Pancreatic Adenocarcinoma

Background

• Pancreatic adenocarcinoma (ductal and its variants) is an exocrine malignant tumor which is responsible for > 90% of all pancreatic cancers.
• It most commonly affects patients > 55 years old.
• The worldwide age-standardized annual incidence rate of pancreatic cancer is 5.5 per 100,000 in men and 4 per 100,000 in women.
• Pancreatic cancer is the tenth most common cancer in men and the ninth most common cancer in women in United States.
• Major risk factors for pancreatic cancer include tobacco use, genetic predisposition and family history, obesity, chronic pancreatitis, and preexisting diabetes
• The prognosis of pancreatic adenocarcinoma is very poor, with 5-year overall survival of < 10%.

Evaluation

• The clinical presentation depends on the location of the tumor and the stage of disease and may include unexplained weight loss, jaundice, epigastric pain, dyspepsia, dysphagia, and lethargy.
• Suspect pancreatic cancer in older adults with these signs and symptoms, as well as sudden onset of diabetes, pancreatitis, or other pancreatic disorders.
• Any decisions about a diagnosis should involve a multidisciplinary consultation with expertise in diagnostic imaging, interventional endoscopy, medical oncology, radiation oncology, surgery, and pathology at a high-volume center (Strong recommendation).
• Diagnosis is usually established based on imaging, with pancreatic protocol multidetector computed tomography (MDCT) as the preferred imaging modality (Strong recommendation).
• Biopsy confirmation is not routinely required in patients with resectable disease planned for upfront resection.
• Perform a biopsy to confirm diagnosis in the following situations (Weak recommendation):
  • if neoadjuvant therapy is being planned for resectable or borderline resectable disease
  • if unresectable disease is discovered during surgery
  • if locally advanced disease or metastatic disease are suggested by imaging studies
• Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the preferred technique for biopsy.

Management

Management of resectable and borderline resectable disease

• Enrollment in a clinical trial is the preferred management option in borderline resectable disease and in the adjuvant setting (Weak recommendation). See a list of ongoing trials in patients with pancreatic cancer at clinicaltrials.gov.
• In patients with resectable disease, offer upfront surgical resection of primary tumor and regional lymph nodes, or neoadjuvant therapy prior to surgery (Strong recommendation). If the disease is high risk, strongly consider neoadjuvant therapy (Weak recommendation).
• In patients with borderline resectable disease, offer neoadjuvant therapy, followed by surgical resection (Strong recommendation).
• Consider staging laparoscopy (Weak recommendation).
• Consider preoperative stent placement, if it is clinically indicated such as for patients with symptoms of cholangitis/fever or severe symptomatic jaundice (intense pruritis), or if surgery is being delayed for any reason including neoadjuvant therapy (Weak recommendation), although European Society for Medical Oncology recommends against metal stents because of increased postoperative morbidity (Strong recommendation).
• If neoadjuvant therapy is planned, obtain biopsy confirmation (Strong recommendation).
• Preferred neoadjuvant therapy regimens include
  • for patients with performance status (PS) 0-1, 5-fluorouracil plus leucovorin plus irinotecan plus oxaliplatin (FOLFIRINOX) or modified FOLFIRINOX (mFOLFIRINOX), with or without subsequent chemoradiation (Weak recommendation);
  • for patients with performance status (PS) 0-2, gemcitabine plus albumin-bound paclitaxel, with or without subsequent chemoradiation (Weak recommendation).
• If neoadjuvant therapy is given, offer restaging evaluation after completion and prior to surgery (Strong recommendation).
• The choice of surgical procedure depends on location of the tumor and may include
  • pancreatoduodenectomy (Whipple procedure) for tumors of pancreas head and uncinate
  • distal pancreatectomy with complete splenectomy for tumors of pancreas body and tail
  • total pancreatectomy, extended distal pancreatomy or extended pancreatoduodenectomy for tumors of pancreas neck
• After surgery, if there is no recurrence or metastatic disease progression:
  • In patients with no prior neoadjuvant therapy, management options include
    • adjuvant chemotherapy only (Strong recommendation)
    • adjuvant chemoradiation, although guidelines conflict in their recommendations (Weak recommendation)
      • National Comprehensive Cancer Network (NCCN) considers adjuvant chemoradiation an option after induction chemotherapy. Chemoradiation may optionally be followed by subsequent chemotherapy.
      • American Society of Clinical Oncology (ASCO) considers adjuvant chemoradiation an option in patients with R1 resection and/or node-positive disease after completing 4-6 months of adjuvant chemotherapy.
      • European Society for Medical Oncology (ESMO) does not recommend adjuvant chemoradiation outside the context of a clinical trial.
  • In patients with prior neoadjuvant therapy, offer adjuvant chemotherapy for up to 6 months (combined duration with neoadjuvant therapy) (Strong recommendation).
  • Preferred adjuvant chemotherapy regimens include
    • for patients with PS 0-1, mFOLFIRINOX (Strong recommendation);
    • gemcitabine plus capecitabine (Strong recommendation).
• Monitor for toxicities, postoperative complications, and recurrence at follow-up visits every 3-6 months for 2 years, extending the interval thereafter. (Weak recommendation).

Management of recurrence after resection

• If recurrence is suspected after resection, consider performing a confirmatory biopsy before beginning any treatment (Weak recommendation).
• Therapy is best reserved for patients with good performance status 0-1 (for most therapies) or 0-2 (for select therapies), good biliary drainage, and adequate nutritional intake.
• Consider providing palliative and supportive care to all patients (Weak recommendation).
• Enrollment in a clinical trial is the preferred first-line management option (Weak recommendation). See a list of ongoing trials in patients with pancreatic cancer at clinicaltrials.gov.
• For local recurrence of only the pancreas, consider surgical consultation with multidisciplinary review (Weak recommendation).
• For local recurrence of the pancreatic operative bed, management options include:
  • systemic chemotherapy (optional addition of either chemoradiation or stereotactic body radiation therapy [SBRT], if neither previously given) (Weak recommendation);
  • SBRT only (Weak recommendation).
  • palliative and supportive care only
• For metastatic disease with or without local recurrence, options depend on the length of time between the recurrence and the completion of primary therapy:
  • If recurrence occurs ≥ 6 months after completion of primary therapy, options include either systemic chemotherapy (with either the same regimen used previously or with alternative regimen), or palliative and supportive care only (Weak recommendation).
  • If recurrence occurs < 6 months after completion of primary therapy, options include either switching to alternative systemic chemotherapy regimen (from gemcitabine-based regimen to fluoropyrimidine-based regimen, or from fluoropyrimidine-based regimen to gemcitabine-based regimen), or palliative and supportive care only (Weak recommendation).

Management of locally advanced (unresectable) disease

• Enrollment in a clinical trial is the preferred management option (Strong recommendation). See a list of ongoing trials in patients with pancreatic cancer at clinicaltrials.gov
• Biopsy the cancer to confirm diagnosis (Strong recommendation).
• Consider germline testing, gene profiling of the tumor, and testing for tumor microsatellite instability (MSI) or mismatch repair (MMR) (Weak recommendation).
• In patients with jaundice, consider self-expanding metal stent placement, preferably with ERCP, unless biliary bypass planned during laparoscopy or laparotomy (Weak recommendation).
• First-line management:
  • In fit patients (performance status [PS] 0-1 or 0-2 and favorable comorbidity profile):
    • Management options include
      • systemic chemotherapy only (Strong recommendation);
      • in select patients, induction systemic chemotherapy (preferably 4-6 cycles), followed by either chemoradiation or stereotactic body radiation therapy (SBRT) (Strong recommendation);
      • in select patients, upfront chemoradiation or stereotactic body radiation therapy (SBRT) (Strong recommendation).
    • Preferred systemic chemotherapy regimens include
      • in patients with PS 0-1, 5-fluorouracil plus leucovorin plus irinotecan plus oxaliplatin (FOLFIRINOX) or modified FOLFIRINOX (mFOLFIRINOX) (Weak recommendation);
      • in patients with PS 0-2, gemcitabine plus albumin-bound paclitaxel (Weak recommendation);
      • in patients with BRCA1/2 or PALB2 mutations only, gemcitabine plus cisplatin (Weak recommendation).
  • In unfit patients with poor PS, consider palliative and best supportive care with the addition of either single-agent chemotherapy (gemcitabine, 5-fluorouracil [5-FU], or capecitabine), or palliative radiation therapy (Weak recommendation).
• In fit patients (performance status [PS] 0-1 or 0-2 and favorable comorbidity profile) with no disease progression, consider resection if feasible and adjuvant therapy if clinically indicated afterwards (Weak recommendation).
• Second-line management
  • In fit patients, management options include
    • systemic therapy (Weak recommendation);
    • chemoradiation or SBRT, if it is not given previously, and if primary cancer site is the only site of progression (Weak recommendation).
  • Systemic chemotherapy options include
    • switching from first-line gemcitabine-based regimens to second-line fluoropyrimidine-based regimens;
    • switching from first-line fluoropyrimidine-based regimens to second-line gemcitabine-based regimens;
    • in patients with high levels of microsatellite instability [MSI-H] or deficient mismatch repair [dMMR] tumors, pembrolizumab (Weak recommendation);
    • in patients with NTRK gene fusion positive tumors, larotrectinib or entrectinib (Weak recommendation).
  • In unfit patients with poor PS, consider palliative and best supportive care with the addition of either single-agent chemotherapy (gemcitabine, 5-fluorouracil [5-FU], or capecitabine), or palliative radiation therapy (Weak recommendation).
• For patients with stable disease and no evidence of disease progression, conduct follow-up visits every 2-3 months for first 2 years, and then every 6 months thereafter including physical exam, liver and renal function laboratory testing, computed tomography (CT), and cancer antigen (CA) 19-9 levels (Strong recommendation).

Management of metastatic disease

• Consider enrollment in a clinical trial as an option in all lines of management (Weak recommendation). See a list of ongoing trials in patients with pancreatic cancer at clinicaltrials.gov.
• First-line management:
  • In fit patients (performance status [PS] 0-1 or 0-2, and favorable comorbidity profile), offer systemic chemotherapy, preferred regimens include
    • in patients with PS 0-1, 5-fluorouracil plus leucovorin plus irinotecan plus oxaliplatin (FOLFIRINOX) (Strong recommendation) or modified FOLFIRINOX (mFOLFIRINOX) (Weak recommendation);
    • in patients with PS 0-2 or PS 0-1 with relatively favorable comorbidity profile, gemcitabine plus albumin-bound paclitaxel (Strong recommendation)
    • in patients with BRCA1/2 or PALB2 mutations only, gemcitabine plus cisplatin (Weak recommendation).
  • In patients with either PS 2 or comorbidity profile incompatible with more aggressive regimens, offer gemcitabine monotherapy (Strong recommendation) (with optional addition of capecitabine or erlotinib) (Weak recommendation).
  • In unfit patients with poor PS, consider palliative and best supportive care with the addition of either single-agent systemic therapy (gemcitabine, 5-fluorouracil [5-FU], capecitabine, larotrectinib or entrectinib if NTRK gene fusion positive tumor or pembrolizumab if tumor with high level of microsatellite instability [MSI-H] or deficient mismatch repair [dMMR]), or palliative radiation therapy (Weak recommendation).
• In patients who maintain good PS and no disease progression during 4-6 months of first-line systemic chemotherapy, maintenance therapy options include
  • enrollment in clinical trial (Weak recommendation)
  • continue systemic therapy (Weak recommendation)
  • olaparib (only in patients with germline BRCA1/2 mutation) (Weak recommendation)
  • other maintenance therapy strategy (Weak recommendation)
  • chemotherapy holiday (Weak recommendation)
• Second-line management
  • In fit patients, consider systemic therapy (Weak recommendation); options include
    • switching from first-line gemcitabine-based regimens to second-line fluoropyrimidine-based regimens;
    • switching from first-line fluoropyrimidine-based regimens to second-line gemcitabine-based regimens;
    • in patients with high levels of microsatellite instability [MSI-H] or deficient mismatch repair [dMMR] tumors, pembrolizumab (Weak recommendation);
    • in patients with NTRK gene fusion positive tumors, larotrectinib or entrectinib (Weak recommendation).
  • In unfit patients with poor PS, consider palliative and best supportive care with the addition of either single-agent chemotherapy (gemcitabine, 5-fluorouracil [5-FU], or capecitabine, larotrectinib or entrectinib if NTRK gene fusion positive tumor or pembrolizumab if tumor with high level of microsatellite instability [MSI-H] or deficient mismatch repair [dMMR]), or palliative radiation therapy (Weak recommendation).
• Assess initial response to therapy with computed tomography (CT) with contrast within 2-3 months of starting therapy; afterwards conduct clinical assessments to replace imaging studies (Strong recommendation).