This essay is dedicated to Sheila Kasselman, who devoted her life to battling pancreatic cancer.
It expands on our strategic plan to substantially reduce cancer deaths by discussing what the medical community has learned from studying pancreatic cancer. I have also added my own conclusions, which are not yet part of the medical consensus on this disease.
The American Cancer Society projects that in 2023, pancreatic cancer will cause 50,550 U.S. deaths (26,620 men, 23,930 women) and will be the third leading cause of U.S. cancer death after lung and colorectal cancer. By 2026, it is projected to become the second leading cause of U.S. cancer death because (a) its incidence has been increasing by 1% per year since the late 1990s due to increases in type 2 diabetes and obesity and (b) colorectal cancer deaths continue to decrease. Americans have a 1.7% lifetime risk of pancreatic cancer based on 2017-2019 data.
Pancreatic cancer in the United States
Where is the pancreas?
The pancreas is located behind the stomach in a region deep in the abdomen called the retroperitoneum.
Pancreatic cancer has a 5 year relative survival rate of only 12% (based on data from 2012-2018), the lowest of all major cancers, although it has improved from 3% during 1975-1977. Five year survival varies based on the extent of the disease: local 44%, regional 15% and disseminated (distant disease) 3%. Only 12% are diagnosed with local disease and 48% are diagnosed with distant disease (SEER, accessed 5Mar23). The most common type is pancreatic ductal adenocarcinoma.
Images of Pancreatic ductal adenocarcinoma
Sources: Wei Chen, M.D. and Claudio Luchini, M.D., Ph.D., unless otherwise indicated
This total pancreatectomy specimen includes part of the small intestine (on the left, opened to reveal its folds), the gallbladder (brown-green area in the upper half), the pancreas (in the middle, red and horizontal but the tumor is not apparent) and the spleen (tan-gray on the right, surrounded by fat).
In this cut specimen, the tumor is evident as a large, irregular, yellow mass. The normal pancreas (small amounts in the center) is tan, fat is orange, pancreatic ducts are oval and appear to be sticking out, the spleen (red) is on the right and black ink was applied by the pathologist to determine if the tumor is at the margin of the surgical excision.
Pancreatic cancer in the tail, close to the spleen
The cut surface of this tumor is gray-white and appears above the normal appearing tan-yellow lobular pancreas. Pancreatic ducts and vessels are surrounding the tumor.
This image shows sectioning of the pancreas from proximal (the head, closest to the small intestine) to distal (the tail, closest to the spleen). The tumor (gray-white) starts in the third section from the left and continues toward the distal pancreas. Ducts and vessels with clotted blood are apparent. Ducts with a blue center are actually empty but appear blue due to the background.
A malignant cystic pancreatic tumor (mucinous cystic neoplasm) with the adjacent small intestine
Metastatic pancreatic cancer to the liver shows many large, irregular tumor deposits.
Imaging studies in asymptomatic patients frequently identify pancreatic cystic lesions that may be benign, premalignant or malignant. It is important to work up and follow up on these lesions so that changes associated with pancreatic cancer can be detected early.
We estimated the attributable risk of death for pancreatic cancer for each risk factor below (i.e., the percentage of deaths in the entire population that can be attributed to the exposure) to be
Random chronic stress / bad luck - 25-35%
Non O blood group - 17%
Excess weight - 15% (particularly when it begins at younger ages)
Cigarette smoking (tobacco) - 15%
Type 2 diabetes - 9%
Excessive alcohol use - 5%
Diet - 5%
Family history / germline - 2%
Chronic pancreatitis - 1%
Random chronic stress or bad luck appears to be the most common "risk factor" for pancreatic cancer, accounting for 25-35% of U.S. cases. Random chronic stress refers to rare, unanticipated cellular events that promote malignancy due to errors during cell division of either DNA replication, DNA organization or distribution of cell components. We estimated it causes a baseline rate of 2 cases out of 7.6 cases per 100,000 people per year from all causes in the U.S. (age standardized).
What are common cell division (DNA) errors?
DNA errors and repair. In figure a, the nucleotide G is paired incorrectly with the nucleotide T (A should be paired with T) during DNA replication. In figure b, the nucleotide G should be paired with the nucleotide C but is erroneously paired with T. In figure c, the 2 T nucleotides form an inappropriate dimer or pair, which disrupts the DNA duplication process. The DNA repair process corrects these and other mistakes and reduces the error rate to as low as 1 per 10 billion nucleotides. However, since there are 3 billion nucleotides in each dividing human cell, errors will still happen.
Small errors, such as those during DNA replication and repair, can cause malignancy based on the theory of self-organized criticality. The biological networks underlying human life are poised at a critical state (tipping point) in which small disturbances typically cause no network changes, occasionally cause small network changes and rarely set off a cascade of changes in the initial network and those it interacts with leading to premalignant or malignant changes.
What does pancreatic cancer look like microscopically?
Normal pancreas. Duct lined with columnar ductal epithelium and 2 islets of Langerhans on the right.
Islet and duct. Source: University of Leeds
Low power images of pancreatic ductal carcinoma show disruption of the usual pancreas architecture with a diffuse and haphazard distribution of irregular, malignant appearing glands within fibrous tissue. The normal pancreatic tissue is obliterated.
Malignant pancreatic ducts (high power). Random chronic stress or other risk factors, acting together over decades, can transform the precursors of the normal pancreatic duct cells into malignant ducts with marked variation in nuclear size (pleomorphism) and abnormal positions in the tissue.
It is recommended that all patients with pancreatic cancer undergo risk assessment for associated hereditary syndromes because 7% have familial components and 3% have hereditary components.
As with other cancers, the risk of pancreatic cancer increases with age; the average age at diagnosis is 70 years. Almost all patients are older than 45 and two-thirds are at least 65 years.
Pancreatic cancer is deadly in part because the metastatic process begins early due to microscopic seeding of distant organs while the pancreatic tumor is still developing. Although these initial "seeds" are nonmalignant, they become malignant at the same time that the pancreatic tumor becomes malignant, assisted by chronic inflammation caused by various risk factors and by the malignant process itself. This is why metastases are often found when the main cancer is discovered.
Curative treatment of pancreatic cancer
No single treatment is likely to be curative for pancreatic cancer due to the variable (heterogeneous) nature of the cancer and the large areas of tissue that may be affected. In addition, aggressive tumors and widespread disease are accompanied by systemic changes different in character from those present in tumor cells. Thus, destroying the tumor itself will not cause biological networks outside the tumor to revert to normal and they may continue to support and create new tumors.
To attain high cure rates, we propose combining treatment strategies that affect as many aspects of the malignant process as possible, including
(1) kill as many tumor cells as possible, using multiple, distinct methods to address tumor cell heterogeneity;
(2) attack multiple targets within each targeted network because biologic pathways are weblike, not linear, allowing cancer cells to bypass important steps blocked by antitumor agents;
(3) target the microenvironment that nurtures tumor cells at primary and metastatic sites because tumors require a fertile "soil" for the cancer "seeds" to grow (i.e. target the vasculature, inflammatory cells and their products and the extracellular matrix or cellular infrastructure);
(4) disrupt the chronic inflammation produced by many risk factors that promote the malignant and metastatic processes through varied mechanisms, including by reactivating cancer cell proliferation at distant sites;
(5) target the hyperinsulinemia or insulin resistance that promotes tumor growth;
(6) counter tumor associated immune system dysfunction;
(7) identify and target genetic changes associated with tumor promotion;
(8) move tumor cells that survive treatment toward less hazardous states;
(9) identify, reduce and counter the effects of patient related chronic stressors or risk factors;
(10) identify and eliminate premalignant and early lesions through more effective screening;
(11) enroll as many patients as possible in clinical trials to determine how to optimize effectiveness and reduce side effects of this large number of treatments;
(12) promote overall patient health to improve the efficacy of treatment and allow patients to tolerate more treatment options.
