Leading Investigator Seeks to Promote the Distinctions in GI Cancers

Michael A. Choti, MD, MBA, FACS

When Michael A. Choti, MD, MBA, FACS, assumed his first position at Johns Hopkins Hospital in Baltimore, Maryland, in 1992, surgical and medical oncologists worked almost entirely independent of each other, and the only way to get DNA from a gastrointestinal (GI) cancer was to cut out a sample.

Things are different now, thanks in part to Choti’s work spanning a 30-year career that has combined research, clinical practice, and growing leadership responsibilities. Choti worked with Bert Vogelstein, MD, the 2013 Giants of Cancer Care^® award winner in gastrointestinal cancer, and others at Johns Hopkins on some of the first studies of circulating tumor DNA (ctDNA). Results of this early investigative work have just begun to produce practical tests that Choti expects to greatly improve the treatment of GI cancers and other tumor types. He also collaborated with medical oncologists on efforts to evaluate how sequencing of surgical and medical treatment affected outcomes for patients with GI cancers. In addition, as he moved into administrative positions, he pushed policies for patient treatment that incorporated the discoveries that he and other investigators had made.

Choti is now the chief of surgery at Banner MD Anderson Cancer Center in Phoenix, Arizona. The center is a partnership between the Houston-based cancer center and the dominant medical service provider in Arizona and other parts of the Southwest. “Banner Health is a huge health system,” Choti said in an interview with OncologyLive^®. “My position provides an opportunity to really make a difference in cancer care that, in some respects, is greater than what I could do at Hopkins or in my last position, chairing the Department of Surgery at The University of Texas [UT] Southwestern Medical Center in Dallas. There’s a huge opportunity to improve integrated cancer care in this region, which is large and growing rapidly.”

Although the combination of administration, clinical practice, and research keeps Choti busy, he still finds time to help others keep up to speed by participating in continuing education programs such as the 7th Annual School of Gastrointestinal Oncology^® (SOGO^®), which will be hosted by Physicians’ Education Resource^®, LLC (PER^®) on March 26. Choti will cochair the 1-day hybrid event—which will take place at the Hilton Washington DC National Mall The Wharf—with John Marshall, MD, who is chief of the Division of Hematology/Oncology at Medstar Georgetown University Hospital, professor of medicine and oncology at Lombardi Comprehensive Cancer Center at Georgetown University, and director of The Ruesch Center for the Cure of Gastrointestinal Cancers in Washington, DC.

“Dr Marshall and I have long agreed on the importance of coordinating surgical and medical care in cancer patients. We collaborated in the treatment of many patients during my 2 decades at Hopkins, even though he was in Washington and I was in Baltimore,” Choti said. “We have, therefore, structured the event to emphasize the importance of multidisciplinary care. Most of the attendees will be medical oncologists, but they will be hearing from surgical oncologists, radiation oncologists, gastroenterologists, and radiologists about how the specialties must work together to optimize care.”

Tracking Progress in GI Cancers

During Choti’s career, decades of innovations have resulted in improved surgical treatments for GI cancers, with Choti noting the significant advances in surgical techniques used to remove tumor tissue. For example, many surgeries have become less invasive, either through changes to the procedure or surgical robots. Yet the biggest improvements, particularly in recent years, have come from adjustments to the relative timing of surgical and medical treatment.

“Robotic devices have been a part of cancer surgery for decades now—I actually participated in some of the early trials—but they continue to evolve and improve,” he said. Choti, coauthored a 2008 evaluation of 3-dimensional ultrasound-guided robotic needle placement¹ and a 2012 study of robot-assisted laparoscopic ultrasonography for hepatic surgery,² as well as several more recent robotic trials.

“The really exciting improvements, though, are the ones that stem from our growing understanding of which patients should get surgery and when they should get it and what other treatments should come before and after,” Choti said. “That’s been evolving for decades, but recent and pending changes to standards of care are very exciting.

“For example, with rectal cancer, the standard 20 years ago was to remove the cancer and give chemoradiation therapy after that. Now, most early-stage rectal cancers are treated with chemoradiation first and then chemotherapy after surgery. The innovative thing now in rectal cancers is to actually give all radiation and chemotherapy prior to surgery, which is called TNT, or total neoadjuvant therapy.”

Investigators have initiated several trials in recent years pitting TNT against current standards of care, the results of which have generally favorable outcomes for patients who receive TNT. A 2020 meta-analysis combined results from 7 unique studies with a collective 2416 patients, half of whom received TNT.

The pooled prevalence of pathologic complete response (pCR) was 29.9% (95% CI, 17.2%-38.5%) in the TNT group vs 14.9% (95% CI, 4.2%-21.3%) in patients receiving the standard of care for locally advanced rectal cancers—concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A). Total neoadjuvant therapy was associated with a higher chance of achieving a pCR (odds ratio [OR], 2.44; 95% CI, 1.99-2.98). Three of the studies reported data on disease-free survival; pooled analysis showed significantly higher odds of improved disease-free survival in patients who received TNT (OR, 2.07; 95% CI, 1.203.56; I² = 49%).³

Last year, those findings were supported by new results from the phase 3 RAPIDO trial (NCT01558921). The study compared TNT with current standards of care in 920 patients with biopsy-proven, newly diagnosed primary, locally advanced rectal adenocarcinoma was classified as high risk on pelvic MRI. Median follow-up was 4.6 years. At 3 years after randomization, the cumulative probability of disease-related treatment failure was 23.7% (95% CI, 19.8%27.6%) in the experimental group vs 30.4% (95% CI, 26.1%-34.6%) in the standard-of-care group (HR, 0.75; 95% CI, 0.60-0.95; P = .019). Serious adverse events occurred in 177 (38%) of 460 patients in the experimental group. In the standard-of-care group, 87 (34%) of 254 patients without adjuvant chemotherapy and 64 (34%) of 187 patients with adjuvant chemotherapy suffered serious adverse events.⁴

The trend toward neoadjuvant treatment is also happening in other GI cancers.

“In pancreatic cancer, where it’s operable, many around the country are still doing surgery first, but the NCCN [National Comprehensive Cancer Network] guidelines and others are f inally recognizing that pancreas adenocarcinoma should get chemotherapy prior to surgery. We have been doing that for a while here, but the practice is starting to spread,” Choti said. “Another area where the same thing is happening is stomach cancer, gastric cancer, where traditionally you did surgery first, and now it’s clear the pendulum is moving fast toward giving chemotherapy prior to surgery.”

Results from the Prep-02/JSAP-05 trial (UMIN000009634), which compared neoadjuvant chemotherapy using gemcitabine and S1 (NAC-GS) with up-front surgery, support the use of neoadjuvant chemotherapy in resectable pancreatic cancer. Among the 182 patients in the NAC-GS group, median overall survival (OS) was 36.7 months. Among the 180 patients in the upfront surgery group, median OS was 26.6 months (HR, 0.72; 95% CI, 0.55-0.94; P = .015). Grade 3 or 4 adverse events frequently observed (72.8%) in the NAC-GS group were leukopenia or neutropenia. The resection rate, R0 resection rate, and morbidity of the operation were equivalent in the 2 groups.⁵

In gastric cancer, trials have demonstrated that neoadjuvant chemotherapy produces better outcomes than surgery alone⁶ and that adjuvant chemotherapy⁷ or adjuvant radiotherapy⁸ produces better outcomes than surgery alone. A trial comparing these modalities has yet to be conducted,⁹ but results are eagerly awaited from a phase 3 trial that adds neoadjuvant chemoradiation to perioperative chemotherapy.¹⁰

“The research is going on to continue that trend in the surgical management of cancer to give more and more systemic chemotherapy prior to surgery rather than after,” Choti said. “The areas of study now that might continue that expansion are liver cancer, biliary cancer, and cholangiocarcinoma, where now there is research going on as to which patients we should [give] chemotherapy to prior to surgery. The standard now for cholangiocarcinoma, if it’s operable, is still to [perform] surgery first, just like it was with stomach cancer or pancreatic cancer. There are ongoing studies, and I wouldn’t be surprised if, within the next year or two, it becomes standard to consider neoadjuvant chemotherapy for these other GI cancers.”

The varied nature of GI cancers—a term that Choti dislikes because the tumor types have little in common beyond their connection to some part of the digestive system—has led Choti and Marshall to divide the SOGO^® meeting into different tracks: gastric and esophageal, pancreatic, colorectal, and hepatobiliary. During part of the day, presentations that focus on different tumor types will take place simultaneously, and attendees can select the sessions that interest them most. These specialized presentations will complement talks about broader topics such as National Cancer Institute (NCI) research in GI cancer, the emerging role of ctDNA in GI cancer treatment, and a Medical Crossfire^® during which investigators will debate the optimal role of immunotherapy in GI cancers.

“In some ways, ‘GI cancers’ is a contrived term, an artificial amalgamation of very different tumors,” Choti said. “If you ask a patient about her GI cancer, she’ll look at you like you’ve made a mistake and say, ‘I don’t have GI cancer. I have stomach cancer or colon cancer.’ And it’s not just a problem for patients. It creates challenges with regard to NIH [National Institutes of Health] funding and cancer center organization and, for people like John and me, with organizing conferences.”

Choti, who grew up in Southern California and focused on science courses as an undergraduate at the University of California, Irvine, decided to become a physician because medicine seemed like the best way to use his love of science to help people in tangible ways. He went to medical school at Yale University in New Haven, Connecticut, before completing his internship and residency in general surgery at the University of Pennsylvania in Philadelphia. After a 2-year fellowship in surgical oncology at Memorial Sloan Kettering Cancer Center in New York, New York, Choti went to Johns Hopkins and stayed in Baltimore for 21 years.

During his tenure, Choti found time to earn a master’s degree in business administration from Johns Hopkins University School of Professional Studies in Business and Education, both to satisfy his desire to keep learning new things and to increase his opportunities to assume leadership roles. He became chief of the Division of Surgical Oncology in Johns Hopkins Department of Surgery in 2006 and, 2 years later, the department’s vice chair of clinical affairs and f inance. In 2013, he left Johns Hopkins for UT Southwestern, and in 2018, he assumed his current position.

Creating Synergy from Bench to Bedside

Even as his leadership responsibilities have grown, Choti has made time for clinical practice, and he considers the relationships he has built with patients over the years among the most satisfying aspects of his work.

“It’s not just cutting the tumor out and then having somebody else take care of your patients,” Choti said. “There is longitudinal care. The relationship with patients and families is terrific, and I really, hugely value that. I may be somewhat unusual in this respect, but I’m still in touch with families of patients that have died from cancer 20 years ago and more. I get cards all the time, and I’ve not just attended funerals of my patients but gotten asked to give eulogies at least half a dozen times. It is a deep and lasting bond, and that bond is really tremendous.”

Choti’s clinical research has primarily focused on 3 main areas: health services research, image- or robotics-guided surgery, and molecular genetics.

“I’ve been involved as either coinvestigator or senior investigator in numerous clinical trials, including cooperative, NCI-sponsored trials in clinical health services research. A large portion of my early career related to innovative image-guided surgery, computer-guided robotic surgery, robotics, and things like that. I had a faculty appointment not only of surgery and oncology at Hopkins but also of radiology and engineering, in large part because my research there partnered with engineers and computer scientists to develop image-guided, computer-assisted surgical approaches, particularly for liver cancer,” Choti said, adding that Johns Hopkins was also a great place to do research in another area of interest—cancer genetics. “It was fortunate that I was in a place at Johns Hopkins where really a lot of the key early discoveries in the molecular genetics of cancer took place. That’s obviously a huge area of research and discovery now. And some of the very earliest discoveries of the clinical utility of this circulating cell-free DNA were made by the [Bert] Vogelstein team [I worked with] at Hopkins.”

Because ctDNA remains a major area of interest, Choti is using his leadership role at Banner MD Anderson to ensure his organization participates in ongoing clinical trials that aim to validate ctDNA use not only in diagnosing cancers but in guiding treatment. He is also giving the presentation on the state of ctDNA research at SOGO^®, during which he plans to discuss the few existing uses for ctDNA assays in clinical practice and new research that may soon expand their usage across GI cancer treatment.

Among the emerging uses for ctDNA assays is the detection of minimal residual disease (MRD) in early-stage colon cancer (ESCC). The current treatment strategy for patients with ESCC begins with surgical resection in all patients and adjuvant chemotherapy to eliminate MRD in patients deemed at risk of cancer recurrence; however, the current method of selecting patients for chemotherapy creates both undertreatment and overtreatment, and published data from trials suggest that ctDNA assays could improve the selection process.

In a prospective cohort study published in 2019, the tumor-informed safe-sequencing system (or Safe-SeqS) assay measured ctDNA in patients with resected, stage II colon cancer. Among the patients who did not receive adjuvant chemotherapy (n = 178), postoperative ctDNA was detected in 7.9% of patients, 79% of whom experienced disease recurrence at a median follow-up of 27 months. Among patients with negative results on the ctDNA assay, however, only 9.8% had cancer recurrence (HR, 18; 95% CI, 7.9-40; P < .001). Postoperative ctDNA status was the strongest independent predictor of relapsefree survival, both for patients who did not receive chemotherapy (HR, 28; 95% CI, 11-68) and in the general patient population (HR, 14; 95% CI, 6.8-28).¹¹

Subsequent studies have published similar results. A study reported in 2021, for example, found that postoperative ctDNA assays could be successfully used to stratify 218 patients with stages I to III colon cancer into high- and low-risk groups. Among the 9.17% of patients who were MRD positive after their operations, 75% relapsed, but only 13.6% of patients with MRD negativity relapsed. A positive postoperative ctDNA test was highly associated with a recurrence (HR, 11.0; 95% CI, 5.9-21; P < .0001). Also, among patients who received adjuvant chemotherapy, a positive ctDNA test after completion of treatment was associated with a recurrence rate of 83.3%, whereas a negative ctDNA test after chemotherapy was associated with a 12.5% recurrence rate (HR 12, 95% CI, 4.9-27; P < .0001).¹²

“There are already some areas where ctDNA is currently being used and that insurance is paying for. It’s limited now, but it’s rapidly evolving,” Choti said. “I think ctDNA is going to be increasingly useful across the board. It will expand not just for diagnosis but to evaluate the response to therapy, the management of therapy, and whether to give further treatment after surgery…. To give an example, let’s say a patient has advanced cancer, and they’re getting chemotherapy. Right now, we give chemotherapy for a month or two and see if the spots shrink on scans. With ctDNA, in theory, you can give one dose of chemotherapy and literally see the next day—or in a week at most—whether the burden of mutation goes down, so you can then more nimbly adjust and determine if that therapy is working.”

Another use for ctDNA that Choti thinks likely is regular blood tests that would be taken during normal physicals, with the results used to find any type of cancer anywhere in the body. “There are a lot of challenges you can imagine with that,” Choti said. “Say the test [results indicate] that a patient has mutated cancer DNA in the bloodstream, and you’re scanning the whole body, and you can’t find it. On the other hand, it could lead to much earlier cancer diagnoses for a large number of patients.”

Another area of research that Choti thinks may improve outcomes for patients with GI cancers and other tumor types—one that he is pursuing at Banner MD Anderson—is research into what’s known as prehabilitation: creating diet and exercise programs to make patients stronger before they begin cancer treatment.

“We’re not trying to create marathon runners here, but we’re trying to get that 95-year-old [patient] who’s using a walker in shape during chemotherapy so she’s better able to tolerate surgery,” Choti explained, adding that prehabilitation also includes psychosocial work to help patients deal with the stress of receiving a cancer diagnosis. “The research is looking at blood markers and muscle mass and all kinds of biologic factors, but the real purpose is to develop a program where we can optimize patients—physically, mentally, nutritionally, and otherwise—before they undergo the most stressful parts of treatment…. I’m happy to be in a leadership position where I can leverage this huge health system to help move the ball forward in areas like this.”

References

1. Boctor EM, Choti MA, Burdette EC, Webster Iii RJ. Three-dimensional ultrasound-guided robotic needle placement: an experimental evaluation. Int J Med Robot. 2008;4(2):180-191. doi:10.1002/rcs.184
2. Schneider CM, Peng PD, Taylor RH, et al. Robot-assisted laparoscopic ultrasonography for hepatic surgery. Surgery. 2012;151(5):756-762. doi:10.1016/j.surg.2011.07.040
3. Kasi A, Abbasi S, Handa S, et al. Total neoadjuvant therapy vs standard therapy in locally advanced rectal cancer: a systematic review and meta-analysis. JAMA Netw Open. 2020;3(12):e2030097. doi:10.1001/jamanetworkopen.2020.30097
4. Bahadoer RR, Dijkstra EA, van Etten B, et al; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):e42. Published correction appears in Lancet Oncol. 2021;22(1):29-42.
5. Unno M, Motoi F, Matsuyama Y, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). J Clin Oncol. 2019;37(suppl 4):189. doi:10.1200/JCO.2019.37.4_suppl.189
6. Cunningham D, Allum WH, Stenning SP, et al; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):1120. doi:10.1056/NEJMoa055531
7. Bang YJ, Kim YW, Yang HK, et al; CLASSIC trial investigators. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379(9813):315-321. doi:10.1016/ S0140-6736(11)61873-4
8. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345(10):725-730. doi:10.1056/NEJMoa010187
9. Anderson E, LeVee A, Kim S, et al. A comparison of clinicopathologic outcomes across neoadjuvant and adjuvant treatment modalities in resectable gastric cancer. JAMA Netw Open. 2021;4(12):e2138432. doi:10.1001/jamanetworkopen.2021.38432
10. Leong T, Smithers BM, Haustermans K, et al. TOPGEAR: a randomized, phase III trial of perioperative ECF chemotherapy with or without preoperative chemoradiation for resectable gastric cancer: interim results from an international, intergroup trial of the AGITG, TROG, EORTC and CCTG. Ann Surg Oncol. 2017;24(8):2252-2258. doi:10.1245/s10434-017-5830-6
11. Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016;8(346):346ra92. doi:10.1126/scitranslmed.aaf6219
12. Henriksen TV, Tarazona N, Reinert T, et al. Circulating tumor DNA analysis for assessment of recurrence risk, benefit of adjuvant therapy, and early relapse detection after treatment in colorectal cancer patients. J Clin Oncol. 2021;39(suppl 3):11. doi:10.1200/ JCO.2021.39.3_suppl.11