Management of Infections in Palliative Care Patients with Advanced Cancer

Transcription

1 64 Journal of Pain and Symptom Management Vol. 24 No. 1 July 2002 Review Article Management of Infections in Palliative Care Patients with Advanced Cancer Stephanie Nagy-Agren, MD, and Harold B. Haley, MD Department of Internal Medicine (S.N.-A.), University of Virginia School of Medicine Charlottesville, Virginia and Chief, Infectious Diseases (S.N.-A.), Veterans Affairs Medical Center, Salem, Virginia; and Department of Surgery (H.B.H.), Baylor College of Medicine, Houston, Texas and Carilion Hospice (H.B.H.), Roanoke, Virginia, USA Abstract To characterize infections and their management in oncology patients at the end of life, we conducted a review of the literature. Eight studies assessing infection in 957 patients with various malignancies were identified. Forty-two percent of terminally ill patients developed infections in the final phase of care. The greatest frequency of treatment with antibiotics occurred in acute care hospitals. Enterobacteriaceae and S. aureus were the most frequently isolated bacteria, and urinary and respiratory tracts the most frequently involved sites of infection. A total of 19 39% of individuals with suspected infection and advanced cancer died. The decision whether to treat or not in the palliative care setting may be complex and requires an individualized approach. Further research in this area will help develop a consensus for management that will facilitate education of students and residents regarding complex decisions of care of infections at the end of life. J Pain Symptom Manage 2002; 24: U.S. Cancer Pain Relief Committee, Key Words Death, terminal patient, cancer, infection, palliative care Address reprint requests to: Stephanie Nagy-Agren, MD, Chief, Infectious Diseases Section, VAMC 111L, Salem, VA USA. Accepted for publication: October 22, The findings contained in this article were presented in part at the European Association for Cancer Education 14th Annual Scientific Meeting, Antwerp, Belgium, 4 May Introduction Most patients with cancer undergo their terminal illness in the acute care hospital, where they are at risk of receiving invasive or uncomfortable non-palliative interventions. 1 An early review of medical records of patients dying in extended-care facilities found that a frequent cause of death was untreated infection; patients with cancer were treated less frequently, a significant difference compared to other underlying diagnoses. 2 Authors of this 1979 study hoped their observations would encourage dialogue on this difficult subject, suggesting that the more simple a potential treatment, the more difficult it was to withhold, regardless of the hopelessness of the underlying condition. A more recent report compiled by the Council on Ethical and Judicial Affairs of the American Medical Association lists antibiotics among lifesustaining treatments that can serve to prolong life without reversing the underlying medical condition. 3 Cancer patients are particularly susceptible to infections due to a variety of disease-related and therapy-induced factors. Factors contributing to increased susceptibility to infection in U.S. Cancer Pain Relief Committee, /02/$ see front matter Published by Elsevier, New York, New York PII S (02)

2 Vol. 24 No. 1 July 2002 Management of Infections in Patients with Advanced Cancer 65 patients with advanced cancer are varied and include impaired immunity of multiple possible etiologies, malnutrition, asthenia, decreased level of consciousness, immobility, failure of host barriers, and the use of foreign bodies. 4 Infection is a leading cause of death in cancer patients, making the decision to treat and how to treat infections in a palliative care setting a difficult one. 5 Although there is much information and there are numerous guidelines directing management of patients with hematologic malignancies undergoing chemotherapy, with or without neutropenia, there is little information describing management of infections in patients with advanced cancers. From our clinical experience, the patterns of treatment of infections in advanced cancer patients are without clinical consensus. While recognizing that treatment of defined infections and their symptoms can provide good palliation, we questioned the frequent indiscriminate and nonspecific use of antibiotics, as seen in our clinical practice. To better define the care received by advanced cancer patients who develop infection, we conducted a literature review. The purpose was to describe the infections identified, their management, and to further discern the role of palliative versus non-palliative measures. We hoped that the findings could lead to recommendations to improve care. Methods A computerized Medline search of the English-language literature, through the National Library of Medicine, from January 1976 through January 2001, identified 8 reports describing infections in 957 patients with advanced cancer. Articles that were selected contained objective data regarding clinical infections in advanced cancer patients. Articles were excluded that focused on management of neutropenic fever or other infectious aspects involved in actively treating cancer in the non-palliative phase, or if emphasis centered on infection control epidemiology or practices. Key words for the search strategy included palliative care, death, cancer, neoplasm, infection, antibiotic, and terminal care. Search of additional databases, including Bioethicsline, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) did not reveal additional studies. A manual search of the references of identified reports did not reveal further relevant studies. A descriptive review of the results of these 8 studies was pursued. Results The majority of studies included were retrospective in nature. Sites of the studies included palliative care unit, 3 hospice, 2 teaching hospital, 1 hematology/oncology unit, 6 and home 7 (Table 1). Two of the three palliative care units were further characterized as providing acute palliative care. The most frequent underlying malignancies were gastrointestinal, lung, genitourinary, breast, and hematologic. Infection occurred frequently in palliative care patients with advanced cancer (Table 1). Most studies defined infection as documentation of a clinical diagnosis of infection. Rates of suspected infection varied among the studies from 29% to 83%, with an overall rate among the evaluable studies of 41.6%. The term suspected infection is used because infections were presumed to be the cause of fever in many cases and the rate of actual infection is unknown. Only the study by Homsi et al. required a positive culture as a definition of infection, reflected by the lower frequency of infection of 29%. 8 Criteria for establishing infection in the various studies are presented in Table 1. The urinary and respiratory tracts were the most frequent sites of infection (Table 2). Bacteremia and skin infections were also described. Where reported, overall frequencies of sites of infection were as follows: urinary tract 30.5%, respiratory tract 17.9%, skin 15.7%, and blood 14.4%. Blood isolates indicative of bacteremia were noted to be of both primary and secondary origins. E. coli, S. aureus, and other Gram-negative bacteria were the most frequent microbiological isolates. Some patients were identified as having more than one infection, and polymicrobial infections occurred. Candida species urinary tract infections (UTIs) were the most common fungal infections. Herpes virus skin infections were noted infrequently. Glucocorticoid administration was examined in two studies; one did not find an association with increased frequency of infection 4 and the other identified a significant association with UTI (Table 2). 8

3 66 Nagy-Agren and Haley Vol. 24 No. 1 July 2002 Study n Location of Care Table 1 Characteristics of Studies of Infections in Terminally Ill Cancer Patients Purpose/Type of Investigation Criteria for Infection % Infection [# Infectious Episodes] Ahronheim 1 84 Teaching hospital Retrospective review to quantitate the use of non-palliative interventions in hospitalized incurably ill patients Bauduer 6 81 Oncohematology unit Prospective analysis of the characteristics of deaths occurring in the oncohematology department of a general hospital Girmenia Home Retrospective review of home management of infective complications in patients with advanced malignancies Green 5 3 Palliative care unit Report of three cases of nosocomial respiratory tract infection complicating advanced lung carcinoma Homsi Acute care palliative medicine unit Pereira Acute palliative care unit Retrospective study of the frequency, pattern, and management of infections in advanced cancer Retrospective review of consecutive admissions to a palliative care unit to assess frequency of infection, pathogens, and pattern of antibiotic utilization Prentice Hospice Retrospective review to assess the impact of methicillin-resistant S. aureus (MRSA) infection in palliative care Vitetta Hospice Retrospective review of prevalence of infection and clinical course in consecutive patients who died after admission to a hospice Systemic antibiotic use categorized as empiric vs. non-empiric on the basis of clinical diagnosis of infection Infection not defined; categorized together with disease-related fever ( 38.5 C) Febrile episodes classified as microbiologically vs. clinically documented infection (on the basis of exam), versus FUO Diagnosis made on clinical evidence Infection defined as at least one positive body fluid culture Presence of symptoms and signs assessed to have been caused by a microbial agent Clinical interpretation of colonization vs. infection with MRSA isolate Site-specific diagnosis, presence of suggestive symptoms and signs, and/or positive bacteriological culture isolate 83% (70/84) received antibiotics [NA] 40% (32/81) febrile [NA] 46% (70/151) [109] NA Overall rate of infection 41.6% 29.3% (115/ 393) [152] 55% (55/100) [71] Studied MRSA only [NA] 36.3% (37/ 102) [42] Abbreviations: NA not applicable; FUO fever of unknown origin. Where described, 60 72% of individuals with suspected infections and cancer were treated with antibiotics in hospice or on palliative care units (Table 2). 4,9 In the teaching hospital, however, an overwhelming majority of 83% of individuals with cancer in their terminal hospitalization were treated with antibiotics, often empirically; the frequency of individuals at this site receiving empiric antibiotics, prior to or in the absence of documented infection, was 75%. 1 Similarly, in the review of deaths on a hematology/oncology unit, 40% of individuals were clinically diagnosed with infection, yet 47% received antibiotics. 6 Two studies, one from a palliative care unit and one from hospice, delineated the route of antimicrobial administration; the oral route was utilized in most (72 82%) cases. 4,9 In contrast, the study by Homsi et al., from the acute palliative care unit, indicated that parenteral therapy was utilized in the overwhelming majority of cases. 8 This study described a median antibiotic treatment period of 11 days. In the study of home care management of infections, an oral quinolone was utilized in non-neutropenic patients, and a parenteral cephalosporin plus aminoglycoside was administered to neutropenic patients. This study documented comparable results when treating infections at home, rather than in an inpatient setting. 7 Only one study examined symptom control, finding that appropriate management of infec-

4 Vol. 24 No. 1 July 2002 Management of Infections in Patients with Advanced Cancer 67 Study Site of Infection (no. of episodes) Table 2 Characteristics of Infections in Dying Patients with Cancer Microorganisms (% or no. of isolates) Cause of Death Comments Ahronheim 1 NA NA 7/84 died of pneumonia; 5 died of urosepsis; 15 died of unspecified sepsis Overall, 83% of patients studied received antibiotics Bauduer 6 NA NA 19/81 died of infection 40% of patients sustained infectionor disease-related fever; 47% received anti-infectious agents Girmenia 7 pneumonia (9) septicemia (14) skin (12) P. aeruginosa (9), S. aureus (5), E. coli (3) Green 5 pulmonary P. maltophilia, group B streptococcus coliforms Homsi 8 UTI (66) bacteremia (31) pneumonia (22) skin, wound, ulcer (33) Pereira 4 urinary tract (29) respiratory tract (27) skin (9) blood (4) Prentice 10 urinary tract, wound; wound or nasal colonization common Vitetta 9 urinary tract (17) respiratory tract (9) blood (5) skin, subcutaneous (5) eyes (4) E. coli 19% K. pneumoniae 11% S. aureus 9% (48% gram-negative 45% gram-positive 7% yeast or viral 68/100 polymicrobial) E. coli (16) S. aureus (14) Enterococcus sp. (8) K. pneumoniae (5) P. aeruginosa (4) 19% of infections were fatal; infection contributed to death in 17% of all patients NA 28/100 with infections died during hospital stay NA 46% developed fever of proven or presumed infectious origin; mortality correlated with poor condition (Karnofsky score 40) and neutropenia UTI significantly more common in patients receiving corticosteroids; most yeast isolates associated with UTIs; skin sole source of HSV2; median antibiotic treatment time 11 days 72% of infections diagnosed were treated with antibiotics; route of administration was oral (72%) versus intravenous (26%); no significant difference based on corticosteroid use NA 0 secondary to MRSA Substantial financial and human cost of MRSA isolation precautions discussed E. coli 37% Enterobacter sp. 20% S. aurens 11% P. aeruginosa 11% mortality not significantly associated with presence of bacterial infection 60% of patients with infection were treated with 40% resulting in antibiotic response and symptom control; psychological distress significant in this group of patients (P 0.001) Abbreviations: no. number; NA not applicable; UTI urinary tract infection; MRSA methicillin resistant S. aureus; HSV herpes simplex virus. tion resulted in enhanced palliative symptom control in only 40% of patients. 9 Patients were described as being polysymptomatic in this final phase of care, and specific symptoms controlled by infection management were not delineated. No significant differences in comorbid symptoms were observed among patients presenting with and without infections. This same study found a highly significant correlation between patients managed for infection following admission to the hospice and major psychological distress. Fifty-seven percent of patients with infection suffered major psychological distress compared to 8.9% of patients without infection (P 0.001). Theorized causes of the distress were infection, antibiotic administration, or a more prolonged terminal phase. 9 The study focusing on methicillin-resistant S. aureus (MRSA) colonization and infection noted the substantial human and financial cost of isolation precautions. The study highlighted patient complaints of loneliness and isolation, policies barring patients from daily activities, resulting waits for clinic appointments and transfers, and family distress. 10 Where reported, 19 39% of infected individuals with advanced cancer died (Table 2). One study identified an association between mortality and poor condition (Karnofsky score 40) or neutropenia. 7 Another study found mortality not to be significantly associated with the

5 68 Nagy-Agren and Haley Vol. 24 No. 1 July 2002 presence of bacterial infection in terminally ill patients with cancer. 9 Discussion The use of antibiotics in the last days to weeks of life is a complex issue. Withholding antibiotics may be part of a palliative care plan in some severely ill patients. It is not possible to predict whether antibiotics will produce a cure, or conversely whether withholding them will result in death. 1 Therefore, antibiotics do not fall neatly into the category of life-sustaining treatments, as do mechanical ventilatory support or tube feeding. Antibiotics might be considered part of a good palliative care plan if life-threatening infections produce discomfort, but the decision to treat can lead to burdens, including more diagnostic tests, adverse reactions to antibiotics, and the use of intravenous lines. 1 Quality of care at the end of life should be regularly evaluated; nevertheless, adequate care of the incurably ill patient is difficult to quantify. 6 The underlying diagnosis, stage of illness, level of multisystem deterioration, uncontrolled pain and other symptoms, and the patient s and family s own wishes must be considered in the decision-making process. 4 The decision is made complex by knowledge that infection is a common cause of death in cancer patients and can be perceived as an old-man s best friend. On the other hand, treating an infection may be the most appropriate means of symptom control when life prolongation is not the goal. 4 A better knowledge of the profiles of advanced cancer patients in all sites of care is needed if we are to improve our management. 6 In our review, a high frequency of infection was detected in terminally ill cancer patients. The bacterial and fungal pathogens appeared to be similar to those reported in most studies of hospital-associated infections. The true rate of infection remains uncertain, because in many cases the presence of fever alone led to a clinical diagnosis of infection. Other non-infectious causes of fever remain possible in these cases, including drug-induced fever and fever secondary to underlying malignancy, particularly in the setting of lymphoma, accelerated tumor growth or necrosis, or hepatic or central nervous system spread. This review suggests that the location of care and underlying terminal diagnosis affects the decision to treat infection. For example, the approach in an acute care hospital was to treat acute illness rather than develop a palliative care plan; 1 whereas the need to individualize antibiotic regimens was emphasized on the palliative care unit. 4 This suggests that decisions are made by custom or hospital algorithm, rather than by care plan established between clinician and patient. Similarly, the study by Ahronheim et al. noted that incurably ill patients with cancer received significantly more diagnostic tests than did incurably ill patients with dementia, 1 suggesting that physicians were less likely to implement an overall palliative plan in cancer patients than in patients with dementia. Further, results of 2 studies where empiric antibiotics were prescribed more frequently than pathogen-directed therapy, 6 and antibiotic administration was initiated in the absence of documentation of infection, 1 may suggest that antibiotics are prescribed as a last-resort measure for selected dying patients in acutecare hospitals in the absence of clinical evidence of infection. We would argue that incurably ill patients with infections deserve individualized palliative care, regardless of the site of administration of care, or the terminal diagnosis. For patients with cancer, this remains particularly relevant as long as most undergo their terminal illness in acute care hospitals. In fact, according to this review, the majority of incurably ill patients with infections are treated with antibiotics. In total, 60 72% of individuals with suspected infections and cancer were treated with antibiotics in hospice or on palliative care unit, 4,9 and 83% of individuals with cancer in their terminal hospitalization were treated with antibiotics in the teaching hospital. 1 These findings suggest that the withholding of antimicrobials in these settings is not widely practiced. When selecting an antibiotic regimen, factors such as potential adverse effects, the need for laboratory monitoring, and comfort and convenience to the patient become relevant in developing an individualized regimen. 4 Parenteral antibiotics may be appropriate for some cases, but in this review oral regimens were preferred in most studies. It is not always possible to predict whether antibiotic therapy will result in a favorable effect on symptom control. Only 1 study in this review examined

6 Vol. 24 No. 1 July 2002 Management of Infections in Patients with Advanced Cancer 69 symptom control, finding that 40% of individuals improved with antibiotics. 9 This study documented, however, a significant correlation between patients managed for infection and psychological distress. Serious infection may produce sedation and coma, allowing the patient a peaceful death, whereas antibiotic treatment can awaken the terminally ill patient and prolong the process of dying. 1 It is interesting to hypothesize this awakening, or more prolonged terminal phase, as the cause of psychological distress found in the Vitetta study. The issue of psychological distress is broad, however, and encompasses more than only antibiotic-specific issues. In fact, infection is a common cause of agitated delerium. 11 Approximately one-fifth to one-third of infections were fatal. One study identified an association between mortality and poor condition or neutropenia. 7 Another study found mortality was not significantly associated with the presence of bacterial infection in dying patients with cancer. 9 Aware that approximately one-third of these terminally ill advanced cancer patients may die of their infection, yet 57% of them, including those who respond with symptom control, may suffer psychological distress, decisions regarding antimicrobial management of suspected infection in individuals with advanced cancer must be individualized. As was expected, this descriptive review did not provide clear answers discerning when to withhold versus administer antibiotics to these terminally ill individuals with suspected infection. It may be reasonable to initiate a therapeutic trial of antimicrobial therapy for selected patients with suspected infection. If deterioration occurs despite antibiotic therapy, a decision to discontinue the antibiotics would then be appropriate. 4 Of note, the study by Girmenia et al. described home care services as resulting in similar outcomes for management of infections to care provided in inpatient facilities. 7 Results of the study of MRSA infection and colonization are of interest with regard to the humanizing of care, 9 and deserve further attention and discussion in the development of management guidelines. Our review was limited by the paucity of literature found in the area of management of infections in advanced cancer patients. The series, largely retrospective in nature, are difficult to compare. Reports are focused on identifying prevalence of infections, microbial trends, and percentage of patients with advanced cancer treated with antibiotics. With only one exception, 9 none of the studies addressed the important issue of whether or not antibiotic treatment was of benefit, particularly with respect to improving symptoms and other quality-of-life paramenters. The undertaking of needed research in the area is challenged by the complexity of the involved patients, who may have polysymptomatology and multiple possible comorbidities. Analysis of this literature points to various areas in which further research is needed. One of these areas is outcomes: What are the clinical results of treating infections in advanced palliative situations? How often are symptoms relieved? Can we predict which patients will gain symptom relief and which patients will gain only the additional burdens of treatment? How can we determine whether fever is due to infection, tumor or other cause? In those patients with fever and a presumptive diagnosis of infection even though the site is not localized, what are the results of treatment? These questions are not easily answered even in less complex patients, however. Until such issues are resolved, it should be anticipated that infection may occur as a terminal event in many patients with advanced cancer, and in this context, contemplated as the dying patient s best friend. This review raises education issues. Decisionmaking in caring for patients with advanced cancer and developing appropriate palliative care plans is difficult and requires individualization. Nuances are encountered which affect such plans. The learning and experiential background of the doctor will determine the recommended care, suggesting house staff exposure and teaching are critical. This is where the clinical practices of faculty doctors can have great influence on trainees. Our job is to serve as effective role models to help students and residents learn to make compassionate and clinically sound decisions. We believe treatment of infection in incurably ill cancer patients may be considered when the objective is symptom control. When infections do not contribute to disabling symptoms at end of life, when multisystem deterioration is present, or the patient can no longer

7 70 Nagy-Agren and Haley Vol. 24 No. 1 July 2002 swallow, antibiotics should be considered nonpalliative. It must be anticipated that infection may occur as a terminal event in patients with advanced cancer. The decision whether to treat or not in the palliative care setting may be complex and requires an individualized approach. Further research in this area will help develop a consensus for management that will facilitate education of students and residents regarding complex decisions of care of infections at the end of life. Education of professionals and the public should further legitimize a palliative approach to infections in the dying. References 1. Ahronheim JC, Morrison RS, Baskin SA, et al. Treatment of the dying in the acute care hospital; advanced dementia and metastatic cancer. Arch Intern Med 1996;156: Brown NK, Thompson DJ. Nontreatment of fever in extended-care facilities. N Engl J Med 1979; 300: Council on Ethical and Judicial Affairs, American Medical Association. Decisions near the end of life. JAMA 1992;267: Pereira J, Watanabe S, Wolch G. A retrospective review of the frequency of infections and patterns of antibiotic utilization on a palliative care unit. J Pain Symptom Manage 1998;16: Green K, Webster H, Watanabe S, Fainsinger RL. Management of nosocomial respiratory tract infections in terminally ill cancer patients. J Palliative Care 1994;10: Bauduer F, Capdupuy C, Renoux M. Characteristics of deaths in a department of oncohaematology within a general hospital: a study of 81 cases. Support Care Cancer 2000;8: Girmenia C, Moleti ML, Cedrone M, et al. Management of infective complications in patients with advanced hematologic malignancies in home care. Leukemia 1997;11: Homsi J, Walsh D, Panta R, et al. Infectious complications of advanced cancer. Supp Care Cancer 2000;8: Vitetta L, Kenner D, Sali A. Bacterial infections in terminally ill hospice patients. J Pain Symptom Manage 2000;20: Prentice W, Dunlop R, Armes PJ, et al. Methicillin-resistant Staphylococcus aureus infection in palliative care. Palliative Med 1998;12: Lawlor PG, Gagnon B, Mancini IL, et al. Occurrence, causes, and outcome of delirium in patients with advanced cancer. Arch Intern Med 2000;160: