Pancreatic cancer

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

All patients with suspected pancreatic cancer should be investigated and managed, without delay, in a framework of specialist teams to ensure prompt diagnosis and early treatment.

Treatment is based on the extent of the disease, and the only potentially curative treatment is operative resection.

Alternative treatments, for more extensive disease, include palliative surgery to relieve symptoms and endoscopic or percutaneous biliary stenting to relieve jaundice. Endoscopic stent placement is safer than percutaneous insertion and, thus, should be used where feasible.[42] Chemotherapy and radiotherapy may be used as palliative treatment as well as in the adjuvant setting with surgery.[42] Decisions about management and resectability should be made by a multidisciplinary team.

Owing to the poor prognosis, clinical trials are appropriate alternatives for treatment of patients with any stage of disease and should be considered before selecting palliative approaches.[43]

Resectable disease (stages 1 and 2)

All patients with resectable pancreatic cancer, should be referred to a high-volume specialist centre for surgical resection to increase resection rates and decrease hospital morbidity and mortality.[78][79]

Generally accepted criteria for resectable disease include: a tumour without evidence of involvement of the superior mesenteric artery (SMA), coeliac axis, or common hepatic artery (CHA); a patent superior mesenteric-portal venous confluence (or <180° contact without vein contour irregularity); and no evidence of distant metastases. However, approaches to patients with locoregional disease involvement differ between institutions. Criteria for borderline resectable tumours include superior mesenteric vein (SMV) or portal vein impingement, <180° tumour abutment on SMA, abutment or encasement of hepatic artery (if reconstructible), SMV occlusion of a short segment and reconstructible, or, in tumours in the tail of the pancreas, SMA or coeliac encasement <180°.[1][73]

Surgical management

Surgical resection is the preferred treatment in patients with resectable disease.[42] The type and extent of the surgery depend on 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][81] [ ] Following pancreatoduodenectomy, bowel continuity may be reconstructed using the antecolic or retrocolic route.[82] Surgery with extended lymphadenectomy and/or partial excision of the nerve plexus around the superior mesenteric artery and coeliac axis is associated with increases in adverse effects compared with standard resection, without conferring any survival benefit.[83][84] Extended resections, including the portal vein or total pancreatectomy, may be required in some patients in specialist centres, but do not increase survival when carried out routinely.[18] Left pancreatectomy (with splenectomy) is appropriate for localised tumours in the body or tail of the pancreas (rare).[85] One systematic review comparing open versus laparoscopic distal pancreatectomy suggests that the laparoscopic approach may be safe in selected patients with cancer.[86] [ ] Another systematic review and meta-analysis has also found laparoscopic distal pancreatectomy to be superior to open distal pancreatectomy, with the laparoscopic approach demonstrating higher R0 resection rate and shorter time to adjuvant therapy than the open approach.[87] Some other benefits of the laparoscopic approach include lesser blood loss, shorter hospital stay, and fewer complications.[88][89]
Staging laparoscopy to exclude metastases not detected with imaging may be appropriate before tumour resection for some patients, particularly those at higher risk of disseminated disease (very highly elevated CA 9-9, large primary tumour, large regional lymph nodes, excessive weight loss, extreme pain, or suspicious imaging findings).[1]
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]

Neoadjuvant therapy

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.[91]
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. However, no significant improvement in survival has been reported.[92][93][94]
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]

Adjuvant therapy

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 multicentre, 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 multicentre, 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]
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 the 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 4-8 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. One cohort study of 520 patients investigated the effect of adjuvant chemotherapy in patients with resectable, borderline resectable, or locally advanced pancreatic cancer who received neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was associated with improved overall survival (OS) in patients with node-positive disease, compared with no adjuvant chemotherapy (median OS 26 vs. 13 months). Adjuvant chemotherapy was not associated with improved survival in patients with node-negative disease.[106] Prospective randomised studies are needed.

Locally advanced unresectable disease (stage 3)

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]

Two studies compared pancreatic resection with systemic palliative treatment in patients with locally advanced disease.[107] Although the quality of evidence is low with a high risk of bias, carefully selected patients may benefit from surgical resection when sufficient expertise is available and patients are willing to accept the potentially increased morbidity associated with surgery.[107] [ ] Resection may be feasible following systemic treatment with chemotherapy or chemoradiation in patients with a good performance status.[1]

Patients with biliary obstruction should be offered palliative treatment with endoscopic stent insertion into the bile duct.[1] Patients with gastric outlet or duodenal obstruction may benefit from gastrojejunostomy with or without J-tube, or enteral stent placement.[1]

Palliative surgery or endoscopic stent insertion

Endoscopic insertion of a metal biliary stent is preferred over surgical approaches.[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]

Chemotherapy or chemoradiotherapy or stereotactic body radiotherapy or immunotherapy

After relief of biliary obstruction and, if required, gastric obstruction, systemic treatment with combination chemotherapy or chemoradiotherapy is given to control the tumour.
The FOLFIRINOX regimen (folinic acid, fluorouracil, irinotecan, and oxaliplatin) or modified-dose FOLFIRINOX, or gemcitabine and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) combination therapy, are preferred treatment options for patients with a good performance status.[1][108][109][110] [ ] One randomised, phase 2 study reported that treatment with nab-paclitaxel had similar efficacy and safety as treatment with nab-paclitaxel followed by FOLFIRINOX, in patients with locally advanced pancreatic cancer.[110] Alternative regimens include gemcitabine-based combination chemotherapy, with either a platinum analogue (oxaliplatin or cisplatin) or a fluoropyrimidine (fluorouracil or capecitabine).[3][111][112][113] [ ] 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, to those who responded to chemotherapy as consolidation therapy to further improve local control, or to those who are not candidates for induction chemotherapy.[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]

Metastatic disease (stage 4)

The main objective for patients with metastatic disease is palliation. These patients have a limited survival that is dependent on tumour burden and performance status at presentation.[78][119] Metastatic disease is characterised by evidence of distant metastasis to the liver, lung, or bone.[72][73]

Palliative surgery or endoscopic stent insertion

Endoscopic insertion of a metal biliary stent is preferred over surgical approaches.[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]

Chemotherapy or immunotherapy

The preferred option for patients with good performance status is the FOLFIRINOX regimen (folinic acid, fluorouracil, irinotecan, and oxaliplatin) or modified-dose FOLFIRINOX, or gemcitabine and nab-paclitaxel combination therapy.[1][42] [ ] [ ] In phase 3 trials, both regimens improved survival compared with gemcitabine alone: median overall survival was 11.1 months in the FOLFIRINOX group versus 6.8 months with gemcitabine, and 8.5 months in the nab-paclitaxel/gemcitabine group versus 6.7 months with gemcitabine.[108][109] FOLFIRINOX is recommended as a first-line treatment by 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 combination therapy of 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] [ ] Combination chemotherapy of fluorouracil plus gemcitabine is no more effective at 1 year than gemcitabine monotherapy in people with non-resectable pancreatic cancer. Despite the lack of a clear benefit in overall survival in clinical trials, these combination regimens are still 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.[1] 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 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 fluorouracil and liposomal irinotecan, which improved overall survival compared with single agent fluorouracil (6.1 vs. 4.2 months, respectively).[132]

Adjunct therapies

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 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]

Radiotherapy

Chemoradiotherapy is not used in the treatment of metastatic pancreatic cancer.
Palliative radiotherapy may be administered to relieve symptoms of obstruction, bleeding, or pain refractory to analgesia.[1]

Supportive therapies

All patients with pancreatic cancer should have access to palliative medicine specialists.[1][43] Goals of care and patient preferences should be discussed with all patients and their carers.

Pancreatic pain (abdominal and back pain) can be a troublesome symptom to control in locally advanced non-resectable disease and metastatic disease. Pain control should be commenced along 'the analgesic ladder', but opioids are often required to control the pain. WHO: cancer pain ladder for adults Opens in new window 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][139] [ ] However, NICE in the UK recommends against using splanchnicectomy in people with pancreatic cancer.[42][Evidence C]

Pancreatic enzyme supplements should be used in patients with unresectable pancreatic cancer and may be considered in patients with resectable pancreatic cancer 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][141]

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

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