The first author took the lead role, and all other authors actively participated in writing the article. The first and second authors participated in the study design and acquisition of data, and the third and fourth authors were the study statisticians.
Recent improvement in the survival of patients with advanced nonsmall cell lung cancer enrolled in phase III trials of first-line, systemic chemotherapy
Version of Record online: 6 FEB 2007
Copyright © 2007 American Cancer Society
Volume 109, Issue 5, pages 939–948, 1 March 2007
How to Cite
Hotta, K., Fujiwara, Y., Matsuo, K., Suzuki, T., Kiura, K., Tabata, M., Takigawa, N., Ueoka, H. and Tanimoto, M. (2007), Recent improvement in the survival of patients with advanced nonsmall cell lung cancer enrolled in phase III trials of first-line, systemic chemotherapy. Cancer, 109: 939–948. doi: 10.1002/cncr.22478
- Issue online: 22 FEB 2007
- Version of Record online: 6 FEB 2007
- Manuscript Accepted: 27 NOV 2006
- Manuscript Revised: 22 NOV 2006
- Manuscript Received: 29 SEP 2006
- nonsmall-cell lung cancer;
- survival improvement
Few studies have assessed formally whether treatment outcomes have improved substantially over the years for patients with advanced nonsmall cell lung cancer (NSCLC) enrolled in Phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials.
The literature was searched to identify trials that addressed the role of chemotherapy regimens in the first-line setting for the treatment of advanced NSCLC. Trends were tested by using multiple regression analysis.
In total, 121 Phase III trials were identified that involved 42,768 patients with 263 chemotherapy arms and 11 best supportive care (BSC) arms, all of which were initiated between 1982 and 2002. Although the number of randomized patients and the proportion of patients with metastatic disease had increased over the years, the number of patients with a poor performance status who were accrued into the trials had decreased. Cisplatin-based chemotherapy was been investigated most frequently during the period. The multiple regression analysis revealed a significant improvement in median survival and in the median time to disease progression over the years, with annual prolongations of 0.1203 months (3.609 days) and 0.0617 months (1.851 days), respectively (P< .0001 and P < .0130, respectively). In addition, the use of cisplatin and carboplatin was associated significantly with survival prolongation. The median survival for patients who received BSC also increased progressively over the years (P = .0487).
The survival of patients with NSCLC in Phase III trials improved slowly but steadily over time, although the main factors responsible for this improvement remain unknown. Nonetheless, the current results also suggested that novel targets and new agents will be required in the future fight against advanced NSCLC. Cancer 2007 © 2007 American Cancer Society.
In relation to first-line treatment of advanced nonsmall cell lung cancer (NSCLC), the results from a meta-analysis that was conducted in 1995 indicated that cisplatin-based chemotherapy produced a modest but significant clinical benefit compared with best supportive care (BSC) alone in patients with advanced NSCLC.1 Since that meta-analysis, newer antineoplastic agents with novel mechanisms of action (paclitaxel, docetaxel, irinotecan, gemcitabine, and vinorelbine) have been developed, and Phase III trials of those agents produced a significant survival advantage in patients with NSCLC.2 Currently, a combination of cisplatin and 1 of these newer agents is considered the standard regimen for these patients.3, 4 In addition, carboplatin was developed to help circumvent some of the toxicities of cisplatin and initially was evaluated in clinical trials in 1981.4 Thereafter, several Phase III trials compared the survival benefit produced by carboplatin-based chemotherapy with that produced by cisplatin-based chemotherapy.5, 6
More recently, a better understanding of tumor biology has led to the development of molecular-targeted agents that act on specific molecules involved in tumor proliferation and survival.7 Some of these agents were evaluated previously in Phase III trials; and, when combined with standard chemotherapy regimens, bevacizumab, an antibody directed against vascular endothelial growth factor (VEGF), produced a survival advantage compared with standard chemotherapy alone.8
Thus, currently, it is believed widely that the development of these newer agents has had a significant impact on the treatment of advanced NSCLC and that the outcomes of patients enrolled in Phase III trials have improved substantially over the years. However, in the history of systemic chemotherapy for advanced NSCLC, few studies have investigated whether the overall survival of patients with advanced NSCLC enrolled in randomized Phase III trials truly has improved over the years. Breathnach et al. previously investigated the outcomes of 33 Phase III trials of systemic chemotherapy for advanced NSCLC that were initiated between 1973 and 1994. Their results indicated that patient survival improved with the passage of time.9 However, the majority of the trials that were included in their analysis were investigations of older chemotherapeutic regimens, and they included scarcely any trials that investigated the efficacy of newer developed agents or molecular-targeted agents. Thus, the more recent trends in outcomes from clinical trials for patients with advanced NSCLC remain unclear.
In another relevant study, Wakelee et al. reported survival prolongation in patients with advanced NSCLC after 1990 versus before 1990 by using a database of 3398 patients who were entered on Eastern Cooperative Oncology Group (ECOG) Trials.10 This patient series from a single major oncology group trial may yield uniform and reliable results; however, data from all existing Phase III trials that were conducted by various oncology groups may be more representative of the real-world population of patients with advanced NSCLC, even in the absence of an individual patient data (IPD)-based analysis. In this report, we demonstrate the trends in trial characteristics and patient outcomes by using data from 121 Phase III trials that included >40,000 patients and investigated newer agents, molecular-targeted agents, and older generation agents.
MATERIALS AND METHODS
Search for Trials
We searched for trials that were reported between January 1991 and May 2006, because previous reports investigated studies within the past 15 to 20 years.9, 10 To avoid publication bias, both published and unpublished trials were identified through a computer-based search of the PubMed database and abstracts from the 10 past conferences of the American Society of Clinical Oncology. We conducted the search by using the following search terms: lung neoplasm, carcinoma, nonsmall cell, chemotherapy, and randomized controlled trial. The search also was guided by a thorough examination of reference lists from original articles, review articles, relevant books, and the Physician Data Query registry of clinical trials.
Selection of Trials
Phase III trials were eligible if they compared first-line, systemic chemotherapy for advanced or metastatic NSCLC that contained cytotoxic agents or molecular-targeted agents. Trials were excluded if they only investigated immunotherapy regimens. Trials that initially were designed to assess combined-modality treatment, including radiotherapy and surgery, also were considered ineligible.
To avoid bias in the data-abstraction process, 2 observers (K.H. and Y.F.) independently abstracted the data from the trials and subsequently compared the results. The following information was obtained from each report: the year of trial initiation (year when the first patient was accrued), the number of patients enrolled and randomized, the median age, the proportion of patients who had a poor performance status (≤2; defined mainly according to ECOG or World Health Organization criteria), the proportion of patients who were women, the proportion of patients with stage IV disease (mostly defined according to published staging criteria11, 12), the chemotherapy regimen, the median survival, and the median time to progression (TTP) (per treatment arm). In the data-abstraction process for each trial that we identified, if the trial had none of the relevant information mentioned above, then the trial was excluded from the analysis for that information. In addition, for each trial, data defined according to criteria that varied from that mentioned above also were considered nonevaluable. Docetaxel, paclitaxel, vinorelbine, gemcitabine, and irinotecan were defined as newer chemotherapeutic agents.13 Drugs that reportedly act on known specific molecular targets, such as tyrosine kinase inhibitors, neutralizing antibodies, matrix metalloproteinase inhibitors, and antisense oligonucleotides were defined as molecular-targeted agents.7 All data were checked for internal consistency, and disagreements were resolved by discussion among the investigators.
Quantitative Data Synthesis
The Kruskall-Wallis test and chi-square tests were used for comparisons among groups, as appropriate. Data from Phase III trials were evaluated by using multiple, stepwise regression analysis (with the following stepping method criteria: probability of F to enter the model, ≤.05; to remove from the model, ≥.10). The data analyzed included the year of trial initiation, cisplatin use, carboplatin, newer agents, molecular-targeted agents, the number of agents combined, the number of randomized patients, the median patient age, the proportion of patients with a poor performance status, the proportion of women patients, and the proportion of patients with stage IV disease. These data were used to determine whether each factor had an independent impact on the survival of patients with advanced NSCLC who were treated on the Phase III studies over time. All P values corresponded to 2-sided tests, and significance was set at a P value <.05.
Trial Flow and Trends in the Characteristics of Eligible Trials
A time chart of this study is shown in Figure 1. In total, 121 trials that involved 42,768 patients with advanced NSCLC were identified by the computer-based and manual searches for relevant articles, abstracts, and references. Of the 42,768 enrolled patients, 40,894 patients were allocated randomly to 263 chemotherapy arms, and 1167 patients were allocated to 11 BSC alone arms. The baseline characteristics of the trials are listed in Table 1. The trials were initiated between 1982 and 2002, and the 121 trials were divided simply into 3 generations on the basis of the year of trial initiation. Each period was considered as follows: the early period, when mainly old cytotoxic agents and cisplatin were investigated (1982–1988); the middle period, when new cytotoxic agents and carboplatin were introduced into Phase III trials (1989–1995); and the late period, when molecular-targeted agents were introduced into Phase III trials (1996–2002). Although we observed that the number of randomized patients per trial and the proportions of patients with stage IV disease increased with the passage of time during the study period (Kruskall-Wallis test; P< .0001 and P < .0412, respectively) (Fig. 2A,B), the proportion of patients with a poor performance status decreased during the same period (P < .0001) (Fig. 2C). Conversely, the proportion of patients who were women remained consistent over the years (P = .1991) (Fig. 2D).
|Variable||No. of trials|
|1982–1988* n = 3686†||1989–1995* n = 11,856†||1996–2002* n = 26,519†||Total N = 42,061†|
|No. of trials||20||44||57||121|
|Abstract form only||0||2||11||13|
|No. of treatment arms|
|No. of randomized patients|
|Median (range)||146 (46–740)||214 (49–725)||372 (72–1218)||284 (46–1218)|
|Patients with a poor performance status, %‡|
|Median percentage (range)||32 (8–52)||25 (0–70)||12 (0–100)||19 (0–100)|
|Women patients, %|
|Median percentage (range)||24 (3–80)||19 (4–59)||25 (7–47)||24 (3–80)|
|Patients with stage IV disease, %|
|Median percentage (range)||60 (49–100)||61 (38–100)||71 (27–100)||66 (27–100)|
Trends in the Types of Chemotherapy Arms and BSC Arms
There were 263 chemotherapeutic treatment arms and 11 BSC arms in the 121 Phase III trials (Table 2). The trends in the types of chemotherapy arms are shown in Figure 3. Cisplatin-based regimens were the most frequently investigated regimens throughout the study period (61%), as expected, although the proportion of this type of regimen investigated in Phase III trials decreased during the study period (chi-square test; P = .0055) (Fig. 3). However, combinations of cisplatin with the newer agents have been studied increasingly with the passage of time (P < .0001). There were few Phase III trials that evaluated carboplatin-based chemotherapy before 1995; however, thereafter, it has been investigated extensively (P < .0001). Nonplatinum chemotherapy with newer agents also was evaluated increasingly over the observed period (P < .0001). Molecular-targeted agents combined with chemotherapy were investigated in 10 arms. All of those trials were initiated after 1999.
|No. of arms (%)||MST [range], months||No. of arms (%)||MST [range], months||No. of arms (%)||MST [range], months||No. of arms (%)||MST [range], months|
|Total no. of arms||46 (17)||7.3 [4.8–12.0]||87 (33)||9.0 [5.1–12.2]||130 (49%)||9.3 [4.2–14.8]||263||8.5 [4.2–14.8]|
|Cisplatin and newer agents||0||18 (21)||9.1 [6.3–11.7]||40 (31)||9.8 [7.0–14.8]||59 (22)||9.6 [6.3–14.8]|
|Others||38 (83)||7.5 [4.9–12.0]||48 (55)||8.0 [5.9–11.6]||9 (7)||8 [5.5–11]||95 (36)||8 [4.9–12]|
|Carboplatin and newer agents||0||4 (5)||7.5 [6.8–9])||37 (28)||9.3 [6.6–12.3]||41 (16)||9.0 [6.6–12.3]|
|Other combinations||0||1 (1%)||8.9||0||1 (<1)||8.9|
|Regimens consisting of new agents|
|Monotherapy||0||9 (10)||7.2 [5.7–12.2]||14 (11)||6.7 [4.2–14.3]||23 (9)||7.0 [4.2–14.3]|
|Combination therapy||0||0||18 (14)||8.8 [6.7–11.5]||19 (7)||8.8 (6.7–11.5]|
|Regimens consisting of other agents||8 (17)||6.3 [4.8–10]||7 (8)||7.0 [5.1–10.2]||0||15 (6)||6.5 [4.8–10.2]|
|Molecular-targeted agents (combined with cytotoxic chemotherapy)‡|
|EGFR-TKI-containing||0||0||6 (5)||9.9 [8.7–10.6]||6 (2)||9.9 [8.7–10.6]|
|Other combinations||0||0||4 (3)||10.8 [8.6–12.5]||4 (2)||10.8 [8.6–12.5]|
|BCS alone arms|
|Total no. of arms||4 (36)||4.3 [2.4–4.9]||6 (55)||5.3 [2.6–5.9]||1 (9)||4.9||11||4.8 [2.4–5.9]|
Trend in Survival for Patients in the Chemotherapy Arms
Data on survival were available from all 121 trials with 263 chemotherapy arms. For the current study, we analyzed survival data from each treatment arm and, first, assessed the associations between several clinical patient characteristics and treatment outcomes. Results of the univariate analysis revealed a significant association between median survival and the percentage of patients with a poor performance status (P <.0001), as expected.
Next, we focused on trends in the survival of patients who were allocated to the chemotherapy arms over the entire study period. The median survival was 7.3 months (range, 4.8–12.0 months) in the early period and 9.0 months (range, 5.1–12.2 months) in the middle period; whereas. in the late period, it was 9.3 months (range, 4.2–14.8 months). The median survival for each chemotherapeutic regimen also is listed in Table 2. Overall, the regimens that contained cisplatin combined with newer agents or molecular-targeted agents seemed to yield favorable overall survival. A scattergram of the 2 parameters, ie, the year of trial initiation and median survival in 263 chemotherapy arms, demonstrates the progressive improvement in median survival for patients with advanced NSCLC who were enrolled in Phase III trials over the years (P <.0001) (Fig. 4). The results of a multiple, stepwise, linear regression analysis showed a significant association between the year of trial initiation (more recent years) and longer median survival (an increase of 0.1203 months [3.609 days] per year; P <.0001) (Table 3). In addition, the use of cisplatin and carboplatin and the proportion of patients with a poor performance status and with stage IV disease affected median survival significantly, as reported previously.14, 15
|Factor||Regression coefficient*||Standard error||P†|
|Year of trial initiation||.1203||.0246||<.0001|
|Use of cisplatin||.9631||.2612||<.0001|
|Use of carboplatin||.6777||.3281||.0400|
|Use of newer agents‡||Excluded|
|Use of molecular- targeted agents§||Excluded|
|No. of agents combined (doublet vs others)||Excluded|
|No. of randomized patients||excluded|
|Patients with a poor performance status, %‖||−.0340||.0070||<.0001|
|Patients with stage IV disease, %||−.0261||.0072||<.0001|
|Female patients, %||Excluded|
|Median age of the randomly allocated patients||Excluded|
The median TTP was 3.2 months (range, 1.8–6.0 months) in the early period, 4.9 months (range, 1.9–8.5 months) in the middle period, and 5 months (range, 2.1–9.0 months) in the late period. Thus, the median TTP for patients with NSCLC who were enrolled in Phase III trials also improved progressively over the years (P = .0267). The multivariate analysis also revealed that the year of trial initiation significantly influenced the median TTP, with an increase of 0.0617 months (1.851 days) per year (P = .0130) (Table 4). The use of cisplatin, the use of carboplatin, and the proportion of patients who were women and patients with stage IV disease also were associated significantly with the median TTP.
|Factor||Regression coefficient*||Standard error||P†|
|Year of trial initiation||0.0617||0.0246||.0130|
|Use of cisplatin||1.2720||0.2282||<.0001|
|Use of carboplatin||1.1660||0.2902||<.0001|
|Use of newer agents‡||Excluded|
|Use of molecular- targeted agents§||Excluded|
|No. of agents combined (doublet vs others)||Excluded|
|No. of randomized patients||Excluded|
|Patients with a poor performance status, %‖||Excluded|
|Patients with stage IV disease, %||−0.0254||0.0062||<.0001|
|Female patients, %||−0.0231||0.0092||.0130|
|Median age of randomized patients||Excluded|
Survival of Patients in the BSC Alone Arms
We also evaluated the survival of 1167 patients who were allocated to the BSC arms, which had not been investigated fully. Their median survival was 4.8 months (range, 2.4–5.9 months). We also observed that the median survival of patients who were allocated to the BSC arms was associated significantly with the year of trial initiation (P = .0487) (Fig. 4).
The current results demonstrated a slow but steady improvement in patient outcomes over the years in Phase III trials of systemic chemotherapy for advanced NSCLC performed by various oncology groups around the world, with an increase of 0.1203 months (3.609 days) per year. Our results were consistent with those from a previous IPD-based analysis of ECOG trials, which reported improved survival in more recent NSCLC trials.10 Breathnach et al., who investigated the changes in trial characteristics and outcomes of 33 Phase III trials that were initiated from 1973 to 1994 in North America, reported an improvement in survival over time (P = .0214), with an increase of approximately 0.1 month per year,9 which also was consistent with our study results. Thus, the outcomes of patients with advanced NSCLC from around the world who were enrolled in Phase III trials, along with the outcomes of patients entered on trials that were conducted in North America, seem to have improved consistently over the years.
Breathnach et al. also noted that platinum-based therapy was associated independently with survival prolongation (P = .0318).9 Wakelee et al. observed a significant survival advantage from cisplatin in their patients with NSCLC (hazard ratio, 0.882; P< .0001).10 In addition, we observed a significant survival benefit from cisplatin-based regimens compared with noncisplatin-containing regimens irrespective of the year of trial initiation (an increase of 0.9631 months [28.89 days] with cisplatin; P < .0001) (Table 3). These findings were consistent with the results from 2 meta-analyses, which indicated a survival advantage of cisplatin-based chemotherapy over nonplatinum-based chemotherapy16 and BSC alone.1 Based previous reports10 and our own results, we conclude that cisplatin should remain the key agent for the treatment of patients with advanced NSCLC and that the introduction and frequent use of cisplatin in Phase III trials have clearly contributed to the survival improvement in these patients over the years.
Carboplatin was assessed frequently in the late period of the current study (Table 2) and independently yielded a significant survival advantage, with a survival increase of 0.6777 months (20.33 days) associated with its use according to our multivariate results (P = .0400) (Table 3). Thus, the introduction of carboplatin into Phase III trials also may have contributed to improved treatment outcomes over the years, especially in the late period of this study. The survival prolongation observed with the use of carboplatin, however, seemed to be shorter than that observed with the use of cisplatin, as observed in several randomized Phase III trials of cisplatin/carboplatin and in a recent meta-analysis6, 17, 18; the TAX326 study, 1 of these large Phase III trials, indicated a trend toward improved survival in the docetaxel plus cisplatin arm compared with the docetaxel plus carboplatin arm, although that trial was designed to compare the 2 docetaxel arms not with each other but with the comparator vinorelbine plus cisplatin arm.
Newer cytotoxic agents were introduced in the early 1990s and now are common doublet partners with the platinums in the treatment of NSCLC. Indeed, we found that they were investigated frequently in the middle and late periods of this study (Table 2). These agents also are tolerated better than the platinums and exhibit single-agent activity.2 Indeed, several recent Phase III trials that compared the efficacy of single-agent cisplatin chemotherapy with the efficacy of a combination of cisplatin with newer agents revealed significant survival prolongation associated with the combination regimens.19, 20 Thus, initially, we speculated that regimens containing the newer agents administered as first-line chemotherapy could yield a significant survival advantage over regimens that did not contain these agents; however, we failed to confirm that speculation in the current study (Table 3), which either may reflect on their genuine antitumor activity or simply may represent a chance observation. In addition, although it remains a matter of speculation, these newer cytotoxic agents may offer better antitumor activity in the second-line setting than in the first-line setting: Wakelee et al. demonstrated an increase in the interval from the date of disease progression after the administration of first-line chemotherapy to death with the passage of time during their study period (2.7 months before 1990 vs 4.2 months after 1990)10 in fact, and recent studies have demonstrated that second-line regimens indeed can improve survival.21, 22
In the first-line setting, the use of molecular-targeted agents was not associated with survival prolongation (Table 3); therefore, those agents did not seem to contribute directly to the improvement of patient survival over the study period. This observation contradicts a recent report that bevacizumab prolonged survival when it was combined with chemotherapy.8 The discordance may be attributable mainly to the limited number of trials of molecular-targeted agents that were included in our analyses; in addition, the results reported were somewhat premature. It is worth noting that we assessed all molecular-targeted agents together in our study, although these agents have different mechanisms of action7; and, theoretically, different target patient populations would benefit most from different molecular-targeted agents. Unlike cytotoxic agents, the therapeutic potential of molecular-targeted agents should be evaluated further and stratified at least according to the types of agents with similar target molecules (ie, epidermal growth factor receptor-tyrosine kinase inhibitors, antibodies to VEGF, matrix metalloproteinase inhibitors, etc) or according to the populations most likely to benefit from these agents in the future.
There may be several confounding factors in the current study other than the development of newer chemotherapeutic agents that may have contributed to the prolongation of survival observed with the passage of time, such as improved supportive care, general medical management of cancer patients, more selective inclusion criteria for the more recent trials, stage migration because of improved surgical and imaging staging techniques, and potential lead-time bias.9, 23, 24 Indeed, the median survival of patients allocated to the BSC alone arms in the Phase III trials also appeared to have increased during the observation period despite the very small sample size, and the fitted lines of the chemotherapy arms and the BSC alone arms were nearly parallel (Fig. 4). Surely, considerable progress has been made in supportive care, including granulocyte-colony stimulating factors for febrile neutropenia and sepsis after the administration of chemotherapeutic agents, intrabronchial stents for fatal bronchial stenosis caused by tumor, and bisphosphonates for hypercalcemia.25, 26 Furthermore, the performance status of patients enrolled in Phase III trials has become more selective; consequently, there has been a decrease in the number of patients with a poor performance status accrued to Phase III trials (Table 1, Fig. 2). We also observed an increase in the percentage of patients with stage IV disease enrolled in Phase III trials, which may be attributable to stage migration.23 Thus, the numbers of patients expected to have a favorable prognosis that were accrued to chemotherapy trials may have increased over the years. With regard to potential lead-time bias,23, 24 patients who were enrolled in the later period were more likely to have been treated earlier in the natural history of their disease not only because of the improved staging techniques but also because systemic chemotherapy was initiated more quickly once it was understood that patients with advanced NSCLC would benefit from it. In addition, experimental regimens may have been adopted as either control and or experimental treatment arms in subsequent trials. All of these factors may complicate interpretation of the true impact on patient survival of improvements in the activity of chemotherapeutic drugs during the study period.
In this study, we used only Phase III trial data and no Phase II trial data; because, in Phase III trials, patient survival is evaluated as the primary endpoint, and, in general, very large patient cohorts are followed over longer periods. These possible advantages of Phase III trials may be expected to yield a more reliable and accurate assessment of the median survival and the TTP. In addition, we categorized all 121 trials that we identified through the search into 3 periods stratified by the year initiated; although, in the process of literature search in our study, we did not intend to search for trials by the year initiated but by the year reported. Because this procedure possibly may have led to biased results when we assessed the trends in trial characteristics and patient outcomes, our results should be interpreted with caution.
In conclusion, the results of our analysis clearly suggest that, regardless of the reason, the survival of patients with advanced NSCLC who were enrolled in Phase III trials improved significantly over the years. However, this improvement still is only very modest, indicating clearly that patient management remains unsatisfactory and that novel targets, newer agents, and comprehensive patient care will be essential in the future fight against lung cancer.
We thank Drs. Paul Lorigan, Paolo Lissoni, Thierry Le Chevalier, Cesare Gridelli, Francesco Perrone, Massimo Di Maio, Sumitra Thongprasert, Edith A. Perez, Silvia Novello, Csorey Langer, Christian Manegold, John D. Hainsworth, Erland Joan, Nasser Hanna, and Gianfranco Buccheri for their support, for providing us with relevant data, and for their comments on our analyses
- 3Third generation chemotherapy regimens (3GR) improve survival over second generation regimens (2GR) in stage IIIB/IV non-small cell lung cancer (NSCLC): a meta-analysis of the published literature. Proc Am Soc Clin Oncol. 2002; 21: 306a. Abstract 1222., , , .
- 8Randomized Phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial-E4599. Proc Am Soc Clin Oncol. 2005; 23. Abstract 4., , , et al.
- 10Changes in the natural history of nonsmall cell lung cancer (NSCLC)—comparison of outcomes and characteristics in patients with advanced NSCLC entered in Eastern Cooperative Oncology Group trials before and after 1990. Cancer. 2006; 106: 2208–2217., , , .
- 11GreeneFL, PageDL, FlemingID, et al., eds. AJCC Staging Manual.6th ed. Philadelphia, Pa: Springer; 2002.
- 12SobinLH, Wittekin dC, eds. TNM Classification of Malignant Tumors.5th ed. New York: John Wiley & Sons, Inc.; 1997.
- 18Long-standing debate on cisplatin-versus carboplatin-based chemotherapy in the treatment of advanced non-small-cell lung cancer. J Thorac Oncol. In press., .
- 22Randomized 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: 2354–2362., , , et al.