J Gastrointest Canc (2014) 45:109–112 DOI 10.1007/s12029-013-9571-x
BRIEF COMMUNICATION
Modified GTX as Second-Line Therapy for Advanced Pancreatic Adenocarcinoma Hana Ajouz & Deborah Mukherji & Ali Haydar & Ahmad Sharif Yakan & Ahmad Saleh & Elias Elias & Sally Temraz & Walid Faraj & Mohammad Khalife & Ali Shamseddine
Published online: 24 December 2013 # Springer Science+Business Media New York 2013
Abstract Background Advanced pancreatic cancer remains a lethal disease with no standard treatment beyond first-line palliative chemotherapy. Gemcitabine, docetaxel, and capecitabine (GTX) is a regimen that has come into use for advanced pancreatic cancer despite a paucity of randomized data. Methods We have used a modified schedule of this regimen in the second-line setting aimed at biomodulating the activity of capecitabine by both docetaxel and gemcitabine. This report describes our experience with the use of modified GTX in nine patients with advanced pancreatic cancer as second-line chemotherapy. Conclusion In our series, the median overall survival was 8 months (range 5.2–10.8). Prospective studies of this regimen in the second-line setting are warranted.
H. Ajouz : D. Mukherji (*) : A. S. Yakan : A. Saleh : S. Temraz : A. Shamseddine (*) Division of Hematology and Oncology, American University of Beirut Medical Center, Beirut, Lebanon e-mail: [email protected] e-mail: [email protected] H. Ajouz e-mail: [email protected]
Keywords Pancreatic adenocarcinoma . Second-line chemotherapy . GTX
Introduction Advanced pancreatic cancer has a poor prognosis and remains the fourth leading cause of cancer-related death in the USA [1]. Single-agent gemcitabine chemotherapy has been the reference regimen for advanced pancreatic cancer since 1997 with a median survival of approximately 6 months [2]. More recently, the combination of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been associated with a survival advantage over gemcitabine in a randomized phase III
A. Haydar Division of Radiology, American University of Beirut Medical Center, Beirut, Lebanon e-mail: [email protected] E. Elias : W. Faraj : M. Khalife Division of General Surgery, American University of Beirut Medical Center, Beirut, Lebanon
A. S. Yakan e-mail: [email protected]
E. Elias e-mail: [email protected]
A. Saleh e-mail: [email protected]
W. Faraj e-mail: [email protected]
S. Temraz e-mail: [email protected]
M. Khalife e-mail: [email protected]
110
trial with a median overall survival of 11.1 months in the FOLFIRINOX group compared to 6.8 months in the gemcitabine group (hazard ratio (HR) for death 0.57; 95 % confidence interval (CI) 0.45–0.73; p8 fold which increased intracellular gemcitabine accumulation by 220 %. GTX was also found to specifically inhibit Mitogen activated kinase (MEK) to extracellular signal-related kinase (ERK) phase II study of GTX as first-line treatment for advanced pancreatic adenocarcinoma, tumor p-MEK expression by immunohistochemistry (IHC) appeared to be predictive of response. High p-MEK (3– 4+) correlated with an 85 % radiological response rate, while low p-MEK correlated with disease progression in 90 % of patients [11]. These data from a small sample of patients are hypothesis generating only but suggest that IHC for p-MEK could serve as a predictive biomarker and should be prospectively evaluated. In summary, GTX appears to be an active three-drug regimen in advanced adenocarcinoma of the pancreas. Prospective studies in the second-line setting incorporating biomarker analysis such as p-MEK status are required.
Survival Analysis Median progression-free survival (mPFS) was 2 months (range 1–4) with median overall survival (mOS) of 8 months (range 5.2–10.8) in this cohort.
Conflict of Interest The authors declare that they have no conflict of interest.
References Discussion To date, there is no standard treatment for patients with advanced pancreatic adenocarcinoma with progressive disease after first-line chemotherapy. The median overall survival of 8 months in our series of patients treated with second-line GTX chemotherapy suggests that the prospective evaluation of this regimen is warranted. There are no prospective studies of GTX in the second-line setting for pancreatic adenocarcinoma. De Jesus-Acosta et al. retrospectively reviewed 154 patients with advanced pancreatic adenocarcinoma who received GTX. For the 75 patients who received GTX as a second- or greater-line chemotherapy, two patients had a radiological partial response according to RECIST, and overall survival in this setting was 5.7 months with 1-year survival of 32 % [9]. Dakik et al. retrospectively evaluated 59 patients who received GTX after a median of two prior lines of treatment. In this cohort, no patients had a radiological response, and overall survival was 22 weeks [10]. Fine et al. have recently presented preclinical and translational data concerning the GTX regimen. In pancreatic cells, GTX administered in a sequence and time-specific manner increased pro-apoptotic Bax, Bak, and Fas while decreasing anti-apoptotic Bcl-1 and Bcl-XL expression. Human equilibrative nucleoside transporter 1 (hENT-1) mediates the
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29. 2. Burris 3rd HA et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6): 2403–13. 3. Conroy T et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25. 4. Von Hoff DD, E.T., Arena FP, Chiorean EG, Infante JR, Moore MJ, Seay TE, Tjulandin S, Ma WW, Saleh MN, Harris M, Reni M, Ramanathan RK, TaberneroJ, Hidalgo M, Van Cutsem E, Goldstein D, Wei X, Iglesias JL, Renschler MF, Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). J Clin Oncol, 2013. 30(suppl 34; abstr LBA148). 5. Fine RL et al. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008;61(1):167–75. 6. Fine RL, M.G., Sheerman W, Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. J Clin Oncol, 2009. 27(Suppl): p. Abstract 4623. 7. Sawada N et al. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res. 1998;4(4):1013–9. 8. Ren Q, Kao V, Grem JL. Cytotoxicity and DNA fragmentation associated with sequential gemcitabine and 5-fluoro-2′-deoxyuridine in HT-29 colon cancer cells. Clin Cancer Res. 1998;4(11):2811–8. 9. De Jesus-Acosta A et al. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012;69(2):415–24.
112 10. Dakik HK et al. The use of GTX as second-line and later chemotherapy for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2012;69(2):425–30.
J Gastrointest Canc (2014) 45:109–112 11. Fine R, et al. Prospective phase II trial of GTX in metastatic pancreatic cancer: laboratory and clinical studies. ASCO GI 2013. Abstract 209
BRIEF COMMUNICATION
Modified GTX as Second-Line Therapy for Advanced Pancreatic Adenocarcinoma Hana Ajouz & Deborah Mukherji & Ali Haydar & Ahmad Sharif Yakan & Ahmad Saleh & Elias Elias & Sally Temraz & Walid Faraj & Mohammad Khalife & Ali Shamseddine
Published online: 24 December 2013 # Springer Science+Business Media New York 2013
Abstract Background Advanced pancreatic cancer remains a lethal disease with no standard treatment beyond first-line palliative chemotherapy. Gemcitabine, docetaxel, and capecitabine (GTX) is a regimen that has come into use for advanced pancreatic cancer despite a paucity of randomized data. Methods We have used a modified schedule of this regimen in the second-line setting aimed at biomodulating the activity of capecitabine by both docetaxel and gemcitabine. This report describes our experience with the use of modified GTX in nine patients with advanced pancreatic cancer as second-line chemotherapy. Conclusion In our series, the median overall survival was 8 months (range 5.2–10.8). Prospective studies of this regimen in the second-line setting are warranted.
H. Ajouz : D. Mukherji (*) : A. S. Yakan : A. Saleh : S. Temraz : A. Shamseddine (*) Division of Hematology and Oncology, American University of Beirut Medical Center, Beirut, Lebanon e-mail: [email protected] e-mail: [email protected] H. Ajouz e-mail: [email protected]
Keywords Pancreatic adenocarcinoma . Second-line chemotherapy . GTX
Introduction Advanced pancreatic cancer has a poor prognosis and remains the fourth leading cause of cancer-related death in the USA [1]. Single-agent gemcitabine chemotherapy has been the reference regimen for advanced pancreatic cancer since 1997 with a median survival of approximately 6 months [2]. More recently, the combination of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been associated with a survival advantage over gemcitabine in a randomized phase III
A. Haydar Division of Radiology, American University of Beirut Medical Center, Beirut, Lebanon e-mail: [email protected] E. Elias : W. Faraj : M. Khalife Division of General Surgery, American University of Beirut Medical Center, Beirut, Lebanon
A. S. Yakan e-mail: [email protected]
E. Elias e-mail: [email protected]
A. Saleh e-mail: [email protected]
W. Faraj e-mail: [email protected]
S. Temraz e-mail: [email protected]
M. Khalife e-mail: [email protected]
110
trial with a median overall survival of 11.1 months in the FOLFIRINOX group compared to 6.8 months in the gemcitabine group (hazard ratio (HR) for death 0.57; 95 % confidence interval (CI) 0.45–0.73; p8 fold which increased intracellular gemcitabine accumulation by 220 %. GTX was also found to specifically inhibit Mitogen activated kinase (MEK) to extracellular signal-related kinase (ERK) phase II study of GTX as first-line treatment for advanced pancreatic adenocarcinoma, tumor p-MEK expression by immunohistochemistry (IHC) appeared to be predictive of response. High p-MEK (3– 4+) correlated with an 85 % radiological response rate, while low p-MEK correlated with disease progression in 90 % of patients [11]. These data from a small sample of patients are hypothesis generating only but suggest that IHC for p-MEK could serve as a predictive biomarker and should be prospectively evaluated. In summary, GTX appears to be an active three-drug regimen in advanced adenocarcinoma of the pancreas. Prospective studies in the second-line setting incorporating biomarker analysis such as p-MEK status are required.
Survival Analysis Median progression-free survival (mPFS) was 2 months (range 1–4) with median overall survival (mOS) of 8 months (range 5.2–10.8) in this cohort.
Conflict of Interest The authors declare that they have no conflict of interest.
References Discussion To date, there is no standard treatment for patients with advanced pancreatic adenocarcinoma with progressive disease after first-line chemotherapy. The median overall survival of 8 months in our series of patients treated with second-line GTX chemotherapy suggests that the prospective evaluation of this regimen is warranted. There are no prospective studies of GTX in the second-line setting for pancreatic adenocarcinoma. De Jesus-Acosta et al. retrospectively reviewed 154 patients with advanced pancreatic adenocarcinoma who received GTX. For the 75 patients who received GTX as a second- or greater-line chemotherapy, two patients had a radiological partial response according to RECIST, and overall survival in this setting was 5.7 months with 1-year survival of 32 % [9]. Dakik et al. retrospectively evaluated 59 patients who received GTX after a median of two prior lines of treatment. In this cohort, no patients had a radiological response, and overall survival was 22 weeks [10]. Fine et al. have recently presented preclinical and translational data concerning the GTX regimen. In pancreatic cells, GTX administered in a sequence and time-specific manner increased pro-apoptotic Bax, Bak, and Fas while decreasing anti-apoptotic Bcl-1 and Bcl-XL expression. Human equilibrative nucleoside transporter 1 (hENT-1) mediates the
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29. 2. Burris 3rd HA et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6): 2403–13. 3. Conroy T et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25. 4. Von Hoff DD, E.T., Arena FP, Chiorean EG, Infante JR, Moore MJ, Seay TE, Tjulandin S, Ma WW, Saleh MN, Harris M, Reni M, Ramanathan RK, TaberneroJ, Hidalgo M, Van Cutsem E, Goldstein D, Wei X, Iglesias JL, Renschler MF, Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). J Clin Oncol, 2013. 30(suppl 34; abstr LBA148). 5. Fine RL et al. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008;61(1):167–75. 6. Fine RL, M.G., Sheerman W, Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. J Clin Oncol, 2009. 27(Suppl): p. Abstract 4623. 7. Sawada N et al. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res. 1998;4(4):1013–9. 8. Ren Q, Kao V, Grem JL. Cytotoxicity and DNA fragmentation associated with sequential gemcitabine and 5-fluoro-2′-deoxyuridine in HT-29 colon cancer cells. Clin Cancer Res. 1998;4(11):2811–8. 9. De Jesus-Acosta A et al. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012;69(2):415–24.
112 10. Dakik HK et al. The use of GTX as second-line and later chemotherapy for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2012;69(2):425–30.
J Gastrointest Canc (2014) 45:109–112 11. Fine R, et al. Prospective phase II trial of GTX in metastatic pancreatic cancer: laboratory and clinical studies. ASCO GI 2013. Abstract 209
