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Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 2747-2754 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.7915 Customizing Cisplatin Based on Quantitative Excision Repair Cross-Complementing 1 mRNA Expression: A Phase III Trial in Non–Small-Cell Lung Cancer
From the Hospital Carlos Haya, Malaga; Hospital Lozano Blesa, Zaragoza; Hospital General de Alicante, Alicante; Catalan Institute of Oncology, Hospital Duran i Reynals; Hospital Clinic; Hospital Vall d'Hebron, Barcelona; Hospital Alcorcon; Hospital Puerta de Hierro; Hospital Doce de Octubre; Fundacion Jimenez Diaz’ Autonomous University of Madrid, Madrid; Hospital de Cruces, Barakaldo-Bizkaia; Valencia Institute of Oncology; Hospital Arnau de Vilanova; Hospital General de Valencia, Valencia; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain; Response Genetics, Los Angeles; and the University of California Davis Cancer Center, Sacramento, CA Address reprint requests to Rafael Rosell, MD, Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, 08916 Badalona (Barcelona), Spain; e-mail: rrosell{at}ico.scs.es
Purpose: Although current treatment options for metastatic non–small-cell lung cancer (NSCLC) rely on cisplatin-based chemotherapy, individualized approaches to therapy may improve response or reduce unnecessary toxicity. Excision repair cross-complementing 1 (ERCC1) has been associated with cisplatin resistance. We hypothesized that assigning cisplatin based on pretreatment ERCC1 mRNA levels would improve response. Patients and Methods: From August 2001 to October 2005, 444 stage IV NSCLC patients were enrolled. RNA was isolated from pretreatment biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Patients were randomly assigned in a 1:2 ratio to either the control or genotypic arm before ERCC1 assessment. Patients in the control arm received docetaxel plus cisplatin. In the genotypic arm, patients with low ERCC1 levels received docetaxel plus cisplatin, and those with high levels received docetaxel plus gemcitabine. The primary end point was the overall objective response rate. Results: Of 444 patients enrolled, 78 (17.6%) went off study before receiving one cycle of chemotherapy, mainly due to insufficient tumor tissue for ERCC1 mRNA assessment. Of the remaining 346 patients assessable for response, objective response was attained by 53 patients (39.3%) in the control arm and 107 patients (50.7%) in the genotypic arm (P = .02). Conclusion: Assessment of ERCC1 mRNA expression in patient tumor tissue is feasible in the clinical setting and predicts response to docetaxel and cisplatin. Additional studies are warranted to optimize methodologies for ERCC1 analysis in small tumor samples and to refine a multibiomarker profile predictive of patient outcome.
Cisplatin doublets are the generally accepted standard of care for advanced non–small-cell lung cancer (NSCLC) patients. Large randomized studies, such as E1594,1 have demonstrated the relative equivalence of several different platinum-based doublets, with response rates of 17% to 32% and median survival ranging from 8 to 11 months.2 Whether nonplatinum combinations provide similar benefits remains controversial.2,3 Large interindividual differences in chemotherapy benefit4 highlight the need to develop predictive markers for selecting patients for platinum- or nonplatinum-based chemotherapy, or alternatives to chemotherapy. Despite recent advances in smoking cessation programs, approximately 90% of all lung cancer is still closely associated with the use of tobacco products. Inherent to tobacco-related carcinogenesis is the induction of DNA adducts that are repaired by the nucleotide excision repair (NER) pathway (Appendix Fig A1, online only).5 NER is also capable of removing numerous types of DNA helix-distorting lesions, including those associated with cisplatin and ultraviolet light.6,7 NER functions by a so-called cut-and-paste mechanism in which cisplatin damage recognition, local opening of the DNA helix around the lesion, damage excision, and gap filling occur in successive steps,6 through the concerted action of various NER factors. The structure-specific endonuclease excision repair cross-complementing 1 (ERCC1), together with its XP group F (XPF) partner, performs an essential late step in the NER process, where it nicks the damaged DNA strand at the 5' site of the helix-distorting cisplatin lesion. In addition, the ERCC1/XPF structure-specific nuclease8,9 also plays a role in the homologous recombination repair of interstrand crosslinks.10-13 High tumor tissue levels of ERCC1 mRNA in ovarian and gastric cancer patients have been associated with cisplatin resistance.14,15 Similarly, inhibition of ERCC1 expression has been associated with reduced host cell reactivation of cisplatin-treated cells and increased cisplatin sensitivity.16,17 Cisplatin resistance in NSCLC cell lines has been related to the increase of host cell reactivation,18 and significant differences in survival were observed in cisplatin-treated NSCLC patients according to their DNA repair capacity as measured by a host cell reactivation assay.19 When intratumoral ERCC1 mRNA derived from paraffin-embedded tumor specimens was measured by real-time reverse transcriptase polymerase chain reaction in metastatic colon cancer patients treated with oxaliplatin plus fluorouracil, high levels of ERCC1 correlated significantly with poor response and shorter survival.20 Using the same methodology, we examined ERCC1 mRNA expression in paraffin-embedded pretreatment tumor specimens from stage IV NSCLC patients treated with cisplatin plus gemcitabine. There were striking differences in survival (15 months for patients with low levels of ERCC1 months v 5 months for those with high levels), and the response rate in tumors with low levels of ERCC1 mRNA was higher (52%) than in those with high levels (36%), although this difference was not significant (P = .38).21 On the basis of this biochemical evidence and promising clinical data, we initiated a phase III trial of customized chemotherapy according to ERCC1 mRNA levels in patients with stage IV NSCLC. We hypothesized that patients receiving therapy based on their baseline tumor ERCC1 levels would attain higher response rates than patients in the control arm receiving noncustomized therapy. Using this selective approach, patients in the genotypic arm with low ERCC1 mRNA levels received cisplatin plus docetaxel, and those with high ERCC1 mRNA levels received gemcitabine plus docetaxel. All patients in the control arm received cisplatin plus docetaxel.
This was a multicenter, randomized study. From August 2001 to October 2005, 444 patients were enrolled at 24 European centers (22 in Spain, one in Germany, one in Switzerland). The study protocol was approved by local ethics committees, and all patients gave their signed informed consent. Study data were collected by the investigators and an independent organization (Pivotal, Madrid, Spain) and were held and analyzed by the Spanish Lung Cancer Group.
Eligibility Criteria
Random Assignment and Treatment Plan
Patients were treated for six cycles or until progressive disease, death, or an unacceptable adverse event (Appendix Table A1, online only). Patients could continue treatment beyond six cycles at the discretion of the treating physician. Second-line therapies, also at the discretion of the treating physician, were permitted after the study treatment was discontinued (Appendix Table A2, online only). After discontinuation of study treatment, patients were monitored at 2-month intervals until death.
Clinical Assessments Objective tumor responses were evaluated in accordance with the Response Evaluation Criteria in Solid Tumors guidelines22 after the second, fourth, and sixth treatment cycles by repeating the staging procedures. Progression-free survival was calculated from the date of random assignment to progressive disease or death (Appendix Fig A2, online only). Overall survival was calculated from the date of random assignment to the date of death or last clinical follow-up (Appendix Fig A3, online only).
Assessment of ERCC1 mRNA Expression ERCC1 mRNA gene expression analysis was performed in RNA isolated from the tumor tissue specimens after laser capture microdissection (Palm, Oberlensheim, Germany), according to a proprietary procedure (US patent number 6,248,535) of Response Genetics, as described previously.21
Statistical Analysis
Response rates between the control and genotypic arms were compared with a one-sided Fisher's exact test. Analyses of secondary hypotheses and other exploratory analyses were performed using two-sided tests: Fisher's or Secondary end points included progression-free and overall survival. Kaplan-Meier curves were calculated and compared using a two-sided log-rank test. A univariate and multivariate stepwise procedure Cox regression analysis was used to assess the association between each potential prognostic factor and progression-free and overall survival. A logistic univariate and multivariate analysis was used to evaluate the independent significance of different variables on response. The hazard ratios (HR) and 95% CIs for covariates were calculated from the Cox model, and the odds ratio and 95% CIs were calculated from the logistic regression model for predictors of response. Analyses were performed using SPSS version 11.0 (SPSS Inc, Chicago, IL) for calculations and S-PLUS version 6.1 (Statistical Sciences, Seattle, WA) for plots.
Patient Characteristics From August 2001 to October 2005, 444 patients were enrolled at 24 sites (range of accrual, two to 88 patients/center). Enrollment was carried out in two stages (Fig 2). From August 2001 to June 2004, 342 patients were enrolled. During this initial enrollment period, 114 patients were assigned to the control arm and 228 patients were assigned to the genotypic arm. A total of 59 patients (17.3%; seven in the control and 52 in the genotypic arm) withdrew from the study. Twenty-seven patients randomly assigned to the genotypic arm (12%) were withdrawn because tumor tissue was insufficient for ERCC1 mRNA assessment. In June 2004, the total number of patients enrolled was 283 (107 in the control and 176 in the genotypic arm). Because this was less than the initial sample size of 297 patients calculated to detect at least a 15% difference in response, the ethics committees approved the inclusion of 102 additional patients based on a corrected projection of a 29% dropout rate (34 patients randomly assigned to the control and 68 patients randomly assigned to the genotypic arm). Of these additional patients, 19 patients in the genotypic arm (28%) were withdrawn from the study (15 [22%] due to insufficient tumor sample). By October 2005, a total of 366 patients were enrolled in the study, 346 of whom were assessable for response (Fig 2).
Table 1 shows the baseline patient characteristics. The median age was 61 years (range, 33 to 81 years). One hundred thirty-four patients (36.6%) were PS 0. The median ERCC1 mRNA expression, relative to the expression of the internal control housekeeping gene ß-actin, was 1.65 (range, 0.14 to 13.40). No significant differences in baseline characteristics, number of chemotherapy cycles or ERCC1 expression levels were observed either between the treatment arms (Table 1) or between ERCC1-analyzable and nonanalyzable patients (data not shown). The median follow-up time was 9.04 months (range, 0.23 to 50.78 months) for the entire study and 13.24 months (range, 2.08 to 50.78 months) for patients alive at the time of data analysis.
Objective Response Rate Of the 346 patients assessable for response, 53 patients (39.3%; 95% CI, 31.4% to 47.8%) in the control arm and 107 patients (51.2%; 95% CI, 44% to 57.5%) in the genotypic arm achieved objective response (one-sided Fisher's exact test, P = .02). In the intent-to-treat analysis of all 366 enrolled patients, the response rate was 37.6% (95% CI, 30% to 45.9%) in the control arm and 47.5% (95% CI, 41.5% to 54.6%) in the genotypic arm (one-sided Fisher's exact test, P = .03). In an exploratory analysis of response, progression-free survival, and overall survival, the genotypic arm was subdivided into the low genotypic group (low ERCC1 mRNA levels) and the high genotypic group (high ERCC1 levels). Sixty-five patients (53.2%; 95% CI, 45.2% to 62.8%) in the low genotypic group, and 42 patients (47.2%; 95% CI, 37.1% to 57.6%) in the high genotypic group achieved objective response (Table 2).
Univariate logistic regression models (Table 3) showed that the probability of response for patients in the low genotypic group was 1.76 times (95% CI, 1.08 to 2.90 times) greater than for those in the control arm (P = .03), and the probability of response for the high genotypic group was 1.38 times (95% CI, 0.81 to 2.38 times) greater than for the control arm (P = .24).
Patients with PS 0 had significantly lower median ERCC1 mRNA levels (1.46; range, 0.19 to 11.10) than patients with PS 1 (1.84; range, 0.14 to 13.40; P = .03). In the multivariate analysis, only PS 0 and low genotypic group were found to be independent predictors of better response (Table 3). For the 160 patients who attained objective response, median duration of response was 5.39 months (95% CI, 0.46 to 29.61 months), with no significant difference between arms (data not shown).
Progression-Free and Overall Survival Median overall survival was 9.8 months (95% CI, 8.9 to 10.7 months) in the control arm and 9.9 months (95% CI, 8.7 to 11 months) in the genotypic arm (HR, 0.9; range, 0.7 to 1.2; P = .59). Median survival was 10.4 months (95% CI, 7.9 to 12.8 months) in the low genotypic group, and 9.5 months (95% CI, 8.2 to 10.8 months) in the high genotypic group (Table 2). One-year survival was 39% in the control arm, 40.4% in the genotypic arm, 44% in the low genotypic group, and 33% in the high genotypic group (Table 2).
Toxicities
Stage IV NSCLC remains a fatal disease with low response rates and short survival outcomes.1-3 Clearly, the development of predictive biomarkers to identify a subgroup of patients who will more likely benefit from cisplatin-based chemotherapy is a high priority in lung cancer research. Association of ERCC1 mRNA expression with response to platinum-based treatment has been reported in gastric15 and colorectal20 cancer, and recently an association has been found in stage IIIB NSCLC.23 The results of the present study confirm that ERCC1 mRNA levels predict response to platinum-based therapy in advanced NSCLC. In the majority of advanced NSCLC patients, a pathologic diagnosis is established by fine-needle aspiration or bronchoscopic biopsy, resulting in a limited tumor specimen. Although the statistical design of our study anticipated a 15% dropout rate, the actual dropout rate proved to be much higher, requiring an amended statistical plan and accrual of additional patients. New methodologies for molecular analysis of small tissue samples may help to alleviate this deficiency. In addition, future studies evaluating a biomarker selection approach in NSCLC may also optimize assessability by randomly assigning patients after successful molecular analysis, rather than beforehand. In this study, docetaxel was selected as the partner for cisplatin in both the control arm and the low genotypic group based on its level of activity as a single agent in both the first- and second-line setting in NSCLC.24-26 This activity was confirmed recently by a report that docetaxel plus cisplatin provided better patient outcomes than vinorelbine plus cisplatin.27 However, in retrospect, gemcitabine plus cisplatin may have been preferable for patients in the genotypic arm with low ERCC1 expression. A close correlation has been identified between levels of ERCC1 and ribonucleotide reductase subunit M1 (RRM1), which is involved in gemcitabine metabolism.28,29 Given that gemcitabine itself inhibits repair of cisplatin-induced DNA damage, low ERCC1 levels would be predicted to facilitate interaction between gemcitabine and cisplatin. This study is the first prospective randomized clinical trial testing the concept of customized chemotherapy in NSCLC. As such, it has demonstrated both the feasibility of this approach and the logistic problems associated with a biomarker-driven therapeutic strategy in NSCLC, and has paved the way for future research in this field.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Luis Paz-Ares, Sanofi-aventis Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: David Gandara, Rafael Rosell Financial support: Rafael Rosell Administrative support: Manuel Cobo, Bartomeu Massuti, Jose Miguel Sanchez, Mariano Provencio, Luis Paz-Ares, Guillermo Lopez-Vivanco, Miguel Angel Muñoz, Enriqueta Felip, Vicente Alberola, Carlos Camps, Kathleen Danenberg Provision of study materials or patients: Manuel Cobo, Dolores Isla, Bartomeu Massuti, Ana Montes, Jose Miguel Sanchez, Mariano Provencio, Nuria Viñolas, Luis Paz-Ares, Guillermo Lopez-Vivanco, Miguel Angel Muñoz, Enriqueta Felip, Vicente Alberola, Carlos Camps, Manuel Domine, Miquel Taron Collection and assembly of data: Manuel Cobo, Dolores Isla, Bartomeu Massuti, Ana Montes, Jose Miguel Sanchez, Mariano Provencio, Nuria Viñolas, Luis Paz-Ares, Guillermo Lopez-Vivanco, Miguel Angel Muñoz, Enriqueta Felip, Vicente Alberola, Carlos Camps, Miquel Taron Data analysis and interpretation: Jose Javier Sanchez, Maria Sanchez-Ronco Manuscript writing: Rafael Rosell Final approval of manuscript: Manuel Domine, Rafael Rosell
ERCC1 gene expression analysis. After standard tissue sample deparaffinization using xylene and alcohols, RNA isolation was done according to a proprietary procedure (US patent number 6,248,535) of Response Genetics Inc. Briefly, the tissue samples to be extracted were placed in the solution containing 400 µL of 4 M dithiothreitol/guanidinium isothiocyanate/sarcosine. The samples were heated at 92°C for 30 minutes and then 50 µL of 2 M sodium acetate (pH 4.0), was added, followed by 600 µL of freshly prepared phenol/chloroform/isoamyl alcohol (250:50:1). The tubes were placed on ice for 15 minutes and then centrifuged. The upper aqueous phase was removed carefully and placed in a 1.5-mL centrifuge tube. Glycogen (10 µL) and 300 to 400 µL of isopropanol were added and the tubes were placed at –20°C for 30 to 45 minutes to precipitate the RNA. Precipitated pellets were rinsed with 75% ethanol and then air dried. The RNA pellet was resuspended in RNA storage solution (Ambion Inc, Austin, TX) and cDNA was synthesized as described previously (Metzger R, Leichman CG, et al: J Clin Oncol 16:309-316, 1998). Relative cDNA quantification for ERCC1 and an internal reference gene (ß-actin) was done using a fluorescence-based, real-time polymerase chain reaction (PCR) in an ABI PRISM 7700 Sequence Detection System (Applied Biosystems, Foster City, CA), as described previously (Gibson UE, Heid CA, Williams PM: Genome Res 6:995-1001, 1996; Heid CA, Stevens J, Livak KJ et al: Genome Res 6:986-994, 1996). The primers and Taqman probe sequences used are listed below. In each case, the first primer is the forward PCR primer, the second is the reverse PCR primer, and the third is the fluorescent probe: ERCC1, 5'-GGGAATTTGGCGACGTAATTC, 5'- GGAGGCTGAGGAACAG, and 6FAM (carboxyfluorescein) 5'-CACAGGTGCTCTGGCCCAGCACATA-3'TAMRA (N,N,N',N'-tetramethyl-6-carboxyrhodamine); ß-actin, 5'-TGAGCGCGGCTACAGCTT, 5'-TCCTTAATGTCACGCACGATTT, and 6FAM 5'-ACCACCACGGCCGAGCGG-3'TAMRA. The PCR reaction mixture consisted of 600 nmol/L each primer; 200 nmol/L probe; 2.5 units of AmpliTaq Gold polymerase; 200 µmol/L each deoxyadenosine triphosphate, deoxycytidine triphosphate, and deoxyguanosine triphosphate; 400 µmol/L deoxyuridine triphosphate; 5.5 mmol/L MgCl2; and 1x TaqMan Buffer A containing a reference dye, to a final volume of 25 µL (all reagents were from Applied Biosystems, Foster City, CA). Cycling conditions were 50°C for 10 seconds, 95°C for 10 minutes, followed by 46 cycles at 95°C for 15 seconds and 60°C for 1 minute.
Colon, liver, and lung RNAs (all from Stratagene, La Jolla, CA) were used as control calibrators on each plate. All gene expression analyses were performed in a blinded fashion with the laboratory investigators unaware of the clinical data. Relative gene expression quantification was calculated according to the comparative threshold cycle (CT) method using ß-actin as an endogenous control and commercial RNA controls as calibrators. Final results were determined as follows: 2–(
The cutoff value between high and low ERCC1 mRNA levels was based on findings from our previous study (Lord RV, Brabender J, Gandara D et al: Clin Cancer Res 8:2286-2291, 2002) according to a method described previously (Salonga D, Danenberg KD, Johnson M et al: Clin Cancer Res 6:1322-1327, 2000). Briefly, the cutoff value was determined by adapting the maximally selected
The following additional investigators and institutions participated in this study: Felipe Cardenal (Catalan Institute of Oncology, Hospital Duran i Reynals, Barcelona, Spain); Christian Manegold (Klinikum Mannehim der Universitat Heidelberg, Mannheim, Germany); Pilar Garrido (Hospital Ramon y Cajal, Madrid, Spain); Remei Blanco (Hospital de Terrassa, Terrassa, Spain); Jose Andres Moreno-Nogueira (Hospital Virgen del Rocio, Sevilla, Spain); Pilar Lianes (Hospital de Mataro, Mataro, Spain); Carlos Mesia (Hospital del Mar, Barcelona, Spain); Rolf Stahel (Universitatsspital, Zurich, Switzerland); Ferran Losa (Hospital General de l'Hospitalet, Hospitalet, Spain); Jose Manuel Trigo (Hospital Virgen de la Victoria, Malaga, Spain); Cristina Martin (Hospital Espiritu Santo, Santa Coloma de Gramanet, Spain); Teresa Moran (Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain); Peter Danenberg (University of Southern California, Los Angeles, CA).
We thank the other investigators who participated in this trial, Gary Clark, PhD, for his critical analysis of the study data, and Maria Moreno, Jose Luis Tisaire, MD, Renée O'Brate, and Lourdes Franquet.
Supported by Sanofi-aventis. Additional funding was provided by Spanish Ministry of Health grants, through the Red de Centros de Epidemiología y Salud Pública (RCESP) and the Red Temática de Investigación Cooperativa de Centros de Cáncer (CO-010), and by La Fundación Badalona Contra el Cáncer. None of the funding agencies were involved in the design and conduct, data management and analysis, manuscript preparation and review, or authorization for submission. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Presented in part at the 41st Annual Meeting of the American Society for Clinical Oncology, May 13-17, 2005, Orlando, FL, and at the 31st Congress of the European Society of Medical Oncology, September 30-October 3, 2006, Istanbul, Turkey. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Neumann AS, Sturgis EM, Wei Q: Nucleotide excision repair as a marker for susceptibility to tobacco-related cancers: A review of molecular epidemiological studies. Mol Carcinog 42:65-92, 2005[CrossRef][Medline] 6. de Laat WL, Jaspers NG, Hoeijmakers JH: Molecular mechanism of nucleotide excision repair. Genes Dev 13:768-785, 1999 7. Hasty P, Campisi J, Hoeijmakers J, et al: Aging and genome maintenance: Lessons from the mouse? Science 299:1355-1359, 2003 8. Wijnhoven SW, Hoogervorst EM, de Waard H, et al: Tissue specific mutagenic and carcinogenic responses in NER defective mouse models. Mutat Res 614:77-94, 2007[Medline] 9. Tripsianes K, Folkers G, Ab E, et al: The structure of the human ERCC1/XPF interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. Structure 13:1849-1858, 2005[Medline] 10. Niedernhofer LJ, Odijk H, Budzowska M, et al: The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Mol Cell Biol 24:5776-5787, 2004 11. De Silva IU, McHugh PJ, Clingen PH, et al: Defects in interstrand cross-link uncoupling do not account for the extreme sensitivity of ERCC1 and XPF cells to cisplatin. Nucleic Acids Res 30:3848-3856, 2002 12. Prasher JM, Lalai AS, Heijmans-Antonissen C, et al: Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1-/- mice. Embo J 24:861-871, 2005[CrossRef][Medline] 13. Cummings M, Higginbottom K, McGurk CJ, et al: XPA versus ERCC1 as chemosensitising agents to cisplatin and mitomycin C in prostate cancer cells: Role of ERCC1 in homologous recombination repair. Biochem Pharmacol 72:166-175, 2006[CrossRef][Medline] 14. Dabholkar M, Vionnet J, Bostick-Bruton F, et al: Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Invest 94:703-708, 1994[Medline] 15. Metzger R, Leichman CG, Danenberg KD, et al: ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol 16:309-316, 1998 16. Selvakumaran M, Pisarcik DA, Bao R, et al: Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res 63:1311-1316, 2003 17. Chang IY, Kim MH, Kim HB, et al: Small interfering RNA-induced suppression of ERCC1 enhances sensitivity of human cancer cells to cisplatin. Biochem Biophys Res Commun 327:225-233, 2005[CrossRef][Medline] 18. Zeng-Rong N, Paterson J, Alpert L, et al: Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy. Cancer Res 55:4760-4764, 1995 19. Bosken CH, Wei Q, Amos CI, et al: An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J Natl Cancer Inst 94:1091-1099, 2002 20. Shirota Y, Stoehlmacher J, Brabender J, et al: ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 19:4298-4304, 2001 21. Lord RV, Brabender J, Gandara D, et al: Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 8:2286-2291, 2002 22. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 23. Bepler G, Kusmartseva I, Sharma S, et al: RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 24:4731-4737, 2006 24. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000 25. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362, 2000 26. Gandara DR, Vokes E, Green M, et al: Activity of docetaxel in platinum-treated non-small-cell lung cancer: Results of a phase II multicenter trial. J Clin Oncol 18:131-135, 2000 27. Fossella F, Pereira JR, von Pawel J, et al: Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: The TAX 326 study group. J Clin Oncol 21:3016-3024, 2003 28. Rosell R, Danenberg KD, Alberola V, et al: Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 10:1318-1325, 2004 29. Rosell R, Felip E, Taron M, et al: Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery. Clin Cancer Res 10:4215s-4219s, 2004[CrossRef][Medline] Submitted November 9, 2006; accepted February 20, 2007. Related Editorial
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ABSTRACT
INTRODUCTION
18 years; adequate hematologic function (hemoglobin 
1.5x the upper limit of normal, AST and ALT 
2 for categoric variables and t test for continuous variables. When multiple comparisons were made, P values were corrected by the Bonferroni inequality method. 
CT sample–
