Front-line paclitaxel–vinorelbine versus paclitaxel–carboplatin in patients with advanced non-small-cell lung cancer: a randomized phase III trial

G. P. Stathopoulos1,*, M. Veslemes2, N. Georgatou3, D. Antoniou4, P. Giamboudakis5, K. Katis8, D. Tsavdaridis9, S. K. Rigatos1, I. Dimitroulis7, S. Bastani6, S. Loukides10, K. Vergos11, K. Marossis3, T. Grigoratou4, E. Kalatzi5, M. Charalambatou8, A. Paspalli3, P. Michalopoulou4, M. Stoka3 and A. Gerogianni4

1 First Department of Medical Oncology, 2 University Clinic, 3 Fifth Clinic, 4 Seventh Clinic, 5 Tenth Clinic, 6 Third Clinic 7 Sixth Clinic, Errikos Dynan Hospital, Athens, Sotiria Hospital Clinics, Athens; 8 Thriacion Hospital, Athens; 9 IKA, Thessaloniki; 10 401 Army Hospital, Athens; 11 Naval Hospital, Athens, Greece

*Correspondence to: Dr G. P. Stathopoulos, Semitelou 5, 115 28 Athens, Greece. Tel: +30-210-7752600; Fax: +30-210-7251736;Email: dr-gps{at}ath.forthnet.gr


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: This randomized phase III trial of advanced or metastatic non-small-cell lung cancer (NSCLC) was designed to compare a standard treatment such as carboplatin (CRP)–paclitaxel (PCT) with a new combination, vinorelbine (VRL)–PCT—two agents acting in microtubules.

Patients and methods: Three hundred and sixty patients (stage IIIa, IIIb and IV) were included and evaluated for response rate, survival and toxicity. Arm A patients were treated with the control combination of CRP 6 AUC and PCT 175 mg/m2 repeated every 3 weeks for six cycles, and arm B with the investigational combination of VRL 25 mg/m2 and PCT 135 mg/m2 repeated every 2 weeks for nine cycles. The patients were well balanced with respect to gender, disease stage and performance status. Arm A received 849 cycles (mean 4.59 per patient) and arm B 951 cycles (mean 5.39 per patient).

Results: Complete and partial response rates were 45.95% and 42.86% for arms A and B, respectively. Median survival was 11 and 10 months, 1-year survival 42.7% and 37.85% and 2-year survival 10.12% and 19% for arms A and B, respectively. Toxicity was similar in all patients, except for neutropenia, which was significantly greater in arm B.

Conclusions: PCT combined with VRL produces similar (non-significant) response rates, survival and toxicity (except for neutropenia, as noted above) to standard CRP–PCT treatment in untreated advanced-stage NSCLC.

Key words: non-small-cell lung cancer, paclitaxel, paclitaxel versus carboplatin, vinorelbine


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Chemotherapy has been a standard treatment for inoperable advanced non-small-cell lung cancer (NSCLC) since reports showed its superiority in rendering a statistically longer survival than palliative management [1Go–3Go]. Increased median and overall survival has mainly been achieved with the use of cisplatinum-based cytotoxic combinations [4Go, 5Go] and chemotherapy applying before radiation or surgery, which has shown increased efficacy [6Go–8Go]. Cisplatinum toxicity, particularly nephrotoxicity, is an inhibitory factor in continuing chemotherapy in a reasonably high percentage of patients [9Go–11Go]. The introduction of new effective agents for NSCLC has triggered clinical trials that exclude cisplatinum and test the toxicity and efficacy of non-cisplatinum-based agent combinations. Studies of numerous combinations using new agents have already been published [12Go–18Go]. Several of these combinations have shown more or less similar efficacy to that of the platinum-related ones. The evaluation of toxicities vary: mainly, there is no nephrotoxicity or ototoxicity with the new agents, but with respect to myelotoxicity, gastrointestinal tract toxicity and neurotoxicity, no improvement has been observed over cisplatin with non-cisplatin-based therapy. The new agents that have become part of clinical practice include cisplatinum analogs such as carboplatin (CRP) [19Go], taxanes such as paclitaxel (PCT; Taxol) [17Go, 18Go, 20Go], and docetaxel [21Go–23Go], gemcitabine [24Go–26Go] and vinorelbine (VRL) [12Go, 27Go, 28Go]. For the treatment of advanced NSCLC, several combinations of these drugs, with or without cisplatinum, have been tested [29Go–31Go]; response rates have been documented in data [27Go, 28Go, 30Go–32Go] published over the last few years, with promising results. One of the objectives in combining two or three cytotoxic agents is to avoid similar kinds of adverse reactions to those caused by cisplatinum without decreasing the efficacy. PCT and VRL is one of the combinations that has been only sparsely tested. Both of these agents have a mechanism of action related to the polymerization and depolymerization of microtubules [33Go–36Go]. Because the toxicity was considered to be unacceptable and the efficacy very low in a trial with a small number of patients, the study was abandoned; however, the disadvantage that these patients had was that they had undergone prior chemotherapy before the study [32Go].

Our rationale for combining these two agents was that, as first-line chemotherapy, each is considered to be effective in NSCLC when combined with other cytotoxic drugs. Prior to this study, we worked on a phase II trial [37Go], the results of which, addressing only adenocarcinoma of the lungs, defined acceptable toxicity and reported a response rate of 50%. Median survival reached 50%. The decision to combine VRL with PCT was motivated by the synergic cytotoxicity of this combination in in vitro studies [38Go–40Go]. We then moved on to this phase III trial as follows. Two arms of patients were randomized: the experimental arm involved VRL with PCT, and the control arm CRP with PCT. The latter regimen was chosen as it is considered to be one of the standard treatments in NSCLC [19Go].

The main objectives of this trial were to determine (i) median and overall survival, (ii) response rate and (iii) toxicity (comparison between the two arms), and also 1- and 2-year survival.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility criteria included patients with stage IIIb disease (with pleural effusion or N3 nodal disease), or stage IV with extrapulmonary metastases including asymptomatic brain metastases and stage IIIa N2 inoperable disease staged by mediastinoscopy. Histological or cytological confirmation of NSCLC was required for all patients. Staging by objective imaging methods was performed. Bidimensionally measurable disease was preferable, and occasionally mandatory unidimensional measurable disease was acceptable.

Patients who had undergone prior chemotherapy were excluded, as well as those who had received radiation therapy at the primary site of disease. Patients who had recurrent disease after lobectomy were included, as were those who had received palliative radiation therapy on the skeleton. The following criteria were mandatory: Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, expected survival ≥12 weeks, adequate bone marrow reserve (leukocyte count ≥3500/µl, platelet count ≥100 000/µl and hemoglobin ≥10 g/dl), adequate renal function (serum creatinine ≤1.5 mg/dl) and liver function (serum bilirubin ≤1.5 mg/dl), and serum transaminases ≤3x the upper normal limit or ≤5xthe upper normal limit in cases of liver metastases. The lower age limit for enrollment was 18 years. Patients with a secondary malignancy were excluded unless it had been ≥10 years prior and treatment had only been surgical. This study was conducted with the approval of our Institutional Review Boards, and all patients gave their informed consent before enrollment.

Study design and sample size
This study was designed as a multicenter, randomized, phase III trial, approved by the Institutional Review Boards of the 11 participating hospitals. The study was powered at 80% to detect a difference in response rate and survival between the investigational arm and the control arm. The sample size was initially planned to include 250 patients (125 in each arm), with an increase in the number of patients if a statistical difference of 5% between the two arms, with regard to median survival and response rate, was not reached. The randomization was performed centrally and patients were stratified by three prognostic variables: disease stage (locally advanced versus metastatic disease), performance status (ECOG performance status of 0–2) and investigational site.

Treatment plan
Arm A patients were designated to receive six cycles of CRP and PCT. The doses were standard for CRP, 6 AUC (area under the curve), and for PCT, 175 mg/m2, repeated every 21 days. PCT was initially infused for 3 h followed by CRP at the 1-day outpatient clinic. Premedication included ondasentron 8 mg intravenously (i.v.), dexamethasone 8 mg i.v. and diphenhydramine 50 mg i.v. with modified timing 1 h before the beginning of treatment and repeated 4 and 8 h thereafter. Arm B patients were designated to receive nine cycles of PCT and VRL at the following doses: PCT 135 mg/m2 and VRL 25 mg/m2 repeated every 2 weeks. The dose reduction of PCT was counterbalanced by the earlier (once every 2 weeks instead of every 3 weeks) administration. The administration of VRL once every 2 weeks was based on our previous study [41Go]. Patients who responded to treatment continued to the end of the planned number of cycles. Non-responders discontinued treatment between the second and fourth cycles. The total number of cycles for arm A patients was 849 (mean 4.59 per patient); one hundred and two patients (55.1%) completed six cycles. In arm B, the total number of cycles was 951 (mean 5.39 per patient); 80 patients (45.7%) completed six to nine cycles. Hemopoietic growth factor was not applied prophylactically, but only in cases of grade 3 and 4 neutropenia.

Baseline and treatment assessment and evaluation
Before study entry all patients underwent the following evaluations: medical history, physical examination, tumor measurement or evaluation, ECOG performance status, ECG, full blood count, liver and renal function tests, and urinalysis. Staging was determined by chest and abdominal computed tomography, bone scan and occasionally magnetic resonance imaging. Blood count, blood urea and serum creatinine were measured before each treatment administration and 7 days after each course. Radiologic tests were conducted after the current course of treatment if the clinical signs were indicative of disease progression.

Response and toxicity were assessed using standard World Health Organization criteria, as follows. Complete response (CR), the disappearance of any sign of demonstrable disease; partial response (PR), ≥50% reduction of measurable disease; and stable disease (SD), <50% decrease of measurable disease or up to 25% increase. Duration of response was measured from the time of documentation of response (CR or PR) to progressive disease. Time to disease progression was measured from the time of the first dose administration to disease progression. The determination of objective response on computed tomography was performed by two independent radiologists and two experienced oncologists.

Statistical analysis
The study was designed as a group-sequential clinical trial. An interim analysis based on the O'Brien/Fleming boundary values was performed when 50% of the end points had been reached [42Go]. The study would have ended prematurely if a significant difference in survival had been detected.

The randomization of patients into two treatments was performed according to the method of random permuted blocks within strata. Stratification factors compromised stage IIIa, IIIb or IV metastatic. Dynamic balancing was performed by the hospital. Pearson's {chi}2-test was used for comparisons of categorical variables, or Fisher's exact test when appropriate. The non-parametric Mann–Whitney test was used for comparisons of continuous variables. Time-to-event analyses were performed where survival distribution was estimated by the Kaplan–Meier curve, and treatment comparison was made using the log-rank test. All reported P values are two-sided. A P value of <0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Three hundred and seventy-two patients entered the study between August 2000 and March 2003. Twelve patients, four in arm A and eight in arm B, did not undergo any treatment: some refused and others had renal or heart abnormalities. Three hundred and sixty patients received treatment: 185 in arm A and 175 in arm B. The patients’ demographic and disease characteristics at baseline are shown in Table 1Go.


View this table:
[in this window]
[in a new window]
 
Table 1 Patients’ demographics and disease characteristics at baseline

 
The two arms of the study were well balanced with respect to total number, age, gender, performance status, histology, histological subtypes and histological differentiation (grading).

Response evaluation
Of the 360 patients included in the toxicity and response evaluation, 25 (6.9%) patients underwent one course of treatment: 14 (7.6%) and 11 (6.3%) in arms A and B, respectively. If these patients are subtracted from the total, it does not alter the statistical evaluation of the response rate and survival between the two study arms. Response results are shown in Table 2Go. In arm A, CR and PR was 45.95% while in arm B it was 42.86% (no statistical significance was observed). The total response rate of all patients was 44.4%. Ten patients (2.78%), three (1.62%) from arm A and seven (4%) from arm B, achieved CR.


View this table:
[in this window]
[in a new window]
 
Table 2 Response rate in 360 patients

 
The comparison of response rates was also evaluated between the two arms in relation to histological site. There was no statistically significant difference in the response rate between the two main histological types (adenocarcinoma and squamous cell carcinoma) in each arm and between the two arms (P=0.2828 and P=0.5220 for adenocarcinoma and squamous cell carcinoma, respectively). The stages were as follows. Stage IIIa: arm A, 15 patients (8.1%), arm B, 11 (6.3%) (P=0.694); stage IIIb: arm A, 79 patients (42.7%) arm B, 81 (46.3%) (P=0.693); stage IV: arm A, 91 (49.2%), arm B, 83 (47.4%) (P=0.992). No statistically significant difference was observed in the number of patients of each histological subtype (adenocarcinoma, squamous cell carcinoma, undifferentiated and large cell type) per stage of disease (Table 3Go). In addition, concerning age, gender and differentiation per subtype, no statistically significant difference was seen.


View this table:
[in this window]
[in a new window]
 
Table 3 Comparison of stage and histological subtypes

 
For arm A patients, the median duration of response was 5 months (range 1–24), and for arm B patients was 4 months (range 1–26). No statistically significant difference was detected between the two arms (P=0.178). The median time to tumor progression (TTP) was 7 months for arm A patients (range 1–26), and 6 months (range 1–28) for arm B patients (P=0.223).

Survival time-to-event measures
The median follow-up period was 18 months. The study closed in March 2003 when the last patient entered, and follow-up continued until July 2003. By the end of the study there were 126 (68.11%) events in arm A and 114 (65.14%) in arm B (no statistically significant difference; P=0.551). No difference was observed in survival time in arm A compared with arm B patients.

The median survival time for arm A patients was 11 months [range 1–35; 95% confidence interval (CI) 10–12]. The median survival of arm B patients was 10 months (range 1–36; 95% CI 8–11). No statistically significant difference in median and overall survival was determined between arms A and B (P=0.9545). Two patients from arm A and three from arm B died due to a cardiac event not related directly or chronologically to the treatment. These patients were either in SD or in disease progression.

The number of relapses observed were 44.85 and 44.05 in arms A and B, respectively (no statistically significant difference; P=0.894). The 1- and 2-year survival rates were 42.72% and 10.12%, and 37.85% and 19.09%, for arms A and B, respectively (no statistically significant difference; P=0.9545). Kaplan–Meier curves of median and overall survival are shown in Figure 1Go.



View larger version (11K):
[in this window]
[in a new window]
 
Figure 1 Kaplan–Meier curves of median and overall survival.

 
Toxicity
We recorded hematological (neutropenia, anemia, thrombocytopenia) and non-hematological (neurotoxicity, gastrointestinal tract side effects, renal toxicity allergy, cardiotoxicity, alopecia and myalgia) toxicities in arm A and B patients. The comparative results are indicated in Tables 4 and 5GoGo.


View this table:
[in this window]
[in a new window]
 
Table 4 Grade 3–4 hematological toxicity (all types)

 

View this table:
[in this window]
[in a new window]
 
Table 5 Non-hematological toxicity (all cycles)

 
Neutropenia was the only hematological adverse reaction of statistical significance between the two arms, being higher in arm B. Febrile neutropenia was detected in 16 (8.65%) arm A patients and in 32 (18.29%) arm B patients. Hemopoietic growth factor was administered to all patients with grade 3 and 4 neutropenia. There were no treatment-related deaths. The main observed non-hematological adverse reactions, seen in a high percentage of patients, were peripheral neuropathy and alopecia. No statistically significant difference in these adverse reactions was detected between the two arms. Of the other toxicities observed in a small number of patients, only allergic reaction showed a statistically significant difference (7.6% in arm A and 14.3% in arm B; P=0.039). Other adverse reactions such as asthenia were seen in some patients, although it was difficult to attribute this to the chemotherapy rather than the disease.

Quality of life
Following two to four cycles of treatment, ~50% of the patients from each arm completed a quality of life questionnaire, EORTC QLQ-C30 [43Go], which was partially modified and adjusted to our patient population. Questions related to the ability to be self-sufficient, changes involving tiredness, insomnia, nausea/vomiting, psychological changes, family problems, and the ability to work and to participate in social activities were included. Responses were based on a scale of 1 to 7 (with 1 representing the worst and 7 indicating excellent condition). Of the 183 (89 in arm A and 94 in arm B) patients who completed the questionnaire, 87 (47.54%) indicated no major changes in their lifestyle (5–7 on the scale, despite minor problems due to the treatment). In the remaining patients, lifestyle activities were reduced (96 patients, 52.46%); 1.89% of patients were unable to be self-sufficient. Performance status improved from 1 to 0 and from 2 to 1 in 19% of the patients, remained stable in 45% and deteriorated (from 1 to 2) in 36%. With regard to quality of life, the difference between the two groups was not statistically significant.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Since, for all the described parameters, the patients of the two arms were well balanced, the outcome of the comparison between the investigational and control arms can be considered credible. There have been a number of phase II and randomized studies that have targeted the improvement of the median and overall survival of patients with advanced inoperable and metastatic NSCLC. Although several new agents have been tested and incorporated into the cisplatin schedule, eventually the trials were directed towards combinations without cisplatin, due to the renal toxicity of the latter. Thus, two types of studies evolved: first with cisplatin plus new agents, and next the new agent combination excluding cisplatin. A recent study using old agents with cisplatin but also including radiotherapy achieved one of the highest median survivals, at 11.7 months [2Go]. Similar results with old agents have been reported in other studies [5Go, 6Go], as well as when new agents were combined with cisplatin: new vinca alkaloids with cisplatin have shown comparable activity [12Go]. Gemcitabine with cisplatin versus mitomycin C, ifosfamide and cisplatin in a randomized trial showed no statistically significant difference in survival [13Go]. A comparison of the combination with cisplatin–Gemzar versus cisplatin–VRL versus all three of these drugs together showed no improvement compared with the results of previous studies.

Taxanes then entered NSCLC trials. PCT showed an equally high effectiveness when combined with cisplatin, but it increased the incidence of peripheral neuropathy [14Go]. Docetaxel combined with other agents was also tested, and became a first-line treatment for NSCLC [21Go, 22Go]. CRP, the cisplatin analog, was gradually substituted for cisplatin: it was combined with PCT, and the resulting response rate and survival established it, without cisplatin, as one of the first-line schedules for NSCLC [17Go–19Go]. Each of the four agents, PCT, docetaxel, VRL and gemcitabine, have been combined with one of the other three [21Go, 22Go] with or without CRP [24Go, 30Go, 31Go]. The results were similar with regard to response rate and median and overall survival, but with a modification in toxicity: although there were no renal adverse reactions, there was higher myelotoxicity and peripheral neuropathy.

The combination of PCT with VRL is not yet an established treatment. One study used this combination as second-line therapy in patients with refractory NSCLC [32Go]. The response rate was low and the toxicity high, but the number of patients was small. In another phase I study with PCT and VRL in 21 untreated patients, VRL was repeated on day 5, and both agents on the 21st day. These researchers reported a maximum tolerated dose of 115 mg/m2 PCT and 20 mg/m2 VRL. Toxicity was high, and the response rate was 24% [35Go]. We believe that the VRL repetition on day 5 was the reason for the high toxicity. Our study comparing PCT–VRL in patients who were chemotherapy-naïve seems to show a similarly high response rate (42.86%) to the control regimen of CRP–PCT as first-line treatment (45.95%). There was no statistically significant difference with regard to the duration of response, TTP, and median and overall survival between the investigational arm and the control arm.

The PCT dose of 175 mg/m2 when combined with CRP can be considered optimum. When the present study was designed, the dose of PCT combined with CRP or other agents was not precisely established. One study that compared PCT 135 mg/m2 versus 175 mg/m2 in NSCLC showed a higher response rate, although this was not significant [44Go]. Another study, where different dosages of PCT were included in combination with CRP in NSCLC, started at a dose of 135 mg/m2 and ended at 215 mg/m2, and reported a response rate of 50% before PCT had been escalated to the full dose [45Go]. The comparison of PCT 135 mg/m2 versus 200 mg/m2, non-randomized, showed a higher response after the administration of 200 mg/m2, but myelotoxicity at this dose reached 40%; in addition, the 200 mg/m2 was compared with a much lower dose (135 mg/m2), and not with 175 mg/m2 [46Go]. A report published after our the study started has shown the superiority of PCT at 225 mg/m2 over 175 mg/m2, but only in median TTP, whereas the response rate and median and overall survival were not significantly different [47Go]. The dose of PCT at 175 mg/m2 in combination with other agents such as cisplatin or gemcitabine seems to be accepted by others in the treatment of NSCLC [48Go]. Some investigators prefer the higher dose of 200 mg/m2, but this dose does not seem to produce a higher response rate (20%) or longer median survival (10.4 months) [49Go] than that achieved in the present trial.

We believe that our arm B results with respect to responsiveness, which was high, and toxicity, which was low (compared with the results of the two aforementioned studies using the same agents), are due to the modification we made by repeating the courses on day 15. There was no difference in non-hematological toxicity, peripheral neuropathy being the most common after alopecia. Regarding hematological adverse reactions, thrombocytopenia and anemia were low, and similar in both arms. However, neutropenia was common and statistically significantly higher in arm B, although febrile neutropenia was low in both arms. Similar to several of the above-mentioned studies, there was no difference between 1- and 2-year survival between the two arms [50Go]. A recently published trial involving three arms of treated patients compared gemcitabine with cisplatin, PCT with CRP, and VRL with cisplatin, and reported no difference among the three arms in terms of overall survival, time to disease progression and time to treatment failure [51Go]. These authors reported a median survival of 9.8, 9.9 and 9.5 months, respectively, for the three arms, which is similar to that of our study (11 and 10 months for arms A and B, respectively), and their 1-year survival of 37%, 43% and 37%, respectively, was also similar to ours (42.72% and 37.85% for arms A and B, respectively). Another very recently published randomized trial for stage IIIb or IV NSCLC reported a non-cisplatin combination of agents including CRP and PCT [52Go]. The objective response for arm 1 was similar to that of our study, and for arms 2 and 3 was lower. One- and 2-year survival in all three arms was similar to that in our study. It is interesting to note that a small number of patients treated with different combinations of agents, despite the higher or lower response rates, end up with a survival of ≥2 years. This was reported in the aforementioned study [51Go] and it was also the case in ours; the percentage of patients achieving this varies from 10–19%. These long survivors with unpredictable characteristics at baseline may be a separate subset of patients. Quality of life on the basis of performance status modification after treatment was not different between the two arms in our study. The activity of the PCT and VRL combination indicates a synergic effect in clinical practice, as has been shown in preclinical data.

In conclusion, the PCT and VRL combination as a first-line treatment for NSCLC can be considered equally effective as the treatment with CRP–Taxol. Toxicity, despite the rather high neutropenia, can be considered acceptable. PCT and VRL, agents with a similar mechanism of action, can be safely combined in patients with NSCLC, and, based on median survival, duration of response, TTP, and 1- and 2-year survival, may be evaluated as having equal effectiveness as first-line chemotherapy.

Received for publication December 16, 2003. Revision received February 22, 2004. Accepted for publication February 23, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Non-small Cell Lung Cancer. Collaborative Groups. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 1995; 311: 899–909.[Abstract/Free Full Text]

2. Cullen MH, Billingham LJ, Woodroffe CM et al. Mitanycil, ifosfamide and cisplatin in unresectable non-small cell lung cancer: Effects on survival and quality of life. J Clin Oncol 1999; 17: 3188–3194.[Abstract/Free Full Text]

3. Johnson BE. Integration of New Agents into the Treatment of Advanced Non-Small Cell Lung Cancer. Educational Book. Alexandria, VA: American Society of Clinical Oncology 2000; 345–356.

4. Kelsen DT, Gralla RI, Casper ES et al. Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung, randomized trial investigation in two dosage schedule. Ann Intern Med 1981; 95: 414–420.[ISI][Medline]

5. Ruckdeschel JC, Finkelstein DM, Mason BA, Creech RH. Chemotherapy for metastatic non-small cell bronchogenic carcinoma EST 2575, generation V—a randomized comparison of four cis-platin containing regimens. J Clin Oncol 1985; 3: 72–79.[Abstract]

6. Werden PI, Piantadosi S. Preoperative chemotherapy (cis-platin and fluorouracil) and radiation therapy in stage III non-small cell lung cancer study group. J Natl Cancer Inst 1991; 83: 266–273.[Abstract]

7. Burkes RL, Ginsberg R, Shepherd FA et al. Induction chemotherapy with mitomycin, vindesine and cis-platin for stage III unresectable non-small cell lung cancer: results of the Toronto phase II trial. J Clin Oncol 1992; 10: 580–586.[Abstract]

8. Roussell R, Gomez-Codina J, Camps C et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 1994; 330: 153–158.[Abstract/Free Full Text]

9. Lynch TJ. Treatment of Stage III Non-small Cell Lung Cancer. Educational Book. Alexandria, VA: American Society of Clinical Oncology 1998; 265–275.

10. Crino L, Scagliotti G, Maragolo M et al. Cis-platin–gemcitabine combination in advanced non-small cell lung cancer: A phase II study. J Clin Oncol 1997; 15: 297–303.[Abstract]

11. Bonomi P, Kim KM, Fairclough D et al. Comparison of survival and quality of life in advanced non-small cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: Results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000; 18: 623–631.[Abstract/Free Full Text]

12. Le Chevalier T, Brisgand D, Donillard JY 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: 360–367.[Abstract]

13. Crino L, Scagliotti GV, Ricci S et al. Gemcitabine and cisplatin versus mitomycin, ifosfamide and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 1999; 17: 3522–3530.[Abstract/Free Full Text]

14. Frasci G, Panza N, Comella P et al. Cisplatin, gemcitabine and paclitaxel in locally advanced or metastatic non-small-cell lung cancer: A phase I–II study. J Clin Oncol 1999; 17: 2316–2325.[Abstract/Free Full Text]

15. 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 1994; 17: 1526–1534.

16. De Vore F, Johnson DH, Crawford J et al. Phase II study of irinotecan plus cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 1999; 17: 2710–2720.[Abstract/Free Full Text]

17. Belani CP, Keams CM, Zuhowski EG et al. Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer. J Clin Oncol 1999; 17: 676–684.[Abstract/Free Full Text]

18. Huizing MT, Giaccone G, Van Warmerdam LJC et al. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. J Clin Oncol 1997; 15: 317–329.[Abstract]

19. Greco A, Hainsworth JD. Paclitaxel (1 hour infusion) plus carboplatin in the treatment of advanced non-small-cell lung cancer: results of a multicenter phase II trial. Oncology 1997; 24 (Suppl 12): b12-14–b12-17.

20. Akerley W, Choy H, Safran H et al. Weekly paclitaxel in patients with advanced lung cancer: preliminary data from a phase II trial. Semin Oncol 1997; 24 (Suppl 12): b12-10–b12-13.

21. Georgoulias V, Kourousis Ch, Androulakis N et al. Front-line treatment of advanced non-small-cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial. J Clin Oncol 1999; 17: 914–920.[Abstract/Free Full Text]

22. Miller VA, Krug LM, Ng KK et al. Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer. J Clin Oncol 2000; 18: 1346–1350.[Abstract/Free Full Text]

23. Fosella FV, Lee JS, Berille J et al. Summary of phase II data of docetaxel (taxotere) an active agent in the 1st and 2nd line treatment of advanced non-small-cell lung cancer: results of a phase II multi-center trial. J Clin Oncol 2000; 18: 131–135.[Abstract/Free Full Text]

24. Taiffaioli RV, Tortoriello A, Facchini G et al. Phase I–II study of gemcitabine and carboplatin in stage IIIb–IV non-small-cell lung cancer. J Clin Oncol 1999; 17: 921–926.[Abstract/Free Full Text]

25. Cardenal F, Lopex-Cabrerizo MP, Auton A et al. Randomized phase III study of gemcitabine–cisplatin versus etoposide cisplatin in the treatment of locally advanced metastatic non-small-cell lung cancer. J Clin Oncol 1999; 17: 12–18.[Abstract/Free Full Text]

26. Van Zandwijk N, Smit EF, Kramer GWP et al. Gemcitabine and cisplatin as induction regimen for patients with biopsy-proven stage IIIa N2 non-small-cell lung cancer: A phase II study of the European Organization for Research and Treatment of Cancer, Lung Cancer Cooperative Group (EORTC 08955). J Clin Oncol 2000; 18: 2658–2664.[Abstract/Free Full Text]

27. Depierre A, Chastang CL, Quoix E et al. Vinorelbine plus cisplatin in advanced non-small-cell lung cancer: a randomized trial. Ann Oncol 1994; 5: 37–42.[Abstract]

28. Furuse K, Kawahora M, Nishiwaji Y et al. Phase I/II study of vinorelbine, mitomycin and cisplatin for stage IIIb of IV non-small-cell lung cancer. J Clin Oncol 1999; 17: 3195–3299.[Abstract/Free Full Text]

29. Kouroussis Ch, Androulakis N, Kakolyris S et al. First-line treatment of advanced non-small-cell lung carcinoma with docetaxel and vinorelbine. Cancer 1998; 83: 2083–2090.[CrossRef][ISI][Medline]

30. Frasci G, Lorusso V, Panza N et al. Gemcitabine plus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 2000; 18: 2529–2536.[Abstract/Free Full Text]

31. 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 2000; 18: 405–411.[Abstract/Free Full Text]

32. Chang AY, De Vore R, Johnson D. Pilot study of vinorelbine (navelbine) and paclitaxel in patients with refractory non-small-cell lung cancer. Semin Oncol 1996; 23 (Suppl 5): 19–21.

33. de Castro J, Belda-Iniesta C, Cejas P et al. New insights in beta-tubulin sequence analysis in non-small-cell lung cancer. Lung Cancer 2003; 41: 41–48.[ISI][Medline]

34. Horwitz SB, Cohen D, Rao S et al. Taxol: mechanism of action and resistance. Natl Cancer Inst Monogr 1993; 15: 63–67.[Medline]

35. Breton JL, Westeel V, Jacoulet P et al. Phase I study of paclitaxel (taxol) plus vinorelbine (navelbine) in patients with untreated stage IIIb and IV non-small-cell lung cancer. Lung Cancer 2001; 31: 295–301.[CrossRef][ISI][Medline]

36. Jordan MA, Thrower D, Wilson L. Mechanism of inhibition of cell proliferation by vinca alkaloids. Cancer Res 1991; 51: 2212–2217.[Abstract]

37. Stathopoulos GP, Veslemes M, Georgatou N et al. Paclitaxel and vinorelbine combination in advanced inoperable adenocarcinoma of the lung. A phase II study. Anticancer Res 2003; 23: 3479–3484.[ISI][Medline]

38. Chang AY, Garrow GC. Pilot study of vinorelbine (Navelbine) and paclitaxel (Taxol) in patients with refractory breast cancer and lung cancer. Semin Oncol 1995; 22 (Suppl 2): 66–70.[ISI][Medline]

39. Kano Y, Akutsu M, Suzuki K et al. Schedule-dependent interactions between vinorelbine and paclitaxel in human carcinoma cell lines in vitro. Breast Cancer Res Treat 1999; 56: 79–90.[CrossRef][ISI][Medline]

40. Culine S, Roch I, Pinquet F et al. Combination paclitaxel and vinorelbine therapy: in vitro cytotoxic interactions and dose-escalation study in breast cancer patients previously exposed to anthracyclines. Int J Oncol 1999; 14: 999–1006.[ISI][Medline]

41. Stathopoulos GP, Rigatos SK, Pergantas N et al. Phase II trial of biweekly administration of vinorelbine and gemcitabine in pretreated advanced breast cancer. J Clin Oncol 2002; 20: 37–41.[Abstract/Free Full Text]

42. O'Berin PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35: 549–556.[ISI][Medline]

43. Aaronson NK, Ahmedzais S, Bergman B et al. The European Organisation for Research and Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–376.[Abstract]

44. Johnson DH, David PM, Hande KR et al. Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol 1995; 13: 1860–1870.[Abstract]

45. Langer CJ, Leighton JC, Comis Rl et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response and survival analysis. J Clin Oncol 1995; 13: 1860–1870.[Abstract]

46. Hainsworth JD, Thompson DS, Greco AF. Paclitaxel by 1-hour infusion: an active drug in metastatic non-small-cell lung cancer. J Clin Oncol 1995; 13: 1609–1614.[Abstract]

47. Kosmidis P, Mylonakis N, Skarlos D et al. Paclitaxel (175 mg/m2) plus carboplatin (6 AUC) versus paclitaxel (225 mg/m2) plus carboplatin (6 AUC) in advanced non-small-cell lung cancer (NSCLC): a multicenter randomized trial. Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol 2000; 11: 799–805.[Abstract]

48. Smit EF, van Meerbeeck Jan PAM, Lianes P et al. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and treatment of Cancer, Lung Cancer Group—EORTC 08975. J Clin Oncol 2003; 21: 3909–3917.[Abstract/Free Full Text]

49. Kosmidis P, Mylonakis N, Nicolaides C et al. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomzied trial. J Clin Oncol 2002; 20: 3578–3585.[Abstract/Free Full Text]

50. Comella P, Frasci G, Panza N et al. Randomized trial comparing cisplatin, gemcitabine and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer. Interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol 2000; 18: 1451–1457.[Abstract/Free Full Text]

51. Scagliotti GV, De Marinis F, Rinaldi M et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002; 20: 4285–4291.[Abstract/Free Full Text]

52. Belani CP, Baretis J, Perry MC 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: 2933–2939.[Abstract/Free Full Text]





This Article
Abstract
Full Text (PDF)
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (7)
Disclaimer
Request Permissions
Google Scholar
Articles by Stathopoulos, G. P.
Articles by Gerogianni, A.
PubMed
PubMed Citation
Articles by Stathopoulos, G. P.
Articles by Gerogianni, A.