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
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.
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.
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.
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:
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.
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
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
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.
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.
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
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
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
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.
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,
meeting grants, cooperative group renewals, or instances where the keyword match was not a fit for the topic. The matches could be classified as (1) descriptive or health services research, (2) studies of interventions or clinical trials, or (3) basic science investigations. The search results are presented in Table 8-1, illustrating the dearth of research on end-of-life issues and symptoms in patients with advanced cancer.
This section reviews recent research on the following cancer-related symptoms: pain, anorexia and cachexia, cognitive failure (including delirium and cognitive impairment such as problems with memory and reasoning), dyspnea, fatigue, gastrointestinal symptoms, and psychiatric symptoms (including depression and anxiety). It includes information about the current status of treatment, what is known about the mechanisms responsible for the symptom, and what types of clinical and basic research should be carried out to improve the management of the symptom.
Biomedical symptom research is closest to the clinical research model in place at NIH and many other funding agencies and is therefore more likely to be funded than descriptive or health services research. However, a search of currently funded grants for each symptom (basic and clinical) suggests little support for these investigations, even though relatively small increments in our basic and clinical knowledge base are liable to substantially improve care for very ill patients.
One somewhat artificial barrier to progress in this type of research is the balkanization of the research establishment. For example, several NIH institutes are working relatively independently on problems in neuroscience, molecular biology, and the general biology of cancer treatment that might contribute to a better understanding of mechanisms common to the expression of these symptoms. An excellent example is the potential role of inflammatory processes in pain, wasting, cognitive deficit, depression, and fatigue, where relevant research is being funded by several NIH Institutes.
TABLE 8-1 Results of CRISP Searches for Current Research on End-of-Life, Palliative Care, and Symptom Control (numbers of currently-funded projects as of April 2000)
Search Term + Cancer
Descriptive and Health Services Research
Interventions and Clinical Trials
End of life
Of all the symptoms faced by patients with advanced cancer, pain is perhaps the best understood, and research in this area has a higher level of support than the study of other symptoms (see previous section). Several issues related to the subjective measurement of pain have been successfully addressed, and pain-related patient outcome variables can be specified for clinical, health services research, and epidemiologic studies. It is estimated that a majority of cancer patients could have their pain controlled, at least until the last week or two of life.
Current treatment of cancer pain is beginning to be codified into evidence-based and practice-based guidelines (practice based refers to guidelines that blend expert opinion and research evidence, where the evidence alone is not sufficient), which suggests a maturity of knowledge that does not exist for other symptoms. The common syndromes that account for the majority of cancer pain are well described and dictate specific treatment approaches. In contrast to other areas of research under discussion, there is a group of well-trained investigators who are able to conduct both basic and clinical research in the area. As described above, the biggest problems—which are amenable to health services research—are in getting physicians and patients to use pain medications to their best advantage. However, there are still major basic and clinical research issues to be dealt with, and research in cancer pain is also as affected by compartmentalization and lack of organizational support, funding, and structure as is research in other areas of end-of-life care. One approach to alleviating this problem is to facilitate networking among cancer pain investigators and basic scientists who are working in separate disciplines.
Basic research into the mechanisms of cancer pain has been limited by two major gaps in knowledge: (1) a poor understanding of the specific nature of cancer pain and (2) the lack of appropriate animal models.
Nature of Cancer Pain
Cancer pain potentially involves somatic, visceral, and neuropathic components. There have been marked advancements in understanding the mechanisms of cutaneous somatic pain over the past 20 years. These were largely first driven by the landmark studies of Lewis, and later Hardy and colleagues, that described the phenomena of primary and secondary hyperalgesia. The neurochemical basis of pain is becoming better understood; however, clinical applications of these findings have not yet had an impact on treatment.
Neuropathic pain, produced by nerve destruction and prominent in both cancer and AIDS, is poorly understood and difficult to treat (Woolf
and Mannion, 1999). Interactions between inflammatory mediators (such as cytokines and neurotrophins) are thought to sensitize pain receptors (nociceptors) to induce the sprouting of nociceptor terminals in inappropriate regions of the dorsal horn, to potentially alter phenotype of nonnociceptive afferent fibers, and to induce changes in the level of myelination of fibers. The mechanisms whereby these processes interact to produce changes in sensation are just beginning to be understood. Although some older drugs (tricyclics) and newer drugs (anticonvulsants, especially gabapentin) seem to help clinically, well-controlled clinical trial evidence in cancer is sparse. Most agree that advances in treating neuropathic pain will depend on understanding what causes it.
Visceral pain, originating from inflammation or damage to internal body structures, is the least understood of the major classes of pain that contribute to the cancer pain state. At present, the pathways by which noxious inputs from the viscera are transmitted and the forebrain structures involved in the processing of this pain remain little studied and technically difficult.
A recent study by Honore and colleagues (2000) is the first to establish a model of cancer pain. The promise of such models has already been demonstrated by the identification of osteoprotegerin as a potential therapy for bone cancer pain. Osteoprotegerin is a secreted “decoy” receptor that inhibits osteoclast activity (the breakdown of bone) and also blocks behaviors indicative of pain in mice with bone cancer. Osteoprotegerin inhibition of tumor-induced bone destruction inhibits neurochemical changes in the spinal cord thought to be involved in the generation and maintenance of cancer pain. In an unrelated clinical study, osteoprotegerin has already been given to humans, suggesting that a pain-focused clinical trial could come soon.
Behavioral measures for controlling cancer pain are promising but need further clinical testing. For example, there is some evidence to suggest that educational interventions can be effective for the alleviation of chronic cancer pain (see de Wit et al., 1997), but no research has yet been done to isolate the most useful aspects of these complex interventions. Relaxation has been somewhat more intensively researched, and interventions such as guided imagery and progressive muscle relaxation appear to be effective (Sloman, 1995), but the evidence for the value of other relaxation-based methods is less clear. Hypnosis is the best supported technique for alleviat-
ing procedure-related pain (Hawkins et al., 1998; Liossi and Hatira, 1999). However, evidence for the effectiveness of hypnosis in relieving chronic cancer pain is sparse (Syrjala et al., 1992).
Despite the existence of guidelines, the treatment of cancer pain remains largely empirical. There is an urgent need to confirm collected anecdotal information on analgesics, adjuvant analgesics, and neuroablative procedures, in randomized clinical trials.
Basic Research Needs
Major questions for basic research include the following:
What are the basic mechanisms of visceral and neuropathic pain, and how can we find better ways to treat these conditions?
What are the modifications of the nervous system that sustain chronic pain perception?
What newer compounds might have more precise analgesic action with fewer side effects?
What are the molecular mechanisms of pain signaling, and receptor modification due to pain, and how can they be modified?
What are the forebrain structures that modulate responses to “painful” signals?
What is the receptor affinity of different opioids?
Clinical Research Needs
The major issue to be addressed in clinical and health services research is, If we have the means to manage the pain of the majority of cancer patients, why do so many patients still have poorly controlled pain? Studies to improve cancer pain management are needed, as they are for other areas of distress at the end of life. Other issues include the following:
How effective are current treatments for neuropathic pain?
What are the effects of cancer on tolerance to opioid analgesics, and how can pain be managed in already-tolerant patients? What are the roles of type and route of opioids?
What opioids have the “best” side-effect profiles?
Trials of intrathecal delivery of novel analgesics need to be conducted.
What works to improve the practice of pain management?
Review of Current Funding: CRISP Listings
Searching the CRISP database of current federal funding using the
terms cancer and pain produces 147 hits. Inspection of the result finds a total of 42 that relate to basic or clinical research that might have relevance to clinical cancer pain. Of these studies, 9 are descriptive (including correlational and behavioral studies), 19 deal with trials of interventions, and 14 are basic science studies.
CURRENTLY FUNDED CLINICAL TRIALS
Combination Chemotherapy in Treating Pain in Patients with Hormone-Refractory Metastatic Prostate Cancer
Phase III Randomized Study of Mitoxantrone and Prednisone with or Without Clodronate in Patients with Hormone Refractory Metastatic Prostate Cancer and Pain
Flecainide in Treating Patients with Chronic Neuropathic Pain
Pain Control in Patients with Recurrent or Metastatic Breast or Prostate Cancer
Morphine for the Treatment of Pain in Patients with Breast Cancer
Treatment of Prostate Cancer with Docetaxel Alone and in Combination with Thalidomide Treating Patients With Stage IV Prostate Cancer
Effect of Androgen Suppression on Bone Loss in Patients With or Without Bone Metastases
Combination Chemotherapy in Treating Pain in Patients with Hormone Refractory Metastatic Prostate Cancer
Anorexia and Cachexia
Cancer patients often experience a profound loss of appetite (anorexia), especially in the last weeks of life, as well as a deterioration and wasting of body tissue (cachexia). There is clear evidence that cancer patients have undergone metabolic changes in their physiological responses to food. The metabolic changes with cachexia seem to be mediated by a variety of molecules in the body (including proinflammatory cytokines, neuroendocrine hormones, neurotransmitters, eicosanoids, and tumor-related substances) (produced by the tumor itself and by the body in response to the tumor; Barber et al., 2000). Cachexia is the immediate cause of nearly one-third of cancer deaths (Argiles and Lopez-Soriano, 1999).
Pharmacologic agents commonly used to treat cachexia include corticosteroids and progestational drugs (Gagnon and Bruera, 1998). Eight randomized, double-blind, placebo-controlled studies have confirmed that progestational drugs can increase appetite, food intake, and energy level. Additionally, in many patients, these drugs increase weight, and may also have an effect on nausea and vomiting (Body, 1999). Drugs that lessen the process of skeletal muscle protein catabolism that occurs in cachexia pa
tients (e.g., eicosapentaenoic acid and ibuprofen) are more effective than parenteral nutrition in stabilizing weight loss (Tisdale, 1998).
Parenteral nutrition may be used to improve patients’ nutritional status and enable them to receive complete doses of chemotherapy or radiation therapy. However, in prospective randomized clinical trials, parenteral nutrition has not had a significant effect either on a patient’s survival or on symptoms and toxicities (Body, 1999).
New treatments for cachexia include thalidomide, dronabinol (THC, tetrahydrocannabinol) and cannabis, and melatonin. THC stimulates appetite and increases body weight in patients with HIV and cancer. However, it is unclear whether THC or cannabis is more effective. Gorter (1999) argues that cannabis may be better tolerated than THC alone because cannabis stimulates the appetite like pure THC but includes other cannabinoids that decrease the psychotropic side effects of THC. Neuropeptide agonists and antagonists currently used to treat obesity may also have an effect on cancer anorexia-cachexia, especially when combined with other agents that affect the breakdown of muscle and protein (Inui, 1999). Clinical trials are needed to test the effectiveness of all the treatments discussed above.
Patients with cachexia often have greater concentrations of proinflammatory cytokines (i.e., tumor necrosis factor alpha, interleukin-1, interleukin-6 [IL-6], serotonin, interferon gamma) (Mantovani et al., 1998; Yeh and Schuster, 1999). When the concentrations of these cytokines are reduced, patients often gain weight. According to Tisdale (Tisdale, 1998), IL-6 is the only cytokine that is correlated with the development of cancer cachexia. Although it seems safe to say that cytokines are involved in cancer cachexia, the specific roles of these cytokines in the production of cachexia are still unclear.
Animal models of anorexia and cachexia have been developed. Emery (1999) placed a transplantable Leydig cell tumor in Fischer rats. Rats with this tumor showed a 20–40 percent decrease in food intake and an increase in energy expenditure compared with controls. Potential explanations for these effects include postprandial metabolism of carbohydrate caused by a greater rate of hepatic glycogen synthesis via the indirect pathway and maintenance of this increased rate of hepatic glycogen synthesis for a longer time after a meal. Another animal model of cachexia involves ciliary neurotrophic factor (a type of IL-6), which decreased muscle mass in experimental animals but did not have a direct effect on muscle in vitro (Tisdale, 1998).
A better understanding of the link between cancer cachexia and cytokines should lead to the development and testing of new pharmacologic agents. For example, megestrol acetate downregulates the synthesis and release of cytokines and increases appetite, body weight, and quality of life in patients with cachexia, and medroxyprogesterone acetate reduces the in
vitro production of cytokines and serotonin by peripheral blood mononuclear cells of cancer patients; both of these agents reduce the cisplatin-induced serotonin release in vitro from peripheral blood mononuclear cells of cancer patients (Mantovani et al., 1998).
Another promising area in basic research on cachexia is related to the recent identification of peptides involved in food regulatory systems, including the hormone leptin and leptin receptors, uncoupling proteins, agouti protein, melanocortin receptor isoforms, melanin-concentrating hormone, and the proteins responsible for “tub” and “fat” (mouse models of obesity) (Bessesen and Faggioni, 1998).
Basic Research Needs
Major questions for basic research include the following:
What are the specific roles of various cytokines in the cachectic process?
What are the roles of the food regulatory peptides in the cachectic process?
Clinical Research Needs
Clinical trials should focus on the following types of drugs:
anticatabolic agents (e.g., neuropeptide agonists and antagonists, beta 2- adrenoceptor agonists);
polyunsaturated fatty acids, n- [omega-] 3 fatty acids, fish oil;
anabolic agents (especially hormonal); and
anticytokines (e.g., megestrol acetate, medroxyprogesterone acetate, thalidomide, melatonin).
Review of Current Funding: CRISP Listings
Searching the CRISP database of current federal funding using the terms cancer and cachexia produced 28 hits. Inspection of the result found a total of 10 that relate to basic or clinical research possibly relevant to clinical cancer cachexia. Of these studies, none are descriptive (including correlational and behavioral studies), two deal with trials of interventions, and eight are basic science studies.
CURRENTLY FUNDED CLINICAL TRIALS
Omega-3 Fatty Acids in Treating Patients with Advanced Cancer Who Have Significant Weight Loss
Megestrol and Exercise in Treating Patients with Cancer-Related Weight Loss
High-Dose Megestrol in Treating Patients with Metastatic Breast Cancer, Endometrial Cancer, or Mesothelioma
(Delirium, Temporary and Permanent Cognitive Impairment)
Cognitive decline, including poor memory, attention, and problem solving or even frank dementia and delirium, has long been recognized in patients with end-stage disease. As many as one-third of patients admitted to palliative care units show significant cognitive impairment (Power et al., 1993), and the percentage is much higher for patients in the last week or two of life. From 25 to 85 percent of patients with advanced cancer show confusion (Breitbart, 1995) and delirium is the second most common psychiatric diagnosis among hospitalized elderly cancer patients (Stiefel and Holland, 1991). Confusion, which affects decisionmaking and may interfere with a patient’s recognition and reporting of other symptoms, is underreported, undertreated, and rarely studied in palliative care (Breitbart, 1995; Pereira et al., 1997). It can also affect patients’ families and is often a deterrent to home terminal care (Minagawa et al., 1996).
A number of treatments are in use for patients with cancer-related cognitive impairment, despite a relative lack of reliable evidence regarding their effects. Neuroleptics and benzodiazepines are used to manage delirium (Bruera and Neumann, 1998). Haloperidol may be given in combination with lorazepam for patients with delirium who are experiencing agitation. Diazepam is frequently prescribed, but may cause cognitive impairment or worsen dementia. Opioid rotation (switching drugs when side effects occur or pain is not relieved) and mild hydration may reduce delirium in some patients with advanced disease (Bruera et al., 1995). Stimulant therapy may reverse some of the cognitive impairment (problems with memory, attention, and reasoning) shown by cancer patients. In a study of patients with malignant glioma who developed cognitive deficits, Meyers et al. (1998) found that methylphenidate (10mg twice daily) significantly improved gait, stamina, and cognitive function in half of the subjects despite progressive neurologic injury as documented by magnetic resonance imaging (MRI).
Patients with cognitive impairment often exhibit a generalized slowing on electroencephalograph readings and impaired function of the brain stem
and forebrain in sleep testing procedures (Trzepacz, 1994). In as many as 75 percent of cases, the specific cause of cognitive impairment is unknown (Maddocks et al., 1996). Possible mechanisms of cognitive impairment include brain metastases, meningeal carcinomatosis, hypoxia, sepsis, metabolic abnormalities, hepatic and renal dysfunction, and increased drug levels in the brain or bloodstream (due to disruptions in the blood brain barrier and decreased drug metabolism). Research on cognitive impairment in patients with small cell lung cancer suggests that neuropsychological impairment may be caused by the disease process itself (Meyers et al., 1995; van Oosterhout et al., 1995). It has been hypothesized that long acting morphine metabolites are responsible for delirium (Maddocks et al., 1996; Bruera et al., 1995).
Cognitive impairment may also be caused or exacerbated by various anticancer treatments, including high-dose interferon alpha (INF-a) therapy, cranial irradiation, and high-dose chemotherapy. For example, patients treated with INF-a often exhibit a syndrome of mental slowing and memory impairment, accompanied by mood disturbances. These patients’ patterns of test responses suggest mild subcortical dementia (Valentine et al., 1998). Patients receiving recombinant IL-2 have also been noted to develop a severe dementia resembling dementia of the Alzheimer’s type (Walker et al., 1996). Therapy-induced cognitive impairment may be either acute or chronic. As discussed above, 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).
Basic Research Needs
Major questions for basic research include the following:
What are the underlying mechanisms of delirium and cognitive impairment?
What is the role of the cancer disease process in producing cognitive impairment?
What is the process through which biological therapies (e.g., IFN-a, IL-2) produce cognitive impairment?
Are there biological markers for those patients most at risk for delirium and cognitive impairment?
Clinical Research Needs
Research in this area should focus on the understanding, prevention, and treatment of delirium, specifically
development of and agreement on standardized assessment for delirium;
prevalence, nature, and current treatment for delirium and cognitive impairment;
clinical trials of drugs now used empirically for delirium (haloperidol) and cognitive impairment (methylphenidate);
clinical trials of stimulants to treat cognitive impairment; and
clinical trials of anticancer treatments that include neuropsychological assessments as a required measure of treatment toxicity to determine which treatments may cause cognitive impairment.
Review of Current Funding: CRISP Listings
Searching the CRISP database of current federal funding using the terms cancer and delirium or cognitive impairment produced seven hits. Two relate to basic or clinical research that might have relevance to clinical cancer-related delirium or cognitive impairment. Of these studies, one is descriptive, and one is a basic science study. There are no intervention trials.
CURRENTLY FUNDED CLINICAL TRIALS There are no current trials for delirium or cognitive impairment.
Between one-fifth and three-quarters of patients with advanced disease experience dyspnea, which is moderate to severe in 10 to 60 percent of these patients (Ripamonti, 1999). Not surprisingly, a greater proportion of newly diagnosed lung cancer patients—70 percent—experience dyspnea (Muers et al., 1993). Dyspnea often occurs in the presence of other symptoms: patients with dyspnea were 39 percent more likely to complain of other symptoms and 55 percent more likely to report other symptoms as being severe (Farncombe, 1997). The frequency and severity of dyspnea increase with the progression of the disease and when death is approaching.
Dyspnea may be related to anticancer treatments, including chemotherapy, radiotherapy, and surgery (Komurcu et al., 2000). Treatment of the underlying cancer or treatment of the underlying pulmonary or cardiac disease may relieve dyspnea. Additionally, radiotherapy and chemotherapy may relieve dyspnea even when there is no tumor response. The most common treatments administered to dyspneic patients in the emergency department at the University of Texas M.D. Anderson Cancer Center in the early 1990s were oxygen (31 percent), beta 2-agonists (14 percent), antibiotics (12 percent), and opioids (11 percent) (Escalante et al., 1996).
Dyspnea is understudied. There is a great need for research on the pathophysiology of dyspnea in cancer patients. Potential mechanisms for dyspnea include respiratory muscle weakness due to anorexia and cachexia, chemoreceptor stimulation, and efferent activity from the respiratory center by direct ascending stimulation.
Despite the various treatments that are used, few clinical trials of their effectiveness for relieving dyspnea in cancer patients have been carried out (LeGrand and Walsh, 1999). Opioids are often used for patients with dyspnea, but there have been too few well-controlled clinical trials to determine the ideal drug, route, or regimen. Corticosteroids are also commonly used, but even less is known about the effectiveness of these drugs in relieving dyspnea. Benzodiazepines or nebulized opioids have not proven effective for the treatment of dyspnea in clinical trials. Transfusion therapy has been used to relieve dyspnea in patients with anemia, but the effectiveness of this treatment is unclear. Bronchodilators are used to improve breathing in many patients with lung cancer and chronic obstructive pulmonary disease (COPD), and may also be helpful for patients without COPD who have dyspnea.
Basic Research Needs
Major questions for basic research include the following:
standardization of measurement and assessment of dyspnea,
possible animal model for dyspnea,
relationship of dyspnea to the anemia of chronic illness,
role of respiratory muscle metabolism/function in dyspnea, and
establishing a link between cachexia, tumor necrosis factor, muscle fatigue or weakness, and dyspnea.
Clinical Research Needs
Clinical trials should focus on the following:
descriptive studies of prevalence, severity, and current treatment;
trials examining effectiveness of opioids by different routes;
trials of other agents (corticosteroids); and
trials of methylxanthine drugs, which may have a role in treating dyspnea by stimulating respiratory muscles.
Review of Current Funding: CRISP Listings
Searching the CRISP database of current federal funding using the terms cancer and dyspnea produced four hits. Only one relates to basic or
clinical research that might have relevance to clinical cancer dyspnea, and it is an intervention study.
CURRENTLY FUNDED CLINICAL TRIALS There are no current trials for dyspnea.
Fatigue is the most common symptom among cancer patients (Glaus et al., 1996). Overwhelming fatigue often characterizes patients with far advanced cancer. Because of its prevalence, it is often reported as the symptom that is the most distressing and causes the greatest interference with daily life (Richardson, 1995). Fatigue in cancer patients is associated with psychological disturbance, symptom distress, and decreases in functional status (Irvine et al., 1994).
Symptomatic treatment of fatigue is in its infancy. Severe fatigue is associated with low levels of hemoglobin (Cleeland and Wang, 1999). Fatigue caused by anemia improves if the anemia can be treated with transfusions or epoietin alfa (Glaspy et al., 1997; Demetri et al., 1998). Therapies used for fatigue include changes in a patient’s drug regimen, correction of metabolic abnormalities, and treatments for depression or insomnia. Many health care professionals suggest mild exercise as a way of dealing with fatigue, and a reduction in muscle mass has been suggested as a mechanism for fatigue. A recent controlled study found that aerobic exercise prevented increases in fatigue and psychological distress in patients undergoing highdose chemotherapy (Dimeo et al., 1999). Other nonpharmacological treatments include modification of activity and rest patterns, cognitive therapies, behavioral therapies to modify sleep (sleep hygiene), and nutritional support.
Pharmacologic treatments currently used to treat fatigue include psychostimulant drugs and corticosteroids, which are supported by very limited research (Portenoy and Itri, 1999). It has been suggested that the selective serotonin reuptake inhibitor (SSRI) antidepressants may have a role in fatigue management, but there are no reports of clinical trials of these agents for fatigue. Informal surveys that the authors have conducted at meetings indicate that many oncologists are prescribing stimulants, primarily methylphenidate, to help their patients combat debilitating fatigue, although this practice is not supported by evidence from published clinical trials. However, methylphenidate has been shown in trials to improve opioid sedation used to manage cancer pain (Bruera et al., 1992a, 1992b) and, as already mentioned, has been shown to improve cognitive function in patients with central nervous system tumors (Meyers et al., 1998).
Fatigue may be caused by the cancer itself, or like other symptoms, it
may be caused by treatment. Other mechanisms that contribute to fatigue include sleep disturbance, environmental conditions, level of activity, nutritional status, and the demands of treatment (Nail and Winningham, 1993). Treatment-related anemia is well known for its impairment of quality of life and function and is often associated with severe fatigue in cancer patients (Glaspy et al., 1997). In a survey of cancer patients at M.D. Anderson Cancer Center using the Brief Fatigue Inventory (BFI), patients with hematologic malignancies reported greater fatigue than patients with solid tumors (47 percent of the hematologic group reported “worst fatigue” of 7 or greater versus 28 percent of the solid-tumor group) (Mendoza et al., 1999). In patients with hematologic malignancies, low levels of both hemoglobin and albumin were predictive of severe fatigue (Cleeland and Wang, 1999).
Hormonal deficiencies occur in large numbers of patients treated with IFN-a, and the possibility that hypothyroidism or other adrenal or gonadal dysfunction may be associated with fatigue in these patients should be investigated (Jones et al., 1998). IFN-a and other agents used in treating cancer also excite or inhibit the production of cytokines that are known to be related to fatigue. For example, IL-6 is a proinflammatory cytokine that has been shown to mediate endocrine and neural activity. In normal subjects, IL-6 induces fatigue and inactivity as well as poor concentration (Spath-Schwalbe et al., 1998). Future research should explore the role of proinflammatory cytokines in the production of fatigue experienced by patients treated with IFN-a (Dalakas et al., 1998).
Basic Research Needs
Explore new agents for treating fatigue (anticytokines).
Develop animal models for fatigue.
Explore “common pathways” for fatigue and other symptoms.
Clinical Research Needs
There are needs for trials of the following:
Review of Current Funding: CRISP Listings
Searching the CRISP database of current federal funding using the terms cancer and fatigue produced 34 hits. Eleven relate to basic or clinical research that might have relevance to clinical cancer fatigue. Of these stud-
ies, three are descriptive (including correlational and behavioral studies), eight deal with trials of interventions, and none are basic science studies.
CURRENTLY FUNDED CLINICAL TRIALS
Blood Transfusions With or Without Epoietin Alfa in Treating Patients with Myelodysplastic Syndrome
Phase III Study of Epoietin Alfa with or Without Filgrastim (G-CSF) vs Supportive Therapy Alone in Patients With Myelodysplastic Syndromes
Exercise Plus Epoietin Alfa in Treating Cancer Patients Who Have Anemia-Related Fatigue
Phase III Randomized Study of Hypericum perforatum (St. John’s Wort) for the Relief of Fatigue in Patients Undergoing Chemotherapy or Hormonal Therapy for Malignant Disease
Methylphenidate in Treating Patients with Melanoma
Nausea, vomiting and bowel obstruction are frequent symptoms in patients with advanced cancer. More than 60 percent of patients who are treated with antineoplastic agents also experience nausea and vomiting. Both clinicians and patients identify nausea and vomiting as the most distressing side effects of chemotherapy. Nausea and vomiting are also associated with radiotherapy. Current pharmacologic treatments for nausea include prokinetic drugs, either alone or in combination with corticosteroids (Bruera and Neumann, 1998) and pure THC (which stimulates the appetite). Treatments for vomiting include: dopamine antagonists (such as ondansetron, a 5-hydroxytryptamine [HT] 3 receptor antagonist), phenothiazines, metoclopramide, corticosteroids, cannabinoids, benzodiazapines, antihistamines, and anticholinergics. Behavioral interventions can be effective against nausea and vomiting that occurs before and after treatments.
Future research should focus on the development of standard tools for the assessment of nausea and vomiting as separate symptoms. More research is needed on these symptoms in special populations of cancer patients (such as women, children, and patients of minority status). Clinical trials should be done to determine the effectiveness of the current treatments for nausea and vomiting and the effectiveness of corticosteroids for the treatment of intestinal obstruction. Well-designed clinical trials should also focus on the use of behavioral and other nonpharmacological methods for the management of nausea and vomiting, such as aerobic exercise, guided imagery, progressive relaxation, and acupressure.
The pathophysiology of nausea and vomiting may involve chemical, visceral, central nervous system, and vestibular system processes (Fessele, 1996). In vomiting associated with chemotherapy and radiotherapy, both
central (chemoreceptor trigger zone) and peripheral (gastrointestinal) processes may be involved (Stewart, 1990). Chemotherapy (antineoplastic agents) induced nausea and vomiting is mediated, at least in part, by the neurotransmitter serotonin (Hogan and Grant, 1997). The roles of other neurotransmitters in nausea and vomiting are unclear.
Basic Research Needs
The following should be studied:
Relationship of terminal nausea to other symptoms of advanced disease, and
Mechanisms of terminal and treatment-induced nausea.
Clinical Research Needs
The following are needed:
trials of agents for nausea of advanced disease,
trials of agents for bowel obstruction, and
descriptive studies of prevalence, severity, and current treatment of terminal nausea.
Review of Current Funding: CRISP Listings
Searching the CRISP database of current federal funding using the terms cancer and nausea or vomiting produced 13 hits. Three relate to basic or clinical research that might have relevance to clinical cancer nausea and vomiting. Of these studies, none are descriptive (including correlational and behavioral studies), one is an intervention study, and two are basic science studies.
Searching the CRISP database of current federal funding using the terms cancer and bowel obstruction produced only one hit, and this hit is not related to basic or clinical research on bowel obstruction in cancer.
CURRENTLY FUNDED CLINICAL TRIALS
Endoscopic Placement of Metal Stent in Patients with Cancer-Related Bowel Obstruction
Phase I/II Pilot Study of Enteral Wall Stents in Patients with Colonic Obstruction Secondary to Malignancy
Octreotide as Palliative Therapy for Cancer-Related Bowel Obstruction that Cannot Be Removed by Surgery
Nausea or Vomiting
Lerisetron Compared with Granisetron in Preventing Nausea and Vomiting in Men Being Treated with Radiation Therapy for Stage I Seminoma
Drugs to Reduce the Side Effects of Chemotherapy
Acupressure and Acustimulation Wrist Bands for the Prevention of Nausea and Vomiting Caused by Chemotherapy
Psychiatric and Affective Symptoms (Anxiety, Depression)
Estimates of the prevalence of depression in cancer vary somewhat with the methods used to assess depression, when the assessments are done, and possibly with the type of cancer. In general, studies have found that approximately 25 percent of patients have depressed mood, and that between 10 and 15 percent of patients have a major depression sometime during their treatment (Cleeland, 2000). Although anxiety is common, it is rarely assessed regularly in cancer patients, and few patients are diagnosed or treated for it (Bottomley, 1998). The risk of patients developing psychological symptoms is increased with advanced disease, with certain cancer treatments, with uncontrolled physical symptoms (e.g., pain) or functional limitations, with inadequate social support, or with a past history of psychiatric disorder (Breitbart, 1995).
Both pharmacologic and nonpharmacologic therapies can be used to treat psychological symptoms in patients with cancer. However, some antidepressants may have serious side effects in patients with a concurrent illness such as cancer. For this reason, McCoy (1996) argues that pharmacologic agents that have many toxicities or act at multiple receptor sites (e.g., trycyclic antidepressants, monoamine oxidase inhibitors) should not be used to treat psychological symptoms in these patients. SSRIs (e.g., fluoxetine, or Prozac) and other new antidepressants may be a better choice for patients with cancer because they have fewer anticholinergic, cardiac, or cognitive adverse effects (McCoy, 1996). Psychotherapy for the treatment of depression may actually have an effect on the course of cancer. Psychotherapy may improve patients’ quality of life and help them learn to cope with their illness. In three randomized studies, psychotherapy increased survival time in patients with breast cancer, lymphoma, and malignant melanoma (Spiegel, 1996).
A report from a 1993 National Cancer Institute of Canada panel on neuropsychiatric syndromes and psychological symptoms in cancer patients
made recommendations for future symptom control research (Bruera, 1995). To improve epidemiological research in this area, a uniform terminology and taxonomy has to be widely used and accepted, validated tools should be used to assess these symptoms, and new tools must be developed that are appropriate for palliative care settings. Clinical trials using both pharmacologic and nonpharmacologic treatments are also needed. Fluoxetine (Prozac) is one of several effective treatments for depression; it is currently the most frequently prescribed antidepressant in the United States. Unfortunately, evidence on the use of fluoxetine in patients with cancer is inadequate (Shuster et al., 1992). Research should also explore other psychological symptoms that have not been studied much in cancer patients, such as anxiety, posttraumatic stress disorders, sleep disorders, fatigue, and suicidal ideation.
The prevalence of depression varies with cancer diagnosis and treatment, and the physiological mechanisms related to these differences need exploration. Kelsen and colleagues (1995) found that 38 percent of 83 patients with newly diagnosed pancreatic cancer scored within the depressed range on the Beck Depression Inventory before treatment began, a higher percentage than is usually found in studies of patients with other primary malignancies. In a study of 122 patients receiving radiotherapy, the prevalence of mood disorders was nearly 50 percent (Leopold et al., 1998).
Psychological symptoms such as depression and anxiety may be related to changes in the physiologic functioning of the pancreas, such as changes in the secretion of hormones, neurotransmitters, digestive enzymes, or bicarbonate (Passik and Breitbart, 1996). Depression, cognitive dysfunction, and psychosis have all been associated with antiphospholipid antibodies (Brey and Escalante, 1998). There is evidence of depression related to impaired phospholipid metabolism and impaired fatty acid-related signal transduction processes in patients with cancer and other diseases (e.g., diabetes, cardiovascular disease, immunological abnormalities, multiple sclerosis, osteoporosis; and more generally, aging) (Horrobin and Bennett, 1999). These metabolic changes merit study as a possible primary cause of depression.
Basic Research Needs
The following are needed:
animal models for cancer-related affective disturbances, and
knowledge of the mechanisms of depression unique to cancer and its treatment.
Clinical Research Needs
Clinical research should include the following:
descriptive studies of current management of psychological symptoms in advanced disease;
trials of standard antidepressants, especially SSRIs;
trials of stimulant therapies (methylphenidate);
discussion of trials of novel agents (“empathogens”); and
trials of agents for terminal agitation or restlessness.
Review of Current Funding: CRISP Listings
Searching the CRISP database of current federal funding using the terms cancer and depression produced 71 hits. Fifteen relate to basic or clinical research that might have relevance to clinical depression in cancer. Of these studies, eight are descriptive (including correlational and behavioral studies), five deal with trials of interventions, and two are basic science studies.
Searching the CRISP database of current federal funding using the terms cancer and anxiety produced 48 hits. Twelve relate to basic or clinical research that might have relevance to anxiety in cancer. Of these studies, six are descriptive (including correlational and behavioral studies), six deal with trials of interventions, and none are basic science studies.
CURRENTLY FUNDED CLINICAL TRIALS—DEPRESSION There are no current trials for depression.
CURRENTLY FUNDED CLINICAL TRIALS—ANXIETY
Diet and prostate-specific antigen (PSA) Levels in Patients with Prostate Cancer
St. John’s Wort in Relieving Fatigue in Patients Undergoing Chemotherapy or Hormone Therapy for Cancer
STATUS OF END-OF-LIFE AND SYMPTOM RESEARCH
As we have seen, important areas of research could greatly benefit care at the end of life as well as reduce the symptom distress that cancer patients experience as their disease gets worse. That such research is feasible has been demonstrated. Research and symptom epidemiology, behavioral research, health services research, and basic as well as clinical symptom research have already produced benefits that have been translated into better care. The magnitude of the distress experienced by cancer patients with advanced disease has been documented, as has the impact of this distress on
both patients and their caregivers. Although the amount of improvement has not been well studied, it is very possible that patients now experience less distress related to medical procedures, that pain is somewhat better managed, and that there is wider recognition of and attention to end-of-life issues, such as patient preference for end-of-life decisions. Research has also documented the gaps between current care and optimal care and has identified very specific obstacles that could be addressed to improve care.
Perhaps less obvious has been a maturation of research methods that should facilitate the rapid progress of research in this area. Increasingly, the subjective reports of patients about their quality of life and about the severity and impact of their symptoms are accepted as reasonable outcome measures for both clinical and laboratory research. Developments in this type of methodology have been funded and have yielded tangible results. Quality-of-life outcomes have become more accepted as clinical trial end points, as has the prevention or reduction of specific symptoms. New technologies have been developed, primarily from other areas of investigation, that give us unique opportunities to understand the nature, mechanisms, and expression of symptoms that were not possible a few years ago. For example, new brain-imaging techniques may allow us to understand the cortical expression of symptoms (such as pain, depression, and cortical impairment) as well as the modification of this expression by treatment. New developments in biology have opened windows to a better understanding of distress, including the nature and interaction of receptors and transmitters. Developments in pharmacology have produced an array of exciting agents that could provide better control of most of the symptoms of the dying process. There is a real possibility that individual variation in symptom expression may be better understood through progress in genetic science. We can no longer say, as was said a few years ago, that we do not have the tools to advance this area.
We also have a wide range of targets for investigation. The understanding of pain, although more advanced than that for other symptoms, still has enormous gaps. Our understanding of other symptoms is much more primitive. We have only a limited understanding of the context of the dying process, including economic, social, and ethical factors. Research examining ways of improving the care given to patients with advanced cancer is just beginning. Ways of examining the more complex subjective needs of patients (spiritual, existential) have to be developed, and methods of qualitative research have to be strengthened. Few of the practices that we depend upon for the care of the dying and for the patient with advanced cancer have been subjected to the scrutiny of careful randomized clinical trials, impeding the provision of evidence-based practice recommendations.
FUTURE END-OF-LIFE AND SYMPTOM RESEARCH: PROBLEMS AND POTENTIAL SOLUTIONS
Despite the progress, substantial barriers impede the research needed to advance end-of-life care and symptom control. The main problems and some potential solutions are presented below. The ideas have come from the author, published literature, and clinicians and investigators in the field contacted by the author specifically for this report (see Appendix 8A). The issues are presented in specific categories, but it is clear that the problems and solutions are interlinked. For example, the level of funding depends on a sufficient number of well-trained research investigators and research groups, infrastructure and organizational support, and public advocacy.
Low Level of Research Support
THE PROBLEM A low level of research support has been identified as the major barrier to end-of-life and symptom research. In fiscal year 1999, the National Cancer Institute (NCI) spent $24.5 million in extramural funding for all research with components related to palliative care or hospice. Of this total, $18.3 million went to specific projects or programs, and $6.1 million represents fractions of institutional grants. In addition to the research grants, $1.7 million was spent in 1999 on training grants related to end-of-life or palliative care. Altogether, the 1999 NCI expenditure on palliative and hospice care was just over $26 million, or about 0.9 percent of the total 1999 budget of $2.9 billion (see Chapter 1 of this report).
The proportion of congressionally mandated cancer research in this area funded by the Department of Defense (DOD) is also minimal, and the requests for proposals (RFPs) for these programs may actually discourage submissions. The American Cancer Society (ACS) reports that it spends less than 1 percent of its budget on the topics covered here, and it is estimated that other foundations spend the same or less on such research. A major exception has been the substantial investment of the Robert Wood Johnson Foundation in end-of-life issues.
In 1997, industry spent 1.6 billion in cancer-related research (McGeary and Burstein, 1999), primarily in the development and testing of cancer-related drugs and vaccines. With the increasing acceptance of symptom prevention and control, as well as general quality-of-life outcomes as end points for approval of new drugs, there has been a proportional increase in industry investment in the development and clinical testing of drugs for symptom control. Symptom and quality-of-life data are being gathered on large numbers of advanced cancer patients, and new agents of interest are under development. There are, however, many obvious limitations to the product of this kind of effort. The wealth of symptom and quality-of-life
data generated are rarely published or shared with non-industry investigators; data gathering is biased against recording events that may negatively affect approval; and the drugs under investigation are ones expected to generate high profits.
Those individuals in agencies who might fund grants in these areas acknowledge that more needs to be spent but point to a lack of interest within their agencies and a lack of organizational structure that promotes this type of research. They also point to a lack of competitive applications. They emphasize the lack of vocal public advocacy for these topics. There has been little political support for this type of research from the major cancer disease groups, cancer survivors, or scientific and professional organizations (aside from specific topics related to their interests). Issues of end-of-life care and symptom control are detached from the mainstream of perceived urgent research needs and are viewed as of substantially less importance than research focused on cure or prevention.
POTENTIAL SOLUTIONS Packaging may be important. As has been pointed out, end-of-life, palliative care, and symptom control issues are components of the whole enterprise of cancer care, and elements of research in these areas are critical to all cancer patients. The biology of the symptoms of dying shares much with the biology of cancer symptoms throughout the disease spectrum. Research on improving the quality of cancer care in general will benefit those with advanced disease. It is possible that labeling efforts as “end of life” and as “palliative” may unnecessarily restrict funding considerations and enthusiasm for support. This issue is clearly controversial and political and needs substantial discussion. Support for this discussion, perhaps from a private foundation, could move it forward.
Even before a full discussion, there is an immediate need for additional funds earmarked for advanced disease and symptom control research grants and contracts. Thus far, there is very little targeted funding, but in a one-time limited program in 1998 that resulted in a request for applications developed jointly by several groups at the NIH, the response from the research community was enthusiastic (more than 120 applications were received, approximately 20 of which were eventually funded).
Public and private funding agencies and disease advocacy groups must be informed about the needs and opportunities for research in this area, especially the unnecessary suffering that patients with advanced cancer endure because of inadequate care. The same need exists for academic institutions and cancer research organizations. A reasonable and modest investment could be made by a foundation to explore how public advocacy of these research efforts might be improved.
Infrastructure and Organizational Deficits
THE PROBLEM Currently, there is no institutionalized mechanism or coordination of efforts to develop new treatments for the relief of cancer-related symptoms or for the care of dying patients. There is no group or office at the NIH or NCI with symptom management as a primary responsibility, even though hundreds of thousands of patients are impaired by these symptoms. The lack of such an organizing structure is not difficult to understand: the NIH and NCI have a mandate to cure or to prevent disease. Managing the symptoms of disease has not been an expectation of those who fund the NIH, nor has it been thought of as an important mission of the NIH. At the NCI, as well as throughout the NIH, a disease model is in place that makes organized planning for symptom-related research cumbersome. At the NCI, it is difficult to identify a project officer that has, as his or her primary title, the coordination, promotion, and review of symptom-related and end-of-life research. The focus is, as it should be, the prevention and cure of cancer, but it is yet to be acknowledged that the control of symptoms and amelioration of distress are part of good cancer care and therefore worthy of publicly supported research.
POTENTIAL SOLUTIONS Symptom management will be addressed appropriately only when there is (1) an organizing group within the NIH that has an interest in and dedication to symptom management and care of the dying patient and the resources for action to improve it, and (2) the formation of groups or task forces to plot the types of basic and clinical research that must be done. Such groups have to generate long-range plans that encompass needs for basic, clinical, and health services research efforts. There has been such a task force for basic research in pain sponsored by the NIH, which might be a model for the management of other symptoms. An effort to make “supradisease” linkages among the institutes that address issues of advanced disease and symptom control is needed. For example, there is a need to link cytokine research in AIDS, cancer, and arthritis—all of which might have implications for the management of cachexia, pain, fatigue, cognitive impairment and depression—or the role of opioid receptors common to several symptoms. The research needed for progress in understanding and treating advanced disease and symptom control is multidisciplinary, and program project and multi-institutional funding would be ideal mechanisms to enhance it.
It is reasonable to ask NCI to provide staff officers, organizational structure and resources to deal with advanced disease and symptom control and to give them appropriate titles so that they can be identified by organizations, the public, and the research community.
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
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-
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
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.
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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
Patrick Dougherty, Ph.D.
Associate Professor of Anesthesiology
University of Texas M.D. Anderson Cancer Center
Debra Dudgeon, M.D.
Director, Palliative Care Medicine Program
Betty Ferrell, R.N., FAAN, Ph.D.
City of Hope
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
Christina Meyers, Ph.D., ABPP
Associate Professor of Neuro-oncology (Neuropsychology)
University of Texas M.D. Anderson Cancer Center
Judith Paice, R.N., FAAN, Ph.D.
Professor of Cancer Research
Steve Passik, Ph.D.
Director, Community Cancer Care
Carla Ripomonti, M.D.
Donna Zhukovsky, M.D.
Associate Professor, Symptom Control and Palliative Care
University of Texas M.D. Anderson Cancer Center