A multidisciplinary approach to treating localized disease in cholangiocarcinoma (CCA) is important, and management strategies for advanced disease have the potential to be used in patients who undergo surgical resection. It is known that recurrence rates are high in patients who have undergone surgery, and often they present with large tumors, satellite lesions, or multiple tumors.
Because of the complexity of the disease, therapeutic strategies beyond surgery are needed, including neoadjuvant therapy, which Shishir Maithel, MD, FACS, FSSO, from Emory University, discussed in his presentation.
Gemcitabine/cisplatin (GemCis) has been standard of care in advanced CCA, and the GAP trial investigated the addition of nab-paclitaxel to this regimen, whereas the S1815 trial of GemCis plus nab-paclitaxel is ongoing. With success in this setting, researchers speculate that these treatment regimens may apply to patients with resectable disease. Trials in the adjuvant setting may be difficult to conduct due to the morbidity associated with surgery, the absence of visible disease, and limited end points. In the neoadjuvant setting, however, patients are at their best performance status, responses can be assessed radiologically and pathologically, imaging can show responses preoperatively, and more opportunities exist for correlative studies with blood and tissue. Intrahepatic CCA (iCCA) may be the most successful CCA subgroup in which to investigate neoadjuvant therapy because core biopsy and next-generation sequencing (NGS) are feasible, patients are generally not jaundiced and do not have stents, and there is adequate tissue from specimens for correlative studies.
Applying the advances from metastatic disease, Maithel and colleagues hypothesized that GemCis plus nab-paclitaxel will be feasible and safe, will increase resectability rates, and will improve recurrence-free survival and overall survival in patients with resectable, high-risk disease, all of which led to initiation of the NEO-GAP trial.
NEO-GAP investigated neoadjuvant GemCis plus nab-paclitaxel for 4 cycles in 30 patients with iCCA. In all, 73% of participants completed all therapy, and all patients were able to tolerate the neoadjuvant therapy. In addition, 90% of patients had disease control, and perioperative outcomes were not altered. No major complications were noted, and only 9% of patients had minor complications.1
The OPTIC trial, which has not yet begun, aims to investigate neoadjuvant personalized therapy in patients with FGFR2 fusions, building on the foundation of the GAP study. Patients will receive 1 cycle of the GAP chemotherapy regimen, and based on NGS results, will receive an FGFR2 inhibitor or continue with the chemotherapy for 2 cycles prior to surgery. An umbrella trial, OPTIC-02, is planned to investigate neoadjuvant molecularly targeted therapy in tumors with a variety of mutations and to continue to assess the feasibility and safety of targeted therapy in the neoadjuvant setting.
The CCA genomic landscape is diverse, with no dominant mutation or alteration. Approximately 50% of alterations are potential therapeutic targets, with heterogenicity in the prevalence of these mutations among anatomic subgroups of CCA. Therapies have been approved by the US Food and Drug Administration (FDA) for many of these molecular targets in the advanced CCA setting; however, data on the role of molecular targets in the surgical setting are sparse.
Alice Wei, MD, MSc, FRCSC, from Memorial Sloan Kettering, described approaches to investigating targeted treatment in the surgical setting in her presentation. She first described imatinib, a tyrosine kinase inhibitor approved for metastatic gastrointestinal stromal tumor (GIST); it can be used as an example for the trajectory of how targeted therapy is studied in surgical patients. Imatinib was FDA approved based on a case report for metastatic GIST and was subsequently studied in 3 randomized controlled trials and FDA approved in the adjuvant setting. These events ultimately led to the development of trials to investigate imatinib as neoadjuvant therapy.
This same clinical research pathway can be applied to various disease states, and researchers are investigating whether the same process with imatinib can be used as a framework for CCA. Studies show the therapeutic benefit of targeted therapies in patients with advanced CCA, and data comparing these therapies to standard of care in the adjuvant setting will be informative for surgeons when evaluating their role perioperatively. FGFR2 fusions and alterations and IDH1 mutations have been identified as potential targets where molecular therapy may have a role in the neoadjuvant setting, although currently no data are available to confirm this hypothesis. When investigating the role of molecular therapy in surgical patients, certain limitations need to be considered: 25% to 30% of patients have inadequate tissue for NGS, the turnaround time for NGS is currently 2 to 4 weeks, consideration of liquid biopsy involves issues in interpretation of variants, and safety issues are a concern in patients with hyperbilirubinemia or impaired liver.2
Questions that remain regarding incorporating targeted therapy with surgical approaches in CCA include the optimal patient selection for perioperative therapy, the efficacy of neoadjuvant targeted therapy to downstage or downsize the tumor to improve resectability, whether targeted therapy can replace surgery in some cases, and the potential advantages of targeted agents compared with current therapies. The current data in this space are unsatisfactory such that there is a need to expand research in the role of targeted therapy in the surgical setting to better understand the opportunities that may exist.
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