Preoperative chemotherapy and chemoradiation can benefit patients with localized pancreatic cancer, but such regimens may exacerbate an already high symptom burden and diminish patients’ functional status. To maintain or improve pancreatic cancer patients’ functional status during preoperative therapy, researchers at The University of Texas MD Anderson Cancer Center are investigating an exercise program. This program may also improve the efficacy of chemotherapy.
“Patients with pancreatic cancer can rapidly get debilitated, even when their tumor burden is small,” said Matthew Katz, M.D., an associate professor in the Department of Surgical Oncology. “Unlike patients with colon or breast cancer—who can have widespread metastatic disease and still be completely functional—patients with pancreatic cancer can have a 1-cm tumor and be cachectic and profoundly ill.”
Dr. Katz and colleagues are investigating an individualized exercise program for pancreatic cancer patients undergoing preoperative chemotherapy. The researchers have already demonstrated that despite the high symptom burden, patients with newly diagnosed, potentially curable pancreatic cancer can indeed adhere to a regimen of preoperative exercise, or prehabilitation. In addition, the researchers’ preclinical data indicate that the exercise program could increase chemotherapy efficacy. And now, an upcoming randomized trial could determine whether the program improves functional status as expected.
Rationale for prehabilitation
Prehabilitation has its roots in orthopedic surgery, where it was shown that preoperative exercise to strengthen the affected limb could speed postoperative recovery. In recent years, the concept has been applied to cancer surgery, with the goal of reducing postoperative complications and improving patients’ functional status so they can receive further cancer treatment (see Prehabilitation, OncoLog, September 2015).
“Data show that patients with poor performance status are less likely to do well after surgery,” said An Ngo-Huang, D.O., an assistant professor in the Department of Palliative, Rehabilitation, and Integrative Medicine. “And in a recent study of colorectal cancer patients, a program focused on nutrition, exercise, and psychology improved patients’ fitness.”
However, although exercise programs have been shown to improve some physiological outcomes, they have not been shown to improve oncologic outcomes. But this may soon change, as preclinical studies indicate that exercise can enhance chemotherapy drug delivery by improving the vasculature of pancreatic tumors.
“In most tumors, the blood vessels are very dysfunctional because they grow rapidly and never mature to become fully efficient. If you’re giving a drug that requires blood delivery to get to the tumor cells, you’re doing a better job of delivering the drug to the healthy organs than to the tumor,” said Keri Schadler, Ph.D., an assistant professor in the Department of Pediatrics. In a mouse model of pancreatic cancer, Dr. Schadler and colleagues showed that mice given moderate treadmill exercise during chemotherapy had normalized tumor vasculature and decreased tumor growth compared with control mice. The researchers also found that tumors from mice in the exercise group had increased expression of H2AX, a marker of DNA damage and a surrogate marker of chemotherapy delivery. “My data suggest that in addition to improving fitness, which is really important, exercise might actually be improving the chemotherapy effect by getting more drugs into the tumor,” Dr. Schadler said.
In light of the known benefits of exercise before surgery and the potential of improved oncologic outcomes, Drs. Katz, Schadler, and Ngo-Huang—along with David Fogelman, M.D., an assistant professor in the Department of Gastrointestinal Medical Oncology, and Nathan Parker, M.P.H., a graduate research assistant in the Department of Surgical Oncology—developed an exercise program that pancreatic cancer patients could follow during preoperative chemotherapy or chemoradiation. This exercise program is based on the American Cancer Society (ACS) and American College of Sports Medicine (ACSM) guidelines for exercise for cancer survivors and is being evaluated in a recently completed pilot trial and an upcoming randomized controlled trial.
The single-arm pilot trial (No. 2014-0702) was open to patients with pancreatic adenocarcinoma who were scheduled to receive preoperative chemotherapy or chemoradiation and then undergo pancreatectomy. The trial enrolled 70 patients, who were instructed to walk for at least 20 minutes at least 3 days per week and to do strengthening exercises with resistance tubes for at least 30 minutes 2 days per week. For the strengthening exercises, patients received instructional DVDs and written handouts as well as in-person demonstrations. The exercise regimen was tailored as necessary to accommodate individual patients’ limitations, and patients continued the program until their preoperative treatment ended.
To monitor patients’ progress and address any issues related to exercise,
a trial staffer called each patient every 2 weeks. The phone calls helped motivate patients to overcome obstacles to exercise, which include disease symptoms, feeling too sick to exercise for 1 or 2 days when treatment is administered, and sometimes being away from home for radiation therapy.
The trial’s main objective was to see whether patients are able to adhere to the regimen, and an analysis of the first 20 patients indicated success. Of these patients, 15 completed the exercise program; the other five did not participate and did not return to MD Anderson for surgery. The trial also used questionnaires and functional measures to assess patients’ performance status, and the 15 patients who completed the program maintained their performance status.
“Multiple issues conspire to make it difficult for these patients to exercise, which makes it all the more remarkable that the patients are doing it,” Dr. Katz said. “Are they having difficulty? Often, yes. But they’re doing it.”
“Anecdotally, patients love the exercise program,” Dr. Ngo-Huang said. “It involves them in their own care. And for some patients who’ve never exercised regularly, it’s motivated them to make a lifestyle change.”
Randomized controlled trial
With pancreatic cancer patients’ ability to adhere to the exercise regimen established, the researchers will soon begin enrolling patients in a randomized controlled trial in which some patients will participate in an exercise program and others will receive the standard of care (i.e., they will be encouraged to exercise and given a brochure on how to exercise safely). Patients in both study arms will be given Fitbit Zip activity trackers to monitor their daily distance walked.
The trial’s inclusion criteria are similar to those of the pilot trial except that patients with any type of pancreatic cancer can enroll. Another difference from the pilot trial is that the exercise regimen is being adjusted from 120 minutes to 150 minutes of aerobic activity per week. This modified regimen, called PancFit, more closely matches the ACS and ACSM guidelines.
The new trial’s primary objective is to compare the difference in fitness changes, as measured by 6-minute walk tests given before the start and at the completion of preoperative therapy, between patients in the exercise program and those in the control group. Secondary objectives include comparing performance status and quality of life, as measured by questionnaires, between the two groups.
Most patients who complete the exercise program will go on to have their pancreatic tumors removed. Tumor specimens from these patients can provide a wealth of information about the effects of exercise on pancreatic tumors during preoperative treatment.
“I’ve analyzed tumors from patients in the pilot trial, and the results are pretty impressive,” Dr. Schadler said. “We think exercise may be causing the same type of vasculature changes in humans as in mice.”
In addition to comparing tumor specimens, Dr. Schadler will compare levels of circulating TSP-1 (thrombospondin-1) between the randomized trial’s two treatment arms. High levels of TSP-1 correlate with good prognosis in pancreatic cancer patients, and Dr. Schadler has shown that exercise increases TSP-1 levels in mice. “It’s not clear whether high TSP-1 levels simply correlate with better outcomes or actually cause better outcomes,” she said. “But if we can show that exercise increases TSP-1 in humans, it would be encouraging.”
A strong research program
A major strength of the research program is the quality of care the patients receive. “This research takes place in the context of a pancreatic surgery program that has the highest survival rate on the planet,” Dr. Katz said. “Our patients who undergo surgery have a median survival of more than 43 months, which for pancreatic cancer is a big deal, considering that median survival for patients in the United States overall is less than 20 months.”
Another strength is that the exercise research can be done in conjunction with other clinical research. “Being in the exercise program is not mutually exclusive to being in a clinical trial of investigational agents,” Dr. Katz said. “Some patients who participated in the pilot exercise trial also received preoperative immunotherapy here through another ongoing trial. We think that adding exercise to these novel therapies will yield an exponential increase in benefit with no added risk.”
For more information, contact Dr. Matthew Katz at 713-794-4660 or firstname.lastname@example.org, Dr. An Ngo-Huang at 713-745-8157 or email@example.com, or Dr. Keri Schadler at 713-794-1035 or firstname.lastname@example.org. For more information about clinical trials for pancreatic cancer patients, visit www.clinicaltrials.org.
Cloyd JM, Katz MH, Prakash L, et al. Preoperative therapy and pancreato-duodenectomy for pancreatic ductal adenocarcinoma: a 25-year single-institution experience. J Gastrointest Surg. 2017;21:164–174.
Schadler KL, Thomas NJ, Galie PA, et al. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget. 2016;7:65429–65440.
OncoLog, May-June 2017, Volume 62, Issue 5-6