Pancreatic cancer

The average lifetime risk of pancreatic cancer is one in 65 with a five-year survival of 7%.

The lifetime Incidence is about 1%.

In 2016 the number of deaths from pancreatic cancer exceeded those from breast cancer, making it the third leading cause of cancer related deaths in the US.

Incident pancreatic cancer is rare, with 12.6 new cases diagnosed per 100,000 people in the US.

Highest incidence in North America and Europe.

Incidence varies geographically with the highest rates in more developed areas iand lower rates in less developed areas.

Second leading cause of death from gastrointestinal malignancies.

USPSTF does not recommend screening asymptomatic adults for pancreatic cancer.

Second most common site of GI malignancy after the colon.

A malignancy of middle to late adulthood.

Pancreatic cancer occurs more commonly in individuals living in Western industrialized countries, older individuals, males, and African Americans and native Hawaiians.

A sharp upsurge in incidence after age 50 years.

More than one third of cases diagnosed in patients older than 70 years.

More than half of patients diagnosed are greater than 60 years.

Median age at diagnosis is 71 years.

Less than 20% of patients present with localized, potentially curable tumors: Stage I and II.

30% of patients present with locally advanced stage III disease.

50% of patients present with metastatic disease.

Incidence increasing as a result of aging and the increased prevalence of obesity.

Mortality rates have remained largely unchanged.

Prevalence has increased due to an increasingly older population.

As the population age increases, the incidence of pancreatic cancer is expected to increase as well.

Rates are is higher in men than women 14.2 vs 11.1 per 100,000.

Rates in African-Americans vs whites among both men, 17 vs 14.2 per 100,000 persons and women 14.3 vs 11.1 per 100,000 persons.

Death to incidence ratio approaches 0.95.

First-degree relatives have at least a two fold increase risk of developing the disease, and the risk increases proportionally to the number of affected first-degree relatives.

Five-year survival remains at only 5%-7%.

5 year survival for patients with localized disease confined to the pancreas only 27%.

Associated with a high degree of symptom burden from pain, fatigue, gastrointestinal, and appetite issues, and emotional distress that significantly impairs overall functioning and quality of life.

Resectability is based on the probability of obtaining a margin negative resection (RO) by assessing circumferential degrees of contact, between the tumor and the arterial and venous structures (superior, mesenteric artery, celiac access, and common hepatic artery and venous portal or superior mesenteric vein structures).

Resectable pancreatic cancer is defined as a tumor vein contact of less or equal to 180° without vein contour irregularity, and no arterial contact.

Borderline resectable disease is defined as a tumor-vein contact of 180° or less with vein contour irregularity, a tumor artery contact of 180° or less, tumor – superior mesenteric, vein, or a portal vein contact of greater than 180°, but the site of involvement allows for safe and complete resection and vein reconstruction.

Unresectable/locally advanced, pancreatic cancer, refers to a tumor surrounding the vessel with greater than 180°, which surgery will have a low probability of obtaining an RO margin.

Tumors that circumferentially encase the celiac artery, hepatic artery, or the superior mesenteric artery greater than 180 degrees or have complete occlusion of the superior mesenteric vein or portal vein with no possibility of reconstruction are considered locally advanced and surgically unresectable.

5 year recurrence rate for patients with resectable pancreatic cancers and who achieve complete resection and treated with adjuvant therapy is about 80%: about 75% develop recurrence within two years.

Adjuvant therapy with FOLFIRINOXis recommended as standard adjuvant therapy individuals with excellent functional status after surgical resection of pancreatic duct adenocarcinoma.

In an adjuvant trial following surgery for pancreatic cancer FOLFIRINOX vs gemcitabine resulted in a median survival of 53.5 verses 35.5 months.

Five-year survival is now approaching 10% for the first time compared to 5.26% in 2000.

A low NLR ( neutrophil:lymphocyte) is a significant prognostic factor associated with long-term survival in metastatic pancreatic duct adenocarcinoma.

An autopsy study of patients who died of pancreatic cancer found that locally destructive disease was the cause of death in nearly 30% of patients.

The hypocellularity and dense stroma that surrounds the tumor, make it uniquely chemotherapy resistant.

There is a lack of distinctive signs and symptoms at the early stage allowing for delay and diagnosis.

The three most common symptoms include: decreased appetite, indigestion, and change in bowel habits.

Most patients remain asymptomatic until the disease reaches an advanced stage.

Approximately 70% of tumors arise in the head of the pancreas and often present with biliary obstruction leading to dark urine, jaundice, and loss of appetite, fatigue, weight loss, and exocrine pancreas insufficiency.

Common sites of metastases include: liver (90%), lymph nodes (25%), lung (25%), peritoneum (20%)), and bones (10-15%).6qq

Rare sites of metastases include: skin, brain, and leptomeninges.

Approximately 60 – 70% of pancreatic tumors arise in the head, needs tumors are more often associated with jaundice.

Approximately 20 – 25% of tumors arise in the body and tail of the pancreas.

Five years survival for patients with metastatic disease is about 2.6%.

One year survival rate about 25%.

Lifetime risk of pancreatic cancer in the U.S. is approximately 1%.

Peak incidence occurs in the seventh and eighth decades.

Incidence roughly equal for the sexes.

African-Americans have a higher incidence of pancreatic cancer than white Americans.

African-Americans have approximately 25% higher incidence than whites.

Results from successive gene mutations with origination in ductal epithelium and evolution from premalignant to invasive cancer.

Genetic pre-disposition syndromes include: BRCA1/2, Peutz-Jeghers syndrome, and Lynch syndrome.

Pancreatic cancer is dominated by a series of key driver oncogenes: KRAS, p53, CDK/N2A, and SMAD4.

Up to 10-15% of cases may be due to inherited family cancer.

Having a 1st degree relative with pancreatic cancer increases the odds of developing this lesion 1.76 fold compared to those without a family history.

20-30% of patients have thromboembolic events: One of the most prothrombotic cancers.

Estimated about 10% of patients with familial pancreatic cancer carry a BRCA2 mutation.

Among patients with BRCA mutation metastatic pancreatic cancer, progression free survival is longer with maintenance OLAPARIB than placebo.

Hereditary pancreatitis, of all hereditary conditions, confers the highest risk for developing pancreatic duct adenocarcinoma, with an approximate risk elevation of 40 to 50%.

Genetic risk factors include: hereditary breast and ovary cancer syndrome. ataxia-telangiectasia, familial atypical mold and melanomas syndrome, Lynch syndrome, hereditary pancreatitis, and Puetz-Jeghers syndrome.

As many is 80% of patients with a family history of pancreatic cancer there is no identifiable genetic cause.

Having a first-degree relative with pancreatic duct adenocarcinoma increases the risk of developing the disease up to 2-5 fold, and having to first-degree relatives with disease increases the risk to 6.4 fold.

25% secondary to environmental factors such as smoking, 10% have familial clustering, and 2% result from a mutation from a high risk Mendelian susceptibility gene.

Among lifestyle risk factors current cigarette smoking is the strongest association with PDAC (pancreatic ductal adenocarcinoma).

Most prospective epidemiological analyses report high BMI and lack of physical activity associated with increased risk.

Estimated that each five unit increment in BMI is related to a ten percent increase in the risk of pancreatic adenocarcinoma and the greatest risk is for those who have a BMI greater than 35 kg/ meter squared.

Long-standing type II diabetes is associated with increased risk with patients having diabetes 10 years in duration have a 1.51 fold increased risk compared with nondiabetics.

Anti-diabetic therapy modulates the risk of pancreatic cancer:patients treated with insulin or insulin secreatogogues are at higher risk, while those treated with metformin have significantly lower risk.

The risk of pancreatic cancer in patients taking metformin is a 62% lower than in placebo group who did not use metformin.

Diabetic participants having sulfonylureas or insulin were found to have a 2.5-fold and 5-fold higher risk of pancreatic cancer, respectively, in comparison to placebo group.

New onset diabetes can be the first sign of pancreatic cancer with up to 1% of such patients diagnosed within three years of their diabetes.

New onset diabetes may be an early sign of pancreatic cancer.

Estimated prevalence of secondary diabetes is approximately 8% of patients with pancreatic cancer.

The type of diabetes related to pancreatic dysfunction has been termed type 3C and links pancreatic conditions and diabetes.

Association of increased waist circumference and pancreatic cancer risk, especially in women, suggests the distribution of body fat may play a role.

Exocrine tumors represent 95% of pancreatic tumors.

Among exocrine tumors adenocarcinoma arises from pancreatic ducts accounts for 80% of malignant tumors of the pancreas.

Other exocrine tumors of the pancreas include: acinar cell carcinoma, intraductal papillary mucinous tumor, mutinous cystic tumors, and serous cystic tumors.

Endocrine pancreatic cancers represent 5% of cases and include islet cell and Neuroendocrine carcinoma.

Most cases are sporadic, but up to 10% of ductal adenocarcinomas may be due to an inherited process based on a familial clustering.

May be related familial cancer syndromes with germline mutations and include:Peutz-Jeghers syndrome with cumulative lifetime risk of 36%, familial atypical multiple mole and melanoma syndrome with the lifetime risk of 17%, hereditary breast/ovarian cancer syndrome with the lifetime risk 1.2% and 2.1% for BRCA1 and BRCA2 carriers, respectively, hereditary pancreatitis with the lifetime risk of 40% and familial due to mutations in the PALB2 gene (Kastrinos F).

Almost 5% of patients with pancreatic ductal adenocarcinoma have a germline BRCA1 or BRCA2 mutation.

About 15% of patients have germline mutations, such as BRCA, PALB2, ATM, and Lynch syndrome.

It is recommended that all patients with newly diagnosed PDAC undergo ger line  testing with the gene panel including BRCA1/2, ATM, MLH1, MSH2, MSH6, and PMS2.

EGFR often expressed by pancreatic tumors.

Median survival remains less than 1 year for advanced stages, and for early-stage resectable disease, 5-year survival is only around 25%.

Even with negative margins and R0 resection, recurrence rates are very high and additional therapies are required for all resected patients.

Median survival for patients with resected tumors after adjuvant therapy typically range from 20.1-28 months, although the recent study extended this to 54.1 months(Conroy T).

For each five unit increment in body mass index is related to a ten per cent increase

in the risk of cancer with the greatest risk for those with the body mass index greater than 35 kg/m2.

Although the lifetime risk of being diagnosed with pancreatic adenocarcinomas is very low, around 1.5%, approximately 10% of people who are diagnosed are estimated to have a hereditary predisposition based on a germline BRCA mutation.

In nearly 10-15% of all pancreatic ductal adenocarcinoma cases, a hereditary predisposition syndrome can be implicated.

Genetic syndromes associated with pancreatic ductal adenocarcinoma: Peutz-Jeghers, hereditary pancreatitis, familial atypical multiple mole melanoma, hereditary breast-ovarian cancer and hereditary nonmultipolyposis colorectal cancer syndromes.

With two or more first degree relatives with pancreatic cancer has been defined as familiar pancreatic cancers, and accounts for 4-10% of pancreatic duct adencarcinomas.

Long-term Aspirin Use and Lower Pancreatic Cancer Risk

The longer a person takes low-dose aspirin, the lower the risk for pancreatic cancer.

For every year of aspirin use, the risk for pancreatic cancer decreases by 6% with low-dose aspirin and by 2% with regular-dose aspirin.

The reduction in risk for pancreatic cancer is greater in people who started taking low-dose aspirin 20 years before study enrollment than in those who started 3 years before enrollment (60% vs 48%).

Discontinuation of aspirin use in the 2 years prior to the study enrollment was associated with a 3-fold increased risk for pancreatic cancer, compared with continued use.

People at increased risk for pancreatic cancer, such as those with appreciable family histories of pancreatic cancer or other cancers that might indicate an increased risk could benefit from low-dose aspirin.

Risk 57 times as high in families with 4 or more affected members compared to families with no affected members (Tersmette AC).

Risk for pancreatic cancer:

No identifiable features-Relative risk 1 Lifetime risk 0.5%

BRCA1 Relative risk 2x Lifetime risk 1.2%

BRCA2 Relative risk 3.5-10x Lifetime risk 2-5%

Lynch syndrome relative risk 8.6x Lifetime risk 3.86%

FAMMM Relative risk 20-34x Lifetime risk 10-17%

Familial PC Relative risk 32x Lifetime risk 16%

Hereditary pancreatitis 50-80x Lifetime risk 25-40%

Peutz-Jeghers sx Relative risk 132x Lifetime risk 66%

Acinar cell carcinoma, ductal adenocarcinoma and islet cell carcinoma occur in less than 1%, 95% and 5%, respectively.

Survival in 2 retrospective studies median survival for unresected ductal adenocarcinoma was 3 months, for unresected acinar cell carcinoma 25 months, for nonfunctional islet cell carcinoma 26 months and for functional islet cell carcinoma 54 months (Wisnoski NC, Halfdanarson TR).

Rates in high-risk populations are approximately 20 times higher than rates in low-risk populations.

Changes in pancreatic cancer over time are related to changes in smoking rates.

Current smokers have a 2.2 fold increased risk of pancreatic cancer compared with never smokers.

Approximately 25% of pancreatic cancers are attributable to smoking.

Pancreatic cancers resected from smokers have more mutations than pancreatic cancers from never smokers.

Smoking cessation reduces the risk of pancreatic cancer.

Risk estimates of 1.64 for patients for recent quitters of smoking (1-10 years), and of 1.124 individuals who quit smoking 15-20 years ago.

The oral pathogens Porphyromonas gingivalis and Aggregatibacter actinomyccetemcomitans are associated with an increased risk of pancreastic cancer, while an abundance of Fusobacteria and its genus Leptotrichia are associated with decreased risk.

5-year survival for all patients with a new diagnosis of pancreatic cancer is 4%, regardless of race or ethnicity.

For all stages combined the 1 year survival is about 20%.

Poor survival associated with the advanced stage at the time of diagnosis, in most cases.

Median survival 4-7 months.

5-year survival 7.2% for all patients.

5 year survival for 53% of patients that present with metastases at diagnosis is 2.4%

High-quality CT staging can accurate predict resectability in approximately 80% of patients.

CT scan may reveal a hypodense mass within the pancreas compared to the normal parenchyma.

CT depicts primary tumor as hypovascular compared to background pancreas and liver.

CT scans have a greater than 90% sensitivity for diagnosing primary pancreatic lesions greater than 2 cm, but sensitivity is less with smaller lesions.

CT scans have a greater than 90% sensitivity and greater than 80% specificity demonstrating vascular invasion.

CT scans are sensitive in detecting liver metastasis greater than 1 cm, but smaller lesions are problematic.

MRI somewhat less sensitive than CT (84% vs 91%) for diagnosing pancreas cancer but equivalent for determining resectability (Corsini MM et al).

MR cholangiopancreatography has a sensitivity and specificity of 85% and 96%, respectively, in differentiating and inflammatory pancreatic mass from a pancreatic carcinoma (Ichikawa T et al).

Age is the strongest risk factor with mean age about 65.

5-year survival 15%-24% in patients resected for cure.

Approximately 30% of patients with new diagnosis of PC lack evidence of systemic metastasis and have locally advanced disease, for which median overall survival is approximately one year.

With most favorable prognostic factors with small cancers <2cm, localized disease, no nodal metastases, no extension beyond the capsule, complete resection yields survival rates of only 18-24%.

More than 80 percent of patients have locally advanced or metastatic disease at the time of diagnosis and are ineligible for surgical resection.

Whipple procedure refers to the classical pancreaticoduodenectomy which includes resection of the head of the pancreas, the lower part of the body and pylorus of his stomach, proximal small bowel including the duodenum and the first 10-15 cm of the Jejunum, the common bile duct and cholecystectomy: The jejunum is anastomosed to the pancreas, bile duct and gastric stump.

Modifications of the Whipple procedure improve outcomes and decrease morbidity, and include preservation of the pylorus, total pancreatectomy, extended lymphadenectomy, and variations in pancreatic anastomoses.

Major postoperative complications are known to occur in 20 to 30% of patients after pancreatectomy.

Only 15%-23% of patients with pancreatic head lesions are potentially resectable.

Only 7% outpatients present with localized disease.

Patients with a body mass of >35 are more likely to have lymph node metastases, lower survival rates and higher recurrence rates in patients who undergo resection of disease (Fleming J).

Obese patients have a 12 fold greater risk of lymph node metastases compared to individuals with a BMI less than 35 (Fleming J).

Obese patients undergoing resection have decreased estimated disease, free and overall survival rates (Fleming J).

Local failure rates of 80% have been reported in some series (Kayahara).

Smoking the strongest risk factor amenable to preventive intervention.

Smoking, an environmental risk factor, is associated with 25% of all cases, and smoking cessation leads to a rapid reduction in risk for pancreatic cancer with the risk among former smokers approaching that for never smokers less than 10 years after quitting.

Smokers have a 2.5-3.6% increase risk compared to non smokers ans risk increases with duration and greater exposure to smoke (Hassan MM).

Risk factors include tobacco use, obesity, diabetes, pancreatitis and a positive family history.

Other environmental factors contributing to PC include: increase BMI, a high salt intake, high saturated fat diet, processed meats, heavy alcohol intake and increase utilization of nonsteroidal anti-inflammatory drugs.

Associated with low levels of physical activity.

Among patients with pancreatic ductal adenocarcinoma more than half are overweight or obese.

Obesity more than doubles the risk of death.

In the Cancer Prevention Study II (CPS-II), a long-term perspective: study self reporting alcohol intake of US adults 30 years and older indicated that alcohol consumption, specifically liquor consumption of three or more drinks per day increased pancreatic cancer mortality (Gapstur SM et al).

Some evidence there may be an association with chronic cirrhosis, high fat, high cholesterol diet and previous cholecysteomy.

Increased in patients with type A, B and AB compared to type O.

Occupational exposure to chemicals such as beta-naphthylamine and benzidine is associated with an increased risk.

Some evidence indicates increase consumption of red meat and dairy products associated with an elevated risk.

About 3.8–9.7% of patients with PDAC have pathogenic germline gene variance that occur mostly in DNA damage repair of genes.

Only 1% of patients with PDAC have inheritable germline variance in mismatch repair deficiency genes MLH1, MSH2, MSH6 and PMS2 as part of the Lynch syndrome.

A germline mutation of the CDKN2A (p16) gene has been reported in families with pancreatic cancer.

An excess of pancreatic cancer has been seen in patientsWITH BRCA2 mutation.

Increased risk WITH mutations in the PALB2 gene.

More favorable outcome for patients with performance status 0-1, T1-T2 lesions, no lymph node involvement or tumor encasement of superior mesenteric vessels or portal vein involvement.

Associated with new onset diabetes.

Chronic pancreatitis is a risk factor.

Patients may benefit from the use of pancreatic enzymes.

Nonspecific symptoms of nausea, impaired appetite, abdominal discomfort and weight loss lead to a delay in diagnosis.

Pain associated usually dull, epigastric and typically affects the back associated a result of invasion of splanchnic nerve plexus and retroperitoneum.

Pain typically worse when supine.

Lesions arising along the common bile duct and at the ampulla of Vater resulting in early extrahepatic biliary obstruction have a better prognosis than cancer originating elsewhere in the pancreas.

In the absence of jaundice associated biliary obstruction most tumors are diagnosed when the lesion is locally advanced or metastatic.

In a randomized trial a comparison between preoperative biliary drainage with surgery alone for patients with cancer of the head of the pancreas: the rates of serious complications were 39% in the surgery group and 74% in biliary drainage group, and surgery related complications occurred in 37% in the early surgery group and 47% biliary group, there was no difference in mortality linked of hospital stay between groups (van der Gaag NA).

In the van der Gaag study comparing surgical outcomes with preoperative ERCP for biliary drainage for 4-6 weeks, followed by surgery compared with surgery alone within one week of diagnosis of potentially resectable pancreatic cancer with biliary obstruction: the initial ERCP procedure failed in 25% of the cases, and after a second ERCP successful biliary drainage was achieved in 94% of the patients, and in the ERCP group 46% of patients experienced pancreatitis, perforation, bleeding and cholangitis.

Tumors that develop near major veins and arteries are difficult to remove surgically.

In the above study plastic stents were used and not self expanding metal stents which have a longer patency and fewer stent related problems then plastic stents because they are larger.

Poor outcome associated with gross tumor or residual disease after resection, invasion of major vessels, perineural or lymphatic invasion.

In patients with resectable pancreatic adenocarcinoma the overwhelming majority of patients with RO resections, even with negative lymph nodes, still die from metastatic disease.

BRCA2 gene important in familial pancreas cancer.

Among patients treated with surgery alone 80% develop local recurrence, 25% peritoneal recurrence and 50% liver metastases.

Surgical resection the standard for management.

The standard of care for resectable pancreatic cancer is neoadjuvant chemotherapy with FOLFIRINOX, followed by pancreatic resection and adjuvant chemotherapy within 12 weeks of surgery.

Stage I and II pancreatic cancer does not involve major blood vessels and is generally respectable.

Stage III disease is considered borderline resectable.

Unresectable stage III PC involves major blood vessels.

Locally advanced pancreatic cancer has a greater tumor involvement than borderline pancreatic resectable cancer and is unsuitable for reconstruction of the superior mesenteric vein or portal vein owing to the occlusion by a tumor or thrombus, or to more extensive tumor involvement.

Stage IV disease is associated with distant metastases.

With surgical resection alone the median overall survival is 11-20 months as a result of local and distant cancer recurrence.

Almost all patients with complete resection and negative nodes develop postoperative recurrence as late as 7 years after diagnosis (Katz MH et al).

The above indicates that even localized pancreatic disease is a systemic disease.

Neurolytic celiac plexus block improves pain control in patients with pancreas cancer but does not quality of life or survival.

Pain present in up to 73% of patients at the time of diagnosis.

Up to 85% of patients with advanced pancreas cancer have pain.

50% of patients present with jaundice.

90% of patients have stage 3 or 4 disease at diagnosis.

Optimal treatment and the role of chemoradiation for patients with locally advanced pancreatic cancer is unclear.

Most studies in local advanced pancreatic cancer suggests that radiation therapy is best sequenced after 3 to 4 months of chemotherapy in those patients that do not manifest systemic recurrence during that interval of time.

The capital Federation Francophone de Cancerologie Digestive and Societe Francophone de Radiotherapie Oncologique Demonstrated improved overall survival with gemcitabine alone compared with induction chemoradiation followed by gemcitabine chemoradiation with 5-FU/cis-platinum for localized pancreatic cancer.

The Eastern Cooperative Oncology Group 4201 trial compared gemcitabine alone with gemcitabine-based chemoradiation with improve survival with the chemoradiation arm.

When surgery and chemoradiation are used to maximize locoregional tumor control, liver metastases become the predominant form of tumor recurrence.

Fewer than 5% of patients with pancreatic body and tail lesions are potentially resectable.

Resection of localized disease extends survival to 17 months, compared to 8 months overall for patients with localized disease.

5-year survival rate for patients with localized disease is 8%.

Patients with resectable localized disease have a 5-year survival of 25%.

Patients with regional pancreatic cancer the median survival is 7 months and the 5-year survival is 3%.

Patients with regional pancreatic cancer and treated with resection have a median survival of 11 months and a survival of 10%.

Patients with advanced local disease have a median survival of 6-10 months.

90-95% of pancreatic cancers harbor Kras oncogene point mutation.

The G12D single amino acid mutation of the KRAS family is the most frequent KRAS mutation and occurs in 41% of patients with pancreatic cancer.

High likelihood of TP53.

Substantial percentage of patients have increased expression of Secreted Protein and Rich in Cysteine (SPARC), also known as osteonectin.

SPARC expression 82% by micro array analysis and 100% by immunohistochemistry.

SPARC expression is a marker of poor prognosis, independent of tumor size, lymphatic spread and positive margins after resection.

SPARC + patients have 15 months survival and stromal SPARC – patients a median survival of 30 months following resection (Infante).

SPARC may play a role in concentrating Abraxane in pancreatic cancers.

SPARC in stromal fibroblasts within the pancreatic microenvironment is considered an important cause of chemotherapy resistance and is associated with a poor prognosis.

Nab-paclitaxel binds to SPARC and can increase vasculature and is associated with higher gemcitabine concentrations in the tumor.

Diagnostic laparoscopy can spare 4-13% of patients a laparotomy for unsuccessful attempt at resection.

Randomized study of Gastrointestinal Study Group in 1985 indicated significant improvement in median and long term survival over resection alone with postoperative 5FU/radiotherapy. (median survival 21 months for adjuvant treatment vs. 11 months for surgery alone, 2 year survival of 43% vs. 18% and 5-year survival for adjuvant treatment of 19% vs. 5% for surgery alone.

Adjuvant chemotherapy does improve survival in patients after resection of pancreatic cancer.

Adjuvant chemotherapy after neoadjuvant chemo therapy with FOLFIRINOX and resection of pancreatic cancer is associated with improved survival only in pathology proven node positive disease.

Neoadjuvant therapy in pancreatic carcinoma improves margin negative resection rates.

In patients  with borderline resectable pancreatic carcinoma, neoadjuvant radiation following FOLFIRINOX was associated with more node negative disease and better  pathological response in patients who underwent resection, yet no difference in overall survival was found: routine use of RT was not recommended (Jannssen QP).

Preoperative radiation therapy does not increase survival in patients with pancreatic cancer.

Median survival with gemcitabine monotherapy 5.7 months.

A phase III randomized trial of 126 patients with advanced pancreatic cancer patients were randomized to gemcitabine vs. 5FU was associated with a 23.8% clinical benefit in the gemcitabine group and 4.8% benefit in the 5FU treated group:the median survival was 5.65 and 4.41 months for gemcitabine and 5FU treated patients, respectively.

Median survival with gemcitabine plus cetuximab 7.1 months.

Small survival benefit for gemcitabine plus erlotinib.

Combination of pancreaticoduodenectomy with postoperative chemotherapy and external beam radiation improve survival and locoregional control.

FOLFIRINOX is superior to gemcitabine as adjuvant therapy after pancreatectomy.

Neoadjuvant therapy is an established standard for patients with borderline resectable disease, because it improves overall resection rates, RO resection, and survival.

The addition of adjuvant therapy after neoadjuvant therapy and pancreatic resection, improves survival.

Stereotactic body radiation for unresectable pancreatic cancer in a Stanford University study of 25 Gy 1 fraction plus adjuvant gemcitabine associated with the new survival of 12.7 months (Schellenberg D et al).

Stereotactic body radiation for unresectable pancreatic cancer with 30 Gy with 3 fractions plus gemcitabine had a median survival of foreign points 6 months at the San Bartolo Hospital (Polistina F et al).

Stereotactic body radiation for unresectable pancreatic cancer by the Beth Israel-Deaconess Hospital treated with 24-36 Gy over three fractions with gemcitabine was associated with a median survival all 14.3 months (Mahadevan A et al).

5FU low response rate 0-9% even with leucovorin modulated treatment, using infusional or bolus therapy, with a median survival range of 10-24 weeks.

Initial study of gemcitabine as monotherapy 27% improve as far as pain, performance status or weight is concerned and only 11% have objective tumor response.

In subsequent studies gemcitabine alone associated with a 24% response rate and 18% one year survival rate.

Capecitabine combined with gemcitabine in phase 3 trials in patients with metastatic pancreatic cancer demonstrated a survival benefit in for the combined therapy (Cunningham D), but the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group with the same drugs failed to demonstrate any survival benefits: median survival was 8.4 months in the combination and 7.2 months in the single agent arm.

The combination of gemcitabine and bevacizumab resulted in a median survival of 8.7 months with a 1-year survival rate of 29%.

Trials comparing gemcitabine versus 5-fluorouracil or combinations of gemcitabine with 5-fluorouracil, cis-platinum or irinotecan have shown no benefit over gemcitabine alone.

Gemcitabine vs gemcitabine with oxaliplatin (GEMOX) for unresectable cancer revealed a response rate of 27% for the combination treatment compared to 17% for single agent gemcitabine with progression free survival of 5.8 months for GEMOX vs 3.7 months for gemcitabine with no statistical difference in median survival, although there was a trend toward improvement for the combination treatment.

A combination of 5FU, leucovorin, irinotecan, and oxaliplatin (FOLFIRNOX) associated with an overall survival of 11.1 months compared to 6.8 months for patients on gemcitabine alone, approximately 48% of patients were alive at one year compared to 20% of patients who received gemcitabine, median progression free survival was 6.4 months compared to 3.3 months for those treated with gemcitabine ( Conroy T et al).

The PRODIGE4/ACCORD II phase III trial randomized 342 patients with metastatic pancreatic adenocarcinoma to six months of FOLFIRINOX or gemcitabine alone: a significant overall survival for theFOLFIRINOX armed with a median survival of 11.1 months versus 6.8 months indie gemcitabine arm, waited 18 months survival rate of 18.6% for the combination arm versus 6% in the gemcitabine arm, the response rate was 31.6% for the combination arm and 9.4% with a single agent therapy.

FOLFIRINOX compared to gemcitabine in a phase III study had a 31% partial response rate compared to 9.4% in the gemcitabine treated patients, median progression free survival was 6.4 months versus 3.3 months, and the median overall survival was 11.1 months compared to 6.8 months (Conroy T).

FOLFIRINOX: Oxaliplatin 85 mg per meter squared, irinotecan 180 mg per meter squared, leucovorin 400 mg per meter squared on day one of a biweekly cycle, followed by 5FU bolus of 400 mg per meter squared and a 46 hour continuous infusion of 5FU 2400 mg per meter squared.

FOLFIRINOX use in locally advanced PC Is associated with conversion to resectability in 20% of patients, however, still a high chance of recurrence will occur.

Gemcitabine chemotherapy doublet chemotherapy is most beneficial for patients with good performance status.

Gemcitabine/nab-paclitaxel overall survival 8.5 months in patients with metastatic disease.

NAPOLI -1 trial of nanoliposomal irinotecan plus 5FU/LR overall survival in metastatic pancreatic cancer 6.1 months.

MPACT ( Metastatic Pancreatic Adenocarcinoma Clinical Trial) trial of nab- paclitaxel plus gemcitabine: nab- paclitaxel 125/ m2 plus gemcitabine 1000 mg/m2 days 1,8 and 15 q4weeks or gemcitabine alone-median overall survival 8.5 vs 6.7 months, 1 Year survival 35% vs 22%, 1year progression free survival 5.5% vs 3.7%, and overall response rate 23% vs 7% (Von Hoff DD et al).

Concurrent radiation and chemotherapy palliates locally advanced cancer with an improved survival to 12 months.

Cystic neoplasms represent less than 10% of pancreatic cancers.

EGFR frequently expressed in pancreas cancer.

Correlation exists between the co expression of EGFR and its ligands and the aggressiveness of pancreatic cancer.

Adjuvant therapy-ESPAC-1 (European Study Group for Pancreatic Cancer) studies four groups of 70 patients with surgery alone, chemotherapy alone, chemo radiation alone and chemo radiation followed by chemotherapy: median survival 20.1 months for those receiving chemotherapy and 15.5 months for those who did not receive chemotherapy and 2 and survival estimates were 40% and 21%, respectively among patients who received chemotherapy, compared to 30% and 8%, respectively, among patients who received no chemotherapy.

A combination of gemcitabine and nab-paclitaxel (Abraxane) administrated weekly for three weeks and repeated every four weeks has a 48% overall response rate, and one year survival rate of 53% (Van Hoff DD et al MPACT).

Presently the most effective chemotherapy for metastatic pancreatic carcinoma are FOLFIRINOX and nab-paclitaxel and gemcitabine (2017).

Phase III trial NAPOLI-1 indicated improved overall survival with combination of nano liposomal irinotecan plus fluorouracil and folic acid compared to fluorouracil and folinic acid in patients with metastatic resistant pancreatic cancer.

Adjuvant therapy-adjuvant chemotherapy-pancreatic cancer-ESPAC-1 (European Study Group for Pancreatic Cancer) concluded 5FU based chemotherapy has a survival advantage while chemo radiation offered no such benefit and in fact may be detrimental in adjuvant management of pancreatic cancer.

In a study comparing mFOLFIRINOX regimen to gemcitabine as adjuvant therapy for resected pancreatic cancer, a multicenter international randomized phase III trial (PRODIGE 24/CCTG PA.6trial) was performed(Thierry Conroy, MD (Institut de Cancerologie de Lorraine, France):The trial showed a significant improvement in survival with mFOLFIRINOXvs gemcitabine. Median DFS was 21.6 months with mFOLFIRINOXvs 12.8 months with gemcitabine, and 3-year DFS was 39.7% with mFOLFIRINOXvs 21.4% with gemcitabine.

In the above study patients in the mFOLFIRINOX arm also showed significantly improved median OS vs gemcitabine 54.4 months vs 35.0 months with 3-year OS rates of 63.4% vs 48.6% in the mFOLFIRINOXand gemcitabine arms, respectively.

Standard first line regimens for patients with metastatic sees include gem it’s one and albumin bound paclitaxel or modified FOLFIRINOX.

Pancreatic cancer vaccine comprised of killed pancreatic cancer cells transfected with GM-CSF gene in surgically resected patients had an 88% and 76% survival rate at 1 and 2 years, respectively compared to 63% and 42% after 1 and 2 years with resection only.