Adenocarcinoma of the pancreas is associated with a poor prognosis. Even after resection of small tumours without regional lymph node involvement, five-year survival rates remain low at around 20 percent. 1 The diagnosis of pancreas cancer may be preceded by non-specific symptoms (e.g.: fatigue, anorexia, weight loss, dull epigatric pain). Early satiety, malabsorption, steatorrhea, glucose intolerance, and jaundice (from extra-hepatic biliary obstruction) may also occur.
Risk factors include age, male gender, chronic pancreatitis, diabetes mellitus type 2, germline mutations in P16 and BRCA2, and a familial predisposition (e.g.: multiple endocrine neoplasia type 1, hereditary non-polyposis colon cancer). A referral to genetics should be discussed with patients with a personal history of pancreatic adenocarcinoma at any age AND two or more close relatives with breast, ovarian, or pancreatic cancer at any age. There is a dose-response relationship with smoking 2 and an association with processed meat consumption.
Although disease confined to the pancreas may be amenable to a pancreaticoduodenectomy or distal pancreatectomy, involvement of the celiac axis or superior mesenteric artery, venous occlusion at the confluence of the superior mesenteric and portal veins, or metastatic disease represents unequivocally unresectable disease. Direct extension to the duodenum, bile duct, or peri-pancreatic tissue with or without isolated involvement of the superior mesenteric vein or portal vein may still be amenable to resection. This guideline was developed to outline the management recommendations for patients with pancreatic cancer (adenocarcinoma). For specific recommendations for the management of malignant biliary obstruction, please refer to the Malignant Biliary Obstruction clinical practice guideline.

# Guideline Questions
- What are the recommendations for the diagnostic workup of adult patients with adenocarcinoma of the pancreas? - What are the treatment recommendations for adult patients with potentially curable adenocarcinoma of the pancreas? - What are the management recommendations for adult patients with unresectable cancer of the pancreas?

# Search Strategy
The Pubmed database was searched using the following search strategy: (("adenocarcinoma"

# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with pancreatic cancer. Different principles may apply to pediatric patients.

# Suggested Diagnostic Work-Up
For patients with a family history suggestive of hereditary pancreatic cancer, consider referral to the Hereditary Cancer Clinic for pancreatic cancer susceptibility screening. A family history suggestive of hereditary pancreatic cancer includes:
- A personal history of pancreatic adenocarcinoma at any age AND i. Two or more close relatives with breast/ ovarian/ pancreatic cancer at any age.
ii. Family history suggestive of Lynch syndrome (two or more close relatives with endometrial cancer and/or colon cancer).
iii. Ashkenazi Jewish heritage.
- Personal history of pancreatic adenocarcinoma plus another primary cancer diagnosis.
- Relative with known cancer predisposition syndrome (i.e. BRCA1 or BRCA2 mutation, Lynch syndrome, moderate risk cancer predisposition gene such as ATM, PALB2).
A CT scan of the chest, abdomen, and pelvis can distinguish between resectable and unresectable disease. An MRI of the abdomen (and other tests, as clinically indicated) may be used as supplemental investigations. Bone scans can be done for patients suspected of having bone metastases. A CA19-9 should be performed as a baseline laboratory test. If surgery is performed, the CA 19-9 should be performed post-operatively. While on neoadjuvant or palliative systemic treatment, CT chest abdomen pelvis should be done every 2-3 months. Consider IgG4 levels, if autoimmune pancreatitis is on the differential diagnosis. For patients not undergoing upfront surgery, tissue biopsy should be performed via endoscopic ultrasound, ERCP, or CT guidance.
All patients with pancreatic cancer should be referred to a registered dietician. Patients should be screened for pancreatic enzyme deficiency and initiate replacement if needed. Pancreatic enzyme replacement is typically prescribed at 500-2500 units of lipase per kilogram body weight per meal, up to 10 000 units of lipase per kilogram of body weight per day. 3 Stage Information  Regimens for patients not suitable for combination chemotherapy:
- Six four-week cycles of Leucovorin 20 mg/m2 IV followed by 5-Fluorouracil 425 mg/m2 IV on each of five consecutive days has been shown to increase the median survival from 15.5 months to 20.1 months, the two-year survival from 30% to 40%, and the five-year survival from 8% to 21% when compared to no further treatment. Evidence quality: high.
- Alternatively, six four-week cycles of Gemcitabine (1,000 mg/m2 IV over thirty minutes on days 1,8 - Follow-up after resection: There is no evidence of survival improvement with close follow-up based on literature.  However, routine surveillance enables detection of asymptomatic recurrences. Consider CT scan after completion of adjuvant chemotherapy. Further bloodwork/imaging follow-up should be individualized to each patient. Systemic/palliative treatment has advanced over the last years but only patient with sufficient performance status is eligible; therefore, routine surveillance may improve the likelihood of detecting recurrence at a point when patients are well enough to receive chemotherapy.
- There is no routine role for adjuvant radiotherapy at this time.

# Goals and Recommendations for

# Metastatic Disease Stage IV TanyNanyM1
Locally Advanced: Multidisciplinary collaboration to formulate care plans is important as a small proportion of patients may become resectable after chemotherapy. For that specific patient population, there is no randomized controlled data to guide the use of post-operative chemotherapy after administration of pre-operative chemotherapy. The Provincial Gastrointestinal Tumour Team recommends administration of a total of 6 months of chemotherapy (including the pre-operative regimen). Recommendation type: informal consensus, benefits outweigh harms; Evidence quality: low.

# First line treatment
A discussion addressing goal of care, patient preferences concerning the balance of toxicity and efficacy should guide the decision for first line therapy for patients with good performance status. - Adjuvant chemotherapy with modified-FOLFIRINOX in resected pancreas cancer patients is superior to gemcitabine, although significantly more toxic. - For carefully selected patients with metastatic disease, performance status (ECOG 0 or 1), age  75 years, and a normal or nearly normal bilirubin, FOLFIRINOX prolongs overall survival (11.1 months versus 6.8 months, HR 0.57, 95% CI 0.45-0.73, p = 0.0001) and delays the deterioration in quality of life when compared to Gemcitabine alone. 9,10 The rate of grade 3/4 toxicities emphasizes the need for education, monitoring, and active management (see Table 4 and 5 below) (Evidence quality: High). - The Provincial Gastrointestinal Tumour Team agree that FOLFIRINOX may also be considered for patients with locally advanced disease given that a high response rate may result in the conversion of some patients to resectable disease. At present, no randomized studies have explored the use of FOLFIRINOX in locally advanced pancreatic cancer patients (see Appendix A for a list of current clinical trials using this regimen). Several retrospective reviews have demonstrated the efficacy and tolerability of FOLFIRINOX in this patient group, despite the use of dose modifications and adverse events.  nab-Paclitaxel plus Gemcitabine - Patients may also be considered for treatment with nab-Paclitaxel plus Gemcitabine. An international, phase III trial of 861 metastatic pancreatic cancer patients compared the efficacy and safety of nab-Paclitaxel plus Gemcitabine versus Gemcitabine alone. 14 Median overall survival was 8.5 months in the intervention arm compared to 6.7 months in the control arm (HR 0.72, 95% CI 0.62-0.83, p<0.001).
Median progression-free survival was 5.5 months versus 3.7 months in the nab-Paclitaxel plus Gemcitabine versus Gemcitabine alone group, respectively (HR 0.69, 95% CI 0.58-0.82, p<0.001).
According to independent review, the response rate was 23% versus 7% in the nab-Paclitaxel plus Gemcitabine group versus the control group, respectively (p<0.001) (Evidence quality: high). The Provincial Gastrointestinal Tumour Team adapts the eligibility criteria based on the above mentioned phase III study. 14 The Provincial Gastrointestinal Tumour Team agree that nab-Paclitaxel plus Gemcitabine may also be considered for patients with locally advanced disease. - Patients eligible for nab-Paclitaxel plus Gemcitabine should meet the following criteria:
- 18 years of age - Karnofsky performance status score 70 
Have not previously received chemotherapy for metastatic disease (patient could have received treatment with Fluorouracil or Gemcitabine as a radiation sensitizer in the adjuvant setting if the treatment had been received at least 6 months ago) 
Have histologically or cytologically confirmed metastatic or locally advanced adenocarcinoma of the pancreas 
Have adequate hematologic, hepatic, and renal function, including: o Absolute neutrophil count of 1.5x10 9 per litre o Hemoglobin level of 9 g per deciliter o Bilirubin level at or below the upper limit of the normal range Gemcitabine - For patients not suitable for combination chemotherapy (due to patient preference or comorbidities) with a performance status of ECOG 2, Gemcitabine (1,000 mg/m 2 IV over thirty minutes once weekly for seven of eight weeks and subsequently weekly for three of four weeks) has been shown to offer a "clinical benefit response" (improvement in pain, performance status, and weight) in 23.8%. 15,16 In addition, it may prolong median survival (to 5.65 months) and improve twelve-month survival (to 18%). Treatment should be continued until progression or until significant clinical deterioration secondary to tumour-related symptoms.
Second line treatment for patients who wish to pursue cancer directed therapy:
- After progression on Gemcitabine based treatment, for patients with an ECOG of 0-1, suitable for combination chemotherapy:
- "OFF" regimen: Leucovorin (200 mg/m 2 IV over thirty minutes) followed by a continuous intravenous infusion of 5-Fluorouracil (2,000 mg/m 2 over twenty-four hours) on days 1, 8, 15, and 22 with Oxaliplatin (85 mg/m 2 IV over two hours) on days 8 and 22 of every six week cycle ("OFF" regimen) has been shown to increase median overall survival compared to Leucovorin and 5-Fluorouracil alone; from 3.3 months to 5.9 months (p =0.010) in patients with a good performance status. 17 Note that FOLFOX is not interchangeable with "OFF" as it has been shown to be inferior to Leucovorin and 5-Fluorouracil in terms of OS in the second line. 18 - Nanoliposomal irinotecan (80 mg/m2, equivalent to 70 mg/m2 of irinotecan base) with 5-Fluorouracil and Leucovorin is the preferred second line treatment option as the addition of nanoliposomal irinotecan increased median overall survival to 6.1m (95%CI 4.8-8.9) compared to 4.2m (95%CI 3.3-5.3m) in the fluorouracil and folinic acid alone group (HR 0.67, 95% CI 0.49-0.92; p=0.012). 10 Nanoliposomal irinotecan is not currently funded. Fluorouracil plus irinotecan could be considered if nanoliposomal irinotecan is unavailable.
After progression on FOLFIRINOX: (Recommendation type: informal consensus, benefits outweigh harms; Evidence quality: low).
- Gemcitabine plus NAB-paclitaxel can be offered as second-line therapy to patients who meet all of the following criteria: an ECOG PS of 0 to 1, a relatively favorable comorbidity profile, and patient preference Gemcitabine or a fluoropyrimidine can be considered for patients who have ECOG PS < 2 unsuitable for combination regimens due to patient preference or comorbidities (Recommendation type: informal consensus, benefits outweigh harms; Evidence quality: low). Patients should not have previously progressed on the selected agent.