for the French Thoracic Oncology Collaborative Group (GCOT)
Affiliations of authors: Chest Disease Department, Jean Minjoz University Hospital, Besançon, France (VW, AD); Chest Disease Department, University Hospital, Strasbourg, France (EQ); Chest Disease Department, University Hospital, Grenoble, France (DM-S); Biostatistics, University Hospital, Besançon, France (MM, MP); Chest Disease Department, General Hospital, Belfort, France (J-LB); Chest Disease Department, General Hospital, Vesoul, France (DD); Chest Disease Department, General Hospital, Saint Omer, France (PR); Chest Disease Department, University Hospital, Nancy, France (M-AH); Chest Disease Department, Tenon University Hospital, Paris, France (BM); Chest Disease Department, General Hospital, Nevers, France (DH); Chest Disease Department, General Hospital, Verdun, France (M-CL); Chest Disease Department, General Hospital, Le Mans, France (F-XL)
Correspondence to: Alain Depierre, MD, Service de pneumologie, Centre Hospitalier Universitaire Jean Minjoz, Boulevard Fleming, 25030 Besançon cedex, France ( e-mail: pneumo-depierre{at}ufc-chu.univ-fcomte.fr).
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
One approach to optimizing chemotherapy consists of increasing its intensity, which can be achieved by delivering higher dose intensities or higher total doses of chemotherapy. Maintenance chemotherapy, which involves prolongation of chemotherapy duration, either with the same regimen as that used for induction treatment or with other agents, increases total doses of chemotherapy. Delivering different chemotherapy regimens for induction and maintenance also has a theoretical advantage. According to the Goldie and Coldman hypothesis of drug resistance (1), the appearance of resistant cells depends on spontaneous mutations and increases with time. Therefore, the early use of noncross-resistant antineoplastic agents might increase the probability of destroying more cancer cells before chemoresistance arises (1). On this basis, benefit could be expected from maintenance delivery of one or several drugs different from those given as induction treatment.
Presumably, patients who respond to front-line chemotherapy can be considered as having chemosensitive disease and are the most likely to derive clinical benefit from maintenance chemotherapy. Indeed, among 13 published randomized phase III trials of maintenance chemotherapy in small-cell lung cancer (2), the only trial to have shown a statistically significant survival advantage of maintenance chemotherapy was carried out only in patients who responded to induction chemotherapy (3). Therefore, we conducted a randomized trial among patients who responded to induction chemotherapy or chemoradiation with mitomycinifosfamidecisplatin (MIC) to compare survival of such patients treated with maintenance single-agent vinorelbine with that of patients not receiving maintenance chemotherapy.
![]() |
SUBJECTS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients with histologically confirmed stage IIIB and IV NSCLC were eligible for this study (4). Patients came from Armentières, Brive-la-Gaillarde, Belfort, Bourges, Beauvais, Le Mans, Montluçon, Meaux, Nevers, Saintes, Saint Brieuc, Sens, Saint Omer, Troyes, Vesoul, and Verdun General Hospitals; Besançon, Grenoble, Nancy, Strasbourg (Hautepierre and Hôpital civil), Tenon (Paris), and Tours University Hospitals; and Dijon Cancer Center, France. Patients were required to have received no prior chemotherapy or thoracic radiotherapy, but patients who experienced recurrences after surgery were eligible. Additional eligibility criteria included a performance status of 2 or less according to World Health Organization (WHO) criteria (5), age 75 years or less, no brain metastases, no previous cancer except for basal cell carcinoma of the skin, no interstitial pneumonitis, no severe cardiac disease, and no cirrhosis. Patients with stage IIIB disease were required to have no contraindications to thoracic radiotherapy. Biologic requirements included a leukocyte count above 3000/µL, a neutrophil count above 1500/µL, a platelet count above 150 000/µL, and a serum creatinine level below 130 µmol/L. Signed informed consent was obtained from all patients registered in the trial, and the study was approved by the Besançon University Hospital Medical Ethics Committee.
All eligible patients were evaluated before registration by physical examination; chest x-ray; computed tomography (CT) scans of the chest, upper abdomen, and brain; abdominal ultrasonography; fiberoptic bronchoscopy with biopsies; complete blood cell count; and creatinine determination.
Treatment
The treatment plan is illustrated in Fig. 1. All patients registered in the study received intravenous MIC (mitomycin C at 6 mg·m2 on day 1, ifosfamide at 1.5 g·m2·day1 on days 1 through 3, and cisplatin at 30 mg·m2·day1 on days 1 through 3). Cisplatin was administered first, as a 45-minute infusion in a 5% NaCl solution with standard hydration. Prophylaxis of the bladder toxicity of ifosfamide consisted of 1.2 g·m2·day1 of mesna. Modalities of antiemetic therapy were let to the discretion of investigators according to the participating centers' policies. MIC cycles were repeated every 4 weeks for a total of two cycles for patients with stage IIIB disease and a total of four cycles for patients with "wet" stage IIIB (i.e., pleural or pericardial involvement), stage IIIB with supraclavicular node involvement, or stage IV NSCLC. At each cycle, patients had a blood cell count on days 10 and 28 and a creatinine determination on day 28. If granulocyte counts were between 1000 and 1500/µL on day 28, the doses of mitomycin and ifosfamide were reduced by 50%. If granulocyte counts were less than 1000/µL, the next treatment cycle was delayed for 1 week. If platelet counts were between 100 000/µL and 150 000/µL, the dose of mitomycin was reduced by 50%, and if platelet counts were below 100 000, mitomycin was omitted entirely. If the creatinine level was between 130 and 180 µmol/L, cisplatin was reduced by 50%, and if the creatinine level was over 180 µmol/L, MIC chemotherapy was stopped.
|
Tumor size was evaluated before each chemotherapy cycle using chest x-ray and at completion of the induction treatment (i.e., with MIC or MIC plus radiotherapy) with thoracic and abdominal CT scans, abdominal ultrasonography, and fiberoptic bronchoscopy if the baseline result was abnormal. Tumor response was evaluated according to WHO criteria (5). Patients whose disease showed a complete or a partial response to induction treatment were randomly assigned to receive maintenance vinorelbine or to the observation arm (no maintenance therapy). A complete response was defined as the disappearance of all clinical and radiologic evidence of disease. A partial response was defined as a 50% decrease in the sum of products of the largest perpendicular diameters of the tumors with no evidence of progression in any site. Patients with progressive or stable disease were treated off study at the discretion of investigators.
Patients in the vinorelbine arm were administered vinorelbine intravenously at a dose of 25 mg·m2·wk1 for 6 months, beginning 16 weeks after the first MIC cycle in patients treated with induction chemotherapy and 17 weeks after the first MIC cycle in patients treated with induction chemoradiation. A blood cell count was performed before every vinorelbine perfusion; the vinorelbine dose was reduced by 50% if granulocyte counts were between 1000 and 1500/µL, and vinorelbine was withheld if granulocyte counts were less than 1000/µL. If granulocyte counts were less than 1000/µL for more than 3 weeks, vinorelbine was restarted on an every-other-week cycle. Prevention of leukoneutropenia using granulocyte colony-stimulating factors was not allowed. Maintenance vinorelbine was stopped after any grade 4 toxicity other than neutropenia was observed. In both the vinorelbine and observation groups, tumor response was evaluated by chest x-ray, which was performed monthly during the 6 months after random assignment and every 3 months thereafter. The disease was assessed by planned thoracic CT scan, abdominal ultrasonography, and fiberoptic bronchoscopy at 3, 6, 10, 14, and 18 months after randomization and by thoracic CT scan and fiberoptic bronchoscopy if initially abnormal every 6 months thereafter in the absence of progression.
Investigators were advised to treat patients with progressive disease in both arms with etoposide (80 mg·m2·day1) and cisplatin (30 mg·m2·day1) on days 1 through 3 every 4 weeks. Vinorelbine treatment was not allowed in patients assigned to the observation group at any time.
Statistical Analysis
The objective of this phase III study was to compare survival between patients treated with maintenance vinorelbine and patients receiving no further treatment after response to induction treatment. The primary endpoint was overall survival from the date of randomization. The secondary endpoints were progression-free survival; the rate of partial responses that became complete responses according to WHO criteria; the rate of improved partial responses that did not achieve complete response, i.e., a substantial reduction in tumor size in a patient in whom lesion(s) persisted; and the toxicity of maintenance vinorelbine.
Patients were stratified by stage before randomization. Patients were randomized by a phone call to the randomization center during the 18th week after the first MIC cycle for those treated with induction chemoradiation and during the 17th week for those treated with induction chemotherapy. The method of randomization was by random permuted blocks within strata. The block size was six.
The study was designed to have 90% power to test the hypothesis that the 18-month survival rate would be 10% in the observation arm and 20% in the maintenance vinorelbine arm. Assuming an accrual period of 3 years, a potential follow-up of 2 years for the last included patient, and a one-sided test with a type I error rate of 0.05, 270 MIC-responding patients had to be randomly assigned. With an estimated MIC response rate of 40%, 675 patients had to be registered (7). Because accrual took twice as long as initially planned, the study was stopped on January 31, 2000, after 573 patients had been registered. For survival analyses, an end date of January 1, 2002, was chosen because 178 (98%) of the 181 randomized patients had reached the planned potential minimal follow-up from the date of randomization of 2 years. The actual statistical power was calculated using the reduced sample size, the initially hypothesized survival difference, the planned (and actual) follow-up of 2 years, and both the expected and actual duration of inclusion. Whether calculation was based on the expected or the actual duration of inclusion, the 181 randomized patients conferred to the survival comparison a statistical power of approximately 80% and a statistical significance level of .05.
Survival was calculated from the date of randomization for the comparison between both arms. Progression-free survival was the time elapsed between the date of randomization and the date of progression or death. For patients alive and/or progression-free whose last status date was earlier than January 1, 2002, the actual date of last contact was used as the end date. Survival curves were generated using the KaplanMeier method (8) and were compared with the log-rank test and with Cox proportional hazards regression adjusted for stage (9). The graphical representation of log{log [S(t)]} was used to confirm the assumption of proportionality. Differences in toxicities were compared using the MantelHaenszel test. All statistical comparisons were two-sided. All calculations were performed on an intention-to-treat basis using SAS software (version 8.2, 1999, SAS Institute Inc., Cary, NC).
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A total of 573 patients were included in this study between July 1, 1993, and January 31, 2000 (Fig. 2). There were 239 stage IIIB patients and 334 stage IV patients. Baseline patient characteristics are detailed in Table 1. Among stage IIIB patients, two were lost to follow-up, and data on treatment were missing for another two patients. Among stage IV patients, one died before receiving any treatment, one patient was ineligible because of brain metastases, and information on treatment was missing for another patient. Further results are presented for the 566 patients (235 stage IIIB and 331 stage IV) for whom data were available (Fig. 2).
|
|
Seventeen deaths (3%) potentially related to induction treatment occurred among the 566 patients. These 17 deaths include 14 deaths after chemotherapy (10 were septic deaths; two were due to severe physical alteration, i.e., performance status 3 or 4; and two were of unknown cause) and three deaths after chemoradiation (one septic death, one death from pulmonary toxicity, and one death of unknown cause). Grade 3 and 4 hematologic toxicities of the MIC combination consisted of leukopenia in 191 of the 566 patients (33.7%), anemia in 99 of the 566 patients (17.5%), and thrombocytopenia in 121 of the 566 patients (21.4%). Severe peripheral neuropathy was rare (two patients). Grade 3 and 4 pulmonary toxicity considered as potentially due to chemotherapy occurred in nine of the 566 patients (1.6%), and grade 3 and 4 pulmonary toxicity caused by radiotherapy was seen in 10 of the 172 irradiated patients (5.8%).
Of the 566 patients for whom induction treatment data were available, 57 were not evaluable for response (49 patients died before evaluation, treatments for three patients were interrupted for toxicity, one patient refused to continue treatment, one patient with stage IIIB disease was not irradiated, one patient did not receive treatment for unknown reason, and two patients were lost to follow-up). A total of 227 patients responded to induction treatment, with 22 of the 566 patients showing complete responses (3.9%) and 205 showing partial responses (36.2%). These 227 responding patients included 122 stage IIIB patients (response rate = 52%; 95% confidence interval [CI] = 37% to 67%) and 105 stage IV patients (response rate = 32%; 95% CI = 23% to 40%) (Table 2). Among the 566 patients for whom data were available, median overall survival from the date of the first chemotherapy cycle was 9 months, and 1- and 2-year survival rates were 37% and 14%, respectively.
|
Maintenance Chemotherapy Delivery
Complete data on chemotherapy delivery were available for 89 of the 91 patients in the vinorelbine group. The number of weekly vinorelbine infusions received was as follows: none in two patients (one patient refused and one died of intercurrent cause, i.e., disease other than cancer or toxicity of chemotherapy), one to three in 11 patients, four to eight in 22 patients, eight to 16 in 30 patients, 16 to 24 in 21 patients, and 25 to 31 in three patients. The mean duration of vinorelbine chemotherapy was 13.8 weeks (standard deviation = 8.7), the median total delivered dose was 450 mg (range = 01565), and the median dose intensity was 23 mg·m2·wk1 (range = 030). Vinorelbine was stopped at the end of the treatment program (i.e., 6 months) in 21 patients (23%) and was stopped early in the other 70 (77%) patients as follows: for progressive disease in 35 patients (38%), for toxicity in 19 patients (21%), because of treatment refusal in 10 patients (11%), for death of intercurrent disease in two patients (2%), for development of intercurrent disease in two patients (2%), for toxic death in one patient (who had received induction chemoradiation for stage IIIB disease), and for unknown reasons in one patient.
Toxicity of Maintenance Chemotherapy
Two of the 91 patients in the vinorelbine group did not receive vinorelbine (one patient refused and one died of intercurrent cause), and data on toxicity of maintenance vinorelbine were not available for two patients. Toxicities of maintenance vinorelbine for the remaining 87 patients are presented in Table 3. The main toxicity was hematologic. Grade 3 and 4 leukopenia and infections were more frequently observed in patients who had received induction chemoradiation than in those who received induction chemotherapy (P = .05 and P = .048, respectively). Other toxicities of maintenance vinorelbine were not statistically significantly different according to the type of induction treatment.
|
Of the 91 patients in the vinorelbine arm, four patients died before evaluation, two refused evaluation, and data were missing for two patients, leaving 83 patients evaluable for response. Ten of the 91 patients (11%) achieved a complete response (six patients with stage IIIB disease and four with stage IV disease) (Table 4). A partial response was seen in 38 of the 91 patients (42%) (21 patients with stage IIIB disease and 17 with stage IV disease). Among these 38 partial responders, eight (three stage IIIB patients and five stage IV patients) improved partial responses (i.e. a substantial reduction in tumor size in a patient in whom lesions persisted) that did not achieve complete response were observed. Progression occurred in 35 (38%) of the 91 patients in the vinorelbine arm.
|
Median follow-up from the date of randomization was 10.4 months (range = 0.0789.4) in the vinorelbine arm and 11.9 months (range = 0.391.7) in the observation arm. The hazard ratio of overall survival, after adjustment for stage, in the vinorelbine arm relative to the observation arm was 1.08 (95% CI = 0.79 to 1.47; P = .65). Median survival from the date of randomization was 12.3 months in both the vinorelbine and observation groups. The 1-year, 18-month, and 2-year survival rates were 42%, 28%, and 20% in the vinorelbine group and 51%, 27%, and 20% in the observation group, respectively (log-rank P = .48) (Fig. 3). Among stage IIIB patients, 1- and 2-year survival rates were 49% and 22% in the vinorelbine group and 49% and 28% in the observation group, respectively. Among stage IV patients, 1- and 2-year survival rates were 36% and 18% in the vinorelbine group and 53% and 11% in the observation group, respectively. The hazard ratio of progression-free survival, after adjustment for stage, was 0.77 (95% CI = 0.56 to 1.07; P = .11). Median progression-free survival from the date of randomization was 5 months in the vinorelbine group and 3 months in the observation group. The 1-year, 18-month, and 2-year progression-free survival rates were 23%, 16%, and 13% in the vinorelbine group and 19%, 16%, and 15% in the observation group, respectively (log-rank P = .32) (Fig. 4).
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The toxicity of maintenance vinorelbine seemed to be higher than that of vinorelbine given to chemotherapy-naive patients in phase III trials comparing vinorelbine with vinorelbinecisplatin (10,11). In our study, the toxicity of maintenance vinorelbine led to treatment being stopped in 21% of patients on the maintenance chemotherapy arm, whereas treatment had to be stopped for toxicity in only 8% of chemotherapy-naive patients treated with single-agent vinorelbine in the phase III setting (10). As typically reported with single-agent vinorelbine, the main toxicity was hematologic. With single-agent vinorelbine in the chemotherapy-naive patients included in phase III trials, treatment-related deaths were reported in 1% of patients, grade 3 and 4 leukopenia in 10% of patients, sepsis requiring hospitalization in 4.3% of patients; no pulmonary toxicity was observed (10,11). With maintenance vinorelbine in the present study, treatment-related deaths also occurred in 1% of patients, but rates of grade 3 and 4 leukopenia, sepsis, and pulmonary toxicity were higher (35.4%, 6.2%, and 6.2% of patients after induction MIC, respectively; 59.5%, 21.6%, and 8.1% after chemoradiation, respectively).
Our choice of MIC as the induction regimen probably played a role in increasing the toxicity of maintenance vinorelbine. Indeed, in our study MIC-related toxicity (leukopenia, thrombocytopenia, and pulmonary toxicity) was more frequent than that reported with other first-line combinations such as vinorelbinecisplatin, especially when sequential radiotherapy was associated (10,11). However, whatever cytotoxic agents are given, there is a cumulative toxicity of prolonged chemotherapy. In a study comparing three cycles of MVP (mitomycin, vinblastine, and cisplatin) with six or more cycles of the same regimen in 308 patients with advanced NSCLC, anemia and fatigue were statistically significantly increased in patients treated with six courses (12). In a similar study, 230 patients with stage IIIB or IV NSCLC were randomly assigned to receive either four cycles of carboplatinpaclitaxel or continuous carboplatinpaclitaxel until progression. Statistically significantly more peripheral neuropathy was observed in patients on the continuous therapy arm (13).
In our study, the increased toxicity of vinorelbine delivered in the maintenance setting did not result in reduced vinorelbine delivery. Indeed, the mean duration and the median delivered dose intensity of maintenance vinorelbine therapy were similar to those reported previously for vinorelbine given to chemotherapy-naïve patients (in our study, these were 13.8 weeks and 23 mg·m2·wk1, respectively; with front-line single-agent vinorelbine they were 14 weeks and 22.5 mg·m2·wk1, respectively) (10,11). Therefore, the increased toxicity of maintenance vinorelbine is probably not responsible for the absence of a survival advantage in the present study.
Both published studies addressing the issue of treatment duration demonstrated no survival benefit of prolonged chemotherapy (12,13). Another phase III study, which compared three to six cycles of carboplatin plus vinorelbine in 297 eligible patients, showed no difference in survival (14). However, there were two major differences in study design between these trials and ours. The first difference concerns eligibility of patients for random assignment to maintenance chemotherapy. In the three other studies, patients were randomly assigned from the beginning of induction chemotherapy, whereas in the trial described here, based on small-cell lung cancer experience, only patients who responded to induction chemotherapy were randomly assigned to maintenance vinorelbine. Although numerous phase II studies of second-line chemotherapy with different agents have been published, whether the response to first-line chemotherapy influences the response to second-line therapy is not clear. Several phase II studies have found no difference in response rates to second-line therapy between patients who responded to first-line cisplatin-based chemotherapy and those who did not (1518). If maintenance chemotherapy is of any use to patients with NSCLC, it is unlikely to be applicable to all patients, but it is not obvious whether responders are effectively the best candidates. Only a few patients improved their response from a partial to a complete response in the present study, and further reduction of tumor volume in partial responders has never been shown to improve survival. If one considers the fact that objective response is a favorable prognostic factor (19,20), it is conceivable that patients with stable disease after induction chemotherapy might benefit from maintenance chemotherapy if they can achieve a response with the maintenance treatment. In a randomized phase II study comparing three different schedules of carboplatinpaclitaxel in 401 patients with stage IIIB or IV NSCLC, the 130 patients who had a response or stable disease after the initial carboplatinpaclitaxel treatment were randomly assigned to receive further paclitaxel treatment until progression or to observation (21). Although that study was not designed to test the efficacy of maintenance chemotherapy, the results were encouraging, with 1- and 2-year survival rates of 72% and 32% in the maintenance paclitaxel arm and of 60% and 26% in the observation arm. The results of a phase III study of maintenance gemcitabine versus observation in 206 patients with a response or stable disease conducted in Eastern Europe are awaited (22).
The second study design consideration is related to the choice of the maintenance drug. The three previously cited phase III trials addressing the question of treatment duration showed that prolongation of the same chemotherapy was of no clinical benefit (1214). In the present study, to allow the early delivery of an additional cytotoxic agent, a drug different from those given as induction treatment was chosen for maintenance chemotherapy. When this study was designed, in 1993, vinorelbine was the only drug available among a now-larger group of single-agent chemotherapy treatments with attractive therapeutic indexes. Vinorelbine has now been reported to have poor activity in the second-line setting, with no responses observed in two phase II studies of patients with NSCLC (23,24) and two responses among 10 patients in a third such study (25). It appears that docetaxel may be a better choice for second-line chemotherapy. Indeed, in a phase III study comparing vinorelbine or ifosfamide versus docetaxel at 75 or 100 mg·m2 every 3 weeks as second-line chemotherapy for patients with advanced NSCLC, response rate was 0.8% for the patients treated with vinorelbine or ifosfamide, 6.7% for those treated with the lower dose of docetaxel (P = .036 versus vinorelbine/ifosfamide), and 10.8% for those treated with the higher dose of docetaxel (P = .001 versus vinorelbineifosfamide) (26). In the same study, 1-year survival rates were 19%, 32%, and 21%, respectively (P = .025 for vinorelbineifosfamide versus docetaxel at 75 mg·m2). In another phase III trial, in which second-line therapy with docetaxel was compared with best supportive care for patients with advanced NSCLC, 1-year survival in docetaxel-treated patients was 29% compared with 12% in the control group (P = .047) (27). Response rates of 0%38% have been reported for patients with advanced NSCLC treated with second-line paclitaxel and of 0%21% for those treated with second-line gemcitabine (28).
The consistent results with docetaxel given as second-line treatment suggest that it should be tested in the maintenance setting. Targeted agents are also worth testing as maintenance therapy. Indeed, in patients with NSCLC progressing after treatment with one or more platinum-based chemotherapy regimens, response rates of 12%18.4% were observed in patients treated with 250 mg of gefitinib daily in the IDEAL phase II studies (29,30). Erlotinib has been reported to statistically significantly improve outcome compared with best-supportive care in second- and third-line treatment of patients with advanced NSCLC (31). The Southwest Oncology Group is currently conducting a phase III trial of maintenance gefitinib versus placebo after concurrent cisplatinetoposide and radiotherapy plus consolidation chemotherapy with docetaxel in unresectable stage III NSCLC.
In conclusion, the trial described in this articlethe first, to our knowledge, to study maintenance chemotherapy with a drug different from that delivered as induction in advanced NSCLCshowed that maintenance vinorelbine did not improve the outcome of responding patients. Maintenance therapy may not be of use for patients with advanced NSCLC. However, other chemotherapeutic agents, especially docetaxel and targeted agents, should be evaluated before the concept is abandoned.
![]() |
NOTES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
(1) Goldie D, Coldman A. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:172733.[ISI][Medline]
(2) Sculier JP, Berghmans T, Castaigne C, Luce S, Sotiriou C, Vermylen P, et al. Maintenance chemotherapy for small cell lung cancer: a critical review of the literature. Lung Cancer 1998;19:14151.[CrossRef][ISI][Medline]
(3) Einhorn LH, Crawford J, Birch R. Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin and vincristine in limited small-cell lung cancer. J Clin Oncol 1988;6:4516.[Abstract]
(4) Mountain CF. A new international staging system for lung cancer. Chest 1986;89:225S33S.[Medline]
(5) WHO handbook for reporting results of cancer treatment. Vol 48. Geneva (Switzerland): WHO; 1979.
(6) Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 1990;323:9405.[Abstract]
(7) Currie DC, Miles DW, Drake JS, Rudd R, Spiro SG, Earl HM, et al. Mitomycin, ifosfamide and cisplatin in non-small-cell lung cancer. Cancer Chemother Pharmacol 1990;25:3801.[CrossRef][ISI][Medline]
(8) Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:45781.[ISI]
(9) Cox DR. Regression models and life tables. J R Stat Soc [B] 1972;34:187220.[ISI]
(10) Depierre A, Chastang C, Quoix E, Lebeau B, Blanchon F, Paillot N, et al. Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial. Ann Oncol 1994;5:3742.[Abstract]
(11) Le Chevalier T, Brisgand D, Douillard JY, Pujol JL, Alberola V, Monnier A, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 1994;12:3607.[Abstract]
(12) Smith IE, O'Brien ME, Talbot DC, Nicolson MC, Mansi JL, Hickish TF, et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 2001;19:133643.
(13) Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 2002;20:133543.
(14) Andresen O, Sörenson S, Bergman B, Sundstrom S, Vilsvik J, Aasebo U, et al. Duration of chemotherapy and survival in advanced non-small cell lung cancer (NSCLC). A multicenter, prospective randomised study. Lung Cancer 2003;41 Suppl 2:S28.
(15) Gandara DR, Vokes E, Green M, Bonomi P, Devore R, Comis R, et al. Activity of docetaxel in platinum-treated non-small-cell lung cancer: results of a phase II multicenter trial. J Clin Oncol 2000;18:1315.
(16) Alexopoulos K, Kouroussis C, Androulakis N, Papadakis E, Vaslamatzis M, Kakolyris S, et al. Docetaxel and granulocyte colony-stimulating factor in patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapy: a multicenter phase II trial. Cancer Chemother Pharmacol 1999;43:25762.[CrossRef][ISI][Medline]
(17) Van Kooten M, Traine G, Cinat G, Cazap E, Comba AZ, Vicente H, et al. Single-agent gemcitabine in pretreated patients with non-small-cell lung cancer: results of an Argentinean multicentre phase II trial. Br J Cancer 1999;81:8469.[CrossRef][ISI][Medline]
(18) Biesma B, Smit EF, Postmus PE. A dose and schedule finding study of gemcitabine and etoposide in patients with progressive non-small cell lung cancer after platinum containing chemotherapy. Lung Cancer 1999;24:11521.[CrossRef][ISI][Medline]
(19) O'Connell JP, Kris MG, Gralla RJ, Groshen S, Trust A, Fiore JJ, et al. Frequency and prognostic importance for pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 1986;4:160414.[Abstract]
(20) Paesmans M, Sculier JP, Libert P, Bureau G, Dabouis G, Thiriaux J, et al. Response to chemotherapy has predictive value for further survival of patients with advanced non-small cell lung cancer: 10 years experience of the European Lung Cancer Working Party. Eur J Cancer 1997;33:232632.[CrossRef][ISI][Medline]
(21) Belani C, Barstis J, Perry M, La Rocca R, Nattam S, Rinaldi D, et al. Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. J Clin Oncol 2003;21:29339.
(22) Krzakowski M, Wenczl M, Brodowicz T, Tzekova V, Ramlau R, Ghilezan N, et al. Gemcitabine and cisplatin (GC) ± subsequent maintenance therapy with single-agent gemcitabine in advanced non-small cell lung cancer (NSCLC): preliminary results of a randomized trial of the Central European Cooperative Oncology Group (CECOG). Lung Cancer 2003;41 Suppl 2:S29.[ISI][Medline]
(23) Pronzato P, Landucci M, Vaira F, Vigani A, Bertelli G. Failure of vinorelbine to produce responses in pretreated non-small cell lung cancer patients. Anticancer Res 1994;14:14135.[ISI][Medline]
(24) Rinaldi M, Della Giulia M, Venturo I, Pel Medico P, Serrone L, Capomolla E, et al. Vinorelbine as single agent in the treatment of advanced non small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1994;13:360.
(25) Santoro A, Maiorino A, Santoro M. Second-line with vinorelbine in the weekly monochemotherapy for the treatment of advanced non-small cell lung cancer. Lung Cancer 1994;11:130.
(26) Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:235462.
(27) Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095103.
(28) Huisman C, Smit EF, Giaccone G, Postmus PE. Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. J Clin Oncol 2000;18:372230.
(29) Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer. J Clin Oncol 2003;21:223746.
(30) Kris MG, Natale RB, Herbst RS, Lynch TJ, Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. JAMA 2003;290:214958.
(31) Shepherd FA, Pereira J, Ciuleanu TE, Tan EH, Hirsh V, Thongprasert S, et al. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial [abstract]. Proc Am Soc Clin Oncol 2004;22:7022.
Manuscript received December 4, 2003; revised January 7, 2005; accepted January 28, 2005.
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |