Decision support only; not a substitute for the hepatopancreatobiliary (HPB) multidisciplinary team or current prescribing protocols. Scope: pancreatic ductal adenocarcinoma (PDAC), with a brief neuroendocrine comparison. Verify all doses and indication-specific PBS access.
1 Treatment pathway — resectability comes before regimen
An apparently small primary can still be inoperable. Establish distant spread, vessel involvement and fitness together; a regional lymph node or venous contact alone does not settle the surgical decision. [ESMO]
Suspected pancreatic malignancy → pancreas-protocol contrast CT + chest staging → specialist HPB MDT
Assess ECOG, bilirubin, nutrition and patient goals in parallel. Obtain tissue before systemic or neoadjuvant therapy; immediate resection of a characteristic operable lesion may proceed without biopsy after MDT review. [Australian OCP] [BC Cancer]
ResectablePotentially curative intent
No metastases; anatomy permits complete resection; medically fit. Assess arterial contact and venous reconstructibility.
Surgery + adjuvant chemotherapy. Neoadjuvant treatment for selected high-risk cases / trials, rather than an automatic rule for every resectable tumour.
Borderline resectableMargin risk
Limited vessel involvement with possible reconstruction; high risk of an involved margin if surgery is performed first.
Biopsy → induction systemic treatment → restage → consider resection. Regimen and any radiotherapy chosen by the specialist MDT.
Locally advancedUnresectable; M0
Extensive arterial involvement or unreconstructible venous disease, without distant metastases.
Systemic treatment if fit; reassess for conversion surgery. Selected local radiotherapy for control / symptoms; no routine survival benefit assumed.
MetastaticM1
Distant disease; treatment choice depends on function, organ reserve, molecular findings and preferences.
Systemic therapy ± matched treatment; early palliative care. Poor fitness despite correction of reversible problems → prioritise symptom-directed care.
Resectability definitions vary between systems and tumour sites. Vessel contact angles are a radiology/HPB assessment, not a bedside substitute for MDT review. TNM stage and resectability describe different things.
[ESMO] [NCI PDQ]2 Medical sciences — connect biology to presentation
- PrecursorPancreatic intraepithelial neoplasia (PanIN); some arise from mucinous lesions such as IPMN / mucinous cystic neoplasm.
- DriversKRAS activation; loss of CDKN2A/p16, TP53, SMAD4. KRAS drives signalling; CDKN2A restrains the cell cycle; TP53 mediates damage responses; SMAD4 transduces TGF-β signals.
- HistologyInfiltrating malignant glands in dense desmoplastic stroma. Perineural invasion helps explain pain. [IARC]
- SpreadLocal vessels / nerves, regional nodes; liver, peritoneum and lungs are important metastatic sites. [PDQ]
Risk & inherited susceptibility [eviQ 3906]
- AcquiredSmoking, obesity, chronic pancreatitis, increasing age; diabetes can be a risk factor and a presentation. [OCP]
- DNA repairBRCA2, BRCA1, PALB2, ATM; BRCA/PALB2-related homologous-recombination defects may favour platinum sensitivity.
- SyndromesSTK11 → Peutz–Jeghers; CDKN2A → melanoma–pancreatic cancer predisposition; mismatch-repair genes → Lynch syndrome.
- Testing2026 eviQ panel-testing target includes pancreatobiliary cancer at any age, regardless of family history. Counsel about implications for relatives and uncertain variants.
- HeadDistal bile-duct obstruction → jaundice, pruritus, dark urine, pale stools. A painless palpable gallbladder suggests malignant obstruction, but is not diagnostic.
- Body/tailEpigastric / back pain and weight loss; jaundice may be absent. Do not wait for the classic painless-jaundice presentation.
- CluesNew or worsening diabetes with weight loss; unexplained pancreatitis; steatorrhoea; unprovoked VTE. Trousseau syndrome = malignancy-associated thrombosis, classically migratory thrombophlebitis.
3 Workup — answer diagnosis, extent and treatment readiness
| Test / decision | What it answers | Interpretation / trap |
|---|
Pancreas-protocol contrast CT
[NICE] [Cancer Australia] | Primary lesion, pancreatic/biliary dilatation, local arteries and portal/SMV involvement; abdominal metastases. Add chest staging. | In stable obstructive jaundice, obtain staging CT before drainage where possible. Cholangitis/sepsis requires urgent treatment and drainage, not delay for ideal staging. |
EUS-guided tissue
[BC Cancer] [OCP] | Clarifies a small / equivocal lesion; obtains tissue for histology and molecular testing. Consider an accessible metastatic site where appropriate. | Required before chemotherapy; not universally required before upfront resection. Negative / inadequate sampling does not exclude malignancy when imaging remains suspicious. |
MRI/MRCP; selective extra staging
[Cancer Australia] [ESMO] | MRI for indeterminate liver lesions, ductal/cystic anatomy or CT uncertainty. MDT may use PET-CT or staging laparoscopy in selected cases. | These complement rather than replace good-quality contrast CT. Do not order every modality reflexively. |
Baseline bloods & fitness
[eviQ] | FBC, renal function/electrolytes, bilirubin/LFTs, albumin, glucose/HbA1c; nutritional loss, ECOG, comorbidity and baseline neuropathy. | Obstruction, infection and malnutrition may make someone temporarily unfit. Reassess after treating reversible causes. |
CA19-9
[Alfred / laboratory guidance] | Prognostic / response adjunct when the tumour secretes it; interpret alongside imaging and clinical change. | Not a screening or stand-alone diagnostic test. Benign biliary obstruction/inflammation can raise it; Lewis-antigen-negative people may not express it. A normal result does not exclude PDAC. Recheck after obstruction resolves if initially confounded. |
- TT1 ≤2 cm; T2 >2–4 cm; T3 >4 cm; T4 involves coeliac axis, SMA and/or common hepatic artery, regardless of size.
- N / MN1: 1–3 regional nodes; N2: ≥4. Any distant metastasis = M1 / stage IV.
Do not mistake the mimic for the diagnosis
Distinguish PDAC from focal chronic / autoimmune pancreatitis, ampullary or distal bile-duct cancer, and pancreatic NET. If diagnostic uncertainty would alter treatment, resolve it with specialist imaging and tissue; an isolated CA19-9 or IgG4 result cannot settle the question. [BC Cancer] [NICE]
4 Localised disease — surgery, sequencing and drainage
Potentially curative treatment [ESMO] [ASCO]
- OperationHead/uncinate: pancreaticoduodenectomy (Whipple). Body/tail: distal pancreatectomy, often with splenectomy. High-volume HPB centre; assess operative fitness.
- AdjuvantAfter upfront resection, aim for 6 months of chemotherapy when recovery permits. Fit: modified FOLFIRINOX PRODIGE 24. Less fit: gemcitabine–capecitabine or monotherapy according to tolerance.
- BorderlineInduction treatment before surgery; restage for distant progression, biology and technical resectability. Persistent perivascular soft tissue after treatment can be fibrosis rather than viable tumour.
- After surgeryWatch pancreatic leak/infection, delayed gastric emptying, exocrine insufficiency and diabetes. Address splenectomy vaccination/infection precautions if applicable. [Surgical complications]
Two common overstatements
- Drain first?Routine preoperative drainage is not required for a fit person proceeding promptly to resection. Drain when cholangitis, problematic symptoms, delayed surgery or neoadjuvant treatment requires it; specialist endoscopic stenting, usually a self-expanding metal stent when indicated. [NICE]
- Neo for all?NORPACT-1 did not show survival benefit for short-course neoadjuvant FOLFIRINOX in clearly resectable head cancers; delivery was challenging. Do not extrapolate the borderline-resectable strategy to every operable case. [Trial]
5 Systemic therapy — know selection, mechanism and toxicity
Fit metastatic disease: FOLFIRINOX / a locally modified regimen, NALIRIFOX, or gemcitabine–nab-paclitaxel are options. ESMO’s triplet recommendation assumes ECOG 0–1, bilirubin <1.5×ULN and no major comorbidity. Selected ECOG 2 patients may receive a gemcitabine-based option; ECOG 3–4 usually favours symptom-directed care. [ESMO 2025] [Pan-Asian adaptation]
| Drug / regimen | Medical science | Clinical application / toxicity |
|---|
FOLFIRINOX
[eviQ 1512 / 3521] | Folinic acid (leucovorin), fluorouracil, irinotecan, oxaliplatin. | Effective but toxic. Adjuvant and metastatic “modified” schedules differ: do not interchange protocol doses. Use the current setting-specific eviQ order set. |
5-FU / capecitabine
[NCI pharmacology] [eviQ DPD] | Fluoropyrimidines; 5-FU inhibits thymidylate synthase and affects RNA. Capecitabine is a 5-FU prodrug; folinate enhances 5-FU activity. | Diarrhoea, mucositis, cytopenias; capecitabine hand–foot syndrome; possible coronary vasospasm. DPD deficiency → severe early toxicity. Arrange pretreatment testing under local policy; a negative targeted DPYD panel does not remove all risk. |
Irinotecan
[NCI] [eviQ] | Prodrug → SN-38; topoisomerase I inhibition. | Acute cholinergic effects; delayed diarrhoea and neutropenia. Reduced UGT1A1 function increases toxicity risk. Assess diarrhoea severity, hydration and infection; follow the regimen’s management protocol. |
Oxaliplatin
[NCI] [eviQ] | Platinum–DNA crosslinks → impaired replication/transcription. | Cold-triggered acute sensory symptoms; cumulative peripheral neuropathy, cytopenias and infusion reactions. |
Gemcitabine–nab-paclitaxel
[eviQ 1375] [Pharmacology] | Gemcitabine: nucleoside analogue impairing DNA synthesis. Nab-paclitaxel: albumin-bound taxane stabilising microtubules. | Myelosuppression/infection, neuropathy, fatigue. Gemcitabine can rarely cause pneumonitis or thrombotic microangiopathy. A biliary stent plus fever deserves urgent assessment. |
NALIRIFOX
[ESMO] [NAPOLI 3] | Liposomal irinotecan + oxaliplatin + 5-FU / folinate. | First-line metastatic option in fit patients. Liposomal and conventional irinotecan are not dose-interchangeable. Diarrhoea is prominent; funding must be checked locally. |
At progression: reassess fitness/goals and molecular/trial options (§6). A gemcitabine-based regimen may follow FOLFIRINOX/NALIRIFOX in suitable patients. Liposomal irinotecan + 5-FU/folinate has post-gemcitabine evidence from NAPOLI-1 (Lancet 2016), but eviQ 3387 is now marked superseded; check the current specialist pathway rather than treating an archived protocol as first choice.
Fever, severe early diarrhoea/mucositis, chest pain or new dyspnoea during treatment → urgent oncology assessment. Fluoropyrimidine overdose/overexposure may require uridine triacetate; greatest established benefit when started within 96 hours.
[eviQ]6 Molecular treatment & Australian access
Test early enough to use the result
- GermlineOffer a genetics/testing pathway to all PDAC patients; a negative family history is not a reason to omit it. Germline testing and tumour profiling answer different questions. [eviQ 3906, 2026]
- BRCA1/2Metastatic germline BRCA1/2-mutated PDAC, no progression after ≥16 weeks first-line platinum → consider maintenance olaparib, a PARP inhibitor. Do not extend the POLO eligibility rule automatically to ATM or PALB2. [Australian PI]
- TumourAssess dMMR/MSI-H and actionable alterations such as NTRK fusions when results could guide further therapy. Matched immunotherapy/targeted therapy applies to small molecular subsets, not unselected PDAC. [ASCO]
- POLO limitLonger progression-free survival versus placebo; no statistically significant overall-survival benefit in final analysis. Selected platinum-sensitive population, not first-line monotherapy. [POLO]
2026 update & the funding distinction
- RAS updateDaraxonrasib, a multi-selective RAS(ON) inhibitor: positive phase III RASolute 302 after prior treatment. ESMO issued an August 2026 update covering second-line use. [Trial] [ESMO 2026]
- Local accessUS FDA approval is verified; Australian TGA registration/PBS access was not confirmed in this review. Seek oncology/pharmacy advice on trials or access pathways before assuming availability.
- PBSeviQ lists gemcitabine on the general schedule and nab-paclitaxel as authority-listed for the metastatic regimen. Check the current indication and line-of-therapy restriction. Olaparib’s Australian pancreatic indication is confirmed; its pancreatic PBS restriction and NALIRIFOX funding were not verified here. [eviQ] [PI] [PBS]
7 Registrar care — complications and symptoms
Problems needing prompt action
- CholangitisFever/rigors, jaundice or sepsis, especially with a stent → cultures, resuscitation, local IV antibiotic protocol and urgent biliary source control. [Australian sepsis standard]
- ObstructionPersistent vomiting / early satiety → consider duodenal obstruction; fluids, electrolyte correction and urgent specialist review for endoscopic or surgical palliation. [NICE]
- NeutropeniaFever or clinical deterioration after chemotherapy → treat through the local neutropenic-sepsis pathway immediately. [eviQ]
Nutrition & pancreatic function
- PEISteatorrhoea, bloating, weight loss or post-resection maldigestion → pancreatic enzyme replacement (PERT) and specialist dietitian. Do not attribute all weight loss to irreversible cachexia.
- PERTA practical adult start: 40,000–50,000 lipase units/meal, about half with snacks; take during food, titrate to intake and symptoms. Severe PDAC-related insufficiency often needs more. Confirm product strength and local advice. [UEG 2025 / AGA]
- MonitorWeight/intake, stool response, fat-soluble vitamins and glycaemia. Diabetes may require insulin; anticipate hypoglycaemia with poor intake. [PEI guidance] [Postoperative care]
VTE, pain and planning
- VTEAdvanced pancreatic cancer on systemic therapy is high risk. Consider primary prophylaxis with LMWH or an appropriate DOAC when bleeding risk is low; review platelets, renal function, interactions and procedures. Not automatic for every patient. [ITAC]
- PainAnalgesia with constipation prevention; consider neurolytic coeliac plexus intervention for uncontrolled pain / opioid toxicity. [NICE]
- PalliationIntroduce early alongside oncology. Discuss goals, psychosocial/carer support, symptom contacts and advance care planning. Revisit whether treatment is helping the person. [OCP]
8 Evidence worth recognising — setting matters
| Trial | Population / comparison | Main finding & exam interpretation |
|---|
PRODIGE 24
JAMA Oncology 2022, 5-year follow-up | 493 selected postoperative patients; adjuvant mFOLFIRINOX vs gemcitabine. | Median OS 53.5 vs 35.5 months; HR 0.68. Supports adjuvant mFOLFIRINOX in fit patients; cannot generalise this survival to all newly diagnosed PDAC. |
PRODIGE 4 / ACCORD 11
NEJM 2011 | 342 patients; metastatic, ECOG 0–1; FOLFIRINOX vs gemcitabine. | Median OS 11.1 vs 6.8 months; HR 0.57. More toxicity; regimen selection requires fitness. |
MPACT
NEJM 2013 | 861 patients; metastatic; gemcitabine–nab-paclitaxel vs gemcitabine. | Median OS 8.5 vs 6.7 months; HR 0.72. Increased neuropathy and myelosuppression. |
NAPOLI 3
Lancet 2023 | 770 untreated metastatic patients; NALIRIFOX vs gemcitabine–nab-paclitaxel. | Median OS 11.1 vs 9.2 months; HR 0.83. Not a comparison with conventional FOLFIRINOX; avoid cross-trial ranking. |
POLO
JCO 2022, final OS | 154 germline BRCA1/2-mutated metastatic patients without progression after ≥16 weeks platinum; olaparib maintenance vs placebo. | Median PFS 7.4 vs 3.8 months; HR 0.53. Final OS difference not significant. Learn maintenance + selected genotype + platinum sensitivity. |
NORPACT-1
Lancet Gastroenterology & Hepatology 2024 | Randomised phase II, resectable head PDAC; neoadjuvant FOLFIRINOX vs upfront surgery. | No survival benefit from the neoadjuvant strategy; implementation limitations. Does not negate induction treatment for borderline-resectable disease. |
RASolute 302
NEJM 2026 | 500 previously treated metastatic patients; daraxonrasib vs investigator-choice chemotherapy. | Overall-population median OS 13.2 vs 6.7 months; HR 0.40. Major second-line evidence; Australian access must be established separately. [ESMO/FDA] |
OS = overall survival; PFS = progression-free survival; HR = hazard ratio. Medians describe trial populations, not an individual’s expected survival. Do not compare medians across postoperative and metastatic trials.
9 Screening & the pancreatic NET distinction
Screening is not symptom investigation
- PopulationNo routine screening for average-risk asymptomatic adults. CA19-9 and new blood-based tests do not substitute for an established screening programme. [OCP]
- High riskFamilial kindreds / selected pathogenic-variant carriers → familial cancer service. MRI/MRCP and/or EUS surveillance in experienced programmes; eligibility and starting age are gene/family-specific, not “screen everyone with one affected relative”. [eviQ 1517 + gene-specific guidance]
Pancreatic neuroendocrine tumour ≠ PDAC [NCI / ENETS]
- BiologyEndocrine lineage; grade/differentiation and Ki-67 matter. Most are non-functioning; hormone excess can dominate a functioning tumour’s presentation.
- SyndromesInsulinoma → endogenous hyperinsulinaemic hypoglycaemia; gastrinoma → acid hypersecretion/ulcers/diarrhoea; glucagonoma → diabetes + necrolytic migratory erythema; VIPoma → watery diarrhoea + hypokalaemia.
- AssociationMEN1: parathyroid, pituitary and pancreatic/duodenal NETs. Do not apply PDAC chemotherapy or prognosis automatically to a well-differentiated NET.
Primary sources & curriculum.
RACP 2025 Adult Internal Medicine Knowledge Guides supplied by the user: Medical Oncology (pancreatic cancer explicitly listed as a key condition; pp 1–2, 4–6) and Gastroenterology (GI malignancy, jaundice/biliary obstruction, pancreatic science and investigations; pp 1–5). This sheet’s Medical Sciences/Clinical Applications emphasis is an educational mapping, not an official RACP question forecast.
Australian Optimal Care Pathway, 2nd ed 2021; amended June 2026 — presentation, referral, MDT and supportive care. A care pathway, not a chemotherapy prescribing guideline.
Cancer Australia: diagnosis, staging & treatment planning.
ESMO pancreatic CPG, 2023;
Pan-Asian adaptation, ESMO Open 2025;
ESMO metastatic express update, 2025.
NICE NG85 (2018), current recommendations — diagnostic/drainage/supportive principles, not the primary source for current chemotherapy.
BC Cancer: diagnostic & staging workup.
ASCO potentially curable PDAC update, 2019.
NCI PDQ professional summary — staging / disease framework.
eviQ 3906, v6, June 2026;
eviQ 1517: familial risk management.
eviQ 1512 metastatic FOLFIRINOX / 3521 adjuvant FOLFIRINOX;
1375 gemcitabine–nab-paclitaxel;
1744 DPD deficiency.
Alfred Pathology: CA19-9; NHS laboratory interpretation.
Molecular pathogenesis review (2016);
IARC World Cancer Report: pancreas.
NCI symptoms; Penn clinical signs; CRUK symptoms.
CRUK postoperative complications.
NCI drug dictionary: 5-FU, irinotecan, oxaliplatin, paclitaxel; Cancer Care Ontario gemcitabine monograph.
ASCO metastatic update, 2020 — biomarker testing.
Australian olaparib product information.
ESMO daraxonrasib update, 19 August 2026; ESMO current announcement; FDA approval, 26 August 2026.
UEG-led PEI guideline, 2025; AGA PEI advice, 2023.
ITAC VTE guideline, 2022.
NCI pancreatic NET PDQ; NCI NET overview; ENETS nonfunctioning pancreatic NET guidance, 2023.
RCPA irinotecan pharmacogenomics guidance, 2025 — UGT1A1/SN-38.
Key trials. Primary trial citations and effect sizes appear in §8. No head-to-head superiority of NALIRIFOX over conventional FOLFIRINOX is claimed.
Caveats. Checked 1 Nov 2026. Some publisher full texts were inaccessible; ESMO 2026 inclusion is limited to verified publication, society summary and primary trial/regulatory findings; its full recommendation wording/class is not reproduced. Indication-specific PBS criteria for olaparib and NALIRIFOX, and Australian daraxonrasib registration/funding, were not established. eTG subscriber dosing was not accessed. No cytotoxic prescribing doses are provided; use current eviQ protocols. Surveillance eligibility is gene/family-specific.