Pancreas/Biliary, in full.

Evaluate suspected pancreatic adenocarcinoma with a dedicated pancreatic-protocol (multiphasic, contrast-enhanced) CT of the abdomen as the preferred imaging for diagnosis and staging (MRI/MRCP is an acceptable alternative); PET/CT may be added after, never as a substitute for, protocol CT/MRI in higher-risk situations. Obtain tissue confirmation, preferably by EUS-guided FNA/FNB with core biopsy where feasible; biopsy is generally required before neoadjuvant or palliative therapy, whereas patients with clearly resectable disease may proceed to surgery without preoperative biopsy. Measure baseline CA 19-9 (interpret after biliary decompression / with normal bilirubin; it can be falsely low in Lewis-antigen-negative patients and falsely elevated with cholestasis). Offer GERMLINE testing for inherited susceptibility to EVERY patient with confirmed pancreatic adenocarcinoma regardless of family history, using a comprehensive multi-gene panel; separately, for patients with locally advanced or metastatic disease who are candidates for anti-cancer therapy, obtain TUMOR/SOMATIC molecular profiling (broad NGS; RNA-based assays improve fusion detection; cell-free/liquid biopsy if tissue is insufficient). Assign resectability, resectable, borderline resectable, locally advanced (unresectable), or metastatic, by multidisciplinary review, ideally at a high-volume center. RESECTABLE disease: upfront resection (pancreaticoduodenectomy for head/uncinate; distal pancreatectomy ± splenectomy for body/tail) followed by adjuvant therapy, or neoadjuvant therapy in selected high-risk patients; preferred adjuvant regimen is modified FOLFIRINOX in patients able to tolerate it, ideally begun within 12 weeks of surgery, for a total of ~6 months of perioperative systemic therapy. BORDERLINE RESECTABLE and LOCALLY ADVANCED disease: neoadjuvant systemic therapy, with or without subsequent chemoradiation/RT, then restaging and reassessment for resection. METASTATIC disease by performance status: good PS (ECOG 0-1, adequate organ function), first-line FOLFIRINOX/modified FOLFIRINOX, NALIRIFOX, or gemcitabine + nab-paclitaxel, with clinical trial preferred; after ~4-6 months without progression, transition to a maintenance strategy (including olaparib for germline BRCA1/2 carriers who have NOT progressed on first-line platinum-based therapy), a clinical trial, or a treatment break; intermediate PS (ECOG 2), clinical trial preferred, otherwise less-intensive first-line therapy (preferred gemcitabine + nab-paclitaxel [category 1], or single-agent gemcitabine or capecitabine, or FOLFOX/FOLFIRI/CapeOx), since the intensive triplets (FOLFIRINOX/modified FOLFIRINOX and NALIRIFOX) are limited to ECOG 0-1 and are generally not appropriate at ECOG 2, with the same maintenance-versus-progression reassessment applied after ~4-6 months without progression; poor PS (ECOG 3-4), palliative/best supportive care, with single-agent chemotherapy or a biomarker-directed agent only if clinically appropriate. Treat by molecular target wherever an actionable alteration is present, across lines: pembrolizumab (or dostarlimab) for MSI-H/dMMR and pembrolizumab for TMB-H, olaparib for germline BRCA1/2 (maintenance after platinum), larotrectinib/entrectinib for NTRK fusions, selpercatinib for RET fusions, dabrafenib + trametinib for BRAF V600E, erdafitinib for FGFR2 alterations, fam-trastuzumab deruxtecan for HER2-positive disease, zenocutuzumab for NRG1 fusion-positive disease, and (in recent NCCN versions) KRAS G12C inhibitors (adagrasib/sotorasib), several of these after prior systemic therapy. Integrate supportive care throughout: relieve obstructive jaundice with an endoscopic self-expanding metal stent in non-operative or neoadjuvant pathways, but do NOT perform routine preoperative biliary drainage before planned upfront resection; treat exocrine insufficiency with pancreatic enzyme replacement titrated to symptoms (common starting dose ~40,000-50,000 units of lipase with main meals, roughly half with snacks, increased as needed); manage refractory pain with celiac plexus neurolysis or palliative RT; relieve gastric outlet obstruction with surgical or EUS-guided gastrojejunostomy (or enteral stenting); and provide VTE prophylaxis, nutritional support, and early palliative care.

Stage cholangiocarcinoma with multiphasic MRI/MRCP plus CT chest/abdomen/pelvis, obtain tissue via ERCP brush cytology with FISH, cholangioscopy-directed biopsy, or EUS-FNA (avoiding primary perihilar tumor sampling if liver transplant is being considered due to theoretical seeding risk), and manage through a multidisciplinary tumor board with treatment stratified by tumor location: resect (anatomic hepatectomy for intrahepatic, hemihepatectomy with bile duct resection for perihilar, Whipple for distal) with adjuvant capecitabine (category 1, per BILCAP) when resectable. For unresectable or metastatic disease, first-line systemic therapy is gemcitabine plus cisplatin combined with a PD-L1/PD-1 checkpoint inhibitor, either durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966), both listed as category 1 preferred options by NCCN; comprehensive molecular/genomic profiling is recommended for all unresectable/metastatic candidates for systemic therapy to identify actionable targets (e.g., FGFR2 fusions, IDH1 mutations, HER2 amplification) for later-line therapy. Selected unresectable early-stage perihilar tumors may undergo neoadjuvant chemoradiation and liver transplant per the Mayo Clinic protocol at experienced centers, and jaundice or cholangitis is managed with biliary drainage (ERCP preferred over PTC).