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Pancreatic Cancer
- 1. What links these4 together?Michael LandonPavarottiPatrick Swayze Joan Crawford
- 2. Pancreatic Cancer: Advancesin TreatmentHisham Rana, MD
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- 4. Epidemiology4th commonest causeof cancer death in US, 2nd only to colorectal cancer in GI cancers37,680 pts diagnosed annually – almost all die Rare before the age of 45. Incidence rises sharply thereafter.Males > females (ratio 1.3:1)African Americans (14.8 per 100,000 v 8.8 gen pop)40-45%: present with metastatic disease40%: present with locally advanced disease5-25%: present with tumors amenable to resection
- 5. Risk Factors: Genetic5-10%pts have 1st degree relative with disease. Presents at an earlier age.BRCA1 & BRCA2Peutz-Jeghers syndrome: risk >36%Ataxia-telangiectasia: risk increasedFamilial adenomatous polyposis & Lynch Syndrome II (HNPCC)Above factors account for only < 20% of cases
- 6. Risk Factors: EnvironmentalCigarettesmoking: RR 1.5. Quitting reduces risk by 48% by 2 years.Obesity & Lack of physical activityWestern DietCoffee & Alcohol consumption: conflicting evidence.Aspirin & NSAIDsPartial gastrectomy & cholecystectomyH. pylori
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- 10. Jaundice: Painful vs.Painless
- 11. Initial presentation: Bodyor tail vs. Head
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- 16. OtherDiagnosis & StagingLabs:bilirubin, alkaline phosphatase, Hb/HctRadiographicUltrasound, CT & CT Angio, ERCP, EUS, MRI and MRCP, PET ScanningSerum Tumor MarkersFNA Biospy: Percutaneous & EUS-guidedStaging Laparoscopy
- 17. Pathology: Cell Types3different epithelial cell typesAcinar cells (80% by gland volume)Ductal cells (10-15%)Endocrine (islet) cells (1-2%)95% of malignant pancreatic neoplasms arise from acinar and ductal cells
- 18. Pathology: Ductal &Acinar CellDuctal Carcinoma – 85-90%
- 19. 60-70% tumors inhead of gland, 5-10% in body, and 10-15% in tail
- 20. Masses with ill-definedmargins or diffusely infiltrating
- 21. Varying degrees ofdifferentiation in the same tumor
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- 24. Large & metastaticat time of diagnosis
- 25. Resembles endocrine cells– needs EM or IHC studiesPrognosisTiming of disease-associated symptomsMedian survival: 8-12 months for locally advanced unresectable disease, and 3-6 months for those who present with metastases
- 26. TreatmentWhat do wedo now?
- 27. Approach to thePatientMass lesion not seen on CT or UltrasoundMass lesion in a candidate for major pancreatic resectionCriteria for resectabilityMass lesion in a patient who is unfit for a major pancreatic resection
Editor's Notes
- #5 In the United States, approximately 37,680 patients are diagnosed with pancreatic adenocarcinoma annually, and almost all are expected to die from the disease [1] . Surgical resection is the only potentially curative treatment for pancreatic cancer. Unfortunately, because of the late presentation of the disease, only 15 to 20 percent of patients are candidates for pancreatectomy. Furthermore, the prognosis of pancreatic cancer is poor even in those with potentially resectable disease. The five-year survival following pancreaticoduodenectomy is only about 25 to 30 percent for node-negative, and 10 percent for node-positive tumors. Pancreatic cancer is rare before the age of 45, but the incidence rises sharply thereafter. The incidence is greater in males than females (male-to-female ratio 1.3:1), and in blacks (14.8 per 100,000 in black males compared to 8.8 per 100,000 in the general population) [2] .Some data suggest that the overall incidence of pancreatic cancer is declining over time, at least in the United States
- #6 A role for familial aggregation and/or genetic factors is suggested by the fact that 5 to 10 percent of patients with pancreatic cancer have a first degree relative with the disease. In multiple case-control and cohort studies of kindreds with familial aggregations, the odds ratio of developing pancreatic cancer ranges from 1.5 to 5.25. Patients from affected families present at an earlier age than those with noninherited disease, and smoking appears to contribute to the risk of developing pancreatic cancer in affected families.Segregation models support a dominant susceptibility gene for pancreatic cancer that is carried by approximately seven in every 1000 individuals . Hereditary factors can predispose to pancreatic cancer directly or indirectly, as with hereditary chronic pancreatitis.Germline mutations in known cancer-causing genes, such as BRCA1 and especially BRCA2 are present in some of these kindreds. BRCA2 mutations are found in 12 to 17 percent of patients with familial pancreatic cancer.In individuals with Peutz-Jeghers syndrome, the lifetime risk may be as high as 36 percentAtaxia-telangiectasia is associated with an increased risk of pancreatic cancer.Although not as well defined, there may also be an increase in risk in familial adenomatous polyposis and the Lynch syndrome II (non site-specific hereditary nonpolyposis colorectal cancer [HNPCC]).
- #7 Cigarette smoking — In multiple cohort and case-control studies, the relative risk for developing pancreatic cancer among smokers was at least 1.5. Excess risk decreases with smoking cessation. In a large prospective study, the relative risk of pancreatic cancer among current smokers was 2.5. The risk fell by 48 percent by two years after discontinuing smoking, and leveled off 10 to 15 years after stopping, eventually falling to the level of nonsmokers. It has been estimated that cessation of smoking could eliminate approximately 25 percent of pancreatic cancer deaths in the United StatesObesity and physical activity — Several studies suggest a link between high body mass, lack of physical activity, and pancreatic cancer risk. A body mass index (BMI) of at least 30 kg/m2 was associated with a significantly increased risk of pancreatic cancer compared with a BMI of less than 23 kg/m2.Height -- was also associated with an increased risk (relative risk 1.81, 95% CI 1.31-2.52)Diet -- Studies evaluating the relationship between diet and pancreatic cancer are inconclusive. A "Western" dietary pattern (high intake of fat and/or meat, particularly smoked or processed meats) has been linked to the development of pancreatic cancer in many but not all studies. Several but not all case-control studies report a protective effect from the consumption of fresh fruits and vegetables, and prospective studies have not observed such an association. Lower serum levels of lycopene (a carotenoid present in fruits) and selenium have been found in subjects who subsequently developed pancreatic cancer.Aspirin and NSAID use — Laboratory data suggest a possible inhibitory effect of aspirin and other NSAIDs on pancreatic tumorigenesis. However, available epidemiologic data in humans are conflicting. Compared to nonusers, participants who ingested 14 or more aspirin tablets weekly (but not fewer) for four or more years had a significantly increased relative risk of pancreatic cancer (RR 1.86). The findings did not change appreciably when obesity and smoking were taken into account. Despite these data, studies of other large cohorts have not found any link between aspirin use and pancreatic cancer risk, even among individuals using aspirin ≥ 30 times monthly for over 20 years.History of partial gastrectomy or cholecystectomy — A two to five fold increased risk of developing pancreatic cancer 15 to 20 years after partial gastrectomy has been described [92] . An increased incidence has also been observed in patients who underwent cholecystectomy. A possible explanation for both associations is elevated levels of circulating cholecystokinin, since exogenous cholecystokinin promotes the growth of transplantable human pancreatic adenocarcinoma cell lines.Helicobacter pylori — An association between H. pylori infection and pancreatic cancer has been reported [99,100] , and a link proposed between H pylori, chronic hyperacidity, and an increased risk of pancreatic cancer.
- #9 Routine laboratory tests may reveal a rise in the serum bilirubin concentration and alkaline phosphatase activity, and the presence of mild anemia. The diagnosis of pancreatic cancer, however, is typically made radiographically and histologically.Ultrasound — The initial study in patients who present with jaundice is usually abdominal US. Dilated bile ducts or the presence of a mass in the head of the pancreas suggest the presence of a pancreatic tumor. Depends on Usongrapher.CT and CT angiography — CT scan has a better sensitivity than, and similar specificity to US especially in non-jaundiced patients. CT may reveal bile and pancreatic duct dilation, a mass lesion within the pancreas, and evidence of extrapancreatic spread including liver or lymph node metastases and ascites. Non-contrast enhanced studies yield little information and have poor sensitivity/specificity rates for small tumors. Contrast enhanced, helical and phased studies provide the most reliable staging information.Helical CT combined with a bolus administration of intravenous contrast (CT angiography) can provide particularly useful information regarding major vessel involvement that reflects surgical unresectability.ERCP — It is most useful if the CT or US does not reveal a mass lesion or if chronic pancreatitis is in the differential diagnosis. Findings suggestive of a malignant tumor include superimposable strictures or obstruction of the common bile and pancreatic ducts (the "double duct" sign), a pancreatic duct stricture in excess of 1 cm in length, pancreatic duct obstruction, and the absence of changes suggestive of chronic pancreatitis. Tissue samples can be taken but sensitivity is lower than EUS guided FNA biopsy.EUS is very operator-dependent. EUS appears to be most useful for diagnosis of small tumors (eg, less than 2 to 3 cm in diameter) and may also be helpful for evaluating the possibility of nodal and major vascular involvement except for the superior mesenteric vein and artery.MRI and MRCP — Routine MRI offers no significant diagnostic advantage over contrast-enhanced CT for the staging workup of pancreatic cancer. MRCP is better than CT for defining the anatomy of the biliary tree and pancreatic duct, has the capability to evaluate the bile ducts both above and below a stricture. At least as sensitive as ERCP in detecting pancreatic cancers [22,23] , and unlike conventional ERCP, does not require contrast material to be administered into the ductal system. Thus, the morbidity associated with endoscopic procedures.PET scanning: controversial. Increased serum glucose levels lead to increased false negatives. PET useful in detection of small volume metastatic disease.Serum Tumor Markers: cancer associated antigen 19-9 (CA 19-9). Very high = unresectable. Serial monitoring of CA 19-9 levels (once every one to three months [41] ) is useful to follow patients after potentially curative surgery.Percutaneous biopsy — Percutaneous FNA biopsy of a pancreatic mass can be performed using either US or CT guidance. Very high specificity. Some concern of tracking tumor cells along needle path in potentially resectable patients. Even though risk is low transduodenal EUS guided avoids these concerns.EUS-guided biopsy — EUS-guided FNA is increasingly being used as a tool for both the diagnosis and staging of pancreatic cancer, even in patients who otherwise have resectable tumorsStaging laparoscopy — Laparoscopy alone or with laparoscopic ultrasonography is emerging as a new staging modality for periampullary tumors (ie, those involving the head of the pancreas, lower one-third of the bile duct, ampulla of Vater, and first three parts of the duodenum). Small occult metastases (<1 cm in diameter) on the surface of the liver or peritoneum which are rarely visible by CT, MRI, or transabdominal US may be visualized by this modality.
- #10 Three different epithelial cell types can be found in the normal pancreas: acinar cells (which account for about 80 percent of the gland volume), ductal cells (comprising 10 to 15 percent), and endocrine (islet) cells (about 1 to 2 percent) [2] . Over 95 percent of the malignant neoplasms of the pancreas arise from the exocrine elements of the gland (ductal and acinar cells), and demonstrate features consistent with adenocarcinoma. Endocrine neoplasms account for only 1 to 2 percent of pancreatic tumors, and nonepithelial malignancies are exceedingly rare.
- #11 Ductal carcinoma accounts for 85 to 90 percent of pancreatic tumors [4] . In autopsy series, 60 to 70 percent of tumors are localized in the head of the gland, 5 to 10 percent in the body, and 10 to 15 percent in the tail. The average size of carcinomas in the head of the gland is 2.5 to 3.5 cm, compared to 5 to 7 cm for tumors in the body or tail.Grossly, these tumors present either as firm masses with ill-defined margins blending into the surrounding pancreatic parenchyma, or as diffusely infiltrating lesions. Ductal adenocarcinomas elicit a strong desmoplastic reaction which is responsible for their hard consistency on gross inspection. Microscopically, ductal adenocarcinomas are graded as well, moderately, or poorly-differentiated. Well-differentiated tumors show irregular tubular neoplastic glands with mild cellular atypia, low mitotic activity, and significant mucin production.Varying degrees of differentiation, even within the same tumor, can be seen; distinction of malignant cells from normal cells or from cells distorted by pancreatitis may be difficult in some cases. These tumors often are morphologically heterogeneous, with intermixed malignant cells, normal cells, inflammatory cells, and areas of desmoplasia.Microscopic tumor extension is often evident in lymphatic channels and perineural spaces [7] . Extension to lymph nodes occurs at an early stage and is associated with a poor prognosis .Acinar cell carcinoma — Cancers with an acinar cell phenotype comprise about 1 percent of pancreatic exocrine cancers. They usually occur in elderly individuals. These tumors are frequently large and already metastatic at the time of diagnosis. Areas of necrosis within the tumor are common.The tumor cells can resemble endocrine cells. Their identification as acinar cells may require electron microscopy or immunohistochemical studies, showing that they contain zymogen granules and digestive enzymes. Despite this feature, these tumors have a more aggressive course than pancreatic endocrine tumors
- #12 The majority of patients have unresectable disease by the time disease-associated symptoms occur and the diagnosis is made. Several studies have addressed whether earlier detection of nonspecific signs of an evolving pancreatic neoplasm might improve resectability and overall outcomes.Most signs and symptoms occurred within three years prior to diagnosis. The symptoms and signs that were significantly more likely to be reported by individuals harboring pancreatic cancer included abdominal pain, appetite loss, jaundice, pale-colored stools, unusual belching, weight loss, and unusual bloating.Atypical diabetes mellitus (eg, new onset glucose intolerance arising in a thin older adult) precedes the diagnosis of pancreatic cancer in a substantial number of cases. In a population-based study from the Mayo Clinic, adults with new onset diabetes were eight times more likely to be diagnosed with pancreatic cancer within three years than the general population.CT scans done at the time of newly diagnosed diabetes in otherwise asymptomatic patients were more likely to show potentially resectable tumors than scans performed six months later [11] . Whether higher resectability rates translate into higher cure rates was not addressed. However, CT screening of all older subjects with new onset diabetes in order to discover a small number of pancreatic cancers is not feasible.
- #14 Mass lesion not seen on CT or ultrasound — When no mass lesion is detected on CT or ultrasound, an ERCP should be performed to exclude biliary tract stones or some other non-neoplastic cause of symptoms. The ERCP may also confirm the suspected diagnosis of pancreatic tumor if a periampullary mass is detected or if malignant appearing strictures of the pancreatic and/or bile duct are found.Mass lesion in a candidate for major pancreatic resection — When a mass lesion of the pancreas is detected on CT or US, it is reasonable to conclude that a neoplasm (most likely malignant) is present and no further diagnostic tests are needed for patients who are otherwise fit to undergo a major pancreatic resection. Attempts to make a tissue diagnosis in such patients are not useful since a benign sample does not exclude the presence of a neighboring malignancy and, in the absence of a diagnostic sample, one must assume that the lesion is malignant. Attempts to make a preoperative tissue diagnosis may in fact be detrimental if tumor cells are disseminated during percutaneous biopsy.Thus, for surgically fit patients, we operate without attempting to establish a preoperative diagnosis of malignancy. However, it must be recognized by both the clinician and the patient that uncertainty regarding the diagnosis in these instances persists and that some patients with benign lesions may be subjected to the radical resections.Focal chronic pancreatitis and autoimmune pancreatitis are the two benign processes most commonly mistaken for pancreatic malignancy on the basis of CT or US. In fact, the majority of patients found to have benign disease after undergoing radical resection for presumed malignancy suffer from one of these conditions. These diagnoses can sometimes be suspected on the basis of history (eg, extreme young age, prolonged ethanol abuse, history of other autoimmune diseases). In this subset of patients, further imaging studies (either ERCP or MRCP), may be particularly helpful if they reveal multifocal biliary strictures (suggestive of autoimmune pancreatitis) or diffuse pancreatic ductal changes (suggestive of chronic pancreatitis). The frequency of radical resection for benign disease may be reduced when this approach is combined with EUS-guided transduodenal biopsy.Determining resectability — The next issue for patients who have a mass lesion and who are surgical candidates is determining resectability. Most surgeons limit radical resections to the management of patients with potentially curable lesions. This usually requires that the tumor does not involve sites that would not be encompassed within the resection and that the tumor does not involve adjacent critical vascular structures such as the SMA/SMV, portal vein, celiac axis, or hepatic artery.There are two approaches that might be taken to resolve this issue: a traditional approach and an alternative approach.Traditional approach — The traditional approach involves a contrast-enhanced helical CT scan with timed image sequences that permit evaluation of vascular structures and subtle metastatic implants (ie, CT angiography with phased images and thin cuts). The lack of major vascular involvement by tumor was associated with a resectability rate of over 90 percent. Partial involvement of the SMV and/or SMA on CT angiography was associated with a resectability rate of 10 to 50 percent depending upon the extent of the vascular involvement. For jaundiced patients with no involvement or minimal involvement of the major vessels and no evidence of distant metastases, we proceed directly to an attempt at surgical resection. For non-jaundiced patients (ie, those with body or tail tumors), or those with major but incomplete involvement of the vascular structures, we perform preoperative laparoscopy to exclude tiny metastases that might have been overlooked by CT. If the laparoscopy was negative, we then embark on a radical surgical resection.Alternative approach — Management of patients using the above described "traditional approach" will result in operating on some 10 to 15 percent of patients with tumors that cannot be considered surgically "curable" (ie, they are found to invade the critical peripancreatic vascular structures, distant organs, or distant nodes at the time of attempted resection). Some have advocated performance of additional preoperative "staging" studies to identify such patients and spare them an unnecessary laparotomy. According to this alternative approach, patients with lesions felt to be potentially curable on the basis of helical CT angiography are studied further by MRCP, EUS, laparoscopy, and/or laparoscopic US.Mass lesion in a patient who is unfit for a major pancreatic resection — For patients who are unfit to undergo a major resection, a tissue diagnosis should be made to permit palliation by endoscopic, chemotherapeutic, or radiotherapeutic means. This can be accomplished either by percutaneous (CT or US guided) fine needle aspiration biopsy or by endoscopically obtained brushings or biopsies. Endoscopic biopsy can frequently be aided by EUS guidance.
- #15 The use of preoperative biliarystenting is controversial. Although experimental studies in jaundiced animals suggest that preoperative biliary drainage improves surgical outcomes, clinical studies have not consistently shown a benefit in patients with obstructive jaundice who then undergo resection. In fact, some report deleterious effects, including an increased risk of cholangitis and longer postoperative hospital stay.The standard operation for pancreatic cancer within the head or uncinate process of the pancreas is pancreaticoduodenectomy/whipple. It involves removal of the pancreatic head, duodenum, first 15 cm of the jejunum, common bile duct, and gallbladder (show figure 1). A partial gastrectomy is also performed. Pancreatic and biliaryanastomoses are placed 45 to 60 cm proximal to the gastrojejunostomy.In the past, pancreaticoduodenectomy was associated with high morbidity and mortality rates. However, modern series show that in experienced hands, the standard Whipple procedure is associated with a five-year survival of 20 to 30 percent in completely resected patients with a perioperative mortality rate of less than 4 percent.Modifications attempt to improve outcome or minimize the morbidity. Ultraradical surgery, including resection of the portal vein, total or regional pancreatectomy, and retroperitoneal lymphadenectomy. Pylorus-preserving pancreaticoduodenectomy, which decreases the incidence of postoperative dumping, marginal ulceration, and bile reflux gastritis that can occur in many patients undergoing partial gastrectomy.BODY/TAIL: Because adenocarcinomas involving the body or tail of the pancreas usually do not cause obstruction of the intrapancreatic portion of the common bile duct, early diagnosis is rare; the vast majority have locally advanced or metastatic disease at the time of presentation. In the rare patients who appear to have potentially resectable disease by computed tomography scan, laparoscopic exploration should precede attempted resection, since a significant proportion will have occult peritoneal metastases. Surgical resection of cancers located in the body or tail of the pancreas consists of a distal subtotal pancreatectomy, usually combined with splenectomy. The scant data available regarding the outcome of surgical resection suggest a short survival, high perioperative mortality rate [68] , and poor prognosis compared to those with cancers involving the head of the pancreas.The prognosis for pancreatic cancer has been poor even with surgically negative margins in appropriately selected patients. Large series show five-year survival rates of only 10 to 25 percent, and median survival between 10 and 20 months. The most important prognostic factor in completely resected patients is nodal status. Five-year survival after pancreaticoduodenectomy is only about 10 percent for node-positive disease, while it is 25 to 30 percent for node-negative disease. Other predictors of a favorable outcome include a tumor size less than 3 cm, negative margins, location in the head (rather than body or tail) well-differentiated tumors, and intraoperative blood loss of less than 750 mL.3 to 5 survival rates as above. Worse as the staging goes up even in the setting of completely resected, node-negative pancreatic cancer, the majority of patients die of their pancreatic cancer.
- #16 As a general rule, pancreatic cancers are considered unresectable if any of the following are present [2] :1. Extrapancreatic involvement, including extensive peripancreatic lymphatic involvement, and/or distant metastases.2. Encasement or occlusion of the superior mesenteric vein (SMV), or the SMV-portal vein confluence. Some centers are revisiting this criterion and are demonstrating the feasibility of SMV reconstruction [3] .3. Direct involvement of the superior mesenteric artery (SMA), inferior vena cava, aorta, or celiac axis, as defined by the absence of a fat plane between the low density tumor and these structures on CT scan.
- #17 EBRT alone does not provide optimal palliation or tumor control; local failure rates are as high as 72 percent. Now considering r adiation sensitizers, including 5-fluorouracil (5-FU), gemcitabine, and most recently, paclitaxel.A addition of concurrent chemotherapy to EBRT improves outcomes compared to EBRT alone in patients with locally advanced pancreatic cancer. From the standpoint of symptom palliation, cancer-related pain is diminished in 35 to 65 percent of patients, and cachexia and obstructive symptoms may also improve. However, the survival benefit from chemoradiotherapy relative to EBRT alone is modest, and local control remains problematic.5-FU: Based upon the experience in other gastrointestinal malignancies such as rectal cancer, infusional rather than bolus 5-FU has become the most commonly used approach for radiation sensitization. Most studies have evaluated combined 5-FU and EBRT, which are synergistic in other gastrointestinal malignancies. Two early randomized trials directly comparing EBRT with and without concomitant 5-FU-based chemotherapy came to opposite conclusions. It provides a modest survival benefit over supportive care alone and infusional 5-FU is often considered the standard of care for locally advanced pancreatic cancer in the United States.The observation that gemcitabine has potent radiation sensitizing effects, in conjunction with its demonstrated clinical benefit in metastatic pancreatic cancer provided the rationale for investigating its use in patients with locally advanced disease. Treatment was relatively toxic: grade 3 or 4 hematologic toxicity in 60 percent, grade 3 or 4 gastrointestinal toxicity in 42 percent, and one treatment-related death attributed to sepsis. Although median overall survival was a disappointing 8.2 months, two patients were still alive at 35 and 41 months of posttreatment follow-up.Paclitaxel is a potent radiation sensitizer, and may be particularly beneficial for the many pancreatic cancers that harbor p53 mutations. Response rates were low. Toxcity was high. Median survival was 11.2 months.
- #18 The treatment of pancreatic cancer pain includes pharmacotherapy, chemotherapy and/or radiotherapy, psychosocial support, celiac/splanchnicneurolytic blocks, and epidural or intrathecal infusion of medications .Initiation of long-acting narcotics such as extended-release oralmorphine, oxycodone preparations, or transdermalfentanyl coupled with their immediate-acting counterparts to address breakthrough pain. Intermittent, postprandial epigastric discomfort, suggesting pancreatic enzyme insufficiency, may be successfully palliated with the initiation of pancreatic enzyme replacement therapy (PERT) alone.Neurolytic celiac plexus block (NCPB) is typically reserved for tumor-associated pain that fails to respond adequately to systemic narcotic analgesics. NCPB is likely to have prompt and long-lasting analgesic efficacy for pancreatic cancer. Partial or complete pain relief in 90% of people.PERT: Patients with pancreatic cancer are vulnerable to pancreatic enzyme deficiency and the associated malabsorption resulting from tumor-associated pancreatic duct obstruction as well as the tumor- or surgery-associated loss of normal pancreatic parenchyma Symptoms of exocrine insufficiency may include abdominal discomfort and/or distension, pain, excessive flatus, belching, diarrhea, steatorrhea, and weight loss. Several preps on market (Pancrease, Lipram, Protilase). Does depends on symptoms of malaborption or steatorrhea. PPI can optimize the efficieny of PERT therapy. In patients still not responding then evaluate and empirically treat bacterial overgrowth. Bovine-based products exist but are inferior to porcine-based.Endoscopic stenting of Biliary and Pancreatic Obstruction. Biliary tract obstruction may lead to jaundice, pruritus, abdominal discomfort, nausea, malabsorption, and hepatic dysfunction. In unresectable patients, obstructive jaundice is routinely managed by endoscopic placement of plastic or metal biliary stents. In addition to the relief of jaundice and pruritus, biliary decompression has been shown to improve quality of life by increasing appetite and reducing indigestion. Metal stents chosen over plastic for their superior patency (8 months versus 4 months). Main indication is obstructive pain related to meals in patients. Though its rarely used. Only 15% of patients will have symptoms that will benefit from this intervention.
- #19 The goal of systemic therapy for metastatic pancreatic cancer is to minimize disease-related symptoms and prolong survival. The superior survival outcomes achieved with 5-fluorouracil (5-FU)-based combinations compared with best supportive care (BSC) alone provided an initial validation of chemotherapy benefit for advanced pancreatic cancer patients. The median survival times associated with 5-FU were consistently in the 6-month range. However, in a meta-analysis, 5-FU combinations did not demonstrate a survival benefit when compared with 5-FU alone.Because of its favorable toxicity profile and modest ability to palliate typical pancreatic cancer symptoms, single-agent gemcitabine has been the global reference regimen for this disease since its approval in 1996. Gemcitabine is a deoxycytidine analogue structurally related to cytarabine (cytosine arabinoside) originally investigated for its antiviral effects. It is a prodrug that requires cellular uptake and intracellular phosphorylation (metabolites are active). Gemcitabinetriphosphate competitively inhibits DNA chain elongation, leading to DNA fragmentation and cell death.The median survival times for gemcitabine and 5-FU patients were 5.65 and 4.41 months, respectively. The survival rate at 12months was 18%for gemcitabine patients and 2% for 5-FU patients.Myelosuppression is the main toxicity associated with gemcitabine. However, postmarketing surveillance has documented rare occurrences of acute lung, liver, and kidney injury. Therefore, gemcitabine-induced acute lung injury should be considered if new symptoms such as cough or dyspnea develop, and consistent monitoring of renal and hepatic function should be included in the follow-up of patients treated with gemcitabine. Gemcitabine is a renally cleared drug. One phase I evaluation study in patients with hepatic or renal dysfunction showed that patients with baseline hyperbilirubinemia were at risk for liver function deterioration with gemcitabine. AST/ALT raised makes no difference.Optimizing efficiency: Optimal dose and schedule of gemcitabine have not been identified. < 1 week intervals and infusion times > 60 minutes to increase uptake resulted in greater toxcitiy without clinical benefit. Fixed dose rate infusions showed a lot of promise in Phase II trials but failed to show statistical benefit in Phase III. Infusion rates are also limited because of the rate-limiting step in the phorphoylationintracellularly. Regular schedule is 1000mg/m2 over 30 minutes weekly.
- #20 Because of its unique mechanism of action and favorable nonhematogical toxicity profile, investigators have undertaken intense efforts to develop gemcitabine-based combinations that offer at least additive benefit for pancreatic cancer patients. With the exception of the gemcitabine plus capecitabine experimental arm reported by Cunningham et al. [35] in abstract form only as of this review, these efforts have failed to identify a gemcitabine-based chemotherapy doublet that has produced significantly better median or 1-year survival outcomes.Even the gemcitabine and capecitabinecombionation has proven controversial with clinical trials showing varying results. In some cases it only improved median survival times by 4 weeks with increasing toxicity.Gemcitabine followed by oxaliplatin (GemOx) showed median overall survival time of 9.0 months versus 7.1 months for gemcitabine alone.Gemcitabine followed by either oxaliplatin or cisplatin showed median overall survival to be 8.3 versus 6.7 months.One caveat in applying these data to clinical practice and research is to not dismiss a particular agent or class of drugs as inactive in pancreatic cancer simply because combining it with gemcitabine failed to produce superior clinical outcomes. The most relevant example of this is the role of oxaliplatin and 5-FU in patients with gemcitabine-refractory metastatic pancreatic cancer, detailed later in this manuscript.
- #21 Molecularly targeted agents have a solid preclinical rationale as treatment for advanced pancreatic cancer. However, with the exception of erlotinib, the completed phase III trials have not confirmed an important clinical benefit.The human epidermal growth factor receptor 1 (HER-1/EGFR) signaling cascade has been targeted for anticancer drug development because it is observed that overexpression in a high percentage of pancreatic cancers and its association with poor prognosis. Erlotinib, an orally available molecule, interrupts HER-1/EGFR signaling by inhibiting the tyrosine kinase integrated in the intracellular receptor domain.Based on a phase III randomized, placebo-controlled trial, erlotinib in combination with gemcitabine received U.S. Food and Drug Administration approval as treatment for chemotherapy-naïve locally advanced and metastatic pancreatic cancer in 2005. Median survival duration was 6.24 versus 5.91 months. 1 year survival advantage was 23% versus 17%.A review of toxicities may further discourage the use of gemcitabine plus erlotinib. Patients receiving erlotinib and gemcitabine experienced higher frequencies of rash (72%), diarrhea (56%), infection (43%), and stomatitis (23%), generally grade 1 or 2. Cost is a problem. The addition of erlotinib increases the costs of treating advanced pancreatic cancer by $12,156 wholesale or $16,613 retail per patient. Factoring in 0.4-month longer median survival time compared with gemcitabine alone, the addition of erlotinib costs $364,680 per YLG wholesale and $498,379 per YLG retail. In order to be cost-effective, even at the $100,000/YLG level, 6 months of erlotinib would have to be reduced to 20%of the current retail cost (i.e., to $18.52 per tablet). The minimal additional clinical benefit, side effects, and financial impact have discouraged patients and clinicians when deciding on the inclusion of erlotinib in combination with gemcitabine as palliative treatment for metastatic pancreatic cancer.Erlotinib as a single agent for treatment of chemotherapy-resistant pancreatic cancer is just beginning to be evaluated.Cetuximab is a monoclonal antibody that binds the extracellular domain of EGF receptor. In combination with gemcitabine median survival times were 6.5 months versus 6 months with gemcitabine alone.
- #22 Vascular endothelial growth factor (VEGF) plays a key role in the growth and metastasis of many tumors, including pancreatic cancer. Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody with clinical benefit in metastatic colon, breast, and non-small cell lung cancer. Double-blind trials showed median overall survival times to be 5.7 months for gemcitabine plus bevacizumab versus gemcitabine plug placebo. (CALGB Trial)The AVITA study was also a randomized, double-blind, placebo-controlled trial involving bevacizumab, gemcitabine, and erlotinib sponsored by Rouche. It failed to meet the primary endpoint for survival.Sorafenib is an inhibitor of RAF-1 and VEGF receptor 2. In combination with gemcitabine, no response was seen. Median survival time was 4 months and the 6 month survival rate was 23%.Antiangiogenesis will continue to be evaluated in pancreative cancer in randomized clinical trial by comparing gemcitabine with VEGF Trap (aflibercept) with gemcitabine. Aflibercept is a fusion protien made of human VEGF receptor extracellular domains fused to the Fc portion of human IgG. It is designed to bind and inactivate circulating VEGF. Another is Sunitinib which is an oral tyrosine kinase inhibitor for the VEGF receptor as well as platelet-derived growth factor being evaluated for 2nd line treatment.
- #23 Immunotherapy, defined in the context of clinical oncology, involves the stimulation of a patient’s immune system to achieve antitumor activity. Nonspecific strategies include the use of exogenous immunostimulants or cytokines, the transfer of nonspecific immune effector cells, and the inhibition of immunosuppressive pathways. Alternatively, specific immunotherapeutic strategies strive to enhance the response to defined tumor antigens or induce antitumor antibody activity, often via vaccination.Gastrin was shown to demonstrate the necessary criteria for a potential immunotherapy target against pancreatic cancer. Gastrin receptors and precursor gastrin forms were shown to be broadly expressed, demonstrated in up to 90% of pancreatic cancer resection tissues. Also, gastrin demonstrated a possible pathogenic role, because in vivo gastrin had a proliferative effect on pancreatic cancer cells, and antigastrin antibodies raised against G17DT, an immunoconjugate of gastrin-17, inhibited the proliferation of pancreatic cancer cells. Early human studies were promising. However, randomized double-blind study of gemcitabine plus placebo versus gemcitabine plus G17FT did not demonstrate survival advantage. The combination resulted in median overall survival time of 178 days versus 201 days for gemcitabine plug placebo. Response was weaker in women.Immunogenic telomerase peptides have been characterized and a phase I–I/I study investigating the safety, tolerability, and immunogenicity of a telomerase peptide vaccination, GV1001. TeloVac Trial taking place in the UK. A phase III trial will occur in the US soon.Johns Hopkins has pioneered the development of lethally irradiated allogenic pancreatic tumor cells transfected with the GM-CSF gene as immunotherapy for pancreatic cancer. GM-CSF stimulated the immune response. First the vaccine was given and then patients were treated with 5-FU. Median survival time is approximately 26 months. It’s comparing favorably to adjuvant gemcitabine in phase III trials.Hopkins is also working on using attenuated Listeria carrying mesothelin peptide. The rational is that listeria is a very efficient bacteria at eliciting an immune response.
- #24 There is a dire need for treatment in patients with advanced pancreatic cancer and confirmed disease progression with first-line gemcitabine. In a randomized trial basic supportive care with or without oxaliplatin, plus 5-FU and folinic acid. Results were astounding. Median suvival time for second-line therapy was 21 weeks versus 10 weeks favoring OFF. With the failure of using two gemcitabine-agents, some researchers have pushed for 3 or 4 multidrug regimes. Overall toxcities were increased without overall clinical improvement. A very small 35 patient study has shown some benefit in using capecitabine, gemcitabine, and docetaxel (antimitotic agent).