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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
Pathogenesis
Pancreatic neoplasms can be benign or malignant and thus a tissue histologic diagnosis is paramount. Pancreatic adenocarcinomas with exocrine features represent more than 95% of all pancreatic neoplasms, with only 5% arising from the endocrine pancreas (ie, neuroendocrine tumors). Pancreatic neuroendocrine tumors and pancreatic adenocarcinoma must be distinguished histologically because treatment of the 2 neoplasms is completely different. Other malignant pancreatic tumors are signet ring cell carcinoma, adenosquamous carcinoma, undifferentiated (anaplastic) carcinoma, and mucinous noncystic (colloid) carcinoma; the latter tumor has a better prognosis.12 It is essential to characterize and distinguish among benign cystic neoplasms, as some require surgical resection due to the risk of malignant transformation. IPMN, pancreatic intraepithelial neoplasia, and mucinous cystic neoplasms are thought to be premalignant lesions of invasive ductal adenocarcinomas, and the pathological report should highlight the degree of dysplasia for adequate risk stratification.13 This information could be the deciding factor in whether a pancreatectomy is recommended by a multidisciplinary team.
Most pancreatic cancers harbor activating or silencing genetic mutations, and multiple combinations of altered genes can be detected by next-generation sequencing (average of 63 genetic alterations per cancer).14 Mutational activated KRAS is the most frequent (> 90%) genetic alteration in pancreatic cancer, even in early neoplastic precursors (IPMN > 75%). KRAS is a highly complex, dynamic proto-oncogene involved in signaling of various receptor kinases such as the epidermal growth factor receptor and the insulin-like growth factor receptor-I. It also engages in canonical downstream effector pathways, mainly Raf/MEK/ERK, PI3K/PDK1/Akt, and the Ral guanine nucleotide exchange factor pathway, which drive much of the pathogenesis of malignancy. These pathways lead to sustained proliferation, metabolic reprogramming, anti-apoptosis, remodeling of the tumor microenvironment, evasion of the immune response, cell migration, and metastasis. An activating point mutation in codon G12 is the most common (98%) locus of KRAS mutation in pancreatic adenocarcinoma, but all drugs targeting this mutation have failed in clinical practice.15 Additionally, inactivation of tumor suppressor genes such as p53, DPC4 (SMAD4/MADH4), CDKN2A (p16/MTS1), and BRCA2 can be found in 75%, 30%, 35%, and 4% of pancreatic adenocarcinoma cases, respectively.14 Another pancreatic cancer hallmark is inactivation of DNA damage repair genes, which include MLH1 and MSH2.16
Diagnosis and Staging
Case Presentation
A 71-year-old male veteran with no significant past medical history other than hypertension and hyperlipidemia and an excellent performance status presents to the emergency department after noticing a yellowish skin and sclera color. He denies weight loss, abdominal pain, or any other pertinent symptom or sign. Physical examination reveals a healthy developed man with yellowish discoloration of the skin and sclera and a soft, nontender benign abdomen; physical examination is otherwise unremarkable. Laboratory evaluation reveals a direct bilirubin level of 4.5 mg/dL and normal values for complete blood count and renal, liver, and coagulation panels. Abdominal and pelvis computed tomography (CT) with intravenous contrast shows a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein, which remains patent. Follow-up endoscopic ultrasound (EUS) confirms an irregular mass at the head of the pancreas measuring 3.2 × 2.6 cm with sonographic evidence suggesting invasion into the portal vein. During the procedure, the bile duct is successfully stented, the mass is biopsied, and bile duct brushing is performed. Pathology report is consistent with pancreatic adenocarcinoma.
- What is the typical presentation of pancreatic cancer?
The most common symptoms of pancreatic cancer at the time of presentation include weight loss (85%), asthenia/anorexia (86%), and/or abdominal pain (79%).17 The most frequent signs are jaundice (55%), hepatomegaly (39%), and cachexia (13%). Courvoisier sign, a nontender but palpable distended gallbladder at the right costal margin, is neither sensitive nor specific for pancreatic cancer (13% of cases). Trousseau syndrome, a superficial thrombophlebitis, is another classic sign that reflects the hypercoagulable nature of pancreatic cancer (3% of cases).17 The pathophysiology of this syndrome is not completely understood, but it may occur secondary to the release of cancer microparticles in the blood stream which in turn stimulate the coagulation cascade. Other nonspecific symptoms are dark urine, nausea, vomiting, diarrhea, steatorrhea, and epigastric and back pain. Because symptoms early in the course of the disease are nonspecific, pancreatic cancer is typically diagnosed late, after the cancer has invaded local structures or metastasized. The initial presentation varies depending on tumor location, with 70% of pancreatic head malignancies presenting with jaundice and pain correlating to an advanced stage.18 Although data supporting an association between new-onset diabetes mellitus and pancreatic cancer are inconclusive, pancreatic cancer should still be a consideration in patients with new-onset diabetes mellitus and other symptoms such as pain and weight loss. Early signs of incurable disease include a palpable mass, ascites, lymphadenopathy (classic Virchow node), and an umbilical mass (Sister Mary Joseph node). Incidentally discovered pancreatic masses on imaging are rare, but the incidence is increasing due to frequent imaging for other reasons and improved diagnostic techniques.
- What is the approach to diagnosis and staging?
History and physical examination findings are not sufficiently sensitive or specific to diagnose pancreatic cancer. High clinical suspicion in a patient with risk factors can lead to a comprehensive evaluation and potential early diagnosis. In general, an initial diagnostic work-up for suspected pancreatic cancer will include serologic evaluation (liver function test, lipase, tumor markers) and abdominal imaging (ultrasound, CT scans, or magnetic resonance imaging [MRI]). Ultrasound is a first-line diagnostic tool with a sensitivity of 90% and specificity of 98.8% for pancreatic cancer, but it is investigator-dependent and is less accurate in detecting tumors smaller than 3 cm in diameter.19 Multiphasic helical CT of the abdomen has better sensitivity (100%) and specificity (100%) for detecting tumors larger than 2 cm, but this modality is less accurate in detecting pancreatic masses smaller than 2 cm (77%).20 Percutaneous fine-needle aspiration (FNA) performed by ultrasound or CT guidance is avoided due to theoretical concerns about intraperitoneal seeding and bleeding.
If a pancreatic mass is detected by ultrasound or CT, additional interventions may be indicated depending on the clinical scenario. EUS-guided biopsy can provide histological confirmation and is currently utilized frequently for diagnosis and early resectability staging. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated for patients with biliary obstruction requiring stent placement, and this procedure may provide tissue confirmation by forceps biopsy or brush cytology (lower accuracy than EUS). In a meta-analysis that evaluated the diagnostic value of tests for pancreatic cancer, ERCP had the highest sensitivity (92%) and specificity (96%) compared to ultrasound and CT,21 but this modality carries a risk for pancreatitis, bleeding, and cholangitis. Magnetic resonance cholangiopancreatography has not replaced ERCP, but it but may be an alternative for patients who cannot undergo ERCP (eg, gastric outlet obstruction, duodenal stenosis, anatomical surgical disruption, unsuccessful ERCP). ERCP is used frequently because many patients present with obstructive jaundice due to pancreatic mass compression, specifically if the mass is located in the head, and must undergo ERCP and stenting of the common bile duct.
The carbohydrate antigen (CA) 19-9 level has variable sensitivity and specificity in pancreatic cancer, as levels can be elevated in many benign pancreaticobiliary disorders. Elevated CA 19-9, in the appropriate clinical scenario (ie, a suspicious pancreatic mass and a value greater than 37 U/mL) demonstrated a sensitivity of 77% and specificity of 87% when differentiating pancreaticobiliary cancer from benign clinical conditions such as acute cholangitis or cholestasis.22 CA 19-9 level has prognostic value, as it may predict occult disease and correlates with survival rates, but no specific cutoff value has been established to guide perioperative therapy for high-risk resectable tumors.23
The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) system is the preferred method for staging pancreatic cancer (Table 1). 
Positron emission tomography with CT scan is occasionally utilized in practice to assess tumor burden by evaluating anatomical structures and assessing physiologic uptake, which aids in establishing the extent of disease in equivocal cases. Staging laparoscopy with or without peritoneal biopsy is sometimes used to establish appropriate staging in cases that are questionable for occult metastatic disease. This procedure helps avoid unnecessary morbid surgeries.
Neoadjuvant Therapy
Case Continued
The patient is referred to oncology. Blood work reveals a CA 19-9 level of 100 U/mL (reference range < 35 U/mL) and a staging CT scan of the chest reveals a benign-appearing 3-mm nodule (no prior imaging for comparison). CT scan of the abdomen and pelvis does not define venous vasculature involvement appropriately and hence MRI of the abdomen and pelvis is performed. MRI reveals a pancreatic head mass measuring 3.0 × 2.7 cm, without arterial or venous vasculature invasion. However, the mass is abutting the portal vein and superior mesenteric vein and there is a new nonspecific 8-mm aortocaval lymph node.
- What are the current approaches to treating patients with resectable, unresectable, and metastatic disease?
Accurate staging and assessment of surgical resectability in pancreatic cancer are paramount as these steps prevent a futile morbid Whipple procedure in patients with advanced disease and a high risk of recurrence. Conversely, it allows patients with low-volume disease to undergo a potentially curative surgery. Approximately 20% of patients present with resectable disease, 40% present with locally advanced unresectable tumors (eg, involvement of critical vascular structures), and 40% present with metastatic disease.3 Treatment for resectable pancreatic cancer continues to be upfront surgery, although neoadjuvant therapy with either chemoradiation, radiation alone, or chemotherapy is an option per guidelines from the American Society of Clinical Oncology (ASCO),28 the NCCN,26 and the European Society for Medical Oncology (ESMO),29 particularly for patients with borderline resectable tumors (Table 3). 
Systemic chemotherapy is recommended for fit candidates with locally advanced unresectable or metastatic disease, with an emphasis on supportive palliative measures. Palliative interventions include biliary stenting, duodenal stent for relieving gastric-outlet obstruction, and celiac axis nerve blocks, when indicated. Routine preoperative biliary stent placement/drainage in patients undergoing subsequent surgery for pancreatic cancer located in the head is associated with an increased risk of surgical complications when compared with up-front surgery without prior biliary drainage, and thus stent placement/drainage is not recommended.26 Aggressive supportive management of symptoms, such as cancer-associated pain, anorexia-cachexia syndromes, and anxiety-depression disorders, should remain a primary palliative focus.
Case Continued
A multidisciplinary tumor board discusses the patient’s case and deems the cancer borderline resectable; neoadjuvant therapy is recommended. The patient is started on treatment with gemcitabine and nab-paclitaxel as first-line neoadjuvant therapy. After 4 cycles, the CA 19-9 level drops to 14 U/mL, and MRI reveals a smaller head mass of 1.3 × 1.4 cm with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remains stable. At tumor board, it is evident that the patient has responded to therapy and the recommendation is to treat with gemcitabine chemoradiotherapy before surgery.
- What neoadjuvant therapy strategies are used in the treatment of pancreatic adenocarcinoma?
There are no established evidence-based recommendations for neoadjuvant therapy in patients with borderline resectable pancreatic cancer or patients with unresectable locally advanced pancreatic cancer. However, there are ongoing trials to investigate this treatment approach, and it is offered off-label in specific clinical scenarios, such as in the case patient described here. In patients with borderline resectable disease, preoperative chemotherapy followed by chemoradiation is a routine practice in most cancer centers,32 and ongoing clinical trials are an option for this cohort of patients (eg, Southwest Oncology Group Trial 1505, NCT02562716). The definitions of borderline resectable and unresectable pancreatic cancer have been described by the NCCN,26 although most surgeons consider involvement of the major upper abdominal blood vessels the main unresectability criterion; oncologists also consider other parameters such as suspicious lesions on scans, worsening performance status, and a significantly elevated CA 19-9 level suggestive of disseminated disease.28 The goal of a conversion approach by chemotherapy with or without radiation for borderline and unresectable cancers is to deliver a tolerable regimen leading to tumor downstaging, allowing for surgical resection. No randomized clinical trial has shown a survival advantage of this approach. Enrollment in clinical trials is preferred for patients with borderline and unresectable cancer, and there are trials that are currently enrolling patients.
The main treatment strategies for patients with locally advanced borderline and unresectable pancreatic cancer outside of a clinical trial are primary radiotherapy, systemic chemotherapy, and chemoradiation therapy. Guidelines from ASCO, NCCN, and ESMO recommend induction chemotherapy followed by restaging and consolidation chemoradiotherapy in the absence of progression.26,28,29 There is no standard chemoradiation regimen and the role of chemotherapy sensitizers, including fluorouracil, gemcitabine, and capecitabine (an oral fluoropyrimidine substitute), and targeted agents in combination with different radiation modalities is now being investigated.
Fluorouracil is a radio-sensitizer that has been used in locally advanced pancreatic cancer based on experience in other gastrointestinal malignancies; data shows conflicting results with this drug. Capecitabine and tegafur/gimeracil/oteracil (S-1) are oral prodrugs that can safely replace infusional fluorouracil. Gemcitabine, a more potent radiation sensitizer, is very toxic, even at low-doses twice weekly, and does not provide a survival benefit, as demonstrated in the Cancer and Leukemia Group B (CALGB) 89805 trial, a phase 2 study of patients with surgically staged locally advanced pancreatic cancer.33 Gemcitabine-based chemoradiotherapy was also evaluated in the Eastern Cooperative Group (ECOG) E4201 trial, which randomly assigned patients to receive gemcitabine alone (at 1000 mg/m2/wk for weeks 1 through 6, followed by 1 week rest, then weekly for 3 out of 4 weeks) or gemcitabine (600 mg/m2/wk for weeks 1 to 5, then 4 weeks later 1000 mg/m2 for 3 out of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/fraction for total of 50.4 Gy).34 Patients with locally advanced unresectable pancreatic cancer had a better OS outcome with gemcitabine in combination with radiation therapy (11.1 months) as compared with patients who received gemcitabine alone (9.2 months). Although there was a greater incidence of grade 4 and 5 treatment-related toxicities in the combination arm, no statistical differences in quality-of-life measurements were reported. Gemcitabine-based and capecitabine-based chemoradiotherapy were compared in the open-label phase 2 multicenter randomized SCALOP trial.35 Patients with locally advanced pancreatic cancer were assigned to receive 3 cycles of induction with gemcitabine 1000 mg/m2 days 1, 8, and 15 and capecitabine 830 mg/m2 days 1 to 21 every 28 days; patients who had stable or responding disease were randomly assigned to receive a fourth cycle followed by capecitabine (830 mg/m2 twice daily on weekdays only) or gemcitabine (300 mg/m2 weekly) with radiation (50.4 Gy over 28 fractions). Patients treated with capecitabine-based chemoradiotherapy had higher nonsignificant median OS (17.6 months) and median progression-free survival (12 months) compared to those treated with gemcitabine (14.6 months and 10.4 months, respectively).
The benefit of radiation therapy in the treatment of locally advanced pancreatic cancer was further explored by the Fédération Francophone de Cancérologie Digestive 2000-01 phase 3 trial. This study compared induction chemoradiotherapy (60 Gy, 2 Gy/fraction; concomitant fluorouracil infusion, 300 mg/m2/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m2/day, days 1–5 during weeks 1 and 5) to gemcitabine alone (1000 mg/m2 weekly for 7 weeks) followed by maintenance gemcitabine in both arms.36 Unexpectedly, the median OS was significantly shorter in the chemoradiotherapy arm than in the chemotherapy alone arm (8.6 months versus 13 months, respectively, P = 0.03) and the combination arm had more toxicities. The phase 3 open-label LAP07 study explored the role of radiation therapy in patients with locally advanced pancreatic cancer who had controlled disease after 4 months of induction therapy.37 LAP07 had 2 randomizations: first, patients with locally advanced pancreatic cancer were assigned to receive weekly gemcitabine alone (1000 mg/m2) or this same dose of gemcitabine plus erlotinib 100 mg/day; second, patients with progression-free disease (61% of initial cohort) after 4 months of therapy were assigned to receive 2 months of the same chemotherapy or chemoradiotherapy (54 Gy plus capecitabine). This study showed that the addition of erlotinib to gemcitabine did not improve survival and in fact affected survival adversely. Of note, no survival benefit was observed after the first randomization from chemotherapy to consolidating chemoradiotherapy. Chemoradiotherapy achieved better locoregional tumor control with significantly less local tumor progression (32% versus 46%, P < 0.03) and no increase in toxicity. Based on prior moderate-quality evidence, guidelines recommend consolidative chemoradiotherapy only for surgical resection candidates following induction chemotherapy; for those who are not surgical candidates, guidelines recommend continuing systemic therapy.26,28,29
Gemcitabine and fluorouracil-based chemotherapies were the standard induction regimens until evidence from studies of metastatic systemic treatment protocols with FOLFIRINOX (ACCORD trial38) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine (MPACT trial39) was extrapolated to clinical practice. These regimens were shown to achieve higher objective response rates when compared to single-agent gemcitabine in patients with metastatic pancreatic cancer. Due to the broad heterogeneity of results in small retrospective series with neoadjuvant trials in borderline resectable pancreatic cancer, the quality of the evidence is low and any recommendation is limited. Many individual series have demonstrated improved complete resection rates and promising survival rates. In the largest single-institution retrospective review of patients with borderline resectable pancreatic adenocarcinoma who completed neoadjuvant gemcitabine-based chemoradiotherapy (50 Gy in 28 fractions or 30 Gy in 10 fractions), 94% achieved a margin-negative pancreatectomy; the median OS in those who completed preoperative therapy and had surgery was 40 months, with a 5-year OS of 36%.40 A meta-analysis by Andriulli and colleagues included 20 prospective studies of patients with initially resectable (366 lesions) or unresectable (341 lesions) disease who were treated with neoadjuvant/preoperative gemcitabine with or without radiotherapy.41 In the group with initially unresectable disease, 39% underwent surgery after restaging and 68% of explored patients were resected; the R0 resection rate was 60%. After restaging, 91% of patients with resectable disease underwent surgery, with 82% of explored patients undergoing surgical resection and 89% of these achieving R0 resection. The estimated 1- and 2-year survival probabilities after resection among patients with initially unresectable disease were 86.3% and 54.2%.41
The largest single-institution retrospective review of FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, and leucovorin), an alternative to gemcitabine, for neoadjuvant induction therapy for patients with locally advanced unresectable disease was conducted at Memorial Sloan Kettering Cancer Center. In this study (n = 101), 31% of patients initially deemed unresectable who completed FOLFIRINOX induction therapy with or without chemoradiation underwent resection. The R0 resection rate in these patients was 55%, and patients who did not progress during induction FOLFIRINOX therapy had a median OS of 26 months.42 A systematic review and meta-analysis of FOLFIRINOX chemotherapy with or without radiotherapy in patients with locally advanced unresectable pancreatic cancer reported that 25.9% of patients underwent resection after FOLFIRINOX therapy, and the R0 resection rate in these patients was 78.4%.43 The median OS in this study was 24.2 months, which was longer than the previously reported median OS rates for gemcitabine.
There is no strong evidence published for the use of combination nab-paclitaxel plus gemcitabine in the neoadjuvant setting, but it is used in clinical practice based on evidence from the MPACT trial, which showed the combination improved OS and progression-free survival in patients with metastatic pancreatic cancer.39 An early-phase 1-arm clinical trial of neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) followed by radiotherapy showed an increased response rate and survival for locally advanced disease; however, the NCCN expert panel has reached a consensus but not a uniform recommendation regarding this regimen due to significant toxicities and low patient accrual.26 Selected patients with pancreatic cancer with BRCA1/2 mutations are more sensitive to platinum-based chemotherapy. Although studies of neoadjuvant platinum-based chemotherapy in this population have not been reported, the NCCN guidelines list it as an alternative option based on extrapolated data.26 A clinical trial of gemcitabine, nab-paclitaxel, and cisplatin in the neoadjuvant setting in patients with resectable pancreatic cancer is currently enrolling patients (NGC triple regimen NCT0339257).
Summary
Chemotherapy alone or followed by chemoradiotherapy may be used as initial treatment for patients with borderline and unresectable pancreatic adenocarcinoma without distant metastases who are potential surgical candidates. Chemoradiotherapy remains a preferred treatment option for patients with poorly controlled pain from local tumor invasion, in view of the well-documented analgesic palliative effect of radiation therapy. FOLFIRINOX with or without radiation therapy may offer the highest documented response rates, but it also results in higher rates of treatment-related toxicities. FOLFIRINOX can be offered to selected fit patients (< 65 years old, no comorbidity contraindication, good functional status [ECOG 0–1]) who can tolerate triple therapy with a more toxic adverse-effect profile. A clinical trial evaluating neoadjuvant FOLFIRINOX with or without preoperative chemoradiotherapy in patients with borderline resectable pancreatic cancer is ongoing (PANDAS-PRODIGE 44, NCT02676349). Gemcitabine with or without radiation therapy is a tolerable combination, although it is potentially more toxic when combined with radiation. The addition of nab-paclitaxel to gemcitabine without radiation may emerge as a preferred neoadjuvant treatment for selected patients; a clinical trial investigating this modality in patients with resectable and borderline resectable disease is ongoing (NCT02723331).
Adjuvant Therapy
Case Continued
Prior to the planned surgical resection and after undergoing chemoradiation therapy, the patient has an excellent performance status and repeat MRI shows a 1.3 × 1.4 cm head mass with no further vasculature involvement, no evidence of lymphadenopathy, and no distant metastasis. The CA 19-9 level is stable at 18 U/mL. The patient undergoes an uncomplicated partial pancreaticoduodenectomy, and analysis of a surgical pathology specimen reveals T3N0 disease with closest margin of 0.1 cm.
- Would the patient benefit from adjuvant therapy?
Adjuvant chemotherapy for 6 months after pancreatic cancer resection should be offered to all patients based on mature data. Gemcitabine and capecitabine are the current standard of care in adjuvant therapy; alternatively, single-agent gemcitabine can be offered to patients with poor performance status or patients who cannot tolerate the toxicities associated with this combination.28 Adjuvant treatment should be initiated within approximately 8 weeks of surgical resection. The value of radiation therapy remains controversial, but it can be offered within the context of a clinical trial or to patients with positive margins after surgical resection and/or lymph node–positive disease. Based on low-quality supportive evidence, it is strongly recommended that patients who receive neoadjuvant therapy complete a total of 6 months of chemotherapy, factoring in the duration of the preoperative regimen.28 Different adjuvant strategies have been investigated, including chemotherapy alone with a fluoropyrimidine and/or gemcitabine with or without combined chemoradiation therapy.
The European Study Group for Pancreatic Cancer 1 (ESPAC)-1 trial was a randomized clinical trial that evaluated several adjuvant strategies in pancreatic cancer treatment. This trial assigned patients who underwent pancreatic adenocarcinoma resection to adjuvant chemotherapy alone (intravenous fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 daily for 5 days, monthly for 6 months), chemoradiotherapy (20 Gy in 10 daily fractions over 2 weeks with 500 mg/m2 intravenous fluorouracil on days 1–3, repeated after 2 weeks), both chemotherapy and chemoradiation, and observation.44 The results showed no added benefit for adjuvant chemoradiotherapy, with a median OS of 15.5 months in the chemoradiotherapy cohort, as compared to a median OS of 16.1 months in the chemotherapy-alone cohort (hazard ratio [HR] 1.18 [95% CI 0.90 to 1.55], P = 0.24). In addition, there was evidence of a survival benefit for the chemotherapy-alone arm when compared to the combined modality arm, with a median OS of 19.7 versus 14.0 months, respectively (HR 0.66 [95% CI 0.52 to 0.83], P = 0.0005). Although ESPAC-1 has been criticized for being underpowered to perform statistical comparison, it is still considered a landmark trial demonstrating benefit with single-agent chemotherapy alone. A follow-up analysis of ESPAC-1 showed that adjuvant chemotherapy alone conferred a significant 5-year survival benefit while the combined modality had a deleterious effect on survival. 45 Hence, adjuvant chemotherapy alone became the standard of care in the United States following resection.
The results of the multicenter randomized controlled phase 3 CONKO-001 (CharitéOnkologie 001) trial, which were reported in 2007, supported the use of adjuvant gemcitabine for 6 months in patients with resected pancreatic adenocarcinoma. In this study, patients treated with adjuvant gemcitabine (1000 mg/m2 days 1, 8, and 15 every 4 weeks for 6 months) had superior disease-free survival compared with those who received surgery alone.30 A long-term outcome update of this study demonstrated a significant improvement in 5-year OS for patients treated with adjuvant gemcitabine (20.7% [95% CI 14.7% to 26.6%]) compared to those who received surgical resection alone (10.4% [95% CI 5.9% to 15.0%]). This benefit persisted at 10-year follow-up, with an OS of 12.2% (95% CI 7.3% to 17.2%) in the adjuvant gemcitabine group, as compared to 7.7% (95% CI 3.6% to 11.8%) in the resection alone group.31
Fluorouracil and gemcitabine remained equivalent adjuvant treatment options until the results of the ESPAC-3 trial were reported in 2010.32 This large phase 3 trial, conducted mainly in the United Kingdom, compared weekly gemcitabine (1000 mg/m2 weekly for 3 of every 4 weeks) to leucovorin-modulated fluorouracil (Mayo Clinic regimen: leucovorin 20 mg/m2 followed by fluorouracil 425 mg/m2 intravenous bolus days 1 through 5 every 28 days) as adjuvant therapy in resected pancreatic adenocarcinoma. After a median follow-up of 34.2 months, the median OS was similar in the 2 groups (fluorouracil/leucovorin 23.0 months versus gemcitabine 23.6 months; P = 0.39). However, the fluorouracil/leucovorin group experienced more grade 3/4 treatment-related toxicities (mucositis, stomatitis, diarrhea, and hosptializations; 14% versus 7.5%; P < 0.001).46 Following this trial, gemcitabine became the standard of care for adjuvant chemotherapy for resected pancreatic cancer.
The U.S. Radiation Therapy Oncology Group (RTOG) 9704 trial was conducted to investigate the potential benefit of adding radiation therapy to gemcitabine. This trial demonstrated an improved trend among patients with pancreatic head tumors (but not with cancers of the pancreatic body or tail) who received adjuvant gemcitabine followed by chemoradiotherapy (50.4 Gy in 1.8 Gy daily fractions for 5.5 weeks with concurrent infusional fluorouracil 250 mg/m2 daily) and subsequent gemcitabine monotherapy compared to postoperative fluorouracil-based chemoradiotherapy. Results showed a 5-year OS of 22% versus 18%, respectively, although this improvement was not statistically significant (P = 0.08). This trial failed to show a benefit of adding radiotherapy to gemcitabine.47
The ESPAC-4 trial, reported in 2017, evaluated the combination of gemcitabine and capecitabine compared to gemcitabine alone as adjuvant therapy for resected pancreatic adenocarcinoma.48 Patients were randomly assigned after surgical resection, regardless of margin or node status, to 6 months of gemcitabine alone (1000 mg/m2/day on days 1, 8, and 15 of each 28-day cycle) or gemcitabine plus capecitabine (1660 mg/m2/day on days 1 through 21 of each 28-day cycle). Combination therapy had a significant survival benefit compared to single therapy, with median OS durations of 28 months and 25.5 months, respectively (HR for death 0.82 [95% CI 0.68 to 0.98]). The 5-year OS for patients who received combination treatment was 29 months (95% CI 22.9 to 35.2) versus 16 months (95% CI 10.2 to 23.7) for those in the monotherapy group. As expected, grade 3 or 4 treatment-related toxicities (diarrhea, hand-foot syndrome, and neutropenia) were significantly more common with combined therapy, although there were no significant differences in the rates of serious adverse events. The adjuvant combination of gemcitabine and capecitabine became the current and preferred new standard of care following resection of pancreatic ductal adenocarcinoma,28 but single-agent gemcitabine and fluorouracil/leucovorin continue to be viable options,26,28,29 particularly for elderly patients, patients with borderline performance status, or patients with multiple comorbidities.
Evidence showing that a more intensive regimen can improve outcome in the adjuvant setting remains elusive. The phase 3 APACT study (Adjuvant Therapy for Patients with Resected Pancreatic Cancer, NCT01964430) comparing gemcitabine alone to gemcitabine plus nab-paclitaxel in patients with surgically resected pancreatic adenocarcinoma has concluded, with the results projected to be released in 2018. Another phase 3 trial investigating the efficacy of FOLFIRINOX versus gemcitabine alone as adjuvant therapy is underway in France and Canada (PRODIGE24/ACCORD24, NCT01526135). Other strategies with newer targeted therapies and immunotherapy are in the development phase.
Follow-Up and Surveillance
Case Conclusion
After recovery from surgery, the patient is offered and completes 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine. He is started on surveillance at 3 and 6 months, and he maintains an excellent performance status. He develops clinical evidence of pancreatic enzyme insufficiency and is placed on oral replacement therapy. He has no other complaints, and there is no evidence of recurrence on MRI and CA 19-9 levels.
- What is the recommended duration of surveillance following curative resection?
Surveillance after curative resection of pancreatic adenocarcinoma is recommended by NCCN guidelines.26 However, pancreatic adenocarcinoma has a poor prognosis, and surveillance after curative surgical resection with or without perioperative therapy has not been shown to impact survival. Most recurrences will occur within 2 years after treatment. Surveillance recommendations differ among expert groups.26,28,29 NCCN guidelines recommend evaluating patients by history and physical examination every 3 to 6 months for the first 2 years, then every 6 to 12 months for 3 years. CA 19-9 level and CT scan should be obtained every 3 to 6 months for 2 years and then every 6 to 12 months for 3 years. Follow-up with CA 19-9 levels and CT scans after 5 years is not routinely performed unless guided by signs, symptoms, or laboratory findings that raise suspicion for recurrence. Follow-up visits should also include evaluation of treatment-related toxicities, symptom management, nutrition support of pancreatic insufficiency, and psychosocial support.
Conclusion
Pancreatic cancer is a leading cause of cancer-related death that frequently presents with locally advanced or metastatic disease due to nonspecific symptoms and lack of a screening modality. Histological tissue biopsy confirmation and accurate resectability staging guide treatment planning and prognosis. The only potentially curative therapy is surgical resection plus adjuvant therapy for those with resectable disease. Surgical candidates with borderline resectable and unresectable disease can be offered induction preoperative chemotherapy followed by consolidation chemoradiation, based on clinical consensus practice. Enrollment in clinical trials should be encouraged for all patients, as evidence from clinical trials is essential to making progress in pancreatic cancer treatment.
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4. National Institutes of Health/National Cancer Institute. Surveillance, Epidemiology and End Results Program (SEER). Cancer stat facts: pancreatic cancer. seer.cancer.gov/statfacts/html/pancreas.html. Accessed 17 February 2018.
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8. Canto MI, Harinck F, Hruban RH, et al, on behalf of the International Cancer of the Pancreas Screening (CAPS) Consortium. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–47. Epub 2012 Nov 7.
9. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 2004;64:2634–8.
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14. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015;518:495–501.
15. Choi M, Bien H, Mofunanya A, Powers S. Challenges in Ras therapeutics in pancreatic cancer. Semin Cancer Biol 2017 Nov 21. pii: S1044-579X(17)30235-3.
16. Humphris JL, Patch AM, Nones K, et al. Hypermutation in pancreatic cancer. Gastroenterology 2017;152:68. Epub 2016 Nov 15.
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18. Modolell I, Guarner L, Malagelada JR. Vagaries of clinical presentation of pancreatic and biliary tract cancer. Ann Oncol 1999;10 Suppl 4:82–4.
19. Karlson BM, Ekbom A, Lindgren PG, et al. Abdominal US for diagnosis of pancreatic tumor: prospective cohort analysis. Radiology 1999;213:107–11.
20. Bronstein YL, Loyer EM, Kaur H, et al. Detection of small pancreatic tumors with multiphasic helical CT. AJR Am J Roentgenol 2004;182:619–23.
21. Niederau C, Grendell JH. Diagnosis of pancreatic carcinoma. Imaging techniques and tumor markers. Pancreas 1992;7:66–86.
22. Kim HJ, Kim MH, Myung SJ, et al. A new strategy for the application of CA19-9 in the differentiation of pancreaticobiliary cancer: analysis using a receiver operating characteristic curve. Am J Gastroenterol 1999;94:1941–6.
23. Khorana AA, Mangu PB, Berlin J, et al. Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016;34:2541–56.
24. Allen PJ, Kuk D, Castillo CF, et al. Multi-institutional validation study of the American Joint Commission on Cancer (8th Edition) changes for T and N staging in patients with pancreatic adenocarcinoma. Ann Surg 2017;265:185–91.
25. Soriano A, Castells A, Ayuso C, et al. Preoperative staging and tumor resectability assessment of pancreatic cancer: prospective study comparing endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography. Am J Gastroenterol 2004;99:492–501.
26. Tempero MA, Malafa MP, Al-Hawary M, et al. Pancreatic adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2017;15:1028–61.
27. Al-Hawary MM, Francis IR, Chari ST, et al. Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the Society of Abdominal Radiology and the American Pancreatic Association. Radiology 2014;270:248–60.
28. Khorana AA, Mangu PB, Berlin J, et al. Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2017;35:2324–8.
28. Ducreux M, Cuhna AS, Caramella C, et al; ESMO Guidelines Committee. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26 Suppl 5:v56–68.
30. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007;297:267–77.
31. 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;310:1473–81.
32. Huguet F, Girard N, Guerche CS, et al. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 2009;27:2269–77.
33. Blackstock AW, Tepper JE, Niedwiecki D, et al. Cancer and leukemia group B (CALGB) 89805: phase II chemoradiation trial using gemcitabine in patients with locoregional adenocarcinoma of the pancreas. Int J Gastrointest Cancer 2003;34(2-3):107–16.
34. Loehrer PJ Sr, 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;29:4105–12.
35. Hurt CN, Falk S, Crosby T, et al. Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer. Br J Cancer 2017;116:1264–70.
36. 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;19:1592–9.
37. Hammel P, Huguet F, van Laethem JL, et al, LAP07 Trial Group. 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;315:1844–53.
38. Conroy T, Desseigne F, Ychou M, et al, Groupe Tumeurs Digestives of Unicancer, PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817–25.
39. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691–703.
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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
Pathogenesis
Pancreatic neoplasms can be benign or malignant and thus a tissue histologic diagnosis is paramount. Pancreatic adenocarcinomas with exocrine features represent more than 95% of all pancreatic neoplasms, with only 5% arising from the endocrine pancreas (ie, neuroendocrine tumors). Pancreatic neuroendocrine tumors and pancreatic adenocarcinoma must be distinguished histologically because treatment of the 2 neoplasms is completely different. Other malignant pancreatic tumors are signet ring cell carcinoma, adenosquamous carcinoma, undifferentiated (anaplastic) carcinoma, and mucinous noncystic (colloid) carcinoma; the latter tumor has a better prognosis.12 It is essential to characterize and distinguish among benign cystic neoplasms, as some require surgical resection due to the risk of malignant transformation. IPMN, pancreatic intraepithelial neoplasia, and mucinous cystic neoplasms are thought to be premalignant lesions of invasive ductal adenocarcinomas, and the pathological report should highlight the degree of dysplasia for adequate risk stratification.13 This information could be the deciding factor in whether a pancreatectomy is recommended by a multidisciplinary team.
Most pancreatic cancers harbor activating or silencing genetic mutations, and multiple combinations of altered genes can be detected by next-generation sequencing (average of 63 genetic alterations per cancer).14 Mutational activated KRAS is the most frequent (> 90%) genetic alteration in pancreatic cancer, even in early neoplastic precursors (IPMN > 75%). KRAS is a highly complex, dynamic proto-oncogene involved in signaling of various receptor kinases such as the epidermal growth factor receptor and the insulin-like growth factor receptor-I. It also engages in canonical downstream effector pathways, mainly Raf/MEK/ERK, PI3K/PDK1/Akt, and the Ral guanine nucleotide exchange factor pathway, which drive much of the pathogenesis of malignancy. These pathways lead to sustained proliferation, metabolic reprogramming, anti-apoptosis, remodeling of the tumor microenvironment, evasion of the immune response, cell migration, and metastasis. An activating point mutation in codon G12 is the most common (98%) locus of KRAS mutation in pancreatic adenocarcinoma, but all drugs targeting this mutation have failed in clinical practice.15 Additionally, inactivation of tumor suppressor genes such as p53, DPC4 (SMAD4/MADH4), CDKN2A (p16/MTS1), and BRCA2 can be found in 75%, 30%, 35%, and 4% of pancreatic adenocarcinoma cases, respectively.14 Another pancreatic cancer hallmark is inactivation of DNA damage repair genes, which include MLH1 and MSH2.16
Diagnosis and Staging
Case Presentation
A 71-year-old male veteran with no significant past medical history other than hypertension and hyperlipidemia and an excellent performance status presents to the emergency department after noticing a yellowish skin and sclera color. He denies weight loss, abdominal pain, or any other pertinent symptom or sign. Physical examination reveals a healthy developed man with yellowish discoloration of the skin and sclera and a soft, nontender benign abdomen; physical examination is otherwise unremarkable. Laboratory evaluation reveals a direct bilirubin level of 4.5 mg/dL and normal values for complete blood count and renal, liver, and coagulation panels. Abdominal and pelvis computed tomography (CT) with intravenous contrast shows a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein, which remains patent. Follow-up endoscopic ultrasound (EUS) confirms an irregular mass at the head of the pancreas measuring 3.2 × 2.6 cm with sonographic evidence suggesting invasion into the portal vein. During the procedure, the bile duct is successfully stented, the mass is biopsied, and bile duct brushing is performed. Pathology report is consistent with pancreatic adenocarcinoma.
- What is the typical presentation of pancreatic cancer?
The most common symptoms of pancreatic cancer at the time of presentation include weight loss (85%), asthenia/anorexia (86%), and/or abdominal pain (79%).17 The most frequent signs are jaundice (55%), hepatomegaly (39%), and cachexia (13%). Courvoisier sign, a nontender but palpable distended gallbladder at the right costal margin, is neither sensitive nor specific for pancreatic cancer (13% of cases). Trousseau syndrome, a superficial thrombophlebitis, is another classic sign that reflects the hypercoagulable nature of pancreatic cancer (3% of cases).17 The pathophysiology of this syndrome is not completely understood, but it may occur secondary to the release of cancer microparticles in the blood stream which in turn stimulate the coagulation cascade. Other nonspecific symptoms are dark urine, nausea, vomiting, diarrhea, steatorrhea, and epigastric and back pain. Because symptoms early in the course of the disease are nonspecific, pancreatic cancer is typically diagnosed late, after the cancer has invaded local structures or metastasized. The initial presentation varies depending on tumor location, with 70% of pancreatic head malignancies presenting with jaundice and pain correlating to an advanced stage.18 Although data supporting an association between new-onset diabetes mellitus and pancreatic cancer are inconclusive, pancreatic cancer should still be a consideration in patients with new-onset diabetes mellitus and other symptoms such as pain and weight loss. Early signs of incurable disease include a palpable mass, ascites, lymphadenopathy (classic Virchow node), and an umbilical mass (Sister Mary Joseph node). Incidentally discovered pancreatic masses on imaging are rare, but the incidence is increasing due to frequent imaging for other reasons and improved diagnostic techniques.
- What is the approach to diagnosis and staging?
History and physical examination findings are not sufficiently sensitive or specific to diagnose pancreatic cancer. High clinical suspicion in a patient with risk factors can lead to a comprehensive evaluation and potential early diagnosis. In general, an initial diagnostic work-up for suspected pancreatic cancer will include serologic evaluation (liver function test, lipase, tumor markers) and abdominal imaging (ultrasound, CT scans, or magnetic resonance imaging [MRI]). Ultrasound is a first-line diagnostic tool with a sensitivity of 90% and specificity of 98.8% for pancreatic cancer, but it is investigator-dependent and is less accurate in detecting tumors smaller than 3 cm in diameter.19 Multiphasic helical CT of the abdomen has better sensitivity (100%) and specificity (100%) for detecting tumors larger than 2 cm, but this modality is less accurate in detecting pancreatic masses smaller than 2 cm (77%).20 Percutaneous fine-needle aspiration (FNA) performed by ultrasound or CT guidance is avoided due to theoretical concerns about intraperitoneal seeding and bleeding.
If a pancreatic mass is detected by ultrasound or CT, additional interventions may be indicated depending on the clinical scenario. EUS-guided biopsy can provide histological confirmation and is currently utilized frequently for diagnosis and early resectability staging. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated for patients with biliary obstruction requiring stent placement, and this procedure may provide tissue confirmation by forceps biopsy or brush cytology (lower accuracy than EUS). In a meta-analysis that evaluated the diagnostic value of tests for pancreatic cancer, ERCP had the highest sensitivity (92%) and specificity (96%) compared to ultrasound and CT,21 but this modality carries a risk for pancreatitis, bleeding, and cholangitis. Magnetic resonance cholangiopancreatography has not replaced ERCP, but it but may be an alternative for patients who cannot undergo ERCP (eg, gastric outlet obstruction, duodenal stenosis, anatomical surgical disruption, unsuccessful ERCP). ERCP is used frequently because many patients present with obstructive jaundice due to pancreatic mass compression, specifically if the mass is located in the head, and must undergo ERCP and stenting of the common bile duct.
The carbohydrate antigen (CA) 19-9 level has variable sensitivity and specificity in pancreatic cancer, as levels can be elevated in many benign pancreaticobiliary disorders. Elevated CA 19-9, in the appropriate clinical scenario (ie, a suspicious pancreatic mass and a value greater than 37 U/mL) demonstrated a sensitivity of 77% and specificity of 87% when differentiating pancreaticobiliary cancer from benign clinical conditions such as acute cholangitis or cholestasis.22 CA 19-9 level has prognostic value, as it may predict occult disease and correlates with survival rates, but no specific cutoff value has been established to guide perioperative therapy for high-risk resectable tumors.23
The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) system is the preferred method for staging pancreatic cancer (Table 1).
Positron emission tomography with CT scan is occasionally utilized in practice to assess tumor burden by evaluating anatomical structures and assessing physiologic uptake, which aids in establishing the extent of disease in equivocal cases. Staging laparoscopy with or without peritoneal biopsy is sometimes used to establish appropriate staging in cases that are questionable for occult metastatic disease. This procedure helps avoid unnecessary morbid surgeries.
Neoadjuvant Therapy
Case Continued
The patient is referred to oncology. Blood work reveals a CA 19-9 level of 100 U/mL (reference range < 35 U/mL) and a staging CT scan of the chest reveals a benign-appearing 3-mm nodule (no prior imaging for comparison). CT scan of the abdomen and pelvis does not define venous vasculature involvement appropriately and hence MRI of the abdomen and pelvis is performed. MRI reveals a pancreatic head mass measuring 3.0 × 2.7 cm, without arterial or venous vasculature invasion. However, the mass is abutting the portal vein and superior mesenteric vein and there is a new nonspecific 8-mm aortocaval lymph node.
- What are the current approaches to treating patients with resectable, unresectable, and metastatic disease?
Accurate staging and assessment of surgical resectability in pancreatic cancer are paramount as these steps prevent a futile morbid Whipple procedure in patients with advanced disease and a high risk of recurrence. Conversely, it allows patients with low-volume disease to undergo a potentially curative surgery. Approximately 20% of patients present with resectable disease, 40% present with locally advanced unresectable tumors (eg, involvement of critical vascular structures), and 40% present with metastatic disease.3 Treatment for resectable pancreatic cancer continues to be upfront surgery, although neoadjuvant therapy with either chemoradiation, radiation alone, or chemotherapy is an option per guidelines from the American Society of Clinical Oncology (ASCO),28 the NCCN,26 and the European Society for Medical Oncology (ESMO),29 particularly for patients with borderline resectable tumors (Table 3).
Systemic chemotherapy is recommended for fit candidates with locally advanced unresectable or metastatic disease, with an emphasis on supportive palliative measures. Palliative interventions include biliary stenting, duodenal stent for relieving gastric-outlet obstruction, and celiac axis nerve blocks, when indicated. Routine preoperative biliary stent placement/drainage in patients undergoing subsequent surgery for pancreatic cancer located in the head is associated with an increased risk of surgical complications when compared with up-front surgery without prior biliary drainage, and thus stent placement/drainage is not recommended.26 Aggressive supportive management of symptoms, such as cancer-associated pain, anorexia-cachexia syndromes, and anxiety-depression disorders, should remain a primary palliative focus.
Case Continued
A multidisciplinary tumor board discusses the patient’s case and deems the cancer borderline resectable; neoadjuvant therapy is recommended. The patient is started on treatment with gemcitabine and nab-paclitaxel as first-line neoadjuvant therapy. After 4 cycles, the CA 19-9 level drops to 14 U/mL, and MRI reveals a smaller head mass of 1.3 × 1.4 cm with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remains stable. At tumor board, it is evident that the patient has responded to therapy and the recommendation is to treat with gemcitabine chemoradiotherapy before surgery.
- What neoadjuvant therapy strategies are used in the treatment of pancreatic adenocarcinoma?
There are no established evidence-based recommendations for neoadjuvant therapy in patients with borderline resectable pancreatic cancer or patients with unresectable locally advanced pancreatic cancer. However, there are ongoing trials to investigate this treatment approach, and it is offered off-label in specific clinical scenarios, such as in the case patient described here. In patients with borderline resectable disease, preoperative chemotherapy followed by chemoradiation is a routine practice in most cancer centers,32 and ongoing clinical trials are an option for this cohort of patients (eg, Southwest Oncology Group Trial 1505, NCT02562716). The definitions of borderline resectable and unresectable pancreatic cancer have been described by the NCCN,26 although most surgeons consider involvement of the major upper abdominal blood vessels the main unresectability criterion; oncologists also consider other parameters such as suspicious lesions on scans, worsening performance status, and a significantly elevated CA 19-9 level suggestive of disseminated disease.28 The goal of a conversion approach by chemotherapy with or without radiation for borderline and unresectable cancers is to deliver a tolerable regimen leading to tumor downstaging, allowing for surgical resection. No randomized clinical trial has shown a survival advantage of this approach. Enrollment in clinical trials is preferred for patients with borderline and unresectable cancer, and there are trials that are currently enrolling patients.
The main treatment strategies for patients with locally advanced borderline and unresectable pancreatic cancer outside of a clinical trial are primary radiotherapy, systemic chemotherapy, and chemoradiation therapy. Guidelines from ASCO, NCCN, and ESMO recommend induction chemotherapy followed by restaging and consolidation chemoradiotherapy in the absence of progression.26,28,29 There is no standard chemoradiation regimen and the role of chemotherapy sensitizers, including fluorouracil, gemcitabine, and capecitabine (an oral fluoropyrimidine substitute), and targeted agents in combination with different radiation modalities is now being investigated.
Fluorouracil is a radio-sensitizer that has been used in locally advanced pancreatic cancer based on experience in other gastrointestinal malignancies; data shows conflicting results with this drug. Capecitabine and tegafur/gimeracil/oteracil (S-1) are oral prodrugs that can safely replace infusional fluorouracil. Gemcitabine, a more potent radiation sensitizer, is very toxic, even at low-doses twice weekly, and does not provide a survival benefit, as demonstrated in the Cancer and Leukemia Group B (CALGB) 89805 trial, a phase 2 study of patients with surgically staged locally advanced pancreatic cancer.33 Gemcitabine-based chemoradiotherapy was also evaluated in the Eastern Cooperative Group (ECOG) E4201 trial, which randomly assigned patients to receive gemcitabine alone (at 1000 mg/m2/wk for weeks 1 through 6, followed by 1 week rest, then weekly for 3 out of 4 weeks) or gemcitabine (600 mg/m2/wk for weeks 1 to 5, then 4 weeks later 1000 mg/m2 for 3 out of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/fraction for total of 50.4 Gy).34 Patients with locally advanced unresectable pancreatic cancer had a better OS outcome with gemcitabine in combination with radiation therapy (11.1 months) as compared with patients who received gemcitabine alone (9.2 months). Although there was a greater incidence of grade 4 and 5 treatment-related toxicities in the combination arm, no statistical differences in quality-of-life measurements were reported. Gemcitabine-based and capecitabine-based chemoradiotherapy were compared in the open-label phase 2 multicenter randomized SCALOP trial.35 Patients with locally advanced pancreatic cancer were assigned to receive 3 cycles of induction with gemcitabine 1000 mg/m2 days 1, 8, and 15 and capecitabine 830 mg/m2 days 1 to 21 every 28 days; patients who had stable or responding disease were randomly assigned to receive a fourth cycle followed by capecitabine (830 mg/m2 twice daily on weekdays only) or gemcitabine (300 mg/m2 weekly) with radiation (50.4 Gy over 28 fractions). Patients treated with capecitabine-based chemoradiotherapy had higher nonsignificant median OS (17.6 months) and median progression-free survival (12 months) compared to those treated with gemcitabine (14.6 months and 10.4 months, respectively).
The benefit of radiation therapy in the treatment of locally advanced pancreatic cancer was further explored by the Fédération Francophone de Cancérologie Digestive 2000-01 phase 3 trial. This study compared induction chemoradiotherapy (60 Gy, 2 Gy/fraction; concomitant fluorouracil infusion, 300 mg/m2/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m2/day, days 1–5 during weeks 1 and 5) to gemcitabine alone (1000 mg/m2 weekly for 7 weeks) followed by maintenance gemcitabine in both arms.36 Unexpectedly, the median OS was significantly shorter in the chemoradiotherapy arm than in the chemotherapy alone arm (8.6 months versus 13 months, respectively, P = 0.03) and the combination arm had more toxicities. The phase 3 open-label LAP07 study explored the role of radiation therapy in patients with locally advanced pancreatic cancer who had controlled disease after 4 months of induction therapy.37 LAP07 had 2 randomizations: first, patients with locally advanced pancreatic cancer were assigned to receive weekly gemcitabine alone (1000 mg/m2) or this same dose of gemcitabine plus erlotinib 100 mg/day; second, patients with progression-free disease (61% of initial cohort) after 4 months of therapy were assigned to receive 2 months of the same chemotherapy or chemoradiotherapy (54 Gy plus capecitabine). This study showed that the addition of erlotinib to gemcitabine did not improve survival and in fact affected survival adversely. Of note, no survival benefit was observed after the first randomization from chemotherapy to consolidating chemoradiotherapy. Chemoradiotherapy achieved better locoregional tumor control with significantly less local tumor progression (32% versus 46%, P < 0.03) and no increase in toxicity. Based on prior moderate-quality evidence, guidelines recommend consolidative chemoradiotherapy only for surgical resection candidates following induction chemotherapy; for those who are not surgical candidates, guidelines recommend continuing systemic therapy.26,28,29
Gemcitabine and fluorouracil-based chemotherapies were the standard induction regimens until evidence from studies of metastatic systemic treatment protocols with FOLFIRINOX (ACCORD trial38) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine (MPACT trial39) was extrapolated to clinical practice. These regimens were shown to achieve higher objective response rates when compared to single-agent gemcitabine in patients with metastatic pancreatic cancer. Due to the broad heterogeneity of results in small retrospective series with neoadjuvant trials in borderline resectable pancreatic cancer, the quality of the evidence is low and any recommendation is limited. Many individual series have demonstrated improved complete resection rates and promising survival rates. In the largest single-institution retrospective review of patients with borderline resectable pancreatic adenocarcinoma who completed neoadjuvant gemcitabine-based chemoradiotherapy (50 Gy in 28 fractions or 30 Gy in 10 fractions), 94% achieved a margin-negative pancreatectomy; the median OS in those who completed preoperative therapy and had surgery was 40 months, with a 5-year OS of 36%.40 A meta-analysis by Andriulli and colleagues included 20 prospective studies of patients with initially resectable (366 lesions) or unresectable (341 lesions) disease who were treated with neoadjuvant/preoperative gemcitabine with or without radiotherapy.41 In the group with initially unresectable disease, 39% underwent surgery after restaging and 68% of explored patients were resected; the R0 resection rate was 60%. After restaging, 91% of patients with resectable disease underwent surgery, with 82% of explored patients undergoing surgical resection and 89% of these achieving R0 resection. The estimated 1- and 2-year survival probabilities after resection among patients with initially unresectable disease were 86.3% and 54.2%.41
The largest single-institution retrospective review of FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, and leucovorin), an alternative to gemcitabine, for neoadjuvant induction therapy for patients with locally advanced unresectable disease was conducted at Memorial Sloan Kettering Cancer Center. In this study (n = 101), 31% of patients initially deemed unresectable who completed FOLFIRINOX induction therapy with or without chemoradiation underwent resection. The R0 resection rate in these patients was 55%, and patients who did not progress during induction FOLFIRINOX therapy had a median OS of 26 months.42 A systematic review and meta-analysis of FOLFIRINOX chemotherapy with or without radiotherapy in patients with locally advanced unresectable pancreatic cancer reported that 25.9% of patients underwent resection after FOLFIRINOX therapy, and the R0 resection rate in these patients was 78.4%.43 The median OS in this study was 24.2 months, which was longer than the previously reported median OS rates for gemcitabine.
There is no strong evidence published for the use of combination nab-paclitaxel plus gemcitabine in the neoadjuvant setting, but it is used in clinical practice based on evidence from the MPACT trial, which showed the combination improved OS and progression-free survival in patients with metastatic pancreatic cancer.39 An early-phase 1-arm clinical trial of neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) followed by radiotherapy showed an increased response rate and survival for locally advanced disease; however, the NCCN expert panel has reached a consensus but not a uniform recommendation regarding this regimen due to significant toxicities and low patient accrual.26 Selected patients with pancreatic cancer with BRCA1/2 mutations are more sensitive to platinum-based chemotherapy. Although studies of neoadjuvant platinum-based chemotherapy in this population have not been reported, the NCCN guidelines list it as an alternative option based on extrapolated data.26 A clinical trial of gemcitabine, nab-paclitaxel, and cisplatin in the neoadjuvant setting in patients with resectable pancreatic cancer is currently enrolling patients (NGC triple regimen NCT0339257).
Summary
Chemotherapy alone or followed by chemoradiotherapy may be used as initial treatment for patients with borderline and unresectable pancreatic adenocarcinoma without distant metastases who are potential surgical candidates. Chemoradiotherapy remains a preferred treatment option for patients with poorly controlled pain from local tumor invasion, in view of the well-documented analgesic palliative effect of radiation therapy. FOLFIRINOX with or without radiation therapy may offer the highest documented response rates, but it also results in higher rates of treatment-related toxicities. FOLFIRINOX can be offered to selected fit patients (< 65 years old, no comorbidity contraindication, good functional status [ECOG 0–1]) who can tolerate triple therapy with a more toxic adverse-effect profile. A clinical trial evaluating neoadjuvant FOLFIRINOX with or without preoperative chemoradiotherapy in patients with borderline resectable pancreatic cancer is ongoing (PANDAS-PRODIGE 44, NCT02676349). Gemcitabine with or without radiation therapy is a tolerable combination, although it is potentially more toxic when combined with radiation. The addition of nab-paclitaxel to gemcitabine without radiation may emerge as a preferred neoadjuvant treatment for selected patients; a clinical trial investigating this modality in patients with resectable and borderline resectable disease is ongoing (NCT02723331).
Adjuvant Therapy
Case Continued
Prior to the planned surgical resection and after undergoing chemoradiation therapy, the patient has an excellent performance status and repeat MRI shows a 1.3 × 1.4 cm head mass with no further vasculature involvement, no evidence of lymphadenopathy, and no distant metastasis. The CA 19-9 level is stable at 18 U/mL. The patient undergoes an uncomplicated partial pancreaticoduodenectomy, and analysis of a surgical pathology specimen reveals T3N0 disease with closest margin of 0.1 cm.
- Would the patient benefit from adjuvant therapy?
Adjuvant chemotherapy for 6 months after pancreatic cancer resection should be offered to all patients based on mature data. Gemcitabine and capecitabine are the current standard of care in adjuvant therapy; alternatively, single-agent gemcitabine can be offered to patients with poor performance status or patients who cannot tolerate the toxicities associated with this combination.28 Adjuvant treatment should be initiated within approximately 8 weeks of surgical resection. The value of radiation therapy remains controversial, but it can be offered within the context of a clinical trial or to patients with positive margins after surgical resection and/or lymph node–positive disease. Based on low-quality supportive evidence, it is strongly recommended that patients who receive neoadjuvant therapy complete a total of 6 months of chemotherapy, factoring in the duration of the preoperative regimen.28 Different adjuvant strategies have been investigated, including chemotherapy alone with a fluoropyrimidine and/or gemcitabine with or without combined chemoradiation therapy.
The European Study Group for Pancreatic Cancer 1 (ESPAC)-1 trial was a randomized clinical trial that evaluated several adjuvant strategies in pancreatic cancer treatment. This trial assigned patients who underwent pancreatic adenocarcinoma resection to adjuvant chemotherapy alone (intravenous fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 daily for 5 days, monthly for 6 months), chemoradiotherapy (20 Gy in 10 daily fractions over 2 weeks with 500 mg/m2 intravenous fluorouracil on days 1–3, repeated after 2 weeks), both chemotherapy and chemoradiation, and observation.44 The results showed no added benefit for adjuvant chemoradiotherapy, with a median OS of 15.5 months in the chemoradiotherapy cohort, as compared to a median OS of 16.1 months in the chemotherapy-alone cohort (hazard ratio [HR] 1.18 [95% CI 0.90 to 1.55], P = 0.24). In addition, there was evidence of a survival benefit for the chemotherapy-alone arm when compared to the combined modality arm, with a median OS of 19.7 versus 14.0 months, respectively (HR 0.66 [95% CI 0.52 to 0.83], P = 0.0005). Although ESPAC-1 has been criticized for being underpowered to perform statistical comparison, it is still considered a landmark trial demonstrating benefit with single-agent chemotherapy alone. A follow-up analysis of ESPAC-1 showed that adjuvant chemotherapy alone conferred a significant 5-year survival benefit while the combined modality had a deleterious effect on survival. 45 Hence, adjuvant chemotherapy alone became the standard of care in the United States following resection.
The results of the multicenter randomized controlled phase 3 CONKO-001 (CharitéOnkologie 001) trial, which were reported in 2007, supported the use of adjuvant gemcitabine for 6 months in patients with resected pancreatic adenocarcinoma. In this study, patients treated with adjuvant gemcitabine (1000 mg/m2 days 1, 8, and 15 every 4 weeks for 6 months) had superior disease-free survival compared with those who received surgery alone.30 A long-term outcome update of this study demonstrated a significant improvement in 5-year OS for patients treated with adjuvant gemcitabine (20.7% [95% CI 14.7% to 26.6%]) compared to those who received surgical resection alone (10.4% [95% CI 5.9% to 15.0%]). This benefit persisted at 10-year follow-up, with an OS of 12.2% (95% CI 7.3% to 17.2%) in the adjuvant gemcitabine group, as compared to 7.7% (95% CI 3.6% to 11.8%) in the resection alone group.31
Fluorouracil and gemcitabine remained equivalent adjuvant treatment options until the results of the ESPAC-3 trial were reported in 2010.32 This large phase 3 trial, conducted mainly in the United Kingdom, compared weekly gemcitabine (1000 mg/m2 weekly for 3 of every 4 weeks) to leucovorin-modulated fluorouracil (Mayo Clinic regimen: leucovorin 20 mg/m2 followed by fluorouracil 425 mg/m2 intravenous bolus days 1 through 5 every 28 days) as adjuvant therapy in resected pancreatic adenocarcinoma. After a median follow-up of 34.2 months, the median OS was similar in the 2 groups (fluorouracil/leucovorin 23.0 months versus gemcitabine 23.6 months; P = 0.39). However, the fluorouracil/leucovorin group experienced more grade 3/4 treatment-related toxicities (mucositis, stomatitis, diarrhea, and hosptializations; 14% versus 7.5%; P < 0.001).46 Following this trial, gemcitabine became the standard of care for adjuvant chemotherapy for resected pancreatic cancer.
The U.S. Radiation Therapy Oncology Group (RTOG) 9704 trial was conducted to investigate the potential benefit of adding radiation therapy to gemcitabine. This trial demonstrated an improved trend among patients with pancreatic head tumors (but not with cancers of the pancreatic body or tail) who received adjuvant gemcitabine followed by chemoradiotherapy (50.4 Gy in 1.8 Gy daily fractions for 5.5 weeks with concurrent infusional fluorouracil 250 mg/m2 daily) and subsequent gemcitabine monotherapy compared to postoperative fluorouracil-based chemoradiotherapy. Results showed a 5-year OS of 22% versus 18%, respectively, although this improvement was not statistically significant (P = 0.08). This trial failed to show a benefit of adding radiotherapy to gemcitabine.47
The ESPAC-4 trial, reported in 2017, evaluated the combination of gemcitabine and capecitabine compared to gemcitabine alone as adjuvant therapy for resected pancreatic adenocarcinoma.48 Patients were randomly assigned after surgical resection, regardless of margin or node status, to 6 months of gemcitabine alone (1000 mg/m2/day on days 1, 8, and 15 of each 28-day cycle) or gemcitabine plus capecitabine (1660 mg/m2/day on days 1 through 21 of each 28-day cycle). Combination therapy had a significant survival benefit compared to single therapy, with median OS durations of 28 months and 25.5 months, respectively (HR for death 0.82 [95% CI 0.68 to 0.98]). The 5-year OS for patients who received combination treatment was 29 months (95% CI 22.9 to 35.2) versus 16 months (95% CI 10.2 to 23.7) for those in the monotherapy group. As expected, grade 3 or 4 treatment-related toxicities (diarrhea, hand-foot syndrome, and neutropenia) were significantly more common with combined therapy, although there were no significant differences in the rates of serious adverse events. The adjuvant combination of gemcitabine and capecitabine became the current and preferred new standard of care following resection of pancreatic ductal adenocarcinoma,28 but single-agent gemcitabine and fluorouracil/leucovorin continue to be viable options,26,28,29 particularly for elderly patients, patients with borderline performance status, or patients with multiple comorbidities.
Evidence showing that a more intensive regimen can improve outcome in the adjuvant setting remains elusive. The phase 3 APACT study (Adjuvant Therapy for Patients with Resected Pancreatic Cancer, NCT01964430) comparing gemcitabine alone to gemcitabine plus nab-paclitaxel in patients with surgically resected pancreatic adenocarcinoma has concluded, with the results projected to be released in 2018. Another phase 3 trial investigating the efficacy of FOLFIRINOX versus gemcitabine alone as adjuvant therapy is underway in France and Canada (PRODIGE24/ACCORD24, NCT01526135). Other strategies with newer targeted therapies and immunotherapy are in the development phase.
Follow-Up and Surveillance
Case Conclusion
After recovery from surgery, the patient is offered and completes 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine. He is started on surveillance at 3 and 6 months, and he maintains an excellent performance status. He develops clinical evidence of pancreatic enzyme insufficiency and is placed on oral replacement therapy. He has no other complaints, and there is no evidence of recurrence on MRI and CA 19-9 levels.
- What is the recommended duration of surveillance following curative resection?
Surveillance after curative resection of pancreatic adenocarcinoma is recommended by NCCN guidelines.26 However, pancreatic adenocarcinoma has a poor prognosis, and surveillance after curative surgical resection with or without perioperative therapy has not been shown to impact survival. Most recurrences will occur within 2 years after treatment. Surveillance recommendations differ among expert groups.26,28,29 NCCN guidelines recommend evaluating patients by history and physical examination every 3 to 6 months for the first 2 years, then every 6 to 12 months for 3 years. CA 19-9 level and CT scan should be obtained every 3 to 6 months for 2 years and then every 6 to 12 months for 3 years. Follow-up with CA 19-9 levels and CT scans after 5 years is not routinely performed unless guided by signs, symptoms, or laboratory findings that raise suspicion for recurrence. Follow-up visits should also include evaluation of treatment-related toxicities, symptom management, nutrition support of pancreatic insufficiency, and psychosocial support.
Conclusion
Pancreatic cancer is a leading cause of cancer-related death that frequently presents with locally advanced or metastatic disease due to nonspecific symptoms and lack of a screening modality. Histological tissue biopsy confirmation and accurate resectability staging guide treatment planning and prognosis. The only potentially curative therapy is surgical resection plus adjuvant therapy for those with resectable disease. Surgical candidates with borderline resectable and unresectable disease can be offered induction preoperative chemotherapy followed by consolidation chemoradiation, based on clinical consensus practice. Enrollment in clinical trials should be encouraged for all patients, as evidence from clinical trials is essential to making progress in pancreatic cancer treatment.
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
Pathogenesis
Pancreatic neoplasms can be benign or malignant and thus a tissue histologic diagnosis is paramount. Pancreatic adenocarcinomas with exocrine features represent more than 95% of all pancreatic neoplasms, with only 5% arising from the endocrine pancreas (ie, neuroendocrine tumors). Pancreatic neuroendocrine tumors and pancreatic adenocarcinoma must be distinguished histologically because treatment of the 2 neoplasms is completely different. Other malignant pancreatic tumors are signet ring cell carcinoma, adenosquamous carcinoma, undifferentiated (anaplastic) carcinoma, and mucinous noncystic (colloid) carcinoma; the latter tumor has a better prognosis.12 It is essential to characterize and distinguish among benign cystic neoplasms, as some require surgical resection due to the risk of malignant transformation. IPMN, pancreatic intraepithelial neoplasia, and mucinous cystic neoplasms are thought to be premalignant lesions of invasive ductal adenocarcinomas, and the pathological report should highlight the degree of dysplasia for adequate risk stratification.13 This information could be the deciding factor in whether a pancreatectomy is recommended by a multidisciplinary team.
Most pancreatic cancers harbor activating or silencing genetic mutations, and multiple combinations of altered genes can be detected by next-generation sequencing (average of 63 genetic alterations per cancer).14 Mutational activated KRAS is the most frequent (> 90%) genetic alteration in pancreatic cancer, even in early neoplastic precursors (IPMN > 75%). KRAS is a highly complex, dynamic proto-oncogene involved in signaling of various receptor kinases such as the epidermal growth factor receptor and the insulin-like growth factor receptor-I. It also engages in canonical downstream effector pathways, mainly Raf/MEK/ERK, PI3K/PDK1/Akt, and the Ral guanine nucleotide exchange factor pathway, which drive much of the pathogenesis of malignancy. These pathways lead to sustained proliferation, metabolic reprogramming, anti-apoptosis, remodeling of the tumor microenvironment, evasion of the immune response, cell migration, and metastasis. An activating point mutation in codon G12 is the most common (98%) locus of KRAS mutation in pancreatic adenocarcinoma, but all drugs targeting this mutation have failed in clinical practice.15 Additionally, inactivation of tumor suppressor genes such as p53, DPC4 (SMAD4/MADH4), CDKN2A (p16/MTS1), and BRCA2 can be found in 75%, 30%, 35%, and 4% of pancreatic adenocarcinoma cases, respectively.14 Another pancreatic cancer hallmark is inactivation of DNA damage repair genes, which include MLH1 and MSH2.16
Diagnosis and Staging
Case Presentation
A 71-year-old male veteran with no significant past medical history other than hypertension and hyperlipidemia and an excellent performance status presents to the emergency department after noticing a yellowish skin and sclera color. He denies weight loss, abdominal pain, or any other pertinent symptom or sign. Physical examination reveals a healthy developed man with yellowish discoloration of the skin and sclera and a soft, nontender benign abdomen; physical examination is otherwise unremarkable. Laboratory evaluation reveals a direct bilirubin level of 4.5 mg/dL and normal values for complete blood count and renal, liver, and coagulation panels. Abdominal and pelvis computed tomography (CT) with intravenous contrast shows a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein, which remains patent. Follow-up endoscopic ultrasound (EUS) confirms an irregular mass at the head of the pancreas measuring 3.2 × 2.6 cm with sonographic evidence suggesting invasion into the portal vein. During the procedure, the bile duct is successfully stented, the mass is biopsied, and bile duct brushing is performed. Pathology report is consistent with pancreatic adenocarcinoma.
- What is the typical presentation of pancreatic cancer?
The most common symptoms of pancreatic cancer at the time of presentation include weight loss (85%), asthenia/anorexia (86%), and/or abdominal pain (79%).17 The most frequent signs are jaundice (55%), hepatomegaly (39%), and cachexia (13%). Courvoisier sign, a nontender but palpable distended gallbladder at the right costal margin, is neither sensitive nor specific for pancreatic cancer (13% of cases). Trousseau syndrome, a superficial thrombophlebitis, is another classic sign that reflects the hypercoagulable nature of pancreatic cancer (3% of cases).17 The pathophysiology of this syndrome is not completely understood, but it may occur secondary to the release of cancer microparticles in the blood stream which in turn stimulate the coagulation cascade. Other nonspecific symptoms are dark urine, nausea, vomiting, diarrhea, steatorrhea, and epigastric and back pain. Because symptoms early in the course of the disease are nonspecific, pancreatic cancer is typically diagnosed late, after the cancer has invaded local structures or metastasized. The initial presentation varies depending on tumor location, with 70% of pancreatic head malignancies presenting with jaundice and pain correlating to an advanced stage.18 Although data supporting an association between new-onset diabetes mellitus and pancreatic cancer are inconclusive, pancreatic cancer should still be a consideration in patients with new-onset diabetes mellitus and other symptoms such as pain and weight loss. Early signs of incurable disease include a palpable mass, ascites, lymphadenopathy (classic Virchow node), and an umbilical mass (Sister Mary Joseph node). Incidentally discovered pancreatic masses on imaging are rare, but the incidence is increasing due to frequent imaging for other reasons and improved diagnostic techniques.
- What is the approach to diagnosis and staging?
History and physical examination findings are not sufficiently sensitive or specific to diagnose pancreatic cancer. High clinical suspicion in a patient with risk factors can lead to a comprehensive evaluation and potential early diagnosis. In general, an initial diagnostic work-up for suspected pancreatic cancer will include serologic evaluation (liver function test, lipase, tumor markers) and abdominal imaging (ultrasound, CT scans, or magnetic resonance imaging [MRI]). Ultrasound is a first-line diagnostic tool with a sensitivity of 90% and specificity of 98.8% for pancreatic cancer, but it is investigator-dependent and is less accurate in detecting tumors smaller than 3 cm in diameter.19 Multiphasic helical CT of the abdomen has better sensitivity (100%) and specificity (100%) for detecting tumors larger than 2 cm, but this modality is less accurate in detecting pancreatic masses smaller than 2 cm (77%).20 Percutaneous fine-needle aspiration (FNA) performed by ultrasound or CT guidance is avoided due to theoretical concerns about intraperitoneal seeding and bleeding.
If a pancreatic mass is detected by ultrasound or CT, additional interventions may be indicated depending on the clinical scenario. EUS-guided biopsy can provide histological confirmation and is currently utilized frequently for diagnosis and early resectability staging. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated for patients with biliary obstruction requiring stent placement, and this procedure may provide tissue confirmation by forceps biopsy or brush cytology (lower accuracy than EUS). In a meta-analysis that evaluated the diagnostic value of tests for pancreatic cancer, ERCP had the highest sensitivity (92%) and specificity (96%) compared to ultrasound and CT,21 but this modality carries a risk for pancreatitis, bleeding, and cholangitis. Magnetic resonance cholangiopancreatography has not replaced ERCP, but it but may be an alternative for patients who cannot undergo ERCP (eg, gastric outlet obstruction, duodenal stenosis, anatomical surgical disruption, unsuccessful ERCP). ERCP is used frequently because many patients present with obstructive jaundice due to pancreatic mass compression, specifically if the mass is located in the head, and must undergo ERCP and stenting of the common bile duct.
The carbohydrate antigen (CA) 19-9 level has variable sensitivity and specificity in pancreatic cancer, as levels can be elevated in many benign pancreaticobiliary disorders. Elevated CA 19-9, in the appropriate clinical scenario (ie, a suspicious pancreatic mass and a value greater than 37 U/mL) demonstrated a sensitivity of 77% and specificity of 87% when differentiating pancreaticobiliary cancer from benign clinical conditions such as acute cholangitis or cholestasis.22 CA 19-9 level has prognostic value, as it may predict occult disease and correlates with survival rates, but no specific cutoff value has been established to guide perioperative therapy for high-risk resectable tumors.23
The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) system is the preferred method for staging pancreatic cancer (Table 1).
Positron emission tomography with CT scan is occasionally utilized in practice to assess tumor burden by evaluating anatomical structures and assessing physiologic uptake, which aids in establishing the extent of disease in equivocal cases. Staging laparoscopy with or without peritoneal biopsy is sometimes used to establish appropriate staging in cases that are questionable for occult metastatic disease. This procedure helps avoid unnecessary morbid surgeries.
Neoadjuvant Therapy
Case Continued
The patient is referred to oncology. Blood work reveals a CA 19-9 level of 100 U/mL (reference range < 35 U/mL) and a staging CT scan of the chest reveals a benign-appearing 3-mm nodule (no prior imaging for comparison). CT scan of the abdomen and pelvis does not define venous vasculature involvement appropriately and hence MRI of the abdomen and pelvis is performed. MRI reveals a pancreatic head mass measuring 3.0 × 2.7 cm, without arterial or venous vasculature invasion. However, the mass is abutting the portal vein and superior mesenteric vein and there is a new nonspecific 8-mm aortocaval lymph node.
- What are the current approaches to treating patients with resectable, unresectable, and metastatic disease?
Accurate staging and assessment of surgical resectability in pancreatic cancer are paramount as these steps prevent a futile morbid Whipple procedure in patients with advanced disease and a high risk of recurrence. Conversely, it allows patients with low-volume disease to undergo a potentially curative surgery. Approximately 20% of patients present with resectable disease, 40% present with locally advanced unresectable tumors (eg, involvement of critical vascular structures), and 40% present with metastatic disease.3 Treatment for resectable pancreatic cancer continues to be upfront surgery, although neoadjuvant therapy with either chemoradiation, radiation alone, or chemotherapy is an option per guidelines from the American Society of Clinical Oncology (ASCO),28 the NCCN,26 and the European Society for Medical Oncology (ESMO),29 particularly for patients with borderline resectable tumors (Table 3).
Systemic chemotherapy is recommended for fit candidates with locally advanced unresectable or metastatic disease, with an emphasis on supportive palliative measures. Palliative interventions include biliary stenting, duodenal stent for relieving gastric-outlet obstruction, and celiac axis nerve blocks, when indicated. Routine preoperative biliary stent placement/drainage in patients undergoing subsequent surgery for pancreatic cancer located in the head is associated with an increased risk of surgical complications when compared with up-front surgery without prior biliary drainage, and thus stent placement/drainage is not recommended.26 Aggressive supportive management of symptoms, such as cancer-associated pain, anorexia-cachexia syndromes, and anxiety-depression disorders, should remain a primary palliative focus.
Case Continued
A multidisciplinary tumor board discusses the patient’s case and deems the cancer borderline resectable; neoadjuvant therapy is recommended. The patient is started on treatment with gemcitabine and nab-paclitaxel as first-line neoadjuvant therapy. After 4 cycles, the CA 19-9 level drops to 14 U/mL, and MRI reveals a smaller head mass of 1.3 × 1.4 cm with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remains stable. At tumor board, it is evident that the patient has responded to therapy and the recommendation is to treat with gemcitabine chemoradiotherapy before surgery.
- What neoadjuvant therapy strategies are used in the treatment of pancreatic adenocarcinoma?
There are no established evidence-based recommendations for neoadjuvant therapy in patients with borderline resectable pancreatic cancer or patients with unresectable locally advanced pancreatic cancer. However, there are ongoing trials to investigate this treatment approach, and it is offered off-label in specific clinical scenarios, such as in the case patient described here. In patients with borderline resectable disease, preoperative chemotherapy followed by chemoradiation is a routine practice in most cancer centers,32 and ongoing clinical trials are an option for this cohort of patients (eg, Southwest Oncology Group Trial 1505, NCT02562716). The definitions of borderline resectable and unresectable pancreatic cancer have been described by the NCCN,26 although most surgeons consider involvement of the major upper abdominal blood vessels the main unresectability criterion; oncologists also consider other parameters such as suspicious lesions on scans, worsening performance status, and a significantly elevated CA 19-9 level suggestive of disseminated disease.28 The goal of a conversion approach by chemotherapy with or without radiation for borderline and unresectable cancers is to deliver a tolerable regimen leading to tumor downstaging, allowing for surgical resection. No randomized clinical trial has shown a survival advantage of this approach. Enrollment in clinical trials is preferred for patients with borderline and unresectable cancer, and there are trials that are currently enrolling patients.
The main treatment strategies for patients with locally advanced borderline and unresectable pancreatic cancer outside of a clinical trial are primary radiotherapy, systemic chemotherapy, and chemoradiation therapy. Guidelines from ASCO, NCCN, and ESMO recommend induction chemotherapy followed by restaging and consolidation chemoradiotherapy in the absence of progression.26,28,29 There is no standard chemoradiation regimen and the role of chemotherapy sensitizers, including fluorouracil, gemcitabine, and capecitabine (an oral fluoropyrimidine substitute), and targeted agents in combination with different radiation modalities is now being investigated.
Fluorouracil is a radio-sensitizer that has been used in locally advanced pancreatic cancer based on experience in other gastrointestinal malignancies; data shows conflicting results with this drug. Capecitabine and tegafur/gimeracil/oteracil (S-1) are oral prodrugs that can safely replace infusional fluorouracil. Gemcitabine, a more potent radiation sensitizer, is very toxic, even at low-doses twice weekly, and does not provide a survival benefit, as demonstrated in the Cancer and Leukemia Group B (CALGB) 89805 trial, a phase 2 study of patients with surgically staged locally advanced pancreatic cancer.33 Gemcitabine-based chemoradiotherapy was also evaluated in the Eastern Cooperative Group (ECOG) E4201 trial, which randomly assigned patients to receive gemcitabine alone (at 1000 mg/m2/wk for weeks 1 through 6, followed by 1 week rest, then weekly for 3 out of 4 weeks) or gemcitabine (600 mg/m2/wk for weeks 1 to 5, then 4 weeks later 1000 mg/m2 for 3 out of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/fraction for total of 50.4 Gy).34 Patients with locally advanced unresectable pancreatic cancer had a better OS outcome with gemcitabine in combination with radiation therapy (11.1 months) as compared with patients who received gemcitabine alone (9.2 months). Although there was a greater incidence of grade 4 and 5 treatment-related toxicities in the combination arm, no statistical differences in quality-of-life measurements were reported. Gemcitabine-based and capecitabine-based chemoradiotherapy were compared in the open-label phase 2 multicenter randomized SCALOP trial.35 Patients with locally advanced pancreatic cancer were assigned to receive 3 cycles of induction with gemcitabine 1000 mg/m2 days 1, 8, and 15 and capecitabine 830 mg/m2 days 1 to 21 every 28 days; patients who had stable or responding disease were randomly assigned to receive a fourth cycle followed by capecitabine (830 mg/m2 twice daily on weekdays only) or gemcitabine (300 mg/m2 weekly) with radiation (50.4 Gy over 28 fractions). Patients treated with capecitabine-based chemoradiotherapy had higher nonsignificant median OS (17.6 months) and median progression-free survival (12 months) compared to those treated with gemcitabine (14.6 months and 10.4 months, respectively).
The benefit of radiation therapy in the treatment of locally advanced pancreatic cancer was further explored by the Fédération Francophone de Cancérologie Digestive 2000-01 phase 3 trial. This study compared induction chemoradiotherapy (60 Gy, 2 Gy/fraction; concomitant fluorouracil infusion, 300 mg/m2/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m2/day, days 1–5 during weeks 1 and 5) to gemcitabine alone (1000 mg/m2 weekly for 7 weeks) followed by maintenance gemcitabine in both arms.36 Unexpectedly, the median OS was significantly shorter in the chemoradiotherapy arm than in the chemotherapy alone arm (8.6 months versus 13 months, respectively, P = 0.03) and the combination arm had more toxicities. The phase 3 open-label LAP07 study explored the role of radiation therapy in patients with locally advanced pancreatic cancer who had controlled disease after 4 months of induction therapy.37 LAP07 had 2 randomizations: first, patients with locally advanced pancreatic cancer were assigned to receive weekly gemcitabine alone (1000 mg/m2) or this same dose of gemcitabine plus erlotinib 100 mg/day; second, patients with progression-free disease (61% of initial cohort) after 4 months of therapy were assigned to receive 2 months of the same chemotherapy or chemoradiotherapy (54 Gy plus capecitabine). This study showed that the addition of erlotinib to gemcitabine did not improve survival and in fact affected survival adversely. Of note, no survival benefit was observed after the first randomization from chemotherapy to consolidating chemoradiotherapy. Chemoradiotherapy achieved better locoregional tumor control with significantly less local tumor progression (32% versus 46%, P < 0.03) and no increase in toxicity. Based on prior moderate-quality evidence, guidelines recommend consolidative chemoradiotherapy only for surgical resection candidates following induction chemotherapy; for those who are not surgical candidates, guidelines recommend continuing systemic therapy.26,28,29
Gemcitabine and fluorouracil-based chemotherapies were the standard induction regimens until evidence from studies of metastatic systemic treatment protocols with FOLFIRINOX (ACCORD trial38) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine (MPACT trial39) was extrapolated to clinical practice. These regimens were shown to achieve higher objective response rates when compared to single-agent gemcitabine in patients with metastatic pancreatic cancer. Due to the broad heterogeneity of results in small retrospective series with neoadjuvant trials in borderline resectable pancreatic cancer, the quality of the evidence is low and any recommendation is limited. Many individual series have demonstrated improved complete resection rates and promising survival rates. In the largest single-institution retrospective review of patients with borderline resectable pancreatic adenocarcinoma who completed neoadjuvant gemcitabine-based chemoradiotherapy (50 Gy in 28 fractions or 30 Gy in 10 fractions), 94% achieved a margin-negative pancreatectomy; the median OS in those who completed preoperative therapy and had surgery was 40 months, with a 5-year OS of 36%.40 A meta-analysis by Andriulli and colleagues included 20 prospective studies of patients with initially resectable (366 lesions) or unresectable (341 lesions) disease who were treated with neoadjuvant/preoperative gemcitabine with or without radiotherapy.41 In the group with initially unresectable disease, 39% underwent surgery after restaging and 68% of explored patients were resected; the R0 resection rate was 60%. After restaging, 91% of patients with resectable disease underwent surgery, with 82% of explored patients undergoing surgical resection and 89% of these achieving R0 resection. The estimated 1- and 2-year survival probabilities after resection among patients with initially unresectable disease were 86.3% and 54.2%.41
The largest single-institution retrospective review of FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, and leucovorin), an alternative to gemcitabine, for neoadjuvant induction therapy for patients with locally advanced unresectable disease was conducted at Memorial Sloan Kettering Cancer Center. In this study (n = 101), 31% of patients initially deemed unresectable who completed FOLFIRINOX induction therapy with or without chemoradiation underwent resection. The R0 resection rate in these patients was 55%, and patients who did not progress during induction FOLFIRINOX therapy had a median OS of 26 months.42 A systematic review and meta-analysis of FOLFIRINOX chemotherapy with or without radiotherapy in patients with locally advanced unresectable pancreatic cancer reported that 25.9% of patients underwent resection after FOLFIRINOX therapy, and the R0 resection rate in these patients was 78.4%.43 The median OS in this study was 24.2 months, which was longer than the previously reported median OS rates for gemcitabine.
There is no strong evidence published for the use of combination nab-paclitaxel plus gemcitabine in the neoadjuvant setting, but it is used in clinical practice based on evidence from the MPACT trial, which showed the combination improved OS and progression-free survival in patients with metastatic pancreatic cancer.39 An early-phase 1-arm clinical trial of neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) followed by radiotherapy showed an increased response rate and survival for locally advanced disease; however, the NCCN expert panel has reached a consensus but not a uniform recommendation regarding this regimen due to significant toxicities and low patient accrual.26 Selected patients with pancreatic cancer with BRCA1/2 mutations are more sensitive to platinum-based chemotherapy. Although studies of neoadjuvant platinum-based chemotherapy in this population have not been reported, the NCCN guidelines list it as an alternative option based on extrapolated data.26 A clinical trial of gemcitabine, nab-paclitaxel, and cisplatin in the neoadjuvant setting in patients with resectable pancreatic cancer is currently enrolling patients (NGC triple regimen NCT0339257).
Summary
Chemotherapy alone or followed by chemoradiotherapy may be used as initial treatment for patients with borderline and unresectable pancreatic adenocarcinoma without distant metastases who are potential surgical candidates. Chemoradiotherapy remains a preferred treatment option for patients with poorly controlled pain from local tumor invasion, in view of the well-documented analgesic palliative effect of radiation therapy. FOLFIRINOX with or without radiation therapy may offer the highest documented response rates, but it also results in higher rates of treatment-related toxicities. FOLFIRINOX can be offered to selected fit patients (< 65 years old, no comorbidity contraindication, good functional status [ECOG 0–1]) who can tolerate triple therapy with a more toxic adverse-effect profile. A clinical trial evaluating neoadjuvant FOLFIRINOX with or without preoperative chemoradiotherapy in patients with borderline resectable pancreatic cancer is ongoing (PANDAS-PRODIGE 44, NCT02676349). Gemcitabine with or without radiation therapy is a tolerable combination, although it is potentially more toxic when combined with radiation. The addition of nab-paclitaxel to gemcitabine without radiation may emerge as a preferred neoadjuvant treatment for selected patients; a clinical trial investigating this modality in patients with resectable and borderline resectable disease is ongoing (NCT02723331).
Adjuvant Therapy
Case Continued
Prior to the planned surgical resection and after undergoing chemoradiation therapy, the patient has an excellent performance status and repeat MRI shows a 1.3 × 1.4 cm head mass with no further vasculature involvement, no evidence of lymphadenopathy, and no distant metastasis. The CA 19-9 level is stable at 18 U/mL. The patient undergoes an uncomplicated partial pancreaticoduodenectomy, and analysis of a surgical pathology specimen reveals T3N0 disease with closest margin of 0.1 cm.
- Would the patient benefit from adjuvant therapy?
Adjuvant chemotherapy for 6 months after pancreatic cancer resection should be offered to all patients based on mature data. Gemcitabine and capecitabine are the current standard of care in adjuvant therapy; alternatively, single-agent gemcitabine can be offered to patients with poor performance status or patients who cannot tolerate the toxicities associated with this combination.28 Adjuvant treatment should be initiated within approximately 8 weeks of surgical resection. The value of radiation therapy remains controversial, but it can be offered within the context of a clinical trial or to patients with positive margins after surgical resection and/or lymph node–positive disease. Based on low-quality supportive evidence, it is strongly recommended that patients who receive neoadjuvant therapy complete a total of 6 months of chemotherapy, factoring in the duration of the preoperative regimen.28 Different adjuvant strategies have been investigated, including chemotherapy alone with a fluoropyrimidine and/or gemcitabine with or without combined chemoradiation therapy.
The European Study Group for Pancreatic Cancer 1 (ESPAC)-1 trial was a randomized clinical trial that evaluated several adjuvant strategies in pancreatic cancer treatment. This trial assigned patients who underwent pancreatic adenocarcinoma resection to adjuvant chemotherapy alone (intravenous fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 daily for 5 days, monthly for 6 months), chemoradiotherapy (20 Gy in 10 daily fractions over 2 weeks with 500 mg/m2 intravenous fluorouracil on days 1–3, repeated after 2 weeks), both chemotherapy and chemoradiation, and observation.44 The results showed no added benefit for adjuvant chemoradiotherapy, with a median OS of 15.5 months in the chemoradiotherapy cohort, as compared to a median OS of 16.1 months in the chemotherapy-alone cohort (hazard ratio [HR] 1.18 [95% CI 0.90 to 1.55], P = 0.24). In addition, there was evidence of a survival benefit for the chemotherapy-alone arm when compared to the combined modality arm, with a median OS of 19.7 versus 14.0 months, respectively (HR 0.66 [95% CI 0.52 to 0.83], P = 0.0005). Although ESPAC-1 has been criticized for being underpowered to perform statistical comparison, it is still considered a landmark trial demonstrating benefit with single-agent chemotherapy alone. A follow-up analysis of ESPAC-1 showed that adjuvant chemotherapy alone conferred a significant 5-year survival benefit while the combined modality had a deleterious effect on survival. 45 Hence, adjuvant chemotherapy alone became the standard of care in the United States following resection.
The results of the multicenter randomized controlled phase 3 CONKO-001 (CharitéOnkologie 001) trial, which were reported in 2007, supported the use of adjuvant gemcitabine for 6 months in patients with resected pancreatic adenocarcinoma. In this study, patients treated with adjuvant gemcitabine (1000 mg/m2 days 1, 8, and 15 every 4 weeks for 6 months) had superior disease-free survival compared with those who received surgery alone.30 A long-term outcome update of this study demonstrated a significant improvement in 5-year OS for patients treated with adjuvant gemcitabine (20.7% [95% CI 14.7% to 26.6%]) compared to those who received surgical resection alone (10.4% [95% CI 5.9% to 15.0%]). This benefit persisted at 10-year follow-up, with an OS of 12.2% (95% CI 7.3% to 17.2%) in the adjuvant gemcitabine group, as compared to 7.7% (95% CI 3.6% to 11.8%) in the resection alone group.31
Fluorouracil and gemcitabine remained equivalent adjuvant treatment options until the results of the ESPAC-3 trial were reported in 2010.32 This large phase 3 trial, conducted mainly in the United Kingdom, compared weekly gemcitabine (1000 mg/m2 weekly for 3 of every 4 weeks) to leucovorin-modulated fluorouracil (Mayo Clinic regimen: leucovorin 20 mg/m2 followed by fluorouracil 425 mg/m2 intravenous bolus days 1 through 5 every 28 days) as adjuvant therapy in resected pancreatic adenocarcinoma. After a median follow-up of 34.2 months, the median OS was similar in the 2 groups (fluorouracil/leucovorin 23.0 months versus gemcitabine 23.6 months; P = 0.39). However, the fluorouracil/leucovorin group experienced more grade 3/4 treatment-related toxicities (mucositis, stomatitis, diarrhea, and hosptializations; 14% versus 7.5%; P < 0.001).46 Following this trial, gemcitabine became the standard of care for adjuvant chemotherapy for resected pancreatic cancer.
The U.S. Radiation Therapy Oncology Group (RTOG) 9704 trial was conducted to investigate the potential benefit of adding radiation therapy to gemcitabine. This trial demonstrated an improved trend among patients with pancreatic head tumors (but not with cancers of the pancreatic body or tail) who received adjuvant gemcitabine followed by chemoradiotherapy (50.4 Gy in 1.8 Gy daily fractions for 5.5 weeks with concurrent infusional fluorouracil 250 mg/m2 daily) and subsequent gemcitabine monotherapy compared to postoperative fluorouracil-based chemoradiotherapy. Results showed a 5-year OS of 22% versus 18%, respectively, although this improvement was not statistically significant (P = 0.08). This trial failed to show a benefit of adding radiotherapy to gemcitabine.47
The ESPAC-4 trial, reported in 2017, evaluated the combination of gemcitabine and capecitabine compared to gemcitabine alone as adjuvant therapy for resected pancreatic adenocarcinoma.48 Patients were randomly assigned after surgical resection, regardless of margin or node status, to 6 months of gemcitabine alone (1000 mg/m2/day on days 1, 8, and 15 of each 28-day cycle) or gemcitabine plus capecitabine (1660 mg/m2/day on days 1 through 21 of each 28-day cycle). Combination therapy had a significant survival benefit compared to single therapy, with median OS durations of 28 months and 25.5 months, respectively (HR for death 0.82 [95% CI 0.68 to 0.98]). The 5-year OS for patients who received combination treatment was 29 months (95% CI 22.9 to 35.2) versus 16 months (95% CI 10.2 to 23.7) for those in the monotherapy group. As expected, grade 3 or 4 treatment-related toxicities (diarrhea, hand-foot syndrome, and neutropenia) were significantly more common with combined therapy, although there were no significant differences in the rates of serious adverse events. The adjuvant combination of gemcitabine and capecitabine became the current and preferred new standard of care following resection of pancreatic ductal adenocarcinoma,28 but single-agent gemcitabine and fluorouracil/leucovorin continue to be viable options,26,28,29 particularly for elderly patients, patients with borderline performance status, or patients with multiple comorbidities.
Evidence showing that a more intensive regimen can improve outcome in the adjuvant setting remains elusive. The phase 3 APACT study (Adjuvant Therapy for Patients with Resected Pancreatic Cancer, NCT01964430) comparing gemcitabine alone to gemcitabine plus nab-paclitaxel in patients with surgically resected pancreatic adenocarcinoma has concluded, with the results projected to be released in 2018. Another phase 3 trial investigating the efficacy of FOLFIRINOX versus gemcitabine alone as adjuvant therapy is underway in France and Canada (PRODIGE24/ACCORD24, NCT01526135). Other strategies with newer targeted therapies and immunotherapy are in the development phase.
Follow-Up and Surveillance
Case Conclusion
After recovery from surgery, the patient is offered and completes 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine. He is started on surveillance at 3 and 6 months, and he maintains an excellent performance status. He develops clinical evidence of pancreatic enzyme insufficiency and is placed on oral replacement therapy. He has no other complaints, and there is no evidence of recurrence on MRI and CA 19-9 levels.
- What is the recommended duration of surveillance following curative resection?
Surveillance after curative resection of pancreatic adenocarcinoma is recommended by NCCN guidelines.26 However, pancreatic adenocarcinoma has a poor prognosis, and surveillance after curative surgical resection with or without perioperative therapy has not been shown to impact survival. Most recurrences will occur within 2 years after treatment. Surveillance recommendations differ among expert groups.26,28,29 NCCN guidelines recommend evaluating patients by history and physical examination every 3 to 6 months for the first 2 years, then every 6 to 12 months for 3 years. CA 19-9 level and CT scan should be obtained every 3 to 6 months for 2 years and then every 6 to 12 months for 3 years. Follow-up with CA 19-9 levels and CT scans after 5 years is not routinely performed unless guided by signs, symptoms, or laboratory findings that raise suspicion for recurrence. Follow-up visits should also include evaluation of treatment-related toxicities, symptom management, nutrition support of pancreatic insufficiency, and psychosocial support.
Conclusion
Pancreatic cancer is a leading cause of cancer-related death that frequently presents with locally advanced or metastatic disease due to nonspecific symptoms and lack of a screening modality. Histological tissue biopsy confirmation and accurate resectability staging guide treatment planning and prognosis. The only potentially curative therapy is surgical resection plus adjuvant therapy for those with resectable disease. Surgical candidates with borderline resectable and unresectable disease can be offered induction preoperative chemotherapy followed by consolidation chemoradiation, based on clinical consensus practice. Enrollment in clinical trials should be encouraged for all patients, as evidence from clinical trials is essential to making progress in pancreatic cancer treatment.
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3. Kamarajah SK, Burns WR, Frankel TL, et al. Validation of the American Joint Commission on Cancer (AJCC) 8th edition staging system for patients with pancreatic adenocarcinoma: a Surveillance, Epidemiology and End Results (SEER) analysis. Ann Surg Oncol 2017;24:2023–30.
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6. Michaud DS, Giovannucci E, Willett WC, et al. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA 2001;286:921–9.
7. Batabyal P, Vander Hoorn S, Christophi C, Nikfarjam M. Association of diabetes mellitus and pancreatic adenocarcinoma: a meta-analysis of 88 studies. Ann Surg Oncol 2014;21:2453–62. Epub 2014 Mar 9.
8. Canto MI, Harinck F, Hruban RH, et al, on behalf of the International Cancer of the Pancreas Screening (CAPS) Consortium. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–47. Epub 2012 Nov 7.
9. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 2004;64:2634–8.
10. McKay SH,Humphris JL, Johns AL, et al. Inherited pancreatic cancer. Cancer Forum 2016;40(1).
11. Shindo K, Yu J, Suenaga M, et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol 2017;35:3382–90.
12. Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas. AFIP Atlas of Tumor Pathology. 4th series, fascicle 6. Washington, DC: Armed Forces Institute of Pathology; 2007.
13. Vege SS, Ziring B, Jain R, Moayyedi P, Clinical Guidelines Committee, American Gastroenterology Association. American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology 2015;148:819–22.
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28. Ducreux M, Cuhna AS, Caramella C, et al; ESMO Guidelines Committee. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26 Suppl 5:v56–68.
30. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007;297:267–77.
31. 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;310:1473–81.
32. Huguet F, Girard N, Guerche CS, et al. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 2009;27:2269–77.
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48. Neoptolemos JP, Palmer DH, Ghaneh P, et al, European Study Group for Pancreatic Cancer. 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;389:1011–24. Epub 2017 Jan 25.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7–30.
2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69.
3. Kamarajah SK, Burns WR, Frankel TL, et al. Validation of the American Joint Commission on Cancer (AJCC) 8th edition staging system for patients with pancreatic adenocarcinoma: a Surveillance, Epidemiology and End Results (SEER) analysis. Ann Surg Oncol 2017;24:2023–30.
4. National Institutes of Health/National Cancer Institute. Surveillance, Epidemiology and End Results Program (SEER). Cancer stat facts: pancreatic cancer. seer.cancer.gov/statfacts/html/pancreas.html. Accessed 17 February 2018.
5. Fuchs CS, Colditz GA, Stampfer MJ, et al. A prospective study of cigarette smoking and the risk of pancreatic cancer. Arch Intern Med 1996;156:2255–60.
6. Michaud DS, Giovannucci E, Willett WC, et al. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA 2001;286:921–9.
7. Batabyal P, Vander Hoorn S, Christophi C, Nikfarjam M. Association of diabetes mellitus and pancreatic adenocarcinoma: a meta-analysis of 88 studies. Ann Surg Oncol 2014;21:2453–62. Epub 2014 Mar 9.
8. Canto MI, Harinck F, Hruban RH, et al, on behalf of the International Cancer of the Pancreas Screening (CAPS) Consortium. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–47. Epub 2012 Nov 7.
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