INTRODUCTION — Approximately 55,440 people develop cancer of the exocrine pancreas each year in the United States, and almost all are expected to die from the disease . Pancreatic cancer has become the third leading cause of cancer death in the United States, with the lowest five-year survival rates of any solid tumor (11 percent) . The majority of tumors (85 percent) are adenocarcinomas arising from the ductal epithelium. (See "Pathology of exocrine pancreatic neoplasms".)
Surgical resection offers the only chance of cure. However, only 15 to 20 percent of patients have resectable disease at initial diagnosis; the majority have either locally advanced or metastatic cancer. The median survival for patients with untreated, locally advanced, unresectable pancreatic cancer is 8 to 12 months and only three to six months for those with metastatic disease at presentation. For patients with locally advanced and metastatic disease, systemic chemotherapy can improve survival. In the current modern era of chemotherapy, we have achieved the best outcomes to date with the FOLFIRINOX (fluorouracil plus leucovorin, irinotecan, and oxaliplatin) regimen, demonstrating an 11.1-month median survival . Survival may be longer in patients who retain a performance status that permits administration of second-line chemotherapy. At least one series reported a median survival of 18 months in fit patients receiving both the FOLFIRINOX and gemcitabine/nanoparticle albumin bound paclitaxel (nabpaclitaxel) regimens . (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)
While patients receiving chemotherapy generally report better overall quality of life, extended survival with chemotherapy does not always correspond to reduced symptom burden. Because of the anatomic location of the pancreas in the central abdomen at the root of the mesentery, most patients suffer from a significant symptom burden, and they frequently need medical attention and hospitalization for symptom management . Typical patients will require numerous interventions targeting pain, anorexia and weight loss, depression and anxiety, biliary obstruction, gastric outlet obstruction, ascites, and venous thromboembolism.
This topic review will summarize an approach to these issues. A discussion on antitumor therapies for management of patients with localized pancreatic cancer (surgery, adjuvant and neoadjuvant therapy) and locally advanced pancreatic cancer (who may be eligible for chemotherapy and radiation-based therapy), and chemotherapy for advanced disease are presented separately. (See "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis" and "Treatment for potentially resectable exocrine pancreatic cancer" and "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer" and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)
IMPORTANCE OF PALLIATIVE CARE — All patients with newly diagnosed pancreatic cancer should have a full assessment of symptom burden, psychological status, and social supports as early as possible [6-9]. Many patients with locally advanced or metastatic disease will benefit from formal palliative care consultation and services. Early referral and initiation of palliative care services improve clinical and quality of care outcomes.
Palliative care is an interdisciplinary specialty that is focused on preventing and relieving suffering, and supporting the best possible quality of life for patients and their families facing serious illness, such as pancreatic cancer. Clinicians who are specialty trained in palliative care provide in-depth pain and symptom management, communication regarding goals of care, and coordinated care across settings and over time. Palliative care aims to relieve suffering in all stages of disease and can be provided at the same time as curative or life-prolonging treatments (figure 1). (See "Benefits, services, and models of subspecialty palliative care", section on 'Palliative care services'.)
When initiated early in the disease course, palliative care has been shown to improve clinical, quality of care, and survival outcomes. Furthermore, multiple studies have shown that palliative care services improve patients' symptoms, allow patients to avoid hospitalization and to remain safely and adequately cared for at home, lead to better patient and family satisfaction, and significantly reduce prolonged grief and posttraumatic stress disorder among bereaved family members. Palliative care also lowers costs and reduces rates of unnecessary hospitalizations, diagnostic and treatment interventions, and nonbeneficial intensive care when patients are near the end of life. (See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)
The impact of palliative care on reducing aggressiveness of end of life care in patients with advanced pancreatic cancer was shown in a retrospective population-based cohort study of administrative data on 5381 patients diagnosed between 2005 and 2010 in Ontario, Canada . Measures of aggressive end of life care included chemotherapy within 14 days of death and at least one intensive care unit (ICU) admission, more than one emergency department (ED) visit, and more than one hospitalization within 30 days of death. Of the 5381 patients (median survival 75 days), 2816 (52 percent) had received a palliative care consultation. Palliative care consultation was associated with a significant reduction in use of chemotherapy near death (odds ratio [OR] 0.34, 95% CI 0.25-0.46) and a significantly lower risk of ICU admission (OR 0.12, 95% CI 0.08-0.18), multiple ED visits (OR 0.19, 95% CI 0.16-0.23), and multiple hospitalizations near death (OR 0.24, 95% CI 0.19-0.31).
MANAGEMENT OF SPECIFIC SYMPTOMS — All patients with locally advanced and metastatic pancreatic cancer should be offered aggressive treatment of pain and other symptoms related to the cancer, and/or cancer-directed therapy [7,8].
Pain — Pain can be a significant feature of advanced pancreatic cancer, and all patients should have the level of pain and degree of pain relief from analgesics addressed at every clinic visit. Pain is often the major presenting symptom of the disease. Patients describe a gnawing midepigastric pain, which radiates bilaterally under the ribs and into the mid-back, owing to the proximity of pancreatic tumors to the celiac plexus.
Analgesics — The mainstay of pain management is typically opioid medication, and palliation of pain can often be successfully achieved by opioid analgesics alone. For patients with persistent nausea and vomiting, for whom taking oral medications is difficult, pain control may be achieved using transdermal patches, provided they have sufficient adipose tissue for transdermal absorption. Because of the proximity of the tumor to the celiac plexus, the pain may be neuropathic in nature, warranting consideration of adjuvant medications such as gabapentin, pregabalin, nortriptyline, or duloxetine. (See "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Patients with neuropathic pain'.)
Sympathetic neurolytic blocks — Pain can also be managed with local procedures targeting the celiac plexus or splanchnic nerves. Many studies have demonstrated the efficacy of both techniques for pain from pancreatic cancer [11-27].
●Celiac plexus neurolysis - The celiac plexus is a dense network of nerves that innervates the upper abdominal organs. It lies anterior to the aorta at the level of the first lumbar vertebra. Pain may be relieved by inhibiting synaptic pathways within the plexus without nerve destruction (ie, celiac plexus block using a bolus injection of local anesthetic) or chemical destruction of the pathways and ganglia using dehydrated (absolute [95%]) alcohol, a procedure termed celiac plexus neurolysis [CPN].
CPN can be performed percutaneously, surgically, or under endosonographic guidance. In the past, it has been most commonly performed intraoperatively or percutaneously with fluoroscopic or computed tomographic guidance. More recent experience has demonstrated that it can also be safely performed during endoscopic ultrasonography (EUS). (See "Cancer pain management: Interventional therapies", section on 'Neurolytic blocks'.)
CPN appears to be more effective than pharmacologic therapy alone, both for immediate and long-term relief of pain, with reported success rates (typically defined as "less pain") ranging from 50 to 80 percent in multiple studies [11-16]. In one randomized trial, early referral for CPN provided better pain control; less opioid consumption; fewer opioid-related complications, such as constipation and sedation; and a better quality of life as compared with waiting until after failure to obtain pain relief with strong opioids . The EUS approach to CPN, as well as indications for CPN, are discussed elsewhere. (See "Endoscopic ultrasound-guided celiac plexus interventions for pain related to pancreatic disease".)
●Splanchnic nerve block – The paired splanchnic nerves contain the sympathetic fibers that originate from T5 to L2 and coalesce in the celiac plexus; they pierce the crura of the diaphragm at the T11 and T12 levels prior to joining the celiac ganglion. Chemical splanchnicectomy can be accomplished intraoperatively [18,24], or through percutaneous ultrasound or CT-guided placement of a neurolytic solution (typically absolute [95%] alcohol) posterior to the aorta over the anterolateral surface of the 12th thoracic vertebra.
The best data on the efficacy of splanchnic nerve neurolysis come from a contemporary randomized trial in which 96 patients with unresectable stage III or IV pancreatic cancer presenting with moderate to severe cancer-related pain were randomly assigned to splanchnic nerve block versus saline injection placebo control; management of systemic analgesic therapy in both groups used a protocol common to all centers . The primary outcomes was pain relief, as measured with a visual analogue scale (VAS) from 1 to 10.
Pain relief was greatest with neurolysis for the first three months (largest at the first month, but the effect size was small, mean difference in VAS 0.7 [95% CI 0.3-1.0]), and opioid consumption was also lower in this group for the first five months (largest difference at one month, mean difference in oral morphine milligram equivalents, 95.8 [95% CI 67.4 to 124.1]). No differences in quality of life were observed, but patients undergoing neurolysis had a significantly lower survival rate that appeared limited to those with stage IV disease. This is discussed further below.
●Is either approach superior? – Although limited, the available data suggest that both procedures are comparable in terms of pain relief, which typically lasts for up to three months [18,22].
●Is survival adversely impacted? – Although many studies have shown that sympathetic neurolysis can improve pain and slow opioid dose escalation, its impact on survival remains controversial. While several studies that have examined this end point suggest that CPN neither improves nor decreases survival [12,27], while others suggest that patients who received early neurolysis for locally unresectable pancreatic cancer had longer survival times compared with other forms of therapy [24,26]. Notably, almost all of these reports included patients with locally advanced unresectable nonmetastatic tumors.
However, concerns about inferior survival have been raised in at least two other reports:
•In a single center retrospective case-control study of 417 patients with unresectable pancreatic cancer who underwent CPN and were compared with 840 control patients with unresectable pancreatic cancer who did not undergo CPN, CPN was negatively associated with survival (median 193 versus 246 days, HR 1.32, 95% CI 1.13-1.54) . This difference persisted in multivariate analysis, and was similar in all stage group categories (stage I/II, III, or IV), and whether or not the patient was treated with chemotherapy, radiation, or resection. Approximately 50 percent of the patients in either group had stage IV disease. However, the CPN group had more weight loss (median 20 versus 15 pounds), more opioid use (89 versus 36 percent), and more often had pain at presentation (99 versus 80 percent), all of which could have contributed to poorer performance status in this group independent of CPN.
•In the randomized trial of splanchnic nerve block versus saline injection control in 96 patients with unresectable pancreatic cancer described above, overall survival was significantly less in the sympathetic neurolysis group (median survival 102 versus 151 days, HR for death 1.56, 95% CI 1.03-2.35) . This detrimental impact was limited to those with stage IV (HR 1.94, 95% CI 1.29-2.93) but not stage III inoperable disease (HR 1.08, 95% CI 0.59-1.97).
In our view, these data are hypothesis generating rather than definitive. The trial was not powered to assess survival as a primary endpoint. Furthermore, one of the eligibility requirements for the trial was patients in palliative care who would not be receiving any anticancer treatments, including radiation therapy, chemotherapy, or targeted therapies. Data were not provided on the differences in anticancer therapy between the two groups. For all of these reasons, we would still offer nerve blocks to patients with either stage III or stage IV disease, although others disagree .
Radiation therapy — A short course of palliative radiation therapy (RT) may also significantly alleviate pain due to local invasion of pancreatic cancer. External beam RT with or without concomitant chemotherapy is associated with resolution of cancer-related pain in 35 to 65 percent of patients, frequently with improvement in cachexia and obstructive symptoms [29-31]. However, it may take several weeks to achieve its maximal effect. Because relief from pain is generally faster with sympathetic neurolysis, it is the preferred approach, when feasible.
Jaundice — Unrelieved jaundice from an obstructed biliary tree causes pruritus and an increased risk for cholangitis, although cholangitis is less common in native bile ducts than in previously stented bile ducts. Ultrasound, computed tomography (CT), or magnetic resonance cholangiopancreatography (MRCP) are commonly performed in jaundiced patients to distinguish obstructive jaundice from jaundice due to liver failure in patients with underlying liver disease and/or extensive metastatic disease. These studies typically demonstrate dilated intra- and extrahepatic biliary ducts. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Jaundice'.)
Palliation of jaundice is important to maintain liver health, prevent cholangitis, and restore bilirubin levels to a normal range to allow for the administration of cytotoxic chemotherapy. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Jaundice'.)
Options for palliation of jaundice in patients who have obstructive jaundice from locally advanced, unresectable disease are surgical bypass or placement of a stent across the area of biliary tract obstruction. Palliation of obstructive jaundice in patients who are not undergoing an attempt at surgical resection is usually accomplished by the endoscopic or percutaneous placement of an expandable metal stent, while surgical bypass is generally reserved for those in whom stent placement is not possible due to technical reasons and for those found to be unresectable at the time of operative exploration.
Surgical options — The surgical options for achieving biliary decompression include an anastomosis between the gallbladder and jejunum (cholecystojejunostomy) or common bile duct and jejunum (choledochojejunostomy) [32-34]. A cholecystojejunostomy should only be considered if the cystic duct enters the common bile duct at a site distant from the tumor. A choledochojejunostomy should only be performed if the common duct is >1 cm in diameter. Drainage is successful in returning the serum bilirubin concentration in approximately 90 percent of patients; in the remainder, persistent hyperbilirubinemia may be seen due to impaired hepatic function .
One advantage of surgical bypass is the ability to perform prophylactic or therapeutic gastrojejunostomy to avoid gastroduodenal obstruction and celiac plexus neurolytic block for pain control (see 'Pain' above and 'Gastric outlet obstruction' below). However, the risk associated with surgery in these typically debilitated patients is not small. In one report, the postoperative mortality and perioperative morbidity rates were 3.1 and 22 percent, respectively, and the median survival was 6.5 months . As a result, surgical bypass is generally reserved for those in whom stent placement is not possible due to technical reasons, and for those found to be unresectable at the time of operative exploration.
Stents — Stents can provide minimally invasive, effective palliation of jaundice . Most jaundiced patients can be successfully managed using stents, and relatively few require surgical biliary-enteric bypass as a planned palliative procedure. Randomized trials and a meta-analysis have shown no difference in survival between endoscopic stent placement and surgical bypass for malignant obstructive jaundice; stented patients have more frequent readmissions for stent occlusion, recurrent jaundice, and cholangitis (below), but lower morbidity and procedure-related mortality [37-41].
Plastic versus metal stents — A variety of plastic and metal stents, both covered and uncovered, are available for endoscopic deployment. A systematic review and a meta-analysis concluded that, compared with plastic stents, metal stents had a lower risk of recurrent obstruction but were not superior with regard to technical success, therapeutic success, mortality, or complications [41,42]. As a result, the decision to use one versus another should be guided by expected length of survival, quality of life, costs, and physician expertise (see "Endoscopic stenting for malignant biliary obstruction", section on 'Types of biliary stents'):
●The placement of a plastic stent is inexpensive and effective, and the stent can be easily removed or exchanged. Plastic stents, however, eventually develop occlusion by sludge and/or bacterial biofilm, and maintaining biliary drainage with plastic stents usually requires repeated endoscopic retrograde cholangiopancreatographies (ERCPs) since the median duration of patency is approximately three months.
●Metal stents extend the duration of stent patency (approximately 8 to 12 versus 2 to 5 months). However, metal stents have significantly higher costs and may not be removable. Thus, the diagnosis of unresectable or metastatic disease must be firmly established before a metal stent is deployed.
For patients with unresectable malignant biliary obstruction, self-expanding metal stents appear to be more cost effective than plastic stents, especially for individuals with a short life expectancy who place a high value on avoiding repeated interventions.
●A patient's treatment plan may not be known during the initial ERCP (eg, if biliary drainage is required before staging can be completed). Options in this setting include placing a plastic (and thus easily removed) stent or a self-expandable metal stent (which provides longer term patency). A Monte Carlo decision analysis compared several strategies in patients with obstructive jaundice from pancreatic cancer to an undetermined surgical plan, and the results suggested that a short-length self-expanding metal stent is the preferred initial treatment for overall cost minimization .
In general, the placement of a covered metal stent could be considered in patients with potentially resectable pancreatic cancer, especially if surgery is likely to be delayed (eg, for neoadjuvant chemotherapy, with the prevalence of this approach increasing). However, this is a controversial area, and some surgeons prefer a plastic stent in this setting. It may be helpful to speak with the surgeon prior to stent placement if a patient appears to have a potentially resectable tumor. (See "Surgical resection of lesions of the head of the pancreas", section on 'Preoperative biliary drainage' and "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Role of preoperative biliary drainage'.)
Year 2018 guidelines from the European Society of Gastrointestinal Endoscopy suggest use of a self-expanding metal stent for preoperative drainage for malignant strictures only in the presence of cholangitis, or severe symptomatic jaundice, or a delay in surgery; or prior to neoadjuvant chemotherapy in jaundiced patients . Plastic stents are reserved for those with benign biliary strictures.
Covered versus uncovered stents — Several trials have evaluated differences in stent patency rates between covered and uncovered metal stents for the treatment of distal malignant biliary disease; despite showing significantly less tumor ingrowth, patency rates are not higher for covered stents. This can likely be explained by the many other etiologies of stent occlusion other than tumor ingrowth, including tumor overgrowth and stent obstruction by debris and biliary sludge. One potential benefit of the covered metal stents is that they are more easily removable than are uncovered metal stents, but possible disadvantages include a higher incidence of cholecystitis from extrinsic occlusion of the cystic duct and stent migration. As noted above, the use of a metal stent in a patient who is a candidate for resection should be reviewed with the surgeon prior to placement. (See "Endoscopic stenting for malignant biliary obstruction", section on 'Metal stents' and "Endoscopic stenting for malignant biliary obstruction", section on 'Adverse events'.)
Percutaneous versus endoscopically placed stents — Endoscopic stenting is generally preferable to percutaneous approaches because of a more favorable adverse event rate, except for in patients in whom endoscopic stent placement has failed or is technically unfeasible because of duodenal obstruction or prior surgical bypass of the bile ducts and ampulla, in which a retrograde approach to the area is not possible [45,46]. However, percutaneous drainage may sometimes be the best approach for patients with advanced hilar metastases from pancreas cancer.
Infectious complications of stent placement — Endoscopic and percutaneous internal/external stents are associated with a risk for cholangitis because intubation of the ampulla of Vater introduces intestinal flora into a previously sterile area. In one series of 96 patients followed prospectively over a median 9.6 months (89 percent with a metal stent; the remainder were plastic), 41 (43 percent) developed a stent-related event. The rate of cholangitis was 39 percent, the stent obstruction rate was 29 percent, and simultaneous obstruction/cholangitis developed in 32 percent. Consequences relating to stent-related events included chemotherapy delay (24 percent), discontinuation of therapy (17 percent), and death (22 percent). The median time to stent-related event was 4.4 months (95% CI 3.6-5.5) . Importantly, cholangitis is also a concern for patients for whom draining is incomplete. (See "Infectious adverse events related to endoscopic retrograde cholangiopancreatography (ERCP)", section on 'Acute cholangitis'.)
Gastric outlet obstruction — Approximately 15 to 20 percent of patients with pancreatic cancer will develop duodenal obstruction leading to gastric outlet obstruction, although it is typically not present at diagnosis . Symptoms include early satiety, nausea, postprandial vomiting, and weight loss. Endoscopic duodenal stenting is successful in the majority of cases, and the median duration of stent patency is approximately six months .
Prevention — To avoid this complication, many surgeons create a prophylactic palliative gastrojejunostomy at the same time as a biliary bypass in those who are deemed to be unresectable at exploration . The benefit of a prophylactic gastrojejunostomy in this setting was shown in a meta-analysis of three prospective trials comparing prophylactic gastroenterostomy plus biliodigestive anastomosis versus no bypass or a biliodigestive bypass alone . For patients undergoing prophylactic gastroenterostomy, the risk of a gastric outlet obstruction during follow-up was significantly lower (odds ratio 0.06, 95% CI 0.02-0.21), while rates of postoperative morbidity (including delayed gastric emptying) and mortality were not higher. The average duration of hospital stay was three days longer in the group that had prophylactic gastroenterostomy.
Despite these data, the real benefit of this procedure in patients with unresectable pancreatic cancer has been questioned. An open surgical procedure to treat biliary or gastric obstruction is not needed in the vast majority of patients with unresectable pancreatic cancer who do not undergo initial laparotomy (98 percent in one report ). Furthermore, delayed gastric emptying is not infrequent after a prophylactic gastrojejunostomy .
However, when unresectable disease is found at the time of operative exploration, our practice is to routinely perform a posterior retrocolic gastrojejunostomy whenever biliary bypass is performed, regardless of the presence or absence of symptoms of gastric outlet obstruction.
Treatment — The two main treatment options for gastric outlet obstruction are enteral stenting and surgical bypass, which can often be performed laparoscopically. For many patients who are not undergoing an attempt at surgical resection, particularly those with advanced disease, a poor performance status, and a short life expectancy (eg, two to six months), duodenal stents are a reasonable alternative to surgical gastrojejunostomy, provided that an experienced endoscopist familiar with the technique is available . However, long-term relief of obstruction may be more likely in surgically managed patients. In our view, there are benefits and drawbacks to both approaches, and the decision for endoscopic stent placement versus surgical bypass must be individualized based upon local expertise, as well as disease stage, performance status, comorbidity, and estimated life expectancy.
For many patients with symptomatic gastric outlet obstruction who are not undergoing an attempt at definitive resection, endoscopically-placed expandable metal stents provide good symptom palliation and may be preferred over palliative gastrojejunostomy, particularly for patients with advanced disease and a poor performance status.
However, there are few studies directly comparing endoscopic stent placement to surgical gastrojejunostomy. One Dutch multicenter trial demonstrated faster initial symptom relief with stent placement but higher rates of major complications, recurrent symptoms, and need for reinvention . Long-term relief was more likely after surgical bypass. This subject is addressed in detail separately. (See "Enteral stents for the palliation of malignant gastroduodenal obstruction" and "Gastric outlet obstruction in adults", section on 'Malignant obstruction'.)
Delayed gastric emptying — Up to 60 percent of patients with pancreatic cancer have slowed gastric emptying without evidence of gastroduodenal tumor invasion . A possible explanation is tumor infiltration into the nerve plexuses. This invariably leads to anorexia, and in approximately one-third of patients, nausea and vomiting are present, which may be erroneously attributed to gastric or duodenal obstruction. However, a gastrojejunostomy is ineffective in relieving symptoms in such patients. Diagnosis can be made with gastric emptying study or as a diagnosis of exclusion when ruling out mechanical obstruction.
Unfortunately, anorexia, nausea, and vomiting due to delayed gastric emptying are often difficult to control, although prokinetic agents such as metoclopramide may help . Several nonpharmacologic interventions are available for decompression in patients with persistent vomiting; decompression using a "venting" percutaneous endoscopic gastrostomy (PEG) tube can be more comfortable than a nasogastric tube (table 1).
For the newly diagnosed patient who presents with severe symptoms but has not yet undergone chemotherapy, bridge nutrition may be beneficial. Combined venting/feeding tubes (gastrostomy/jejunostomy) can both palliate nausea/vomiting and provide an opportunity for nutritional support during active therapy in patients who have refractory gastroparesis; the postpyloric feeding bypasses the area of dysmotility. For patients who cannot eat because of delayed gastric emptying and who are otherwise candidates for chemotherapy, this is a preferred approach over total parenteral nutrition (TPN) due to the infectious risks of parenteral nutrition, as well as the missed opportunity of utilizing an otherwise functional intestinal tract. (See "Overview of managing common non-pain symptoms in palliative care", section on 'Nausea with or without vomiting' and "Gastroparesis: Etiology, clinical manifestations, and diagnosis" and "Treatment of gastroparesis".)
Depression and anxiety — The diagnosis of cancer is unsettling to any patient, and the knowledge of the aggressive nature of locally advanced and metastatic pancreatic cancer may lead to depression and anxiety. Patients who are depressed experience a significant worsening of their quality of life and have more intense pain compared with those who are not depressed .
Depression has been reported as the presenting symptom of pancreatic cancer in a significant proportion of new cases. A systemic review of 71 studies found that depressive symptoms were a prodrome in about 38 to 45 percent of patients newly diagnosed with pancreatic cancer, while prodromal anxiety was observed in about 12 percent [56,57]. The characteristic presentation is the older patient with minimal clinical findings presenting with "loss of ambition," "loss of push," "lack of go," and a kind of premonition or foreboding of having cancer .
All patients can benefit from a discussion of their psychosocial concerns and their available support systems [7,8]. Some may warrant treatment with antidepressants or anxiolytics, and others may need referral for ongoing formal support from a social worker or psychiatrist. (See "Management of psychiatric disorders in patients with cancer" and "Assessment and management of depression in palliative care" and "Overview of anxiety in palliative care".)
Venous thromboembolism — Pancreatic cancer is one of the malignancies with the highest risk for venous thromboembolism (VTE; including deep venous thrombosis [DVT], pulmonary embolism, and visceral vein thrombi [portal vein or superior mesenteric vein thrombus]). The incidence of VTE is four- to sevenfold higher in pancreatic cancer as in other common adenocarcinomas [59,60]. The likelihood of VTE is highest in the first three months after diagnosis; treatment with chemotherapy further increases the risk [61-65]. The presence of VTE (especially splanchnic venous thrombosis) is associated strongly with higher short-term and long-term mortality [59,62,66-68] and a high risk of recurrent VTE. (See "Risk and prevention of venous thromboembolism in adults with cancer".)
General issues — All patients should be educated as to the warning signs and symptoms of VTE . Physical examination of the legs for asymmetric pitting edema, erythema, and warmth is a crucial part of each office visit, and the threshold to perform a CT angiogram in the setting of tachycardia or pleuritic chest pain should be extremely low.
Ambulatory patients — Routine anticoagulation for primary VTE prevention has not been used in most ambulatory outpatients with pancreatic cancer. Evidence from randomized trials has demonstrated that anticoagulation can significantly reduce VTE risk, although this risk is generally lower in outpatients than in inpatients. At the same time, anticoagulation likely increases the risk of bleeding. Thus, the decision to use prophylactic anticoagulation is generally individualized according to the specific thrombotic and bleeding risks for the individual patient, along with the relative values placed on avoiding thrombosis and avoiding bleeding. Other considerations include the associated risks and burdens of continuing anticoagulation when the optimal duration is not well established (table 2).
For most ambulatory patients with pancreatic cancer and no other risk factors for VTE, we suggest not doing routine VTE prophylaxis. However, VTE prophylaxis might be considered on an individual basis for higher risk patients. These individuals may be identified by one of the following features (see "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Whom to anticoagulate'):
●A prior history of unprovoked VTE (if they are not chronically anticoagulated)
●An ONKOTEV score of 2 or more . The ONKOTEV score for estimating risk of VTE in pancreatic cancer assigns one point to each of four factors: presence of metastatic disease, tumor compression of vascular/lymphatic structures, history of previous VTE (whether provoked or not), and Khorana score >2. In a validation study conducted in 165 Portuguese patients with pancreatic cancer, the cumulative incidence of VTE was 3.3, 12.7, 50.9, and 82.4 percent for ONKOTEV scores of 0, 1, 2 and 3 or more, respectively .
We would also consider anticoagulation for those without these high-risk features who place a high value on avoiding VTE, after a discussion of the relative risks and benefits.
This recommendation is consistent with guidelines from the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and other groups.
When anticoagulation is used in these individuals, low molecular weight (LMW) heparin or a direct oral anticoagulant, such as apixaban, rivaroxaban, or edoxaban, may be selected . A prophylactic dose level should be used. Patients should be aware that their baseline bleeding risk may be higher than that for the general population (table 4).
Clinical trials — Given the significant morbidity and mortality associated with VTE in advanced pancreatic cancer and the relative resistance to warfarin seen in patients with pancreatic cancer-associated hypercoagulable states (at least in patients with Trousseau's syndrome), investigators have evaluated the use of LMW heparin and direct factor Xa inhibitors to reduce the incidence of VTE.
At least three randomized trials have tested the value of prophylactic LMW heparin versus observation alone in ambulatory patients with advanced pancreatic cancer [62,72,73]. Two additional trials (the AVERT and CASSINI trials) tested the value of prophylactic apixaban or rivaroxaban (direct factor Xa inhibitors) versus placebo for thromboprophylaxis in ambulatory patients with a variety of active cancers and a Khorana score of 2 or higher [74,75]. In the AVERT trial, 13 to 15 percent of those enrolled had pancreatic cancer, compared with 32 percent in the CASSINI trial. All five trials (only four of which have been published) demonstrated an approximately 34 to 88 percent reduction in the risk of symptomatic VTE (12 versus 28 percent in one of the trials of LMW heparin, 5 versus 22 percent in the second, 6 versus 15 percent in the third, 4 versus 10 percent in the AVERT study, and 6.0 versus 8.8 percent in the CASSINI trial). In the three LMW heparin trials, there were no significant differences in the incidence of severe hemorrhage as compared with the control group, but in both the AVERT and CASSINI trials, major bleeding occurred in twice as many anticoagulated patients, although the overall incidence was low (in the AVERT trial, 3.5 versus 1.8 percent, hazard ratio [HR] 2.00, 95% CI 1.01-3.95; in the CASSINI trial, 2 versus 1 percent, HR 1.96, 95% CI 0.59-6.49). In none of the trials was overall survival improved by the use of LMW heparin or a direct factor Xa inhibitor.
A preliminary report of a subgroup analysis of 273 patients with pancreatic cancer enrolled in the CASSINI trial was presented at the 2019 annual ASCO meeting . During the intervention phase, more than twice as many patients randomized to placebo had primary endpoint events (asymptomatic or symptomatic DVT, pulmonary embolism, or any death related to DVT, 10.1 versus 3.7 percent, HR 0.35 [95% CI 0.13-0.97]); the number needed to treat to avoid one event was 16. The risk of major bleeding was not higher in the rivaroxaban group (1.5 versus 2.3 percent). Despite these results, we still individualize the decision to use prophylactic anticoagulation according to the specific thrombotic and bleeding risks for the patient, along with the relative values placed on avoiding thrombosis and avoiding bleeding.
Choice of agent — When anticoagulation is used in ambulatory individuals, LMW heparin or a direct oral anticoagulant, such as apixaban, rivaroxaban, or edoxaban, is an appropriate choice based on the above studies and is supported by updated guidelines from ASCO and the International Society on Thrombosis and Haemostasis (ISTH) [69,77]. A prophylactic dose level should be used. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Choice of agent and dose'.)
Warfarin is generally not used for prophylactic anticoagulation in cancer patients, in part because of the requirement for dose adjustment based on international normalized ratio (INR) monitoring. Warfarin has significant drug interactions with commonly used chemotherapeutic agents, especially fluoropyrimidines, and coadministration is contraindicated because of the difficulty in monitoring the INR (see Lexicomp drug interactions). Of course, there are circumstances in which oral anticoagulants such as warfarin may be used for prophylaxis, such as cost prohibition of injectable drugs and/or patient preference, in situations where there is no direct contraindication, such as coadministration of fluorouracil chemotherapy.
Guidelines from expert groups — Multiple professional societies have issued guidelines for prevention and treatment of VTE in cancer patients. Updated year 2019 guidelines from ASCO, the 2012 American College of Chest Physicians (ACCP) Clinical Practice Guidelines, a 2009 Consensus Statement of major guidelines panels, Clinical Practice Guidelines in Oncology from the NCCN , year 2016 clinical practice guidelines for treatment of metastatic and locally advanced pancreatic cancer from ASCO, year 2021 guidelines from the American Society of Hematology (ASH), as well as guidelines from other groups do not recommend routine VTE prophylaxis for all ambulatory patients with pancreatic cancer [7,8,69,79-83].
While most of the guidelines suggest that high-risk patients consider VTE prophylaxis, there is disagreement on the definition of high risk:
●The NCCN , year 2016 ASCO pancreatic cancer clinical practice guidelines [7,8], year 2019 ASCO guidelines on VTE treatment and prophylaxis, and the 2021 ASH guidelines all suggest that VTE prophylaxis might be appropriate for high-risk individuals (eg, those with a Khorana score ≥3 (table 3)).
●Notably, the updated year 2019 guidelines on venous thromboprophylaxis prevention and treatment from ASCO state that higher-risk outpatients with any type of cancer (which they consider to be any patient with a Khorana score 2 or higher prior to starting a new chemotherapy regimen) "may be offered thromboprophylaxis provided that there are no significant risk factors for bleeding and no drug interactions" . According to this risk stratification method, which has been externally validated, pancreatic cancer is considered a very high-risk tumor and is assigned a point value of 2, meaning that all patients with pancreatic cancer would fall under this category of recommendation. However, an important point is that the balance of benefit and harm with thromboprophylaxis for high-risk patients, as defined by this model, has not yet been established, including for those with pancreatic cancer.
●A year 2022 updated clinical practice guideline from the ISTH on treatment and prophylaxis of VTE in patients with cancer also recommends VTE prophylaxis with LMW heparin or a direct oral anticoagulant (rivaroxaban or apixaban) for ambulatory patients with locally advanced or metastatic pancreatic cancer receiving chemotherapy, but only in those who have a low risk of bleeding .
In our view, VTE prophylaxis might be considered on an individual basis for higher risk individuals (eg, those with a Khorana score ≥3 (table 3)), for those who have a prior history of unprovoked VTE (if they are not chronically anticoagulated), and for those without these high-risk features who place a high value on avoiding VTE, after a discussion of the relative risks and benefits. The subject of primary prophylaxis for ambulatory cancer patients is discussed in more detail elsewhere. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Outpatients (VTE prophylaxis)'.)
Hospitalized patients — In contrast to ambulatory patients, prophylactic anticoagulation is appropriate for patients with active pancreatic cancer who are hospitalized or who are undergoing major surgery. Routine pharmacologic thromboprophylaxis should not be offered to patients who are admitted for the sole purpose of minor procedures or chemotherapy infusion . This subject is addressed elsewhere. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Surgical patients' and "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Hospitalized medical patients'.)
Choice of agent — Commonly used parenteral agents for VTE prophylaxis in hospitalized patients with cancer include LMW heparin, unfractionated heparin, and fondaparinux; the choice among these agents depends on patient-specific factors. Doses of these agents are shown in the table (table 5). In randomized trials, pharmacologic prophylaxis with LMW heparin, unfractionated heparin, or fondaparinux has been shown to be superior to placebo or mechanical devices in preventing VTE [84-95]. Among these, we prefer LMW heparin because meta-analyses suggest it is superior to unfractionated heparin (twice-daily or three-times-daily dosing regimens), particularly in hospitalized high-risk populations. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Efficacy'.)
We generally do not use direct oral anticoagulants (DOACs; eg, direct thrombin inhibitors or direct factor Xa inhibitors) for prophylaxis in surgical patients with pancreatic cancer. While there are current efforts evaluating the use and the efficacy and safety of the factor Xa inhibitors rivaroxaban and apixaban, there are no data comparing the risks and benefits of these drugs versus heparins specifically in hospitalized patients with pancreatic cancer. This recommendation is consistent with ASCO guidelines . This subject is discussed in more detail separately. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Overview of approach to prevention'.)
Warfarin generally is not used as prophylactic anticoagulation of relatively brief duration (ie, days to a few weeks) in individuals with cancer due to its delayed onset of antithrombotic action along with its requirement for dose adjustment based on INR monitoring. Although the efficacy of LMW heparin is greater than warfarin for treatment of cancer-associated VTE, its benefit over warfarin has not been demonstrated in the prophylactic setting. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)
Treatment — Evaluation of the patient with a suspected DVT or pulmonary embolism is discussed in detail elsewhere. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Catheter-related upper extremity venous thrombosis in adults", section on 'Diagnostic evaluation' and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Clinical features, diagnosis, and classification of thoracic central venous obstruction".)
The standard approach to treatment of a documented VTE (symptomatic or incidentally found) in a patient with pancreatic cancer is early initiation of anticoagulation. The decision to anticoagulate a patient with pancreatic cancer, VTE, and a limited life expectancy can be difficult because of the need for close laboratory monitoring (if warfarin or unfractionated heparin is used) as well as the risks of recurrent VTE, bleeding, and death. In addition, as noted above, warfarin has significant drug interactions with the commonly-used chemotherapeutic agent fluorouracil, and coadministration is contraindicated (see Lexicomp drug interactions). There are a number of theoretical reasons why heparin-containing products might be more effective than warfarin for this complication, which may or may not be associated with the anticoagulant properties of the heparins [96,97]. (See "Risk and prevention of venous thromboembolism in adults with cancer".)
A 2008 Cochrane review of six randomized controlled trials in cancer patients receiving long-term treatment for VTE concluded that use of LMW heparin was associated with a statistically significant reduction in subsequent VTE, no statistically significant survival benefit when compared with vitamin K antagonists, and no significant difference in bleeding outcomes . (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Principles of therapy'.)
In addition, accumulating data support the similar efficacy and safety of direct oral anticoagulants compared to LMW heparin. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Principles of therapy'.)
Recommendations for treatment of VTE in patients with malignancy are available from ASCO (updated in 2019), the NCCN , the ISTH (updated in 2022), and the ACCP (2021) [69,77,99,100]. Our suggested approach largely follows updated ASCO and ISTH guidelines [69,77]:
●For patients with VTE (symptomatic or incidental) in the setting of pancreatic cancer who do not have contraindications to anticoagulant use and have a reasonable quality of life and life expectancy, initial anticoagulation may involve LMW heparin, unfractionated heparin, fondaparinux, or a direct oral anticoagulant (eg, rivaroxaban, apixaban, edoxaban). (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)
If parenteral treatment is chosen, LMW heparin is generally preferred over unfractionated heparin, even for the initial 5 to 10 days of anticoagulation, if the patient does not have severe renal impairment (defined as creatinine clearance <30 mL/min). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)
The management of patients with isolated subsegmental pulmonary embolus, or splanchnic or visceral vein thrombi diagnosed incidentally should be considered on a case-by-case basis, considering the presence or absence of symptoms and the potential benefits and risks of anticoagulation. (See "Epidemiology and pathogenesis of portal vein thrombosis in adults" and "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management" and "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management".)
●Anticoagulation should be avoided if there is active major serious and/or life-threatening bleeding, severe platelet dysfunction or inherited bleeding disorder, platelet count <20,000/microL, or severe uncompensated coagulopathy or in patients undergoing surgery or invasive procedure, such as lumbar puncture, spinal anesthesia, or epidural catheter placement . Relative contraindications include active peptic or other ulceration at high risk of bleeding, active but not life-threatening bleeding (eg, hematuria), intracranial or central nervous system bleeding in the past four weeks, major surgery or serious bleeding in the preceding two weeks, and persistent thrombocytopenia (<50,000/microL). For patients with brain metastases from pancreatic cancer without evidence of intracranial hemorrhage and established VTE, anticoagulation should be offered, although uncertainties remain as to the optimal choice of agent and selection of patients most likely to benefit.
When anticoagulation is absolutely contraindicated in the acute treatment setting (diagnosed within four weeks), one treatment option is insertion of an inferior vena cava (IVC) filter if the thrombus burden is considered life threatening. However, based on uncertain short-term benefit and evidence for long-term harm, the insertion of an IVC filter should not be offered to patients with established or chronic thrombosis (diagnosis >4 weeks prior) nor to those with temporary contraindications to anticoagulation therapy (eg, surgery). (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)
●Fibrinolytic (thrombolytic) therapy or catheter/surgical embolectomy may be indicated for patients with acute pulmonary embolism and hemodynamic instability or for those with massive iliofemoral or proximal femoral DVT with a high risk of limb gangrene, although the risk and benefit of these invasive measures should be carefully weighed in this population of patients who have a very limited life expectancy. The role of thrombolytic therapy and embolectomy in these settings is addressed in detail elsewhere. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Embolectomy'.)
●For long-term anticoagulation, LMW heparin, edoxaban, or rivaroxaban for at least six months is preferred because of better efficacy over vitamin K antagonists. However, for patients who do not have Trousseau's syndrome, vitamin K antagonists are an acceptable alternative for long-term therapy if LMW heparin or a DOAC is not available. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Follow-up'.)
●Unlike standard practice in patients without cancer presenting with unprovoked DVT, the decision to continue anticoagulation beyond the usual three or six months must be balanced against the risk of bleeding, cost of therapy, quality of life, life expectancy, and patient preference. However, because the risk of recurrent VTE is unacceptably high in patients with active pancreatic cancer who stop anticoagulant therapy, we suggest extended (ie, lifelong) anticoagulant therapy for most patients with pancreatic cancer who have VTE. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Duration of anticoagulation'.)
●Patients with recurrent VTE despite standard doses of anticoagulant therapy should be assessed for treatment compliance, heparin-induced thrombocytopenia, or any evidence of mechanical compression related to the malignancy. Checking a Factor Xa level four hours after a dose of LMW heparin provides an accurate indication of therapeutic levels of anticoagulation. While initial dosing should be weight-based, clot burden may impact the dose required to achieve therapeutic anticoagulation. In the setting of true LMW heparin failure, management options include treatment with an alternative anticoagulant regimen, increasing the dose of the LMW heparin , or adding an IVC filter to the LMW heparin (although this is not our preferred approach). (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Management of recurrence'.)
Anorexia, cachexia, and weight loss — Weight loss and anorexia are common in patients with pancreatic cancer, and the etiology is often multifactorial. All patients with locally advanced or metastatic pancreatic cancer merit a consultation with a nutritionist and/or dietician, if this service is available [7,8]. Dietary intake should be assessed along with the possible need for dietary supplements. Some patients develop exocrine pancreatic insufficiency and require pancreatic enzyme replacement, which can help improve digestion and absorption of nutrients. An appetite stimulant (eg, megestrol acetate) may be considered, although there is an increased association with thromboembolism with this agent, leading to a warning to "use with caution in patients with a history of thromboembolic disease."
Cancer-related anorexia-cachexia syndrome — Loss of appetite (anorexia) with weight loss is common among pancreatic cancer patients, but the profound weight loss suffered by patients with cancer-related cachexia cannot be entirely attributed to poor caloric intake. A disproportionate and excessive loss of lean body mass is the hallmark of cancer cachexia, which occurs in up to 80 percent of patients with pancreatic cancer, particularly those with metastatic disease. Inappropriately accelerated resting energy expenditure may contribute to the energy deficits; anorexia and poor oral intake also contribute, as do alterations in nutrient metabolism (eg, increased protein breakdown) and, possibly, altered pancreatic exocrine function . A number of studies focusing on the mechanisms underlying the metabolic and body composition changes observed in cancer-related cachexia suggest a potentially important role for cytokine activation and for several tumor-derived and potentially cachexia-inducing substances, the target of which appears to be skeletal muscle gene products. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".)
In general, among patients with cancer, cancer-associated cachexia syndrome is an independent risk factor for mortality. However, at least some experimental data suggest that early loss of peripheral tissue associated with pancreatic cancer may not necessarily impair survival . (See "Survival estimates in advanced terminal cancer", section on 'Clinical signs and symptoms'.)
Although many agents have been evaluated for the treatment of cancer-associated cachexia syndrome, only corticosteroids and progesterone analogs have a proven benefit in palliation of the anorexia associated with this syndrome. The primary benefits associated with these drugs are increased appetite and weight gain, not improved survival or quality of life, and there are potential harms associated with both drugs. Pharmacologic management of cancer-associated cachexia syndrome is discussed in detail elsewhere. (See "Management of cancer anorexia/cachexia".)
Pancreatic exocrine insufficiency — A contributory factor to the extreme weight loss often seen in patients with pancreatic cancer may be pancreatic exocrine insufficiency, which leads to maldigestion, fat malabsorption, and steatorrhea. The main clinical manifestation is weight loss. We suggest that patients who are suspected of having pancreatic exocrine insufficiency be treated empirically with oral pancreatic enzyme replacement.
Pancreatic exocrine insufficiency is a major consequence of loss of pancreatic parenchyma and/or obstruction of the main pancreatic duct. It can occur after surgery, after irradiation, or as a result of tumor compressing or obstructing the main duct [103,104]. Although there are a limited range of studies investigating the incidence of exocrine insufficiency in pancreatic cancer, the available evidence suggests that pancreatic enzyme insufficiency is common, affecting 64 to 100 percent of patients with pancreatic cancer, even those who have not had surgery [105-108]. Fat malabsorption does not become evident until lipase secretion is less than 10 percent of normal levels. (See "Approach to the adult patient with suspected malabsorption" and "Overview of the treatment of malabsorption in adults".)
Pancreatic enzyme insufficiency causes nonspecific symptoms such as abdominal cramping, flatulence, urgency to defecate, and weight loss. The typical characteristics of fatty stools associated with steatorrhea (loose, greasy, foul-smelling, voluminous stools that are difficult to flush) may not be evident because patients tend to limit fat ingestion. As a result, the main clinical manifestation is malnutrition and weight loss. (See "Approach to the adult patient with suspected malabsorption", section on 'Clinical manifestations'.)
Given the high incidence of pancreatic enzyme insufficiency, diagnostic testing is not necessary. Patients who are suspected of having fat malabsorption should be treated empirically with oral pancreatic enzyme replacement therapy. Adequate dosing and patient compliance are critical to the success of therapy. (See 'Treatment' below and "Overview of the treatment of malabsorption in adults", section on 'Directed therapy based on the underlying etiology'.)
However, despite this general recommendation from expert groups, including the NCCN  and the British Society of Gastroenterology , the available evidence suggests that pancreatic enzyme replacement therapy is underutilized. In a review of 129 patients with metastatic pancreatic cancer who were referred to a specialist palliative care service in Australia, over 70 percent had symptoms that could be attributed to malabsorption (abdominal pain, bloating, gaseousness, and steatorrhea), but only 21 percent were prescribed pancreatic enzyme replacement therapy .
Treatment — Formulations of pancreatic replacement enzymes are comprised of multiple replacement enzymes, with dosing in increments of 12,000 international units. As a general rule, 30,000 international units of pancreatic lipase, swallowed during each full meal, should suffice in reducing steatorrhea and preventing weight loss. One-half of that dose should be administered with snacks. Determining the adequate amount of lipase can be confusing since the amount of lipase in commercially available pancreatic supplements is typically expressed in United States Pharmacopeia (USP) units. 30,000 international units is equivalent to approximately 90,000 USP units. (See "Chronic pancreatitis: Management", section on 'Pancreatic enzyme replacement therapy'.)
Several commercial preparations are microencapsulated (table 6) and are designed to be acid-resistant, thus avoiding enzyme inactivation by gastric juice. Although data are limited, the efficacy of high-dose enteric-coated enzyme supplements was shown in two small placebo-controlled trials of patients with pancreatic insufficiency or pancreatic surgery  and another in advanced pancreatic cancer ; in both studies, use of enzyme supplements was associated with improved weight gain and decreased fat and protein malabsorption. In another small randomized trial, enteric-coated enzyme supplements resulted in higher body weight gain than did non-enteric-coated supplements following pancreaticoduodenectomy .
Microencapsulated formulations will only delay the release of the enzymes in the proximal small intestine and are, therefore, intended more for patients who have retained the ability to secrete gastric acid. Nonencapsulated formulations may be more successful in patients who are achlorhydric or who have dyssynchronous gastric emptying (eg, Billroth II anatomy) since there is no need to protect the enzymes from acid. (See "Chronic pancreatitis: Management", section on 'Pancreatic enzyme replacement therapy'.)
Patients should be instructed to take enzyme supplementation at the start, at the middle, and near the end of a meal. Patient compliance is a key factor in the management of pancreatic enzyme insufficiency with oral pancreatic enzymes. In addition, underdosing of enzymes, acidic intestinal pH (the enteric-coated tablets require a pH>5 for the pancreatic enzymes to be released ), and intestinal bacterial overgrowth may also hinder the return of fat digestion to normal [115,116]. In cases of an insufficient response to enzyme supplementation, dosing and compliance should be reviewed, and consideration should be given to inhibition of gastric acid secretion.
Role of dietary modification — Classically, the approach to patients with pancreatic enzyme insufficiency was to restrict fat intake (typically to <20 g per day) in an attempt to reduce steatorrhea. However, this approach restricts intake of fat-soluble vitamins, which are already malabsorbed in patients with enzyme insufficiency . Furthermore, the available data suggest that the half-life of enzyme activity (both endogenous and exogenously administered) within the small bowel is enhanced by the presence of fat . Finally, in a dog model, both fat absorption and digestion were higher when enzyme supplements were taken with a high-fat as compared with a low-fat diet . For all of these reasons, fat restriction should no longer be considered the rule in managing patients with pancreatic enzyme insufficiency. Frequent meals of a low volume and avoidance of foods that are difficult to digest (eg, legumes) are generally recommended .
Ascites — Ascites in patients with metastatic pancreatic cancer may be due to peritoneal metastases . However, among patients with locally advanced tumors, ascites may be caused by portal vein thrombus if the tumor compresses the portal vein locally . Ascites can be either transudative or exudative due to these differing causalities. (See "Malignancy-related ascites".)
Patients with malignant ascites from pancreatic cancer can experience abdominal discomfort, nausea, vomiting, and dyspnea from the pressure of the fluid against the anterior abdominal wall and diaphragm. For most patients, median survival is short, and the focus should be on symptom control . Symptom relief from intermittent paracentesis tends to be short lived, and the procedure must be repeated for symptom relief. If reaccumulation requires more than once-weekly paracentesis, placement of a long-term drainage catheter is a suitable option, although complication rates are higher with indwelling catheters .
Diuretics such as spironolactone and furosemide decrease the absorption of water and sodium in the kidneys and may provide some symptomatic relief. Patients with portal hypertension due to massive liver metastases or malignant Budd-Chiari syndrome may be more likely to respond to diuretics than are patients with peritoneal carcinomatosis. Assessing the serum-to-ascites albumin gradient (SAAG) is helpful in confirming etiology and guiding treatment approaches. (See "Evaluation of adults with ascites", section on 'Serum-to-ascites albumin gradient'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pancreatic cancer".)
SUMMARY AND RECOMMENDATIONS — Palliative treatment designed to control the symptoms of unresectable or recurrent pancreatic cancer can provide relief of obstructive jaundice, gastric outlet obstruction, pain, and pancreatic exocrine insufficiency.
●Early palliative care involvement – Full assessment of symptom burden, psychological status, and social supports is required for all patients as early as possible. Early referral and initiation of palliative care services improves clinical and quality of care outcomes, and may prolong survival. (See 'Importance of palliative care' above.)
•All patients should have pain addressed at every clinic visit. The mainstay of pain management is opioid medication. Because of the proximity of the tumor to the celiac plexus, the pain may be neuropathic, warranting consideration of adjuvant medications such as gabapentin, pregabalin, nortriptyline, or duloxetine. (See 'Pain' above.)
•Early celiac plexus neurolysis (CPN) provides better pain control, less opioid consumption, and a better quality of life as compared with waiting until after failure to obtain pain relief with strong opioids. Where local expertise is available, CPN is generally preferred over radiation therapy (RT) because relief from pain is generally faster with CPN. (See 'Sympathetic neurolytic blocks' above.)
●Managing biliary and gastric outlet obstruction
•Palliation of jaundice in patients with unresectable pancreatic cancer is usually accomplished by the placement of an expandable metal stent. Surgical bypass is reserved for those in whom stent placement is not possible due to technical reasons and for those found to be unresectable at the time of operative exploration. (See 'Jaundice' above.)
•Endoscopically placed expandable metal stents are preferred over palliative gastrojejunostomy for patients with symptomatic gastric outlet obstruction who are not undergoing an attempt at surgical resection. (See 'Gastric outlet obstruction' above.)
●VTE prophylaxis and treatment
•The incidence of venous thromboembolism (VTE) is four- to sevenfold higher in pancreatic cancer as in other common adenocarcinomas. All patients should be educated as to the warning signs and symptoms of VTE. (See 'General issues' above.)
•For most ambulatory patients with pancreatic cancer and no other risk factors for VTE, we suggest not doing routine VTE prophylaxis (Grade 2B). However, VTE prophylaxis might be considered on an individual basis for higher risk individuals (eg, those with a Khorana score ≥3 (table 3)), for those who have a prior history of unprovoked VTE (if they are not chronically anticoagulated), and for those without these high-risk features who place a high value on avoiding VTE, after a discussion of the relative risks and benefits.
For hospitalized patients with pancreatic cancer who do not have an increased bleeding risk, we recommend short-term pharmacologic thromboprophylaxis rather than no anticoagulation (Grade 1B). (See 'Hospitalized patients' above and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)
•The standard approach to treatment of a documented (symptomatic or incidentally found) VTE in a patient with pancreatic cancer is early initiation of anticoagulation. For patients with active cancer, we suggest lifelong therapy rather than a short period of anticoagulation (Grade 2C). We prefer LMW heparin or a direct oral anticoagulant (eg, rivaroxaban, apixaban, edoxaban) over a vitamin K antagonist or unfractionated heparin for most patients who will need long-term anticoagulation. (See 'Treatment' above.)
●Weight loss and anorexia
•All patients with locally advanced or metastatic pancreatic cancer merit a consultation with a nutritionist and/or dietician, if this service is available. The use of appetite stimulants, such as megestrol acetate, must be individualized and based on assessment of the risks and benefits of individual agents. (See 'Anorexia, cachexia, and weight loss' above.)
We suggest that patients who are suspected of having fat malabsorption be treated empirically with oral pancreatic enzyme replacement therapy (Grade 2B). Adequate doses of lipase should be delivered with meals and snacks. (See 'Pancreatic exocrine insufficiency' above.)
•Ascites in patients with metastatic pancreatic cancer may be due to peritoneal metastases or secondary to portal vein thrombus from local tumor compression. In either case, patients may benefit from intermittent paracentesis or, if the ascites reaccumulates quickly, from placement of a long-term drainage catheter. (See 'Ascites' above.)
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