Pancreatic cancer represents only 3% of cancer diagnoses in the United States, with an estimated 43,920 new cases diagnosed in 2012, yet it remains the fourth leading cause of cancer deaths, with an estimated 37,390 deaths in the same year. Despite the availability of newer and better antineoplastic combinations, the 5-year survival rate for all stages of pancreatic cancer remains dismal at 6%. Although the time before death may be limited, pancreatic cancer patients suffer an average of 11 significant symptoms directly attributable to the disease; oncologists thus have a host of escalating challenges to address quickly and effectively. The daunting survival statistics for patients with advanced pancreatic cancer (APC) demand a thoughtful approach, with a prioritization of quality of life from the day of diagnosis, not just in the final days to weeks of life. This paper provides an evidence-based review of the most common and concerning symptoms and complications that occur in patients with late-stage pancreatic cancer.
The incidence of venous thromboembolism (VTE) is four- to seven-fold higher in pancreatic cancer than in other common adenocarcinomas. The likelihood of VTE is highest during the first 3 months after diagnosis of pancreatic cancer[4,5]; treatment with chemotherapy further increases the risk of VTE in APC. Compared to hypercoaguable patients without concurrent malignancy, cancer patients are four times more likely to develop recurrent thromboembolic complications and twice as likely to have major bleeding with anticoagulation.[7,8] In addition to this increase in morbidity, the presence of VTE is associated strongly with higher mortality,[3,5,9] especially if a clot is discovered within 6 weeks of the diagnosis of pancreatic cancer.
Given the significant morbidity and mortality associated with VTE in APC, investigators have evaluated the use of prophylactic low-molecular-weight heparin (LMWH) to reduce the incidence of clots. In a prospective, randomized controlled trial of 312 patients with APC, prophylactic enoxaparin was given with concurrent gemcitabine. Compared to placebo, enoxaparin reduced the number of symptomatic VTEs by 8.6% at 3 months and by 10.1% at 12 months. The LMWH was well tolerated, without any significant increase in major bleeding. Another study randomized 123 patients with APC to receive gemcitabine with or without concurrent dalteparin (Fragmin) in a blinded fashion. The risk of symptomatic or incidental VTE was reduced by 85% for the first 100 days and by 58% for the median follow-up of 19.3 months. Higher rates of minor bleeding or bruising were observed in the dalteparin arm (9% vs 3%); however, the occurrence of severe hemorrhagic complications was not significant. Neither study demonstrated a survival advantage with prophylactic LMWH, although the studies were insufficiently powered for this endpoint.
LMWH prophylaxis may be useful for preventing serious morbidity associated with thrombosis in APC patients, particularly in the highest-risk patients. However, the current literature does not yet show improved survival with empiric therapy. The results of current and future studies to evaluate cost and quality of life will be important factors in deciding the utility of prophylaxis in an individual patient. For now, thromboprophylaxis should not be routinely prescribed outside of a clinical trial. The standard of care for patients with APC remains early initiation of LMWH after the identification of thrombus, with life-long continuation.[7,11]
The majority of patients with APC have pain at the time of diagnosis, and appropriate analgesia is a critical longitudinal component of care. Although pain management follows the model of the World Health Organization (WHO) three-step ladder, many patients with APC require a multidisciplinary approach, including consultations with interventionalists, palliative care providers, and sometimes radiation oncologists. Procedures aimed at blocking the pain signals transmitted along the celiac plexus have been shown to diminish both the need for opioids and the incidence of opioid-related adverse effects.
Celiac plexus neurolysis (CPN) can be performed surgically, percutaneously under image guidance, or endoscopically with ultrasound guidance. Partial or complete pain relief is achieved in 70% to 90% of patients who are treated with CPN. If pain is prominent at presentation, the evidence supports performing CPN at the time of diagnosis, during either exploratory surgery or initial endoscopy (in the latter case, under ultrasound guidance). In common clinical practice, CPN tends to be reserved for patients refractory to opioids or those suffering a disproportionate level of toxicity, such that an opioid-sparing approach is desired.. However, the evidence supports earlier use of CPN. CPN decreases the average use of morphine by 40 to 80 mg per day per patient and results in significantly decreased rates of constipation. Although the duration of pain relief with initial CPN is only 2 to 3 months, this improvement makes a clinical difference to most patients with APC. There are a few studies evaluating the merit of repeat CPN with recurrent pain. The largest of these suggests that repeat injections provide relief in 29% of cases, with only half the durability of response compared to the first procedure. Further study of the intervention in this clinical setting is needed.
Malignant Biliary Obstruction
Biliary obstruction occurs in 70% to 90% of patients with pancreatic cancer but is most commonly associated with pancreas head tumors. Biliary obstruction adversely impacts patients’ quality of life,[17,18] causing cholangitis, malabsorption, pruritus, and ultimately hepatic failure.[17,19] In most cases, symptoms resolve with relief of the obstruction, which is most easily achieved if an endoscopic biliary stent can be placed. Refractory cases may benefit from either surgical bypass or an external drain placed under percutaneous transhepatic cholangiography (PTC), although these procedures should be performed in a minority of cases and only after careful consideration of the overall medical picture.
Endoscopic stenting is technically and clinically successful in the majority of patients (88%) with extrahepatic biliary obstruction caused by pancreatic cancer. This approach results in less morbidity, fewer complications, and shorter hospital stays compared to the more invasive approaches.[18,20] Occlusions occur less frequently with metallic stents than with plastic ones (31% vs 87%), and even less often with those made of covered metal (3%). Median patency for plastic stents is 2.5 months, thereby necessitating routine stent exchanges every 3 months to prevent biliary sludging and cholangitis. Alternatively, uncovered metal stents tend to remain patent for an average of 6 months; covered metallic stents maintain a 97% patency rate at 12 months. Cholangitis is a life-threatening emergency and occurs in 30% of patients with biliary stents. Treatment includes immediate antibiotics with an emergent stent change to avoid sepsis or hepatic abscess formation. Given concerns about immunosuppression from chemotherapy or radiation, patients expected to undergo neoadjuvant therapy do best with metallic stents to minimize the risk of life-threatening complications.
When endoscopic stent placement has failed, biliary stenting by PTC is an option, although the prognosis following placement of a transhepatic stent for malignancy is markedly poor even if adequate biliary drainage is achieved. In a group of patients requiring biliary drainage via PTC, almost half of whom had pancreatic cancer, significant morbidity and high complication rates (62%) were reported. An average of 2.4 procedures were required in order to achieve adequate biliary drainage, with a mean hospital stay of 42 days (range: 0−188 days). The 30-day mortality was 43%, which likely reflects the overall severity of the patients’ illness, probably the result of intrahepatic metastases. Although PTC biliary drainage aims to reduce the level of systemic bilirubin, this intervention rarely improves length or quality of life and only adds more complications if a patient is able to receive systemic chemotherapy. Instead, a discussion regarding overall expectations in the face of terminal hepatic dysfunction is often most appropriate.
Malignant Gastric Outlet Obstruction
Bowel compression or invasion by pancreatic cancer results in gastric outlet obstruction (GOO) and requires urgent intervention for optimal palliation of intractable vomiting. Approximately 26% of patients with pancreatic cancer develop GOO over the course of the disease.[20,24] The objectives of treatment are to relieve vomiting, reestablish oral intake if possible, and ultimately improve both the length and quality of a patient’s life. A self-expanding metallic enteral stent can be used to palliate symptoms, with faster return of oral intake post-procedure compared to surgical gastroenterostomy. Enteral stents result in fewer immediate complications than gastroenterostomy and are often preferred by patients. There is a 15% risk of re-obstruction of the stent; nonetheless, this remains the preferred option in most patients with APC.[20,26] Palliative surgical interventions are reserved for select patients with excellent performance status, minimal burden of cancer, and a longer expected prognosis. Unfortunately, prognosticating is difficult; thus, most patients undergo enteral stent placement for immediate results, with an expected stent patency of 6 months.
Pancreatic Exocrine Insufficiency
Pancreatic exocrine insufficiency (PEI) occurs in 80% to 90% of patients with pancreatic cancer. PEI causes nonspecific symptoms, such as abdominal cramping and maldigestion, and simultaneously worsens any weight loss from cancer-related anorexia and cachexia. PEI occurs in patients after surgery, after radiation, or as a result of compression of a primary tumor left in situ. Given its high incidence in APC, diagnostic testing for PEI is not necessary. Patients should be treated empirically and followed clinically for improvement in symptoms and weight gain. Pancreatic enzyme replacement therapy is critical to relieve abdominal symptoms and to reverse ongoing weight loss. A starting dose of 40,000−75,000 IU pancreatic lipase should be given with meals and 20,000−25,0000 IU with snacks. A low pH irreversibly inactivates pancreatic lipase, so supplements should never be taken on an empty stomach. Patients can take the enzymes throughout the meal for optimal mixing with any food bolus. Many patients note reduced symptoms, with less urgent stools and decreased flatulence and abdominal cramping.
Clinical treatment failures are almost always the result of underdosing of replacement enzymes or patient noncompliance with timing of the medication. An increase in enzyme dose and careful re-education on the timing of medication are usually effective interventions. In addition, gastric acid suppression with either an H2 blocker or a proton-pump inhibitor clearly prevents the inactivation of enzymes[28,29] and improves the efficacy of enzyme replacement therapy, resulting in superior weight gain. PEI, with its nonspecific symptoms, is poorly recognized in this population of patients. Fortunately treatment offers an opportunity to improve nutritional status and quality of life dramatically.
Cancer-Associated Anorexia-Cachexia Syndrome
Cancer-associated cachexia is observed in up to 80% of pancreatic cancer patients at the time of diagnosis. The weight loss and muscle wasting result from an inappropriately accelerated catabolic rate with systemic inflammation and profound anorexia. This syndrome, called cancer-associated anorexia-cachexia syndrome (CACS), includes altered taste perception, weakness, early satiety, nausea, and a loss of appetite despite profound weight loss.[30,31] Marked protein wasting is a hallmark of CACS and results in functional impairment with decreased quality of life. CACS is an independent risk factor for mortality and poor therapeutic response to antineoplastic agents regardless of cancer stage. Unfortunately, death is almost inevitable when patients lose 30% of their premorbid weight.
In CACS, weight gain is associated with improved physical function and quality of life. Initially, patients, family, and care teams focus on oral intake with high-calorie, protein-rich foods and supplements, with mixed success. There is significant evidence that megestrol acetate improves appetite and results in modest weight gain; however, the slightly increased risk of thrombosis has limited its practical use. In certain patients, parenteral nutrition may stabilize weight loss and nutritional status, but this approach should only be considered after a careful discussion about prognosis, expectations, and parameters for cessation of therapy.
Beyond the current approach of megestrol and increased caloric intake, compounds that reverse CACS by calming inflammatory cytokines and altering catabolism are promising. In a small study, orally administered omega-3 fatty acids, specifically eicosapentaenoic acid, reversed weight loss but failed to result in a definite improvement in patient-reported quality of life. Because tumor necrosis factor (TNF)-α has been identified as a mediator in CACS, preliminary clinical studies show that thalidomide attenuates weight loss significantly in patients with advanced pancreatic cancer, although the drug has not been approved by the US Food and Drug Administration (FDA) for this indication. In a randomized trial in patients with gastrointestinal cancers, combined therapy with megestrol acetate, thalidomide, and olanzapine increased lean body mass and halted weight loss significantly. Many promising pathways to treating CACS are under investigation; these are summarized in Table 1.
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29.
2. Davis M. Integrating palliative medicine into an oncology practice. Am J Hosp Palliat Care. 2005; 22:447-56.
3. Chew H, Wun T, Harvey D, et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166:458-64.
4. Blom J, Osanto S, Rosendaal F. High risk of venous thrombosis in patients with pancreatic cancer: a cohort study of 202 patients. Eur J Cancer. 2006; 42:410-4.
5. Maraveyas A, Waters J, Roy R, et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer. 2012;48: 1283-92.
6. Blanco A, Martin A, Alfonso P, et al. Incidence and prediction of venous thromboembolism in ambulatory patients with pancreas cancer receiving chemotherapy. J Clin Oncol. 2012;30(Suppl 4): abstract #368.
7. Lyman G. Venous thromboembolism in the patient with cancer. Cancer. 2011;117:1334-49.
8. Lin J, Dalal M, Connolly G, et al. Evaluation of venous thromboembolism risk among ambulatory patients with pancreatic cancer in a real-world setting. J Clin Oncol. 2012:30(Suppl 4): Abstr 273.
9. Epstein A, Soff G, Capanu M, et al. Analysis of incidence and clinical outcomes in patients with thromboembolic events and invasive exocrine pancreatic cancer. Cancer. 2012;118:3053-5061.
10. Riess H, Pelzer U, Opitz B, et al. A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy: final results of the CONKO-004 trial. J Clin Oncol. 2010;28 (Suppl 15): Abstr 4033.
11. Lyman G, Khorana A, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490-505.
12. WHO’s pain ladder. Available from: http://www.who.int/cancer/palliative/painladder/en/ Accessed February 19, 2013.
13. Wyse J, Carone M, Paquin S, et al. Randomized, double-blind, controlled trial of early endoscopic ultrasound-guided celiac plexus neurolysis to prevent pain progression in patients with newly diagnosed, painful, inoperable pancreatic cancer. J Clin Oncol. 2011;29:3541-6.
14. Yan B, Myers R. Neurolytic celiac plexus block for pain control in unresectable pancreatic cancer. Am J Gastroenterol. 2007;102:430-8.
15. Yang F, Wu B, Lai G, et al. Assessment of consecutive neurolytic celiac plexus block (NCPB) technique outcomes in the management of refractory visceral cancer pain. Pain Med. 2012;13:518-21
16. McGreevy K, Hurley R, Erdek M, et al. The effectiveness of repeat celiac plexus neurolysis for pancreatic cancer: a pilot study. Pain Pract. 2013;13:89-95.
17. Moss A, Morris E, Mac Mathuna P. Palliative biliary stents for obstructing pancreatic carcinoma. Cochrane Database Syst Rev. 2006:CD004200.
18. Buxbaum J, Biggins S, Bagatelos K, et al. Inoperable pancreatic cancer patients who have prolonged survival exhibit an increased risk of cholangitis. J Pancreas (online). 2011;12:377-83.
19. Sut M, Kennedy R, McNamee J, et al. Long-term results of percutaneous transhepatic cholangiographic drainage for palliation of malignant biliary obstruction. J Palliat Care. 2010:13;1311-4.
20. Maire F, Hammel P, Ponsot P, et al. Long-term outcome of biliary and duodenal stents in palliative treatment of patients with unresectable adenocarcinoma of the head of pancreas. Am J Gastroenterol. 2006;101:735-42.
21. Siddiqui A, Mehendiratta V, Loren D, et al. Fully covered self-expandable metal stents are effective and safe to treat distal malignant biliary strictures, irrespective of surgical respectability status. J Clin Gastroenterol. 2011;45:824-7.
22. Aadam A, Evans D, Khan A, et al. Efficacy and safety of self-expandable metal stents for biliary decompression in patients receiving neoadjuvant therapy for pancreatic cancer: a prospective study. Gastrointest Endosc. 2012;76:67-75.
23. Robson P, Heffernan N, Holmes R, et al. Effect of percutaneous biliary drainage for malignant biliary obstruction on quality of life. J Clin Oncol. 2007;25(Suppl 18s):Abstr 9029.
24. Jeurnink S, Steyerberg E, van Hooft J, et al. Surgical gastrojejunostomy or endoscopic stent placement for the palliation of malignant gastric outlet obstruction (SUSTENT study): a multicenter randomized trial. Gastrointest Endosc. 2010;71:490-9.
25. Jeurnink S, Steyerberg E, Vleggaar F, et al. Predictors of survival in patients with malignant gastric outlet obstruction: a patient-oriented decision approach for palliative treatment. Dig Liv Dis. 2011;43:548-52.
26. Jeurnink S, Steyerberg E, Hof Gv, et al. Gastrojejunostomy versus stent placement in patients with malignant gastric outlet obstruction: a comparison in 95 patients. J Surg Oncol. 2007;96:389-96.
27. Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut. 2005;54:vi1-vi28.
28. Dominguez-Muñoz J. Pancreatic exocrine insufficiency: diagnosis and treatment. J Gastroenterol Hepatol. 2011;26(Suppl 2):12-16.
29. Sikkens E, Cahen D, Kuipers E, et al. Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2010;24:337-47.
30. Pelzer U, Arnold D, Goevercin M, et al. Parenteral nutrition support for patients with pancreatic cancer. Results of a phase II study. BMC Cancer. 2010;10:86.
31. Fearon K, Voss A, Hustead D. Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. Am J Clin Nutr. 2006;83:1345-50.
32. Gordon J, Trebble T, Ellis R, et al. Thalidomide in the treatment of cancer cachexia: a randomized placebo controlled trial. Gut 2005;54:540-5.
33. Illman J, Corringham R, Robinson D, et al. Are inflammatory cytokines the common link between cancer-associated cachexia and depression? J Support Oncol. 2005;3:37-50.
34. Fearon K, von Meyenfeldt M., Moses A, et al. Effect of a protein and energy dense ω-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomized double blind trial. Gut. 2003;52:1479-1486.
35. Sanchetee S. Thalidomide versus thalidomide with olanzapine and megastrol acetate in treatment of cachexia in gastrointestinal cancer: a randomized trial. 2010 Gastrointestinal Cancer Symposium. Abstract #209.
36. Krasnow S, Marks D. Neuropeptides in the pathophysiology and treatment of cachexia. Curr Opin Palliat Care. 2010;4:266-71.
37. Clark, K, Loscalzo M, Trask P, et al. Psychological distress in patients with pancreatic cancer—an understudied group. Psycho-Oncol. 2010;19:1313-20.
38. McDaniel J, Musselman D, Porter M, et al. Depression in patients with cancer. Arch Gen Psychiatry. 1995;52:89-99.
39. Turaga K, Malafa M, Jacobsen P, et al. Suicide in patients with pancreatic cancer. Cancer. 2011;117:642-7.
40. Chochinov H. Dying, dignity, and new horizons in palliative end-of-life care. CA Cancer J Clin. 2006;56: 84-103.
41. The National Comprehensive Cancer Network. Distress management clinical practice guidelines in oncology, version 2.2013. Available from: http://www.nccn.org/professionals/physician_gls/pdf/distress.pdf. Accessed February 27, 2013.
42. Holland J, Alici-Evcimen Y. Depression in cancer patients. In: Supportive care in cancer therapy. Totowa, NJ: Humana Press, 2009:139-51.
43. Kim S, Shin I, Kim J, et al. Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Psychiatry Clin Neurosci. 2008;62:75-83.
44. Ohorodnyk P, Eisenhauer E, Booth C. Clinical benefit in oncology trials: is this a patient-centered or tumour-centered end-point? Eur J Cancer. 2009;
45. Labori K, Hjermstad M, Wester T, et al. Symptom profiles and palliative care in advanced pancreatic cancer—a prospective study. Support Care Cancer. 2006;14:1126-33.
46. Burris H, Moore M, Anderson J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;6:2403-13.
47. Romanus D, Kindler H, Archer L, et al. Does health-related quality of life improve for advanced pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Pain Symptom Manage. 2012;43:205-17.
48. Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013;31:23-9.
49. Temel J, Greer J, Muzikansky. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-42.
50. Bruera E, Yennurajalingam S. Palliative care in advanced cancer patients: how and when? Oncologist. 2012;17:267-73.
51. Kamal A, Bull J, Kavalieratos D, et al. Palliative care needs of patients with cancer living in the community. J Oncol Prac. 2011;7:382-8.
52. Smith T, Temin S, Alesi E, et al. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol. 2012;30:880-7.
53. Heffield K, Boyd C, Benarroch-Gampel J, et al. End-of-life care in Medicare beneficiaries dying with pancreatic cancer. Cancer. 2011;117:5003-12.
54. Baile W, Aaron J. Patient-physician communication in oncology: past, present, and future. Curr Opin Oncol. 2005;17:331-5.
55. Watts T. End-of-life care pathways as tools to promote and support a good death: a critical commentary. Eur J Cancer Care. 2012;21:20-30.
56. Kehl K. Moving toward peace: an analysis of the concept of a good death. Am J Hosp Palliat Care. 2006;23:277-86.