1. Introduction – Expert opinion on investigational drugs special issue on biliary tract cancer
With ‘Gallbladder and Bile Duct Cancer Awareness Month’ and ‘World Cholangiocarcinoma Day’ approaching in February, the Editorial team of Expert Opinion on Investigational Drugs has taken strides to dig deeper into this field. To promote awareness of ongoing research, we are publishing a series of authoritative and insightful papers and interviews dedicated to this challenging therapeutic area.
Our special Guest Editors, Dr. Alessandro Rizzo and Dr. Giovanni Brandi of S. Orsola-Malpighi Hospital, University of Bologna, have done a sterling job in engaging and gathering a strong ensemble of eclectic contributors and cutting edge topics.
This poorly understood and under-researched disease is increasing in incidence; hence, enlightenment and understanding are key elements of progress.
As part of this special issue, we have asked Dr. Tim Pawlik, a surgical oncologist and liver cancer expert at The Ohio State University Wexner Medical Center, to provide further insights on how pharmacological and surgical approaches are spearheading progress. This complements our recent interview with Dr. Susan Pandya of Agios on precision medicine and new drug targets. https://www.tandfonline.com/doi/full/10.1080/13543784.2020.1851456
2. Can you tell us about yourself and why you chose to pursue a career in liver cancer surgery and medicine?
I am currently the Chair of Surgery at The Ohio State University Wexner Medical Center. My main clinical interests include alimentary tract surgery, with a special interest in hepatic, pancreatic, and biliary diseases. I received my undergraduate degree from Georgetown University and my medical degree from Tufts University School of Medicine. I completed surgical training at the University of Michigan Hospital and spent 2 years at the Massachusetts General Hospital as a surgical oncology research fellow. I then went on for advanced training in surgical oncology at The University of Texas M. D. Anderson Cancer Center in Houston. I also have an interest in medical ethics and completed a fellowship in medical ethics at the Harvard School of Public Health as well as a Masters in Theology from Harvard Divinity School in Boston.
2.1. Is surgical resection really the only curative option for intrahepatic CCA (iCCA) patients currently? What is the percentage of patients who are candidates for this procedure?
In general, margin negative resection of iCCA is the best/only curative-intent option for patients. Unfortunately, many patients present with advanced disease (60–80%) and are not candidates for surgical resection. These patients should be treated with systemic chemotherapy, as well as potentially locoregional therapy in select cases. Patients with advanced disease should also be screened with mutational analysis to identify potential avenues for targeted therapy. For patients who undergo resection, a surgeon should strive to obtain a margin negative resection, as well as perform a lymph node dissection at the time of surgery to provide adequate staging information. After resection, patients should be referred to medical oncology for discussions regarding adjuvant therapy.
2.2. Liver-directed therapies to control iCCA progression may be appropriate for some patients. Can you enlighten our readers on the emerging approaches in trials and newly available options of these approaches?
Several loco-regional treatment strategies including hepatic artery-based therapies, radiation therapy, and ablation can be considered in the management of locally advanced inoperable iCCA. Transarterial chemoinfusion (TACI), transarterial chemoembolization (TACE), and transarterial radioembolization using Yttrium-90 (Y-90) tagged glass or resin microspheres (TARE) are accepted treatments. The rationale for hepatic artery-based therapies is that the hepatic artery, rather than the portal vein, provides the majority of the blood supply to an intrahepatic tumor. A recent meta-analysis of 657 patients with inoperable iCCA showed that TACI offered reasonable outcomes in terms of tumor response and OS (22.8 months in TACI vs. 13.9, 12.4, and 12.3 months in Y90, TACE and drug-eluting TACE, respectively), but the therapy was limited due to toxicity. Other loco-regional ablative therapies have been investigated to treat patients with iCCA who are not candidates for surgery. For example, several studies have demonstrated the palliative effect and survival benefit of various forms of radiation therapy including conventional external beam irradiation (EBRT), 3D conformal radiation therapy, and stereotactic body radiotherapy (SBRT). There are currently no strong data, however, to establish the role of radiotherapy as a standard therapy in the management of patients with advanced iCCA, although a prospective clinical trial is currently open that should address this question. Radiofrequency ablation (RFA) is another potential modality to treat small (<3 cm) locally advanced unresectable iCCA. Unfortunately, current recommendations regarding the choice of loco-regional therapies for iCCA are limited due to the lack of prospective trial data.
2.3. Can you explain which factors contribute to therapeutic resistance of iCCA?
Similar to pancreatic adenocarcinoma, iCCA has traditionally been chemo-resistant with poor response rates. The reasons for this are likely multifactorial and reflect the genetic heterogeneity of the tumor, which results in the inability to target any one molecular pathway. Given that conventional chemotherapy has demonstrated limited benefit in the management of unresectable or metastatic iCCA, there has been growing interest in identifying novel therapies. In turn, next-generation sequencing techniques have increased our understanding of iCCA pathogenesis by identifying key molecular pathways as candidates for novel targeted therapies. Some of these pathways include EGFR inhibitors, FGFR inhibitors, IDH inhibitors, as well as immune therapy.
2.4. How do you envisage invasive surgical or liver-directed techniques working together with emerging, new or established targeted drug therapies?
There will need to be more integration of liver-directed techniques (i.e. hepatic artery pump therapy then resection, systemic targeted therapy pre- and post-resection) in order to improve outcomes of patients with iCCA. Similar to the advances in the treatment of colorectal liver metastasis, the real progress in the care of patients with iCCA will come with the incorporation of systemic and locoregional modalities with surgical resection.
2.5. How heavily are surgeons involved with researching new drug approaches to this cancer? What are the key research groups or research progress headed up by surgeons that our readers may find of interest?
There are multiple clinical trials that focus on novel-targeted systemic agents. Surgeons need to partner with medical oncologists to ensure patients enroll in these trials. In addition, surgeons are involved in clinical trials that seek to examine the role of neoadjuvant treatment of patients with iCCA. Similar to pancreatic cancer in which most patients are treated with preoperative chemotherapy, there needs to be further investigation into whether this treatment paradigm would benefit patients with iCCA given the high rate of recurrence even after margin negative surgery.
2.6. In your opinion, what are the biggest challenges facing oncologists and surgeons who are trying to find curative measures for iCCA?
The low incidence of iCCA, as well as heterogeneity of tumor biology, are the main challenges in optimizing clinical trials, thereby causing a paucity of iCCA-specific data. Future studies should continue to draw from our emerging knowledge of the molecular pathogenesis of iCCA and target deregulated signaling pathways with the goal of personalizing treatment for patients with iCCA. Oncologist and surgeons need to work together to enroll patients in clinical trials, create prospective iCCA tumor registries, as well as tissue banks so that we can better understand this challenging disease.
3. Other expert opinion articles by Dr Tim Pawlik
https://www.tandfonline.com/doi/full/10.1080/13543784.2019.1677606
https://www.tandfonline.com/doi/full/10.1080/14656566.2019.1694003
https://www.tandfonline.com/doi/full/10.1080/13543784.2020.1721457
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.