J Gastrointest Canc (2014) 45:80–86 DOI 10.1007/s12029-013-9568-5
ORIGINAL RESEARCH
ERCC1 in Advanced Biliary Tract Cancer Patients Treated with Chemotherapy: Prognostic and Predictive Roles Vanessa da Costa Miranda & Maria Ignez Braghiroli & Luiza Dib Batista Bugiato Faria & Sheila Aparecida Coelho Siqueira & Jorge Sabbaga & Paulo M. Hoff & Rachel P. Riechelmann
Published online: 11 December 2013 # Springer Science+Business Media New York 2013
Abstract Background In oncology, we tend to look for factors that reflect better prognosis or predict response to treatments in order to make a selection from which patients will derive the benefit, avoiding futile therapies and/or toxicities. Definitive prognostic and predictive factors in advanced biliary cancer remain unknown. Methods We retrospectively analyzed all consecutive patients in our institution with advanced biliary tract cancer treated with palliative cisplatin plus gemcitabine. We evaluated the prognostic and predictive role of the immunohistochemistry (IHC) expression of ERCC1 (excision cross-complementing gene-1) on tumor response and also examined several clinical and laboratory prognostic factors for overall survival. Results From January 2009 to July 2011, 72 patients were identified; their median overall survival was 9.5 months. Independent variables associated with shorter survival identified by the multivariable Cox regression analysis were ECOG 2-3 (HR 8.4; 95 % CI 3.4 to 20.7; p 1 (HR 9.5; 95 % CI 1.6 to 55.3; p =0.012). Electronic supplementary material The online version of this article (doi:10.1007/s12029-013-9568-5) contains supplementary material, which is available to authorized users. V. da Costa Miranda : M. I. Braghiroli : L. D. B. B. Faria : J. Sabbaga : P. M. Hoff : R. P. Riechelmann (*) Disciplina de Radiologia e Oncologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Arnaldo 251,12o andar, São Paulo, SP 01246-000, Brazil e-mail: [email protected] J. Sabbaga : P. M. Hoff Centro de Oncologia, Hospital Sírio Libanês, São Paulo, Brazil S. A. C. Siqueira Disciplina de Patologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Pathology slides were available from 44 patients: 23 (52 %) stained positive for ERCC1 on IHC (score ≥0.5). In this subgroup, expression of ERCC-1 was not prognostic and was not associated with either clinical benefit (partial response and stable disease) or tumor response (partial response only) to chemotherapy. Conclusions In this cohort of unselected patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin, IHC expression of ERCC1 was not either predictive or prognostic. Patients with ECOG 2-3 and/or multiple comorbidities had worse survival Keywords ERCC-1 protein . biliary duct neoplasms . cisplatin and gemcitabine
Introduction Biliary tract tumors (BTCs) are rare, representing 3 % of all gastrointestinal tumors, but incidence has progressively increased over the past years [1, 2]. Unfortunately, most patients are diagnosed with advanced stage disease, and only a few are considered candidates for curative surgery [1]. In advanced disease, combination therapy based on 5-fluorouracil or gemcitabine (associated with oxaliplatin or cisplatin) resulted in increased progression-free survival in several phase II trials [1]. The landmark ABC-02 trial established gemcitabine plus cisplatin as the standard first-line treatment for biliary tract cancer. The authors showed an absolute gain of 4 months in overall survival for those treated with the combination regimen when compared to gemcitabine alone [3]. Based on this study, most cancer centers have adopted this regimen as the standard first-line treatment for the majority of metastatic/ locally advanced biliary tract cancer. Taylor of therapeutic management as to avoid futile therapies and/or toxicities requires the identification of prognostic
J Gastrointest Canc (2014) 45:80–86
and/or predictive factors. Some retrospective analyses have suggested that bilirubin level >10 mg/dL, intrahepatic cholangiocellular carcinoma, poor Eastern Cooperative Oncology Group (ECOG) performance status, and elevated alkaline phosphatase level are independent predictors of poor prognosis [4, 5]. However, prognostic and predictive factors in biliary cancer also remain unknown. DNA repair is an extremely complex process, and many of these processes may be altered in various types of tumors. For platinum compounds, in vitro data clearly show that nucleotide excision repair (NER) pathway is the DNA repair pathway responsible for the repair of cisplatin-DNA damage [6]. The mechanism of action of cisplatin is through formation of bulky intrastrand platinum–DNA adducts; the removal of these adducts from genomic DNA is mediated by the NER pathway [6]. High ERCC1 expression has been associated with resistance to platinum-containing therapy lung, ovarian, and colorectal cancers [7–9]. However, ERCC1 expression has not been investigated in BTCs. In this study, we have retrospectively evaluated the prognostic and predictive role of immunohistochemistry (IHC) expression of ERCC1 (excision cross-complementing gene-1) on the response to chemotherapy with cisplatin plus gemcitabine. We also have looked at several clinical and laboratory prognostic factors that could influence overall survival in patients with metastatic biliary tract cancer.
81
was graded on a scale of 0 to 3 (with a higher number indicating a higher intensity). The extension of positive tumor nuclei was calculated for each specimen and scored as assigned (0 if 0 %, 0.1 if 1 % to 9 %, 0.5 if 10 % to 49 %, and 1.0 if 50 % or more). This score was multiplied by the staining intensity of nuclei to obtain a final semiquantitative H score. The median value of all H scores was chosen a priori as the cutoff point for separating ERCC1-positive tumors from ERCC1-negative tumors [12, 13]. We used summary statistics to describe patient characteristics. Survival time was defined from the date of first visit to the date of death, and overall survival was displayed as a Kaplan– Meier curve. The predictive value of ERCC1 expression and tumor response was calculated by the Chi-square test, utilizing the median as the cut off value. We also evaluated the predictive value of ERCC1 as a continuous variable using univariate logistic regression. For the prognostic evaluation, we performed a multivariable COX regression analysis for overall survival, using all the clinical and laboratory parameters described above as well as the ERCC-1 expression as a continuous variable. A multivariable analysis for predictive factors of response was not performed because of the small number of patients whose tumor tissue was available (N =44). A twotailed p value1 Tumor location Intraheptic Extrahepatic Gallbladder Clinical stage Locally advanced Metastatic Charlson index 0/1 >1 Drainage before chemotherapy Yes No
60 years (30–80) 45 (62.5 %) 27 (37.5 %) 84.7 (0.1–50,000) 0.32 (0.07–25.2) 50 (69.4.3 %) 22 (37.5 %) 30 (41.7 %) 19 (26.4 %) 23 (31.9 %) 25 (34.7 %) 47 (63.3 %) 65 (90.3 %) 7 (9.7 %) 32 (44.4 %) 40 (55.6 %)
82
J Gastrointest Canc (2014) 45:80–86
Table 2 Information on treatment Median chemotherapy cycles
4 (1–9)
G3-G4 toxicities Neutropenia Thrombocytopenia Anemia Nausea and vomiting Hospitalization during treatment (any cause) Hospitalization due to toxicity Treatment discontinuation Second-line treatment 5 FU+Leucovorin Carboplatin and gemcitabine
12 (16.6 %) 9 (11.5 %) 7 (9.7 %) 6 (8.3 %) 30 (41.7 %) 5 (7 %) 18 (25 %) 20 (27.7 %) 19 1
Results Clinical/Laboratorial Data and Survival Analysis From January 2009 to July 2011, 72 patients were identified and their characteristics are summarized in Table 1. The median baseline CA 19.9 was 84.7 ng/mL, 42 (62.5 %) were women and 69.4 % of patients had an ECOG status of 0 or 1. Fig. 1 Patients overall survival according to ECOG
Nearly 40 % had an intrahepatic tumor, and two-thirds were metastatic at diagnosis. The median number of chemotherapy cycles was four (range 1–9), and the most common grade 3–4 treatment-related toxicity was hematologic (N =28; 37.8 %). During treatment, 30 (41.7 %) patients were hospitalized, with 5 (7 %) due to chemotherapy-induced adverse events. Additionally, 18 (25 %) patients had chemotherapy discontinued due to toxicities (Table 2). Nearly one-third of patients (27.7 %) received second-line treatment, mostly with fluoropyrimidines. The median overall survival of our cohort was 9.5 months (range 0.3–35.3 months). Survival estimates according to ECOG status showed a median survival of 13.5 months among ECOG 0-1 patients, while the median survival for ECOG 2-3 patients was 3.5 months (Fig. 1). Multivariable Cox regression analysis for overall survival identified ECOG 2-3 and presence of major comorbidities as independent variables associated shorter survival (Table 3). Patients with an ECOG 2/3 had an 8.4 times higher risk of death (confidence interval [CI] 95 % adjusted HR 3.4 to 20.7; p 1 was associated with a 9.5 increased risk of death (CI 95 % adjusted HR 1.6 to 55.3; p = 0.012) in comparison to patients with lower score. There was a trend for worse survival among patients who did not have a
J Gastrointest Canc (2014) 45:80–86
83
Table 3 Cox regression multivariate analysis for survival
Table 4 Patients tested for ERCC1
Variables
p
Hazard ratio (CI 95 %)
Number of Intensity Extension Score Origin of patients ERCC1 tumor tissue
ECOG 2/3 vs 0/1 Charlson index (>1 vs 0/1) Biliary drainage (no vs yes) Tumor location (other vs gallbladder) Treatment interruption (no vs yes) CA 19.9 (continuous variable) Metastatic vs locally advanced
p 2 and who are not candidates for further chemotherapy had a dismal prognosis and should probably not be offered percutaneous transhepatic biliary drainage, mainly because these patients suffer more hospitalization rates and complications related to the procedure [20]. In pancreatic tumors, baseline CA19.9 and its decrease along treatment have shown prognostic importance [21]. Although biliary cancers usually express CA 19.9, the prognostic role of this tumor marker in biliary cancer is still uncertain. Some studies suggest that pretreatment CA 19-9 levels and its decrease after treatment are prognostic; however, other studies have not shown the same [21, 22]. The largest study to evaluate patients with advanced biliary cancer (ABC-02) did not asses the possible prognostic role of this marker [23]. In our population, the baseline CA 19.9 was not an independent variable for worse survival. Nevertheless, the prognostic influence of Ca19-9 might have been compromised because some patients presented cholestasis at the time this marker was tested. Because this was a retrospective analysis, the information on grade 1 or 2 adverse events could have been underestimated. The study was conducted in a single center in Brazil and had a small sample; therefore, the study may have been underpowered to detect differences in response rate or survival according to ERCC1 expression. Nevertheless, given the paucity of data about prognostic and predictive factors in biliary cancer, our study adds relevant information on how to select patients for palliative chemotherapy. In conclusion, we found that in this cohort of unselected patients with advanced biliary tract cancer who were treated with first-line gemcitabine plus cisplatin, IHC expression of ERCC1 was neither predictive nor prognostic, while ECOG 23 and multiple comorbidities were associated with worse prognosis. Based on our results, we suggest that chemotherapy for biliary cancer should be offered to patients in good
85
clinical conditions and with minor comorbid illnesses. We also suggest that patients with ECOG 0-1 should have their biliary tract drained before treatment starts. Prospective collection of data, for example, as part of phase III trials, should be conducted in this patient population with the aim to identify/validate prognostic and predictive markers, as for example, Ca19-9 and ERCC1, to better tailor the treatment of patients with metastatic biliary cancer.
Conflict of Interest The authors declare that they have no conflict of interest.
References 1. Valle JM. Advances in the treatment of metastatic or unresectable biliary tract câncer. Ann Oncol. 2010;21(Supplement 7):vii345–8. 2. Fernandez-Ruiz M, Guerra-Vales JM, Colina-Ruizdelgado F. Comorbidity negatively influences prognosis in patients with extrahepatic cholangiocarcinoma. World J Gastroenterol. 2009;15(42): 5279–86. 3. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. N Engl J Med. 2010;362(14):1273–81. 4. Farhat MH, Shamseddine AI, Tawil AN. Prognostic factors in patients with advanced cholangiocarcinoma: role of surgery, chemotherapy and body mass index. World J Gastroenterol. 2008;14(20): 3224–30. 5. Park I, Lee JL, Ryu MH, et al. Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first-line palliative chemotherapy. Cancer. 2009;115(18):4148–55. 6. Reed E. Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev. 1998;24(5): 331–44. 7. Rosell R, Taron M, Camps C, et al. Influence of genetic markers on survival in non-small cell lung cancer. Drugs Today (Barc). 2003;39(10):775–86. 8. Smith S, Su D. Rigault de la Longrais IA et al. ERCC1 genotype and phenotype in epithelial ovarian cancer identify patients likely to benefit from paclitaxel treatment in addition to platinum-based therapy. J Clin Oncol. 2007;25(33):5172–9. 9. 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. 2002;8(7):2286–91. 10. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83. 11. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. 12. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non–small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006;355(10):983–91. 13. Jun HJ, Ahn MJ, Kim HS, et al. ERCC1 Expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation. Br J Cancer. 2008;99: 167–72. 14. Suzuki E, Furuse J, Ikeda M, et al. Treatment efficacy/safety and prognostic factors in patients with advanced biliary tract cancer
86 receiving gemcitabine monotherapy: an analysis of 100 cases. Oncology. 2010;79(1–2):39–45. 15. Kim KH, Do IG, Kim HS, et al. Excision repair cross-complementation group 1 (ERCC1) expression in advanced urothelial carcinoma patients receiving cisplatin-based chemotherapy. APMIS. 2010;118(12):941–8. doi:10.1111/j.1600-0463.2010.02648.x. Epub 2010 Oct 25. 16. 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. 1998;16(1):309–16. 17. Britten RA, Liu D, Tessier A, et al. ERCC1 Expression as a molecular marker of cisplatin resistance in human cervical tumor cells. Int J Cancer. 2000;89(5):453–7. 18. 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. 2001;19(23):4298–304.
J Gastrointest Canc (2014) 45:80–86 19. Rosell R, Taron M, Ariza A, et al. Molecular predictors of response to chemotherapy in lung cancer. Semin Oncol. 2004;31(1 Suppl 1):20–7. 20. Crosara Teixeira M, Mak MP, Marques DF, et al. Percutaneous Transhepatic Biliary Drainage in Patients with Advanced Solid Malignancies: Prognostic Factors and Clinical Outcomes. J Gastrointest Canc. 2013; 1-6. 21. Harder J, Kummer O, Olschewski M, et al. Prognostic relevance of carbohydrate antigen 19-9 levels in patients with advanced biliary tract cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:2097–100. 22. Sasaki T, Isayama H, Nakai Y, et al. Prognostic factors in patients with advanced biliary tract cancer receiving chemotherapy. Cancer Chemother Pharmacol. 2011;67:847–53. 23. Copur MS, Obermiller A. Brief commentary: largest randomized trial of biliary tract cancer treatment with cisplatin plus gemcitabine versus gemcitabine alone: an excellent opportunity to evaluate the prognostic value of tumor marker CA 19-9. Clin Colorectal Cancer. 2011;10(1):70–1.
ORIGINAL RESEARCH
ERCC1 in Advanced Biliary Tract Cancer Patients Treated with Chemotherapy: Prognostic and Predictive Roles Vanessa da Costa Miranda & Maria Ignez Braghiroli & Luiza Dib Batista Bugiato Faria & Sheila Aparecida Coelho Siqueira & Jorge Sabbaga & Paulo M. Hoff & Rachel P. Riechelmann
Published online: 11 December 2013 # Springer Science+Business Media New York 2013
Abstract Background In oncology, we tend to look for factors that reflect better prognosis or predict response to treatments in order to make a selection from which patients will derive the benefit, avoiding futile therapies and/or toxicities. Definitive prognostic and predictive factors in advanced biliary cancer remain unknown. Methods We retrospectively analyzed all consecutive patients in our institution with advanced biliary tract cancer treated with palliative cisplatin plus gemcitabine. We evaluated the prognostic and predictive role of the immunohistochemistry (IHC) expression of ERCC1 (excision cross-complementing gene-1) on tumor response and also examined several clinical and laboratory prognostic factors for overall survival. Results From January 2009 to July 2011, 72 patients were identified; their median overall survival was 9.5 months. Independent variables associated with shorter survival identified by the multivariable Cox regression analysis were ECOG 2-3 (HR 8.4; 95 % CI 3.4 to 20.7; p 1 (HR 9.5; 95 % CI 1.6 to 55.3; p =0.012). Electronic supplementary material The online version of this article (doi:10.1007/s12029-013-9568-5) contains supplementary material, which is available to authorized users. V. da Costa Miranda : M. I. Braghiroli : L. D. B. B. Faria : J. Sabbaga : P. M. Hoff : R. P. Riechelmann (*) Disciplina de Radiologia e Oncologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Arnaldo 251,12o andar, São Paulo, SP 01246-000, Brazil e-mail: [email protected] J. Sabbaga : P. M. Hoff Centro de Oncologia, Hospital Sírio Libanês, São Paulo, Brazil S. A. C. Siqueira Disciplina de Patologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Pathology slides were available from 44 patients: 23 (52 %) stained positive for ERCC1 on IHC (score ≥0.5). In this subgroup, expression of ERCC-1 was not prognostic and was not associated with either clinical benefit (partial response and stable disease) or tumor response (partial response only) to chemotherapy. Conclusions In this cohort of unselected patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin, IHC expression of ERCC1 was not either predictive or prognostic. Patients with ECOG 2-3 and/or multiple comorbidities had worse survival Keywords ERCC-1 protein . biliary duct neoplasms . cisplatin and gemcitabine
Introduction Biliary tract tumors (BTCs) are rare, representing 3 % of all gastrointestinal tumors, but incidence has progressively increased over the past years [1, 2]. Unfortunately, most patients are diagnosed with advanced stage disease, and only a few are considered candidates for curative surgery [1]. In advanced disease, combination therapy based on 5-fluorouracil or gemcitabine (associated with oxaliplatin or cisplatin) resulted in increased progression-free survival in several phase II trials [1]. The landmark ABC-02 trial established gemcitabine plus cisplatin as the standard first-line treatment for biliary tract cancer. The authors showed an absolute gain of 4 months in overall survival for those treated with the combination regimen when compared to gemcitabine alone [3]. Based on this study, most cancer centers have adopted this regimen as the standard first-line treatment for the majority of metastatic/ locally advanced biliary tract cancer. Taylor of therapeutic management as to avoid futile therapies and/or toxicities requires the identification of prognostic
J Gastrointest Canc (2014) 45:80–86
and/or predictive factors. Some retrospective analyses have suggested that bilirubin level >10 mg/dL, intrahepatic cholangiocellular carcinoma, poor Eastern Cooperative Oncology Group (ECOG) performance status, and elevated alkaline phosphatase level are independent predictors of poor prognosis [4, 5]. However, prognostic and predictive factors in biliary cancer also remain unknown. DNA repair is an extremely complex process, and many of these processes may be altered in various types of tumors. For platinum compounds, in vitro data clearly show that nucleotide excision repair (NER) pathway is the DNA repair pathway responsible for the repair of cisplatin-DNA damage [6]. The mechanism of action of cisplatin is through formation of bulky intrastrand platinum–DNA adducts; the removal of these adducts from genomic DNA is mediated by the NER pathway [6]. High ERCC1 expression has been associated with resistance to platinum-containing therapy lung, ovarian, and colorectal cancers [7–9]. However, ERCC1 expression has not been investigated in BTCs. In this study, we have retrospectively evaluated the prognostic and predictive role of immunohistochemistry (IHC) expression of ERCC1 (excision cross-complementing gene-1) on the response to chemotherapy with cisplatin plus gemcitabine. We also have looked at several clinical and laboratory prognostic factors that could influence overall survival in patients with metastatic biliary tract cancer.
81
was graded on a scale of 0 to 3 (with a higher number indicating a higher intensity). The extension of positive tumor nuclei was calculated for each specimen and scored as assigned (0 if 0 %, 0.1 if 1 % to 9 %, 0.5 if 10 % to 49 %, and 1.0 if 50 % or more). This score was multiplied by the staining intensity of nuclei to obtain a final semiquantitative H score. The median value of all H scores was chosen a priori as the cutoff point for separating ERCC1-positive tumors from ERCC1-negative tumors [12, 13]. We used summary statistics to describe patient characteristics. Survival time was defined from the date of first visit to the date of death, and overall survival was displayed as a Kaplan– Meier curve. The predictive value of ERCC1 expression and tumor response was calculated by the Chi-square test, utilizing the median as the cut off value. We also evaluated the predictive value of ERCC1 as a continuous variable using univariate logistic regression. For the prognostic evaluation, we performed a multivariable COX regression analysis for overall survival, using all the clinical and laboratory parameters described above as well as the ERCC-1 expression as a continuous variable. A multivariable analysis for predictive factors of response was not performed because of the small number of patients whose tumor tissue was available (N =44). A twotailed p value1 Tumor location Intraheptic Extrahepatic Gallbladder Clinical stage Locally advanced Metastatic Charlson index 0/1 >1 Drainage before chemotherapy Yes No
60 years (30–80) 45 (62.5 %) 27 (37.5 %) 84.7 (0.1–50,000) 0.32 (0.07–25.2) 50 (69.4.3 %) 22 (37.5 %) 30 (41.7 %) 19 (26.4 %) 23 (31.9 %) 25 (34.7 %) 47 (63.3 %) 65 (90.3 %) 7 (9.7 %) 32 (44.4 %) 40 (55.6 %)
82
J Gastrointest Canc (2014) 45:80–86
Table 2 Information on treatment Median chemotherapy cycles
4 (1–9)
G3-G4 toxicities Neutropenia Thrombocytopenia Anemia Nausea and vomiting Hospitalization during treatment (any cause) Hospitalization due to toxicity Treatment discontinuation Second-line treatment 5 FU+Leucovorin Carboplatin and gemcitabine
12 (16.6 %) 9 (11.5 %) 7 (9.7 %) 6 (8.3 %) 30 (41.7 %) 5 (7 %) 18 (25 %) 20 (27.7 %) 19 1
Results Clinical/Laboratorial Data and Survival Analysis From January 2009 to July 2011, 72 patients were identified and their characteristics are summarized in Table 1. The median baseline CA 19.9 was 84.7 ng/mL, 42 (62.5 %) were women and 69.4 % of patients had an ECOG status of 0 or 1. Fig. 1 Patients overall survival according to ECOG
Nearly 40 % had an intrahepatic tumor, and two-thirds were metastatic at diagnosis. The median number of chemotherapy cycles was four (range 1–9), and the most common grade 3–4 treatment-related toxicity was hematologic (N =28; 37.8 %). During treatment, 30 (41.7 %) patients were hospitalized, with 5 (7 %) due to chemotherapy-induced adverse events. Additionally, 18 (25 %) patients had chemotherapy discontinued due to toxicities (Table 2). Nearly one-third of patients (27.7 %) received second-line treatment, mostly with fluoropyrimidines. The median overall survival of our cohort was 9.5 months (range 0.3–35.3 months). Survival estimates according to ECOG status showed a median survival of 13.5 months among ECOG 0-1 patients, while the median survival for ECOG 2-3 patients was 3.5 months (Fig. 1). Multivariable Cox regression analysis for overall survival identified ECOG 2-3 and presence of major comorbidities as independent variables associated shorter survival (Table 3). Patients with an ECOG 2/3 had an 8.4 times higher risk of death (confidence interval [CI] 95 % adjusted HR 3.4 to 20.7; p 1 was associated with a 9.5 increased risk of death (CI 95 % adjusted HR 1.6 to 55.3; p = 0.012) in comparison to patients with lower score. There was a trend for worse survival among patients who did not have a
J Gastrointest Canc (2014) 45:80–86
83
Table 3 Cox regression multivariate analysis for survival
Table 4 Patients tested for ERCC1
Variables
p
Hazard ratio (CI 95 %)
Number of Intensity Extension Score Origin of patients ERCC1 tumor tissue
ECOG 2/3 vs 0/1 Charlson index (>1 vs 0/1) Biliary drainage (no vs yes) Tumor location (other vs gallbladder) Treatment interruption (no vs yes) CA 19.9 (continuous variable) Metastatic vs locally advanced
p 2 and who are not candidates for further chemotherapy had a dismal prognosis and should probably not be offered percutaneous transhepatic biliary drainage, mainly because these patients suffer more hospitalization rates and complications related to the procedure [20]. In pancreatic tumors, baseline CA19.9 and its decrease along treatment have shown prognostic importance [21]. Although biliary cancers usually express CA 19.9, the prognostic role of this tumor marker in biliary cancer is still uncertain. Some studies suggest that pretreatment CA 19-9 levels and its decrease after treatment are prognostic; however, other studies have not shown the same [21, 22]. The largest study to evaluate patients with advanced biliary cancer (ABC-02) did not asses the possible prognostic role of this marker [23]. In our population, the baseline CA 19.9 was not an independent variable for worse survival. Nevertheless, the prognostic influence of Ca19-9 might have been compromised because some patients presented cholestasis at the time this marker was tested. Because this was a retrospective analysis, the information on grade 1 or 2 adverse events could have been underestimated. The study was conducted in a single center in Brazil and had a small sample; therefore, the study may have been underpowered to detect differences in response rate or survival according to ERCC1 expression. Nevertheless, given the paucity of data about prognostic and predictive factors in biliary cancer, our study adds relevant information on how to select patients for palliative chemotherapy. In conclusion, we found that in this cohort of unselected patients with advanced biliary tract cancer who were treated with first-line gemcitabine plus cisplatin, IHC expression of ERCC1 was neither predictive nor prognostic, while ECOG 23 and multiple comorbidities were associated with worse prognosis. Based on our results, we suggest that chemotherapy for biliary cancer should be offered to patients in good
85
clinical conditions and with minor comorbid illnesses. We also suggest that patients with ECOG 0-1 should have their biliary tract drained before treatment starts. Prospective collection of data, for example, as part of phase III trials, should be conducted in this patient population with the aim to identify/validate prognostic and predictive markers, as for example, Ca19-9 and ERCC1, to better tailor the treatment of patients with metastatic biliary cancer.
Conflict of Interest The authors declare that they have no conflict of interest.
References 1. Valle JM. Advances in the treatment of metastatic or unresectable biliary tract câncer. Ann Oncol. 2010;21(Supplement 7):vii345–8. 2. Fernandez-Ruiz M, Guerra-Vales JM, Colina-Ruizdelgado F. Comorbidity negatively influences prognosis in patients with extrahepatic cholangiocarcinoma. World J Gastroenterol. 2009;15(42): 5279–86. 3. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. N Engl J Med. 2010;362(14):1273–81. 4. Farhat MH, Shamseddine AI, Tawil AN. Prognostic factors in patients with advanced cholangiocarcinoma: role of surgery, chemotherapy and body mass index. World J Gastroenterol. 2008;14(20): 3224–30. 5. Park I, Lee JL, Ryu MH, et al. Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first-line palliative chemotherapy. Cancer. 2009;115(18):4148–55. 6. Reed E. Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev. 1998;24(5): 331–44. 7. Rosell R, Taron M, Camps C, et al. Influence of genetic markers on survival in non-small cell lung cancer. Drugs Today (Barc). 2003;39(10):775–86. 8. Smith S, Su D. Rigault de la Longrais IA et al. ERCC1 genotype and phenotype in epithelial ovarian cancer identify patients likely to benefit from paclitaxel treatment in addition to platinum-based therapy. J Clin Oncol. 2007;25(33):5172–9. 9. 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. 2002;8(7):2286–91. 10. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83. 11. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. 12. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non–small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006;355(10):983–91. 13. Jun HJ, Ahn MJ, Kim HS, et al. ERCC1 Expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation. Br J Cancer. 2008;99: 167–72. 14. Suzuki E, Furuse J, Ikeda M, et al. Treatment efficacy/safety and prognostic factors in patients with advanced biliary tract cancer
86 receiving gemcitabine monotherapy: an analysis of 100 cases. Oncology. 2010;79(1–2):39–45. 15. Kim KH, Do IG, Kim HS, et al. Excision repair cross-complementation group 1 (ERCC1) expression in advanced urothelial carcinoma patients receiving cisplatin-based chemotherapy. APMIS. 2010;118(12):941–8. doi:10.1111/j.1600-0463.2010.02648.x. Epub 2010 Oct 25. 16. 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. 1998;16(1):309–16. 17. Britten RA, Liu D, Tessier A, et al. ERCC1 Expression as a molecular marker of cisplatin resistance in human cervical tumor cells. Int J Cancer. 2000;89(5):453–7. 18. 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. 2001;19(23):4298–304.
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