As palliative care moves from care of the dying to focus on any patient with life-threatening illness, nurses working in this area will need to become familiar with common pain syndromes seen in those surviving their illness. In particular, the prevalence of cancer is increasing globally, with approximately 17 million new cases projected for 2020.1,2 As antitumor therapies become more effective, with greater survival rates as a result, the prevalence of persistent pain syndromes is also increasing. These syndromes can be due to surgery, chemotherapy, radiotherapy, stem cell transplant, and hormonal therapies. Palliative care and hospice teams will be asked to provide care for these patients and their families in greater numbers, requiring awareness of these syndromes along with management techniques that may vary in focus from care of the actively dying. To illustrate the complex array of complications that can occur as a result of cancer treatment, a case is presented that describes the course experienced by one patient many years after therapy, as well as the management provided by the palliative care and hospice teams. More extensive discussion of these painful syndromes follows. Specifics regarding the treatment of cancer pain are beyond the scope of this article and can be found in detail in other publications.3
Mrs P. was admitted to the palliative care unit 28 years after her original diagnosis of cervical cancer. She had survived her cancer, but had suffered through a very long, complex, and painful medical history. Mrs P. was diagnosed with cervical cancer at the age of 30 years and underwent a radical hysterectomy. One year later, the patient had recurrence of the cervical cancer within the pelvis, and she underwent chemotherapy (cisplatin and 5-fluorouracil [5-FU]) followed by radiation therapy. Mrs P. experienced persistent radiation-induced proctosigmoiditis, likely exacerbated by the effects of the radiosensitizing action of 5-FU, and underwent surgery for colostomy placement. She also had continued bladder damage, radiation cystitis, and ultimately needed urostomy placement 9 years after radiation therapy. Because of ureteral strictures, Mrs P. required bilateral nephrostomy tube placement, with stents changed every 6 weeks. One year later, after developing a bowel obstruction, Mrs P. required an exploratory laparotomy with extensive bowel resection and gastrostomy tube placement. It was clear that there was insufficient bowel for absorption of nutrients, and total parenteral nutrition was initiated. Mrs P. then underwent total right hip replacement surgery after developing hip fracture. Several years later, Mrs P. developed a vesicovaginal fistula and, despite aggressive management, had persistent skin excoriation due to leakage of urine (Figure 1).
Mrs P. went through countless hospitalizations since her original diagnosis, experienced multiple intensive care unit admissions, had numerous infections including an abdominal abscess, and experienced many complications such as skin ulcerations, chronic renal insufficiency, deep vein thrombosis, pulmonary embolism, and depression. Pain was a persistent problem, despite extensive treatment. Mrs P. had low back pain with radiculopathy in the left leg. She reported a constant throbbing sensation in the lower extremities bilaterally with neuropathy. Furthermore, she experienced pain at the nephrostomy tube sites; this pain was very intense at times, interrupting her sleep. The constant skin excoriation due to leakage from the vesicovaginal fistula was extremely painful and very difficult to treat. She also had multiple skin wounds and areas of cellulitis. Mrs P. was taking extended-release and immediate-release morphine, pregabalin, and methadone to help with these areas of chronic pain; neurolytic blocks had proved ineffective.
At the time of admission, she was a 58-year-old widow with four adult children. Because she was bedbound and required care 24 hours a day, her children provided care for her each night, and a hired caregiver was with her during the day while her children worked. After becoming more debilitated and spending more time in bed, she was admitted to the inpatient palliative care unit after another fall at home. She informed the team that she no longer wanted to pursue further life-prolonging therapies and wished to discontinue artificial nutrition. She was fully aware that her cancer had been cured, but the incapacitating adverse effects had become unmanageable and overwhelming. The team sought assistance from social services to determine if any additional resources could be provided, but she was receiving all available support. Psychiatry was consulted, found her to be competent, and, although depressed, able to understand and make this decision. A family meeting was held, and her children expressed their support for her and this decision. Her prognosis, although difficult to predict, was thought to be approximately weeks, depending on how much oral intake she could sustain. Because of the amount of care she required, family could no longer safely care for her in the home, and she was transferred to an inpatient hospice facility. She died comfortably 2 weeks later.
Cancer Treatment and Persistent Pain Syndromes
The history of cancer treatment is one of amazing discoveries in a relatively short period. Before the second half of the 1900s, the only widespread treatment options included surgery and radiation therapy. With advances in chemotherapy development, survival was prolonged, and in the 1960s and 1970s, genuine cures were realized for some leukemias, lymphomas, and, later, germ cell tumors. More recent advances, including the introduction of tyrosine kinase inhibitors, the application of hormonal therapies, and the use of stem cell transplant, continue these improvements in survival.4
Acute pain syndromes can result from these treatments, notably postoperative incisional pain, mucositis from chemotherapy, and desquamating skin reactions due to radiotherapy. In most cases, these painful consequences of treatment will resolve. Unfortunately, there are also chronic pain syndromes that can result from these treatments, and some patients will experience pain for the remainder of their lives (Table 1).5 Until research reveals those at risk as well as preventive strategies, palliative care nurses will need to be able to identify and manage these potentially devastating painful complications of cancer treatment.
Postthoracotomy and postmastectomy syndromes have long been identified as possible long-term complications of these procedures.6 Prospective studies suggest that risk factors for persistent pain include significant acute pain after surgery.7 Phantom sensations can result from amputations for sarcomas or other malignancies. Investigations suggest that providing nerve blocks or infiltration of the wound with local anesthetic before amputation can limit the intensity and/or duration of phantom sensations. Early studies suggest that minimally invasive procedures can also produce persistent pain syndromes, although comparative studies of the prevalence of pain after newer versus conventional procedures are few.
Radiation therapy has evolved dramatically in the past few decades with the use of linear accelerators, 3-dimensional conformal radiotherapy, proton beam therapy, and stereotactic radiosurgery. These all allow more specific targeting of malignant tissues while sparing normal cells. Unfortunately, late effects of radiotherapy have been identified, and patients who have been treated with older methods of delivery are at risk. These late effects have been demonstrated to occur from 6 months to 20 years after treatment. Painful complications, which may arise from radiotherapy alone or as a result of concomitant treatment with chemotherapy, include plexopathies, osteoradionecrosis, and fractures.6-8 Mrs P. is an example of someone whose cancer was cured, but the resultant pain syndromes resulted in significantly impaired quality of life.
Few studies explore these painful phenomena, and most information is gleaned from case series or reports. The prevalence of plexopathies ranges from 2% to 5%.9 Breast and lung cancer patients are at risk for brachial plexopathies, where pain radiates down the affected arm.10,11 Risk factors for plexopathy after breast cancer include younger age and having received chemotherapy.12 Patients with colorectal or gynecologic tumors are at risk for lumbosacral plexopathy, where pain radiates to the pelvis, groin, or leg. Little is known about the prevalence of lumbosacral plexopathy, likely because of the historically short survival times associated with these malignancies in the past. Patients describe significant neuropathic pain, including burning, tingling, and electrical sensations, radiating along the affected area or extremity.
Osteoradionecrosis with resultant fracture can occur in any bone that has been in the treatment field. That of Mrs P. is a classic example of hip fracture seen in individuals treated for cervical, other gynecologic, or colorectal cancers. As with other complications of radiotherapy, this effect is likely due to the combined effects of radiosensitizers (such as 5-FU) and radiation therapy.
Chemotherapy can lead to chronic pain states through a variety of syndromes. Long-term steroid use can lead to aseptic necrosis and osteoporotic fractures. Chemotherapy-induced peripheral neuropathy (CIPN) is increasing in prevalence as people with cancer are surviving longer, receiving more treatment, and receiving more neurotoxic agents. Persistent CIPN can result in impaired mobility and reduced quality of life. These neuropathies are symmetrical, distal, and, in most cases, painful, although some patients describe numbness without pain. The distribution is usually in a "stocking and glove" pattern, typically in the feet/toes and fingers/hands (Table 1). Common terms used by patients to describe this pain are tingling, burning, and painful numbness sensations. Chemotherapy-induced peripheral neuropathy typically develops during treatment with a neurotoxic agent and may escalate in intensity after the final dose, in a process called "coasting." Dose, duration, and schedule of delivery of the chemotherapeutic agent, as well as previous exposure to neurotoxic agents, may all affect the development of CIPN.13 Furthermore, comorbid conditions such as diabetes, nutritional deficits, or HIV infection may increase the risk of CIPN.14 Unfortunately, few studies systematically evaluate CIPN in a prospective manner.15
The underlying mechanisms of CIPN are not yet fully understood, but are currently being studied in both human and animal models.16 Several hypotheses include mitochondrial dysfunction, cytokine-mediated inflammation, deficiencies in neurotrophic factors, and other causes.17-22 Prevention strategies will be more effective once the pathophysiology is more clearly understood. Neuroprotective agents, such as acetyl-L-carnitine, ethosuximide, and olesoxime, have been found to prevent CIPN in rodent models.23-25 Human trials have been hampered by design limitations, including insufficiently powered studies due to small sample size, lack of randomization, absence of a control group, and heterogeneous samples of patients who have received a variety of chemotherapeutic agents. To date, no drug has been proven to prevent CIPN in human trials.26 Regrettably, treatment studies have suffered from similar trial design limitations, and no study has revealed superior efficacy of a particular analgesic, including amitriptyline, nortriptyline, gabapentin, and lamotrigine.27-30 A pilot study of topical baclofen, amitriptyline, and ketamine resulted in some evidence for the efficacy of this therapy, and larger trials are under way.31 Current treatment of CIPN is empiric and includes agents commonly used for other neuropathic conditions, notably antiepilepsy drugs, antidepressants, opioids, local anesthetics, and other pharmacological therapies. Safety measures should be instituted to prevent falls, and rehabilitation can assist with gait training and muscle strengthening. Palliative care nurses in the home can assess for risks such as loose carpets, water heaters set too hot, and lack of grab bars or nonskid surfaces in showers or tubs.14
Stem Cell Transplant
Hematopoietic stem cell transplant has advanced survival rates for leukemias, lymphomas, and multiple myelomas. Formerly called bone marrow transplant, this newer technique obviates the need for painful bone marrow extraction. Peripheral blood is extracted before high-dose chemotherapy and/or radiotherapy to gather stem cells, which are reinfused after the patient receives treatment to produce new blood cells. Autologous transplants include the individual's own blood, whereas allogeneic transplants use donated cells from another individual. Although greatly enhancing the potential for cure of the underlying cancer, it is now becoming apparent that long-term complications can occur. Graft-versus-host disease (GVHD) is the most common, and most serious, complication of stem cell transplantation. Graft-versus-host disease is considered chronic when it continues for 100 days after transplant or occurs after this time. Chronic GVHD can occur in up to 80%, with the usual sites affected including the skin, liver, oral or vaginal mucosa, gastrointestinal tract, lungs, and eyes.32-34 Those at risk for chronic GVHD include patients receiving an allogeneic transplant, those with histocompatability disparities between donor and recipient, previous severe acute GVHD, and older age of the patient and/or donor, as well as mismatch in sex between donor and recipient.35 Patients with skin involvement affecting more than 50% of their body surface area, as well those with persistent thrombocytopenia and hyperbilirubinemia, are at risk for reduced survival.34
The skin changes in chronic GVHD are very similar to those seen in scleroderma. Painful joint contractures, skin atrophy, and ulceration occur, most commonly affecting the trunk, buttocks, hips, and thighs. Loss of mobility occurs, leading to generalized muscle wasting. Topical corticosteroids or topical tacrolimus has been reported to relieve skin changes if the affected area is localized. Ulcers can affect the oral and vaginal membranes, leading to severe persistent pain. Oral dexamethasone topical solutions can reduce oral pain, whereas estrogen gels have been used to diminish vaginal pain. Skin assessment is essential as fungal, bacterial, and viral infections are common when open lesions develop. These are worsened by chronic immunosuppressive therapy and can lead to septicemia or death. Ocular pain and photophobia can also occur, with patients describing severe burning, dryness, or a feeling of "sandpaper rubbing the eyes."35 The quality of life of patients with painful chronic GVHD is severely impaired, yet little has been studied about the palliative care needs of these patients.
Hormonal therapies have contributed greatly to the prolonged survival rates seen in people with breast, prostate, and gynecologic cancers. These agents can relieve pain by reducing tumor burden; however, their use can also precipitate joint pain. Aromatase inhibitors (AIs) are now standard treatment for early-stage breast cancers in postmenopausal women with estrogen and progesterone receptor-positive tumors.36-38 These drugs, including anastrozole (Arimidex; AstraZeneca, Wilmington, DE), letrozole (Femara; Novartis, Princeton, NJ), and exemestane (Aromasin; Pfizer, New York, NY), block the conversion of androgen to estrogen in peripheral tissues and have been shown to be superior to earlier agents such as tamoxifen.39,40 Most women with breast cancer will receive this therapy for 5 to 10 years. Although highly effective in prolonging survival, AIs are associated with potential adverse effects, including those anticipated with estrogen deprivation, including hot flashes, night sweats, vaginal dryness, and sexual dysfunction. Osteopenia, osteoporosis, and fractures can also occur, and most guidelines recommend monitoring with serial bone density scans along with the use of supplemental vitamin D, calcium, and exercise.41 In addition to these potentially painful adverse effects, significant arthralgias appear to be common with the use of AIs. Women describe joint pain and stiffness affecting any joint but more often in the hands, arms, knees, ankles, hips, and back.42 These appear to be worse in the morning and improve with movement. In one study of postmenopausal women with stage I to III breast cancer taking AIs, 47% reported joint pain, and 44% described joint stiffness.43 The pain was described by 67% of the women as moderate to severe. Risk factors included having received prior taxane-based chemotherapy (eg, paclitaxel or docetaxol). In another large study, risk factors included previous hormone replacement therapy, prior chemotherapy, and obesity.44
For most women, joint pain resolves when AI therapy is discontinued; however, clinical experience suggests that a small percentage of women will experience persistent pain.45 In addition, because reduction in estrogen is associated with osteoporosis, it is likely that these patients are at significant risk for fractures and resultant pain. Finally, assessment must carefully discern whether this is treatment-related arthralgia versus bone metastases.
Women describe using standard analgesics, including acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, along with glucosamine/chondroitin, omega-3 fish oil, probiotics, and exercise.43 A randomized controlled clinical trial of twice-weekly acupuncture delivered over 6 weeks revealed significant improvement in mean worst pain scores (3.0 in the treatment group vs 5.5 in the sham acupuncture group; P < .001).46 Other treatments under study include vitamin D (ergocalciferol) and testosterone. Much more information is needed about the prevalence of pain syndromes associated with hormonal therapy, along with an understanding of the mechanisms of these painful syndromes so that effective prevention and treatment strategies can be designed.
Role of Palliative Care Nurses
The case of Mrs P. demonstrates the need for palliative care nurses to understand that cancer pain can result not only from tumor, but also from the treatment of malignancy. As cancer survival increases, palliative care nurses will care for more patients like Mrs P. who are technically cured of their malignancy, but have severe chronic pain that affects all aspects of quality of life. Palliative care nurses are uniquely qualified to care for these patients because of their expertise in assessment and management of complex pain syndromes (see Table 2 for additional resources). Nurses specially trained in palliative care also understand that illness affects family members and that they need to be a focus of care along with the patient. Mrs P.'s family was under considerable stress seeing their mother in pain, as well as balancing her needs along with their need to continue employment and manage their families. They were included throughout the trajectory of care, from the outpatient clinic, to the home, during decision making on the palliative care unit, and, finally, while in an inpatient hospice unit.
Mrs P.'s case also illustrates the role of suffering and existential distress. Pain resulted in limited mobility for Mrs P., decreasing her ability to leave her home. Her long illness challenged friendships, limiting outside relationships. She questioned her religious teachings and spiritual beliefs, wondering how God would have allowed this to happen. Financial limitations loomed; she knew she would not be able to remain in her home much longer. All of these factors contributed to her suffering. Her suffering illustrates the need for interdisciplinary care, the hallmark of palliative care. No one discipline could meet all of Mrs P.'s physical, emotional, spiritual, and financial needs. The team approach was absolutely crucial, along with referrals from psychiatry, wound care, the ethics team, and other experts.
Pain experienced by those with cancer is undergoing a shift in character from primarily tumor-related to the addition of treatment-related pain syndromes. As the benefits of palliative care for all patients, not just the dying, become widely understood, nurses in this area will likely see more cancer patients with persistent treatment-related pain syndromes. Awareness of these syndromes allows palliative care nurses to use their existing pain management skills to this evolving phenomenon.
1. Boyle P, Levin B, eds. World Cancer Report
. Lyon, France: International Agency for Research on Cancer; 2008.
2. Jemal A, Bray F, Center MM, et al Global cancer statistics. CA Cancer J Clin
3. Ferrell B, Paice JA. The management of cancer pain. CA Cancer J Clin
4. DeVita VT, Chu E. A history of cancer chemotherapy. Cancer Res
5. Paice JA. Chronic treatment-related pain in cancer survivors. Pain
6. Burton AW, Fanciullo GJ, Beasley RD, et al Chronic pain in the cancer survivor: a new frontier. Pain Med
7. Levy MH, Chwistek M, Mehta RS, et al Management of chronic pain in cancer survivors. Cancer J
8. Baxter NN, Habermann EB, Tepper JE, et al Risk of pelvic fractures in older women following pelvic irradiation. JAMA
9. Jaeckle KA. Neurologic manifestations of neoplastic and radiation-induced plexopathies. Semin Neurol
10. Dropcho EJ, Dropcho EJ. Neurotoxicity of radiation therapy. Neurol Clin
11. Fathers E, Thrush D, Huson SM, et al Radiation-induced brachial plexopathy in women treated for carcinoma of the breast. Clin Rehab
12. Olsen NK, Pfeiffer P, Johannsen L, et al Radiation-induced brachial plexopathy: neurological follow-up in 161 recurrence-free breast cancer patients. Int J Radiat Oncol Biol Phys
13. Gutierrez-Gutierrez G, Sereno M, Miralles A, et al Chemotherapy-induced peripheral neuropathy: clinical features, diagnosis, prevention and treatment strategies. Clin Transl Oncol
14. Stubblefield MD, Burstein HJ, Burton AW, et al NCCN task force report: management of neuropathy in cancer. JNCCN
. 2009;7 suppl 5:S1-S26; >quiz S27-S28>.
15. Hausheer FH, Schilsky RL, Bain S, et al Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol
16. Xiao W, Naso L, Bennett GJ. Experimental studies of potential analgesics for the treatment of chemotherapy-evoked painful peripheral neuropathies. Pain Med
17. Flatters SJ, Bennett GJ. Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain
18. Siau C, Bennett GJ. Dysregulation of cellular calcium homeostasis in chemotherapy-evoked painful peripheral neuropathy. Anesth Anal
19. Siau C, Xiao W, Bennett GJ. Paclitaxel- and vincristine-evoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells. Exp Neurol
20. Xiao W, Boroujerdi A, Bennett GJ, Luo ZD. Chemotherapy-evoked painful peripheral neuropathy: analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit. Neuroscience
21. Cata JP, Weng HR, Dougherty PM. Behavioral and electrophysiological studies in rats with cisplatin-induced chemoneuropathy. Brain Res
22. Meregalli C, Canta A, Carozzi VA, et al Bortezomib-induced painful neuropathy in rats: a behavioral, neurophysiological and pathological study in rats. Eur J Pain
23. Flatters SJ, Bennett GJ. Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain
24. Flatters SJ, Xiao WH, Bennett GJ. Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy. Neurosci Lett
25. Xiao WH, Bennett GJ. Chemotherapy-evoked neuropathic pain: abnormal spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its suppression by acetyl-L-carnitine. Pain
26. Wolf S, Barton D, Kottschade L, et al Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer
27. Kautio AL, Haanpaa M, Saarto T, et al Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage
28. Rao RD, Flynn PJ, Sloan JA, et al Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer
29. Hammack JE, Michalak JC, Loprinzi CL, et al Phase III evaluation of nortriptyline for alleviation of symptoms of cis
-platinum-induced peripheral neuropathy. Pain
30. Rao RD, Michalak JC, Sloan JA, et al Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer
31. Barton D, Wos E, Qin R, et al A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer
32. Fimiani M, De Aloe G, Cuccia A. Chronic graft versus host disease and skin. J Eur Acad Dermatol Venereol
33. Friedrichs B, Tichelli A, Bacigalupo A, et al Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial. Lancet Oncol
34. Vargas-Diez E, Garcia-Diez A, Marin A, et al Life-threatening graft-vs-host disease. Clin Dermatol
35. Horwitz ME, Sullivan KM. Chronic graft-versus-host disease. Blood Rev
36. Baum M, Buzdar A, Cuzick J, et al Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer
37. Goss PE, Ingle JN, Martino S, et al A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. New Engl J Med
38. Howell A, Cuzick J, Baum M, et al Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet
39. Burstein HJ, Winer EP. Aromatase inhibitors and arthralgias: a new frontier in symptom management for breast cancer survivors. J Clin Oncol
40. Kataja V, Castiglione M; ESMO Working Group. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol
. 2009;20 suppl 4:10-14.
41. Coleman RE, Bolten WW, Lansdown M, et al Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev
42. Mao JJ, Stricker C, Bruner D, et al Patterns and risk factors associated with aromatase inhibitor-related arthralgia among breast cancer survivors. Cancer
43. Crew KD, Greenlee H, Capodice J, et al Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol
44. Sestak I, Cuzick J, Sapunar F, et al Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis. Lancet Oncol
45. Donnellan PP, Douglas SL, Cameron DA, Leonard RC. Aromatase inhibitors and arthralgia. J Clin Oncol
46. Crew KD, Capodice JL, Greenlee H, et al Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer. J Clin Oncol
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