For the MILES Investigators
Correspondence to: Cesare Gridelli, M.D., c/o Unità Sperimentazioni Cliniche, Istituto Nazionale dei Tumori, Via M. Semmola, 80131 Napoli, Italy (e-mail: cgridelli{at}libero.it).
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ABSTRACT |
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INTRODUCTION |
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To examine whether a noncisplatin, moderately toxic chemotherapy could be effective in the treatment of elderly patients with advanced NSCLC, we performed the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) trial (8). In that study, we showed that treatment with vinorelbine, a semisynthetic vinca alkaloid, improved the outcome of patients compared with supportive care without antineoplastic drugs. Patients receiving vinorelbine had longer survival (median = 28 versus 21 weeks) and better scores for some quality-of-life items than patients who did not receive vinorelbine. Overall, toxicity associated with vinorelbine was mild.
Retrospective subgroup analyses of studies with gemcitabine, a cytosinearabinoside analogue, which acts by upsetting deoxynucleotide pools and interfering with DNA chain elongation (9), have suggested that this drug can also be effective in elderly patients with advanced NSCLC, with mild toxicity (10,11). In these studies, gemcitabine was administered on days 1, 8, and 15 of 4-week cycles at a dose of 1000 mg/m2. Based on our previous data with vinorelbine, showing that administration of vinorelbine chemotherapy on day 15 is frequently omitted in elderly patients because of toxicity (12) and to administer treatment for the same duration in all the arms of the present study, gemcitabine was scheduled on days 1 and 8 every 3 weeks for six cycles, at a dose of 1200 mg/m2. The planned dose intensity was similar to the standard (10,11). In a phase III study in adult patients with advanced NSCLC, we tested various doses of a combination of vinorelbine plus gemcitabine (13). At the lowest doses (vinorelbine at 25 mg/m2 and gemcitabine at 1000 mg/m2 administered on days 1 and 8 every 3 weeks for six cycles) the treatment was active, with a 28% response rate; its toxicity was acceptable, with no grade 4 adverse effects. Thus, this dose level was considered safe for testing in elderly patients with advanced NSCLC.
The present study was planned to compare the efficacy and toxicity of vinorelbine plus gemcitabine with those of the two agents individually in elderly patients with advanced NSCLC. We hypothesized that the combination of the two drugs should prolong patients survival relative to both of the two drugs given individually.
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PATIENTS AND METHODS |
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We conducted a phase III, randomized, open-label, multicenter trial. To be eligible, patients had to be aged 70 years or older; to have cytologically or histologically confirmed NSCLC; to have stage IIIb (with pleural effusion or metastatic supraclavicular lymph nodes) or stage IV disease; to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; and to have adequate organ function. We excluded patients with clinically overt brain metastases and those who had received previous chemotherapy. The independent ethical committees of participating institutions (see "Appendix") approved the protocol, and patients gave their written informed consent before enrollment. Enrollment was opened December 1, 1997, and was closed November 3, 2000.
Stratification, Randomization, and Therapy
Patients were stratified according to institution, ECOG performance status (0, 1, or 2), and disease stage (IIIb versus IV). Randomization was performed centrally at the Clinical Trials Office, National Cancer Institute (Naples, Italy), using a computerized procedure of minimization. Patients were randomly assigned in a 1 : 1 : 1 proportion to receive intravenous doses of vinorelbine (30 mg/m2 of body surface area), gemcitabine (1200 mg/m2 of body surface area), or a combination of vinorelbine (25 mg/m2 of body surface area) plus gemcitabine (1000 mg/m2 of body surface area). All treatments were administered on days 1 and 8 every 3 weeks, for a maximum of six cycles. On days 1 and 8 of each cycle, blood was drawn, and chemotherapy was given only if the patient had a minimum neutrophil count of 1.5 x 109/L, a minimum platelet count of 100 x 109/L, a hemoglobin level of 8.0 g/dL or more, and no sign of organ toxicity (excluding alopecia). If one or more requirements could not be met on day 1, chemotherapy was postponed for up to 2 weeks, after which investigators were free to choose the treatment strategy. Dose reductions were not planned as part of protocol. Administration of chemotherapy on day 8 was also postponed if the minimum requirements were not met. Treatment could be interrupted at any time if the disease progressed. Treatment was discontinued if the patient experienced unacceptable toxicity, refused treatment, or withdrew consent. Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician. Palliative radiotherapy could be delivered if needed; however, simultaneous chemotherapy and radiotherapy were discouraged because of the risk of cumulative toxicity. Second-line treatment or prophylactic use of hematopoietic colony-stimulating factors was not planned as part of protocol.
Evaluation of Patients
Before the study, all patients underwent staging procedures, including a clinical examination, a two-view chest x-ray, a computed tomography of the thorax and abdomen, and a bone scan. Bone scan or computed tomography scan of the brain was required only for patients with suspected bone or brain metastases. Before each administration of chemotherapy, patients underwent a clinical examination consisting of a routine biochemistry workup and blood counts. At baseline and after the third and sixth cycles of chemotherapy, patients underwent an electrocardiogram. Geriatric scales, namely those exploring activities of daily living [ADL (14) and instrumental ADL (IADL) (15)] were used. These scales were filled in by the investigators at baseline and after the third and the sixth cycles. The European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and lung-cancer-specific module (QLQ-LC13) were used to assess quality of life. The EORTC QLQ-C30 questionnaire consists of multi-item functioning scales, and multi- and single-item scales that evaluate general cancer-related symptoms (16). The EORTC QLQ-LC13 module consists of single items that evaluate specific symptoms of lung cancer (17). Both questionnaires are designed to be completed by the patient.
Evaluation of Toxicity and Response
Toxicity was classified according to World Health Organization criteria (18) by clinical investigators at each cycle for each patient. For each patient and each type of toxicity, the worst degree of toxicity experienced throughout the treatment was used for the analysis. Objective responses were evaluated by clinical investigators after the third and sixth treatment cycles by repeating the staging procedures. The best response for each patient was used for the analysis. Response evaluation could be anticipated with respect to planned time points for clinically evident or suspected disease progression. When evaluating patients, a complete response was defined as the disappearance of all known sites of disease; a partial response was defined as a decrease of 50% or more in the sum of the products of the largest perpendicular diameters of measurable lesions, no 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 the largest perpendicular diameters of measurable lesions and no new lesions; and progressive disease was defined as an increase of 25% or more in the size of one or more measurable lesions, or a new lesion. Confirmation of response was not mandatory. Patients who died before the restaging procedures were completed were defined as progressed on the date of death. Patients who stopped treatment because of toxicity or refusal before restaging procedures were defined as non-evaluated and were entered as nonresponders in the response rate calculations. The objective response rate was defined as the proportion of complete and partial responses relative to the total number of patients.
Statistical Analysis
The primary endpoint was survival, which was defined as the time from the date of randomization to the date of death or to the date of study closure. For patients who were lost to follow-up at a given time, survival was defined as the time between the date of randomization and the last date on which the patient was known to be alive. The secondary endpoint, progression-free survival, was defined as the time from the date of randomization to disease progression or to death from disease progression or unknown causes. For patients who were lost to follow-up before disease progression, progression-free survival was conservatively defined as the time from the date of randomization to the last date on which the patient was known to be free of disease progression.
We used the procedure devised by Laska and Meisner (19) to test whether the vinorelbine-plus-gemcitabine combination (i.e., the experimental treatment combination) was better than each chemotherapy agent alone. Two null hypotheses were simultaneously tested: H0V, in which vinorelbine was assumed to be as effective as the drug combination, and H0G, in which gemcitabine was assumed to be as effective as the drug combination. The alternative hypothesis (H1) was that the vinorelbine-plus-gemcitabine combination was more effective than its constituents alone. Thus, for statistical analyses, the drug combination was the only experimental arm. According to the procedure adopted, two one-tailed comparisons were planned a priori: combination (vinorelbine plus gemcitabine) versus vinorelbine, and combination (vinorelbine plus gemcitabine) versus gemcitabine. The results of both tests had to be statistically significant at the predefined one-tailed alpha level of 0.05 to reject the combined null hypotheses. This procedure is called min test (19) and precludes a comparison of single-agent vinorelbine with single-agent gemcitabinea question that should be considered within an equivalence study design and one that this investigation was not designed to answer.
Our sample size was calculated assuming a median survival with both single agents of 27 weeks. We estimated that 370 events would be needed in each comparison group to detect an improvement in median survival to 36 weeks, which corresponds to a hazard ratio of 0.75, with a one-tailed alpha error of 5% and a power of 0.87 in each test. The overall power for the two comparisons was 0.76. Based on expected accrual rate, a final sample size of 690 patients had to be accrued in 140 weeks. Two interim survival analyses were planned using an alpha spending function (20), which was based on an OBrien and Fleming (21) sequential group design (EaSt, 1993; Cytel Software Corp., Cambridge, MA). Interim analyses were done by the study statistician (C. Gallo), with blinded treatment labels to determine whether the study should be stopped early. Investigators were informed only that accrual remained open. The results of these analyses did not require that the study be discontinued because one-tailed P-boundaries of 0.00002 and 0.002, respectively, were not reached in any of the comparisons.
Survival curves were drawn with the KaplanMeier product limit method (22) and compared with the MantelHaenszel test (23). According to the study design, one-tailed P values were calculated. Hazard ratios of death and of progression with 95% confidence intervals (CIs) were estimated by using the Cox model (24), with treatment, sex, age, institution by number of enrolled patients, stage of disease, histologic type, ECOG performance status (0, 1, or 2), and major comorbidities (cardiovascular, respiratory, digestive/hepatobiliary, and diabetes) as covariates. Proportional hazards assumption was checked graphically by plotting treatment-specific log-cumulative baseline hazards against time (25). Another model, with fewer patients because of missing values, was estimated by adding baseline data of geriatric scales ADL and IADL; data from geriatric scales collected after the third and sixth chemotherapy cycles have not been accounted for in this analysis. Both ADL and IADL baseline values were entered into the Cox proportional hazards model as continuous variables. ADL scores ranged from 0 (unable to perform any activity) to 6 (able to perform all activities). The IADL questionnaire was recoded during the analysis to accommodate a frequent within-form missing phenomenon. This scale explores domains that in Italy are applicable only to women (e.g., cooking and washing clothes). Thus, a raw score was calculated by considering only questions that had been answered by the patients, on the grounds that within-form missing values were primarily a result of inapplicability of the question. The raw score was then linearly transformed in a scale ranging from 0 to 100, with 0 representing the lowest level of ability and 100 representing the highest.
All patients were evaluated for survival according to the intention-to-treat rule. For the evaluation of response, patients achieving a complete or partial response were considered responders and all other patients were considered nonresponders. Response rate of patients in the combination arm was compared with that of patients in the single-agent arms in two separate comparisons by 2 x 2 contingency tables, evaluated by the chi-square test, with two-tailed P values (S-PLUS 6.0 Professional, release 1; Insightful Corporation, Seattle, WA).
Similarly, two separate comparisons were made for toxicity (graded 04) by means of 5 x 2 contingency tables accounting for the ordering of toxicity categories. Exact two-tailed P values were calculated by the Wilcoxon rank-sum test (StatXact Turbo 1992; Cytel Software Corp.).
For the quality-of-life analysis, the EORTC core questionnaire (QLQ-C30) and lung-cancer-specific module (QLQ-LC13) multi-item scales were 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 was performed. Differences between the scores reported after the third chemotherapy cycle and baseline scores were compared by the Wilcoxon rank-sum test.
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RESULTS |
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Of the 759 patients evaluated for the trial, 707 were randomly assigned between December 1997 and November 2000 (Fig. 1). The reasons for ineligibility included wrong stage (n = 19), deteriorated performance status (n = 2), consent refusal (n = 9), previous chemotherapy (n = 3), brain metastases (n = 11), previous malignant disease (n = 6), comorbidity contraindicating chemotherapy (n = 3), uncertain cytologic diagnosis (n = 1), below minimum required baseline neutrophil count (n = 1), and baseline transaminases higher than required (n = 1). Some patients were declared ineligible for the trial for multiple reasons. Eight patients were excluded after randomization because their center withdrew from the study, and one patient was excluded because he withdrew consent. Thus, 698 patients, enrolled by 77 participating centers, were available for the intention-to-treat analyses. Among 233 patients who were assigned to receive vinorelbine, six were found to be ineligible after randomization (three were younger than age 70 years and three had stage IIIB disease without pleural effusion and metastatic supraclavicular lymph nodes), and six eligible patients had treatment violations (two received gemcitabine and four received no chemotherapy). Among 233 patients assigned to receive gemcitabine, four were found to be ineligible (two had had previous chemotherapy and two had stage IIIB disease without pleural effusion and metastatic supraclavicular lymph nodes), and six eligible patients had treatment violations (one received vinorelbine, one received vinorelbine plus gemcitabine, and four received no chemotherapy). Among 232 patients assigned to receive vinorelbine plus gemcitabine, eight were found to be ineligible (two had had previous chemotherapy, one was younger than age 70 years, and five had stage IIIB disease without pleural effusion and metastatic supraclavicular lymph nodes), and one eligible patient had a treatment violation (no chemotherapy). Treatment violations are summarized in Fig. 1
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According to the intention-to-treat principle, all patients, including nine patients who did not receive any chemotherapy and four patients who received the incorrect treatment (Fig. 1), were included in the analysis of treatment administration. Overall, compliance was similar across all three treatments arms. A median number of three cycles was administered within each arm. The median time spent on treatment was 11 weeks for vinorelbine, with 41% of the patients receiving the planned six cycles; 10.3 weeks for gemcitabine, with 39% of the patients receiving all six cycles; and 10 weeks for vinorelbine plus gemcitabine, with 38% of the patients receiving all six cycles. Although dose reductions were not planned, they occurred in 6% of administrations after day 1 of the first cycle; the rates of cycles with dose reduction were similar across the three arms. Chemotherapy was omitted on day 8 in 288 (11%) cycles, and the overall rate of omission of day 8 chemotherapy specifically by cycle was similar across the three arms. Treatment was stopped before the sixth cycle because of progressive disease or death in 42%, 46%, and 39% of patients; because of toxicity in 7%, 7%, and 11% of patients; and because of other causes (including patients choice) in 9%, 8%, and 12% of patients in the vinorelbine, gemcitabine, and vinorelbine plus gemcitabine arms, respectively. Second-line chemotherapy was not planned. However, of patients in the vinorelbine arm, 28 (12%) received second-line treatment, of whom 19 received gemcitabine; of patients in the gemcitabine arm, 30 (13%) received second-line treatment, of whom 20 received vinorelbine; and of patients in the combination arm, 14 (6%) received second-line treatment with other drugs.
Efficacy
Two interim survival analyses, planned a priori, were conducted in March and November 1999, with 212 and 408 patients and 98 and 213 deaths, respectively. The results of these analyses did not require that the study be discontinued, because one-tailed P-boundaries of 0.00002 and 0.002, respectively, were not reached in any of the comparisons.
By July 20, 2001, 557 (80%) patients had died. Compared with single-agent vinorelbine and single-agent gemcitabine, the combination of vinorelbine plus gemcitabine did not improve survival (Table 3 and Fig. 2
). For patients in the vinorelbine arm, median survival was 36 weeks (95% CI = 30 to 45 weeks), with an estimated probability of being alive at 1 year of 0.38. For patients in the gemcitabine arm, median survival was 28 weeks (95% CI = 25 to 34 weeks), with an estimated probability of being alive at 1 year of 0.28. For patients in the combination arm, median survival was 30 weeks (95% CI = 27 to 36 weeks), with an estimated probability of being alive at 1 year of 0.30. Univariate analysis showed no statistically significant difference in survival (combination versus vinorelbine, one-tailed P = .93; combination versus gemcitabine, one-tailed P = .65). Prespecified multivariable analysis, adjusted for institution by number of enrolled patients, sex, age, ECOG performance status, tumor stage and histologic type, and major comorbidities (cardiovascular, respiratory, digestive/hepatobiliary, and diabetes), showed no statistically significant differences in treatment effects for either statistical comparison. Hazard ratios of death were 1.17 (95% CI = 0.95 to 1.44) for vinorelbine plus gemcitabine versus vinorelbine and 1.06 (95% CI = 0.86 to 1.29) for vinorelbine plus gemcitabine versus gemcitabine. Of the 698 patients, 611 completed ADL and IADL questionnaires. Exploratory multivariable analysis that included ADL and IADL data in the model resulted in hazard ratios that were similar to those of the model including all the 698 patients, confirming that the combination treatment of vinorelbine plus gemcitabine does not improve survival.
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Toxicity
The nine patients who did not receive chemotherapy were excluded from the analysis of toxicity, whereas four patients who received incorrect treatment were included, according to the intention-to-treat principle. The combination of vinorelbine plus gemcitabine resulted in more thrombocytopenia and hepatic toxicity than single-agent vinorelbine; the combination treatment also resulted in more neutropenia, vomiting, fatigue, extravasation sequelae, cardiac toxicity, and constipation than single-agent gemcitabine (Table 4).
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Quality-of-life questionnaires were completed at the end of the third chemotherapy cycle by 346 (59%) of the 585 patients who had completed the baseline questionnaires. The rate of missing data was similar among patients in each of the three arms. There were no statistically significant differences in functional and symptom scales between patients assigned to the combination treatment and those patients assigned to single-drug treatments. Hair loss, as estimated by the patients, was statistically significantly worse for those who received the combination of vinorelbine plus gemcitabine than for those who received gemcitabine (P = .03). For those who received vinorelbine, there were no statistically significant differences as compared with those who received the combination.
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DISCUSSION |
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A general consideration underlying the design of this study was that elderly patients with advanced NSCLC are usually not eligible for aggressive cisplatin-based chemotherapy because of the age-related reduction of the functional reserve of many organs and comorbidities (3,4). Until some years ago, cisplatin-based chemotherapy was the only choice of treatment for advanced NSCLC, based on results of trials performed during the 1980s and the early 1990s (1). Consequently, during those years, only one-fourth of patients in the United States who were over the age of 65 with metastatic lung cancer received chemotherapy (28). The low rate of treated patients could be only partially attributed to referral patterns because age, comorbidity, sex, and race/ethnicity were independent determinants of treatment when an oncologist took care of the patients (28). Thus, cisplatin-based chemotherapy is probably not a useful tool for the treatment of elderly NSCLC patients. By contrast, Langer et al. (29) recently suggested that cisplatin-based therapy should not be denied to well-performing elderly patients with advanced NSCLC. This suggestion was made on the basis of a retrospective analysis of the ECOG 5592 trial of three cisplatin-based regimens, which showed that main treatment outcomes did not differ between the adult patients and the elderly patients (84 septuagenarians and two octogenarians), who represented 15% of the study population (29). Because approximately 30% of those diagnosed with NSCLC are elderly patients (2), underrepresentation of elderly patients in clinical studies of NSCLC may be associated with a selection of those patients who have a better prognosis and can better tolerate treatment. Thus, generalizability of results to the whole population of elderly people remains questionable (30). Currently, there are no reliable and prospective data on the safety of cisplatin-based chemotherapy in elderly patients.
For our study, the minimum required age of 70 years ensured that the enrolled patients would be more representative of elderly patients with advanced NSCLC than those patients recruited in clinical trials with no upper age limit, i.e., studies that enroll both adults and elderly patients. Indeed, studies of the latter type (31,32) usually have eligibility criteria designed for adult patients, and eligible elderly patients may represent a selected subgroup, presumably with a better prognosis and higher treatment compliance than the whole elderly population. Thus, information from such selected patients, particularly for clinical trials with aggressive and potentially toxic treatment approaches [e.g., cisplatin-based chemotherapy (29)], can be misleading and unsafe when generalized to clinical practice. Designing clinical trials with a minimum patient age of 70 years and no upper limit is an appropriate method to reduce selection bias and improve the generalizability of data on the treatment of elderly cancer patients.
In this study, geriatric scales measuring the ability to perform everyday activities were evaluated to determine whether they provide information useful for tailoring chemotherapy to elderly patients. The addition of baseline values of the geriatric scales to the multivariable analysis did not affect the primary study results, which indicated that the degree of ADL and IADL dependency does not affect treatments under investigation in the MILES study. Nevertheless, because such scales could have some prognostic validity, we are planning a more in-depth analysis of their prognostic value, which will be reported elsewhere.
Our findings contrast with those of Frasci et al. (33), who carried out a small randomized study of 120 elderly patients with advanced NSCLC that was stopped after an interim analysis showed better patient survival with vinorelbine plus gemcitabine than with vinorelbine alone. In that study, the data were impressive because of the unfavorable prognosis of patients in the vinorelbine (control) arm (18 weeks median survival) that produced a surprisingly low hazard ratio of death (0.48). This negative outcome associated with vinorelbine treatment is not consistent with other trials testing this drug in elderly and adult patients (8,3436); however, it is similar to the outcome frequently associated with supportive care alone (8,37). Frasci et al. (33) used approximately 20% higher doses of both drugs in the combination (30 mg/m2 vinorelbine and 1200 mg/m2 gemcitabine, on days 1 and 8 every 21 days) than were used in our trial. In a phase I trial, we found that such high doses were not well tolerated in adult patients (13). Moreover, we found no dose-effect in three doses of the tested vinorelbine-plus-gemcitabine combination in a randomized phase II study (13). Therefore, biases in patient selection rather than higher doses may explain the results of Frasci et al. (33).
There are at least three possible ways to explain why the combination of vinorelbine plus gemcitabine was not better than either single agent. One possibility is that polychemotherapy was not better than single-agent treatment because of toxicity and lack of compliance. However, although combined treatment was more toxic than single-agent treatment, its toxicity was acceptable, and the slightly lower compliance in patients treated with the combination cannot account for the lack of efficacy. A second possibility is that our survival results could have been blunted by second-line treatment and eventual crossover in the single-drug arms. Such effects would mimic sequential treatment with the same drugs given in the combination arm. However, few patients (10.3%) received second-line chemotherapy, and the time to progression, which is not affected by this potential bias, was similar in all three arms. A third possibility is that the combination of vinorelbine plus gemcitabine, although acting through different mechanisms, exerted antagonistic, nonsynergistic, or nonadditive effects on the patient outcomes. Antagonistic or at least nonsynergistic effects of the combination of vinorelbine plus gemcitabine have been shown in a breast cancer estrogen-dependent cell line (38). However, laboratory evidence of these effects is weak, and there are conflicting data showing additive activity over a wide range of doses tested in the mouse Lewis lung carcinoma model (39).
Because the results of the MILES trial do not rule out the possibility that other regimens of polychemotherapy could be more effective than single-agent chemotherapy in the treatment of elderly patients with advanced NSCLC, feasibility of different combinations should be explored. Based on considerations and data available to date (1,29,34,40), cisplatin-based combinations, which are commonly used in the treatment of adult patients with advanced NSCLC, should be prospectively studied, and investigators should look for schedules and doses that can improve compliance in elderly patients. Similarly, carboplatin-containing combinations should be prospectively tested in clinical trials dedicated to elderly patients, on the basis of recent evidence regarding the efficacy of carboplatin and paclitaxel and the suggestion that the effect of carboplatin is similar in groups of adult and elderly patients (41).
While waiting for these new studies to be done, we recommend that single-agent chemotherapy (vinorelbine or gemcitabine) should be preferred over the combination treatment as palliative treatment for elderly patients with advanced NSCLC. Design of the MILES study does not allow formal comparison of the arms with single-agent chemotherapy. Clinical sense, toxicity profile of each drug, patient comorbidities, cost considerations, and patient preferences should drive the choice of vinorelbine or gemcitabine, which should both be considered as valuable therapeutic options.
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APPENDIX |
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National Cancer Institute, Naples: *Medical Oncology B (Cesare Gridelli, Emiddio Barletta, Maria Luisa Barzelloni [present address: DaProcida Hospital, Salerno], Rosario Vincenzo Iaffaioli) and Clinical Trials Unit (Francesco Perrone, Paolo Maione [present address: S. Giuseppe Moscati Hospital, Avellino], Ermelinda De Maio, Massimo Di Maio); Medical Statistics, Second University of Naples (Ciro Gallo, Giuseppe Signoriello); *III Internal Medicine, University Federico II of Naples (Silvio Cigolari, Angela Cioffi, Vincenzo Guardasole, Valentina Angelini); *S. Carlo Hospital, Potenza (Luigi Manzione, Antonio Rossi, Domenico Bilancia, Gerardo Rosati); Pneumology V, Monaldi Hospital, Naples (Francovito Piantedosi, Alfredo Lamberti, Vittorio Pontillo, Luigi Brancaccio); Mariano Santo Hospital, Cosenza (Santi Barbera, Francesco Renda, Francesco Romano); Sacco Hospital, Milan (Elena Piazza, Gabriella Esani, Anna Gambaro); Medical Oncology, NoaleVenice (Orazio Vinante, Francesco Rosetti, Giuseppe Azzarello); S. Giuseppe Hospital, Milan (Maurizia Clerici, Roberto Bollina, Paolo Belloni); Civil Hospital, RoveretoTrento (Sergio Federico Robbiati, Mirella Sannicolò); Molinette Hospital, Turin (Oscar Bertetto, Libero Ciuffreda, Giuseppe Parello); S. Paolo Hospital, Milan (Luciano Frontini, Mary Cabiddu [present address: S. Pio X, Milan], Alberto Raina [present address: S. Pio X, Milan]); S. Maria della Misericordia Hospital, Udine (Cosimo Sacco, Angela Sibau); San Lazzaro Hospital, AlbaCuneo (Gianfranco Porcile, Federico Castiglione, Oliviero Ostellino); Civil Hospital, Padua (Silvio Monfardini, Adolfo Favaretto, Micaela Stefani); San Luigi Gonzaga Hospital, OrbassanoTurin (Giorgio Scagliotti, Silvia Novello, Giovanni Selvaggi); Forlanini Hospital, Rome (Filippo De Marinis, Maria Rita Migliorino, Olga Martelli); Medical Oncology, Azienda Ospedaliera "BianchiMelacrinoMorelli," Reggio Calabria (Giampietro Gasparini, Alessandro Morabito [present address: S. Filippo Neri Hospital, Rome], Domenico Gattuso); *Experimental Medical Oncology, Oncologic Institute, Bari (Giuseppe Colucci, Domenico Galetta, Francesco Giotta); *Medical Oncology, University of Palermo (Vittorio Gebbia); *La Maddalena Hospital, Palermo (Nicola Borsellino, Antonio Testa); *S. Vincenzo Hospital, TaorminaCatania (Francesco Ferraù, Emilia Malaponte); Thoracic Surgery, University of Foggia (Matteo A. Capuano, Michele Angiolillo, Francesco Sollitto); Medical Oncology, Centro di Riferimento Oncologico, AvianoPordenone (Giuseppe Cartei, Alessandra Bearz, Simona Scalone); Medical Oncology, University of Messina (Vincenzo Adamo, Giuseppe Altavilla, Antonino Scimone); Pneumology, University of Palermo (Mario Spatafora, Vincenzo Bellia, Maria Raffaella Hopps); G. Rummo Hospital, Benevento (Giovanni Pietro Ianniello, Vincenza Tinessa); S. Luigi and SS. Currò Gonzaga Hospital, Catania (Giuseppe Failla, Roberto Bordonaro); Chemotherapy, University of Palermo (Nicola Gebbia, Maria Rosaria Valerio); *S. Maria Goretti Hospital, Latina (Modesto DAprile, Enzo Veltri); Medical Oncology, University of Perugia (Maurizio Tonato, Samir Darwish); *Cardarelli Hospital, Campobasso (Sante Romito, Francesco Carrozza); S. Gerardo Hospital, MonzaMilan (Sandro Barni [present address: Civil Hospital, Treviglio (Bergamo)], Antonio Ardizzoia); Unità Socio Sanitaria Locale 33, RhoMilan (Giuliana Mara Corradini, Gianfranco Pavia); *Civil Hospital, Avellino (Mario Belli, Giuseppe Colantuoni); S. Chiara Hospital, Trento (Enzo Galligioni, Orazio Caffo); Medical Oncology, Spedali Riuniti, Bergamo (Roberto Labianca, Antonello Quadri); Medical Oncology, University La Sapienza, Rome (Enrico Cortesi, Giuliana DAuria); Civil Hospital, LegnanoMilan (Sergio Fava, Anna Calcagno); S. Carlo Borromeo Hospital, Milano (Gino Luporini, M. Cristina Locatelli); S. Maria Hospital, Terni (Francesco Di Costanzo, present address: Careggi Hospital, Florence; Silvia Gasperoni, present address: Careggi Hospital, Florence); Serbelloni Hospital, GorgonzolaMilan (Luciano Isa, Paola Candido); Unità Socio Sanitaria Locale 15, CamposampieroPadua (Fernando Gaion, Giovanni Palazzolo); *Miulli Hospital, Acquaviva delle FontiBari (Giuseppe Nettis, Anselmo Annamaria); *Medical Oncology II, "Regina Elena" Institute, Rome (Massimo Rinaldi, Massimo Lopez); S. Martino Hospital, Genoa (Raffaella Felletti, Giorgio Bernabò Di Negro); *Civil Hospital, PollaSalerno (Nestore Rossi, Antonio Calandriello); San Gennaro Hospital, Naples (Luigi Maiorino); S. Croce Hospital, FanoPesaro (Rodolfo Mattioli); S. Giovanni Hospital, Turin (Alfredo Celano); S. Bortolo Hospital, Vicenza (Stefania Schiavon); Oncology, Monaldi Hospital, Naples (Alfonso Illiano); Cottolengo Hospital, Turin (Carlo Alberto Raucci); *Oncologic Center, Catania (Michele Caruso); Medical Oncology, University of Milan (Paolo Foa, present address: S. Paolo Hospital, Milan); Medical Oncology, Biomedical Campus, Rome (Giuseppe Tonini); Thoracic Surgery, Ascalesi Hospital, Naples (Carlo Curcio, present address: Monaldi Hospital, Naples); Civil Hospital, TreviglioBergamo (Marina Cazzaniga); Pneumology, Spedali Riuniti, Bergamo; Medical Oncology I, National Cancer Institute, Genoa; *Fatebenefratelli Hospital, Benevento; *Medical Oncology, University of Cagliari, Cagliari; Businco Hospital, Cagliari; Agnelli Hospital, PineroloTurin; SS. Trinità Hospital, SoraFrosinone; S. Andrea Hospital, Vercelli; Civil Hospital, Gorizia; Medical Oncology, University of Sassari, Sassari; Civil Hospital, Bolzano; Fortunato Hospital, Rionero in VulturePotenza; *Da Procida Hospital, Salerno; C. Cantù Hospital, AbbiategrassoMilan; Pugliese Ciaccio Hospital, Catanzaro; Civil Hospital, Rovigo; S. Maria delle Grazie Hospital, PozzuoliNaples; Civil Hospital, S. Felice a CancelloCaserta; *Galateo Hospital, S. CesareoLecce; Civil Hospital, LagonegroPotenza; *Civil Hospital, SciaccaAgrigento.
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C. Gridelli was the principal investigator, F. Perrone headed the coordinating office, and C. Gallo was the head biostatistician. C. Gridelli, F. Perrone, and C. Gallo drafted the final manuscript. All investigators participated in a steering committee that discussed the protocol, periodically reviewed blinded progress reports, reviewed the draft of the manuscript, and contributed to its final version. All but F. Perrone and C. Gallo enrolled patients into the study. The other MILES investigators who enrolled patients or collaborated with those listed in the title are listed in the Appendix.
Present address: C. Gridelli, A. Rossi, S. Giuseppe Moscati Hospital, Avellino, Italy.
Present address: L. Frontini, S. Pio X, Milan, Italy.
Present address: G. Gasparini, S. Filippo Neri Hospital, Rome, Italy.
Present address: S. Cigolari, S. Giovanni di Dio e Ruggi dAragona, Salerno, Italy.
The coordinating center is partially supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Clinical Trials Promoting Group (CTPG), and Gruppo Italiano di Oncologia Geriatrica (GIOGER).
We thank Federika Crudele, Fiorella Romano, Giuliana Canzanella, and Assunta Caiazzo for data management and trial secretariat. We are indebted to Jean Ann Gilder for editing the text. We also thank the GOIM (Gruppo Oncologico Italia Meridionale) for actively participating in the study.
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Manuscript received April 26, 2002; revised December 4, 2002; accepted December 27, 2002.
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