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Cross-Cutting Research Issues: A Research Agenda for Reducing Distress of Patients with Cancer

Charles S.Cleeland, Ph.D.

University of Texas M.D. Anderson Cancer Center

INTRODUCTION

This chapter reviews the current status of research on end-of-life issues, advanced cancer, and symptom control and explores linkages with research on the distress experienced by other cancer patients in treatment and by many cancer survivors. Relatively little such research is carried out, despite a rich research agenda. The organizational and other barriers to the development, support, and performance of this type of cancer research, which have led to the current situation, are explored, and steps are proposed that could facilitate basic, behavioral, and clinical research on the symptoms and treatment of patients with advanced cancer.

Background

Despite billions of dollars spent on research in cancer biology and cancer therapeutics, there has been little investment in research that might significantly alleviate the physical and psychological distress of patients at the end of life. The types of distress experienced by these patients are shared, in a temporary or more lasting fashion, with patients being treated for cancer and, at least to some extent, by some who survive the disease. This chapter focuses on symptoms in patients who are dying, but the distinction between these symptoms and those experienced at other points in the disease and treatment continuum is artificial, and much of what is described here will also be applicable to distress experienced by cancer patients more generally.



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Improving Palliative Care for Cancer 8 Cross-Cutting Research Issues: A Research Agenda for Reducing Distress of Patients with Cancer Charles S.Cleeland, Ph.D. University of Texas M.D. Anderson Cancer Center INTRODUCTION This chapter reviews the current status of research on end-of-life issues, advanced cancer, and symptom control and explores linkages with research on the distress experienced by other cancer patients in treatment and by many cancer survivors. Relatively little such research is carried out, despite a rich research agenda. The organizational and other barriers to the development, support, and performance of this type of cancer research, which have led to the current situation, are explored, and steps are proposed that could facilitate basic, behavioral, and clinical research on the symptoms and treatment of patients with advanced cancer. Background Despite billions of dollars spent on research in cancer biology and cancer therapeutics, there has been little investment in research that might significantly alleviate the physical and psychological distress of patients at the end of life. The types of distress experienced by these patients are shared, in a temporary or more lasting fashion, with patients being treated for cancer and, at least to some extent, by some who survive the disease. This chapter focuses on symptoms in patients who are dying, but the distinction between these symptoms and those experienced at other points in the disease and treatment continuum is artificial, and much of what is described here will also be applicable to distress experienced by cancer patients more generally.

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Improving Palliative Care for Cancer There is ample evidence that patients who are dying have symptoms that devastate them and consume their families. Many patients experience needless pain that could be controlled by the optimal application of existing therapies. Others experience fatigue, cognitive deficits, depression, physical wasting, and other symptoms that are poorly understood and less easily managed with current treatments. There is a need for a broadly based strategic plan for research in this area that will integrate health services research in the improved delivery of distress management with basic and clinical research that develops new therapeutic strategies. New and existing methods of distress management must be tested clinically for their effectiveness to provide for evidence-based practice recommendations. Compared with the rest of the cancer research establishment, research directed at cancer-related distress is poorly organized, poorly conceptualized, underfunded, and dependent on an insufficient number of well-trained researchers. Increased organizational and public recognition of the suffering that often dominates the end of life for cancer patients has created an opportunity for a sympathetic response to new proposals in this area. New information in cancer biology and neuroscience could be applied directly to alleviating distress if researchers could be encouraged to recognize and explore potential linkages of information. OVERVIEW OF RESEARCH RELATED TO END OF LIFE, PALLIATIVE CARE, AND SYMPTOM CONTROL The types of research that are needed to improve care and reduce distress at the end of life fall into three major categories: descriptive and epidemiologic studies that define the specific needs of patients and caregivers, determine the prevalence and severity of the symptom-generated distress that they experience, and point the way to additional investigation of the causes and potential treatment of this distress; studies of the specific symptoms that patients experience and the treatment of these symptoms, primarily from biomedical and behavioral perspectives; and studies of the delivery of care to these patients and ways to improve this care by the optimal use of existing treatments. This broad research agenda depends on a wide range of investigators and methods, and its performance will depend on a creative combination of funding from different sources as well as the development of a larger group of researchers interested in and trained to deliver the kinds of research needed.

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Improving Palliative Care for Cancer The notion that the distress of cancer patients at the end of life, and also throughout the spectrum of their disease, is a topic worthy of serious research is relatively new. Public support for this kind of research has grown for several reasons, including increasing knowledge of the widespread nature of the severity of this distress, increasing consumer demand that quality of life is a legitimate issue, and the public debate over end-of-life decisions and assisted suicide. There is also an increasing expectation that the control of pain and other symptoms and at least some aspects of suffering should be included in what medical care has to offer, should be a right of patients under the care of the health system, and should be a competency of their health care providers. This increasing expectation of and support for better management of the distress of cancer and of dying with cancer has created a condition that is in some ways like the emergence of a new disease. Systems are not prepared to deliver the care required, the biology and behavioral aspects of the disease have to be understood, existing treatments have to be tested to see if they are effective, and new ones must be proposed and tested. When a new disease emerges, there are few if any providers competent in its management, and the funding components of the health care system are not prepared to finance its treatment. The research required to understand its biology, its behavioral ramifications, and the best way to treat it is not in place, and investigators have to be attracted to the area, develop appropriate methods of research, and be funded to carry out the requisite research. While the new disease analogy may be helpful to explain the demand for new types of research, there are special characteristics of the needed research that makes it hard to conceptualize, to organize, and to fund. Some of these special difficulties include the subjective nature of many of the measurement and outcome variables, the poor fit of current disease models of research for doing this type of health-related investigation, the lack of an organizational structure for responding to this type of research demand, the high level of interdisciplinary research that is required to do the work, and the absence of a high-priority pathway for putting this type of research in place. Organization of This Review This review offers examples from two areas of research that are critical to the delivery of better end-of-life and symptom control care:

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Improving Palliative Care for Cancer epidemiology, social-behavioral, and health services research that defines the area and its impact, and symptom research that examines components of the problem from a more traditional biomedical perspective. The review covers recent research findings in each area, examples of needed research, a description of barriers to organizing and funding research, and suggested policy for changes in priority and structure that may improve and focus research of this type. Methods The following methods were used to gather data for this chapter: review of recent research (Medline databases), review of current National Institutes of Health (NIH) funding using the NIH CRISP retrieval system, review of currently active clinical trials using the Clinicaltrials.gov database, and survey responses from researchers in the field. Epidemiology and Descriptive Research: Prevalence, Impact, and Management of Symptoms Patients with advanced cancer typically experience multiple symptoms related to cancer and cancer treatment. These symptoms can include physical (e.g., nausea, dyspnea), cognitive (e.g., delirium, memory problems, impaired concentration), and affective (e.g., depression, anxiety) experiences associated with the disease and its treatments. Symptom severity is related to the extent of disease and the aggressiveness of therapies such as surgery, chemotherapy, radiotherapy, and biological therapies. Common symptoms of cancer and cancer treatment significantly impair the daily function and quality of life of patients. Pain is a good example. When pain is present, it adversely affects patients’ mood, activity, and ability to relate to others (Serlin et al., 1995). Similarly, fatigue, gastrointestinal symptoms, cachexia, anorexia, shortness of breath, and psychological distress add tremendously to the distress that patients experience. At present, the severe distress, multiple symptoms, and inadequate treatment faced by many patients at the end of life are well documented. Several studies have examined cancer-related symptoms in patients with advanced disease. Coyle and colleagues (1990) found that fatigue, weakness, pain, sleepiness, and cognitive impairment were frequent symptoms of patients with terminal disease enrolled in a supportive care program. Fatigue (58

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Improving Palliative Care for Cancer percent) and pain (54 percent) were the most prevalent symptoms. Donnelly and colleagues (1995) prospectively studied the prevalence and severity of these symptoms in 1,000 patients with advanced cancer. Pain, fatigue, and anorexia were consistently found to be among the 10 most prevalent symptoms at all 17 primary cancer sites studied. When pain, anorexia, weakness, anxiety, lack of energy, severe fatigue, early satiety, constipation, and dyspnea were present, a majority of patients rated them as moderate or severe. Similarly, a prospective study of cancer patients in palliative care centers in Europe, Australia, and the United States found that more than half of the patients reported pain and weakness (Vainio and Auvinen, 1996). Weight loss, anorexia, constipation, nausea, and dyspnea were also common. As part of the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT), McCarthy and colleagues (2000) evaluated more than 1,000 cancer patients during the three days before death and also at one to three months before death, and three to six months before death. As expected, as they progressed toward death, their estimated six-month prognosis decreased significantly and the severity of their disease worsened. Patients’ functional status also declined significantly as they approached death, such that most patients had four or more symptoms within the three days before death. Patients with cancer experienced significantly more pain and confusion as death approached. Severe pain was common; more than one-quarter of patients with cancer experienced significant pain three to six months before death and more than 40 percent were in significant pain during their last three days of life. However, dying patients were only modestly depressed and anxious during their last three days of life. The distress caused by symptoms for cancer patients at the end of life is shared by patients who are not yet terminal. Very few epidemiological studies have examined the multiple symptoms of cancer patients with less progressed disease. However, the symptoms associated with aggressive treatments such as chemotherapy and radiotherapy have been well documented. For example, multiple studies have found that the majority of patients undergoing chemotherapy or radiotherapy report significant fatigue during the course of treatment (Cleeland et al., 2000; Irvine, et al., 1994; Smets et al., 1996). A few studies have assessed multiple symptoms in samples of cancer patients with different stages of disease. Portenoy and colleagues (1994) administered the Memorial Symptom Assessment Scale to a random sample of inpatients and outpatients with breast, prostate, colon, or ovarian cancer. The most frequently reported symptoms for the sample were lack of energy, worry, feeling sad, and pain. Patients with metastatic disease reported more symptom distress than patients with less advanced disease. In a recent study of more than 500 patients in active treatment, more than 20 percent of patients reported a variety of severe symptoms, including

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Improving Palliative Care for Cancer fatigue, worry, distress, poor sleep, lack of appetite, and dry mouth (Cleeland et al., 2000). It is less well recognized that many cancer survivors continue to experience physical, affective, or cognitive symptoms even when their disease is in remission or treatment has ended. These symptoms may be due to physiological changes associated with prior treatments, delayed side effects of treatment, or long-term consequences of the disease. For example, survivors of bone marrow transplantation may report cognitive impairment, physical symptoms, or emotional distress many years after the transplant (Andrykowski et al., 1995; McQuellon et al., 1996; Prieto et al., 1996). Evidence for Inadequate Symptom Management Recent studies have described the prevalence and severity of pain due to cancer and have documented that pain is often undertreated with available analgesics (Cleeland et al., 1994). These studies present a model for the study of other major symptoms, such as depression and fatigue. Approximately 55 percent of outpatients with metastatic cancer have disease-related pain, and 36 percent have pain of sufficient severity to impair their function and quality of life despite current analgesic therapy. Despite national and international guidelines for its management, many patients with pain are not prescribed an analgesic appropriate to the severity of their pain (Cleeland et al., 1994). Evidence suggests that patients in minority groups may have an even greater risk for undertreatment of pain (Anderson et al., 2000; Cleeland et al., 1997). Two studies of outpatients with metastatic or recurrent cancer receiving treatment at Eastern Cooperative Oncology Group (ECOG) institutions found that more than 40 percent of those with pain were not prescribed analgesics strong enough to match the severity of their pain (Cleeland et al., 1994, 1997). A discrepancy between the physician’s and patient’s rating of the severity of the pain was a major predictor of undermedication for pain (Cleeland et al., 1994). Pain has to be appreciated before it can be treated. In addition, patients seen at centers that treated predominantly minority patients were three times more likely than those treated elsewhere to have inadequate pain management (Cleeland et al., 1997). Other factors that predicted inadequate pain treatment included age of 70 years or older, female sex, and better performance status. These results support the opinion of oncology physicians that poor assessment of symptoms is a major barrier to adequate symptom management (Cleeland et al., 2000; von Roenn et al., 1993). They also suggest that careful and accurate symptom assessment is particularly important for cancer patients from minority groups, elderly patients, female patients, and patients who appear to be functioning well.

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Improving Palliative Care for Cancer A study by Bemabei and colleagues (1998) took advantage of a large database to examine the treatment of pain in cancer patients cared for in nursing homes. Using the Resident Assessment Instrument and the Minimum Data Set (MDS), part of the Health Care Financing Administration’s (HCFA’s) Demonstration Project, the investigators found that 38 percent of nursing home residents with cancer from a five-state area complained of, or showed evidence of, daily pain. The study found that 26 percent of these patients with daily pain got no analgesics at all. Patients over 85 years were more likely to receive no analgesia, as were minorities. Only about half of the patients in pain were receiving opioids, and only 13 percent of patients over 85 were receiving these stronger analgesics. Many cancer specialists recognize that symptom control is often suboptimal. Medical oncologists were surveyed about their treatment of cancer pain in a study conducted by ECOG (von Roenn et al., 1993). Only half of the physicians surveyed indicated that cancer pain control was good or very good in their practice setting. Seventy-five percent of the physicians indicated that the most important barrier to cancer pain management was inadequate pain assessment. More than 60 percent of physicians were reluctant to prescribe analgesics or cited the unwillingness of patients to report pain or take opioids as barriers. Inadequate knowledge about cancer pain management was reported by more than half the physicians who responded. The survey acknowledged that a substandard level of education about cancer pain management and a reluctance to address it in practice existed at all levels of professional health care. A recent study (Cleeland et al., 2000) repeated the ECOG study format with physician members of the Radiation Therapy Oncology Group. On average, physicians estimated that two-thirds of cancer patients suffered pain for longer than one month. Assessing a case scenario, 23 percent would wait until the patient’s prognosis was six months or less before starting maximal analgesia, indicating a very conservative approach to pain management. Adjuvants and prophylactic side-effect management were underutilized in the treatment plan for the case presented. Perceived barriers to good pain management were very similar to the ECOG study, with poor pain assessment being ranked number one. Compounded by inadequate training for physicians in the palliative treatment of cancer, these problems influence decisions made in the management of incurable cancer and profoundly affect end-of-life care. In spite of recent concerns over symptom management at the end of life, provoked in large part by the debate over euthanasia, there is substantial evidence that symptoms that could, in principle, be well managed are undertreated, especially for patients who are still in active treatment. There is evidence that many symptoms could be controlled more adequately if we systematically applied the knowledge that we now have about symptom management.

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Improving Palliative Care for Cancer Impact of Symptoms on Family Caregivers of Advanced Cancer Patients Family members most often serve as the primary caregiver for the cancer patient, which may lead to a disruption in family relationships. This burden has been shown to produce emotional and physical disturbances in the caregiver. The appearance of patients’ symptoms, such as fatigue, nausea, and pain, underlines the severity of the disease and its potential mortality, adding significantly to the burden of family members who may feel unable to help the patient get relief. Numerous studies have examined the caregiving burden experienced by the family members of patients with cancer (Carey et al., 1991; Cassileth et al., 1985; Miaskowski et al., 1997a, 1997b; Oberst, et al., 1989; Stetz, 1987). A family caregiver’s distress is related to the severity of symptoms experienced by the cancer patient. In a cross-sectional study, Miaskowski and colleagues (1997a, 1997b) found that family members of oncology patients with pain report greater tension, depression, and total mood disturbance than family members of patients without pain. Ferrell and colleagues (1991a, 1991b) conducted a qualitative study of 85 family caregivers of cancer patients to describe their perspective toward cancer pain and their role in its management. When asked about their role in managing cancer pain, caregivers reported making treatment decisions such as deciding what medication to give the patient and when to give it. Caregivers expressed their own and their patients’ fears about addiction to pain medication and felt that it was their responsibility to help the patient avoid addiction. Most of the studies of caregivers have been conducted with white middle-class families. Relatively few studies have focused on the experiences and emotions of minority families of cancer patients, particularly those families with limited financial resources or fragmented health care (Juarez et al., 1998). Limited research indicates that ethnicity and social class do affect how patients, family members, and health care providers perceive illness and, more importantly, how family members and health care providers respond to the multiple needs of the patient (Gonzalez, 1997; Guarnaccia et al., 1992; Sales et al., 1992). A Good Example of Research on End-of-Life Issues Specific end-of-life issues have been carefully researched. Decisions about advance directives is an example. The SUPPORT database offers a large amount of information about cancer patients’ preferences for cardiopulmonary resuscitation (CPR) and the relationship of this preference to patient characteristics. Haidet and colleagues (1998) analyzed SUPPORT data for 520 patients with colorectal cancer to determine preferences for CPR. Sixty-three percent wanted CPR in the event of cardiopulmonary arrest. Factors independently associated with preference for resuscitation included younger age, better quality of life, absence of lung metastases, and

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Improving Palliative Care for Cancer greater patient estimate of two-month prognosis. Of the patients who preferred not to receive CPR, less than half had a do-not-resuscitate (DNR) note or order written. Physicians incorrectly identified patient CPR preferences in 30 percent of cases. A similar study (Covinsky et al., 2000) examined the characteristics of patients who do request DNR orders. Patients who are older, have cancer, are women, believe their prognoses are poor, and are more dependent in activities of daily living functioning are less likely to want CPR. However, there are considerable variability and geographic variation in these preferences. Physician, nurse, and surrogate understanding of their patients’ preferences is only moderately better than chance. Most patients do not discuss their preferences with their physicians, and only about half of patients who do not wish to receive CPR receive DNR orders. Weeks and colleagues (1998) examined the hypothesis that among terminally ill cancer patients, an accurate understanding of a poor prognosis is associated with a preference for therapy that focuses on comfort over attempts at life extension, using SUPPORT data. Subjects were 917 adults hospitalized with Stage III or IV non-small cell lung cancer or colon cancer metastatic to liver. Patients who thought they were going to live for at least six months were more likely to favor life-extending therapy over comfort care, compared with patients who thought there was at least a 10 percent chance that they would not live six months. (Patients overestimated their chances of surviving six months, while physicians estimated prognosis quite accurately.) Patients who preferred life-extending therapy were more likely to undergo aggressive treatment, but their six-month survival was no better than similar patients who did not seek aggressive treatment. The effects of the Patient Self Determination Act (PSDA; mandated patient education about advance directives at hospital entry) have also been examined within the context of SUPPORT (Teno et al., 1997). There was no evidence that the PSDA substantially increased documentation of advance directives, and it appears that documentation of advance directives is unlikely to be a substantial element in improving the care of seriously ill patients. Examples of Studies to Change Practice and Improve End-of-Life Care and Symptom Control The most ambitious research project to understand and improve care at the end of life was the well-publicized SUPPORT (1990). The descriptive information from SUPPORT (reviewed above) is the best information we have about the dying process. Approximately 20 percent of the sample were patients with cancer. The intervention study, supported by the Robert Wood Johnson Foundation, was designed to improve end-of-life decisionmaking

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Improving Palliative Care for Cancer and reduce the frequency of a mechanically supported, painful, and prolonged process of dying. The intervention component of this study included 4,804 patients and their physicians randomized by specialty group to the intervention group (N=2,652) or control group (N=2,152). A specially trained nurse had multiple contacts with the patient, family, physician, and hospital staff to discuss outcomes and preferences, attend to pain control, and facilitate advanced care planning and patient-physician communication. Compared to the control group, patients in the intervention group experienced no improvement in patient-physician communication or in the six targeted outcomes (i.e., incidence or timing of written DNR orders, physicians’ knowledge of their patients’ preferences not to be resuscitated, number of days spent in an intensive care unit [ICU], receiving mechanical ventilation, being comatose before death, level of reported pain). There was no reduction in hospital resources for the intervention. The authors concluded that the type of intervention used to improve communication, education, and advocacy was insufficient to change current practice. In summary, end-of-life care is inadequate, and much research is needed to improve it. As we have seen, there is also ample evidence of inadequate treatment for the symptoms of cancer. The same reasons for inadequate end-of-life care also apply to the management of pain and other symptoms, including poor assessment, inadequately trained health care providers, low priority for this type of care, lack of patient demand for better care, and negative sanctions against aggressive pain management. As is true of many other medical education efforts, relatively passive continuing medical education programs dealing with these issues have had little effect on practice (Cleeland, 1993; Weissman and Dahl, 1995). There have been a few studies examining the effectiveness of improving the practice of cancer pain management. A training program that includes the active participation of health care professionals and includes “role models” has demonstrated lasting changes in the cancer pain management knowledge of physicians and nurses (Janjan et al., 1996; Weissman et al., 1993). These studies did not examine patient report of pain as an outcome variable but do suggest that durable change in knowledge is possible. Beginning with publication of the World Health Organization’s (WHO’s) Cancer Pain Management guidelines in 1986 (WHO, 1986), several guidelines have been issued for cancer pain management, including the Agency for Health Care Policy and Research (AHCPR) Guideline for Cancer Pain Management (Jacox et al., 1994), guidelines from the American Pain Society (1999), and more recently, guidelines from the National Comprehensive Cancer Network. There is, however, only one published study that evaluates the effectiveness of physician adherence to a pain management guideline for cancer pain (DuPen et al., 1999). In this study, 81 cancer patients were enrolled in a prospective, longitudinal, randomized study

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Improving Palliative Care for Cancer from the outpatient clinics of 26 medical oncologists in western Washington State. A multilevel treatment algorithm, based on the AHCPR Guideline for Cancer Pain Management was compared with “standard practice” (control) therapies for pain and symptom management used by community oncologists. The primary outcome of interest was pain. Patients randomized to the guideline group achieved a statistically significant reduction in usual pain intensity when compared with standard community practice. A second randomized trial, evaluating the effects of an education program for cancer patients with chronic pain (de Wit et al., 1997), also used pain as an outcome variable. Information about pain and pain management was given to patients in the intervention group by several media: verbal instruction, written material, an audio cassette tape, and the use of a pain diary. The pain education program consisted of three elements: (1) educating patients about the basic principles of pain and pain management, (2) instructing patients how to report their pain in a pain diary, and (3) instructing patients how to communicate about pain and how to contact health care providers. Patients in the intervention group participated in the pain education program in the hospital and three and seven days post-discharge by telephone. Results showed a significant increase in pain knowledge and a significant decrease in pain intensity in patients who received the pain education program. RESEARCH NEEDS Studies of the prevalence, severity, and treatment of pain present a model of the descriptive research that has to be done in other areas of symptom management and end-of-life care. First, we need to determine the prevalence and severity of various symptoms in patients throughout the course of their disease: at diagnosis, during treatment, when cancer is in remission, and near the end of life. This includes the behavioral, economic, and social impact of these symptoms. There is an urgent need to learn more about how care for advanced disease is reimbursed. It is important to include longitudinal designs in this research so that we can determine changes in symptom patterns over time. We also need to identify the adequacy of care for these symptoms, including identifying what factors (e.g., patient related, clinician related, system related) are predictive of poor symptom management and poor end-of-life care. Current projects were identified in areas related to end of life, palliative care, and symptom control by searching CRISP, the NIH engine for indexing currently funded research. Key words for the major areas of such research were combined with “cancer.” Individual funding abstracts were inspected to see if they were research projects, defined as “matches.” Excluded were training grants, fellowships without a specific research topic,

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Improving Palliative Care for Cancer Lack of Investigators and Research Groups THE PROBLEM Agency representatives report the lack of highly competitive applications in the areas of end of life and symptom control. Funders, as well as reviewers, often state that such applications are not competitive with “mainline” applications. Many health care professionals acutely interested in doing research with very ill populations by virtue of their clinical contacts are not well prepared in clinical research methods. Although they often pose clinically important, reasonable, interesting, and potentially researchable questions, the methods they propose are inappropriate or lacking in scientific rigor. Not surprisingly, most of the studies in the palliative care literature reviewed for this chapter were (1) retrospective chart reviews (2) studies of caregiver’s estimates of patient distress, and (3) studies of the attitudes and opinions of health care professionals, most of which would have benefited from improved research methods. Another portion of the literature consists of a presentation of care principles with no support from clinical trials. There is a need for a larger body of well-trained researchers who have advanced disease and symptom issues as their focus of interest to conduct their own studies and to collaborate with clinicians interested in carrying out research POTENTIAL SOLUTIONS Both short-term and long-term solutions to the small supply of investigators are required. In the long term, larger numbers of researchers focused on end-of-life and symptom control issues must be trained. A plan for developing these researchers, including estimates of the needs within various basic, behavioral, clinical, and health services research disciplines, should be laid out as soon as possible. There are many training mechanisms and career tracks in place at the NIH, at NCI, and also at the ACS that could provide for the training and development of these researchers, but they have yet to be applied to advanced disease and symptom control. With so few investigators now in the field, there is also an immediate need for better communication among those doing this kind of research, both from one institution to the next and from one discipline to another. Several possibilities exist (e.g., research interchanges at regularly scheduled cancer research and clinical meetings). There may also be a place for new research organizations that focus on research issues related to advanced disease. Symptom-focused cross-disciplinary meetings could also greatly facilitate communication. As an example, M.D. Anderson recently sponsored such a meeting on fatigue and cancer. Researchers shared data on fatigue measurement and prevalence, potential mechanisms (including anemia, endocrine disturbances, cytokine levels, neurotransmitters), and current and

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Improving Palliative Care for Cancer potential treatment. Institutional and organizational support for interdisciplinary communication should produce great benefit. The current relative isolation of investigators in this area might also be addressed by taking advantage of current technology to create a “virtual” research network. This could be seen as a very interesting experiment in scientific communication. Mainline cancer research is facilitated by frequent interchanges of ideas and new data among research groups at large institutions, and it is reasonable to assume that this facilitates research progress. Such a virtual network, using current Internet technology, could support frequent video research exchanges, postings of preliminary data, and collective hypothesis generation. It could also sponsor exchanges between clinicians (defining the problems, sharing observations) and basic, behavioral, and health research scientists. It could explore the potential utility of patient and family interchanges with researchers and provide data from patients’ experiences with existing and new symptom-related therapies. Lack of Clinical Trials THE PROBLEM The clinical trial database that covers end-of-life care, palliative care, and symptom control is very small. Most guidelines for management of symptoms depend heavily on “expert” opinion because of this deficit, and treatment is often empirical for the same reason. Few active clinical trials deal with single or multisymptom interventions or with practice change interventions. In studies examining single symptoms, pain is the best studied in clinical trials, but many of the trials are industry sponsored, with very few trials of off-patent medications such as morphine that are used routinely in the care of seriously ill patients. Fatigue is an excellent example of an area in need of clinical trials. We know that some cancer-related fatigue is due to anemia and that anemia can be treated in some patients. Yet anemia is just one of the many causes of fatigue, and little if any clinical or basic science research is being done to discover the causes of this fatigue or to advance new treatments. Many oncologists are using methylphenidate (Ritalin) to treat patients with cancer-related fatigue, but there is not one published randomized trial (although one is now recruiting patients) that examines the effectiveness of this drug, the appropriate doses, or the indications for use. Dyspnea, psychological distress, poor appetite, wasting, psychological distress, nausea and vomiting, and cognitive impairment are all on the list of potential candidates for clinical trials that could be under way. As has been seen, there are few active trials in any of these areas. Several NCI collaborative groups have attempted symptom management clinical trials, but with mixed results, and several potentially informa-

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Improving Palliative Care for Cancer tive trials have failed for various reasons. In the fall of 1999, the Eastern Cooperative Oncology Group (ECOG) held a retreat to evaluate the place of symptom management trials in the cooperative groups. There was a general recognition that symptom management trials were seen by the NCI as relatively low priority, Several barriers to doing this kind of work in the collaborative groups were identified, including the following: The main research institutions are evaluated on research toward cure or increased lifespan, and not on the basis of symptom control, reducing the incentive for doing these trials. There are rarely staff designated as responsible for these trials, especially persons familiar with symptom measurement, treatment, or recruitment for these trials. Staff lack knowledge about these trials, and patients are not informed about them. Such trials are viewed as “extra work.” Some centers have no interest in symptom management trials. Symptom management studies do not contribute to the academic advancement of oncologists. There is the perception that enthusiasm at NCI for these types of studies is modest, demonstrated in modest trial credits, lack of extra funding for these efforts, and a low priority relative to treatment and prevention trials. POTENTIAL SOLUTIONS The collaborative groups sponsored by the NCI could provide the mechanism for large studies of current and proposed symptom management treatments and research in the issues of advanced disease. Findings from this work could make cancer treatment much more tolerable, could greatly improve the quality of life of those who survive cancer, and could provide enhanced comfort for those who die of the disease. Large numbers of patients with advanced cancer are available to members of these groups who are not now eligible for treatment or prevention trials. SUPPORT provides ample evidence that large numbers of very ill patients can be enrolled in randomized trials. In addition to clinical trials, these collaborative groups are the ideal setting for studies of the prevalence, impact, and current treatment of distress in patients with advanced cancer, but such descriptive studies within the collaborative groups are currently discouraged by the NCI. The ECOG retreat developed a number of recommendations for how to increase these trials in the collaborative groups but recognized that this would require structural change and a cognitive shift for both the groups and the NCI and other sponsors. The recommendations included incorporating symptom management into the senior leadership (and funding for

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Improving Palliative Care for Cancer this position), special nurse coordinators for these trials at several sites, and the designation of a subset of motivated sites to carry out this work. This subset might represent a special collaborative group within the framework of the existing groups. In the face of a lack of NCI enthusiasm for this area, it was suggested that the collaborative groups turn to the managed care or pharmaceutical industry to obtain funding for these trials. One possible function of a new type of group could be to undertake open-label trials of potential candidate symptom control agents. REFERENCES American Pain Society. 1999. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. (4th ed.) Glenview, Illinois: American Pain Society. Anderson KO, Mendoza TR, Valero V, Richman SP, Russell C, Hurley J, DeLeon C, Washington P, Palos G, Payne, R, Cleeland, CS. Minority cancer patients and their providers: pain management attitudes and practice. Cancer 2000; 88:1929–1938. Andrykowski MA, Greiner CB, Altmaier EM, Burish TG, Antin JH, Gingrich R, McGarigle C, Henslee-Downey PJ. Quality of life following bone marrow transplantation: findings from a multicentre study. Br J Cancer 1995; 71:1322–1329. Argiles JM Lopez-Soriano FJ. The role of cytokines in cancer cachexia. Med Res Rev 1999; 19: 223–248. Barber MD, Ross JA, Fearon KC. Disordered metabolic response with cancer and its management. World J Surg 2000; 24:681–689. Bernabei R, Gambassi G, Lapane K, Landi F, Gatsonis C, Dunlop R, Lipsitz L, Steel K, Mor V. Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology [see comments] [published erratum appears in JAMA 1999; 281:136]. JAMA 1998; 279:1877–1882. Bessesen DH. Faggioni R (1998). Recently identified peptides involved in the regulation of body weight. Semin Oncol 1998; 25:28–32. Body JJ. The syndrome of anorexia-cachexia. Curr Opin Oncol 1999; 11:255–260. Bottomley A. Anxiety and the adult cancer patient. European Journal of Cancer Care (English Language Edition) 1998; 7:217–224. Breitbart W. Identifying patients at risk for, and treatment of major psychiatric complications of cancer. Supportive Care in Cancer 1995; 3:45–60. Brey RL, Escalante A. Neurological manifestations of antiphospholipid antibody syndrome. Lupus 1998; 7Suppl 2:S67–S74. Bruera E. A National Cancer Institute of Canada Workshop on Symptom Control and Supportive Care in Patients with Advanced Cancer: methodological and administrative issues. Journal of Pain and Symptom Management 1995; 10:129–130. Bruera E, Franco JJ, Maltoni M, Watanabe S, Suarez-Almazor M. Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation. J. Pain Symptom Manage 1995; 10:287– 291. Bruera E, Miller MJ, Macmillan K, Kuehn N. Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Pain 1992a; 48:163–166. Bruera E, Miller MJ, Macmillan K, Kuehn N. Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Pain 1992b; 8:163–166.

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Improving Palliative Care for Cancer APPENDIX 8-A Acknowledgments This report greatly benefitted from the creative editorial assistance, organizational abilities and insight of Martha Engstrom, M.S. of the Pain Research Group at University of Texas, M.D. Anderson Cancer Center, Houston. The following contributed to the suggestions for specific research needs, the current barriers to research, and recommendations to improve research in this area: Ira Byock, M.D. Missoula Demonstration Project Missoula, MT Patrick Dougherty, Ph.D. Associate Professor of Anesthesiology University of Texas M.D. Anderson Cancer Center Houston, TX Debra Dudgeon, M.D. Director, Palliative Care Medicine Program Queen’s University Kingston, Ontario Betty Ferrell, R.N., FAAN, Ph.D. City of Hope Duarte, CA

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Improving Palliative Care for Cancer Perry Fine, M.D. Professor of Anesthesiology University of Utah Medical School Medical Director, Vistacare Salt Lake City, UT Howard Gutstein, M.D. Associate Professor of Anesthesiology University of Texas M.D. Anderson Cancer Center Houston, TX Christina Meyers, Ph.D., ABPP Associate Professor of Neuro-oncology (Neuropsychology) University of Texas M.D. Anderson Cancer Center Houston, TX Judith Paice, R.N., FAAN, Ph.D. Professor of Cancer Research Northwestern University Chicago, IL Steve Passik, Ph.D. Director, Community Cancer Care Indianapolis, IN Carla Ripomonti, M.D. Istituto Tumori Milano, Italy Donna Zhukovsky, M.D. Associate Professor, Symptom Control and Palliative Care University of Texas M.D. Anderson Cancer Center Houston, TX