There are few large series or randomised controlled trials14
comparing survival following surgical treatment with modern palliative therapies, including chemotherapy and photodynamic therapy, in patients with BTC. In this study, we describe the management of a large cohort of consecutive, non-selected patients with BTC referred to a tertiary referral centre. Palliative photodynamic therapy in BTC patients appeared to result in a survival outcome similar to curatively intended surgery but positive (R1/R2) resection margins.
A particular strength of the present study is that the diagnosis of BTC was confirmed by positive histology or cytology in 90% of cases, so that we are confident that the cohort did not include a significant number of patients with benign disease. Cytological or histological confirmation of malignancy in BTC is difficult, due in part to the small volume and desmoplastic nature of tumours, and this is reflected in recent series from the UK9,15
, and Germany10
, in which at most 50–70% of patients had pathological confirmation of malignancy. Recent reports suggest that up to 17% of patients undergoing surgery with curative intent for cholangiocarcinoma have benign disease, and that almost half of the benign cases have features of an autoimmune cholangiopathy, possibly IgG4-associate17
, emphasising the need for accurate diagnosis.
Surgery was performed on 32% of patients, 88% of whom underwent resections with curative intent, and 38% of this latter group had negative (R0) resection margins (11% of the total). Previous studies have reported R0 resection rates of 32–39% (13–28% of total patients with cholangiocarcinoma)3,8,10
with 46–56% R0 rates in highly selected, exclusively surgical cohorts11,18
. Consistent with our own data, several studies have shown that achieving an R0 resection improves survival in comparison to R1 or R2 resection3,19, 20, 21
; which may be explained in part by earlier diagnosis (with less advanced disease for R0 resections) and lead-time bias. The importance of achieving an R0 resection has resulted in concomitant liver resection becoming the standard of care 22
and protocols being developed to treat cholangiocarcinoma with liver transplantation23
. In patients who underwent surgery with curative intent, R0 resection was the only independent predictor of improved survival, although well differentiated tumours24
and negative lymph node status11
have also been identified by other groups as predicting a better outcome.
A survival advantage of palliative resection (R1/R2) over biliary stenting alone has been reported in some studies10,19,20,21,25
, including our own, and challenged in others3,26,27
. Comparisons of treatments tend to be hampered by dissimilar patient groups, with ‘biliary stenting only’ being usually reserved for patients with more advanced disease and poorer performance status, a finding also seen in our study. However, an important finding of our study was that survival for patients with curatively intended surgery but positive resection margins did not differ from those who had PDT. PDT is an emerging treatment for cholangiocarcinoma28
, which in combination with plastic biliary stenting has been shown in two small randomised studies to improve survival over stent placement alone29,30
. The issue of whether this treatment improves survival in patients who have already had successful biliary stenting needs further study31
and is being investigated by our group in a multi-centre randomised trial of PDT plus stenting vs. stenting alone (Photostent 2, ClinicalTrials.gov number, NCT00513539), which is currently recruiting patients. A recent analysis of a German cohort of 184 patients with hilar cholangiocarcinoma has also demonstrated no significant difference in median survival between R1/R2 resection (n=18; 12.2 months) and palliative PDT plus stenting (n=68; 12.0 months)10
. As attempted surgical resection is associated with high morbidity and mortality rates of up to 10%32
, palliative PDT may be a good alternative for patients at high risk of non-curative resections. In order to select such patients for PDT, improvements in the accuracy of current preoperative staging are needed33
; for example MRI/MRCP can under-stage the disease in up to 20% of cases34
. Positron-emission tomography (PET, incl. PET-CT) has been shown to be highly sensitive for detecting metastatic deposits35
, but has relatively low specificity. Whether new diagnostic tools like intraductal cholangioscopy will improve diagnostic accuracy remains to be established.
Endoscopic stenting alone relieved malignant biliary obstruction in 48% of patients in our study. The published range of effective endoscopic biliary drainage in BTC is very wide (21–97%)9,15,16,36,37
, depending on stricture location, endoprothesis used and different definitions of success (e.g. technical endoprosthesis insertion rate vs. successful drainage rate38
). Self-expanding metal stents, which have a larger internal diameter than plastic stents, were used in almost half of our patients. There is little consensus, however, as to the optimum approach (endoscopic vs. percutaneous), stent type (metal vs. plastic) or stent number (unilateral vs. bilateral) that should be initially used to palliate patients with hilar cholangiocarcinoma39
, due in part to the lack of high quality randomised data in this area.
Since the cause of death in BTC after successful stenting is commonly due to recurrent biliary obstruction and intra-biliary sepsis, a key aim of palliative therapy is that of control of locally progressive disease. Thirty percent of our patients received chemotherapy and/or radiotherapy. Oncological opinion supports the use of palliative chemotherapy, but until recently there has been no agreement on regimen or proven survival benefit over biliary drainage alone14
. However, a recent meta-analysis of 104 trials involving 2810 patients reported a beneficial effect of chemotherapy with a pooled (complete and partial) response rate of 23%, particularly when using gemcitabine and platinum-based regimens40
. Furthermore, results of the UK phase III ABC-02 trial of gemcitabine, alone or in combination with cisplatin in 410 patients with locally advanced or metastatic BTC, reported a median survival of 11.7 vs. 8.2 months (log rank p=0.002) with gemcitabine and cisplatin over gemcitabine alone, This is the largest ever study in advanced biliary tract cancer and demonstrated a clear advantage for gemcitabine and cisplatin without added clinically significant toxicity, setting a new international standard of care13
In conclusion, biliary tract cancer survival increases with successful R0 resection. PDT appears to be a promising palliative measure for non-R0 resectable disease, but needs further evaluation in conjunction with chemotherapy agents and targeted therapies in phase II/III trials. The concept of neo-adjuvant therapies to achieve higher rates of clear resection margins appears worthy of further study, although improvements in preoperative staging of BTC are also needed.