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Pain management and palliative care in pancreatic cancer
Curr Probl Cancer 37 (2013) 266–272
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
Pain management and palliative care in pancreatic cancer Michael A. Erdek, MD, Lauren M. King, ANP-BC, ACHPN, Susannah G. Ellsworth, MD
Pain medicine Pharmacologic Successful treatment of pain associated with pancreatic cancer begins with obtaining a comprehensive pain-directed history and physical examination. Pain intensity is typically graded on an 11-point scale ranging from 0-10, with 0 equaling no pain and 10 equaling the “worst pain imaginable.” When assessed verbally by patient report, this is properly referred to as a numerical rating scale. When assessed with a 10-cm card with no gradations where the patient points to the level of his or her pain, this is referred to as a visual analog scale. Additional important information to be garnered by the practitioner includes pain location, duration, temporal nature (constant vs intermittent), exacerbating and alleviating factors, pain medication consumption, and adverse effects related to pain medication. Opioids are considered to be the first-line medical therapy for visceral cancer pain, including pain from cancer of the pancreas.1 Treatment is typically started with short-acting opioids such as oxycodone or morphine, taken on an as-needed basis by patients with pain that is largely intermittent and episodic. Once a patient's pain becomes continuous or when pain interferes with the ability to sleep, institution of a long-acting, sustained-release opioid is appropriate. Special consideration may be given to the use of methadone, the N-methyl-d-aspartate– antagonist properties of which may provide specific value in patients whose pain has a neuropathic component. However, the long and unpredictable half-life of this agent and its multiple drug-drug interactions necessitate particular expertise with regard to its dosing and administration.2 Opioids are a “double-edge sword” in that their substantial pain-relieving properties must be employed, balancing their considerable potential for significant side effects. Common doselimiting side effects of opioids include sedation and cognitive impairment, pruritus, nausea, constipation, and respiratory depression. The prescription of a stool softener concomitant with these medications is of great importance. Although opioids are the primary pharmacologic means of pain control, there may be a role for certain adjuvant medications. Nonsteroidal anti-inflammatory drugs are beneficial in 0147-0272/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.currproblcancer.2013.10.003
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providing an opioid-sparing effect. The additional use of antineuropathic pain agents such as membrane stabilizers or neurotransmitter reuptake inhibition agents may be of value in patients with nerve involvement of the tumor and resultant neuropathic pain.
Interventional For patients whose pain is refractory to opioids or who develop dose-limiting side effects from opioids, a block of the celiac plexus with local anesthetic is often employed. Celiac plexus neurolysis (CPN), a nerve destructive procedure, may follow, depending on the result of the local anesthetic block. Neurolysis typically lasts for several months and is carried out with an agent such as alcohol or phenol. This procedure targets the sympathetic ganglion that subserves the upper gastrointestinal tract, including the pancreas, based on the rationale that the visceral afferent fibers travel with the sympathetic efferent nerve fibers. The celiac ganglion is made up of the greater, lesser, and least sympathetic nerves that traverse the diaphragmatic crura to ultimately coalesce at the level of the celiac trunk.3 The diagnostic block is typically carried out with bupivacaine or a combination of lidocaine and bupivacaine. If neurolysis is elected, alcohol in a concentration of 50%-100% or phenol usually in a concentration of 10% is employed.4 Multiple studies have demonstrated the success of this procedure for pancreatic cancer pain. Particularly evident has been the benefit in both pain intensity and quality of life (QOL) for patients who underwent the procedure.5 Additionally, predictors of successful outcome from CPN have been assessed. Patients receiving lower doses of systemic opioids at the time of the procedure, as well as those undergoing the procedure in the absence of sedation, have been found to be more likely to achieve positive outcomes.6 Patients who undergo CPN and ultimately have recurrence of their pain may undergo a repeat procedure. Success rate tends to be lower in such instances, and mean duration of pain relief has been shown to be less than half of that of an initial CPN, usually in the face of disease progression as established on radiographic imaging.7 Side effects and complications have been described in CPN. While orthostatic hypotension due to vasodilation and diarrhea due to unopposed parasympathetic tone are seen with sympathectomy, side effects such as alcohol intoxication, seizure, pneumothorax, incontinence, nerve damage, and even paralysis have also been described.8 It is strongly recommended that an experienced pain practitioner is consulted in the undertaking of this procedure. Patients affected with who are not aided by standard pharmacologic or block therapy may be considered candidates for intrathecal drug delivery.9 A temporary, percutaneous catheter is often placed to assess response and help ascertain appropriate dosing of opioids and potential agents such as local anesthetics, alpha-blockers, and calcium channel blockers. If successful, the patient is ultimately surgically treated with an implantable pump and catheter system, delivering analgesic agents directly into the central nervous system and bypassing systemic administration and its inherent limitations of effect and toxicity.
Radiation therapy Treatment paradigms for patients with locally advanced pancreatic cancer (LAPC) are changing rapidly as options for systemic treatment increase both in number and in efficacy.10,11 Early cooperative group studies suggested that concurrent chemoradiation is likely more effective than radiation alone in patients with LAPC.12 However, subsequent randomized trials of chemoradiation vs chemotherapy alone in this population have generated mixed results, even when intensified chemoradiation regimens are used.13-15 This may be because of high rates of occult metastatic disease at the time of diagnosis in patients with LAPC. Although most patients with pancreatic cancer die of metastatic disease, local failure is still fairly common, even in patients who have undergone surgical resection in addition to adjuvant therapy.16-18
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Chemoradiation Current standards therefore recommend that patients begin treatment with chemotherapy alone and receive radiation therapy only if there is no evidence of distant progression after a few months of chemotherapy and restaging. This approach theoretically selects out patients with treatment-refractory metastatic disease who are least likely to benefit from aggressive attempts at local control of the tumor. In the largest single-institution study to date investigating the use of induction chemotherapy to select patients without distant metastatic disease, who presumably would be most likely to benefit from chemoradiation therapy, Krishnan et al.19 demonstrated better overall and progression-free survival in patients who received induction chemotherapy followed by chemoradiation as compared with those who received up-front chemoradiation. At a dose of 30 Gy in 10 fractions, local control was achieved in 53% of patients in the up-front chemoradiation group and in 59% of patients in the induction chemotherapy group. However, no data on control of pain or other symptoms were provided, and it is by no means clear that radiographic disease control is correlated with symptom control.
Symptom control Few studies provide direct guidance regarding the optimal management of patients with severe symptoms related to an uncontrolled primary tumor (regardless of whether or not metastatic disease is present). In these cases, local treatments like radiation may be able to control troublesome symptoms such as pain, biliary obstruction, or gastric outlet or duodenal obstruction. To date, only 1 clinical trial in LAPC has specified pain control as a study end point. This was a small randomized study from Taiwan; it demonstrated higher rates of pain control (39% vs 6%) in patients who received gemcitabine-RT (50.4-61.2 Gy) compared with 5-FU-RT.20 The results of this study are somewhat difficult to interpret given the small sample size of 34 patients and the fact that outcomes in the 5-FU group were significantly worse than would be expected based on historical data. Another study conducted by the Eastern Cooperative Oncology Group compared gemcitabine alone to gemcitabine plus radiation therapy (1 cycle of gemcitabine followed by combination gemcitabine-RT to a total dose of 50.4 Gy) and attempted to evaluate QOL outcomes.14 The overall survival was 11.1 months in the chemoradiation arm and 9.2 months in the gemcitabine-alone arm, a difference that was statistically significant. Pain control was not a study end point. Health-related QOL declined similarly in both groups during treatment. The results of this study must be interpreted with caution as it was closed early because of slow accrual and QOL data may have been biased by patient attrition. Chemoradiation has also been compared with best supportive care (with no antineoplastic therapy) in a small randomized trial conducted in Japan.21 The study enrolled 31 patients, 16 of whom were randomized to 5-FU-based chemoradiation and 15 of whom received supportive care. Ten patients had pain before starting treatment, 8 of whom had improvement in pain after treatment. The median duration of pain control was 5.2 months. Although this study is unlikely to be replicated in the current era, it does support the use of radiation to control pain caused by pancreatic cancer in patients with locally advanced disease. In selected patients, salvage reirradiation with hypofractionated stereotactic body radiation therapy may be an option, as suggested by a recent retrospective series.22 Median radiation dose was 25 Gy (given in 5 fractions) prescribed to gross tumor alone (plus a small margin). Although the number of patients treated was fairly small at 18, the rate of pain control among patients with pain at baseline was 57%. Therapy was well tolerated with no acute grade 3 toxicity and a single episode of late grade 3 late toxicity (small bowel obstruction). In summary, the (albeit limited) available evidence suggests that radiation is a potentially effective option for symptom palliation in patients with pancreatic cancer. The expected response rate is probably between 40% and 80%. As rates of acute treatment-related toxicity are fairly low with the use of modern radiation techniques including intensity-modulated radiation therapy and stereotactic body radiation therapy,23,24 radiation therapy should be considered as a
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palliative option in patients whose pain is not adequately controlled by optimal medical management or interventional procedures such as celiac block or both. Further studies are needed to better quantify the expected clinical benefit of radiation therapy in this setting, particularly in terms of pain control, which should be considered for use as a secondary end point in clinical trials of radiation therapy among patients with pancreatic cancer.
Palliative care Pancreatic cancer disease and treatment can cause many physical and emotional challenges. Palliative medicine's goal is to relieve suffering and to improve QOL by addressing each patient's specific needs. Control of pain and non-pain symptoms, clear and effective communication, and addressing psychosocial needs are pillars of palliative care. These services can be provided concurrently with regular oncologic care to aid both patients and providers in choosing therapies consistent with patients' health care goals and to address any physical-psychosocialspiritual needs. Palliative care should be offered upon diagnosis, given the poor relative survival rate and the symptom profile associated with pancreatic malignancies. Some burdensome physical symptoms of pancreatic cancer include pain, depression, anxiety, weight loss, malabsorption, nausea, vomiting, pruritus, and jaundice. Psychosocial consequences of a cancer diagnosis can enhance physical symptoms and negatively affect QOL. Conversely, controlling physical symptoms can allow for a person to concentrate on defining their social and cultural identity in the context of serious illness, working through unresolved issues, finishing legacy work, and addressing their spiritual needs. Owing to a shortage of palliative care specialists within many communities, it is essential that all oncologists acquire primary palliative care skills: basic communication techniques and management of common symptoms. Communication Cancer generates a greater sense of dread than other life-threatening illnesses with similar prognoses.25 Being aware of and recognizing psychosocial burdens may allow for emotional growth and ease distress. Open, honest communication during the entire course of a disease trajectory is paramount (Table). In a study conducted in Canada, 90% of family members reported that it was very important to complete critical and desired tasks, resolve conflicts, and say their goodbyes toward the end of the patient's life.26 Having open discussions about prognosis, advance care planning, and preference of treatments allow patients and families to complete these critical tasks before the end of life. These conversations often cannot be fully addressed in a single clinic visit and needs to be an on-going discussion. Giving people time to process the information, as well as encouraging them to record questions for future visits, can allow for adequate family planning and identification of psychosocial needs. According to patients, family members, and health care providers, goals for communication at the end of life include talking in an honest and straightforward way, being willing to talk Table Seven steps allow successful communication, a key concept to ensure emotional growth and the ease of distress throughout palliative care in patients with cancer.28 7-Step approach to communication 1. 2. 3. 4. 5. 6. 7.
Prepare for the discussion Establish what the patient (and) family knows Determine how information is to be handled Deliver the information Respond to emotions Establish goals for care and treatment priorities Establish plan
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about dying, giving bad news in a sensitive way, listening to patients, encouraging questions, and being responsive to patients' readiness to talk about death.27 Von Guten et al.28 describe a 7-step approach for physicians for structuring communication regarding care at the end of life. Physicians should (1) prepare for discussions by confirming medical facts and establishing an appropriate environment, (2) establish what the patient (and family) knows by using openended questions, (3) determine how information is to be handled, (4) deliver the information in a sensitive but straightforward manner, (5) respond to emotions of the patients and families, (6) establish goals for care and treatment priorities, and (7) establish an overall plan. These 7 steps can be used when delivering difficult news, discussing advance care planning, managing conflict, eliciting preferences in care, and discussing death. Clayton et al.29 reported that controlling physical symptoms, providing emotional support, preserving dignity, exploring realistic goals, and discussing day-to-day living are important to maintain hope in terminally ill patients with cancer and their families. Asking what one hopes for and developing a plan to “hope for the best but plan for the worst” can help patients think about a limited future and may allow them to focus on what is personally most important to them. It is not the job of the provider to “correct” a person's hope for a miracle, instead allow them an empathetic ear and avoid false reassurances. Perpetuating false hope may prevent the patient and family from finding meaning and value in the time remaining to them.30 Hoping for unrealistic goals may prevent reconciliation, financial planning, emotional growth, resolution, and closure. A patient may say, “I am hoping that my pancreatic cancer will be cured by this second chemotherapy,” and a response could be, “I am also hopeful for this, and I am also interested in other goals that you want to focus on.” Acknowledging a patient's hope and allowing him or her to discuss uncompleted goals or tasks can help the patient identify the need for future planning. Letting the patient know that one would be there for them throughout this illness is also paramount as feelings of abandonment near the end of life and transition to hospice care can exist. Introducing hospice to a patient or family member can be challenging to a provider.30,31 A recommendation is to standardize the hospice introduction process to include all patients with prognosis of 6 months or less rather than waiting until all therapies are exhausted. Normalizing this informational visit and applying it to a standard of care in practice can help familiarize patients with hospice services and clarify any misconceptions. Introducing hospice to patients and family early while relatively “healthy” can also facilitate transition to hospice in the future as patients and families already have a basic understanding of its services.
Symptom management In addition to exercising therapeutic communication, identifying and adequately managing symptoms common to pancreatic cancer can improve a person's QOL. Two symptoms that are common in pancreatic cancer are nausea and depression. Furthermore, approximately 40% of patients with pancreatic cancer have depressive symptoms.32 According to Massie,33 the prevalence of depression in people with pancreatic cancer ranges from 33%-50%. Symptoms of clinical depression may include anorexia and weight loss (also common symptoms of cancer), negative thoughts and behavior, sleep disturbances, anhedonia, fatigue, and feelings of hopelessness. Depression can be related to psychosocial factors (financial concerns or emotional support), medical factors (prognosis or metabolic derangements), and psychological factors (coping ability or perceptions of illness).34 Treatment of depression requires looking into these 3 factors and identifying any underlying issues. Although no controlled clinical trials evaluate the efficacy of combined interventions in the pancreatic cancer population, most experts recommend an approach that combines supportive psychotherapy, patient and family education, and stimulants or antidepressants or both.35 Chaplains, social workers, and mental health counselors can help patients work through psychosocial and spiritual challenges. In choosing an antidepressant, one should target individual symptoms and limit unwanted side effects. Persons with limited life expectancy can have a trial of methylphenidate starting at
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2.5 mg orally and increased every few days up to a maximum dose of 30 mg. Methylphenidate has a rapid onset of action and can improve energy, alertness, and weakness.36 When the patient has a greater life expectancy, selective serotonin reuptake inhibitors are chosen owing to their limited side-effect profile; however, they may take up to 4-6 weeks to become effective. During the course of disease, 70%-80% of patients with pancreatic head tumors develop obstructive jaundice and 10%-20% develop duodenal obstruction.37 Both can cause intractable nausea and vomiting, which can be difficult to treat owing to the multiple underlying mechanisms and pathophysiology. Chemotherapy, motility dysfunction, opioids, constipation, anxiety, and cholangitis are other causes of nausea and vomiting in this population. Nausea and vomiting cause substantial psychological distress for patients during end of life, with poorly controlled symptoms contributing to fears of starvation and dehydration.38,39 Evaluation for metabolic abnormalities, constipation, adverse drug effect, increased tumor burden, and obstruction is paramount in locating the root causes for symptoms of nausea. Surgical and endoscopic options for outlet obstructions include biliary drainage, gastrojejunostomy, and duodenal stenting. Nasogastric tube decompression can also aid in resolving partial bowel obstructions, with a motility agent (metoclopramide) and an anticholinergic (glycopyrrolate) to decrease secretions and colicky pain.40 In appropriate cases, adding dexamethasone can reduce inflammation surrounding the tumor and bowel edema. Additionally, a Japanese multicenter study showed improved QOL scores and decreased overall symptoms of nausea in 56% of patients treated with octreotide.41 For nonobstructive nausea and vomiting, Gupta et al.42 developed a literaturebased, single-drug, stepwise protocol to aid in the treatment of nausea and vomiting. The authors describe excluding reversible causes of nausea, then using metoclopramide or haloperidol as first-line treatment, olanzapine or chlorpromazine as second-line therapy, and ondansetron as third-line nausea therapy. Ultimately, clinicians build strong relationships with patients with cancer and their families in the hopes of finding a way through the symptoms and distress, to cope with the illness experience, and to make each day as good as it can be. Working in a multidisciplinary team including social work, nursing, and pastoral care can aid this vulnerable cancer group.43 References 1. Wolfgang CL, Herman JM, Laheru DA, et al. Recent progress in pancreatic cancer. CA Cancer J Clin 2013;63:318–48. 2. Halpert D, Erdek MA. Pain management for hepatobiliary cancer. Curr Treat Options Oncol 2008;9:234–41. 3. Bahn BM, Erdek MA. Celiac plexus block and neurolysis for pancreatic cancer. Curr Pain Headache Rep 2013;17: 310–16. 4. Benzon H, Raja S, Fishman S. (eds.) Essentials of Pain Medicine, 3rd ed. Philadelphia: Elsevier; 2011. 5. Wong GY, Schroeder DR, Carns PE, et al. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer. J Am Med Assoc 2004;291:1092–9. 6. Erdek MA, Halpert DE, Gonzalez-Fernandez M, et al. Assessment of celiac plexus block and neurolysis outcomes and technique in the management of refractory visceral cancer pain. Pain Med 2010;11:92–100. 7. McGreevy K, Hurley RW, Erdek MA, et al. The effectiveness of repeat celiac plexus neurolysis for pancreatic cancer: A pilot study. Pain Pract 2013;13:89–95. 8. Neal JM, Rathmell JP. Complications in Regional Anesthesia and Pain Medicine, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2013. 9. Hameed M, Hameed H, Erdek M. Pain management in pancreatic cancer. Cancers 2011;3:43–60. 10. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817–25. 11. von Hoff D, Ervin T, Arena F, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New Engl J Med 2013;369:1691–703. 12. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic carcinoma: A randomized trial of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads plus 5-fluorouracil), and high dose radiation plus 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 1981;48(8):1705–10. 13. Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to radiotherapy alone. J Natl Cancer Inst 1988;80: 751–5. 14. Loehrer PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 2011;29:4105–12. 15. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU, and intermittent cisplatin) followed by maintenance gemcitabine versus gemcitabine alone for
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M.A. Erdek et al. / Curr Probl Cancer 37 (2013) 266–272 locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 2012;19:1592–9. Berger AC, Winter K, Hoffman JP, et al. Five year results of US intergroup/RTOG 9704 with postoperative CA19-9 o 90 U/mL and comparison to the CONKO-001 trial. Int J Radiat Oncol Biol Phys 2012;84:291–7. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs. observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. J Am Med Assoc 2007;297:267–77. Iacobuzio-Donahue C, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806–13. Krishnan S, Rana V, Janjan NA, et al. Induction chemotherapy selects locally advanced unresectable pancreatic cancer patients for optimal benefit from consolidative chemoradiation therapy. Cancer 2007;110:47–55. Li CP, Chao Y, Chi KH, et al. Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: Gemcitabine versus 5-fluorouracil, a randomized controlled study. Int J Radiat Oncol Biol Phys 2003;57:98–104. Shinchi H, Takao S, Noma H, et al. Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2002;53: 146–50. Wild AT, Hiniker S, Chang DT, et al. Re-irradiation with stereotactic body radiation therapy as a novel treatment option for isolated local recurrence of pancreatic cancer after multimodality therapy: Experience from two institutions. J Gastrointest Oncol 2013 [Epub ahead of print]. doi:10.3978/j.issn.2078-6891.2013.044. Yovino S, Poppe M, Jabbour S, et al. Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys 2011;79:158–62. Schellenberg D, Kim J, Christman-Skieller C, et al. Single-fraction stereotactic radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2011;81(1):181–8. Mishel MH. Reconceptualization of the uncertainty in illness theory. Image J Nurse Sch 1990;22:256. Heyland DK, Dodek P, Rocker G, et al. What matters most in end-of-life care: Perceptions of seriously ill patients and their family members. Can Med Assoc J 2006;174:627–33. Enrich W, Curtis JR, Shannon SE, et al. Communicating with dying patients within the spectrum of medical care from terminal diagnosis to death. Arch Intern Med 2001;161(6):868–74. von Gunten CF, Ferris FD, Emanuel LL. Ensuring competency in end-of-life care: Communication and relational skills. J Am Med Assoc 2000;284(23):3051–7. Clayton JM, Butow PN, Tattersall MH, et al. Fostering coping hope and nurturing hope when discussing the future with terminally ill cancer patients and their caregivers. Cancer 2005;103:1965–75. Casarett DJ, Quill TE. “I'm Not Ready for Hospice”: Strategies for timely and effective hospice discussions. Ann Intern Med 2007;146(6):443–9. Shin J, Casarett D. Facilitating hospice discussions: A six-step road map. J Support Oncol 2011;9(3):97–102. Pezzilli R, Campana D, Morselli-Labate AM, et al. Patient-reported outcomes in subjects with neuroendocrine tumors of the pancreas. World J Gastroenterol 2009;15(40):5067–73. Massie MJ. Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr 2004;32:57–71. Makrilia N, Indeck B, Syrigos K, et al. Depression and pancreatic cancer: A poorly understood link. JOP 2009;10(1): 69–76. Block SD. Perspectives on care at the close of life. Psychological considerations, growth, and transcendence at the end of life: The art of the possible. J Am Med Assoc 2001;285:2898–905. Ellison NM, Chevlen E, Still CD, et al. Supportive care for patients with pancreatic adenocarcinoma: Symptom control and nutrition. Hematol Oncol Clin North Am 2002;16:105–21. Crippa S, Dominguez I, Rodriguez JR, et al. Quality of life in pancreatic cancer: Analysis by stage and treatment. J Gastrointest Surg 2008;12(5):783–93. Portney RK, Thaler HT, Kornbilth AB, et al. Symptom prevalence, characteristics, and distress in a cancer population. Qual Life Res 1994;3(3):183–9. McPhee S, Winker M, Rabow M, et al. Care at the close end of life, evidence and experience. Jama Archives and Journals. United States of America: McGraw Hill; 74. Davis MP, Furste A. Glycopyrrolate: A useful drug in the palliation of mechanical bowel obstruction. J Pain Symptom Manage 1999;18(3):153–4. Hisanaga T, Shinjo T, MOrta T, et al. Multicenter prospective study on the efficacy and safety of octreotide for inoperable malignant bowel obstruction. Jpn J Clin Oncol 2010;40(8):739–45. Gupta M, Davis M, LeGrand S, et al. Nausea and vomiting in advanced cancer—“The Cleveland Clinic Protocol”. J Support Oncol 2013;11(1):8–13. Pawlik TM, Laheru D, Hruban RH, et al. Evaluating the impact of a single-day multidisciplinary clinic on the management of pancreatic cancer. Ann Surg Oncol 2008;15(8):2081–8. [Epub 2008 May 7].
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
Pain management and palliative care in pancreatic cancer Michael A. Erdek, MD, Lauren M. King, ANP-BC, ACHPN, Susannah G. Ellsworth, MD
Pain medicine Pharmacologic Successful treatment of pain associated with pancreatic cancer begins with obtaining a comprehensive pain-directed history and physical examination. Pain intensity is typically graded on an 11-point scale ranging from 0-10, with 0 equaling no pain and 10 equaling the “worst pain imaginable.” When assessed verbally by patient report, this is properly referred to as a numerical rating scale. When assessed with a 10-cm card with no gradations where the patient points to the level of his or her pain, this is referred to as a visual analog scale. Additional important information to be garnered by the practitioner includes pain location, duration, temporal nature (constant vs intermittent), exacerbating and alleviating factors, pain medication consumption, and adverse effects related to pain medication. Opioids are considered to be the first-line medical therapy for visceral cancer pain, including pain from cancer of the pancreas.1 Treatment is typically started with short-acting opioids such as oxycodone or morphine, taken on an as-needed basis by patients with pain that is largely intermittent and episodic. Once a patient's pain becomes continuous or when pain interferes with the ability to sleep, institution of a long-acting, sustained-release opioid is appropriate. Special consideration may be given to the use of methadone, the N-methyl-d-aspartate– antagonist properties of which may provide specific value in patients whose pain has a neuropathic component. However, the long and unpredictable half-life of this agent and its multiple drug-drug interactions necessitate particular expertise with regard to its dosing and administration.2 Opioids are a “double-edge sword” in that their substantial pain-relieving properties must be employed, balancing their considerable potential for significant side effects. Common doselimiting side effects of opioids include sedation and cognitive impairment, pruritus, nausea, constipation, and respiratory depression. The prescription of a stool softener concomitant with these medications is of great importance. Although opioids are the primary pharmacologic means of pain control, there may be a role for certain adjuvant medications. Nonsteroidal anti-inflammatory drugs are beneficial in 0147-0272/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.currproblcancer.2013.10.003
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providing an opioid-sparing effect. The additional use of antineuropathic pain agents such as membrane stabilizers or neurotransmitter reuptake inhibition agents may be of value in patients with nerve involvement of the tumor and resultant neuropathic pain.
Interventional For patients whose pain is refractory to opioids or who develop dose-limiting side effects from opioids, a block of the celiac plexus with local anesthetic is often employed. Celiac plexus neurolysis (CPN), a nerve destructive procedure, may follow, depending on the result of the local anesthetic block. Neurolysis typically lasts for several months and is carried out with an agent such as alcohol or phenol. This procedure targets the sympathetic ganglion that subserves the upper gastrointestinal tract, including the pancreas, based on the rationale that the visceral afferent fibers travel with the sympathetic efferent nerve fibers. The celiac ganglion is made up of the greater, lesser, and least sympathetic nerves that traverse the diaphragmatic crura to ultimately coalesce at the level of the celiac trunk.3 The diagnostic block is typically carried out with bupivacaine or a combination of lidocaine and bupivacaine. If neurolysis is elected, alcohol in a concentration of 50%-100% or phenol usually in a concentration of 10% is employed.4 Multiple studies have demonstrated the success of this procedure for pancreatic cancer pain. Particularly evident has been the benefit in both pain intensity and quality of life (QOL) for patients who underwent the procedure.5 Additionally, predictors of successful outcome from CPN have been assessed. Patients receiving lower doses of systemic opioids at the time of the procedure, as well as those undergoing the procedure in the absence of sedation, have been found to be more likely to achieve positive outcomes.6 Patients who undergo CPN and ultimately have recurrence of their pain may undergo a repeat procedure. Success rate tends to be lower in such instances, and mean duration of pain relief has been shown to be less than half of that of an initial CPN, usually in the face of disease progression as established on radiographic imaging.7 Side effects and complications have been described in CPN. While orthostatic hypotension due to vasodilation and diarrhea due to unopposed parasympathetic tone are seen with sympathectomy, side effects such as alcohol intoxication, seizure, pneumothorax, incontinence, nerve damage, and even paralysis have also been described.8 It is strongly recommended that an experienced pain practitioner is consulted in the undertaking of this procedure. Patients affected with who are not aided by standard pharmacologic or block therapy may be considered candidates for intrathecal drug delivery.9 A temporary, percutaneous catheter is often placed to assess response and help ascertain appropriate dosing of opioids and potential agents such as local anesthetics, alpha-blockers, and calcium channel blockers. If successful, the patient is ultimately surgically treated with an implantable pump and catheter system, delivering analgesic agents directly into the central nervous system and bypassing systemic administration and its inherent limitations of effect and toxicity.
Radiation therapy Treatment paradigms for patients with locally advanced pancreatic cancer (LAPC) are changing rapidly as options for systemic treatment increase both in number and in efficacy.10,11 Early cooperative group studies suggested that concurrent chemoradiation is likely more effective than radiation alone in patients with LAPC.12 However, subsequent randomized trials of chemoradiation vs chemotherapy alone in this population have generated mixed results, even when intensified chemoradiation regimens are used.13-15 This may be because of high rates of occult metastatic disease at the time of diagnosis in patients with LAPC. Although most patients with pancreatic cancer die of metastatic disease, local failure is still fairly common, even in patients who have undergone surgical resection in addition to adjuvant therapy.16-18
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Chemoradiation Current standards therefore recommend that patients begin treatment with chemotherapy alone and receive radiation therapy only if there is no evidence of distant progression after a few months of chemotherapy and restaging. This approach theoretically selects out patients with treatment-refractory metastatic disease who are least likely to benefit from aggressive attempts at local control of the tumor. In the largest single-institution study to date investigating the use of induction chemotherapy to select patients without distant metastatic disease, who presumably would be most likely to benefit from chemoradiation therapy, Krishnan et al.19 demonstrated better overall and progression-free survival in patients who received induction chemotherapy followed by chemoradiation as compared with those who received up-front chemoradiation. At a dose of 30 Gy in 10 fractions, local control was achieved in 53% of patients in the up-front chemoradiation group and in 59% of patients in the induction chemotherapy group. However, no data on control of pain or other symptoms were provided, and it is by no means clear that radiographic disease control is correlated with symptom control.
Symptom control Few studies provide direct guidance regarding the optimal management of patients with severe symptoms related to an uncontrolled primary tumor (regardless of whether or not metastatic disease is present). In these cases, local treatments like radiation may be able to control troublesome symptoms such as pain, biliary obstruction, or gastric outlet or duodenal obstruction. To date, only 1 clinical trial in LAPC has specified pain control as a study end point. This was a small randomized study from Taiwan; it demonstrated higher rates of pain control (39% vs 6%) in patients who received gemcitabine-RT (50.4-61.2 Gy) compared with 5-FU-RT.20 The results of this study are somewhat difficult to interpret given the small sample size of 34 patients and the fact that outcomes in the 5-FU group were significantly worse than would be expected based on historical data. Another study conducted by the Eastern Cooperative Oncology Group compared gemcitabine alone to gemcitabine plus radiation therapy (1 cycle of gemcitabine followed by combination gemcitabine-RT to a total dose of 50.4 Gy) and attempted to evaluate QOL outcomes.14 The overall survival was 11.1 months in the chemoradiation arm and 9.2 months in the gemcitabine-alone arm, a difference that was statistically significant. Pain control was not a study end point. Health-related QOL declined similarly in both groups during treatment. The results of this study must be interpreted with caution as it was closed early because of slow accrual and QOL data may have been biased by patient attrition. Chemoradiation has also been compared with best supportive care (with no antineoplastic therapy) in a small randomized trial conducted in Japan.21 The study enrolled 31 patients, 16 of whom were randomized to 5-FU-based chemoradiation and 15 of whom received supportive care. Ten patients had pain before starting treatment, 8 of whom had improvement in pain after treatment. The median duration of pain control was 5.2 months. Although this study is unlikely to be replicated in the current era, it does support the use of radiation to control pain caused by pancreatic cancer in patients with locally advanced disease. In selected patients, salvage reirradiation with hypofractionated stereotactic body radiation therapy may be an option, as suggested by a recent retrospective series.22 Median radiation dose was 25 Gy (given in 5 fractions) prescribed to gross tumor alone (plus a small margin). Although the number of patients treated was fairly small at 18, the rate of pain control among patients with pain at baseline was 57%. Therapy was well tolerated with no acute grade 3 toxicity and a single episode of late grade 3 late toxicity (small bowel obstruction). In summary, the (albeit limited) available evidence suggests that radiation is a potentially effective option for symptom palliation in patients with pancreatic cancer. The expected response rate is probably between 40% and 80%. As rates of acute treatment-related toxicity are fairly low with the use of modern radiation techniques including intensity-modulated radiation therapy and stereotactic body radiation therapy,23,24 radiation therapy should be considered as a
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palliative option in patients whose pain is not adequately controlled by optimal medical management or interventional procedures such as celiac block or both. Further studies are needed to better quantify the expected clinical benefit of radiation therapy in this setting, particularly in terms of pain control, which should be considered for use as a secondary end point in clinical trials of radiation therapy among patients with pancreatic cancer.
Palliative care Pancreatic cancer disease and treatment can cause many physical and emotional challenges. Palliative medicine's goal is to relieve suffering and to improve QOL by addressing each patient's specific needs. Control of pain and non-pain symptoms, clear and effective communication, and addressing psychosocial needs are pillars of palliative care. These services can be provided concurrently with regular oncologic care to aid both patients and providers in choosing therapies consistent with patients' health care goals and to address any physical-psychosocialspiritual needs. Palliative care should be offered upon diagnosis, given the poor relative survival rate and the symptom profile associated with pancreatic malignancies. Some burdensome physical symptoms of pancreatic cancer include pain, depression, anxiety, weight loss, malabsorption, nausea, vomiting, pruritus, and jaundice. Psychosocial consequences of a cancer diagnosis can enhance physical symptoms and negatively affect QOL. Conversely, controlling physical symptoms can allow for a person to concentrate on defining their social and cultural identity in the context of serious illness, working through unresolved issues, finishing legacy work, and addressing their spiritual needs. Owing to a shortage of palliative care specialists within many communities, it is essential that all oncologists acquire primary palliative care skills: basic communication techniques and management of common symptoms. Communication Cancer generates a greater sense of dread than other life-threatening illnesses with similar prognoses.25 Being aware of and recognizing psychosocial burdens may allow for emotional growth and ease distress. Open, honest communication during the entire course of a disease trajectory is paramount (Table). In a study conducted in Canada, 90% of family members reported that it was very important to complete critical and desired tasks, resolve conflicts, and say their goodbyes toward the end of the patient's life.26 Having open discussions about prognosis, advance care planning, and preference of treatments allow patients and families to complete these critical tasks before the end of life. These conversations often cannot be fully addressed in a single clinic visit and needs to be an on-going discussion. Giving people time to process the information, as well as encouraging them to record questions for future visits, can allow for adequate family planning and identification of psychosocial needs. According to patients, family members, and health care providers, goals for communication at the end of life include talking in an honest and straightforward way, being willing to talk Table Seven steps allow successful communication, a key concept to ensure emotional growth and the ease of distress throughout palliative care in patients with cancer.28 7-Step approach to communication 1. 2. 3. 4. 5. 6. 7.
Prepare for the discussion Establish what the patient (and) family knows Determine how information is to be handled Deliver the information Respond to emotions Establish goals for care and treatment priorities Establish plan
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about dying, giving bad news in a sensitive way, listening to patients, encouraging questions, and being responsive to patients' readiness to talk about death.27 Von Guten et al.28 describe a 7-step approach for physicians for structuring communication regarding care at the end of life. Physicians should (1) prepare for discussions by confirming medical facts and establishing an appropriate environment, (2) establish what the patient (and family) knows by using openended questions, (3) determine how information is to be handled, (4) deliver the information in a sensitive but straightforward manner, (5) respond to emotions of the patients and families, (6) establish goals for care and treatment priorities, and (7) establish an overall plan. These 7 steps can be used when delivering difficult news, discussing advance care planning, managing conflict, eliciting preferences in care, and discussing death. Clayton et al.29 reported that controlling physical symptoms, providing emotional support, preserving dignity, exploring realistic goals, and discussing day-to-day living are important to maintain hope in terminally ill patients with cancer and their families. Asking what one hopes for and developing a plan to “hope for the best but plan for the worst” can help patients think about a limited future and may allow them to focus on what is personally most important to them. It is not the job of the provider to “correct” a person's hope for a miracle, instead allow them an empathetic ear and avoid false reassurances. Perpetuating false hope may prevent the patient and family from finding meaning and value in the time remaining to them.30 Hoping for unrealistic goals may prevent reconciliation, financial planning, emotional growth, resolution, and closure. A patient may say, “I am hoping that my pancreatic cancer will be cured by this second chemotherapy,” and a response could be, “I am also hopeful for this, and I am also interested in other goals that you want to focus on.” Acknowledging a patient's hope and allowing him or her to discuss uncompleted goals or tasks can help the patient identify the need for future planning. Letting the patient know that one would be there for them throughout this illness is also paramount as feelings of abandonment near the end of life and transition to hospice care can exist. Introducing hospice to a patient or family member can be challenging to a provider.30,31 A recommendation is to standardize the hospice introduction process to include all patients with prognosis of 6 months or less rather than waiting until all therapies are exhausted. Normalizing this informational visit and applying it to a standard of care in practice can help familiarize patients with hospice services and clarify any misconceptions. Introducing hospice to patients and family early while relatively “healthy” can also facilitate transition to hospice in the future as patients and families already have a basic understanding of its services.
Symptom management In addition to exercising therapeutic communication, identifying and adequately managing symptoms common to pancreatic cancer can improve a person's QOL. Two symptoms that are common in pancreatic cancer are nausea and depression. Furthermore, approximately 40% of patients with pancreatic cancer have depressive symptoms.32 According to Massie,33 the prevalence of depression in people with pancreatic cancer ranges from 33%-50%. Symptoms of clinical depression may include anorexia and weight loss (also common symptoms of cancer), negative thoughts and behavior, sleep disturbances, anhedonia, fatigue, and feelings of hopelessness. Depression can be related to psychosocial factors (financial concerns or emotional support), medical factors (prognosis or metabolic derangements), and psychological factors (coping ability or perceptions of illness).34 Treatment of depression requires looking into these 3 factors and identifying any underlying issues. Although no controlled clinical trials evaluate the efficacy of combined interventions in the pancreatic cancer population, most experts recommend an approach that combines supportive psychotherapy, patient and family education, and stimulants or antidepressants or both.35 Chaplains, social workers, and mental health counselors can help patients work through psychosocial and spiritual challenges. In choosing an antidepressant, one should target individual symptoms and limit unwanted side effects. Persons with limited life expectancy can have a trial of methylphenidate starting at
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2.5 mg orally and increased every few days up to a maximum dose of 30 mg. Methylphenidate has a rapid onset of action and can improve energy, alertness, and weakness.36 When the patient has a greater life expectancy, selective serotonin reuptake inhibitors are chosen owing to their limited side-effect profile; however, they may take up to 4-6 weeks to become effective. During the course of disease, 70%-80% of patients with pancreatic head tumors develop obstructive jaundice and 10%-20% develop duodenal obstruction.37 Both can cause intractable nausea and vomiting, which can be difficult to treat owing to the multiple underlying mechanisms and pathophysiology. Chemotherapy, motility dysfunction, opioids, constipation, anxiety, and cholangitis are other causes of nausea and vomiting in this population. Nausea and vomiting cause substantial psychological distress for patients during end of life, with poorly controlled symptoms contributing to fears of starvation and dehydration.38,39 Evaluation for metabolic abnormalities, constipation, adverse drug effect, increased tumor burden, and obstruction is paramount in locating the root causes for symptoms of nausea. Surgical and endoscopic options for outlet obstructions include biliary drainage, gastrojejunostomy, and duodenal stenting. Nasogastric tube decompression can also aid in resolving partial bowel obstructions, with a motility agent (metoclopramide) and an anticholinergic (glycopyrrolate) to decrease secretions and colicky pain.40 In appropriate cases, adding dexamethasone can reduce inflammation surrounding the tumor and bowel edema. Additionally, a Japanese multicenter study showed improved QOL scores and decreased overall symptoms of nausea in 56% of patients treated with octreotide.41 For nonobstructive nausea and vomiting, Gupta et al.42 developed a literaturebased, single-drug, stepwise protocol to aid in the treatment of nausea and vomiting. The authors describe excluding reversible causes of nausea, then using metoclopramide or haloperidol as first-line treatment, olanzapine or chlorpromazine as second-line therapy, and ondansetron as third-line nausea therapy. Ultimately, clinicians build strong relationships with patients with cancer and their families in the hopes of finding a way through the symptoms and distress, to cope with the illness experience, and to make each day as good as it can be. Working in a multidisciplinary team including social work, nursing, and pastoral care can aid this vulnerable cancer group.43 References 1. Wolfgang CL, Herman JM, Laheru DA, et al. 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