Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

resectable (stages 1 and 2)

1st line – surgical resection

Plus – pancreatic enzyme replacement ± olanzapine

Consider – preoperative biliary stenting

Consider – neoadjuvant radiotherapy or chemoradiotherapy

Plus – adjuvant chemotherapy

Consider – adjuvant chemoradiotherapy

locally advanced unresectable (stage 3)

1st line – endoscopic stent insertion or palliative surgery

Plus – chemotherapy or chemoradiotherapy or stereotactic body radiotherapy or immunotherapy

Plus – pain management + pancreatic enzyme replacement ± olanzapine

metastatic (stage 4)

1st line – endoscopic stent insertion or palliative surgery

Plus – chemotherapy or immunotherapy

Plus – pain management + pancreatic enzyme replacement ± olanzapine

Consider – olaparib

Back
ACUTE
|
resectable (stages 1 and 2)
1st line – 

surgical resection

Surgical resection is the preferred treatment in patients with resectable disease.[42]​​​

The nature and extent of the surgery depends on the location and site of the tumour.

The most widely used procedures are the proximal pancreaticoduodenectomy with antrectomy (Kausch-Whipple procedure) or the pylorus-preserving pancreaticoduodenectomy (Traverso-Longmire procedure) for tumours in the head of the pancreas.

Pylorus-preserving pancreaticoduodenectomy may lead to similar quality of life and survival compared with Kausch-Whipple pancreaticoduodenectomy.[80][119] [ Cochrane Clinical Answers logo ]

Extended lymphadenectomy is associated with increases in adverse effects compared with standard lymphadenectomy, without conferring any survival benefit.[83]

Back
ACUTE
|
resectable (stages 1 and 2)
Plus – 

pancreatic enzyme replacement ± olanzapine

Treatment recommended for ALL patients in selected patient group

Pancreatic enzyme supplements may be considered to maintain weight and increase quality of life, together with attention to dietary intake and additional nutritional supplements.[18]​​[42]​​[140]​​

Patients should be offered nutritional evaluation by a registered dietitian, if available.[1]​​​

Patients with cancer-related anorexia may benefit from daily low-dose olanzapine.[1]

Primary options

pancreatin: dose depends on brand; consult specialist for guidance on dose

OR

olanzapine: 2.5 mg orally once daily

Back
ACUTE
|
resectable (stages 1 and 2)
Consider – 

preoperative biliary stenting

Additional treatment recommended for SOME patients in selected patient group

Patients with symptoms of cholangitis (or whose definitive surgery is delayed by >10 days due to logistical reasons) may require an internal biliary stent. If a stent is placed before surgery, a self-expanding metal stent should be placed endoscopically.[42]​​​

A temporary stent is also recommended in patients undergoing neoadjuvant induction therapy before surgery, in the setting of a clinical trial.

Routine stenting of jaundiced patients before resection is not recommended; there is no improvement in surgical outcome, and it may increase the risk of infective complications.[42]​​​[90]

Back
ACUTE
|
resectable (stages 1 and 2)
Consider – 

neoadjuvant radiotherapy or chemoradiotherapy

Additional treatment recommended for SOME patients in selected patient group

Neoadjuvant therapy (treatment given prior to surgery to reduce the size or extent of the tumour, in order to enhance chances of successful surgical removal of all tumour tissue) remains under investigation in pancreatic cancer.

Neoadjuvant combination chemotherapy or fluorouracil-based chemoradiotherapy can be offered to: patients in whom there is a clinical suspicion (but no radiological evidence) of metastatic disease; patients with borderline performance status who could improve with systemic therapy. In one randomised controlled trial of 246 patients with resectable or borderline resectable pancreatic cancer, neoadjuvant chemoradiotherapy, followed by surgery and adjuvant chemotherapy, did not confer a significant overall survival benefit compared with immediate surgery followed by adjuvant chemotherapy. It was, however, associated with significantly better disease-free survival.[95]

Technically unresectable tumours are rarely rendered resectable by neoadjuvant therapy.[96][97]

See local specialist protocol for regimen and dosing guidelines.

Back
ACUTE
|
resectable (stages 1 and 2)
|
completely resected
Plus – 

adjuvant chemotherapy

Treatment recommended for ALL patients in selected patient group

Adjuvant therapy is treatment given after surgery to minimise the risk of relapse due to occult disease. Adjuvant therapy has been shown to improve overall survival in both control and experimental groups in phase 3 clinical trials.[91]​ Patients with resected pancreatic cancer who did not receive neoadjuvant therapy should be offered 6 months of adjuvant chemotherapy.[96]

The American Society for Clinical Oncology (ASCO) recommends a modified combination of folinic acid, fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX).[96] This guidance is based on one multi-centre, open-label randomised trial of 493 patients with resected pancreatic ductal adenocarcinoma. The study found that adjuvant therapy with mFOLFIRINOX significantly improved survival compared with gemcitabine monotherapy (53.5 months vs. 35.5 months).[98] If this combination is contraindicated, ASCO recommends doublet therapy with gemcitabine and capecitabine, or monotherapy with gemcitabine, or fluorouracil plus folinic acid.[96] Folinic acid enhances the effect of fluorouracil and is, therefore, commonly administered with this drug. Both gemcitabine and fluorouracil inhibit thymidylate synthase, the enzyme required for the synthesis of the nucleotide thymidine.

Adjuvant doublet regimen of gemcitabine and capecitabine is recommended by the UK National Institute for Health and Care Excellence (NICE), in the absence of concerns for toxicity or tolerance.[42]​​ One multi-centre, open-label randomised trial of 732 patients with resected pancreatic ductal adenocarcinoma found that adjuvant therapy with capecitabine plus gemcitabine significantly improved survival compared with gemcitabine monotherapy (28.0 vs. 25.5 months).[99]​​

See local specialist protocol for dosing guidelines.

Primary options

mFOLFIRINOX

oxaliplatin

and

fluorouracil

and

irinotecan

and

folinic acid

OR

gemcitabine

and

capecitabine

OR

gemcitabine

OR

fluorouracil

and

folinic acid

Back
ACUTE
|
resectable (stages 1 and 2)
|
incompletely resected
Consider – 

adjuvant chemoradiotherapy

Additional treatment recommended for SOME patients in selected patient group

Adjuvant chemoradiotherapy remains controversial in incompletely resected cancers. Data from ESPAC-1 and meta-analysis suggest that chemoradiotherapy seems to prolong survival only in incompletely excised (R1 or R2 resection) cancers.[100]​​[101] When choice of treatment is chemoradiotherapy, fluorouracil-based chemoradiotherapy with additional systemic gemcitabine is recommended.[102][103][104]

Adjuvant chemotherapy or chemoradiotherapy should only be considered in patients who have adequately recovered from surgery.[42]​​ Treatment should ideally be initiated within 4 to 8 weeks of surgery. However, data relating to the timing of adjuvant chemotherapy suggest that post-operative treatment delays of up to 12 weeks do not adversely affect outcomes, provided 6 cycles of adjuvant chemotherapy are completed.[105]

The role of adjuvant chemotherapy in patients who received neoadjuvant chemotherapy is under investigation.

See local specialist protocol for dosing guidelines.

Primary options

fluorouracil

and

folinic acid

and

gemcitabine

Back
ACUTE
|
locally advanced unresectable (stage 3)
1st line – 

endoscopic stent insertion or palliative surgery

Locally advanced unresectable disease includes tumours involving nearby structures to an extent that renders them unresectable despite the absence of evidence of metastatic disease. Metastasis to a regional lymph node beyond the field of resection is considered unresectable.[1]​​​

Endoscopic palliation is preferred over surgical approaches.

Patients with biliary obstruction should be offered palliative treatment with endoscopic metal stent insertion into the bile duct.[1]​​ Percutaneous biliary drainage (with subsequent internalisation of the drain) or open-biliary enteric bypass may be considered in selected patients with a longer life expectancy.[1]​​ 

Palliative gastrojejunostomy may be appropriate for patients with gastric outlet or duodenal obstruction and good performance status. If a patient has poor performance status, enteral stenting or venting percutaneous endoscopic gastrostomy should be considered. Biliary drainage should be assured before enteral stent placement.[1]​​ 

Back
ACUTE
|
locally advanced unresectable (stage 3)
Plus – 

chemotherapy or chemoradiotherapy or stereotactic body radiotherapy or immunotherapy

Treatment recommended for ALL patients in selected patient group

After relief of biliary obstruction and, if required, gastric obstruction, systemic treatment with combination chemotherapy or chemoradiotherapy is given to control the tumour.

Patients with good performance status appear to benefit from the FOLFIRINOX regimen (folinic acid, fluorouracil, irinotecan, and oxaliplatin) or modified-dose FOLFIRINOX, or gemcitabine and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) combination therapy.[1]​​​[108]​​[109][110]​​ [ Cochrane Clinical Answers logo ] Other options include gemcitabine-based combination chemotherapy, with either a platinum analogue (oxaliplatin or cisplatin) or a fluoropyrimidine (fluorouracil or capecitabine).[3]​​[111]​​[112][113]​​[123]​​[124]​​[125]​​[126] [ Cochrane Clinical Answers logo ] The addition of erlotinib (an oral HER1/EGFR tyrosine kinase inhibitor) remains controversial. Initial studies suggested a very modest survival benefit (2 weeks), but no significant difference in overall survival was observed when patients with locally advanced pancreatic cancer were randomised to gemcitabine or gemcitabine plus erlotinib.[114][115][116]

The NALIRIFOX regimen (liposomal irinotecan, fluorouracil, folinic acid, oxaliplatin) is another tolerable option recommended by the National Comprehensive Cancer Network (NCCN) for patients with locally advanced cancer with good performance status.[1]​​[117] Although the NALIRIFOX regimen is advantageous over gemcitabine plus nab-paclitaxel, no distinct advantage over the FOLFIRINOX regimen has been noted.[1]​​

Patients with intermediate performance status may be treated with capecitabine, gemcitabine, or gemcitabine plus nab-paclitaxel.

Monotherapy with gemcitabine given weekly, 3 out of every 4 weeks, is recommended for the first-line treatment for patients with poor performance status or an unfavourable comorbidity profile. Other first-line treatment options include capecitabine or a continuous fluorouracil infusion.[1]

Chemoradiotherapy or a short course of stereotactic body radiotherapy (SBRT) can be offered to patients with good or intermediate performance status with local progression (without distant metastases) during or after chemotherapy, or to those who responded to chemotherapy as consolidation therapy to further improve local control.[1][118] Studies investigating the role of chemoradiotherapy or SBRT in the management of locally advanced pancreatic cancer are ongoing.

Other first-line regimens recommended by the NCCN that can be used under certain circumstances for patients with good or intermediate performance status include: dabrafenib plus trametinib for patients with BRAF V600E mutation; entrectinib, larotrectinib, or repotrectinib for patients with tumours that have a neurotrophic receptor tyrosine kinase gene fusion; pembrolizumab for patients who have tested positive for mismatch repair deficiency or microsatellite instability; and selpercatinib for patients who have tumours with RET gene fusion.[1]

See local specialist protocol for dosing guidelines.

Primary options

FOLFIRINOX

oxaliplatin

and

fluorouracil

and

irinotecan

and

folinic acid

OR

NALIRIFOX

irinotecan liposomal

and

fluorouracil

and

folinic acid

and

oxaliplatin

OR

gemcitabine

and

paclitaxel nanoparticle albumin-bound

OR

gemcitabine

OR

capecitabine

OR

gemcitabine

-- AND --

oxaliplatin

or

cisplatin

or

capecitabine

or

erlotinib

OR

gemcitabine

and

fluorouracil

and

folinic acid

OR

fluorouracil

and

folinic acid

Secondary options

dabrafenib

and

trametinib

OR

entrectinib

OR

larotrectinib

OR

repotrectinib

OR

pembrolizumab

OR

selpercatinib

Back
ACUTE
|
locally advanced unresectable (stage 3)
Plus – 

pain management + pancreatic enzyme replacement ± olanzapine

Treatment recommended for ALL patients in selected patient group

Pancreatic pain (abdominal and back pain) can be a troublesome symptom to control.

Pain control should be commenced along 'the analgesic ladder', but opioids are often required to control the pain.

Local pain-management protocols should be consulted for suggested analgesics. Dosing has to be titrated according to individual requirements and symptom relief versus adverse effect balances.

Additional options include using appropriate long-acting opioid analgesics, percutaneous (or endoscopic ultrasound-guided) coeliac block, or splanchnicectomy.[1][42]​​[135]​​​[136][137][138] [ Cochrane Clinical Answers logo ] However, NICE in the UK recommends against using splanchnicectomy in people with pancreatic cancer.[42]​​​[Evidence C]

Pancreatic enzyme supplements should be used to maintain weight and increase quality of life, together with attention to dietary intake and additional nutritional supplements.[18]​​[140]

Patients should be offered nutritional evaluation by a registered dietitian, if available.[1]​​​

Patients with cancer-related anorexia may benefit from daily low-dose olanzapine.[1]

Primary options

pancreatin: dose depends on brand; consult specialist for guidance on dose

OR

olanzapine: 2.5 mg orally once daily

Back
ACUTE
|
metastatic (stage 4)
1st line – 

endoscopic stent insertion or palliative surgery

Endoscopic palliation is preferred over surgical approaches.

Patients with biliary obstruction should be offered palliative treatment with endoscopic metal stent insertion into the bile duct.[1]​​ Percutaneous biliary drainage (with subsequent internalisation of the drain) or open-biliary enteric bypass may be considered in selected patients with a longer life expectancy.[1]​​​

Palliative gastrojejunostomy may be appropriate for patients with gastric outlet or duodenal obstruction and good performance status. If a patient has poor performance status, enteral stenting or venting percutaneous endoscopic gastrostomy should be considered. Biliary drainage should be assured before enteral stent placement.[1]​​​

Back
ACUTE
|
metastatic (stage 4)
Plus – 

chemotherapy or immunotherapy

Treatment recommended for ALL patients in selected patient group

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel), capecitabine, or erlotinib (an oral HER1/EGFR tyrosine kinase inhibitor) may be added to gemcitabine, with proactive dose and schedule adjustments to minimise adverse effects.[43]

The preferred regimen for patients with good performance status is FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) or modified-dose FOLFIRINOX, or gemcitabine and nab-paclitaxel combination therapy.[1]​​​[42]​​​ [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] ​​ In phase 3 trials, both regimens improved survival compared with gemcitabine alone.[108]​​[109] FOLFIRINOX is recommended as a first-line treatment by the UK National Institute for Health and Care Excellence (NICE) for people who are still active or only slightly restricted from physical activity (Eastern Cooperative Oncology Group performance status of 0-1).[42]​​ NICE recommends gemcitabine plus nab-paclitaxel for untreated metastatic adenocarcinoma of the pancreas in adults, restricted to use where other combination treatments are unsuitable and gemcitabine monotherapy would otherwise be given.[120]

The NALIRIFOX regimen (liposomal irinotecan, fluorouracil, folinic acid, oxaliplatin) is another tolerable option recommended by the National Comprehensive Cancer Network (NCCN) for patients with metastatic disease with good performance status.[1]​​[117] One randomised open-label phase 3 study (NAPOLI-3) has reported statistically significant improvement in overall survival and progression-free survival with NALIRIFOX compared with gemcitabine plus nab-paclitaxel in patients with metastatic pancreatic cancer.[121]​​[122]​ Although the NALIRIFOX regimen is advantageous over gemcitabine plus nab-paclitaxel, no distinct advantage over the FOLFIRINOX regimen has been noted.[1]​​

Other options include gemcitabine and either a platinum analogue (oxaliplatin or cisplatin), a fluoropyrimidine (fluorouracil or capecitabine), erlotinib, or a combination of oxaliplatin with fluorouracil and folinic acid.[111]​​[112][114][115][123]​​​[124]​​[125]​​[126] [ Cochrane Clinical Answers logo ] ​ Combination chemotherapy of fluorouracil plus gemcitabine is no more effective at 1 year than gemcitabine monotherapy in people with non-resectable pancreatic cancer. This combination regimen may be used in clinical practice because subsets of patients respond very well (and there is no biomarker to select these patients).[127][128][129]

Other first-line regimens recommended by the NCCN that can be used under certain circumstances for patients with good or intermediate performance status include: dabrafenib plus trametinib for patients with BRAF V600E mutation; entrectinib, larotrectinib, or repotrectinib for patients with tumours that have a neurotrophic receptor tyrosine kinase gene fusion; pembrolizumab for patients who have tested positive for mismatch repair deficiency or microsatellite instability; and selpercatinib for patients who have tumours with RET gene fusion. Except for selpercatinib, all other options can be considered in patients with poor performance status.[1]​​​

Patients with intermediate performance status may be treated with capecitabine, gemcitabine, or gemcitabine plus nab-paclitaxel.

Monotherapy with gemcitabine given weekly, 3 out of every 4 weeks, is recommended for palliative treatment for patients with poor performance status or an unfavourable comorbidity profile.[1][42]​​[43][130]​ Other first-line treatment options include capecitabine or a continuous fluorouracil infusion.[1]

Patients who received first-line gemcitabine-based chemotherapy alone and continue to have a good performance status may benefit from second-line combination therapy of oxaliplatin, fluorouracil, and folinic acid.[42]​​​[131] NICE suggests gemcitabine-based chemotherapy as a second-line treatment for people whose cancer has progressed after first-line FOLFIRINOX.[42]​​ An alternative option is the combination of liposomal irinotecan and fluorouracil, which improved overall survival compared with single agent fluorouracil (6.1 versus 4.2 months, respectively).[132]

See local specialist protocol for dosing guidelines.

Primary options

gemcitabine

and

paclitaxel nanoparticle albumin-bound

OR

FOLFIRINOX

oxaliplatin

and

fluorouracil

and

irinotecan

and

folinic acid

OR

NALIRIFOX

irinotecan liposomal

and

fluorouracil

and

folinic acid

and

oxaliplatin

OR

gemcitabine

OR

capecitabine

OR

fluorouracil

and

folinic acid

OR

gemcitabine

-- AND --

oxaliplatin

or

cisplatin

or

capecitabine

or

erlotinib

OR

gemcitabine

and

fluorouracil

and

folinic acid

OR

oxaliplatin

and

fluorouracil

and

folinic acid

OR

fluorouracil

and

irinotecan liposomal

Secondary options

dabrafenib

and

trametinib

OR

entrectinib

OR

larotrectinib

OR

repotrectinib

OR

pembrolizumab

OR

selpercatinib

Back
ACUTE
|
metastatic (stage 4)
Plus – 

pain management + pancreatic enzyme replacement ± olanzapine

Treatment recommended for ALL patients in selected patient group

Pancreatic pain (abdominal and back pain) can be a troublesome symptom to control.

Pain control should be commenced along 'the analgesic ladder', but opioids are often required to control the pain.

Local pain-management protocols should be consulted for suggested analgesics. Dosing has to be titrated according to individual requirements and symptom relief versus adverse effect balances.

Additional options include using appropriate long-acting opioid analgesics, percutaneous (or endoscopic ultrasound-guided) coeliac block, or splanchnicectomy.[1]​​[42]​​[135]​​​​​​[136][137][138] [ Cochrane Clinical Answers logo ] However, NICE in the UK recommends against using splanchnicectomy in people with pancreatic cancer.[42]​​​[Evidence C]

Palliative radiotherapy may be administered to relieve symptoms of obstruction, bleeding, or pain refractory to analgesia.[1]​​ 

Pancreatic enzyme supplements should be used to maintain weight and increase quality of life, together with attention to dietary intake and additional nutritional supplements.[18]​​[140]​​

Patients should be offered nutritional evaluation by a registered dietitian, if available.[1]​​ 

Patients with cancer-related anorexia may benefit from daily low-dose olanzapine.[1]

Primary options

pancreatin: dose depends on brand; consult specialist for guidance on dose

OR

olanzapine: 2.5 mg orally once daily

Back
ACUTE
|
metastatic (stage 4)
Consider – 

olaparib

Additional treatment recommended for SOME patients in selected patient group

Olaparib, a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, is approved in the US as a maintenance treatment for use in adults with metastatic pancreatic adenocarcinoma and confirmed or suspected deleterious BRCA1 or BRCA2 germline mutations who have not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. One phase 3 trial showed that in patients whose disease had not progressed during first-line platinum-based chemotherapy, maintenance olaparib significantly increased progression-free survival compared with placebo (7.4 months compared to 3.8 months), in patients with a germline BRCA1 or BRCA2 mutation.[133] No significant benefit with respect to overall survival has been observed.[134] There was no difference in overall mortality between the olaparib and placebo groups at an interim data analysis. Adverse events were more common in the olaparib group than the placebo group and included fatigue, nausea, anaemia, abdominal pain, diarrhoea, decreased appetite, constipation, vomiting, back pain, and arthralgia.[133]

Platinum-sensitive patients with a germline BRCA1 or BRCA2 mutation may continue treatment with chemotherapy or proceed to maintenance therapy with olaparib. The patient and clinician should make a shared decision, considering response to chemotherapy, toxicities, patient preference, clinical evidence, and cost.[43]

See local specialist protocol for dosing guidelines.

Primary options

olaparib

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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