Abstract

There is not yet sufficient evidence-based experience for the coordinated treatment of three symptoms that cluster in cancer: pain, depression, and fatigue. Each symptom taken individually has accepted treatment modalities. With some overlap between these symptoms, established treatments for one symptom may “cross-over” and reduce the burden of one, or both of the others. To optimize patient care in advance of the evidence basis, attention to these symptoms is value-added for patients and their families. Standardized screening using the Distress Thermometer for physical, practical, emotional, or spiritual symptoms helps effectively identify patients whose symptoms warrant attention. Cancer Supportive Services, an innovative program at the Continuum Cancer Centers of New York at Beth Israel and St. Luke’s-Roosevelt, provides comprehensive intervention throughout the trajectory of care for pain, depression, and fatigue. These services are provided in tandem with efforts to cure or contain the cancer. Cancer Supportive Services sets up a natural entry point to survivors’ follow-up or end-of-life care. Such an effort reinforces a basic principle that active symptom management is integral to each patient encounter in the cancer treatment setting.

There are many dimensions to patients’ experience with cancer. Certain experiences, or symptoms, are shared by most patients with cancer. As discussed elsewhere, three of those symptoms, pain, fatigue, and depression often track together in the same individual. Taking the type of cancer, stage, and treatment into account, subjective evaluation of these predictable commonalities is colored by the extent to which his or her cancer can be treated or cured, individual psychology, and effective social or spiritual support.

Until the recent past, these symptoms were silently tolerated as a consequence of cancer and its treatment. If identified at all, they were considered as part of the burden one pays when living with life-threatening illness and perhaps as surrogates for the extent of disease or treatment response. Modern biotechnology, and the extended survival of patients with some cancers, has brought focus to these symptoms and expanded the opportunity for intervention. The strengthened sense of consumerism coupled with faster multimedia communications’ information explosion have sparked demand for the treatment of pain, fatigue, and depression before rigorous studies of the triad have been completed.

The question at hand—What is the optimal treatment of symptom clusters?—challenges the underpinnings of medical decision making developed throughout the twentieth century as well as the notion of evidence-based medicine popularized at the century’s close. Accurate diagnoses, made with uniform and accepted criteria in mind, precede the formation of a treatment plan. Treatment, when instituted, is based on evidence from controlled trials as the gold standard taking precedence over clinician familiarity or past experience.

Separating the constitutional signs and symptoms of cancer itself from those of depression has become more feasible through collective experience and research, though the process is still somewhat inexact. Challenging the popular notion that all cancer patients suffer depression has led to a dilemma: defining degrees of depression in the wide variety of cancer illnesses at its various stages and with its confounding treatments, and then designing proper treatment for these mood changes. Tradition asks that a diagnosis be established before a treatment plan is set. Estimating the contribution of mood to the experience of cancer underscores the very basic property of mood as a background emotion to the life experiences that occur around it.

With a parallel interest in diagnosing and treating pain and fatigue, the ever-present contribution of mood complicates the understanding of these symptoms in cancer. Not every patient experiences pain or fatigue to the same degree, and culture and personal values overlay these symptoms as well. Looking at each symptom separately, it should be clear that their presentation and measurement have substantial overlap, so it is reasonable to assume that respective treatments would overlap as well.

Critical thinking forces us to first look at accepted treatment modalities for each symptom in isolation, drawing on what is known about the symptom in general: depression in the physically healthy, fatigue in those without depression or cancer, and pain from a variety of causes. The subsequent challenge is to adapt these “pure” circumstances across the spectrum of cancer and its treatments, adjusting for age and comorbidities.

With an evidence-based focus, the next step to approaching the treatment of symptom clusters is to survey published data examining cluster treatments across the lifespan and among various cancers. Articles describing findings of these clusters do not exist. An innovative methodological adaptation is to take the usual and generally acceptable treatment modalities used for a single cancer symptom and examine its efficacy in the remaining two symptoms. The notion of “clustering” of pain, fatigue, and depression is born out of the impression that a treatment modality commonly used in one symptom can reduce the burden of the others.

Basic Principles of Symptom Management in Cancer

Guiding principles for treatment are listed in Table 1. These principles serve as the basis for the provision of optimal symptom management throughout the trajectory of disease and ease the transition to end-of-life care, should there be disease progression. They are a logical outgrowth of good patient care, serving as a background for review of evidence-based and consensus-based treatments. Symptom management must not only be considered with progressive cancer at the end of life, but as a part of optimal care throughout the course of the disease.

The basic principles of symptom management in cancer include, first, that active symptom evaluation and management (treatment) are integral to each patient encounter in the cancer setting. Second, active symptom management has a role in every stage of cancer treatment from the day of diagnosis on. Symptom management becomes the primary cancer therapy after surgery, chemotherapy, radiation, hormonal, or biologic therapies, either as a transition to follow-up for survivors with the help of a primary care provider or oncologist or as a bridge to end-of-life care. Third, overlap in treatments for pain, depression, and fatigue make it less important to sort out pure diagnoses. Fourth, each symptom has “accepted” treatment modalities as well as others that are less accepted and that may or are likely to minimize symptom burden. Finally, use of less accepted modalities can be recommended more easily if they have favorable side-effect profiles or minimal toxicities.

The non-exclusivity of symptoms as free-standing entities in the usual course of clinical care has been a motivation for this conference, and it should be nurtured as a driving force for the future. Fig. 1 illustrates the conceptual framework of symptom overlap.

Treatment of each symptom singly—depression, fatigue, and pain—has certain, more widely accepted approaches, as well as those that are generally less well established. Whether these treatment modalities are considered innovative or complementary can be a matter of perspective and discipline.

Symptom management is common to all types of cancer and at all stages of disease. It is a routine component of each patient encounter, overarching the standard modalities of surgical, chemotherapeutic, or radiation treatments.

Patterns of Overlap

In Fig. 1, Venn diagrams show the overlap of the three basic symptom elements: depression, fatigue, and pain. It shows that they may exist singly, in doublets, or all together in a patient with cancer.

Pain is commonly treated with medications and exercise techniques (1,2). Medications and various types of psychotherapies have traditionally been the mainstays of treatment for mood disorders (3). Fatigue has been responsive to exercise, cognitive-behavioral therapies, and nutritional intervention (4).

Looking at the “crossovers,” or treatments that are routinely accepted for one symptom yet have potential in another, is an opportunity to be creative in theoretical development, research planning, and current patient care. Exercise has a role in the treatment of mood disorders. Cognitive-behavioral therapies are being used in pain management and fatigue reduction. Pharmacologic agents, including erythropoietin and a variety of psychotropics, may be used to combat anemia and related fatigue. Use of less accepted modalities can more easily recommended if they have favorable side-effect profiles or minimal toxicities.

Some novel cross-over approaches could involve cognitive-behavioral psychotherapies in the management of cancer pain as well as fatigue and depression, nutritional supplementation to reduce pain or modulate depression as well as fatigue, tailored exercise to treat depression as well as pain and fatigue, medication through accepted or off-label uses for fatigue as well as depression and pain, or adaptation of innovative models outside of cancer, or those used for special populations.

Cognitive-Behavioral Therapies for Pain

Relaxation, guided imagery, and cognitive-behavioral training have been shown to reduce pain from mucositis (5) in a controlled clinical trial. A more general review by Loscalzo (6) shows the value of cognitive-behavioral interventions as an adjunct to standard care for cancer-related pain. Hypnosis, a particular type of cognitive-behavioral modality, has been shown helpful by Levitan (7). Lema (8) found that invasive techniques for analgesia in cancer are best in a multimodal approach that includes psychotherapy. In a pediatric population, Kuttner (9) reported that “imaginative involvement,” a hypnotic technique adapted for children, reduced observer-related pain and anxiety.

Distraction from pain or other illness-related pain or distress is intuitively practiced by patients and families, using a variety of modalities: music, storytelling, prayer, or more recently, radio and television. Audio and videotapes, produced exclusively for the ill, are commercially produced and commonly available.

Nutritional Therapies for Pain and Depression

Nutritional therapies (including dietary supplements or nutriceuticals) to treat pain are an untapped area with potential for investigation in cancer, yet little work has been done thus far. Societal interest in complementary alternative approaches to illness prevention and treatment has begun to establish the evidence basis for some compounds. A common example would be the use of combined chondroitin sulfate and glucosamine preparations for arthritic joint pain (10). Whether such supplements or others would have their place as adjuvant treatment of cancer pain has not yet yielded meaningful findings.

Practitioners of orthomolecular psychiatry outside the mainstream of accepted treatments have attempted to correct underlying defects in neurotransmission using oral supplements that are mostly vitamin based. Delivering adequate amounts of these substances to neuronal tissue has not yet been accomplished. The public has shown some interest in “smart foods,” which claim to optimize brain function. Choline (11), and gingko (12) are sold as supplements with the idea of providing better substrate for central nervous system performance. These or other substances may or may not have a role in cancer, yet they remain to be tested.

Exercise for Depression and Fatigue

The overlap in the development of pain and fatigue in cancer and its resulting treatments make this dyad worth examining. A number of exercise or movement programs have been found helpful in the cancer treatment setting. Mock (13) found that women randomly assigned to a self-directed walking program during radiotherapy for early-stage breast cancer helped improve physical functioning, fatigue, and emotional distress. Schwartz et al. (14) found that a home-based exercise program reduced fatigue in women treated with chemotherapy for breast cancer. Courneya and Friedenreich (15), in a review article, reported that exercise has consistently demonstrated a positive effect on quality of life in the domains both of physical and functional well being as well as of psychological and emotional well-being. In another review article, Pinto and Maruyama (16) found that exercise attenuated psychological distress, fatigue, and weight gain in survivors of breast cancer. Dimeo et al. (17) devised a daily treadmill program that was tested on five patients, who showed distinct improvements in fatigue; and they also found that fatigue was related to impaired physical performance (18). Graydon et al. (19) found that women used both exercise and sleep to relieve fatigue after radiation therapy or chemotherapy.

Overlapping treatment protocols have yet to be formally tested, but can take direction from the work done in symptom evaluation. In the development of the Piper Fatigue Scale, Piper et al. (20) confirmed the multidimensionality that stresses the overlap between the physiological and psychological factors. Meek et al. (21) have looked at the psychometric integrity of standardized measurement, including the Profile of Mood States Short Form Fatigue subscale, and support its construct validity. It is not a far jump to examine the effect of treatment indicated for depression on fatigue states.

Medications for Fatigue and Depression

Erythropoietin-alpha is approved to counteract chemotherapy- induced anemia. Theoretically, anemia can be a mediating factor for cancer-related fatigue, as moderate to severe anemia is associated with fatigue in the non-cancer population (anemia of chronic disease or associated with chronic renal failure) as well. Libretto (22) reported on the use of erythropoietin to improve quality of life in patients treated for cancer. Shasha and Harrison (23) are conducting a trial to maintain hemoglobin levels of 10-12 g/dL during radiation therapy to optimize treatment outcomes, including quality of life, and particularly fatigue. A question that is of wider scope is whether erythropoietin would affect cancer-related fatigue, or even mood, without anemia as a mediating factor.

Stimulants in the amphetamine category (methylphenidate, dextroamphetamine, and pemoline) have been used anecdotally to counteract fatigue in cancer, borrowing from work done in chronic, non-cancer-related fatigue. Whether stimulants can affect cancer-related fatigue needs to be more fully tested. Homsi et al. (24) found methylphenidate to be effective for depression in advanced cancer. Lower et al. (25) and colleagues confirmed that the dextro- congener of methylphenidate was statistically significantly superior to placebo in reducing fatigue in patients who had finished at least four cycles of cytotoxic chemotherapy. Sarhill et al. (26) treated 11 consecutive patients with methylphenidate and showed improvement in fatigue even in the presence of anemia. Likewise, antidepressants, particularly those in the selective serotonin reuptake inhibitor class, are commonly used for depression in cancer. Their usefulness in cancer-related fatigue without depression as a comorbidity is currently under pilot investigation (Greenberg D, Graziano S, Kornblith A, Herndon J, Green M. Fluoxetine in Stage IIIB/IV Non-Small-Cell Lung Cancer: A Limited Access Phase II Pilot Study to Improve Quality of Life During Chemotherapy, currently in progress) in the Cancer and Leukemia Group B.

Models of Care: Cancer Supportive Services

A model of care that is perhaps the most applicable to cancer has been established by geriatricians when evaluating the functional, social, and psychosocial dimensions of chronic illness in the elderly (27,28). Comprehensive geriatric assessments are featured in specialty care programs that recognize the functional and psychosocial limitations of aging. These factors play an important role in treatment adherence. Such a diagnostic framework can be applied to cancer patients of any age, where multimodal treatment has a parallel effect on functional capacities and psychosocial dimensions. Balducci and Beghe (29) have also begun to apply this model to the geriatric cancer patient. This model adds nutritional, functional, and cognitive-mood assessments to the standard clinical evaluation to provide a truer picture of the effects of cancer and its treatment on an individual. The application of preventive treatments in each of these domains has not yet carried into the mainstream of the care for cancer. Pediatrics and pediatric oncology, which naturally center care on the family unit rather than the individual, are perhaps a corner of oncology care in which these parameters are considered.

Fleishman and colleagues (30) in Palliative Medicine, Psycho-oncology, Social Work, Nutrition, Pastoral Care, Health Education, and Nursing supplement standard care through a specially designed effort, Cancer Supportive Services. Such a program is currently in operation and is designed to anticipate patients’ and families’ needs with universal screening (31) during cancer diagnosis, treatment, and follow-up by incorporating supportive care measures as a routine part of care in tandem with curative intent. Such services are often offered through traditional end-of-life or hospice programs. Cancer Supportive Services does so throughout the trajectory of care.

Patients complete a Distress Thermometer and Problem List [adapted from Holland (32)] at pivotal visits, with primary review by the oncology nurse or oncologist (Fig. 2). The expected symptoms from cancer and during its treatment are reviewed with the patient by the oncologist or nurse to inquire which, if any, need specific attention. Integrating such assessment into routine care operationalizes the “Basic Principles” of Fig. 1.

Patients are assessed by a nutritionist before or at the start of treatment, so that their dietary intake can be optimized. For those patients in which weight loss and cachexia are anticipated, portion sizes are increased and oral supplements are added to forestall or minimize weight loss. Those patients with hormone-dependent cancers (breast or prostate cancer) who are likely to gain weight are encouraged to eat larger quantities of protein-rich and carbohydrate-moderated foods before treatment begins (with standard renal function). Patients without established bone metastases or myeloma are given low-tensile elastic resistance bands, with written and pictorial instructions, to begin simple stretching before treatment begins and to continue it throughout treatment. Massage, yoga Reiki, and postlumpectomy/mastectomy water movement classes are available free of charge on the premises or close by. Social Worker and Pastoral Care Chaplains meet with patients early in the course of treatment to assess coping skills. Much of the basic care information is available on the center’s Web site at http://www.Cancer.WeHealNewYork.org.

An information specialist also meets with patients at one of its treatment sites and presents the patients with a library card for the Karpas Cancer Health Information Library. A specialty boutique makes items for comfort and safety (breast prostheses, wigs, metal-free deodorants for use during radiation therapy, and sun-protective clothing) readily available. Programs for smoking cessation, fatigue, memory loss (“chemobrain”), and sexual rehabilitation are also conducted on-site. Active symptom management is applied from the day of cancer diagnosis on.

Targeted intervention based on the findings uncovered by using the Distress Thermometer is offered in the domains covered (Table 2). Despite the lack of evidence for the provision of these services, objectively they make intuitive sense, and subjectively patients seem more satisfied with their quality of life during and after treatment. The major costs of the Cancer Supportive Services Program are funded via philanthropy. Outcome data from surveys have not been completed, because the resources have been fully directed to patient care.

Risk Versus Benefit

Some of the more innovative treatments that have been suggested for management of symptom clusters such as improved nutrition, sensible exercise regimen, or strengthened psychosocial support have little risk with considerable potential benefit, and thus are easier to justify in the face of a small evidence base. Other interventions (erythropoietin, stimulants, and antidepressants) carry a small potential for increased risk in the context of the risks of cancer itself, cytotoxic chemotherapy, or radiation therapy. With such relative risk assessment, such suggestions may be more easily made despite there being a minimal evidence base until studies are done. Trials of these treatment modalities controlled for cancer type, stage, and underlying treatment regimen could create a solid scientific base that would render these modalities accessible to the majority of Americans who rely on accepted treatments reimbursable by insurance carriers.

Adoption of on- or off-label drug treatment techniques, with adequate patient/family education and disclosure, can improve quality of life as well as satisfaction with care. Though the evidence base may be anecdotal, or considered “best practice” by a consensus of field leaders, recommendations may need to be driven by a standard that falls short of a controlled trial until controlled trials become available.

Conclusions

In conclusion, there are three take-away messages: 1) Treatment for the cluster of fatigue, depression, and pain in cancer has not yet been addressed together. Other speakers have summarized the research and clinical experience of the prevalence, assessment, and treatment of these symptoms independently. To optimally care for patients, the evidence basis for each of these symptoms, singly, in doublets, or as the triad cluster, warrant further investigation. Until that can be accomplished in a rigorous manner, anticipating common symptoms, educating patients and families, and providing treatment with a favorable benefit to risk ratio provides comfort and relief. Surveying patients with a written tool supplements the information gathering by the oncology team during routine visits.

2) The application of basic supportive care techniques—fatigue management, energy conservation, and psychosocial intervention—can be woven into care plans for patients with various types and all stages of disease, so that the symptom burden can be reduced. Such interventions pave the way for recovery. For those patients with progressive or refractory disease, the transition from curative to end-of-life care will not be as cumbersome if those same modalities have been used from diagnosis to minimize the symptom burden.

3) Active symptom management has a role in every stage of cancer treatment from the day of diagnosis on. Symptom management becomes the primary cancer therapy for survivors after surgery, chemotherapy, radiation, hormonal, or biologic therapies, either as a transition back to follow-up by a primary care provider or oncologist, or as a bridge to end-of-life care.

Fig. 1.

Overlap of pain, depression, and fatigue as symptoms of cancer and its treatment.

Fig. 1.

Overlap of pain, depression, and fatigue as symptoms of cancer and its treatment.

Fig. 2.

Distress thermometer and problem list [adapted with permission from Oncology (32)].

Fig. 2.

Distress thermometer and problem list [adapted with permission from Oncology (32)].

Table 1.

Basic principles of symptom management in cancer

1. Active symptom evaluation and management (treatment) are integral to each patient encounter in the cancer setting; 
2. Active symptom management has a role in every stage of cancer treatment from the day of diagnosis and on. Symptom management becomes the primary cancer therapy after surgery, chemotherapy, radiation, hormonal or biologic therapies, either as a transition back to follow-up by a primary care provider or oncologist for survivors, or serves as a bridge to end-of-life care; 
3. Overlap in treatments for pain, depression, and fatigue make it less important to sort out pure diagnoses; 
4. Each syndrome has “accepted” treatment modalities, and others that are less accepted, which may or are even likely to minimize symptom burden; 
5. Use of less accepted modalities can be more easily recommended if they have favorable side-effect profiles or minimal toxicities. 
1. Active symptom evaluation and management (treatment) are integral to each patient encounter in the cancer setting; 
2. Active symptom management has a role in every stage of cancer treatment from the day of diagnosis and on. Symptom management becomes the primary cancer therapy after surgery, chemotherapy, radiation, hormonal or biologic therapies, either as a transition back to follow-up by a primary care provider or oncologist for survivors, or serves as a bridge to end-of-life care; 
3. Overlap in treatments for pain, depression, and fatigue make it less important to sort out pure diagnoses; 
4. Each syndrome has “accepted” treatment modalities, and others that are less accepted, which may or are even likely to minimize symptom burden; 
5. Use of less accepted modalities can be more easily recommended if they have favorable side-effect profiles or minimal toxicities. 
Table 2.

Intervention for problems indicated on distress thermometer

Optimal assessment → Intervention 
• Practical: Housing, insurance, work school, child/elder care, transportation Psychosocial: Coping with diagnosis and treatments, anxiety, depression → Social work intervention: targeted psychotherapy and/or medications 
• Spiritual: Relating to God, loss of faith → Pastoral care intervention: Targeted counseling 
• Nutritional: Appetite, weight loss/gain, indigestion, constipation, diarrhea, mouth sores → Nutritionist intervention: Supplements, medications, dietary adjustments 
• Functional: Ambulation, bathing/dressing, dyspnea, sexual function, appearance → Rehabilitation specialist intervention: Toning/resistance exercises, medications 
• Cancer or Treatment-related Symptoms: Pain, fatigue, sleep, nausea/vomiting, fever, neuropathy, skin/mucosal changes → Symptom Management MD/RN Intervention: Medications, referrals to other disciplines 
Optimal assessment → Intervention 
• Practical: Housing, insurance, work school, child/elder care, transportation Psychosocial: Coping with diagnosis and treatments, anxiety, depression → Social work intervention: targeted psychotherapy and/or medications 
• Spiritual: Relating to God, loss of faith → Pastoral care intervention: Targeted counseling 
• Nutritional: Appetite, weight loss/gain, indigestion, constipation, diarrhea, mouth sores → Nutritionist intervention: Supplements, medications, dietary adjustments 
• Functional: Ambulation, bathing/dressing, dyspnea, sexual function, appearance → Rehabilitation specialist intervention: Toning/resistance exercises, medications 
• Cancer or Treatment-related Symptoms: Pain, fatigue, sleep, nausea/vomiting, fever, neuropathy, skin/mucosal changes → Symptom Management MD/RN Intervention: Medications, referrals to other disciplines 

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