Risk Factors

As PC is relatively uncommon yet incredibly aggressive, numerous risk factors have been identified that aid in preventative measures (Table 81-1). Cigarette smoking is one of the most clearly proven and most preventable risk factors. The risk increases with longer duration and higher number of cigarettes smoked, but can return to normal after 10 years of cessation.^33,34 Cigarette smoke includes more than 50 carcinogens, the most important being nitrosamines, which promote tumor growth via various pathways, including activating the KRAS oncogene, and cause inflammation in the pancreas.^35–35 It is believed to cause 15% to 25% of PC, with a relative risk of 1.5- to threefold in smokers as compared to nonsmokers.^2,33–37 Chronic pancreatitis, often the result of chronic and heavy alcohol consumption or biliary duct blockages, leads to an increased risk of two- to 16-fold, although less than 5% of patients with chronic pancreatitis will develop PC. The chronic inflammation is thought to activate macrophages that produce cytokines that induce cell proliferation, angiogenesis, and inhibit apoptosis.^{34–36,38–42} Chronic pancreatitis may also be a manifesting symptom of PC from biliary obstruction caused by the tumor. Consequently, PC should be in the differential for a person who develops pancreatitis without any known risk factor.^32,42,43 Patients with hereditary pancreatitis, caused by a mutation in PRSS1 in the autosomal dominant form leading to premature activation of trypsin while still in the pancreas as opposed to in the duodenum, or by a mutation in SPINK1 or CFTR in the autosomal-recessive form, have a 40- to 85-fold increased risk and a cumulative risk of 30% to 55% of developing PC in their lifetime.^35,36,44,45 Alcohol is clearly a causative factor for cancers of the upper aerodigestive tract; however, it appears that only heavy alcohol use, defined as 3 or more alcoholic drinks per day, has a slightly increased relative risk of 1.2, whereas mild or moderate intake poses no increased risk.^33,35–37 Obesity, defined as body mass index equal to or greater than 30 and accounting for 33% of adults in the United States, may lead to an increased risk of 1.2- to 1.7-fold and possibly higher in the severely obese.^35,36,46 This link may result from increased circulating insulin and insulin growth factors, lower amounts of antiinflammatory cytokines, and a chronic low-grade inflammatory state throughout the bodies of obese people.⁴⁶

The relationship between diabetes mellitus and PC is difficult to ascertain as type 2 diabetes can be both an early sign of PC and a risk factor. PC is thought to lead to diabetes through destruction of glands causing decreased production of insulin; however, the presence of diabetes does not appear to correlate with the size or stage of the tumor as this theory would suggest,⁴⁷ so other mechanisms must be at play. Long-term diabetes is thought to increase the risk for PC because the increased secretion of insulin and insulin-like growth factors promote cell growth and the heightened state of inflammation leads to proinflammatory cytokines that contribute to angiogenesis and tumorigenesis.⁴⁸ Studies have demonstrated that 55% to 85% of PC patients were diagnosed with glucose intolerance or diabetes either concurrently or within the 2 years preceding their cancer diagnosis.^35,47,48 But, given the very high incidence of diabetes in the population, the relative risk of developing PC is still only 1.3- to 2.6-fold normal, when considered independently of obesity,^35,37,47,48 and does not imply that all newly diagnosed diabetic patients warrant screening. However it should be considered in the atypical patient with newly diagnosed diabetes who has a steady or decreased weight, no change in activity and no family history of diabetes.³⁶ Diets high in animal protein, history of gallstones, Helicobacter pylori infection, and some occupational exposures may lead to an increased risk.^{2,41,43,49,50} Allergies such as hay fever, increased vitamin D intake, blood type O, and diets high in fruits, vegetables, and citrus fruits may have a protective effect.^{2,35,36,44,51–54}

Although the majority of PC are sporadic, 5% to 10% of patients have a family history.2,34,44 Familial PCc are defined as two or more first-degree relatives with the disease.³⁵ Having one first-degree relative with PC gives a person a threefold increased risk, two first-degree relatives has a 4- to 6.4-fold increase risk, and three or more first-degree relatives poses a 14- to 32-fold increased risk.^34,44,45 Although some patients with familial pancreatic cancer do not have identifiable genes, many syndromes have been described. Carriers of the BRCA2 gene (associated with breast, ovarian, and pancreatic cancers) have a 3.5- to 10-fold increased risk and account for 5% to 17% of families with familial PC. Mutations in PALB2 (binds to BRCA2) carry a sixfold increased risk,^2,44 whereas BRCA1 carriers may have a twofold increased risk.^{2,35,36,44,55,56} Germline mutations in STK11 cause the autosomal dominant Peutz-Jeghers syndrome, characterized by hamartomatous polyps, pigmented macules, and a more than 90% chance of developing some form of cancer including a 132-fold increased risk for PC.^{2,35,36,44,50} Familial atypical mole-multiple melanoma patients typically have a mutation in CDKN2A and carry a 13- to 47-fold increased risk of PC.^{2,35,36,44,45} Germline mutations in DNA mismatch repair genes causing Lynch syndrome carry a two- to eightfold increased risk.^35,36,44,57 Cystic fibrosis, characterized by a mutation in CFTR that produces viscous mucus that obstructs pancreatic ducts, carries an increased risk of 5.3-fold,^35,44 whereas familial adenomatous polyposis (germline mutation in APC gene) has a four fold increased risk.^44,45 Mutations in the tumor suppressor gene TP53 causing Li-Fraumeni syndrome results in a doubling of the risk.⁴⁴

Precursor Lesions

Approximately 85% of PC develops from the ductal epithelial, termed pancreatic ductal adenocarcinoma (PDAC). PDACs are thought to arise from precursor lesions: pancreatic intraepithelial neoplasms (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms (MCNs). PanINs, the most common precursor lesions, are defined as “microscopic papillary or flat noninvasive epithelial neoplasms [of <5 mm diameter, not visible by imaging] arising from the pancreatic ducts…characterized by mucin-containing cuboidal to columnar cells [with varying degrees of nuclear and architectural atypia].”45,62 PanINs, are classified from low-grade atypical lesions (PanIN-1A or -1B) to high-grade atypical lesions (PanIN-2 or -3) as molecular alterations accumulate and more dysplasia appears (Figs. 81-1 and 81-2).^{2,35,54,58,63,69,70,356} One reason for their identification as precursor lesions is the presence of similar mutations as compared with invasive carcinoma. Activating mutations of the KRAS oncogene are one of the earliest abnormalities in the development of PC, as they appear in 30% to 45% of PanIN-1 lesions and more than 90% of PanIN-3 lesions. BRAF mutations are also found in the early precursor lesions in the 5% of patients that are KRAS wild-type. Telomere shortening also occurs early and is present in 90% of PanIN-1 lesions and leads to chromosomal instability making further mutations more likely. Inactivating mutations of CDKN2A begin to occur in PanIN-2 lesions and inactivation of TP53, BRCA2, and SMAD4 are seen in PanIN-3 lesions.^{2,45,54,58–61,70} Low-grade PanIN lesions are common in older individuals; however, higher grade PanINs are typically seen in association with invasive cancer, especially in those with familial PC.^2,71,72 Although all precursor lesions have a risk of progressing to invasive carcinoma, the risk is very low for PanIN-1 lesions and very high for PanIN-3 lesions, as patients with PanIN-3 lesions at the margins of a resection virtually all recur with invasive carcinoma. Consequently, it is recommended that all margins should be clear of PanIN-3, even if this requires re-resection.^62,70

IPMNs and MCNs are two types of noninflammatory cysts in the pancreas that are diagnosed secondary to symptoms or from incidental findings on imaging. Cysts are found incidentally on 1.2% to 2.6% of the over 50 million computed tomography (CT) scans done annually in the United States. Given their malignant potential, recommendations have been developed for their management.⁷³ IPMNs are grossly visible, mucin-producing, epithelial neoplasms, typically with papillary architecture, that arise from either the main pancreatic duct or branch ducts and are graded according to degree of dysplasia. They range from 5 mm to 150 mm, are more commonly located in the pancreatic head, and can manifest with abdominal or back pain, weight loss, or anorexia from ductal obstruction from the mucin or the tumor itself. The average age at onset is 65 years and they have a 2 : 1 male-to-female predominance. Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) can visualize the degree of dilation of the main pancreatic duct to help determine the place of origin. They are less frequent precursors to PC than PanINs, but they do share some of the same molecular aberrations. KRAS mutations are seen in 50% of low-grade IPMNs, whereas inactivating mutations of CDKN2A and TP53 are seen in high-grade lesions. Loss of SMAD4 is only rarely seen in even high-grade lesions, while mutations of GNAS are commonly seen. IPMNs arising from the branch ducts are less aggressive than those arising from the main duct with rates of malignancy and invasive malignancy (either mucinous noncystic carcinoma/colloid carcinoma or PDAC) of 25% and 15% for branch duct origin and 70% and 43% for main duct origin. Patients with main duct IPMNs should undergo resection. Their 5-year survival rate is 77% to 96% for the noninvasive neoplasms and 40% to 70% in the invasive lesions. Symptomatic patients with branch duct IPMNs have a higher risk of malignancy and should undergo resection. Asymptomatic branch duct IPMNs can be monitored with imaging (every 3 to 12 months depending on size) as they have a 0% to 5% chance of malignancy, especially if there is no main duct dilation, no mural nodules and the neoplasm is smaller than 30 mm. They should be removed if they become symptomatic or increase in size. Patients should be followed even after resection as well, yearly for benign IPMNs and twice yearly for invasive IPMNs, to catch any recurrence.^{2,45,70,74,75}

MCNs also produce mucin; however, they are characterized by ovarian-type stroma. They are found almost exclusively in women, typically in the fourth and fifth decades, and 95% are in the pancreatic body and tail. They tend to be slow growing, but the average size is 5 to 12.5 cm. They have an orangelike gross appearance and only rarely communicate with the pancreatic duct. All MCNs should be resected with a distal pancreatectomy and proper lymph node dissection as they may progress to mucinous cystadenocarcinomas which have a very poor prognosis. Patients with benign MCNs do not need to be followed after resection because they do not recur; however, patients with malignant MCNs (6% to 36%) should be followed by imaging every 6 months.2,45,70,74,75

Pathways of Spread

Invasive PC can spread through local invasion or through perineural, lymphatic, or vascular invasion, producing sites of distant metastasis. Given its location in the retroperitoneum, the most common sites of direct local invasion are to the stomach, duodenum, liver, common bile duct, gallbladder, spleen, superior mesenteric vein (SMV), superior mesenteric artery (SMA), and other surrounding arteries, veins, and lymph nodes. Perineural invasion is defined as the presence of cancer cells along nerves and/or within the neuronal sheath. Neurotrophins that are secreted by both the cancer cells and the nerve cells help support the survival and growth of these cells and promote neurogenesis, whereas chemokines like CX3CR1 appear to increase the cancer cells’ migration toward the nerve.99,100 The head of the pancreas is innervated by the superior mesenteric ganglion, the celiac plexus, and it branches which are the main routes for perineural invasion by the cancer cells. The main route of spread for cancers of the body and tail is through the celiac plexus and the splenic plexus. Intrapancreatic and/or extrapancreatic neural invasion is seen in virtually all advanced stage tumors, and even in more than 70% to 75% of stage I tumors, implying that this is an early event in the tumor’s progression. Given that some studies have reported worse prognosis for patients with perineural invasion, pathologists are now recommended to report the tumor’s perineural invasion status.^99–105 In a retrospective analysis of 193 patients with resected PDACs, those without nodal metastases or perineural invasion had a 5-year survival of 75% as compared with 29% of those with perineural invasion. In patients with nodal metastases, 5-year survival was 17% when there was no perineural invasion and only 10% when there was invasion.¹⁰³ Perineural invasion is one reason that many PC patients experience difficult to control abdominal and back pain.¹⁰⁰

Vascular invasion is critical for both resectability and prognosis. The head and neck of the pancreas are supplied from superior pancreaticoduodenal arteries arising from the celiac trunk, and the inferior pancreaticoduodenal arteries arising from the SMA. These areas drain into the SMV, inferior vena cava, portal vein, and inferior mesenteric vein. The body and tail are supplied by the splenic artery arising from the celiac trunk and from pancreatic branches off the SMA and mostly drain into the splenic vein. Given their proximity to the pancreas, the SMV and SMA are the most commonly involved artery and vein by the tumor. The celiac artery, splenic artery, portal vein, hepatic artery, and, more rarely, the inferior vena cava and aorta can also be involved.6,106,107 On pathological review of more than 1100 resections, 53% had evidence of vascular invasion.¹⁰⁸

Lymphatic invasion, and specifically nodal involvement, is the strongest predictor for survival. Lymphangiogenesis occurs during embryonic development and again during regeneration after a trauma and is thought to also occur during tumor growth. Tumor cells enter the lymphatic system by either migration through the interendothelial valves or by destroying the vessel walls. They will enter the smaller intralobular lymphatic vessels located within the pancreas and subsequently drain into the four main lymphatic branches of the pancreas: anterior, posterior, inferior, and superior pancreaticoduodenal lymphatic vessels. These then drain into regional lymph nodes that are typically located larger blood vessels: the celiac artery, common hepatic artery, SMA, and aorta for head/neck tumors and the splenic artery for body/tail tumors. At least 75% of all resections have positive lymph nodes.108–113

Tumor cells travel through the nerves, lymphatics, or vasculature to form distant metastases. The liver is the most common site of metastasis, possibly because tumor cells travel through the portal vein, followed by the peritoneal cavity. Lung metastases are the next most common, especially in long-term survivors.20,26,111,114–116 In a phase III trial for first-line metastatic PC, 88% of the patients had liver metastases, 24% had lung, 19% had peritoneal, and 14% had other sites.²⁶ In a second-line therapy trial, 70% had liver disease, 30% had peritoneal, and 17% had lung involvement.¹¹⁶ Brain^119–119 and skeletal metastases¹²⁰ are quite uncommon and there have only been case reports of metastases to the appendix,¹²¹ kidneys,¹²² skin,^123–126 prostate,¹²⁷ stomach,¹²⁸ heart,¹²⁹ thyroid,¹³⁰ and muscles.¹³¹

Diagnosis

When evaluating a patient for pancreatic cancer, it is recommended to involve a multidisciplinary team that includes medical oncology, surgical oncology, radiation oncology, pathology, and radiology.88,138 Figure 81-3 depicts a diagnostic algorithm. The goals of the imaging, labs, and biopsies are to help clarify the diagnosis, stage, resectability status, prognosis, and possible palliative options. As no patient should be denied a potentially curative surgery if the patient qualifies, the imaging of choice should emphasize specificity over sensitivity. Multiphase pancreatic protocol CT with IV contrast is typically the first study ordered (Fig. 81-4A-E). This should include a noncontrast phase as well as contrast-enhanced arterial (when tumor has poor enhancement as compared to pancreas parenchyma given its hypovascularity), pancreatic parenchymal, and portal venous phases, and include thin cuts of 3 mm or less to help detail the location of the tumor in relationship to the main vessels, find signs of mass effect or ductal obstruction, and detect small tumors and sites of metastasis.^{2,5,88,139–143} 3D reconstruction can add additional information for surgeons planning the operation.^88,142,144 CT has a 74% to 98% accuracy in detecting pancreatic cancer with sensitivities of 77% to 97% and specificities of 85% to 100%, with the lower numbers accounting for the smaller tumors that CT may miss because they have not caused any biliary or vasculature obstruction or impingement. Additionally, CTs have sensitivities of 55% to 97% and specificities of 91% to 100% for predicting vascular invasion, and sensitivities of 76% to 92% and specificities of 82% to 100% for predicting resectability. Typically, 10% to 30% of patients taken to surgery will have their surgery aborted or altered to a palliative only procedure because of more serious vascular involvement or metastatic disease that was not detected on CT scan.^{2,5,6,88,140–142,145–152} The technology has greatly improved and CTs have a higher accuracy now that the multiphase pancreatic protocols are being used. Chest CTs are also recommended to assess for pulmonary metastases prior to resection.² Multiphase pancreatic protocol MRI can be used when CT is contraindicated and may be able to detect smaller lesions and better differentiate between cancer and pancreatitis. However, it hasn’t been shown to be superior to multiphase CT. MRI can also detail the biliary and pancreatic ductal systems via magnetic resonance cholangiography. Its sensitivities and specificities for diagnosis are 84% to 98% and 82% to 88%, and for predicting resectability are 82% to 88% and 78%, respectively.^{2,88,139,142,143,150,153–155}

EUS is used in addition to either CT or MRI to obtain further information about nodal or vasculature involvement, to better identify suspected small lesions that were not seen on the prior imaging, and to help with staging (Fig. 81-4F). PDAC appears as a solid mass with irregular borders, is not homogeneous, and appears hypoechoic compared with the surrounding normal pancreatic parenchyma. Vascular invasion is determined when there is loss of the hyperechoic vessel wall and hypoechoic tumor interface, evidence of tumor within the vessel, irregularity of the vessel wall with tumor within 3 mm, inability to visualize a major vessel where collaterals are present, and vascular encasement. EUS may be superior to CT or MRI in differentiating cystic versus solid lesion, finding lesions smaller than 2 cm, noting pathological lymph nodes, and more accurately predicting the size of the tumor, but it is not very good at assessing SMA involvement. It does have the additional benefit of allowing a biopsy with fine-needle aspiration (FNA) or celiac plexus block to be performed at the same time. EUS has an accuracy of diagnosing PC of 86% to 96% with sensitivity of 85% to 100% and specificity of 98%.^{2,5,6,88,139,142,143,145,151,152,156–158} Although it is invasive, the complication rate is less than 2% and risk of major complications is 1 : 2500.¹⁵⁹ Therefore EUS can be used as an adjunct to CT or MRI. ERCP combines endoscopy and fluoroscopy to map out the biliary system and may be beneficial if there is a duct stricture with no obvious mass as it does allow for ductal brushings. It also enables the placement of a biliary stent to decompress an obstructed system for patients who are receiving chemotherapy or for surgical patients who have a delay before surgery or have cholangitis (Fig. 81-4G).^{2,88,139,142,160}

Positron emission tomography (PET)-CT may also be used in addition to pancreatic protocol CT or MRI to help clarify the presence of metastatic disease if this distinction would change management. With sensitivities of 85% to 100% and specificities of 67% to 99%, there can still be false negatives when tumors are smaller than 1 cm.2,5,6,88,142,161–163 Abdominal ultrasound, on the other hand, may be one of the first tests that is ordered to evaluate jaundice or abdominal pain and can demonstrate a hypoechoic mass or biliary dilatation, but it cannot firmly differentiate between PC, neuroendocrine tumor, and chronic pancreatitis. The addition of color Doppler does aid in detecting vascular invasion, but its accuracy of diagnosis is around 75%. Consequently, this will always need to be followed by further imaging.^6,164–166 The use of staging laparoscopy has changed over time. It has been used in patients in whom unresectable disease is considered likely in order to prevent a larger laparotomy procedure that would need to be aborted. These higher-risk patients are those with CA19-9 higher than 100, head tumors larger than 3 cm, questionable findings on CT, or a body/tail lesion. Past studies did demonstrate that laparoscopy can prevent unnecessary laparotomies in 20% of patients, however these numbers are dropping to 5% to 8% as imaging studies have gotten better, making laparoscopy less likely to be helpful.^{6,88,139,167–169}

Although a biopsy is not required when a patient with a high suspicion for PC goes directly to surgery, it is required prior to any neoadjuvant treatment or treatment of locally advanced or metastatic disease. FNA via EUS or CT-guidance are the two most common approaches to obtain a tissue sample. EUS-FNA is preferred because of the higher diagnostic yield, lower chance of seeding the peritoneum causing carcinomatosis, and the benefit of additional staging information from EUS. EUS-FNA has a 92% accuracy of correctly diagnosing a pancreatic mass and a 84% accuracy when performed in patients with negative CT-guided biopsies. It also carries a low complication rate of 0.5% to 2%.2,88,139,145,148,160,170–173 CT-guided FNA may also be performed to biopsy a metastatic site. ERCP brushings may also be done and should be considered when there is a biliary stricture but no mass, but cytology from brushings has a low yield of positive results.^88,160 Although tumor-associated markers like CA19-9 can also assist in the diagnosis, as discussed previously, the sensitivity and specificity lead to a fair number of false positives and false negatives. The absolute value is often higher in more advanced stages, especially when there are liver metastases,⁸⁶ and the value can provide useful prognostic information.

Staging

Classically, PC has been staged according to the TNM (tumor–node–metastasis) staging system per the American Joint Committee on Cancer, as shown in Table 81-3.¹⁷⁴ The distinction of T1 and T2 tumors at 2 cm is secondary to the association of tumor size with survival in resected patients. Numerous reviews have demonstrated improved survival in patients with smaller tumors with 5-year survival improvements by 10% to 20% and increase in median survival by 5 to 20 months and hazard ratios around 1.6. Unfortunately, only a minority of patients (6% to 25%) present with tumors smaller than 2 cm.^{8,98,101,108,175–181} The classification of patients with nodal disease separately as stage IIB is because of the clear associated of nodal disease with worse survival, as described further below.¹⁷⁵

More recently, most centers and current clinical trials are classifying patients based on their resectability status (Table 81-4) because surgery is critical to achieve a cure in this disease. This characterizes stage I and II patients as resectable and divides stage III patients into those who are borderline resectable and may benefit from neoadjuvant therapy prior to surgery from those who are unresectable and are not surgical candidates. Tumors that encase the SMA or celiac artery would require technically difficult resections and reconstructions that carry a high perioperative mortality risk and are likely to leave some tumor behind and are therefore categorized as unresectable. In addition, there is a greater chance of perineural infiltration with SMA or celiac artery involvement because those arteries have a perineural sheath unlike the SMV or portal vein.^88,139,175 Tumors involving the SMV and portal vein are considered borderline resectable, on the other hand, because SMV and portal vein resection does not affect surgical outcome or overall survival when done at experienced centers and therefore is not an absolute contraindication to surgery.^19,175,182 Unfortunately, only 15% to 20% of patients present with resectable or borderline resectable disease.

Adjuvant Therapy

Given that the majority of patients who undergo resection for tumors that will recur, adjuvant therapy is indicated to decrease the risk of locoregional and metastatic recurrence. It is typically started 1 to 2 months after surgery to allow the patient to recover from the operation and complications associated with the underlying cancer. Although no regimen has been proven substantially more effective than others, 6 months of adjuvant therapy with 5-fluorouracil (5-FU)- or gemcitabine-based chemotherapy is standard with gemcitabine preferred because of a better toxicity profile. The integration of approximately 6 weeks of 5-FU–based chemoradiation therapy (45 to 46 Gy directed to the tumor bed, surgical anastomoses, and peripancreatic nodes with an additional 5 to 15 Gy boost to the tumor bed (Fig. 81-6A) using 3D planning or intensity-modulated radiotherapy (IMRT) during this 6-month period is an option and may be more favored for R1 resections and cases when the risk of locoregional recurrence is high. Radiation is a local therapy, similar to surgery, with chemotherapy being utilized as a radiosensitizer. The appropriate sequencing of adjuvant chemoradiation therapy is unclear. As more than 70% of patients will recur with distant disease, systemic chemotherapy is usually given first to be followed by chemoradiation if the disease is still controlled. As capecitabine has been shown in other studies to be equally effective as continuous infusion (CI) 5-FU, it can be substituted in adjuvant therapy as well. All patients should be restaged with CT or MRI prior to beginning adjuvant therapy and again before starting chemoradiation to rule out metastatic disease.^2,5,88,211

The GI Tumor Study Group (GITSG) trial was the first to show a survival benefit for adjuvant chemoradiation in the 1980s. It randomized patients with resected PC to either observation or chemoradiation with bolus 5-FU for 2 weeks followed by bolus 5-FU weekly for up to 2 years. The medial overall survival (OS) was 20 months in the treatment arm compared to 11 months in the observation arm.²¹² This was followed by the European Organization for Research and Treatment of Cancer (EORTC) trial that randomized patients to observation or 40 Gy of radiation over 2 weeks with CI 5-FU on the days of radiation. Although the OS was 12.6 months in the observation arm compared to 17.1 months in the treatment arm, this was not statistically significant. Therefore this study could not conclude that chemoradiation was beneficial, but it was shown to be well tolerated.²¹³ The ESPAC-1 trial also put the use of chemoradiation into question when it compared adjuvant chemoradiation, chemotherapy, both, or neither. Patients were randomized to either 20 Gy total of radiation with bolus 5-FU over 2 weeks repeated again after a 2-week break, bolus 5-FU daily for 5 days that was repeated every 4 weeks for a total of 6 cycles, chemoradiation as described followed by chemotherapy as described, or observation. With approximately 71 patients in each arm, median OS were 13.9 months, 21.6 months, 19.9 months and 16.9 months, respectively. Patients who received radiation had a median OS of 15.9 months compared with 17.9 months for those who didn’t receive radiation, suggesting that radiation was detrimental. Patients who received systemic chemotherapy had a median OS of 20.1 months compared to 15.5 months for those who didn’t, demonstrating that systemic chemotherapy is beneficial. Quality of life was similar in all groups and patients who received radiation did not have lower rates of local recurrence than those who didn’t. This trial was continued and demonstrated similar results after an additional 256 patients were added; however, these patients were not randomized in the original 2×2 fashion. Therefore systemic chemotherapy was recommended but chemoradiation was not, and should not be used alone.^16,214 This trial has been criticized, however, for its nonstandard chemoradiation regimen and its unusual enrollment.

The CONKO-001 trial also demonstrated the benefit of adjuvant systemic chemotherapy by randomizing 354 patients to either observation or adjuvant gemcitabine given at 1000 mg/m² IV weekly for 3 weeks on, 1 week off for a total of 6 cycles. Disease-free survival and OS were 6.9 months and 20.5 months for the observation arm and 13.4 months and 24.2 months for the treatment arm, respectively. The lack of a greater difference in OS was attributed to the ability for crossover from the observation group at time of recurrence. There were rare grade 3 or 4 toxicities in the treatment group but quality of life improved in both groups. Therefore it was concluded that gemcitabine improves disease-free survival and likely OS without compromising quality of life.¹⁴ Similarly, the ESPAC-3 phase III trial randomized 1088 patients to bolus 5-FU daily with folinic acid for 5 days every 4 weeks or gemcitabine weekly for 3 weeks every 4 weeks for 6 cycles total. OS was 23.0 months in the 5-FU group and 23.6 months in the gemcitabine group, with higher rates of stomatitis and diarrhea in the 5-FU group and higher rates of hematologic toxicity in the gemcitabine group but without any difference in quality of life.¹⁷ The ESPAC-1 trial, CONKO-001, and ESPAC-3 trial made both 5-FU and gemcitabine possibilities for adjuvant chemotherapy.

The RTOG 9704 trial compared these agents when used with chemoradiation. The trial randomized 451 patients to either CI 5-FU at 250 mg/m² per day for 3 weeks followed by chemoradiation to 50.4 Gy with CI 5-FU followed by 2 cycles of 4 weeks on/2 weeks off CI 5-FU or to gemcitabine 1000 mg/m² once weekly for 3 weeks followed by the same chemoradiation with CI 5-FU followed by 3 more cycles of gemcitabine. Radiation treatment planning and delivery were standardized. Radiation was delivered to the tumor bed and peripancreatic lymph nodes with a boost to the tumor bed plus a margin. There were more hematologic and overall toxicities in the gemcitabine arm but the same percentage of patients completed therapy in each arm. There was no statistically significant difference in survival, rate of local relapse (approximately 25%), and rate of distant relapse (approximately 70%) between the groups. Patients with pancreatic head tumors had a median OS of 17.1 months in the 5-FU group and 20.5 months in the gemcitabine group. This trial concluded that gemcitabine may be slightly favored; however, either option is appropriate, and chemoradiation can be given safely with similar outcomes to other trials when done in a standard fashion.15,209 Several large, single-institution, retrospective reviews have also demonstrated a benefit of combining 5-FU chemoradiation with systemic chemotherapy in the adjuvant setting.^18,210,215 Gemcitabine-based chemoradiation has also been demonstrated to be effective in a phase II study when combined with systemic gemcitabine with a similar median OS of 24.4 months.²¹⁶ There have been advancements in the delivery and management of radiation since these trials. IMRT is also becoming more commonly used as compared with the standard 3D dosing that was used in the RTOG 9704 trial. IMRT allows the radiation oncologist to improve targeting to the desired area while decreasing radiation dose to organs at risk of toxicity, such as the kidneys, liver, small bowel, and spinal cord.^219–219 The use of antiemetics during radiation therapy has improved tolerability of radiation therapy and the use of proton pump inhibitors has decreased the rate of radiation duodenitis and ulcer formation.

Smaller trials have also looked at other regimens for adjuvant therapy. The combination of interferon-α, cisplatin, and 5-FU with chemoradiation reported a favorable OS but was significantly too toxic.²²⁰ Biweekly gemcitabine with daily erlotinib for 4 months followed by maintenance erlotinib for 8 months also is effective.²²¹ Erlotinib has also been tested with Xeloda and IMRT and can be safely administered.²²² The ongoing RTOG 0848 trial is randomizing patients to gemcitabine with or without erlotinib for 5 cycles and then randomizing patients again to a final cycle of chemotherapy versus 5-FU–based chemoradiation therapy. The results will help clarify the role of erlotinib and chemoradiation in the adjuvant setting. A phase II trial evaluated the efficacy of 5-FU chemotherapy, 5-FU chemoradiation therapy, and a vaccine of irradiated granulocyte-macrophage colony-stimulating factor transfected allogenic whole-cell tumor lines. Median OS was 24.8 months and those who demonstrated a CD8+ T-cell response had higher likelihoods of remaining disease free.²²³KRAS–mutant vaccines²²⁴ and MUC1 peptide-loaded dendritic cell vaccines²²⁵ also have shown early promising results. Unfortunately, despite the above trials, median OS remains 20 to 24 months for patients with resected PC, demonstrating the need for more research in adjuvant regimens.

Neoadjuvant Therapy

Neoadjuvant therapy remains controversial in the treatment of PC. It does have the advantage of downstaging borderline resectable patients who achieve a partial response with therapy allowing them to undergo surgery with a higher likelihood of an R0 resection.10,11,13,226–228 In fact, 15% to 40% of patients with initially borderline or unresectable tumors can eventually undergo surgery.^{10,12,13,228–233} More importantly, it spares patients who will quickly develop metastatic disease the risks and stress of a large surgery because their restaging scan after neoadjuvant therapy would show the progression and surgery would be avoided. This can range from 15% to 35% of patients initially considered for surgery^{9–11,226,234,235} and as high as 48% in some smaller studies.^229,236,237 As 15% to 20% of resected patients fail to receive adjuvant therapy, neoadjuvant therapy guarantees that a majority of patients will receive some form of chemotherapy ± chemoradiation. Studies show that 73% to 100% of patients are able to complete the majority of their neoadjuvant regimens.^{12,226,230,234,235,237,238} Any micrometastatic disease will be treated earlier with the systemic chemotherapy and it allows for monitoring of response to specific chemotherapy or targeted agents. In regards to radiation therapy, neoadjuvant therapy allows for a smaller irradiated volume (Fig. 81-6B), limits exposure to other organs, and potentially allows for a higher dose of radiation to the pancreatic tumor. The chemoradiation component of neoadjuvant therapy also decreases local recurrence rates in patients who undergo surgery.^11,227,230

However, one potential limitation with neoadjuvant therapy is that patients may progress locally or distantly and may miss their “window” for potentially curative surgery. Although the same percentage of patients ultimately undergo surgery, there are no randomized trials favoring neoadjuvant over adjuvant therapy. In addition, patients who undergo neoadjuvant therapy do not have the same opportunity for their pathology to be reviewed and to be considered for potential studies that require operative tissue prior to starting their therapy. Although it varies by institution, at this time neoadjuvant therapy is usually reserved for borderline resectable patients, whereas resectable patients are taken to surgery immediately and then given adjuvant therapy.2,5,88,138,211,239 Both groups have similar survivals when they are resected.^{9–13,226,228,230,233–235} These decisions should be made in a multidisciplinary manner to achieve the timeliest and most coordinated treatments.^{2,5,88,138,211,239}

Although there are no clear standards established for neoadjuvant therapy, most centers use similar regimens as for locally advanced/unresectable disease.11,229,234,238 FOLFIRINOX (5-FU, irinotecan, oxaliplatin),²⁶ GTX (gemcitabine, docetaxel, capecitabine),²⁴⁰ and gemcitabine are common chemotherapy regimens that are typically followed by CI 5-FU, capecitabine, or gemcitabine-based chemoradiation to 45 to 54 Gy in 1.8 to 2.5 Gy fractions or 36 Gy in 2.4 Gy fractions. Trials have been done using other regimens, such as gemcitabine and cisplatin,^{226,231,235,236,238} gemcitabine and oxaliplatin,^241,242 and CI 5-FU,²³² but the former regimens are more tested and preferred at this time. An upcoming intergroup study will evaluate FOLFIRINOX followed by capecitabine-based chemoradiation followed by surgical resection in patients who are stable or improved after therapy. Generally, surgery should be performed within 6 to 8 weeks following completion of neoadjuvant therapy. Further delays may lead to increased radiation-induced fibrosis, more challenging operations, longer operating times, and increased length of stay. Surgery is often followed with an additional 2 to 3 cycles of adjuvant chemotherapy, but may vary based on the final pathological features and regimens received previously.^2,5,88,243

Locally Advanced and Metastatic Disease

Locally advanced and metastatic PC is treated with similar chemotherapy regimens outlined in the neoadjuvant and adjuvant sections of this chapter and summarized in Table 81-5. Chemotherapy is reserved for patients with adequate performance status, with Eastern Cooperative Oncology Group (ECOG) 0 to 2, while best supportive care and palliative therapy is recommended for patients with ECOG 3 to 4. The addition of chemoradiation can be considered for locally advanced disease only and is discussed later in this section.^2,5,88,244

Palliative Therapy

PC patients develop many symptoms and problems that can burden their quality of life. Multidisciplinary management along with a palliative care medicine team is recommended. Approximately 65% to 80% of patients with pancreatic head tumors develop jaundice requiring biliary decompression.2,88,108,137,297–300 For patients with unresectable disease or receiving neoadjuvant therapy, endoscopically placed self-expanding metal stents are the preferred therapy to relieve this obstruction. Metal stents are recommended as they have a larger diameter, lower occlusion rates, and lower complication rates than plastic stents but they can become embedded in the bile duct and be more difficult to replace.^300–305 The use of surgical biliary bypass can be done in patients who are found to be unresectable at the time of surgery. This is more uncommon today as higher-quality imaging can better predict resectability. Both surgery and endoscopy have similar success rates for palliating jaundice; however, surgical intervention has a longer hospital stay and a higher complication rate and is typically reserved for patients who are already in surgery or in whom endoscopic maneuvers fail.^{299,300,306–308} Percutaneous biliary drainage is another option when internal drainage cannot be done.^2,88,297

Gastric outlet obstruction is seen in 10% to 25% of patients, and duodenal obstruction in less than 5%.300,309 Endoscopically placed enteral stents are often placed to relieve the obstruction and have good short-term outcomes with 15% stent dysfunction; however, they do not last longer than 1 year.^{88,300,310–313} Gastroduodenal surgical decompression and bypass is another option. Similar to above, surgical decompression can be done when patients are found to be unresectable during surgery and can prevent future gastric outlet obstructions. Surgical bypass may also be considered in patients with longer life expectancies as it has a lower failure rate than stents and better long-term outcomes, but it is more expensive, prolongs the hospital stay, has a higher complication rate, and has a longer time to resumption or oral intake.^{2,88,306,308,314–320} Percutaneous endoscopic gastrostomy tube and jejunostomy tubes may also be placed in patients with shorter life expectancies for decompression and nutrition.⁵ It is clear that planned palliative resections lead to increased morbidity and mortality and worse quality of life as compared with surgical bypass alone, therefore resections should not be attempted when gross tumor will be left behind.^323–323

Pain is a very common symptom because of the perineural invasion and celiac plexus infiltration of the tumor and leads to decreased quality of life. Management with oral opioids is the first step; however, one third of patients cannot obtain reasonable pain control with oral medications alone. Neurolytic celiac plexus block with an injection of ethyl alcohol has a 70% to 95% success rate in controlling pain with a low complication rate and can last from 1 to 12 months. This can be done percutaneously, endoscopically, or through an open procedure if surgery was being done for another reason. It can also be considered as a prophylactic measure during surgery or EUS to prevent future pain.2,88,297,300,314,324–330 Palliative radiation with or without chemotherapy can also be given to control pain from local symptoms with a typical course of 30 Gy divided into 10 fractions.⁸⁸ Epidural anesthesia and high-intensity, focused ultrasound therapy are other options.^88,297,331

Venous thromboembolism (VTE) is seen in 8% to 28% of patients, as PC is one of most hypercoagulable malignancies. VTE commonly manifests as a pulmonary embolism, deep venous thrombosis, or thrombophlebitis migrans. However, other less-typical presentations can occur, which include splenic vein thrombosis causing portal hypertension, portal or SMV thrombosis causing pain, jaundice or ascites, or arterial thromboembolism causing ischemia. Low-molecular-weight heparin has been shown to be more effective at preventing recurrent VTE in malignancy and is recommended over oral warfarin therapy. VTE prophylaxis should also be used after pancreatic cancer surgery.2,88,301,332–335

Pancreatic insufficiency from destruction of pancreatic parenchyma or obstruction of bile ducts can lead to malabsorption, steatorrhea, diarrhea, weight loss, and abdominal cramps. Pancreatic enzyme replacement should be initiated after pancreatic resections and in symptomatic patients with unresectable disease.2,88,327,336,337