Case-Based Review

Pancreatic Adenocarcinoma: Update on Neoadjuvant and Adjuvant Treatment


 

References

Introduction

Exocrine pancreatic cancer refers to pancreatic adenocarcinomas that arise from ductal epithelial cells. Pancreatic ductal adenocarcinoma is a highly lethal malignancy, ranking as the fourth most common cause of cancer-related death in the United States1 and the eighth most common worldwide.2 In the United States, the pancreas is the second most common site of gastrointestinal malignancy after the colon.1 The only potentially curative modality for pancreatic adenocarcinomas is complete resection, followed by adjuvant therapy; unfortunately, only around 20% of patients are surgical candidates at the time of presentation due to delayed development of symptoms and consequently diagnosis.3 Most symptomatic patients with pancreatic cancer have locally advanced disease at diagnosis, and only a select group of patients with good performance status and borderline resectable disease can be offered neoadjuvant therapy. Adjuvant chemotherapy is typically recommended for patients who undergo potentially curative resection for pancreatic cancer.

Epidemiology

In the United States, pancreatic cancer has an annual estimated incidence of 55,440 new cases.1 It causes an estimated 44,330 deaths per year, with a 5-year overall survival (OS) rate of 8.2%.1 Worldwide an estimated 138,100 men and 127,900 women die of pancreatic cancer each year.2 In general, pancreatic cancers occur more commonly in persons living in Western/industrialized countries, older persons (age > 60 years), males (ratio 1.3:1 female), and African-Americans and native Hawaiians.4

Etiology

The major preventable environmental risk factor for pancreatic cancer is cigarette smoking, which accounts for 25% of all cases.5 A prospective study that estimated the excess incidence of pancreatic cancer among cigarette smokers and assessed the influence of smoking cessation on the risk for pancreatic cancer showed that persons who quit smoking reduced their risk of pancreatic cancer by 48% after 2 years of cessation, compared with smokers who did not quit, and reduced their risk to near the level of a never smoker after 10 years of cessation.5 Risk is higher for heavy smokers and those with homozygous deletions of the glutathione S-transferase theta 1 gene (GSTT1), which results in the absence of the carcinogen-metabolizing function of the glutathione S-transferase enzyme. High body mass index and sedentary lifestyle have been linked to pancreatic cancer.6 Data regarding aspirin, diet, coffee, and excess alcohol consumption are insufficient, inconclusive, and even conflicting, and thus the effect of these factors on risk for pancreatic cancer remains unclear. Infectious risk factors such as Helicobacter pylori and hepatitis B and C virus have weak associations with pancreatic cancer. Chronic pancreatitis and pancreatic cysts (eg, intraductal papillary mucinous neoplasm [IPMN] of the pancreas) carry a risk for malignant transformation, and hence may require surveillance. Multiple epidemiologic studies have shown a strong association between pancreatic cancer and recently diagnosed diabetes mellitus (relative risk [RR] 1.97 [95% confidence interval {CI} 1.78 to 2.18]); the presence of diabetes also may be a long-term predisposing factor for pancreatic cancer, and cancer screening needs to be considered for selected patients.7

A predisposing genetic anomaly accounts for 15% of all cases of pancreatic cancer.8 Hereditary risk factors are divided into 2 broad categories: defined genetic syndromes and familial pancreatic cancer. Familial predispositions that do not meet genetic syndrome criteria account for approximately 5% to 10% of all cases associated with hereditary factors; in one study, 29% of tested kindreds with an incident pancreatic cancer had a germline BRCA2 mutation.9 Other predisposing genetic syndromes that have been linked to pancreatic cancer include:

  • Peutz-Jeghers syndrome with germline STK11 mutations (RR 132);
  • Hereditary pancreatitis with germline PRSS1, SPINK1, and CFTR mutations (RR 26–87);
  • Familial atypical multiple mole melanoma syndrome with CDKN2A mutations (RR 20–40);
  • Familial breast and ovarian cancer with BRCA2 (RR 10) and BRCA1 (RR 2.8) mutations;
  • Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch II syndrome) with MLH1, MSH2, MSH6, and PMS2 mutations (RR 9–11); and
  • Familial adenomatous polyposis with APC mutations (RR 5).10

Other gene mutations with unknown relative risk for pancreatic cancer include mutations affecting PALB2, ATM, and TP53.

The International Cancer of the Pancreas Screening consortium consensus on screening for pancreatic cancer in patients with increased risk for familial pancreatic cancer recommends screening those at high risk: first-degree relatives (FDRs) of patients with pancreatic cancer from a familial pancreatic kindred with at least 2 affected FDRs; patients with Peutz-Jeghers syndrome; and p16, BRCA2, and HNPCC mutation carriers with 1 or more affected FDRs and hereditary pancreatitis. The guidelines emphasize that screening should be done only in those who are surgical candidates and are evaluated at an experienced multidisciplinary center.8

Deleterious germline mutations in pancreatic cancer can account for 33% of patients with apparent sporadic cancers and no hereditary risk. These include germline mutations affecting BRCA1/2, PALB2, ATM, MLH1, CHK-2, CDKN2A, and TP53.11

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