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After reading this article, the reader should be able to:
• Describe the usual type and location of pancreatic cancer and its most significant environmental risk factor.
• Identify the presenting symptoms of pancreatic cancer with regard to tumor location and disease stage.
• Discuss the difficulties associated with the early detection of pancreatic cancer and the primary imaging modality used for its diagnosis and staging.
• Justify the role of neoadjuvant therapy in pancreatic cancer.
• Summarize the advantages and drawbacks to pancreatoduodenectomy.
Activity Launch Date: October 2016
Expiration Date: October 2017
This CME activity does not have any commercial support.
A 54-year-old woman and long-term smoker develops jaundice, pruritus and an unintentional 10-pound weight loss. She is referred to Indiana University Health for evaluation. Computed tomography (CT) reveals a 3.0 cm hypodense tumor within the head of the pancreas associated with dilatation of the pancreatic and common bile ducts and involvement of the superior mesenteric artery and vein (Figure 1 see page 2). No radiographic evidence of liver or peritoneal metastases is present. Endoscopic ultrasound (EUS)-guided fine needle biopsy of the pancreatic head confirms a stage III poorly differentiated adenocarcinoma.
Overview of Pancreatic Cancer
Pancreatic cancer is one of the most aggressive and lethal malignancies, with median survival less than one year and fewer than five percent of patients alive five years after diagnosis. Today, the disease is the fourth leading cause of US cancer-related deaths and is predicted to move up to second by 2020 and rank first by 2025.1 The American Cancer Society estimates that in 2016, 53,000 people will be diagnosed with pancreatic cancer, and nearly 42,000 will die of the disease.2
Pancreatic cancer rarely occurs before age 45, with incidence rising sharply thereafter and peaking between 60 and 80 years. Men are more frequently affected than women, and prevalence is higher among blacks than whites or Asians. The majority of cases (95 percent) develop as adenocarcinomas arising from ductal cells of the exocrine pancreas. Seventy percent of these malignancies occur in the head of the gland, 20 percent in the body, and 10 percent in the tail.3
Risk Factors and Symptoms
Approximately 90 percent of all pancreatic cancers are sporadic, with tobacco smoke the most significant environmental risk factor. Depending on the duration and extent of tobacco exposure, the risk of pancreatic cancer among smokers is 2.5 to 3.6 times that of non-smokers.4 Other risk factors for the disease are diabetes mellitus; nonhereditary chronic pancreatitis; obesity or inactivity; and possibly, heavy alcohol consumption.5 Certain precursor lesions are also linked the development of this malignancy, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm.6 Among the 10 percent of patients with hereditary pancreatic cancer, a subgroup may have identified genetic alterations, such as the STK11 mutation associated with Peutz-Jeghers syndrome, and the PRSS and SPINK1 mutations linked to hereditary pancreatitis.7
The presenting symptoms of pancreatic cancer depend on tumor location within the gland and disease stage. Tumors in the head of the pancreas may cause upper abdominal pain (possibly radiating to the back) and nausea that are insidious in onset and gradually progress over time to anorexia, weight loss, and asthenia. Jaundice is a characteristic sign that results from compression of the common bile duct. Occasionally, a tumor may extend to the duodenum or stomach, causing gastric outlet obstruction. While tumors in the pancreas body and tail are far less likely to cause obstructive signs and symptoms, upper abdominal pain radiating to the back is often a feature of advanced disease in these locations.
Pancreatic cancer is so deadly because most patients are diagnosed with an advanced stage of disease. There currently are no effective methods for the early detection of sporadically occurring tumors.
Pancreatic cancer is so deadly because most patients are diagnosed with an advanced stage of disease. There currently are no effective methods for the early detection of sporadically occurring tumors. CA 19-9, a Sialyl Lewis carbohydrate antigen, is the only biomarker for the disease with demonstrated clinical usefulness.8 CA 19-9 has an overall sensitivity and specificity of approximately 80 percent when used for therapeutic monitoring and detection of recurrent cancer. Its sensitivity is considerably lower for early-stage disease and obviates its use for screening purposes.* Results of routine blood tests are generally nonspecific and may include mild abnormalities in liver function tests, hyperglycemia, and anemia.
Nonetheless, novel methods for the early detection of pancreatic cancer are under investigation, according to Michael House, MD, general surgeon and director of the Pancreatic Cancer Program at Indiana University Health and associate professor of surgery at Indiana University School of Medicine.
“Within the next five years, we may have a peripheral blood test capable of detecting circulating pancreatic cancer cells that can be used to screen the general population—particularly high-risk individuals,” he reports. “For patients at increased risk because of a family history of the disease, IU Health already has an aggressive screening program in place. The Early Pancreatic Cancer Detection Program incorporates genetic counseling, EUS, and cross-sectional imaging with CT or magnetic resonance imaging (MRI).”
Diagnosis and Staging
CT is the standard examination for diagnosing pancreatic cancer, identified by the presence of a low attenuation, hypovascular lesion that is hypodense in about 11 percent of cases.3 Indirect CT findings of a tumor are dilation of the biliary tree and main pancreatic duct and atrophy of the distal pancreas.
Some patients require additional studies to confirm the diagnosis. MRI has poorer spatial resolution and tissue diagnosis than CT but is good for imaging ductal structures and detecting cystic tumors of the pancreas. EUS is useful when pancreatic cancer is suspected but no visible mass is identified on CT. EUS-guided fine needle aspiration is the preferred method of obtaining tissue for evaluation, which is required before chemotherapy or radiation therapy is initiated.9
Pancreatic cancer is staged on the basis of CT or MRI assessment of surgical resectability, which in turn is determined by involvement of adjacent vascular structures and the presence of distant metastases (Table 1). T1, T2, and T3 tumors are potentially resectable; T4 tumors, which involve the superior mesenteric ar tery or celiac axis, are considered unresectable.10 Contrast-enhanced CT with dual ar terial and venous phases predicts surgical resectability with 90 percent accuracy.11
The patient undergoes endoscopic retrograde cholangiopancreatography (ERCP) with placement of a self-expanding metal stent (Figure 2) for biliary drainage, which resolve the jaundice and pruritus. Because her cancer is considered borderline resectable, she undergoes neoadjuvant chemoradiation beginning with six cycles of multi-agent systemic therapy that includes fluorouracil, irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX) administered over three months. Cross-sectional CT imaging performed at the completion of chemotherapy confirms the disease has not progressed. Stereotactic body radiotherapy (SBRT) is initiated following EUS-guided fiducial placement adjacent to the pancreatic head. A total radiation dose of 33 Gy is delivered in five fractions over two weeks.
Surgical resection with macro- and microscopic tumor clearance offers patients with pancreatic cancer their only chance for prolonged survival and, perhaps, a cure. Yet only 20 to 25 percent are considered candidates for surgery.12 Furthermore, as many as 10 percent of patients with presumed localized, resectable disease may actually harbor radiographically occult metastases.13
“Neoadjuvant therapy provides a window of opportunity to assess biologic response to treatment and informs clinical decision-making regarding the risks and benefits of surgery and the possibility of early postoperative disease recurrence,” explains Dr. House. “While a major goal of neoadjuvant therapy is to convert unresectable to resectable tumors and to increase microscopic complete tumor resection rates, systemic chemotherapy also offers the possibility of prolonging survival for patients whose tumors cannot be surgically removed.”
Data from two phase 2 clinical trials14,15 and two single-center studies16,17 involving patients with potentially resectable pancreatic cancer found that those who completed neoadjuvant therapy and surgery experienced a longer than expected duration of overall survival (up to 44.9 months), as compared with those treated with surgery alone. Importantly, neoadjuvant therapy neither increased surgical morbidity nor contributed to delayed postoperative recovery. Also noteworthy: a meta-analysis of 111 studies involving more than 4300 patients found that approximately one-third of patients initially staged as having non-resectable pancreatic cancer would be expected to have resectable tumors following neoadjuvant therapy.18
Fluorouracil was the standard palliative treatment for pancreatic cancer until 1997, when a randomized controlled trial showed slightly improved survival among patients treated first-line with gemcitabine.19 In recent years, there has been growing interest in incorporating multiagent chemotherapy, such as FOLFIRINOX, in pre- and postoperative regimens. A systematic review and meta-analysis of patients with locally advanced tumors found that FOLFIRINOX extended survival to 20.2 months versus six to 13 months with gemcitabine alone.20
Clinical trials of FOLFIRINOX and combination therapy with gemcitabine plus albumin-bound paclitaxel particles for patients with pancreatic cancer are underway (NCT01591733, NCT01688336, and NCT01560949). IU Health is currently enrolling patients in a phase 2 trial of FOLFIRINOX neoadjuvant chemotherapy before operative resection.
Local disease progression remains a significant cause of morbidity and mortality for patients with pancreatic cancer, with one autopsy series finding that 30 percent died with locally destructive disease and only minimal systemic disease.21
“Stereotactic body radiation therapy is an emerging treatment option for pancreatic cancer that has the potential for increasing the biologically effective tumor dose by using higher doses of radiation per fraction without surrounding tissue injury,” explains Dr. House. “Clinical study data show that SBRT delivers localized therapy safely to the tumor with minimal interruption to systemic chemotherapy.”22,23
Four weeks after completing neoadjuvant chemoradiation, the patient undergoes an uncomplicated pancreatoduodenectomy (Whipple operation) with portal vein resection and reconstruction. Final pathology confirms a margin-negative (R0) resection and shows a moderate primary tumor response to chemoradiation. Thirty-five lymph nodes are examined, one of which is positive. She is discharged from the hospital on postoperative day five.
Full recovery is observed four weeks after surgery, and systemic chemotherapy is resumed.
Pancreatoduodenectomy is performed to remove tumors in the head and neck of the pancreas. (Tumors in the body or tail are removed via distal pancreatectomy, which typically includes splenectomy.) The Whipple is a complex procedure associated with significant perioperative morbidity (e.g., pancreatic fistula formation, bleeding, sepsis) and potential mortality, and longterm outcomes are poor. Even after a R0 resection, the majority of patients with pancreatic adenocarcinoma develop recurrent disease locally, regionally, and/or distantly. Thus, the estimated five- and 10-year survival after pancreatoduodenectomy is just 18 and 11 percent, respectively.
“Although the impact of surgery on duration of life may be limited the Whipple operation favorably affects the quality of remaining life when the tumor can be completely removed,”24 Dr. House points out. “Moreover, when patients with pancreatic cancer undergo this surgery at high-volume multidisciplinary centers,* outcomes are improved.25-27
“The reasons for this improvement are not limited to surgical knowledge, individual skills, and experience,” continues Dr. House. “Other contributing factors include appropriate treatment sequencing, expert perioperative care, intensive care unit availability, and 24/7 access to imaging and interventional radiology.”
The pancreatic cancer genome is complex and heterogeneous, with 63 genetic alterations identified to date.28 In the future, increased understanding of the molecular pathology of the disease will pave the way toward more tailored treatment options. Some promising avenues under investigation include:
• Targeting specific signaling pathways that regulate tumor growth, progression, invasion, metastasis, and chemoresistance to induce tumor regression.
• Modulating the tumor stroma, which is dense and poorly vascularized, to improve drug penetrance to the tumor.
• Immunotherapy to stimulate the pre-existing immune response to tumor-associated antigens (vaccination) or induce passive immunity via the exogenous administration of immunomodulators.
• Stem cell therapy to eliminate pancreatic cancer stem cells, which are capable of self-renewal, highly resistant to conventional chemoradiation, and primarily responsible for tumor recurrence.
• Inhibiting cancer metabolism to selectively starve cancer cells.
• Harnessing nanotechnology to enhance therapeutic drug delivery.
These future treatments must be coupled with strategies for early detection, for despite advances in surgery and chemoradiation, very few patients with pancreatic cancer achieve a cure because their tumors grew in silence for many years. The average time between mutation occurrence and primary tumor formation is 10 years, and another decade ensues before a patient dies of the disease.29
“Earlier detection together with the development of more effective, personalized treatment strategies are key to improving the prognosis for patients pancreatic cancer,” Dr. House concludes.
Dr. House received his medical degree from Harvard Medical School in Boston, MA, took his surgical training at the Johns Hopkins University School of Medicine in Baltimore, MD, and completed fellowships in surgical oncology and hepatopancreatobiliary surgery at Memorial Sloan-Kettering Cancer Center in New York City. His clinical interests are focused on the management of primary and secondary hepatic neoplasms, bile duct tumors, and benign and malignant diseases of the pancreas.
Dr. House is a principal or co-investigator of eight clinical trials at IU School of Medicine, where he also is a council member for the CTSI Biorepository and an associate member of the Molecular and Environmental Carcinogenesis Program. He is a core group member of the Gastrointestinal Cancers Committee of the American College of Surgeons Oncology Group and a member of the leadership committees for the Americas Hepato-Pancreato-Biliary Association and the Association for Academic Surgery.
Dr. House is the author of more than 100 journal articles and textbook chapters, serves on the editorial board of the Annals of Surgical Oncology, and has presented at numerous scientific meetings in the United States and internationally. He received the IU School of Medicine Class of 2015 Outstanding Professor in Clinical Sciences Award, the IU School of Medicine Trustee’s Teaching Award in 2013 and 2014, and the Department of Surgery Resident Teacher of the Year Award in 2013, 2014, 2015, and 2016.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921.
2. American Cancer Society. Cancer Facts and Figures 2016.
3. Ansari D, Tingstedt B, Andersson B, et al. Pancreatic cancer: yesterday, today and tomorrow. Future Oncol. 2016;12(16):1929-1946.
4. Hassan MM, Bondy ML, Wolff RA, et al. Risk factors for pancreatic cancer: case-control study. Am J Gastroenterol. 2007;102(12):2696-2707.
5. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371(11):1039-1049.
6. Hruban RH, Maitra A, Kern SE, Goggins M. Precursors to pancreatic cancer. Gastroenterol Clin North Am. 2007;36(4):831-849, vi.
7. Klein AP. Identifying people at a high risk of developing pancreatic cancer. Nat Rev Cancer. 2013;13(1):66-74.
8. Harsha HC, Kandasamy K, Ranganathan P, et al. A compendium of potential biomarkers of pancreatic cancer. PLoS Med. 2009;6(4):e1000046.
9. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605-1617.
10. Bilimoria KY, Bentrem DJ, Ko CY, et al. Validation of the 6th edition AJCC Pancreatic Cancer Staging System: report from the National Cancer Database. Cancer. 2007;110(4):738-744.
11. Karmazanovsky G, Fedorov V, Kubyshkin V, Kotchatkov A. Pancreatic head cancer: accuracy of CT in determination of resectability. Abdom Imaging.
12. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225-249.
13. Asare EA, Evans DB, Erickson BA, Aburajab M, Tolat P, Tsai S. Neoadjuvant treatment sequencing adds value to the care of patients with operable pancreatic cancer. J Surg Oncol. 2016.
14. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3496-3502.
15. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3487-3495.
16. Miura JT, Krepline AN, George B, et al. Use of neoadjuvant therapy in patients 75 years of age and older with pancreatic cancer. Surgery. 2015;158(6):1545-1555.
17. Christians KK, Heimler JW, George B, et al. Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy. Surgery. 2016;159(3):893-900.
18. Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):e1000267.
19. Burris HA, 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-2413.
20. Suker M, Beumer BR, Sadot E, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol. 2016;17(6):801-810.
21. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27(11):1806-1813.
22. Tozzi A, Comito T, Alongi F, et al. SBRT in unresectable advanced pancreatic cancer: preliminary results of a mono-institutional experience. Radiat Oncol. 2013;8:148.
23. Herman JM, Chang DT, Goodman KA, et al. Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer. 2015;121(7):1128-1137.
24. Chan C, Franssen B, Dominguez I, Ramirez-Del Val A, Uscanga LF, Campuzano M. Impact on quality of life after pancreatoduodenectomy: a prospective study comparing preoperative and postoperative scores. J Gastrointest Surg. 2012;16(7):1341-1346.
25. Schmidt CM, Turrini O, Parikh P, et al. Effect of hospital volume, surgeon experience, and surgeon volume on patient outcomes after pancreatoduodenectomy: a single-institution experience. Arch Surg. 2010;145(7):634-640.
26. Ziegler KM, Nakeeb A, Pitt HA, et al. Pancreatic surgery: evolution at a high-volume center. Surgery. 2010;148(4):702-709; discussion 709-710.
27. Soreide JA, Sandvik OM, Soreide K. Improving pancreas surgery over time: Performance factors related to transition of care and patient volume. Int J Surg. 2016;32:116-122.
28. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801-1806.
29. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114 1117.