REPORTS

Effects of Vinorelbine on Quality of Life and Survival of Elderly Patients With Advanced Non-Small-Cell Lung Cancer

The Elderly Lung Cancer Vinorelbine Italian Study Group

Correspondence to: Cesare Gridelli, M.D., Divisione di Oncologia Medica B, Istituto Nazionale per lo Studio e la Cura dei Tumori, via M. Semmola, 80131 Naples, Italy (e-mail: cgridelli{at}sirio-oncology.it).


    ABSTRACT
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Appendix: Study Organization
 References
 
BACKGROUND: Vinorelbine, a semisynthetic vinca alkaloid, represents a well-tolerated treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC). We explored the quality of life (QoL) of such patients in a multicenter randomized trial that compared vinorelbine treatment with supportive care alone. METHODS: Eligible patients were 70 years of age or older, had stage IV or IIIB NSCLC that was ineligible for radiotherapy, and had a performance status of 0-2 (a status of fully active to a status of capable of all self-care but unable to work). Vinorelbine was given intravenously on days 1 and 8 of a 21-day treatment cycle, for a total of six cycles. QoL was evaluated with European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-LC13, and the QoL data were analyzed by fitting a linear mixed model for each QoL scale. Survival curves were plotted and were compared with the Mantel-Haenszel test. Relative hazards of death and 95% confidence intervals (CIs) were estimated by the Cox model. RESULTS: Investigators, blinded to the results, stopped the trial early because of a low enrollment rate. (From April 1996 to November 1997, 191 of the 350 targeted patients were randomly assigned.) Data from 161 patients have been analyzed. Vinorelbine-treated patients scored better than control patients on QoL functioning scales, and they reported fewer lung cancer-related symptoms but reported worse toxicity-related symptoms. There was a statistically significant (two-sided P = .03) survival advantage for patients receiving vinorelbine; median survival increased from 21 to 28 weeks in the vinorelbine-treated group. The relative hazard of death for vinorelbine-treated patients was 0.65 (95% CI = 0.45-0.93). CONCLUSION: Vinorelbine improves survival of elderly patients with advanced NSCLC and possibly improves overall QoL.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Appendix: Study Organization
 References
 
Controversy surrounds the use of cytotoxic chemotherapy to treat advanced non-small-cell lung cancer (NSCLC). The survival advantage over supportive care is low and has been reliably demonstrated only with cisplatin-containing regimens (1), which induce severe toxic effects. The issue becomes more complex in instances of subgroups of patients who are likely to ill tolerate the potential toxicity of the treatment (2-4). Such is the case of elderly patients, i.e., those aged 70 years or more at diagnosis. Indeed, because of the physiologic reduction of functional reserve and the presence of comorbid conditions, elderly patients are often unsuitable for cisplatin-based chemotherapy. Consequently, they are usually excluded from clinical trials and, in clinical practice, they frequently receive treatments untried in terms of balance between toxicity and activity (5,6).

Vinorelbine is a semisynthetic vinca alkaloid that, as a single agent, was as effective as the vindesine/cisplatin combination in a large European randomized trial but was less effective than the cisplatin/vinorelbine combination (7). A phase II study of single-agent vinorelbine reported a 23% response rate, higher rates of regression of symptoms, and improvement in the performance status in elderly patients with advanced NSCLC, without causing any clinically significant toxicity (8).

The aim of the present multicenter randomized clinical trial was to evaluate the efficacy of vinorelbine compared with supportive care alone in terms of quality of life (QoL) and survival in elderly patients with advanced NSCLC.


    PATIENTS AND METHODS
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Appendix: Study Organization
 References
 
Eligibility Criteria

Well-performing (Eastern Cooperative Oncology Group [ECOG] performance status <=2) patients, aged 70 years or older, who had stage IV or stage IIIb (with pleural effusion or metastatic supraclavear lymph nodes) NSCLC were eligible. Diagnosis of NSCLC had to be cytologically or histologically confirmed. Exclusion criteria were the presence of brain metastases, previous chemotherapy, a history of another cancer (excluding nonmelanomatous skin cancer and in situ cervical cancer), reduced bone marrow or renal or hepatic function, and refusal of informed consent. The protocol was approved by the ethics committees of the participating institutions.

Treatment

Vinorelbine was given intravenously at a dose of 30 mg/m2 on days 1 and 8. The cycle was repeated every 3 weeks, for a maximum of six cycles. Treatment was interrupted earlier if progression of the disease was observed. At days 1 and 8, the minimum requirements for chemotherapy were a neutrophil count of 1.5 x 109/L or more, a platelet count of 100 x 109/L or more, a hemoglobin level of 8.0 g/dL or more, and no sign of organ toxicity (excluding alopecia). If one or more requirements were absent at day 1, chemotherapy was postponed for up to 2 weeks, after which investigators were free to choose the treatment strategy. Chemotherapy was withdrawn if it could not be given on day 8. Toxicity and the patient's refusal also resulted in the discontinuation of treatment. Participating investigators were free to choose supportive care. They were also free to prescribe palliative radiotherapy in both arms; however, it was suggested that contemporary chemotherapy and radiotherapy be avoided because of the risk of cumulative toxicity. Second-line treatment and crossover were not allowed. Antiemetic treatment planned in the protocol was methoclopramide (20 mg given as an intravenous bolus, before vinorelbine). No bowel program was employed.

Staging and Follow-up Procedures

Before entering the study, all patients underwent a clinical examination that included a two-view chest x-ray, computed tomography of the thorax and abdomen, and a bone scan for assessment of disease extension. During the study, before each dose of chemotherapy was administered, patients in the vinorelbine arm underwent a clinical examination that included a routine biochemistry work-up and blood cell counts; those patients assigned to the control arm were scheduled for six clinical evaluations, one evaluation every 3-4 weeks. Routine biochemistry work-ups and blood cell counts were chosen by the investigators according to their clinical practice. A response assessment was planned only in the vinorelbine arm after completion of the third and sixth cycles of chemotherapy, by repeating all staging procedures.

Quality of Life (QoL) Assessment

The European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and lung cancer-specific module (QLQ-LC13) were used for QoL evaluation. A baseline assessment was planned at the time patients were randomly assigned to treatment but before the assigned treatment was communicated to the patient. Thereafter, questionnaires were administered in the clinic before each course of chemotherapy in the vinorelbine arm and before each follow-up visit in the control arm. The EORTC QLQ-C30 questionnaire consists of multi-item functioning scales and both multi- and single-item scales for the evaluation of general cancer-related symptoms (9). The EORTC QLQ-LC13 module consists of single items that evaluate specific symptoms of lung cancer (10). Both questionnaires are designed for self-completion by the patient. Multi-item scales are computed by calculating the mean raw scores of single items and transforming them linearly so that all scales range from 0 to 100. For single items, only linear transformation is performed. For functioning scales (i.e., those exploring physical, role, emotional, cognitive, and social functioning and global health status), a higher value reflects a better level of function; but for symptoms scales and items, a higher value reflects worse symptoms.

Toxicity and Response Evaluation

Toxicity and tumor response were assessed only in the vinorelbine arm, as secondary end points of the trial. World Health Organization (WHO) criteria (11) were used to categorize toxicity; the worst degree of toxicity experienced throughout the treatment was computed for each patient.

Objective responses were evaluated at the end of the third and sixth cycle of treatment by repeating staging procedures. The best response was recorded for each patient. For clinically evident or suspected progression of the disease, response evaluation was anticipated. Complete response was defined as the disappearance of all known sites of disease. Partial response was defined as a decrease of 50% or more in the sum of the products of largest perpendicular diameters of measurable lesions with no appearance of new lesions and no progression of any lesion. Stable disease was defined as a decrease of less than 50% or an increase of less than 25% in the sum of the products of largest perpendicular diameters of measurable lesions, with no appearance of any new lesion. Progressive disease was defined as a 25% or more increase in the size of one or more measurable lesions or the appearance of a new lesion. Confirmation of a response after 1 month was not performed. The objective response rate was defined as the proportion of complete and partial responses for all patients randomly assigned to the vinorelbine arm.

Statistical Methods

QoL was the primary end point of the study. No previous evaluations of the effect were available. Thus, we targeted the study to have a power of 80% to recognize an effect of 30% (i.e., a difference between mean scores of global health status equal to 30% of the standard deviation) at the third assessment after patients were randomly assigned to treatment (12). About 350 patients were needed (SOLO Statistical System Power Analysis, BMDP Statistical Software, Cork, Ireland, 1991). Three interim analyses with overall survival as end point were also planned with the use of an alpha-spending function (13) based on an O'Brien-Fleming (14) sequential group design (EaSt, Cytel Software Corporation, 1993). A potential follow-up of at least 18 weeks was required for analysis.

Patients were randomly assigned to treatment centrally at the Data Coordinating Center. Patients were assigned to one of the two study arms by a computer-driven minimization procedure (15) that used the center, stage of disease at entry (IIIb/IV), and the ECOG performance status (0/1/2) as stratification variables.

The effect of vinorelbine on QoL was evaluated by fitting a linear mixed model for each EORTC scale (16). The five QoL assessments after the baseline were coded as four dummy variables. The model also included two subject-level covariates (treatment and baseline score) and a time-varying indicator covariate as observation-level covariate to model the dropout process; for each patient, this variable was defined as -1 if the QoL assessment was not the last available one and as +1 at the last observation before the patient dropped out. Because there were only five response points for each scale, an unstructured (fully parametrized) within-subject covariance matrix was used in the analysis; that is, variances and covariances were allowed to vary at each observation point. Intermittent missing values were assumed to be completely at random. Patients missing the baseline assessment were excluded from the QoL analysis. BMDP-5V (BMDP Statistical Software 7.0, 1992) was used for the QoL analysis. All P values were two-sided.

Overall survival was defined as the interval from the date of randomization and the date of death or last follow-up information for living patients. Patients were analyzed according to an intention to treat rule. Survival curves were drawn by using the Kaplan-Meier product limit method (17) and compared by using the Mantel-Haenszel test (18). The relative hazard of death and 95% confidence interval (CI) were estimated by Cox proportional hazard model (19) using treatment, stage of disease (IIIb/IV), and ECOG performance status (0/1/2) as covariates.

Study Flow

Patient recruitment started in April 1996. The first interim survival analysis was performed as of May 1997 and did not lead to trial interruption. At the second annual meeting of the group in November 1997, the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) investigators, blinded to results, decided to stop the trial because of the low enrollment rate. At that time, 246 patients had been accrued and 191 had been randomly assigned to treatment (Fig. 1).Go Of these patients, 161, randomly assigned before June 30, 1997, were eligible for survival analysis, fulfilling the requirement of a potential follow-up of at least 18 weeks. Among the remaining 30 patients, 15 had been randomly assigned to the vinorelbine arm and 15 had been assigned to the control arm. However, after the disclosure of the survival results, the latter patients were offered vinorelbine treatment on an ethical basis; as a consequence, eight of them actually received vinorelbine, possibly confounding the validity of comparisons. Thus, the 30 patients randomly assigned after June 30, 1997, were excluded from the comparisons. Follow-up results of the 161 subjects analyzed are reported in this paper, updated as of June 30, 1998. Eighty patients were assigned to receive chemotherapy with vinorelbine and 81 patients were assigned to receive supportive care (control arm). Seven patients (four and three patients in the two arms, respectively) were excluded because no information had been sent to the coordinating center.



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Fig. 1. Study flow diagram. Patients randomly assigned to treatment before June 30, 1997, are the focus of this report. Control treatment is supportive care alone.

 

    RESULTS
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Appendix: Study Organization
 References
 
The characteristics of 154 assessable patients (seven of the 161 patients with a potential follow-up of 18 weeks were excluded because of a lack of data) by treatment arms are summarized in Table 1.Go They were prevalently males (median age, 74 years), and three fourths had a stage IV disease. More than 80% of the patients had a suboptimal (>=1) ECOG performance status. Baseline characteristics were well balanced between the two study arms.


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Table 1. Baseline characteristics of patients

 
Quality of Life

Baseline questionnaires were filled in by 141 (91.6%) subjects. There was no difference in baseline scores of the QoL scales between the two treatment groups in all of the analyzed domains. Suboptimal values of baseline global health status (defined as values greater than the central score of 50) were found in 36.8% and 31.5% of patients in the control and vinorelbine arms, respectively.

Patients' compliance to QoL assessment by treatment arm is reported in Fig. 2Go. Overall, it dropped from 91.6% (baseline questionnaire) to 39.0% (questionnaire 6). The rate of truly missing questionnaires (i.e., those not completed by living patients) increased from 7.1% to 24.0%, and the overall rate of questionnaires not completed because of patient death before the next scheduled assessment also increased from 1.3% to 37.0%. Patients treated with vinorelbine completed more questionnaires than did control subjects because of the lower percentage of patients who died of the disease. Median intervals from the first QoL assessment in the vinorelbine arm were 22, 44, 66, 91, and 115 days from assessment 2 through 6, respectively. Corresponding values in the control arm were 21, 43, 66, 89, and 113 days.



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Fig. 2. Global health status mean score (global and by time of dropout). Patient compliance (%) to quality-of-life assessment by treatment arm is shown at the bottom.

 
Missing data pattern was dependent on baseline values and on time of QoL assessment. As shown in Fig. 2,Go which depicts mean global health status scores at the time patients dropped out (mostly due to death), patients with a lower (worse) baseline score tended to drop out of the study earlier than patients with a higher (better) global health status score, and the probability of dropping out depended on the previously observed scores. Furthermore, global health status of subjects who no longer provided QoL assessments was worsening at the time of the last available observation.

Results of QoL analysis by mixed-effect models are reported in Table 2.Go EORTC functional scales were consistently better for the patients receiving vinorelbine than for the control patients, although statistical significance was reached only for cognitive function and was borderline for global health status. Among symptom scales and items, vinorelbine-treated patients scored clearly better than control patients for some lung cancer-specific items (pain and dyspnea) but they scored significantly worse for some treatment toxicity-related items (constipation, nausea and vomiting, hair loss, and peripheral neuropathy).


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Table 2. Estimated effect of vinorelbine on quality of life (QoL)

 
Survival

As of June 30, 1998, 126 (82%) patients had died, 59 in the vinorelbine and 67 in the control arm. Median follow-up time for 28 alive patients was 57 weeks (range, 16-106 weeks). Survival curves are shown in Fig. 3.Go There was a significant survival advantage in the vinorelbine arm (P = .03). Median survival increased from 21 to 28 weeks; survival rates at 6 and 12 months were 41% and 14%, respectively, in the control arm versus 55% and 32%, respectively, in the vinorelbine arm. After adjustment by stage of disease and ECOG performance status, the estimated relative hazard of death for patients receiving vinorelbine compared with those in the control arm was 0.65 (95% CI = 0.45-0.93). A further survival analysis was performed on the whole dataset that censored the 30 patients who were randomly assigned after July 1, 1997, at the date of study interruption. Results did not change (22 versus 29 weeks of median survival; P = .04).



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Fig. 3. Estimated survival according to treatment arm as calculated by the Kaplan-Meier method. Number of patients at risk by treatment arm is shown at the bottom. Pts = patients. Vertical bars = representative 95% confidence intervals.

 
Tumor Response

There was one complete response and 14 partial responses in the vinorelbine arm, giving an objective response rate of 19.7% (exact 95% CI = 11.5-30.5). The disease remained stable in 23 (30.3%) patients and progressed in 32 (42.1%). Six (7.9%) patients who were not restaged (four patients were lost to follow-up and two who stopped treatment because of toxicity) were considered "nonresponders."

Treatment Compliance and Toxicity

Three of the 78 patients assigned to the control arm received chemotherapy. In the vinorelbine arm, data on chemotherapy administration were missing for three of 76 patients. Two patients never received chemotherapy because they died within 1 week of being randomly assigned. Chemotherapy was discontinued earlier than planned in 11 patients (two patients after one course, one patient after two courses, four patients after three courses, three patients after four courses, and one patient after five courses); none of the patients reported toxicity or disease progression at the time of discontinuation. For all patients who stopped treatment after the third cycle, the disease was stable at the time of interruption. Treatment was stopped in five patients because of toxicity. Fifty-five patients fully respected the protocol plan. In 30 of these patients, chemotherapy was stopped before the sixth course because of progressive disease; 25 received six courses. Overall, 283 courses of chemotherapy were delivered (median, four cycles per patient). Treatment on day 8 was omitted nine times because of lack of hematologic recovery. The dosing protocol was violated for only one patient; i.e., vinorelbine was administered at the reduced dose of 20 mg/m2.

Seventy-one patients were assessed for toxicity. Treatment was stopped in five patients because of severe toxic events: WHO grade 3 constipation in three patients (after two, four, and five courses), grade 4 constipation in one patient (after four courses), and grade 2 heart toxicity (atrial arrhythmia) in one patient (after two courses). Other relevant toxic events, not inducing treatment stopping, were grade 4 leukopenia (one patient), grade 4 neutropenia (three patients), grade 3 vomiting (one patient), and grade 3 alopecia (three patients).


    DISCUSSION
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Appendix: Study Organization
 References
 
In the ELVIS trial, single-agent vinorelbine prolonged survival of elderly patients with advanced NSCLC and had a positive impact on QoL compared with supportive care. However, since the study was not conducted exactly as planned, these results should be interpreted with caution. Furthermore, because ELVIS is, to the best of our knowledge, the first randomized trial specifically designed for the subgroup of elderly patients with advanced NSCLC, skeptics of chemotherapy might require confirmatory studies. However, it is unlikely that such trials could be performed. The ELVIS investigators, indeed, who initially agreed on the uncertainty between the two arms, became increasingly reluctant to randomly assign patients because the control arm lacked chemotherapy. In addition, immediately after the trial was stopped and the results were disclosed, eight of the last 15 patients who had been assigned to supportive care and had not been analyzed because of the short follow-up time were shifted to treatment with vinorelbine.

ELVIS was stopped earlier than planned because of troubles in the enrollment rate. Although a monthly enrollment rate of 20 patients was expected, on average, 10 patients per month were recruited during the first 15 months and 6.5 patients per month were recruited during the last 6-month period. The results of interim survival analyses were not communicated to the investigators and, thus, did not affect the decision to stop the trial.

The planned primary end point of the trial was QoL because the a priori probability of finding a survival advantage was very low and because control of symptoms in patients with a very poor prognosis is per se a good target. Soon after the ELVIS trial started, Crawford et al. (20) reported a survival advantage and limited toxicity for adult patients receiving vinorelbine versus those receiving the placebo-like scheme of 5-fluorouracil/leucovorin. Like Crawford et al., we obtained a survival advantage that was not at the expense of a worse QoL or, even, with a significant delay of disease-induced functional decay. Survival advantage is limited (median, 7 weeks), but it is comparable to that reported in the metanalysis with cisplatin-based regimens in adult patients (1). It is also of interest that a 1-year survival rate of 32% is recorded in the vinorelbine arm as compared with 14% in the control arm.

The multidimensional nature of the QoL assessment raises some problems of interpretation. Multiplicity of comparisons and interdependency of responses at successive times make it necessary to focus on the whole pattern of results. The use of complete cases only gives biased estimates of the treatment effect if missing observations are not completely at random (21). In this study, the dropout pattern was clearly dependent on the previous global health status experience. Thus, we used a linear mixed-effect model to analyze all the available data and to tackle the fact that QoL observations within a subject are not independent. A time-varying indicator covariate was included in the model as an observation-level covariate to adjust for the dropout process. Validity of the analysis still rests on the assumption that, after adjustment by dropout process, missing data mechanism depends only on the observed data (22).

Based on the mixed-effect model, the estimated mean difference and standard deviation of global health status score at the third assessment after patients were randomly assigned were 4.6 and 19.054, respectively, accounting for an effect size of 24% favoring the vinorelbine arm. Overall, vinorelbine treatment improved some lung cancer-related symptoms and worsened toxicity-related symptoms. Because of the unblinded trial design, we cannot exclude that QoL results are somehow affected by the so-called placebo effect; ELVIS investigators, however, felt that any kind of trial-blinding procedure was both unfeasible and unethical, and possibly from a pragmatic point of view, this consideration is quite irrelevant.

The schedule used in this trial (treatment on days 1 and 8 of a 21-day cycle) is innovative, single-agent vinorelbine having thus far been administered weekly. We chose this schedule because the dose-intensity analysis of the previous phase II trial (8) showed that the dose intensity administered with the weekly schedule was 21 mg/m2 per week. The same dose intensity is reached when the drug is administered every 3 weeks on days 1 and 8, which might be easier and less distressing for patients. The excellent compliance to treatment rules in the ELVIS trial supports this hypothesis. In addition, there was an overall decrease in hematologic toxicity in the ELVIS trial versus the phase II trial (grade 3-4 leukopenia decreased from 33% to 7% of the patients). The objective response rate in the vinorelbine arm of the ELVIS trial is consistent with that reported in the previous trial.

The results of this trial can be generalized to state that chemotherapy may be a valuable treatment option for elderly patients with advanced NSCLC. However, we believe that caution is required with cisplatin-containing and multiagent chemotherapy, for which efficacy has still to be confirmed in randomized studies dedicated to elderly patients because of the high potential toxicity of such schemes (2-4). Possibly, the selection of well-performing elderly patients, also by the use of geriatric assessment scales (23), might render safer the indication for more aggressive chemotherapy regimens; however, again this hypothesis needs to be demonstrated within well-designed trials.

Given the results of the ELVIS trial, we advocate that single-agent vinorelbine be used as the control arm of studies aimed at improving the outcome of elderly patients with advanced NSCLC. In clinical practice, single-agent vinorelbine should be suggested as the first therapeutic option when discussing treatment plans with elderly patients with advanced NSCLC.


    NOTES
 
See Appendix for a complete list of authors.

The Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS) investigators thank Giuliana Canzanella, Federika Crudele, and Assunta Caiazzo for data management and secretarial services; Alfonso Savio for software assistance; Jean Gilder for editing the text; and the reviewers and editors for their helpful comments.

Presented in part at the 1998 American Society of Clinical Oncology meeting.


    Appendix: Study Organization
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Appendix: Study Organization
 References
 
Writing Committee

Cesare Gridelli, Francesco Perrone, Ciro Gallo

Data Coordinating and Statistical Analysis Committee

Francesco Perrone, Ciro Gallo (Centro Elaborazione Dati Clinici del Mezzogiorno-Consiglio Nazionale delle Ricerche, Progetto Finalizzato Applicazioni Cliniche della Ricerca Oncologica)

Institutions and Coauthors

Istituto Nazionale Tumori, Napoli (Cesare Gridelli, Antonio Rossi—Oncologia Medica; Francesco Scognamiglio—Chirurgia Toracica; Cesare Guida—Radioterapia; Francesco Perrone—Ufficio Sperimentazioni Cliniche Controllate; Silvio Monfardini—Direzione Scientifica); Ospedale Civile, Benevento (Giovanni Pietro Ianniello, Vincenza Tinessa, Maria Grazia Caprio); Ospedale S. Gennaro, Napoli (Antonio Santoro, Luigi Maiorino, Massimiliano Santoro); Ospedale Monaldi (Francovito Piantedosi, Luigi Brancaccio, Carlo Crispino); Università Federico II, Napoli—III Medicina Interna (Silvio Cigolari, Maria Di Lanno, Valentina Angelini); Ospedale Civile, Potenza (Luigi Manzione, Domenico Bilancia, Angelo Dinota); Ospedale S. Luigi e Santi Currò Gonzaga, Catania (Giuseppe Failla, Rosa Anna Aiello, Paolo Tralongo); Unità Sanitaria Locale (USL) 5—Ovest Vicentino (Franco Figoli, Ludmilla Zuccarino); Ospedale Fatebenefratelli, Benevento (Tonino Pedicini, Antonio Febbraro, Cesira Zollo); Ospedale S. Paolo, Milano (Luciano Frontini, Sabrina Zonato); USL 13, Noale (Venezia) (Giuseppe Azzarello, Orazio Vinante); Ospedale S. Lazzaro, Alba (Cuneo) (Federico Castiglione, Gianfranco Porcile); Centro di Riferimento Oncologico, Aviano (Pordenone) (Alessandra Bearz, Roberto Sorio): Policlinico Monteluce, Perugia-Oncologia Medica (Maurizio Tonato, Samir Darwish); Ospedale S. Maria Goretti, Latina (Enzo Veltri, Modesto D'Aprile); Ospedale Ascalesi, Napoli (Carlo Curcio, Matteo Vasta); Ospedale S. Carlo Borromeo, Milano (Maurizia Clerici, Gino Luporini); Università, Sassari-Clinica Oncologia Medica (Antonio Farris, Maria Grazia Alicicco); Ospedale S. Giovanni Antica Sede, Torino (Sergio Bretti, Cesare Bumma); Università, Cagliari-Cattedra Oncologia Medica (Maria Teresa Ionta, Bruno Massidda); Università, Messina-Istituto di Clinica Oncologica (Vincenzo Adamo, Giuseppe Altavilla); Ospedale, Lecco (Mariangela Stefani); Ospedali Riuniti, Bergamo (Giovanni Michetti); Università, Cagliari-Cattedra di Oncologia Clinica (Rosario Vincenzo Iaffaioli); Poliambulatorio di Oncologia, Bari (Nicola Marzano); Azienda Ospedaliera, Padova (Adolfo Favaretto); Ospedale Oncologico Businco, Cagliari (Stefano Murtas); Policlinico S. Matteo, Pavia-Divisione di Pneumologia (Caterina Nascimbene); Istituto Regina Elena, Roma (Cecilia Nisticò); Ospedale Civile, Rovereto (Trento) (Sergio Federico Robbiati); Fondazione Salvatore Maugeri, Pavia (Maria Rosa Strada); Ospedale Moscati, Avellino (Mario Belli); Policlinico, Bari-Cattedra di Chirurgia Toracica (Michele Loizzi); Ospedale Circolo Varese, Varese (Mauro Bandera); Ospedale Fortunato, Rionero in Vulture (Potenza) (Anna Maria Bochicchio); Ospedale L. Sacco, Milano (Elena Piazza); Ospedale Civile, Gorizia (Silvia Foladore); Ospedale S. Anna, Como (Raffaele Giura); Policlinico S. Matteo, Pavia-Istituto di Tisiologia (Giuseppe Gualtieri); Ospedale S. Gerardo, Monza (Milano) (Sandro Barni); Ospedale S. Giovanni, Salerno (Anna Cariello); Ospedale S. Croce, Fano (Pesaro) (Rodolfo Mattioli); USL 1, Sassari (Antonio Pazzola); USL 21, Legnago (Verona) (Gloria Gioga); Ospedale Binaghi, Cagliari (Guido Puxeddu); Ospedale S. Maria, Terni (Roberta Bartolucci); Ospedale Civile, Bolzano (Claudio Graiff); Ospedale Maggiore, Trieste (Guido Del Conte); Ospedale Civile, Vigevano (Pavia) (Giuseppe Attardo Farriniello); Ospedale, Crema (Fabrizio Mauri); USL 33, Rho Milano) (Giuliana Maria Corradini); Ospedale Civile, Foggia (Matteo Antonio Capuano); Ospedale Cardarelli, Campobasso (Francesco Carrozza); Istituto Nazionale Riposo e Cura per Anziani, Roma (Walter Gianni); Seconda Università di Napoli-Metodologia Epidemiologica Clinica (Ciro Gallo).


    REFERENCES
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Appendix: Study Organization
 References
 

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Manuscript received August 4, 1998; revised October 23, 1998; accepted November 2, 1998.


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