Clinical prognostic factors in advanced non

Clinical prognostic factors in
advanced non-small cell lung
cancer (NSCLC):
Cox regression analysis based on
789 patients treated in three
consecutive randomized trials
Pilz LR,1 Thatcher N,2 Kortsik C,3 Koschel G,4
Mezger J,5 Schott von Römer K,6 Manegold C,7
for the GEMTAX-NSCLC-Cooperative Study Group
1Department
of Biostatistics, German Cancer Research Center, Heidelberg, Germany;
2Christie Hospital, Manchester, UK; 3Sankt Hildegardis Hospital, Mainz, Germany;
4General Hospital Harburg, Hamburg, Germany; 5St Vincentius Hospital, Karlsruhe,
Germany; 6Thoraxklinik, Heidelberg, Germany; 7University Medical Center, Mannheim,
Germany
INTRODUCTION
Prognostic factors (PF) are pivotal in the treatment of
patients with non-small cell lung cancer (NSCLC)
 For selecting appropriate treatment;
 Defining eligibility criteria for new clinical trials;
 Providing insights into the disease process and
therapeutic response;
 In aiding the stratification of patients by risk subgroup.1
Of particular interest are analyses of PF based on clinical
and laboratory data from recent clinical studies.
INTRODUCTION
Docetaxel (D) and gemcitabine (G) are active,
 have relatively favorable toxicity profiles as first- or secondline treatment of advanced NSCLC,2–9
 and are useful agents for treating patients who are unable to
tolerate more toxic regimens.10
To define the optimum dosing schedule for G and D when used in
combination or sequentially, three consecutive studies (GemTax I–
III) examined the toxicity and efficacy of
 concomitant versus
 sequential administration
of G and D as first- and second-line therapy for advance
NSCLC.
INTRODUCTION
Some results and an overview of all three studies have
been presented previously.7,11–13
Overall survival (OS) was similar in all three studies.
We undertook a retrospective analysis of baseline
 demographic and
 clinical factors
to identify those that are prognostic for patient survival.
OBJECTIVES
To identify demographic and clinical characteristics that
are prognostic for survival in patients with advanced
NSCLC based on data from GemTax I–III.
METHODS: Patients and treatment
Study designs and treatment regimens for the three studies
METHODS: Patients and treatment
Figure 1: GemTax I–III: study designs.
METHODS: Assessments
In the prospective analyses, OS was defined as the time
from randomization to death or censoring. As previously
reported, OS was similar in the three studies and the
study populations were pooled for the present analysis.
Retrospective analysis of the effect of baseline
demographic and clinical factors on OS was performed
as described in the statistical methods below.
Time-to-event data were described using Kaplan–Meier
curves.
METHODS: Statistical methods
Univariate testing was performed.
Cox regression analysis was performed to evaluate the
significance of different factors in predicting OS.
Factors included in the analysis were: hemoglobin (Hgb);
lactate dehydrogenase (LDH); gender; age; performance
status (PS); quality of life (QoL); histology; tumor stage;
presence of extrathoracic metastases; number of
comorbidities; prior surgery or radiotherapy; and
smoking history.
METHODS: Statistical methods
Regression analysis of survival data was performed
based on the Cox proportional hazards model and using
the conditional logit regression with the SAS PHREG
procedure.
Stepwise forward selection and backward elimination
methods were used.
Two-sided statistical significance was set at 0.05.
RESULTS: Patient characteristics
Between February 17, 1998 and December 2, 2004, 819
patientswere enrolled at 34 centers in Germany and
Western Europe;
789 patients were evaluable and baseline characteristics
were well balanced between the treatment arms in the
three studies (Table 1).
RESULTS: Patient characteristics
Table 1: Baseline patient characteristics (evaluable population, n=789)
RESULTS: Regression analysis
The multivariate method (stepwise forward selection and
backward elimination model) used for analysis of OS had no
influence on the significance of the Cox proportional hazards
model (data not shown).
Factors having a significant impact on OS (Tables 2 and 3) were:
 Laboratory values: Hgb (Figure 2; p<0.0001) and LDH
(Figure 3; p<0.0001)
 WHO performance status (PS) (Figure 4; p=0.001) and QoL
measured using the European Organisation for Research and
Treatment of Cancer 13-item lung cancer questionnaire
(EORTC LC13) (Figure 5; p=0.0006).
RESULTS: Regression analysis
Table 2: Factors with a significant impact on overall survival (OS)
RESULTS: Kaplan-Meier Statistics
Table 3: Kaplan–Meier estimates for factors with a significant impact on OS
RESULTS: Kaplan-Meier Plots
Figure 2: Kaplan–Meier plot for the factor hemoglobin (Hgb).
RESULTS: Kaplan-Meier Plots
Figure 3: Kaplan–Meier plot for the factor lactate dehydrogenase (LDH).
RESULTS: Kaplan-Meier Plots
Figure 4: Kaplan–Meier plot for the factor
World Health Organization performance status (WHO PS).
RESULTS: Kaplan-Meier Plots
Figure 5: Kaplan–Meier plot for the factor European Organisation for Research
and Treatment of Cancer 13-item lung cancer questionnaire
(EORTC LC13) score.
RESULTS: Regression analysis
Gender significantly influenced OS in the univariate
analysis (p=0.0085); however, gender had less influence
in the multivariate analysis (p=0.07).
Age, histology, tumor stage, presence of extra-thoracic
metastases, number of comorbidities, and surgical and
radiologic pretreatment were not prognostic of OS
(Tables 3–5).
Analysis of the effect of smoking on OS was not possible
because of the small numbers of patients who had never
smoked.
RESULTS: Regression analysis
Table 4: Factors not prognostic for overall survival (OS)
RESULTS: Kaplan-Meier Statistics
Table 5: Kaplan–Meier estimates for factors not prognostic for overall survival (OS)
CONCLUSIONS
Serum Hgb and LDH, WHO PS, and QoL (EORTC
LC13) have prognostic value as general clinical
determinants of OS, as shown in this
retrospective analysis of the GemTax I–III
studies.
Age, histology, tumor status, number of
comorbidities, prior treatment, and extrathoracic metastases had no prognostic influence
on OS.
Hazard ratios were confirmed by Kaplan–Meier
statistics for each of the factors that were shown
to be prognostic.
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Participating institutions
W Dornoff, Borromäerinnen Hospital, Trier, Germany; N Thatcher, Christie Hospital and
Wythenshawe Hospital, Manchester, UK; RM Huber, City Hospital, Munich, Germany; O
Breathnach, Cork University Hospital, Cork, Ireland; S Upadhyay, Diana Princess of Wales
Hospital, Grimsby, UK; E Kaukel, General Hospital Harburg, Hamburg, Germany; LR Pilz,
German Cancer Research Centre, Heidelberg, Germany; C Manegold, University Medical Center,
Mannheim, Germany; L Canosa, Hospital de Torrecardenas, Almeria, Spain; G Perez-Manga,
Hospital Gral. Univ. Gregorio Maranón, Madrid, Spain; JR Degaldo, Hospital Virgen de las Nieves,
Granada, Spain; U Reinhardt, Klinikum Bayreuth, Bayreuth,Germany; U Gatzemeier, Medical
Center Großhansdorf, Großhansdorf, Germany; O Breathnach, Mercy University Hospital, Cork,
Ireland; B Jany, Missionaerztliche Clinic, Würzburg, Germany; R Schlag, Oncological Health Care
Centre, Würzburg, Germany; M Lind, Princess Royal Hospital, Hull, UK; C Kortsik, Sankt
Hildegardis Hospital, Mainz, Germany; R Dierkesmann, Schillerhöhe Hospital Gerlingen,
Stuttgart, Germany; J Preiß, Caritas St Theresia Hospital, Saarbrücken, Germany; H Gosse, St
Georg Hospital, Robert Koch Clinic, Leipzig, Germany; R Grunewald, St Marien Hospital, Amberg,
Germany; J Mezger, St Vincentius Hospital, Karlsruhe, Germany; W Augener, St Willehad
Hospital, Wilhelmshaven, Germany; K Schott, Thoraxklinik, Heidelberg, Germany; R Herrmann,
University Hospital, Basel, Switzerland; R Hehlmann, University Medical Center, Mannheim,
Germany; C Peschel, University Hospital, Munich, Germany; G Hartung, University Hospital,
Rostock, Germany; V Hombach, University Hospital, Ulm, Germany; T Welte, University Hospital,
Magdeburg, Germany; C Zielinski, University Hospital, Vienna, Austria; M Schmidt, University
Hospital, Würzburg, Germany; MJ Eckart, Working Group of Franconian Oncologists, Erlangen,
Germany.
The studies were supported by grants from Lilly Deutschland, Bad Homburg, Germany, and
Aventis Pharmaceuticals (a member of the sanofi-aventis Group), Berlin, Germany.