treated with tamoxifen.
In the NORA population, the CHT combination most used was anthracycline-based, either CHT alone (52.9%) or followed by HT (51.9%). Two-drug regimens were used in 13.7% of the cases treated with CHT alone and 10.1% of those treated with CHT followed by HT, respectively. Anthracycline was also used in combination with cyclophosphamide and 5-fluorouracil as a three-drug regimen as the sole therapy or as part of a combination regimen with HT in 38.9% and 41.9% of the cases, respectively. No patient received only anthracycline.
Our data are quite different from those reported in the prior Italian study, where anthracycline-based regimens were used in 34% of patients. In that study, doxorubicin or epirubicin was administered as a single agent in 113 out of 253 patients (14.9%); two-drug combinations were used in 102 patients (13.5%), and three-drugs regimens were used in 28 patients (3.7%). The study reported that the proportion of patients treated with anthracyclines increased significantly as the number of involved axillary nodes increased and with higher tumour grades and younger age.
These differences could be the result of several reasons. First, our observations cover a longer time period than the previous survey, therefore NORA might have greater power to detect the application of international recommendations in clinical practice and the changes resulting from such applications. The 2001 St. Gallen guidelines [2] for the first time suggested the use of anthracycline-based regimens in high-risk node-negative patients. This statement could have contributed to changes in clinical practice, thus leading to the findings observed in the NORA population.
In addition, the Oxford meta-analysis and two other studies [18–20] have demonstrated the superiority of the cyclophosphamide/anthracycline/5-fluorouracil (CAF) regimen but not the anthracycline/cyclophosphamide (AC) combination over the classic cyclophosphamide/methotrexate/5-fluorouracil (CMF) in node-negative patients. The positive results of these latter studies could have changed clinical attitudes.
Results of adjuvant studies using taxane combinations had not been published at the start of the NORA study. Despite this consideration, taxane administration has been reported in a small number of patients in the NORA population (4.4%), alone or in combination with anthracyclines. The first positive results regarding the adjuvant use of taxanes were, in fact, published later [22, 23], but the earlier success of taxanes in the metastatic setting probably led clinicians to adopt them in the treatment of high-risk, node-positive young women. Their use was almost dismissed in patients enrolled in NORA in 2003 [18], probably after the publication of St. Gallen 2003 guidelines, in which routine use of these drugs was not recommended [3].
Among the features influencing the treatment in node-positive patients, the positivity of both receptors or at least the presence of ER but not menopausal status, is the only factor that leads clinicians to add HT after the completion of CHT.
Results emerging from our multivariate analysis suggest that clinical oncologists are attentive to the HR status; indeed, ER+ status, independent of PgR status, is sufficient to consider the disease hormone-responsive. In contrast and diverging from prior clinical practice, PgR+ status alone is no longer considered a reliable parameter for prescribing HT, as the St Gallen Consensus Conference stated [26].
Our findings concerning the use of sequential CHT/HT in premenopausal and perimenopausal women probably reflect the changes that have occurred in recent years, when data regarding the benefit of adding HT to CHT in young women became available [24, 25].
We observed that in node-negative patients, HR+ status and menopausal status positively influence the likelihood of having CHT followed by HT, independent of tumour size.
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conclusions |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsAcknowledgementsReferences |
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To date, this is the first large cohort study that describes tumour characteristics and clinical attitudes to try to detect factors in the clinical practice that can influence the choice of adjuvant treatment.
We observed a positive impact of international consensus meetings and published data on clinical practice, thanks to the continuing educational programmes of the scientific societies and the internet availability of clinical studies.
The attitudes of Italian oncologists have changed in the last few years: they are more attentive to the published results of clinical studies; in some instances they are quick to adopt proposed regimens, as in the case of AIs; in others, they abandon them when data are not so mature, as in the case of taxanes.
This large multicentre study was a useful instrument to measure and thereby understand better what happens in clinical practice and how patients with early breast cancer are treated. It is also a valid method for monitoring the application of findings from large randomised trials in daily clinical practice.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsAcknowledgementsReferences |
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Co-authors include: G. Nastasi, G. Rodà (Alzano Lombardo, BG); C. Massacesi, F. Marcucci (Ancona); M. Barduagni, L. Meliffi (Anzio, RM); F. Schittulli, R. Altieri (Bari); N. Marzano, M. Altieri (Bari); G. Paladini, A. Fini (Bologna); A. Huscher, S. Magrini (Brescia); M. C. Chetrì, P. Rizzo (Brindisi); C. Floris, M. C. Cherchì (Cagliari); B. Massidda, M. T. Ionta (Cagliari); F. Artioli, K. Cagossi (Carpi, MO); M. Botta, A. Muzio (Casale Monferrato, AL); G. Tansini, G. Sbalzarini (Casalpusterlengo, LO); P. Manente, G. Sgarbossa (Castelfranco Veneto, TV); M. Caruso, M. Chiarenza (Catania); M. Giordano, G. Luchena (Como); V. Liguori, S. Conforti (Cosenza); O. Garrone, M. Ocelli (Cuneo); L. Giustini, R. Bisonni (Fermo, AP); C. Modonesi, S. Gambetti (Ferrara); L. Doni (Firenze); A. Contillo (Foggia); S. Calpona, M. Dall'Agata (Forli'); M. D'Amico, A. Decensi (Genova); A. Tognoni (La Spezia); M. D'Aprile, M. Natali (Latina, RM); A. Bonetti, M. Zaninelli (Legnago, VR); A. Falcone, P. Giannessi (Livorno); B. Pistilli, L. Latini (Macerata); P. Spadaro, M. C. Ingemi (Messina); D. Tabiadon, S. Masseroni (Milano); A. Scanni, K. Borgonovo (Milano); V. De Pangher Manzini (Monfalcone, GO); G. Landi (Napoli); R. Thomas, G. R. Cortino (Napoli); E. Procaccini, A. P. Laprovitera (Napoli); G. Borea, M. Trunfio (Napoli); G. Barberis, A. Salzano (Napoli); D. Sartori, S. Coccato (Noale, VE); G. Lavenia (Palermo); L. Mesi (Palermo); G. Bernardo, A. Bernardo (Pavia); M. Danova, E. Collovà (Pavia); S. Gori, F. Ciacci (Perugia); G. Pandoli, D. Natale (Pescara); A. Gozza, C. Naso (Pietra Ligure, SA); B. Salvadori, S. Donati (Pisa); M. Di Lieto, A. Chiavacci (Pistoia); F. Tropea (Reggio Calabria); M. Nardi, D. Azzarello (Reggio Calabria); G. Genestreti, B. Rudnas (Rimini); R. Tonachella, E. Colella (Roma); P. Carlini, N. Salesi (Roma); E. Cortesi, R. Ferraldeschi (Roma); F. Scinto, V. Zagonel (Roma); M. Roselli, G. Del Monte (Roma); A. Pancotti (S. Omero, TE); C. Florillo, G. Di Giulio (Salerno); C. Verusio, E. Bossi (Saronno, VA); G. Sanna, M. A. Pinna (Sassari); A. Lavarello, M. C. Barzacchi (Sestri Levante, GE); T. Gamucci, T. Trapasso (Sora, FR); P. Salvatore, G. Pezzella (Taranto); M. Brugia, M. Tagliaventi (Terni); M. Porpiglia, C. Benedetto (Torino); S. Danese, E. Bertone (Torino); S. Barni (Treviglio, BG); R. Ceccherini (Trieste); M. Mansutti, G. Fasola (Udine); V. Fosser, L. Merlini (Vicenza); C. F. Pollera, C. Signorelli (Viterbo).
Data entry was by LINK Italia. Statistical analysis: I. Floriani, E. Rulli, L. Porcu, Clinical Trial Unit, Oncology Departement, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan.
Received for publication March 12, 2006. Revision received May 2, 2006. Accepted for publication May 3, 2006.
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