Ananth K. Arjunan and James J. Lee
INTRODUCTION
The majority of pancreatic cancers arise from the exocrine pancreas and are of the pancreatic ductal adenocarcinoma (PDAC) subtype. PDAC comprises 90% of all primary pancreatic cancers. Other subtypes of exocrine pancreatic cancer such as acinar cell carcinoma are rare. The pancreatic neuroendocrine tumors that arise from the endocrine islet cells form a small minority of primary pancreatic cancers. The focus of this chapter is PDAC, which will hereafter be treated as synonymous with the term pancreatic cancer.
EPIDEMIOLOGY
In 2017, there will be 53,670 patients with newly diagnosed pancreatic cancer and 43,090 deaths due to pancreatic cancer in the United States. It only comprises 3.1% of all new cancer diagnoses, yet is the fourth leading cause of cancer-related death. About 88.3% of patients are diagnosed after age 55 and the median age of diagnosis is 70 years. Males have a slightly increased incidence compared to females. In comparison to all races, African Americans have a higher incidence (15.5 vs. 12.4 per 100,000) and higher mortality rate (13.5 vs. 10.9 per 100,000). Only a modest improvement in 5-year overall survival (OS) has been noted over several decades, from 3% for patients diagnosed in 1975 to 7.6% for patients diagnosed in 2008.
Risk Factors
Family history and hereditary syndromes. There is clear association of family history with a lifetime risk of pancreatic cancer—6% with 1 affected first-degree relative (FDR), 40% with ≥3 affected FDRs. Approximately 10% of pancreatic cancer is attributable to a hereditary component. Table 10.1 summarizes inherited syndromes associated with pancreatic cancer.
Smoking. Two-fold increased risk in active smokers. Risk correlates with smoking intensity and is less in former smokers. Twenty-five percent of pancreatic cancer is attributable to smoking.
Chronic pancreatitis. Confers a five-fold increased risk. Patients with an underlying hereditary pancreatitis or tropical pancreatitis have at least 70-fold increased risk.
Alcohol. There is strong evidence that heavy use (≥30 g or >3 drinks per day) is associated with a 20% increased risk.
Increased weight. Risk is increased by 10% and 20% in overweight and obese patients, respectively. This association is not seen in the Asian population.
Insulin resistance. There is at least a 50% increased risk with long-standing diabetes. Similar risk increase is seen in patients with metabolic syndrome.
Dietary intake and nutrition. Meta-analyses of retrospective studies support an association with consumption of processed meat and red meat. There is conflicting evidence on risk reduction with fruit and vegetable intake. No clear association is noted with tea or coffee consumption. Vitamin D level has no clear association.
Chronic infections. Evidence supports a strong association with Helicobacter pylori and there is evidence of slight increased risk with Hepatitis B and Hepatitis C.
ABO blood type. Non-O blood groups have a 30% to 40% increased risk.
Pathophysiology
The pancreas is anatomically divided into the head which lies within the duodenal curvature, the neck, the body which crosses midline posterior to the stomach pylorus, and finally tapers into the tail which terminates near the splenic hilum. About 70% of pancreatic cancer arises from the pancreatic head. The pancreas abuts major vascular structures including the aorta, celiac artery, gastroduodenal artery, splenic artery/vein, superior mesenteric artery/vein (SMA/SMV), and inferior vena cava (IVC). The pancreatic duct courses from the tail to the head and joins the common bile duct to exit in union at the ampulla into the second part of the duodenum. PDAC arises from the pancreatic ductal epithelium.
About 95% of invasive PDAC is preceded by pancreatic intraepithelial neoplasia (PanIN), a flat or papillary duct cell proliferation that is <0.5 cm in size. Other preinvasive changes such as intraductal papillary mucinous neoplasia (IPMN) and mucinous cystic neoplasia (MCN) are less common. IPMN lesions are frequently found on imaging, occurring in 2% of adults, and have a 25% chance of becoming invasive cancer.
Several driver gene mutations are implicated in PDAC—KRAS, CDKN2A, SMAD4, TP53. Activation of the KRAS oncogene and telomere shortening is observed in early PanIN lesions and is followed by inactivation of the tumor suppressor genes CDKN2A, TP53, and SMAD4 as they progress toward a more invasive phenotype. When pancreatic cancer metastasizes, it typically involves the liver, peritoneum, or lung. SMAD4 loss has been shown to correlate with presence of widely metastatic disease.
The most common symptoms of pancreatic cancer are fatigue, weight loss, anorexia, abdominal pain, jaundice, and dark urine. Loss of exocrine tissue or pancreatic duct obstruction leads to malabsorption and steatorrhea, which can necessitate the use of pancreatic enzyme supplementation. An atypical presentation of diabetes can occur from the loss of functioning islet cells with 40% of patients being diagnosed with diabetes in 36 months prior to a pancreatic cancer diagnosis. Pain in the abdomen and back occurs due to involvement of celiac and mesenteric nerve plexi. Symptoms from metastatic disease, such as ascites from peritoneal deposits may occur.
SCREENING AND DIAGNOSIS
There is no role for screening of the general population for pancreatic cancer. The Cancer of the Pancreas Screening (CAPS) consortium produced consensus guidelines in 2011 recommending screening by endoscopic ultrasound (EUS) or MRI of select individuals (FDRs of patients with pancreatic cancer from a familial kindred with ≥2 affected FDRs; patients with Peutz-Jeghers syndrome; and carriers of p16, BRCA2, HNPCC mutations with ≥1 affected FDR). No consensus was achieved on screening frequency or at what ages to implement screening.
Initial diagnostic evaluation in patients with suspected pancreatic cancer includes laboratories and abdominal imaging. The primary tumor marker associated with PDAC is carbohydrate antigen 19-9 (CA 19-9). It is useful for monitoring disease response with treatment, but remains a poor diagnostic test with a median sensitivity and specificity of 79% and 82%, respectively. CA 19-9 is a sialylated Lewisa blood group antigen and thus is not a useful marker in the 10% of Caucasians and 22% of African Americans who do not express the Lewis antigen.
The imaging study of choice is a “pancreatic protocol” CT scan, which involves triple-phase contrast enhancement on multidetector CT. The late arterial phase helps to distinguish the hypoattenuating tumor from normal parenchyma and the portal phase allows visualization of interface between the tumor and adjacent venous structures and detection of liver metastases. Abdominal ultrasound can identify pancreatic cancer as a solid, hypoechoic mass and show associated biliary ductal dilatation from tumor obstruction. However, it is subject to variability based on operator skill, may miss tumors <3 cm, and incompletely evaluates the pancreas when overlying bowel gas is present.
Endoscopic retrograde cholangiopancreatography (ERCP) is of limited diagnostic utility as the sensitivity of ERCP biopsy or brushing for cytology is low and classically described finding of the “double duct sign” (pancreatic and biliary duct dilatation) are not specific to pancreatic tumors. ERCP is likely more useful as a therapeutic intervention in relieving malignant biliary obstructions. EUS with fine-needle aspiration (FNA) has a sensitivity of 92% and specificity of 96% in diagnosing pancreatic cancer, and it is the preferred method of obtaining a histopathologic diagnosis. Percutaneous biopsy is avoided due to a theoretical concern for seeding of tumor in the biopsy needle tract or peritoneal cavity.
STAGING
The staging of pancreatic cancer is based upon the TNM system of the American Joint Committee on Cancer (AJCC). The AJCC designates T4 (tumor involving celiac axis or SMA) as unresectable disease, but studies have shown some T4 tumors can achieve R0 resection after neoadjuvant therapy. Practically speaking, the goal of staging evaluation in pancreatic cancer is to evaluate local disease for resectability and rule out distant metastases.
Triple-phase “pancreatic protocol” CT scan of the abdomen is the mainstay of staging. MRI scan and PET/CT scan can be done but provide no additional benefit in comparison to CT. EUS is good at local tumor and nodal staging, may evaluate for some distant metastases in liver, and can sample ascites fluid. However, it is invasive and evaluation of primary tumor can be confounded by parenchymal inflammation. Staging laparoscopy is considered in those at risk of occult peritoneal involvement (body/tail tumors, primary tumor >3 cm, very high initial CA 19-9, and imaging suggestive of occult disease).
TREATMENT
Pancreatic cancer can be split into treatment categories: (1) resectable, (2) borderline resectable, (3) locally advanced, unresectable, or (4) metastatic. Pancreatic cancer portends a high burden of morbidity and mortality, so palliative/supportive care should be implemented early. Patients are best evaluated by multidisciplinary teams at high-volume centers. Efforts should always be made to offer clinical trial enrollment to eligible patients.
Resectable Disease
Fifteen percent of patients present with resectable disease, which means there is no arterial tumor contact and no SMV or portal vein contact (or ≤180° contact without vein contour irregularity). Treatment involves surgical resection followed by 6 months of adjuvant chemotherapy with gemcitabine (GEM) or GEM plus capecitabine. There is no proven role for chemoradiotherapy (CRT) as of yet.
Surgical Resection. Resection offers a potentially curative treatment, but recurrences are common even with R0 resections. Patients must have good functional status to tolerate a major abdominal surgery. Resection is underutilized in the United States among early stage pancreatic cancer patients with 38.2% of appropriate candidates not undergoing resection. Pancreatic head tumors undergo conventional or pylorus-preserving pancreaticoduodenectomy (Whipple procedure), whereas pancreatic body/tail tumors undergo a distal pancreatectomy, often with splenectomy. Staging laparoscopy should be considered prior to resection with head/tail tumors given possibility of occult peritoneal metastases. Total pancreatectomy is done only if entire gland involved by tumor, but has a high attendant morbidity. Extended pancreatectomy and extended lymphadenectomy do not improve survival. Vein resection with reconstruction is performed when tumor focally involves the portal vein or SMV.
Adjuvant Chemotherapy. All patients who have had resection should receive 6 months of adjuvant chemotherapy with either GEM alone or GEM/Capecitabine. Chemotherapy is typically initiated 4 to 6 weeks after resection, though benefit is conferred even when initiation is delayed to 12 weeks. Completion of all planned cycles tends to be the more important factor in terms of outcomes. Relevant clinical trials involving adjuvant chemotherapy are summarized below:
ESPAC-1 used a 2 × 2 factorial design to randomize 289 patients after resection into four treatment arms: (1) chemoradiotherapy alone; (2) chemotherapy alone; (3) both chemoradiotherapy and chemotherapy; and (4) observation. Five-year OS was 21% in those who received chemotherapy versus 8% in those who did not (P = 0.009).
CONKO-001 randomized 368 patients after resection to 6 months of adjuvant chemotherapy with GEM versus observation. Median DFS was 13.4 and 6.7 months in the GEM and observation groups, respectively, with HR 0.55 (P < 0.001). Five-year OS was 20.7% and 10.4% with GEM and observation, respectively, with HR 0.76 (P = 0.01).
ESPAC-3 (v2) randomized 1,088 patients after resection to 6 months of adjuvant chemotherapy with GEM versus 5-fluorouracil/folinic acid (5FU/FA). There was no significant difference with median survival of about 23 months in each group. More adverse events were noted with 5FU/FA.
RTOG 9704 randomized 451 patients with gross resection to receive chemotherapy with either GEM or 5FU/FA at 3 weeks prior and 12 weeks after planned chemoradiotherapy. No significant difference in OS was noted. The subset with pancreatic head tumors trended toward improved median survival and 5-year OS but did not reach statistical significance.
JASPAC 01 randomized 385 Japanese patients to receive adjuvant chemotherapy with GEM versus S-1 (an oral prodrug of 5FU). Five-year OS in the S-1 group was 44.1% versus 24.4% in the GEM group with HR 0.57 (P < 0.0001). S-1 is not currently approved in the United States and studies are needed to show validity in non-Asian populations.
ESPAC-4 randomized 732 patients to gemcitabine alone (N = 366) or gemcitabine plus capecitabine (N = 364). Enrolled patients received six cycles of either 1,000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1,660 mg/m2 oral capecitabine administered for 21 days followed by 7 days’ rest (one cycle). The median OS was 28.0 months in the gemcitabine plus capecitabine group and 25.5 months in the gemcitabine monotherapy group (HR 0.82; 95% CI, 0.68 to 0.98; P = 0.032). There was increased incidence of grade 3 to 4 toxicities in the combination arm.
Other ongoing trials of intensified chemotherapy in the adjuvant setting include APACT (GEM/nab-paclitaxel) and PRODIGE/ACCORD24 (GEM/modified FOLFIRINOX).
Adjuvant Chemoradiotherapy (CRT). There is no recommendation for CRT in the adjuvant setting. Relevant clinical trials involving adjuvant CRT are summarized below:
ESPAC-1 (see above for trial design) showed trend toward harm with CRT with a 5-year OS of 10% versus 20% in those who did not receive CRT.
EORTC 40891 compared 218 patients receiving CRT versus observation alone. Median survival and 2-year survival rates had no significant differences.
GITSG compared CRT to observation alone and showed 2-year survival rates of 43% with CRT versus 18% with observation (P < 0.03). Several criticisms of the trial include the poor patient accrual (only 43 patients) and atypical treatment schedule with a split course of radiation given and the 5FU component being given during the first week of radiation and continued for up to 2 years after.
RTOG 0848 is an ongoing phase III trial, which hopes to further investigate the role of adjuvant CRT by evaluating outcomes when it is added after 6 months of GEM in comparison to GEM chemotherapy alone.
Neoadjuvant Therapy. Theoretical advantages of neoadjuvant therapy in resectable disease include upfront treatment of micrometastases, higher likelihood of negative resection margins, and ability to give treatment before post-resection complications. Although there are no reliable data from randomized studies in this setting yet, neoadjuvant therapy is gaining more support at major centers, especially for patients with borderline resectable disease.
Borderline Resectable Disease
Borderline resectable disease is localized disease which is not likely to achieve negative resection margins. While there is no universal definition of borderline resectability, it typically means that tumor focally involves the visceral arteries (≤180°) or has short-segment encasement or occlusion of major veins. Treatment involves use of chemotherapy for 2 to 3 months to downstage the tumor before attempted resection. There is a paucity of evidence to guide which exact regimen to use but multi-agent chemotherapy is typically given (e.g., FOLFIRINOX or GEM/nab-paclitaxel). The Alliance Trial A021101 (NCT01821612) is an ongoing study in borderline resectable disease using mFOLFIRINOX and subsequent capecitabine-based chemoradiation before resection and adjuvant GEM. Initial results have shown 68% underwent surgery with 93% of those achieving R0 resection.
Locally Advanced, Unresectable Disease
About 35% of patients present with locally advanced, unresectable disease. Typically, it is treated with multi-agent chemotherapy (GEM/nab-paclitaxel or FOLFIRINOX based on extrapolation of data in the metastatic setting) for at least 3 months. CRT is then considered in those who have not progressed systemically. Upfront CRT is reserved for patients with poorly controlled pain or bleeding from local invasion. Repeat imaging to evaluate for response or progression is recommended every 2 to 3 months. Relevant clinical trials are summarized below:
ECOG 4201 compared CRT followed by GEM versus GEM alone with median OS of 11.1 and 9.2 months, respectively (one-sided P = 0.017). However, grade 4 or higher toxicity was more in CRT arm (41% vs. 9%). It was limited by poor accrual (only 74 patients).
FFCD-SFRO enrolled 119 patients and compared CRT followed by GEM versus GEM alone. OS was shorter in the CRT group than in the GEM-alone group (8.6 vs. 13 months; P =0.03) and more grade 3 to 4 toxicity was seen in the CRT arm.
LAP 07 studied CRT versus GEM maintenance in patients who had already received induction chemotherapy for 4 months without progression. No difference in median OS was noted at 16.5 versus 15.3 months (HR 1.03; P = 0.83). However, CRT was associated with decreased local progression. There was no increased grade 3 to 4 toxicity in the CRT group except for nausea.
Metastatic Disease
At least 50% of patients present with metastatic disease. The first-line treatment of metastatic disease remains combination cytotoxic chemotherapy. Performance status is the major determinant of which regimen is used.
In 1997, GEM was proven to be superior to 5-FU/FA with regards to clinical benefit response and survival. Subsequently, several phase III studies of GEM combined with other cytotoxic or targeted agents were conducted but showed no significant improvement in survival. However, pooled analysis showed modest improvement in survival when GEM was combined with cytotoxic therapy in patients with good functional status. In recent years, use of the combination cytotoxic regimens FOLFIRINOX and GEM/nab-paclitaxel have shown benefit and are the main first-line regimens. Single-agent chemotherapy is recommended in those with poor performance status. Clinical trials should be encouraged in eligible patients.
PRODIGE4/ACCORD11 randomized 342 patients to receive FOLFIRINOX or GEM and showed superiority of FOLFIRINOX with HR for death of 0.57 (P < 0.01) and median survival improved by 4.3 months. Quality of life was preserved for a longer period despite more grade 3 to 4 toxicities in the FOLFIRINOX group.
MPACT randomized 861 patients to receive GEM/nab-paclitaxel versus GEM alone with median OS of 8.5 versus 6.7 months (HR 0.72; P < 0.01).
Second-line therapy involves use of GEM-containing chemotherapy in those initially treated with 5FU/FA-containing regimen, and vice-versa. Recent data suggests benefit with addition of liposomal irinotecan.
NAPOLI-1 evaluated the use of nanoliposomal irinotecan with 5-FU/FA versus each agent alone in patients previously treated with GEM. Median survival improved in the combined treatment group compared to 5-FU/FA alone (6.1 vs. 4.2 months; HR 0.6; P = 0.012).
PANCREOX showed no difference in PFS, worse OS, and more toxicity in patients receiving modified FOLFOX6 compared to 5FU/FA alone in the second-line setting after receiving GEM.
Immunotherapy of Pancreatic Cancer
Pancreatic cancer is generally considered to be a nonimmunogenic tumor. Trials with immune checkpoint inhibitors against CTLA-4 and PD-1 have not shown the same promising results seen in other solid tumors. Current efforts have focused on the PD-1 blockade +/− anti-CTLA-4 in combination with various immune-potentiating modalities including radiation or chemotherapy.
TABLE 10.1 Inherited Syndromes Associated with Pancreatic Cancer
Affected Gene | Relative Risk | Comments | |
Hereditary pancreatitis | PRSS1 (cationic trypsinogen) | 20–75 | Present in youth with recurrent acute pancreatitis leading to chronic pancreatitis. Pancreatic cancer occurs 2–3 decades after onset of chronic pancreatitis. |
Peutz-Jeghers syndrome | STK11/LKB1 (serine threonine kinase 11) | 132 | Tumor suppressor gene. Presents with benign GI polyps, melanosis of mouth/hands/feet. Also associated with breast, lung, endometrial, gonadal cancers. |
Familial atypical multiple mole melanoma (FAMMM) | CDKN2A (p16) | 13–22 | Tumor suppressor gene. Also associated with melanoma, breast, endometrial, lung cancers. |
Hereditary breast/ovarian cancers (HBOC) | BRCA1 BRCA2 PALB2 | 2.3–3.6 3–10 Unknown | Tumor suppressor genes. BRCA2 is the most common hereditary risk factor for pancreatic cancer. |
Familial adenomatous polyposis (FAP) | APC | 5 | Tumor suppressor gene. Associated with numerous colon polyps beginning in adolescence and colon cancer in young adulthood. |
Hereditary non-polyposis colon cancer (HNPCC) | MSH2, MLH1 | Unknown | Mismatch repair proteins. Less frequently from MSH6, PMS1, and PMS2 mutations. Associated with cancers of colon (especially right-sided), endometrium, ovary, stomach, small intestine, biliary tract, upper GU tract, brain, skin. |
Suggested Readings
1.Aggarwal G, Kamada P, Chari ST. Prevalence of diabetes mellitus in pancreatic cancer compared to common cancers. Pancreas. 2013;42(2):198–201.
2.Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS. National failure to operate on early stage pancreatic cancer. Ann Surg. 2007;246(2):173–180.
3.Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013;62(3):339–347.
4.Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008;19(9):1592–1599.
5.Chen J, Yang R, Lu Y, Xia Y, Zhou H. Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration for solid pancreatic lesion: a systematic review. J Cancer Res Clin Oncol. 2012;138(9):1433–1441.
6.Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825.
7.Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. Cancer survival analysis. In: AJCC Cancer Staging Manual. New York: Springer; 2010:15–20.
8.Esposito I, Segler A, Steiger K, Kloppel G. Pathology, genetics and precursors of human and experimental pancreatic neoplasms: an update. Pancreatology. 2015;15(6):598–610.
9. Gastrointestinal Tumor Study Group. Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Cancer. 1985;56(11):2563–2568.
10.Gill S, Ko YJ, Cripps C, et al. PANCREOX: a randomized phase III study of 5-fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol. 2016;34(32):3914–3920.
11.Goonetilleke KS, Siriwardena AK. Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol. 2007;33(3):266–270.
12.Greer JB, Lynch HT, Brand RE. Hereditary pancreatic cancer: a clinical perspective. Best Pract Res Clin Gastroenterol. 2009;23(2):159–170.
13.Hammel P, Huguet F, van Laethem JL, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA. 2016;315(17):1844–1853.
14.Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2013 [Internet]. Bethesda, MD: National Cancer Institute; 2016 [cited February 20, 2017].
15.Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27(11):1806–1813.
16.Katz MHG, Shi Q, Ahmad SA, et al. Preoperative modified FOLFIRINOX treatment followed by capecitabine-based chemoradiation for borderline resectable pancreatic cancer: alliance for clinical trials in oncology trial A021101. JAMA Surg. 2016;151(8):e161137.
17.Khorana AA, Mangu PB, Berlin J, et al. Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(21):2541–2556.
18.Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230(6):776–782; discussion 782–784.
19.Loehrer PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011;29(31):4105–4112.
20.Maisonneuve P, Lowenfels AB. Risk factors for pancreatic cancer: a summary review of meta-analytical studies. Int J Epidemiol. 2015;44(1):186–198.
21.Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 2017;389(10073):1011–1024.
22.Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304(10):1073–1781.
23.Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200–1210.
24.Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310(14):1473–1481.
25.Porta M, Fabregat X, Malats N, et al. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage. Clin Transl Oncol. 2005;7(5):189–197.
26.Regine WF, Winter KA, Abrams R, et al. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011;18(5):1319–1326.
27.Seufferlein T, Bachet JB, Van Cutsem E, Rouger P. Pancreatic adenocarcinoma: ESMO–ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2012;23(suppl. 7):vii33–vii40.
28.Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.
29.Strobel O, Berens V, Hinz U, et al. Resection after neoadjuvant therapy for locally advanced, “unresectable” pancreatic cancer. Surgery. 2012;152(3 Suppl 1):S33–S42.
30.Uesaka K, Boku N, Fukutomi A, et al. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016;388(10041):248–257.
31.Valle JW, Palmer D, Jackson R, et al. Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. J Clin Oncol. 2014;32(6):504–512.
32.Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–1703.
33.Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545–557.