Response:

Abstract

We thank Tyberg et al for their interest in our recent article1Strand D.S. Cosgrove N.D. Patrie J.T. et al.ERCP-directed radiofrequency ablation and photodynamic therapy are associated with comparable survival in the treatment of unresectable cholangiocarcinoma.Gastrointest Endosc. 2014; 80: 794-804Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar and for their comments. We are also grateful to Drs Reddy and Ramchandani for their insightful editorial that accompanies our publication.2Reddy D.N. Ramchandani M. Endoscopic palliation of advanced cholangiocarcinoma: can we go beyond stenting?.Gastrointest Endosc. 2014; 80: 805-806Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar We support the notion that additional work is required to determine the optimal endoscopic management strategy for unresectable cholangiocarcinoma (CCA), and we appreciate this opportunity to expand on the concerns and areas of interest regarding our study.As noted in the editorial2Reddy D.N. Ramchandani M. Endoscopic palliation of advanced cholangiocarcinoma: can we go beyond stenting?.Gastrointest Endosc. 2014; 80: 805-806Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar and letter to the editor, our study was limited by its retrospective design and relatively small sample size. We acknowledged these issues in the Discussion section of our article, and we also emphasized that “retrospective studies are most valuable for hypothesis generation.”1Strand D.S. Cosgrove N.D. Patrie J.T. et al.ERCP-directed radiofrequency ablation and photodynamic therapy are associated with comparable survival in the treatment of unresectable cholangiocarcinoma.Gastrointest Endosc. 2014; 80: 794-804Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Although our study does not definitively answer whether ERCP-directed photodynamic therapy (PDT) is superior to (or even non-inferior to) radiofrequency ablation (RFA), it is the first direct comparison of these 2 modes of endobiliary ablation, which are intended to provide local control in patients with incurable CCA. Until now, biliary endoscopists and referral centers attempting to select between these modalities were essentially doing so on the basis of their own experiences, safety data, or studies that did not directly compare PDT with RFA.3Steel A.W. Postgate A.J. Khorsandi S. et al.Endoscopically applied radiofrequency ablation appears to be safe in the treatment of malignant biliary obstruction.Gastrointest Endosc. 2011; 73: 149-153Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 4Ortner M.E. Caca K. Berr F. et al.Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study.Gastroenterology. 2003; 125: 1355-1363Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 5Kahaleh M. Mishra R. Shami V.M. et al.Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy.Clin Gastroenterol Hepatol. 2008; 6: 290-297Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Because there are no published prospective studies in 2015 that compare ERCP-directed PDT with RFA, our data are valuable because they show comparable survival after either therapy in patients with incurable disease.Our colleagues’ concern about the statistically significant predominance of perihilar CCA in patients in our PDT group as compared with the RFA group is well taken because perihilar and nonperihilar tumors are associated with differing rates of expected survival.6Park J. Kim M.H. Kim K.P. et al.Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study.Gut Liver. 2009; 3: 298-305Crossref PubMed Scopus (132) Google Scholar, 7Nakeeb A. Pitt H.A. Sohn T.A. et al.Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors.Ann Surg. 1996; 224 (discussion 73-5): 463-473Crossref PubMed Scopus (1008) Google Scholar We included 1 patient with unresectable intrahepatic CCA and 2 patients with unresectable distal (extrahepatic duct) tumors in the RFA arm. However, as stated in our article, when we performed an additional survival analysis after excluding these 3 patients with nonperihilar malignancies in the RFA arm, the results did not differ from those found when the entire cohort was analyzed.1Strand D.S. Cosgrove N.D. Patrie J.T. et al.ERCP-directed radiofrequency ablation and photodynamic therapy are associated with comparable survival in the treatment of unresectable cholangiocarcinoma.Gastrointest Endosc. 2014; 80: 794-804Abstract Full Text Full Text PDF PubMed Scopus (78) Google ScholarWe concede that there were differences in other treatment factors for patients in each study arm with respect to types of stents used and other secondary outcome measures, such as rates of stent occlusion and cholangitis. However, the frequency of patients who received chemotherapy and radiation treatment was not statistically different between groups. The notable absence of a control arm that underwent endobiliary stenting alone is a criticism of our study that we readily acknowledge and did consider at the time of study design. Our reasons for the lack of a control group are described in detail within our study’s Discussion section. In our experience, most patients with inoperable, nontransplantable CCA and fair-to-good functional status elect to undergo ablative therapy with either palliative RFA or PDT. In our center, patients who receive biliary stenting alone often have poor functional status and very limited expected survival because of very advanced disease or other comorbidities. Furthermore, because our center has been providing ERCP-directed ablative therapy for many years, we had a concern that any group of stent-only control patients that we might identify would come from too remote a time period or would be too unintentionally biased to provide a good comparison.There are many remaining questions regarding the optimal endoscopic care of patients with CCA. The editorialists bring up the interesting role of the immune response provoked by endoscopic ablative therapy, which we think is an area that prompts further investigation. We hope that the publication of our study increases the awareness of different endoscopic treatment options for patients with CCA and that some of these important issues will be addressed in a multicenter, prospective fashion.Given the many years of data that support PDT and the growing body of evidence about the efficacy of RFA in the treatment of unresectable CCA, a valid question in conducting a prospective study comparing these modalities would be whether or not it would be ethical to include a control arm that would receive only palliative stenting. We believe our editorialists have answered this question with their statement, “Until we have this evidence, the standard of care for palliating patients with advanced CCA would be endoscopic or percutaneous stenting.” Given the suboptimal efficacy of chemoradiation for CCA, the aforementioned PDT and RFA data, and the fact that most insurers including Medicare will cover palliative ERCP-directed PDT or RFA, we respectfully submit that the standard of care is evolving and is probably more than just biliary stenting alone. However, we are all likely to agree that further studies are required to definitively answer what the new standard of care should be. We thank Tyberg et al for their interest in our recent article1Strand D.S. Cosgrove N.D. Patrie J.T. et al.ERCP-directed radiofrequency ablation and photodynamic therapy are associated with comparable survival in the treatment of unresectable cholangiocarcinoma.Gastrointest Endosc. 2014; 80: 794-804Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar and for their comments. We are also grateful to Drs Reddy and Ramchandani for their insightful editorial that accompanies our publication.2Reddy D.N. Ramchandani M. Endoscopic palliation of advanced cholangiocarcinoma: can we go beyond stenting?.Gastrointest Endosc. 2014; 80: 805-806Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar We support the notion that additional work is required to determine the optimal endoscopic management strategy for unresectable cholangiocarcinoma (CCA), and we appreciate this opportunity to expand on the concerns and areas of interest regarding our study. As noted in the editorial2Reddy D.N. Ramchandani M. Endoscopic palliation of advanced cholangiocarcinoma: can we go beyond stenting?.Gastrointest Endosc. 2014; 80: 805-806Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar and letter to the editor, our study was limited by its retrospective design and relatively small sample size. We acknowledged these issues in the Discussion section of our article, and we also emphasized that “retrospective studies are most valuable for hypothesis generation.”1Strand D.S. Cosgrove N.D. Patrie J.T. et al.ERCP-directed radiofrequency ablation and photodynamic therapy are associated with comparable survival in the treatment of unresectable cholangiocarcinoma.Gastrointest Endosc. 2014; 80: 794-804Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Although our study does not definitively answer whether ERCP-directed photodynamic therapy (PDT) is superior to (or even non-inferior to) radiofrequency ablation (RFA), it is the first direct comparison of these 2 modes of endobiliary ablation, which are intended to provide local control in patients with incurable CCA. Until now, biliary endoscopists and referral centers attempting to select between these modalities were essentially doing so on the basis of their own experiences, safety data, or studies that did not directly compare PDT with RFA.3Steel A.W. Postgate A.J. Khorsandi S. et al.Endoscopically applied radiofrequency ablation appears to be safe in the treatment of malignant biliary obstruction.Gastrointest Endosc. 2011; 73: 149-153Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 4Ortner M.E. Caca K. Berr F. et al.Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study.Gastroenterology. 2003; 125: 1355-1363Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 5Kahaleh M. Mishra R. Shami V.M. et al.Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy.Clin Gastroenterol Hepatol. 2008; 6: 290-297Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Because there are no published prospective studies in 2015 that compare ERCP-directed PDT with RFA, our data are valuable because they show comparable survival after either therapy in patients with incurable disease. Our colleagues’ concern about the statistically significant predominance of perihilar CCA in patients in our PDT group as compared with the RFA group is well taken because perihilar and nonperihilar tumors are associated with differing rates of expected survival.6Park J. Kim M.H. Kim K.P. et al.Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study.Gut Liver. 2009; 3: 298-305Crossref PubMed Scopus (132) Google Scholar, 7Nakeeb A. Pitt H.A. Sohn T.A. et al.Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors.Ann Surg. 1996; 224 (discussion 73-5): 463-473Crossref PubMed Scopus (1008) Google Scholar We included 1 patient with unresectable intrahepatic CCA and 2 patients with unresectable distal (extrahepatic duct) tumors in the RFA arm. However, as stated in our article, when we performed an additional survival analysis after excluding these 3 patients with nonperihilar malignancies in the RFA arm, the results did not differ from those found when the entire cohort was analyzed.1Strand D.S. Cosgrove N.D. Patrie J.T. et al.ERCP-directed radiofrequency ablation and photodynamic therapy are associated with comparable survival in the treatment of unresectable cholangiocarcinoma.Gastrointest Endosc. 2014; 80: 794-804Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar We concede that there were differences in other treatment factors for patients in each study arm with respect to types of stents used and other secondary outcome measures, such as rates of stent occlusion and cholangitis. However, the frequency of patients who received chemotherapy and radiation treatment was not statistically different between groups. The notable absence of a control arm that underwent endobiliary stenting alone is a criticism of our study that we readily acknowledge and did consider at the time of study design. Our reasons for the lack of a control group are described in detail within our study’s Discussion section. In our experience, most patients with inoperable, nontransplantable CCA and fair-to-good functional status elect to undergo ablative therapy with either palliative RFA or PDT. In our center, patients who receive biliary stenting alone often have poor functional status and very limited expected survival because of very advanced disease or other comorbidities. Furthermore, because our center has been providing ERCP-directed ablative therapy for many years, we had a concern that any group of stent-only control patients that we might identify would come from too remote a time period or would be too unintentionally biased to provide a good comparison. There are many remaining questions regarding the optimal endoscopic care of patients with CCA. The editorialists bring up the interesting role of the immune response provoked by endoscopic ablative therapy, which we think is an area that prompts further investigation. We hope that the publication of our study increases the awareness of different endoscopic treatment options for patients with CCA and that some of these important issues will be addressed in a multicenter, prospective fashion. Given the many years of data that support PDT and the growing body of evidence about the efficacy of RFA in the treatment of unresectable CCA, a valid question in conducting a prospective study comparing these modalities would be whether or not it would be ethical to include a control arm that would receive only palliative stenting. We believe our editorialists have answered this question with their statement, “Until we have this evidence, the standard of care for palliating patients with advanced CCA would be endoscopic or percutaneous stenting.” Given the suboptimal efficacy of chemoradiation for CCA, the aforementioned PDT and RFA data, and the fact that most insurers including Medicare will cover palliative ERCP-directed PDT or RFA, we respectfully submit that the standard of care is evolving and is probably more than just biliary stenting alone. However, we are all likely to agree that further studies are required to definitively answer what the new standard of care should be. Endoscopic palliation of advanced cholangiocarcinoma: A need for a real trial!Gastrointestinal EndoscopyVol. 81Issue 4PreviewWe read with interest the study by Strand et al1 comparing endoscopic radiofrequency ablation (RFA) and endoscopic photodynamic therapy (PDT), 2 independently validated treatment options for patients with unresectable cholangiocarcinoma (CCA).2,3 Full-Text PDF