Scholar's Research Leads to Revised Incidental Gallbladder Cancer Treatment Recommendations; International Trial

Cecilia Ethun, MD, general surgery resident, Katz Foundation Research Fellow, Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine and her mentor Shishir Maithel, MD, FACS, associate professor of surgery, Winship Cancer Institute, Division of Surgical Oncology, Department of Surgery, Emory University, Hepatobiliary and Pancreatic Surgery

The Atlanta Clinical & Translational Science Institute (ACTSI) provides the network for translating the research pipeline and the educational tools to build the specialized skills needed for success. A clinical and translational research training program proving its value is the ACTSI’s Master of Science in Clinical Research (MSCR). The Emory MSCR degree program, in the Laney Graduate School, provides innovative didactic and mentored research training to those interested in pursuing a career in clinical and/or translational research. The MSCR degree is designed for predoctoral (medical students, PhD students or PharmD students), postdoctoral trainees (resident and fellow physicians or PhD postdocs), and junior faculty (physicians, PhD-level scientists or PharmDs) from ACTSI partner institutions, Emory University (Emory), Morehouse School of Medicine (MSM), Georgia Institute of Technology (Georgia Tech) and the University of Georgia (UGA).

By integrating grant submissions and international trial design into her MSCR coursework, Cecilia Ethun, MD, general surgery resident, Katz Foundation Research Fellow, Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine, is using the MSCR program to strengthen her knowledge of the research process and build a supportive foundation for her career. “I completed research in medical school and knew the basics, but I felt like the MSCR would give me so much more, broaden my horizons, and really strengthen my understanding of research. More than anything, the MSCR program gave me the foundation and confidence to start pursuing the things I really wanted to do,” said Ethun.

Ethun’s MSCR project, Surgical Management of Incidental Gallbladder Cancer: Who, When, and How?, looks at a specific group of people with gallbladder cancer who go into the operating room to have their gallbladders removed (cholecystectomy) because of gallstones and come out with a cancer diagnosis. Every year, 800,000 cholecystectomy are performed in the U.S. and 1 out of every 150 will have this ‘incidental gallbladder cancer’ diagnosis – the most common method of gallbladder cancer identification in the U.S. “I aimed to develop a more robust predictive model when deciding on treatment options. I wanted to look at patients with incidental gallbladder cancer and identify the best patients to go back to the operating room for resection of a little piece of liver, abdomen, and lymph nodes and the best timing for the reoperation,” said Ethun.

Each MSCR scholar must identify a mentor who is an established, independently-funded clinical and/or translational investigator at one of the collaborating ACTSI institutions. Ethun’s mentor, Shishir Maithel, MD, FACS, associate professor of surgery, Winship Cancer Institute, Division of Surgical Oncology, Department of Surgery, Emory University, Hepatobiliary and Pancreatic Surgery, supports Ethun’s independence and forethought. He stated, "Cecilia’s ability is unprecedented. For the mentor, not actually in the program, I’ve learned a ton through her, leeching off what she was learning from the MSCR instructors and basically teaching it to me. A total reversal of roles. The quality of her work in the lab is like nothing I’ve seen.”

Maithel spearheaded a multi-institutional collaborative, the U.S. Extrahepatic Biliary Malignancy Consortium (USEBMC), that includes 10 institutions across the country. Prior to beginning the MSCR, Ethun built a database of the consortium’s priority incidental gallbladder cancer research questions. This data was used in her MSCR project and future analysis. The preliminary data from Ethun’s MSCR project resulted in three presentations, three publications, and plans for a future international National Cancer Institute (NCI) randomized trial. This data proved the ‘Who, When, and How’ for her project.

Ethun and Maithel utilized routine pathology data from initial cholecystectomy at USEBMC institutions from 2000-2015 to create a gallbladder cancer predictive risk score for finding distant or locoregional residual disease at re-resection and predicting overall survival. This score may help to better optimize treatment strategy for patients with incidentally discovered gallbladder cancer (A novel pathology-based preoperative risk score to predict distant and locoregional residual disease and survival for incidentally discovered gallbladder cancer: A 10-institution study from the US Extrahepatic Biliary Malignancy Consortium, Journal of Clinical Oncology). When the risk score was presented it was very well received and excitement grew for a clinical trial. The risk score could be used to identify which patients would benefit from chemotherapy before reoperation and/or those who should not undergo re-resection at all. The risk score identified the ‘Who’ for Ethun’s MSCR project.

Using the USEBMC data, Ethun identified the best time (her project’s ‘When’) for reoperation is between four and eight weeks after the initial cholecystectomy. This timing is associated with improved median overall survival (40.8 months) compared with reoperation less than four weeks (17.4 months) and greater than eight weeks (22.4 months) (Association of Optimal Time Interval to Re-resection for Incidental Gallbladder Cancer With Overall Survival: A Multi-Institution Analysis From the US Extrahepatic Biliary Malignancy Consortium, JAMA Surgery). Additionally, her work also found (the project’s ‘How’) that port-site excision during re-resection for incidental gallbladder cancer is not associated with improved overall survival and has the same distant disease recurrence compared to no port-site excision. Routine port-site excision is not recommended (Routine port-site excision in incidentally discovered gallbladder cancer is not associated with improved survival: A multi-institution analysis of 449 patients from the US Extrahepatic Biliary Malignancy Consortium, J Surgical Oncology).

Presentations and Publications Turn International Trial
The MSCR offers the courses Clinical Trial Design and Scientific and Grant Writing. In July 2016, an opportunity came up for Ethun to apply to the American Association for Cancer Research’s joint venture with American Society of Clinical Oncology for a week-long intensive cancer clinical trials workshop. This workshop targets clinical oncologists, but a small number of surgeons do attend. “Based on what I learned from my MSCR classes such as, how to put together a proposal and how to design a study, we very quickly completed the application, submitted it, and I was accepted. Having the confidence to apply to the workshop came from the skills I learned in the MSCR program,” said Ethun. In a small group atmosphere with cancer clinical trials experts, Ethun came back to Emory with a fully-written protocol to share with USEMBC. “The workshop is only geared towards people who have completed their training – they are in fellowship and/or are attendings. She is the first-ever surgical resident to attend,” said Maithel.

The USEBMC was very supportive of the protocol and it blossomed into an international phase 3 randomized control trial. Surgeons from destinations such as India and Chile attended the International Hepato-Pancreato Biliary Association annual meeting in April 2017 to discuss the trial. Because of the trial, Maithel is now one of the North American representatives for this international gallbladder cancer consortium. “Because of the rarity of the disease, we are hoping to open the trial internationally to assess the effect of perioperative gemcitabine and cisplatin versus surgery alone on overall survival in patients with incidental gallbladder cancer. We are currently in the process of working out logistics before submitting the final version to the NCI,” said Maithel.

Ideally, they will use to the data from the trial to see whether or not the proposed risk score in the initial study could be used to select out the patients who might benefit most from perioperative therapy.

Mentoring and Support
Through dedicated mentors and instructors, MSCR scholars are able to integrate what they learn in the classroom and apply it directly to ongoing clinical research. For Maithel, Ethun is the first Emory School of Medicine Surgical Oncology Training Program resident to integrate the MSCR program so seamlessly by using grant and protocol writing courses to secure international interest. “I hope to push my future fellows to follow in Ethun’s footsteps; not just doing theoretical projects to satisfy the requirements of the course. But thinking prospectively with us, using the coursework and guidance of the MSCR instructors to help us with clinical research protocols and applying for grants. The marriage of the two has been just beautiful these last 18 months,” said Maithel.

An example of the integration is Ethun’s Intro to Clinical Trials course final group project. Hypothetical projects were being suggested. Ethun spoke with Maithel and discussed using the course work to apply for a grant. “I thought, why don’t we just use this as an opportunity to get the foundation for a trial we’ve already been discussing and apply for a grant,” said Ethun.

The MSCR program provided the people and foundation to help her. The motivation came from Ethun, but knowing she had the backing of people supporting the MSCR, like Janet Gross, PhD, grants tutorial director, Emory University Office of Postdoctoral Education and MSCR instructor, was key. “I relied on that structure as well, through her,” said Maithel.

As Gross guided the class through the coursework, Ethun used her newly learned skills to complete a real multi-institutional R01 application, with five institutions including Johns Hopkins and Sloan Kettering. “For me, it made the most sense to write a grant for an actual trial. Having such a phenomenal mentor in Maithel, who is very selfless and was able to hand over a lot of the responsibility to me, and trusted me enough to run with this idea, made the integration possible. We collaborated very closely with all the content and scientific merit but he really allowed me to explore both the trial writing and grant writing on my own and develop that with the MSCR faculty,” said Ethun.

“I learned a lot from Cecilia and Janet in terms of grant writing. Cecilia wrote the grant for us, and we tagged along as she told us what we needed and we offered our clinical expertise, national setup, and collaborations. I was blown away by how supportive the MSCR environment is and continues to be. Janet explained that the support is their responsibility and a pleasure as mentors and teachers in the MSCR program,” said Maithel. 

Ethun is the third Surgical Oncology research fellow to complete the MSCR concurrently with the Emory School of Medicine's Department of Surgery’s two-year research program. Maithel requires any fellow who comes through the program, who does not have an existing masters, to get their MSCR. “I have found it extremely beneficial because I’ve learned from the fellows as they’ve learned from the classes. I am just reaping the benefits from my fellows. As long as I am here running the program, it will continue to be a requirement to get a concurrent masters,” said Maithel.

Trusting Ethun and the MSCR program produced phenomenal results and will continue in the future. Ethun receives her MSCR degree in May 2017.

ACTSI does not stop with the MSCR. The partnership between Emory, MSM, and Georgia Tech also sponsors the Certificate Program in Translational Research, Kauffman FastTrac Tech Venture Course for entrepreneurs, and an MSCR including a KL2-Mentored Clinical and Translational Research Scholars Program and a TL1-Medical Scientist Training. ACTSI is one of a national consortium striving to improve the way biomedical research is conducted across the country. The consortium, funded through the National Center for Advancing Translational Sciences, part of the National Institutes of Health’s Clinical and Translational Science Awards, shares a common vision to translate laboratory discoveries into treatments for patients, engage communities in clinical research efforts, and train the next generation of clinical investigators.