ORIGINAL PAPER Prognostic factors in elderly patients with non-small cell lung cancer: a two-center experience U. Kefeli • S. Kaya • B. O. Ustaalioglu • A. Bilici • A. U. Kefeli • M. E. Yildirim • M. Seker • B. Yilmaz • T. Salepci • K. Uygun • M. Gumus Received: 14 January 2010 / Accepted: 16 March 2010 / Published online: 31 March 2010 � Springer Science+Business Media, LLC 2010 Abstract Non-small cell lung cancer (NSCLC) is usually at advanced stage when it is diagnosed. There is no con- sensus about the standard treatment in elderly patients with advanced NSCLC. Generally, data regarding elderly patients with NSCLC are withdrawn from general NSCLC studies based on subgroup analyses and suggestions. We evaluated prognostic factors in elderly patients with advanced NSCLC. We reviewed retrospectively 338 patients from August 2005 to July 2009 in two centers in Turkey. Medical records of the patients C65 years with advanced NSCLC were collected. Collected data included demographic informations, clinical assessments and infor- mation on treatment, toxicities and outcomes. Survival was estimated by using Kaplan–Meier method and prognostic factors were evaluated with log-rank and Cox regression tests. The median overall survival (OS) for the entire group was 15.4 months (95% CI: 12.7–18.0). In univariate anal- ysis, weight loss, stage, combination therapy, second-line chemotherapy and tumor response (P \ 0.01) and perfor- mance status significantly affected OS (P \ 0.05). The median progression-free survival (PFS) was 10 months (95% CI: 8.4–11.6). In univariate analysis, there was only a significant association between tumor response and PFS (14.6 vs. 8.5 months; P \ 0.001). Multivariate analysis showed that only response to therapy was an important prognostic factor for OS (P \ 0.001). Survival of elderly patients with advanced NSCLC is significantly influenced by performance status, weight loss, stage, combination therapy, second-line chemotherapy and response to ther- apy. Not only age but also these factors may be kept in mind in the treatment planning of the elderly patients with NSCLC. These results may be of benefit in changing clinical practice in elderly patients with NSCLC who are often undertreated. Keywords Elderly patients � Lung cancer � Neoplasm � Non-small cell lung cancer � Prognostic factors Introduction Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths in the Western countries [1]. NSCLC is usually at advanced stage when it is diagnosed. A total of 219,440 new lung cancer cases and 159,390 deaths from lung cancer are projected to occur in the United States in 2009 [2]. NSCLC accounts for more than 85% of all lung cancers [3]. The incidence of lung cancer in elderly patients is rising because of the increased life expectancy [4]. About 50% of newly diagnosed NSCLC cases occur in patients aged more than 65 [5]. Therefore, it is an important health burden on the aging populations. Although 50% of elderly patients with NSCLC have a good performance status (PS), they are being treated with lower rates of definitive treatment [6]. Performance status and clinical stage of disease did not differ greatly in a review of 5,404 patients with lung cancer according to the age older than 50 and below 50 years U. Kefeli (&) � B. O. Ustaalioglu � A. Bilici � M. E. Yildirim � M. Seker � B. Yilmaz � T. Salepci � M. Gumus Department of Medical Oncology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey e-mail: ukefeli@yahoo.com S. Kaya � K. Uygun Department of Medical Oncology, Kocaeli University Medical Faculty, Kocaeli, Turkey A. U. Kefeli Department of Radiation Oncology, Marmara University School of Medicine, Istanbul, Turkey 123 Med Oncol (2011) 28:661–666 DOI 10.1007/s12032-010-9504-5 although younger patients received more aggressive treat- ment while elderly patients did not [7]. There is still no agreement about the standard treatment in elderly advanced stage patients with NSCLC and which factors affect the survival in elderly patients with lung cancer. This study was planned to report the prognostic factors in our patients older than 65 years with NSCLC. We aimed to identify the prognostic factors that could be useful in better selection of treatment modalities in elderly patients with NSCLC. Materials and methods We retrospectively analyzed the records of the elderly patients with NSCLC from August 2005 to July 2009 at the Dr. Lutfi Kirdar Education and Research Hospital and Kocaeli University Medical Faculty. According to the data from the Turkish Statistical Institute, the life expectancy at birth of the Turkish people for men is 69.5 and for women is 74 years; therefore, elderly patients with NSCLC C65 years were included in this study [8]. All medical records were collected by a detailed review of the patients’ charts whether they have received a treatment of palliative or curative intent. The data included demographic infor- mation, histologic classification, clinical staging, present- ing symptoms and treatment modalities. The diagnosis of NSCLC was established mostly by bronchoscopic biopsy and then by transthoracic fine needle aspiration biopsy (TTIAB) or mediastinoscopy, respectively. Complete blood count, liver function tests, LDH value, renal function tests before the start of chemotherapy and before each cycle were all recorded. Toxicities and treatment side effects were obtained from patients’ records that were all recorded before each chemotherapy cycles. All patients were staged according to the TNM classification based on the physical examination, chest X-ray, chest CT scans, abdominal ultrasound or CT, bone and brain scans. Per- formance status was recorded according to the Eastern Cooperative Oncology Group (ECOG) performance score [9]. Sites of distant metastases were recorded. Patients were treated according to stage and performance status as chemotherapy, radiotherapy or combination modalities. Patients with stage IV NSCLC were treated chemotherapy if the PS was less than two. Radiotherapy was performed as concurrent therapy or as palliative therapy when needed. Data on the chemotherapy regimen, number of cycles, toxicity, objective response, second-line therapy, the time of disease progression and death were all collected. The response to therapy was assumed Response Evaluation Criteria in Solid Tumors (RECIST) criteria as partial, when tumor size decreased 30% radiologically. If tumor size was not changed after treatment defined as stable disease and if tumor size increased 20%, it was accepted as progressive disease [10]. The patients were followed until their death or last follow-up. Statistical analysis SPSS 16.0 (SPSS Inc., Chicago, IL, USA) software was used for the statistical analyses. A P value less than 0.05 was considered to be significant. Most values were expressed as mean ± SD. Median and minimum–maxi- mum levels were used when data were not normally dis- tributed. The variables considered were sex, PS, weight loss, smoking habitus, histology, stage of disease, chemo- therapy regimens, number of cycles and second-line che- motherapy. Toxicity was classified according to the World Health Organization criteria at each cycle of chemotherapy [11]. Kaplan–Meier method was used for survival analysis. The univariate analysis of potential prognostic factors was assessed but using the log-rank test. The Cox regression model was used for multivariate analysis. Overall survival (OS) was calculated from the diagnosis of patient to the date of death from any cause or of the last follow-up. Progression-free survival (PFS) was calculated from the diagnosis of patient to the date of disease progression, recurrence or death from any cause. Results A total of 338 elderly patients with NSCLC were eligible including 300 male and 38 female patients. The median age of the patients was 69.4 (range 65–89). Eighty-five percent of the patients had a smoking history. In histopathological examination, 135 (39.9%) of tumor were detected as squamous cell carcinoma and 88 (26%) of them were adenocarcinoma. No pathologic discrimination was done in other patients. PS score of 0–1 was stratified in 70.8%, and PS score of 2–4 was recorded in 29.2% of the patients. Fifty-four percent of patients (53.8%) had a weight loss of C5% in the last 3 months. Fifty-three percent of the patients were clinically staged as stage III, and 47% of the patients were stage IV. Patient characteristics are shown in Table 1. Two hundred and twenty-two patients (65%) received combination chemotherapy and 30 patients (9%) received single-agent chemotherapy. Out of 217 (64.2%) of patients were given platinum-based combination therapy mostly as carboplatin–paclitaxel (29%), carboplatin–docetaxel (7.4%), carboplatin–gemcitabine (7.4%), cisplatin–doce- taxel (9.5%), and cisplatin–gemcitabine (6.5%). Sixty-one percent of the patients that received chemotherapy had C3 cycles of chemotherapy. The number of patients with a PS score 0–1 that received C3 cycles was 151 (59%) and only 662 Med Oncol (2011) 28:661–666 28 patients (11%) with a PS score of 2–4 received C3 cycles of chemotherapy. The most frequent toxicities were the haematological (44.2%), nausea–vomiting (23.5%) and neurological (10.8%) toxicities. The most common grade 3/4 haematological toxicities were neutropenia (34.6% for combination therapy vs. 14.3% for single-agent chemo- therapy, P = 0.03) and anemia (20.3% for combination therapy vs. 8.4% for single-agent chemotherapy, P = 0.046). Treatment results are given in Table 2. The overall response rate (sum of partial and complete response rates) was 47.6%. The response rate of the patients that received combination chemotherapy was 51.3% (114 of 222) and this was 20% (6 of 30) for single- agent chemotherapy. Second-line therapy was administered to 67 patients (19.8%). Thirty-seven of the patients (55%) received single-agent chemotherapy and 30 patients (45%) received combination chemotherapy in the second-line therapy. In the second-line therapy, mostly gemcitabine (17.9%) and docetaxel (17.9%) were used as single-agent therapy, and cisplatin–gemcitabine (10.4%) and carbo- platin–paclitaxel (7.4%) were used as combination therapy (Table 2). The median survival for the entire group was 15.4 months (95% CI: 12.7–18.0; Fig. 1) with 1- and 2-year survival rates of 58.4% and 25.4%, respectively. By July 2009, 168 (49.7%) of patients were dead. The median follow-up for survivors was 10.7 months. In univariate analysis, weight loss, stage, combination therapy, second- line chemotherapy and response to therapy significantly affected OS (P \ 0.01). Also, PS correlated with a better OS (P \ 0.05). The median survival of the patients who had a PS 0–1 (17.0 vs. 10.8 months; P \ 0.05) and who had stage III disease (18.4 vs. 11.1 months; P \ 0.01) was longer than the patients who had a PS 2–4 and stage IV disease (Figs. 2, 3). Patients that received combination therapy showed better survival than the patients who received single-agent therapy (18.4 vs. 14.7 months; Table 1 Characteristics of the patients Characteristic Patients (n = 338) Sex Male 300 (88.8%) Female 38 (11.2%) Age Median (range) 69.4 (65–89) ECOG PS 0–1 233 (68.9%) 2–4 105 (31.1%) Weight loss C5% in previous 3 months 182 (53.8%) B5% in previous 3 months 156 (46.2%) Smoking habitus Current or former 255 (75.4%) Never 83 (24.6%) Histology Squamous cell 135 (39.9%) Adenocarcinoma 88 (26.0%) Stage 3 179 (53%) 4 159 (47%) Table 2 Treatment modalities and regimens of the patients Patients (n) (%) Chemotherapy regimen Combination 222 (65.7%) Single agent 30 (8.90%) Best supportive care 86 (25.4%) Combination therapy Carboplatin–paclitaxel 98 (29%) Carboplatin–docetaxel 25 (7.4%) Carboplatin–gemcitabine 25 (7.4%) Carboplatin–vinorelbine 1 (0.3%) Cisplatin–docetaxel 32 (9.5%) Cisplatin–gemcitabine 22 (6.5%) Cisplatin–vinorelbine 9 (2.7%) Cisplatin–paclitaxel 5 (1.5%) Cisplatin–etoposide 2 (0.6%) Docetaxel–gemcitabine 2 (0.6%) Gemcitabine–vinorelbine 1 (0.3%) Chemotherapy cycles \3 45 (18%) C3 207 (82%) Response to therapy Yes (Partial or complete response) 161 (63.8%) No 91 (36.2%) Second-line therapy 67 (26.5%) Gemcitabine 13 (19.4%) Docetaxel 12 (17.9%) Cisplatin–gemcitabine 7 (10.4%) Cisplatin–paclitaxel 5 (7.46%) Cisplatin–etoposide 4 (5.97%) Carboplatin–docetaxel 2 (2.98%) Vinorelbine 2 (2.98%) Cisplatin–docetaxel 1 (1.49%) Carboplatin–gemcitabine 1 (1.49%) Carboplatin–vinorelbine 1 (1.49%) Paclitaxel 1 (1.49%) Toxicities Haematological 111 (44.2%) Nausea–vomiting 59 (23.5%) Neurological 27 (10.8%) Med Oncol (2011) 28:661–666 663 123 P \ 0.01; Fig. 4). There was no relationship between sex, LDH and hemoglobin values, smoking history, histology of the tumor, chemotherapy cycle and overall survival (P [ 0.05). These data are shown in Table 3. In multi- variate analysis, only response to therapy showed consis- tency with survival (P \ 0.001). The median PFS was 10 months (95% CI: 8.4–11.6). In univariate analysis, there was only a significant association between tumor response and PFS (14.6 vs. 8.5 months; Fig. 1 Median survival time of the patients Fig. 2 Survival of the patients according to the performance status (PS) Fig. 3 Survival of the patients according to the stage Fig. 4 Survival of the patients according to the chemotherapy Table 3 Univariate analysis of the prognostic factors Variable Overall survival Median (months) P value Stage 3 18.4 0.004 4 11.1 Performance status 0–1 17.0 0.012 2–4 10.8 Weight loss B5% in previous 3 months 13.0 0.004 C5% in previous 3 months 23.6 Chemotherapy regimen Combination 18.4 0.003 Single agent 14.7 Platinum-based therapy Cisplatin 20.3 0.374 Carboplatin 16.8 Tumor response Yes 23.0 0.000 No 14.7 Second-line therapy Yes 23.0 0.000 No 14.7 664 Med Oncol (2011) 28:661–666 P \ 0.001). In multivariate analysis, there was no rela- tionship found between variables and PFS. Discussion Elderly patients are a complex patient group with their comorbidities and reduced functional reserves. NCSLC represents a significant health problem in the elderly pop- ulation. There is no standard treatment accepted for the NSCLC. Frasci et al. [12] showed better survival of the patients treated with combination therapy versus single- agent therapy in 120 elderly patients. In 1980s and 1990s, cisplatin-based chemotherapy was the standard treatment of advanced NSCLC [13]. Langer et al. [14] suggested that platinum-based therapy can be used in elderly patients with NSCLC. Lilenbaum et al. [15] randomized elderly patients to receive paclitaxel or paclitaxel and carboplatin. Although it was not statistically significant, the subgroup of the elderly patients showed that combination arm had a better median survival time. In our study, 65% of our patients received combination therapy. The number of patients that received platinum-based combination therapy was 217 (64.2%). Carboplatin-based therapy was preferred as a first-line therapy in patients with decreased renal function, and nephrotoxicity frequency was low. Cisplatin- based regimen as a first-line treatment was administered to the patients with a good performance status and normal renal function. Single-agent cytotoxic drugs were preferred in elderly patients with marked weight loss and decrease oral intake. As these studies stated above, the combination therapy arm in our study showed a better survival than single-agent chemotherapy. But when the platinum chemotherapies are compared, there were no advantages of each agent to each other with respect to toxicities and efficiency. Haematological toxicity was the major toxicity. Combination arm therapy showed more neutropenia and anemia in our study (P \ 0.05). There are a few studies investigating prognostic factors in elderly with advanced NSCLC. Elderly patients with a good performance status are considered candidates for platinum-based combination therapy [16]. Also, Chen et al. [17] found a better prognosis in elderly patients with NSCLC with a good performance status. Our results were consistent with these previous studies. Weight loss, che- motherapy cycle, stage, tumor response and comorbidities were found significant prognostic factors in other studies [12, 18, 19]. We also found the importance of these factors on the survival of elderly patients with NSCLC as in these studies. Li et al. [19] demonstrated that second-line therapy was a strong predictor of survival in elderly patients with advanced NSCLC. Although there was no previous studies showing significancy of second-line treatment on survival in elderly patients with NSCLC, this and our study results may be an encouragement in favor of using more second- line therapies. In univariate analysis of PFS and OS, response to ther- apy was found to be significant. Moreover, multivariate analysis also showed that response to therapy was an independent prognostic factor. Li et al. [19] demonstrated that tumor response to therapy showed a survival benefit. This result may be regarded as a determinant of continu- ation, modification or cessation of the treatment especially in elderly patients who cannot tolerate the chemotherapy regimen. In conclusion, while new studies are done about the prognostic factors in elderly patients with advanced NSCLC, we recommend the usage of more aggressive chemotherapy regimens in these patients especially if they have a good performance status and a weight loss of B5% in previous 3 months. Response to therapy may influence the decisions about the continuation of first-line therapy and selection of the patients that can be given second-line therapy. 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Oncology. 2009;76:355–62. 666 Med Oncol (2011) 28:661–666 Prognostic factors in elderly patients with non-small cell lung cancer: a two-center experience Abstract Introduction Materials and methods Statistical analysis Results Discussion References << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /None /Binding /Left /CalGrayProfile (Gray Gamma 2.2) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (ISO Coated v2 300% \050ECI\051) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Error /CompatibilityLevel 1.3 /CompressObjects /Off /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Perceptual /DetectBlends true /DetectCurves 0.1000 /ColorConversionStrategy /sRGB /DoThumbnails true /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams true /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness true /PreserveHalftoneInfo false /PreserveOPIComments false /PreserveOverprintSettings true /StartPage 1 /SubsetFonts false /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages true /ColorImageMinResolution 149 /ColorImageMinResolutionPolicy /Warning /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 150 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.40 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 149 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 150 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.40 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 599 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 600 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ARA /BGR /CHS /CHT /CZE /DAN /ESP /ETI /FRA /GRE /HEB /HRV (Za stvaranje Adobe PDF dokumenata najpogodnijih za visokokvalitetni ispis prije tiskanja koristite ove postavke. 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