|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Gemcitabine Plus Vinorelbine Versus Vinorelbine Alone in Elderly Patients With Advanced Non–Small-Cell Lung CancerFrom the Division of Medical Oncology, City Hospital, Avellino; Division of Medical Oncology, Oncology Institute, Bari; Division of Medical Oncology, University School of Medicine, Cagliari; Division of Medical Oncology A, National Tumor Institute, Division of Medical Oncology, Cardarelli Hospital, Division of Respiratory Diseases, 2nd University School of Medicine, and Division of Pneumology, Monaldi Hospital, Naples; and Divisions of Medical Oncology, Da Procida Hospital and General Hospital of Salerno, Salerno, Italy. Address reprint requests to Giuseppe Frasci, MD, Division of Medical Oncology A, National Tumor Institute, Via Mariano Semmola 80131, Naples, Italy; email GIFRASCI{at}SIRIO-ONCOLOGY.IT
PURPOSE: To evaluate whether the addition of gemcitabine (G) to vinorelbine (V) improves survival and quality of life (QoL) among elderly patients with advanced non–small-cell lung cancer (NSCLC).
PATIENTS AND METHODS: Patients with NSCLC aged RESULTS: In May 1999, the survival data were analyzed of 120 eligible patients (V group = 60; G + V group = 60) who had been randomized from June 1997 to February 1999. Forty-nine patients had stage IIIB disease, and 71 had stage IV. At a median potential follow-up of 14 months (range, 3 to 22 months), 93 patients had died (G + V group = 41; V group = 52). In the G + V group, median survival time was 29 weeks and projected 1-year survival was 30%; these values were 18 weeks and 13% in the V group. According to multivariate Cox analysis, the risk of death in the G + V arm compared with the V arm was 0.48 (95% confidence interval, 0.29 to 0.79; P < .01). Combination therapy was also associated with a clear delay in symptom and QoL deterioration. The overall response rates were 22% and 15% in the G + V and V groups, respectively. CONCLUSION: In elderly patients with NSCLC, G + V treatment is associated with significantly better survival than is V alone.
LUNG CANCER IS BY far the leading cause of cancer deaths in Europe and North America. More than one half of patients with lung cancer are older than 60 years at diagnosis, and 30% are 70 years or older.1 Approximately 80% of all these patients show non–small-cell histotypes. The role of chemotherapy in the treatment of patients with advanced non–small-cell lung cancer (NSCLC) has been better defined in a recent meta-analysis.2 A cisplatin-based polychemotherapy is generally considered the most advisable frontline approach in these patients. The results of the meta-analysis do not allow the identification of a different impact of chemotherapy in the different subgroups of patients. However, some concerns still persist about the use of polychemotherapy, especially with the inclusion of cisplatin in particular subsets of patients with NSCLC, such as those aged 70 or older or those with poor performance status.3,4 Older people have an increased prevalence of disease, and indeed, they often have multiple and, frequently, interacting diseases. The presence of this degree of comorbidity has a major impact on patients’ ability to tolerate the new disease itself as well as treatment. Moreover, as a consequence of the reduction of functional reserve, an unpredictable chemotherapy-related toxicity may occur.5,6 Very few specific studies have been conducted to test the role of chemotherapy in elderly patients with NSCLC. Vinorelbine (V) as a single agent was tested in elderly patients in two phase II studies, which yielded an overall response rate (ORR) of 16% to 23%, at a price of a moderate toxicity.7,8 A phase III trial that compared single-agent V plus best supportive care with best supportive care alone has recently been suspended (after enrolling 154 patients) because of the low enrollment rate. However, the V arm did have a 7-week longer median survival time (MST) and a better quality of life (QoL) at closure.9 Gemcitabine (G) is one of the most effective cytotoxic agents in NSCLC. As a single agent, it produced an ORR of approximately 20% with an MST of at least 8 months.10 Interestingly, a retrospective analysis of its impact on elderly patients showed that both the ORR and MST did not worsen in this subset of patients.11
In an effort to develop a chemotherapy regimen characterized by both good antitumor activity and moderate toxicity, the Interregional Association for the Study of the Carcinoma of Lung and the Southern Italy Cooperative Oncology Group tested the combination of G + V given on days 1 and 8 every 3 weeks. Doses of G and V up to 1,200 mg/m2 and 30 mg/m2, respectively, proved to be safe, even in patients older than 70 years, because hospitalization as a result of hematologic toxicity was never required. This combination yielded a 36% ORR and produced a QoL improvement in 50% of patients. Regarding age, no correlation was observed with response (nine [36%] of the 25 patients older than 70 years; 10 [36%] of the 27 patients On the basis of these considerations, we started this phase III trial, which was aimed at evaluating the efficacy of the G + V regimen compared with V alone in terms of survival and QoL in elderly patients with advanced NSCLC. In the present article, the results of the planned interim analysis performed on the first 60 eligible patients in each arm are reported.
Eligibility Criteria Chemotherapy-naive patients 70 years or older were eligible if they had histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic NSCLC and Eastern Cooperative Oncology Group (ECOG) performance status  2. No prior chemotherapy or thoracic radiotherapy was allowed. Patients were required to have adequate bone marrow (absolute neutrophil count > 2 x 109 cells/L and hemoglobin level > 100 g/L) and liver function (bilirubin level < two times the upper limit of normal, AST and/or ALT < three times the upper limit of normal, and prothrombin time < 1.5 times control) and creatinine clearance  60 mL/min. Exclusion criteria included the presence of severe cardiac arrhythmia or heart failure, second- or third-degree heart block, and acute myocardial infarction within 4 months before study entry. CNS metastases were not considered an exclusion criterion, if asymptomatic. A life expectancy of at least 12 weeks was also required. All patients gave written informed consent, and the trial was approved by the Ethical Committee for the Biologic Research of the National Tumor Institute of Naples.
Treatment All patients received an antiemetic prophylaxis that consisted of HT3-receptor antagonists. Full doses of chemotherapy were given if neutrophil and platelet counts on the day of treatment were greater than 1.5 x 109 cells/L and greater than 100 x 109 cells/L, respectively. A 50% dose reduction was performed in patients with an absolute neutrophil count from 1,000 x 109 to 1,499 x 109 cells/L and platelet count from 75 x 109 to 99 x 109 cells/L. Treatment was delayed for lower neutrophil or platelet counts, hemoglobin level less than 8 g/L, or persistence of grade 2 or greater nonhematologic toxicity.
Staging and Follow-Up Procedures An accurate evaluation of comorbidities was also made before starting chemotherapy, and a score was calculated for each patient by using the Charlson scale.13 Physical examination, laboratory tests, and chest x-ray were performed at each chemotherapy cycle, and all the diagnostic procedures required to evaluate response to treatment were performed in both arms after the third and sixth cycles and every 2 months until death. Complete blood cell count was performed weekly.
QoL and Symptom Assessment
Response and Toxicity Evaluation
Statistical Methods and Study Design
Study Flow
Demographics The characteristics of the 120 patients included in the present analysis are outlined in Table 1. Only a minority of them were females. Median age was 74 years (range, 70 to 83 years). Forty-nine patients (40%) had stage IIIB disease, and 71 (60%) had stage IV; 29 (24%) had a poor performance status. Thirty-two of the 49 patients with stage IIIB disease had malignant pleural effusions (G + V group = 17 and V group = 15), and an additional nine (G + V group = 4 and V group = 5) had supraclavicular node involvement; therefore, in only eight patients with stage IIIB disease (G + V group = 3 and V group = 5) was a sequential radical chest irradiation planned. Twenty-nine of the 71 patients with stage IV disease had more than two metastatic sites. Eleven patients also had CNS involvement at diagnosis (G + V group = 5 and V group = 6). Approximately 75% of patients had one or more comorbidities, and the Charlson score was greater than 2 in approximately 20% of patients. The two arms were fairly well balanced for the main pretreatment characteristics. {tabft}Abbreviation: PS, performance status.
Survival As of May 31, 1990, 93 patients had died, 41 in the G + V arm and 52 in the V arm, and the median follow-up time for 27 living patients was 61 weeks (range, 15 to 93 weeks). The observed MST for the entire study population was 24 weeks, being 25 weeks in patients with stage IIIB disease and 21 weeks in those with stage IV. The MST was 19 weeks in the 29 patients with an ECOG performance status of 2 and 26 weeks in the others. An even stronger correlation was observed between the degree of comorbidity and survival. Indeed, the MST was 28 weeks in patients without comorbidities, whereas it dropped to 21 weeks and 16 weeks in those with a Charlson scores of 1 or 2 and greater than 2, respectively. The MST was also poor in the 11 patients with CNS involvement (18 weeks). The survival curves of the two arms are shown in Fig 2. The MST was 29 weeks in the G + V group compared with 18 weeks in the V arm. The projected 6-month and 1-year survival rates were 56% and 30% in the G + V group, compared with 32% and 13% in the V group, respectively (P < .01, by Mantel-Haenszel test). If only patients with stage IV disease are considered, the MSTs were 27 and 17 weeks in the G + V and V arms, respectively. In multivariate Cox analysis, after adjustment for stage of disease, ECOG performance status, histology, Charlson score, and weight loss, the risk of death in the G + V compared with V arm was 0.48 (95% confidence interval [CI], 0.29 to 0.79; P < .01). When the 21 patients (G + V group = 11 and V group = 10) who were randomized between February 23, 1999, and May 31, 1999, were also included in the survival analysis, the results did not change, the MSTs being 30 and 18 weeks for the G + V and V groups, respectively.
Symptom and QoL Changes Overall, 106 of 120 patients (G + V group = 54 and V group = 52) each had at least one symptom at diagnosis. Fourteen patients (26%) in G + V arm showed temporary symptom relief during the treatment, compared with eight (15%) in the V arm. In particular, cough (31% v 17%) and shortness of breath (28% v 11%) were more frequently improved by combination therapy. The probability of being alive without symptom deterioration at 6 months was 43% and 22% in the G + V and V arms, respectively (Fig 3).
Baseline questionnaires for QoL assessment were completed by 111 (92%) of 120 patients. There was no difference in baseline scores between the two arms. Patients’ compliance to QoL assessment was constant during the study, being 92% (111 of 120 patients) at baseline and 81% (35 of 43 alive) at 6 months. Almost 60% of patients in the G + V arm did not show impairment of the QoL score during the treatment, compared with approximately 40% in the V arm (Table 2).
Response The response data of the 120 patients included in the analysis are summarized in Table 3. A total of 18 patients (30%) in the G + V arm were not restaged because of early progression or death or treatment discontinuation by any cause, compared with 29 (48%) in the V arm.
No complete responses were observed. A partial response was obtained in 13 patients in the G + V arm and nine in the V arm, giving objective response rates of 22% (95% CI, 12% to 34%) and 15% (95% CI, 7 to 27), respectively. In stages IIIB and IV disease, ORRs were 25% and 19% in the G + V arm and 20% and 11% in the V arm, respectively. An additional 16 patients showed stable disease in the G + V arm, whereas this occurred in only seven patients in the V arm. Radical chest irradiation was performed overall in seven (G + V group = 3 and V group = 4) of the eight patients initially eligible for the combined approach. One patient died after 1 month from the beginning of chemotherapy because of disease progression.
Treatment Compliance and Toxicity One patient in the V arm, aged 74 years, with stage IIIB disease and poor performance status, died because of treatment. He also had a coronary ischemia and diabetes as comorbidities. The death occurred at home 7 days after the administration of the first V dose. The patient showed severe fatigue and hyperthermia and hypotension.
Chemotherapy was discontinued early for toxicity in seven patients in the G + V arm (two toxic deaths, one lost to follow-up, two refusing because of severe fatigue and loss of appetite, one with lack of hematologic recovery, and one with severe liver toxicity) and six in the V arm (onetoxic death, one with severe constipation, one with severe emesis and loss of appetite, two refusing because of severe fatigue, and one lost to follow-up). Seventeen (59%) of the 29 patients with an ECOG performance status of 2 discontinued chemotherapy early, compared with 30 (31%) of 91 of those with a performance status of 0 or 1. A Charlson score greater than 2, compared with Table 4 summarizes the most relevant toxic events. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 38% and 13% of patients in the G + V group and in 28% and 8% of those in the V group, respectively. Overall, five packed RBC transfusions were required because of the occurrence of severe anemia. Nonhematologic toxicity was often relevant. Severe emesis occurred in nine (15%) and five patients (8%) in the G + V and V arms, respectively. Severe fatigue, loss of appetite, and constipation were the most frequent cause of patients’ complaints and sometimes led to treatment discontinuation. Almost one half of patients in both arms experienced at least one of these events during the treatment. {tabft}Abbreviation: WHO, World Health Organization.
Grade 1 or 2 peripheral neuropathy, mainly consisting of paresthesias in the top of the extremities of the hands and feet, occurred in 13% and 10% of patients in the G + V and V arms, respectively. Because of the occurrence of hematologic or nonhematologic toxicity, a delay in day 1 administration, a dose reduction, or an omission of day 8 administration occurred in 51 cycles. As a consequence, the median delivered dose-intensity was 78% in the G + V arm and 81% in the V arm.
Despite the increasing relevance of lung cancer in elderly patients, only a few articles regarding the role of chemotherapy in this subset have been published. According to the results of the Elderly Lung Cancer Vinorelbine Italian Study trial, a significant, although modest, prolongation of life expectancy can be obtained with the use of single-agent V compared with best supportive care alone. In view of that finding, we planned the present randomized trial, which aimed at evaluating whether a further survival gain could be obtained by adding G to V. The present study was closed early because the planned interim analysis showed that the magnitude of the survival gain achieved by the combination therapy met the chosen criteria for early discontinuation (z score > 2.56; P < .01). Indeed, an MST that was almost 3 months longer has been obtained with the combination treatment. This gain seems more relevant if we consider that the MST was for only 4 months in patients treated with V alone in our trial, thus meaning that combination treatment produced a greater than 60% increase in median survival. Indeed, in our study, the MST (18 weeks) and the 6-month (32%) and 1-year (13%) survival rates of patients treated with V alone were substantially worse than those obtained with the same dose and schedule of V in the ELVIS trial (28 weeks, 55%, and 32%) and were similar to those reported in the same study for best supportive care (21 weeks, 41%, and 14%, respectively). Actually, it is not easy to explain this finding. Apparently, substantial differences in the composition of the two study populations were not evident. The proportion of patients with poor performance status was similar in the two studies. The rate of patients with stage IIIB disease was also not substantially different in the two studies, although the majority of our patients with stage IIIB disease had a poor prognosis because of the presence of malignant pleural effusion. Perhaps the presence of patients with CNS involvement (excluded from the ELVIS trial) and the higher proportion of patients with comorbidities in our study (75% v < 50% in the V arm of the ELVIS study) could partially justify the substantially worse survival outcome with V treatment. Indeed, in our V arm, the MST was clearly worse in patients with CNS metastasis (13 v 22 weeks) or with concomitant diseases than in patients without (16 v 26 weeks, respectively). We do not believe, however, that a particularly poor-prognosis NSCLC population was selected in our study. In an analysis of the prevalence of comorbidity conducted in a large NSCLC patient population, 60% of male patients aged between 29 and 93 years each had at least one concomitant disease, and this rate was increased to approximately 70% in elderly patients.5 In any case, a 4-month MST in patients with NSCLC with poor-prognosis stage IIIB or IV disease and with age from 70 and 83 years should not surprise anybody. In meta-analyses concerning much younger patients, some studies even reported a 2-month MST for best supportive care21 and an MST of less than 5 months for patients treated with cisplatin-based polychemotherapy.22,23 Moreover, it should not be forgotten that, because of the abnormal randomization performed in the ELVIS trial (chemotherapy v no treatment), a high proportion (> 20%) of registered patients refused to enter the trial. It cannot be excluded that this randomization bias could have resulted in the selection of a more favorable study population in that study (patients with a heavier symptom burden are less willing to accept the possibility of no treatment), with a consequent overestimation of the survival outcome in both arms. Although caution should be used in interpreting our data because of the relatively small number of patients analyzed and the possible differences in some pretreatment features, we conclude that it is possible that the addition of G to V substantially improves the prognosis of elderly patients with NSCLC with advanced disease compared with single-agent V. The substantial survival gain obtained with the G + V regimen can be explained by the higher number of patients who did not progress in the first 3 months (50% v 30%). Indeed, although the rate of major responses was not significantly better in the combination arm, more than twice the number of patients showed stable disease in this arm compared with those in the V arm. The relevance of the G addition in producing this substantial increase of antitumor activity is confirmed, in our opinion, by the results of several trials. In a retrospective analysis, G alone produced an ORR and an MST in older patients similar to those obtained in younger patients.11 In a recent preliminary phase II report, single-agent G produced a 27% ORR with a median progression-free survival of 4 months in patients with NSCLC who were older than 70 years.24 Nguyen et al25 have recently reported the data of patients older than 70 years who had received the cisplatin-G regimen. The treatment was generally well tolerated and was associated with a good MST, although it must be pointed out that the majority of patients had good performance status (Karnofsky 90 to 100). Weekly G and cisplatin were also tested in elderly patients with NSCLC by Italian investigators, with promising results in terms of clinical benefit.26 To the best of our knowledge, there are no other reports concerning the use of the G + V regimen in elderly patients with NSCLC. However, this combination has been recently tested by several investigators in younger patients with NSCLC, showing ORRs between 30% and 40% and MSTs of approximately 8 months.12,27-30 In our study, the G + V combination was also associated with a clear superiority in terms of symptom control and QoL. Indeed, the probability of showing an improvement or at least a stabilization of symptoms at 6 months was almost double in the G + V arm compared with the V arm. As expected, both hematologic and nonhematologic side effects were more frequent in patients who received combination therapy. However, statistically significant differences in the occurrence of life-threatening toxicity were not observed. It deserves to be remarked, however, that toxicity was not negligible, even in the monotherapy arm. The occurrence of toxic death in three patients (one treated with V alone) who presented with multiple unfavorable conditions at diagnosis suggests that a more accurate selection of the elderly patients who are candidates for chemotherapy should be performed. In particular, the degree of comorbidity (Charlson score) strongly affected both the tolerance to treatment and the survival outcome in our study. Therefore, in future trials, it is advisable to exclude those patients who have a high comorbidity score independent of their performance status. More selective inclusion criteria, however, may not be enough to avoid the occurrence of severe treatment-related toxicity. Personalised chemotherapy dosing is another potential way to optimize the balance between the activity and toxicity of chemotherapy. In a previous phase II trial, we tested the carboplatin plus oral etoposide combination in elderly patients with NSCLC. We alternately escalated the doses of the two drugs during the treatment, provided that severe hematologic and nonhematologic toxicity did not occur. A good MST (10 months) was obtained at a price of a moderate toxicity.15 In conclusion, the G + V combined treatment is associated with a significantly better survival in elderly patients with NSCLC when compared with V alone. The combination therapy also produces a clear delay in the worsening of symptoms and QoL. The not uncommon occurrence of severe toxicity suggests the necessity of a more accurate selection of patients that takes into consideration the degree of comorbidity.
The Southern Italy Cooperative Oncology Group conducted this study with the cooperation of the following investigators: Mario Belli and Filomena Del Gaizo, Division of Medical Oncology, City Hospital, Avellino; Vito Lorusso and Mario De Lena, Division of Medical Oncology, Oncology Institute; Franco Carpagnano and Gaetano Di Rienzo, Division of Thoracic Surgery, San Paolo Hospital, Bari; Vittorio Mascia, Division of Medical Oncology, Oncology Hospital, Cagliari; Guido Pusceddu, Division of Pneumology, Bisaghi Hospital, Cagliari; Riccardo Cioffi, Division of Pneumology, City Hospital, Caserta; Alessandra Mangiameli, Musumeci Clinic, Catania; Gianfranco Filippelli and Salvatore Palazzo, Division of Medical Oncology, Oncologic Hospital, Cosenza; Bruno Massidda, Division of Medical Oncology, University School of Medicine; Giuseppe Frasci, Pasquale Comella, Adriano Gravina, and Giuseppe Comella, Division of Medical Oncology A, National Tumor Institute; Nicola Panza, Gianpaolo Nicolella, and Giovanni Pacilio, Division of Medical Oncology, and Michele Natale, Division of Pneumology, Cardarelli Hospital; Luigi Maiorino, Division of Medical Oncology, San Gennaro Hospital; Enrico Micillo and Andrea Bianco, Division of Respiratory Diseases, 2nd University School of Medicine; Alfredo Lamberti and Francovito Plantedosi, Division of Pneumology, Monaldi Hospital, Naples; Luigi Manzione, Domenico Bilancia, and Angelo Di Nota, Division of Medical Oncology, San Carlo Hospital, Potenza; Giuseppe De Cataldis and Pietro Carnicelli, Division of Medical Oncology, Da Procida Hospital, Salemo; and Antonio Contu, Division of Medical Oncology, City Hospital, Sassan, Italy.
1. Fry WA, Menck HR, Winchester DP, et al: The National Cancer Data Base report on lung cancer. Cancer 77:1947-1955, 1996[Medline]
2.
Non-Small Cell Lung Cancer Cooperative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patient data from 52 randomised clinical trials. BMJ 311:899-909, 1995 3. Oshita F, Kurata T, Kasai T, et al: Prospective evaluation of the feasibility of cisplatin-based chemotherapy for elderly lung cancer patients with normal organ functions. Jpn J Cancer Res 86:1198-1202, 1995[Medline] 4. Souquet PJ, Bombaron P, Brunel-Crova J, et al: Treatment of advanced and disseminated non-small cell lung cancer in elderly patients: Results of the MIC regimen. Lung Cancer 18:24, 1997 (suppl 1, abstr 82) 5. Janssen-Heijrten ML: Prevalence of comorbidity in lung cancer patients and its relationship with treatment: A population-based study. Lung Cancer 21:105-113, 1998[Medline] 6. Extermann M, Overcash J, Lyman GH, et al: Comorbidity and functional status are independent in older patients. J Clin Oncol 16:582-587, 1998 7. Colleoni M, Geion F, Nelli P, et al: Weekly vinorelbine in elderly patients with non-small cell lung cancer. Tumori 80:448-452, 1994[Medline] 8. Gridelli C, Perrone F, Gallo C, et al: Vinorelbine is well tolerated and active in the treatment of elderly patients with advanced non-small cell lung cancer: A two-stage phase II study. Eur J Cancer 33:392-397, 1997
9.
The Elderly Lung Cancer Vinorelbine Italian Study Group: Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small cell lung cancer. J Natl Cancer Inst 91:66-72, 1999 10. Gatzmeier U, Shepherd FA, Le Chevalier T, et al: Activity of gemcitabine in patients with non-small cell lung cancer. Eur J Cancer 32:243-248, 1996 11. Shepherd FA, Abratt RP, Anderson H, et al: Gemcitabine in the treatment of elderly patients with advanced non-small cell lung cancer. Semin Oncol 24:50-55, 1997 (suppl 7)
12.
Lorusso V, Carpagnano F, Frasci G, et al: Phase I/II study of gemcitabine plus vinorelbine as first-line chemotherapy of non–small-cell lung cancer. J Clin Oncol 18:405-411, 2000 13. Charlson ME, Pompei P, Ales K, et al: A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 40:373-383, 1987[Medline] 14. Hollen PJ, Gralla RJ, Kris MG, et al: Quality of life assessment in individuals with lung cancer: Testing the Lung Cancer Symptom Scale. Eur J Cancer 29A:S51-S58, 1993 (suppl 1) 15. Frasci G, Comella P, Panza N, et al: Carboplatin-oral etoposide personalized dosing in elderly non-small cell lung cancer patients: Gruppo Oncologico Cooperativo Sud-Italia. Eur J Cancer 34:1710-1714, 1998
16.
Comella P, Frasci G, Panza N, et al: Cisplatin, gemcitabine, and vinorelbine combination therapy in advanced non–small-cell lung cancer: A phase II randomized study of the Southern Italy Cooperative Oncology Group. J Clin Oncol 17:1526-1534, 1999 17. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 18. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[Medline]
19.
Schaid DJ, Wieand S, Therneau TM: Optimal two-stage screening designs for survival comparisons. Biometrika 77:507-513, 1990 20. Cox DR: Regression models and life tables. J R Stat Assoc 34:187-220, 1972 21. Cormier Y, Bergeron D, LaForge J, et al: Benefits of polychemotherapy in advanced non-small cell bronchogenic carcinoma. Cancer 50:845-849, 1982[Medline] 22. Ganz PA, Figlin RA, Haskell CM, et al: Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer: Does chemotherapy make a difference? Cancer 63:1271-1278, 1989[Medline] 23. Kaasa S, Lund E, Thorud E, et al: Symptomatic treatment versus combination chemotherapy for patients with extensive non-small cell lung cancer. Cancer 67:2443-2447, 1991[Medline] 24. Martoni A, Di Fabio F, Guaraldi M, et al: Gemcitabine as single-agent in the treatment of elderly patients with stage IIIB-IV non-small cell lung cancer: Preliminary results of an Italian multicenter phase II study. Proc Am Soc Clin Oncol 18:517a, 1999 (abstr 1991) 25. Nguyen B, Sandler A, Denham C: The safety and efficacy of gemcitabine plus cisplatin in the elderly chemonaive patients (age > 70 years) as compared to those with age < 70 years. Proc Am Soc Clin Oncol 18:471a, 1999 (abstr 1818) 26. Lippe P, Silva RR, Monterubbianesi MC, et al: Advanced non-small cell lung cancer (ANSCLC) in the elderly: Symptoms-relief after weekly gemcitabine (G) and cisplatin (P). Proc Am Soc Clin Oncol 18:514a, 1999 (abstr 1984) 27. Esteban E, Llano J, Vieitez JM, et al: Phase I/II study of gemcitabine plus vinorelbine in non-small cell lung cancer. Proc Am Soc Clin Oncol 17:482a, 1998 (abstr 1855) 28. Isokangas OP, Mattson K, Joensuu H, et al: A phase II study of vinorelbine (VNR) and gemcitabine (GEM) in inoperable stage IIIB-IV NSCLC. Proc Am Soc Clin Oncol 17:489a, 1998 (abstr 1882) 29. Herbst RS, Khuri M, Jung N, et al: Phase II study of combination weekly gemcitabine and vinorelbine in patients with untreated or previously treated non-small cell lung cancer. Proc Am Soc Clin Oncol 18:462a, 1999 (abstr 1782) 30. Gridelli C, Frontini L, Giulisano M, et al: Optimal doses of gemcitabine + vinorelbine (Gemvin) in the treatment of advanced non–small-cell lung cancer (NSCLC): A "Keep-the-Winner" phase 2 study. Proc Am Soc Clin Oncol 18:477a, 1999 (abstr 1841) Submitted October 26, 1999; accepted March 8, 2000. This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
