Pancreatic Cancer - Outcomes & Research by Jefferson

PANCREATIC CANCER OUTCOMES & RESEARCH

Jefferson Pancreas, Biliary & Related Cancer Center Philadelphia, PA 19107 Patient Appointments: 1-800-JEFF-NOW Patient Transfers: 1-800-JEFF-121 Physician Referrals: 215-503-8888

CS 24-0119

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SIDNEY KIMMEL CANCER CENTER

PANCREATIC CANCER

Outcomes and Research Overview The pancreas, with its dual endocrine and exocrine functions, is one of the body’s most complex organs. Not so long ago in medical education and surgical training, surgeons were taught to fear the pancreas and to stay clear of it as much as possible. In fact, the pancreas was referred to as the “rattlesnake of the abdomen.” But today’s pancreatic surgery is more effective and safer than ever, thanks to advances in surgical techniques and fine-tuning of critical support services including anesthesia, intensive care and nursing. The Jefferson Pancreas, Biliary & Related Cancer Center truly embraces a multi-disciplinary team approach that results in high-quality surgery, shorter hospital stays, excellent outcomes, and attention to important issues that impact a patient’s quality of life. “Not only do we say that we accomplish all those components, we have the data to back it up,” says Charles J. Yeo, MD, Samuel D. Gross Professor and Chair of Surgery at Thomas Jefferson University and co-director of the pancreas center. Dr. Yeo is considered among the pioneers of the Whipple procedure to treat pancreatic cancer. He also popularized the modified mini-Whipple procedure. He and his colleagues at Jefferson Health have done well over 1,500 of the procedures in the last 12 years, producing some of the best outcomes in the nation, according to publicly reported data from the American College of Surgeons National Surgical Quality Improvement Program. While cancers of the pancreas and bile duct still rank among the most difficult cancers to treat, five-year survival rates have been steadily improving over the past decade. Patients who seek out the surgical experience offered at the Jefferson Pancreas, Biliary & Related Cancer Center also benefit from the expertise of the Sidney Kimmel Cancer Center at Jefferson, which is at the forefront of innovative therapies and is recognized as one of the best NCI-designated cancer centers in the country. Another plus for patients is that Jefferson Health surgeons are widely published researchers who are exploring novel approaches to cancer treatment. The pancreas center’s research portfolio includes clinical trials of cancer-fighting therapies, new models of caregiving to enhance recovery, and laboratory-based science projects that help provide the rationale for new treatment approaches. One long-running clinical trial is evaluating a five-day accelerated recovery pathway, as compared to the traditional seven to 10 days, following the Whipple procedure. Published results to date have found favorable outcomes for patients by multiple measures. A key focus of the basic science research is to better understand the microenvironment of pancreatic tumors and why the tumors are so resistant to treatment. The Jefferson Pancreas Tumor Registry allows patients and their families to voluntarily contribute to research on the genetic, environmental and lifestyle factors that may increase the risk for pancreatic cancer. Prevention and early detection are the ultimate goals. Here is a look at some of the research published recently by the team at the Jefferson Pancreas, Biliary & Related Cancer Center.

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Euglycemic Diabetic Ketoacidosis (EDKA) after Pancreaticoduodenectomy: An Under-Recognized Metabolic Abnormality with Outcome Implications

7.3 Lowest pH 7.2

surgery. Additional endpoints included incidence of postoperative pancreatic fistula, delayed gastric emptying, total complications, postoperative length of stay, readmission rates and changes in insulin at discharge.

Euglycemic diabetic ketoacidosis (EDKA) is a serious metabolic condition that can occur in people with or without diabetes. It is thought to occur through mechanisms resembling starvation. It can arise in various settings, including sepsis, pregnancy, pancreatitis, low-calorie intake, treatment with sodium-glucose co-transporter 2 inhibitors, and after major surgery.

Of the 350 cases reviewed, 39 (11.1%) developed PEDKA. Men and patients with pancreatic ductal adenocarcinoma were more likely to develop the condition. The study found that patients with PEDKA had significantly higher peak beta-hydroxybutyrate levels compared to those without the condition and were nearly four times more likely to require insulin at discharge. Decreased urinary output in the early postoperative period was also associated with PEDKA.

Pancreaticoduodenectomy is a complex abdominal operation that results in patients being in a prolonged fasting and inflammatory state. EDKA had never before been documented in patients undergoing pancreatic oduodenectomy. Jefferson Health researchers, led by Harish Lavu, MD, and Avinoam Nevler, MD, conducted a study to examine the incidence of EDKA after pancreaticoduodenectomy. The goal was to identify potential opportunities for early diagnosis and management of the condition in patients undergoing the procedure.

“This is the first large-scale descriptive study to investigate PEDKA,” the researchers reported. “Our study demonstrates that PEDKA manifests as ketoacidosis with elevated BHB, increased base deficit and relative euglycemia. PEDKA also correlates with decreased urinary output and increased short-term and long-term insulin requirements.”

The study, published in Surgery, involved a retrospective review of 350 patients who underwent pancreaticoduodenectomy at Jefferson Health between 2017 and 2020. Primary endpoints of the study were peak beta-hydroxybutyrate levels, peak lactate levels, lowest pH, peak base deficits and urinary output within the first 24 hours after

There was no association found between preoperative use of insulin at home and the incidence of PEDKA. The study also found no significant differences in length of stay, number of total complications, number of severe complications and 30-day readmission rates between PEDKA patients and non-PEDKA patients.

7.1

Pearson’s Coef: 0.33 P Value: 0.008

Max base deficit

Value

The pancreas is important for the endocrine regulation of key metabolic and physiologic processes, most notably glucose homoeostasis.

Pearson’s Coef: -0.19 P Value: 0.129

7.4

0 Pearson’s Coef: -0.28 P Value: 0.022

4 Max lactate 2

0 10000

Pearson’s Coef: -0.3 P Value: 0.016

7500 Total urine output volume

5000 2500 0 0

Peak Beta-Hydroxybutyrate [mg/dl]

Associations between peak-beta hydroxybutyrate and physiologic markers in the 24-hour perioperative period. Graphs demonstrating, from top to bottom, the association of peak peak-beta hydroxybutyrate with lowest pH, maximum base deficit, maximum lactate, and total urinary output volume. Note decreased association with maximum lactate, and decreased association with urinary output. Source: Harish Lavu, MD

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The study said the relatively common occurrence (just over 11%) of PEDKA “highlights the importance of awareness of the necessary preoperative and postoperative signs, including clinical findings and laboratory results.”

It concluded that the study’s findings provide “an opportunity to identify and successfully treat this disease in a timely manner,” and perhaps in doing so “reduce the risk of postoperative complications and improve patient outcomes.”

Hypercapnic Tissue Gene Expression and Survival in Early-Stage Pancreatic Ductal Adenocarcinoma Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second-leading cause of cancer-related deaths in the U.S. within a decade. While advances in diagnosis and treatment in recent years have led to a near two-fold increase in overall five-year survival for pancreatic cancer, it is still just over 11%. PDAC is characterized by tumor resistance to chemotherapy and radiotherapy. The pancreatic tumor microenvironment is uniquely austere because it is relatively hypovascularized, abundant in dense fibrotic stroma, poor in nutrients, hypoxic and hypercapnic (i.e., with increased levels of CO2). Previous in vitro research has suggested that a hypercapnic tumor microenvironment promotes cancer chemoresistance. Research has also suggested that early-stage PDAC patients who also have respiratory disorders associated with systemic hypercapnia, such as COPD, may have worse survivals rates. Jefferson Health researchers led by Avinoam Nevler, MD, conducted a study of tissue from 135 resected PDAC patients (Stage Ia-IIb) to investigate the impact of tissue hypercapnia on PDAC prognosis. The average age of the cohort was 65 and the median overall survival was 19.5 months. The study involved several steps. PDAC cancer-cell lines were cultured in normocapnic (5% CO2) and hypercapnic conditions (10% CO2). RNA was extracted, and whole-exome transcriptome was sequenced. Differentially expressed genes

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were then identified and used to construct a “hypercapnic gene set.” PDAC transcriptomic patient data obtained from the Tumor Cancer Genome Atlas were used to calculate single-sample gene set enrichment scores based on each patient’s tissue expression of the hypercapnic gene set, resulting in a patient-specific tissue hypercapnic score (HS). Researchers then correlated these scores with clinicopathological parameters and overall survival. The study found that patients with pancreatic tissue samples classified as hypercapnic (high HS) had larger tumors, greater lymph node involvement and considerably worse overall and disease-specific survival than patients with a lower HS. In active smokers, high HS also correlated with smoking pack-years. “These findings suggest that hypercapnia potentially induces a more aggressive cancer phenotype through a downstream pro-oncogenic signaling pathway, although the mechanism is not yet elucidated,” the researchers reported in the Journal of the American College of Surgeons. While research is still ongoing, it appears that the tumor hypercapnic score in early-stage disease may serve as an important predictor of oncologic outcomes. Dr. Nevler and his team are continuing their work on this novel pathway, and working to identify the specific genes that are involved in this aggressive cancer phenotype.

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One factor known to contribute to chemotherapy resistance in pancreatic cancer patients is poor drug diffusion into PDAC tumors, which have a dense and heterogeneous microenvironment. Novel methods are drastically needed to improve targeted delivery of cancer treatments to PDAC patients. Jefferson Health researchers Grace McCarthy, PhD, and Aditi Jain, PhD, evaluated in vivo the efficacy of one such method – the 3DNA® Nanocarrier, developed by Code Biotherapeutics. The DNA-based nanotherapeutic is designed to actively target specific tissues.

In a series of experiments, the researchers screened a panel of PDAC cell lines and a patient tissue microarray for established tumor-specific proteins to identify targeting moieties for active targeting by the 3DNA. NRG mice with or without orthotopic Mia PaCa-2-luciferase PDAC tumors were treated intraperitoneally with 100 µl of fluorescently labeled 3DNA. The researchers reported the results in Translational Oncology. They first found that folic acid and transferrin receptors were significantly elevated in PDAC compared to normal pancreatic tissue. Accordingly, both folic acid and transferrin-conjugated 3DNA treatments significantly increased delivery of 3DNA specifically to tumors when compared to control 3DNA treatment. When mice without PDAC tumors were compared to mice with tumors, there was an increased clearance of both folic acid-conjugated 3DNA and unconjugated 3DNA in the tumor-free mice compared to the tumor-bearing mice. The researchers also found that delivery of siLuciferase by folic acid-conjugated 3DNA in an orthotopic murine model of luciferaseexpressing PDAC showed significant and prolonged suppression of luciferase protein expression and activity.

C HPNE

MIA PaCa-2 PANC-1

HS766t

Transferrin Receptor 1.00

6.05

7.33

2.95

6.63

1.00

7.59

4.00

4.23

5.78

1.00

3.87

11.23

1.50

1.08

Transferrin Receptor 15

Panel

Folic Acid Receptor

Epidermal Growth Factor Receptor

b-actin

Tumor

Transferrin Receptor

Folic Acid Receptor Epidermal Growth Factor Receptor

Normal

4671-T

* **** **** ****

Folic Acid Receptor 15

* ** ***

Epidermal Growth Factor Receptor Relative Protein Expression (Normalized to HPNE)

The only curative therapy for pancreatic ductal adenocarcinoma (PDAC) is surgical resection for patients with early-stage disease, complemented with chemotherapy. However, for the majority of patients (>80%) tumors are unresectable and many patients present with metastatic disease (50-60%). At this stage, the standard of care involves giving patients a combination of systemic chemotherapies, but the drugs have limited clinical benefits while causing adverse side effects in many patients. The median survival rate is less than one year for patients with metastatic disease, though the overall five-year survival rate has risen from 2% to 12% in the last few decades.

Relative Protein Expression (Normalized to HPNE)

A Novel 3DNA Nanocarrier Effectively Delivers Payloads to Pancreatic Tumors

n.s.

30 n.s. * 20

****

Transferrin and folic acid receptors are highly expressed in pancreatic ductal adenocarcinoma. A) Representative Western blot analysis of transferrin receptor, folic acid receptor, and epidermal growth factor receptor from whole protein lysates of the normal immortalized pancreatic ductal cell line HPNE and a panel of PDAC cells (MIA PaCa-2, PANC-1, HS766t, 4671-T). Cell line 4671-T-CRC (4671-T) is a conditionally reprogrammed cell line from a primary PDAC tumor generated and gifted by Dr. Rosalie Sears from Oregon Health & Sciences University. Protein quantification depicted under each band was normalized to β-actin and relative to HPNE. B) Quantification of A. Average of relative protein expression ± standard error of the mean (n = 4). Statistical analysis was calculated using multiple student’s two-sample t-test. ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05, n.s. not significant. C) Representative immunohistochemistry staining for transferrin receptor, folic acid receptor, and epidermal growth factor receptor of patient tissues, both normal and PDAC, as well as the full panel of tissues. Source: Grace McCarthy, PhD and Aditi Jain, PhD

“Our study progresses the 3DNA technology as a reliable and effective treatment delivery platform for targeted therapeutic approaches in PDAC,” the researchers concluded. Further experiments are ongoing.

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Implementation of an Opioid Reduction Toolkit in Pancreatectomy Patients Significantly Increases Patient Awareness of Safe Practice and Decreases Amount Prescribed and Consumed Opioid abuse following surgery is a major concern. Opioid overdose has been the leading cause of injury-related deaths in the U.S. since 2015, with an estimated 6% of the population abusing opioids and an estimated 100,306 overdose deaths in 2021 alone, according to the federal Centers for Disease Control and Prevention. One route by which opioids enter the community is via diversion from legal prescriptions given to patients for pain relief by their providers. Jefferson Health researchers led by Ryan Lamm, MD, and Harish Lavu, MD, implemented and evaluated an opioid reduction toolkit aimed at increasing awareness among pancreatectomy patients of safe opioid use for pain control and safe disposal of any unused medication. The toolkit was incorporated into the electronic medical record and included data on opioid reduction and alternative pain control methods for patients; recommended number of opioid pills for pancreatectomy (15); and a modifications equation based on the number of pain medication doses received in the 24 hours preceding discharge. The toolkit was created at Jefferson in 2018 and implementation occurred from March 2018 to February 2021. “The intent was to reduce the number of opioids available to enter the community diversion pool as well as decrease patient

opioid exposure without compromising pain control,” the researchers reported in the journal HPB. A total of 159 patients were included in the study, including 24 patients who had open pancreatectomy before the opioidreduction toolkit was introduced and 135 pancreatectomy patients who received the intervention. No significant demographic or clinical differences existed between the groups. The analysis found that the median morphine milliequivalents (MMEs) prescribed were significantly reduced after the toolkit was introduced, declining from 225 MMEs in the pre-intervention group to 75 MMEs in the post-intervention groups. Median MMEs consumed were also significantly reduced, from 109 MMEs pre-toolkit to 15 MMEs with the toolkit. The analysis found that refill requests remained the same during the study, while patient awareness of safe disposal methods increased from 25% pre-intervention to 62% post-intervention, according to patient surveys conducted 14 days after surgery. “The results of this study and the implementation of the toolkit provide a blueprint by which other institutions can work toward reducing their opioid prescription quantities in pancreatectomy patients, as well as other major surgical

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procedures,” the study concluded, noting that previous research has shown that there are negative effects of opioid use after abdominal surgery besides the possible misuse or abuse of pills, including opioidinduced delayed gastric functioning, urinary retention and nausea/emesis.

The study also concluded that “more personalized pain control plans can help protect surgical patients from experiencing over-exposure to opioids and excessive postoperative pain.” The toolkit is is now in use for all patients undergoing pancreatectomy at Jefferson.

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