Panelists in the 5th Annual CCA Summit’s second session discussed surgical approaches to biliary tract cancer (BTC). William R. Jarnagin, MD, FACS, Memorial Sloan Kettering Cancer Center, presented on the history of surgical management in patients with BTC.1 In the 1950s, Claude Couinaud defined liver segmental anatomy, which set the stage for the first anatomic liver resection done in the 1950s.2,3 Dr Jarnagin went on to describe the mortality rates from operations done on the liver; early results demonstrated a 13% (82 of 621) total mortality rate from operations, including 25% for trisegmentectomy, 21% for lobectomy, 7% for left lateral segmentectomy, and 6% for wedge resection.4 Mortality rates have improved drastically through the progressive improvement in operative/perioperative management, such as improved surgical technique and anesthetic management using low central venous pressure. Today, hepatic resection for intrahepatic cholangiocarcinoma (CCA) is safe and effective; however, limitations still exist: surgery is limited to patients who have liver-confined disease that is node negative, patients with good genomic profiles do better than patients with poor genetic profiles, and recurrence rates remain substantial. For patients with unresectable disease, hepatic arterial infusion pump chemotherapy can offer some benefit.
Cristina R. Ferrone, MD, FACS, Cedars-Sinai Medical Center, presented on perioperative integration with medical oncologists for neoadjuvant and adjuvant therapy. Surgical resection is the standard of care for resectable intrahepatic CCA and is an essential part of treatment for long-term survival. Currently, data do not support neoadjuvant therapy in resectable patients; patients should only be offered neoadjuvant therapy in the context of a clinical trial or in patients with borderline or locally advanced cancers. Some clinical trials have suggested a benefit of adjuvant chemotherapy following curative-intent resection.5-8 The BILCAP trial investigated capecitabine versus surgery alone and found that overall survival was improved in the capecitabine group versus the observation group.9 Dr Ferrone also discussed the role of molecular and immune stratification in patients with advanced BTC in whom surgery is not appropriate. The phase 3 ClarIDHy trial demonstrated a progression-free survival benefit with ivosidenib in IDH-1 mutated advanced CCA versus placebo,10 and a single-arm phase 2 trial in FGFR2-rearranged intrahepatic CCA demonstrated a clinical benefit with the FGFR inhibitor futabatinib.11 Many ongoing trials are evaluating biomarker-driven targeted therapies, and Dr Ferrone noted that molecular and immune stratification should be routinely performed in patients with unresectable or advanced CCA.12
Ashton A. Conner, MD, PhD, FRCSC, Houston Methodist Hospital, presented on transplantation for CCA and explained the results from various clinical trials and series and the role of immunosuppression, and provided patient management tips. Dr Conner first summarized a clinical series or meta-analysis of 20 clinical trials, none of which were randomized controlled trials, of survival after transplantation in 428 patients with unresectable perihilar CCA.13 In this meta-analysis, researchers pooled 1-, 3-, and 5-year data, and overall survival was 77%, 55%, and 45%, respectively.13 He then described a meta-analysis of survival rates after liver transplantation in patients with intrahepatic CCA, which consisted of 18 clinical trials and a total of 355 patients.14 In this meta-analysis, which also did not include randomized controlled trials, the 1-, 3-, and 5-year overall survival rates were 75%, 56%, and 42%, respectively,14 which were similar to the data in the meta-analysis by Cambridge and colleagues in perihilar CCA.13 This analysis further showed that tumor size is a determinant of survival outcomes; patients with tumors that are <2 cm had better outcomes after transplantation, with a 1-, 3-, and 5-year overall survival of 97%, 86%, and 71%, respectively, compared with those with tumors that are >2 cm, with 1-, 3-, and 5-year survival rates of 78%, 56%, and 48%, respectively.14 Dr Conner then described the importance of understanding immunosuppression after transplantation in patients with CCA. Calcineurin inhibitors have shown evidence of promoting cancer growth; whereas mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, have been shown to inhibit tumor cell growth.15 In a large, multicenter trial where patients with hepatocellular carcinoma were stratified based on whether they received mTOR or calcineurin inhibitors for immunosuppression, no difference was found on the effectiveness of these inhibitors.16 Preclinical and early-stage studies are investigating mTOR inhibitors in patients with CCA, although more data are needed.15 Dr Conner concluded with management tips for transplantation. CCA patients may benefit from referral to an experienced care center early, and when evaluating patients, it is important to get tissue for sequencing and start systemic therapy as soon as possible. It is important to continue systemic therapy while patients are on the waitlist for surgery; during transplant, it is important to stage laparotomy under the same anesthetic and to remove lymph nodes for backup examination; and as a follow-up, use mTOR inhibition–based immunosuppression.
Iswanto Sucandy, MD, FACS, University of Central Florida, presented on technology, instrumentation, and robotics as surgical approaches to BTC. Dr Sucandy first discussed the laparoscopic/robotic approach in patients with intrahepatic CCA. An analysis of 4 retrospective studies found that laparoscopic liver resection is associated with less blood loss, fewer blood transfusions, fewer Pringle maneuvers, fewer postoperative complications, and a shorter hospital stay compared with open resection in patients with intrahepatic CCA.17 Laparoscopic surgery, however, was prone to lower rates of lymphadenectomy, which can be problematic because nodal metastases tend to drive the prognosis of these patients, and adequate lymphadenectomy has been shown to improve recurrence-free survival (RFS) and overall survival in patients with clinically node-negative disease.18 Next, Dr Sucandy discussed laparoscopic and robotic approaches to lymphadenectomy. One study found that laparoscopic lymphadenectomy was associated with significantly lower blood loss and a shorter length of hospital stay compared with open lymphadenectomy. Another study reported that techniques using robotics performed equally well to open surgery regarding the number of harvested nodes, blood transfusions, functional recovery, length of stay, and major morbidity. Dr Sucandy then discussed the robotic approach to perihilar CCA. His team conducted a trans-Atlantic multicenter study that examined the outcomes of robotic resection for perihilar CCA. A total of 38 patients were enrolled, and 7 (8±6.6) lymph nodes were harvested; 11 (28%) patients had positive lymph nodes. Vascular resection/reconstruction was performed in 3 (8%) patients. The final margin status of these patients included 31 (81%) R0 patients, 6 (16%) R1 patients, and 1 (3%) R2 patient. Postoperative outcomes from this study showed that 26 (68%) patients were alive without disease, 5 (13%) were alive with disease, and 7 (19%) are deceased. Dr Sucandy concluded with a discussion of the future of advanced technology for the treatment of BTC, which included the description of a camera, SpyGlass DS, that can be inserted into the bile duct for pictures and biopsies for diagnostic purposes.
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