Unfortunately, no studies that specifically examine the symptoms experienced by patients with germ cell tumors at the end of life have been conducted.
The numerous projects that have been completed examined patient populations with a variety of advanced malignancies, requiring readers to extrapolate a generalized "advanced-cancer" experience to the subset of patients in which they are interested. The common symptoms reported in the advanced-cancer population include fatigue, pain, anxiety, and anorexia, each with prevalence rates reported to be greater than 50%.20-28 In addition, most patients with advanced cancer experience a multitude of symptoms simultaneously.21,24,26
It is important to note that the majority of studies have focused on "physical" symptoms such as pain or anorexia rather than on "psychological" symptoms such as anxiety and depression. Studies that included the examination of psychological symptoms found such symptoms to be common in patients with advanced malignancy.24,29-33
Pain, Dyspnea, and Anxiety/Depression in Patients with Advanced Cancer
Although entire chapters in this text are dedicated to the topics of pain management, patient support, and psychosocial issues, the regularity with which patients and their caregivers confront pain, dyspnea, and anxiety/depression at the end of life suggests that these topics merit brief discussion here as well. When interpreting the reported prevalence of symptoms, it is important to note that despite the availability of many effective treatment strategies, there is strong evidence from a multiplicity of sources that these management techniques are underused. Thus, in regard to prevalence rates, the challenge is to define both the true prevalence rates and the prevalence of undertreatment of symptoms.
Large surveys have repeatedly documented that pain is experienced by 70 to 90% of patients with advanced cancer.34-37 The National Hospice Study (N = 1,754) found that pain became more prevalent in cancer patients during the last weeks of life. Of the patients enrolled in this study who could provided self-reported data, 25% indicated that persistent or severe pain was present within 2 days of death.38 This proportion had increased from 17% in the previous 6 days. In the SUPPORT study, 40 to 46% of patients with cancer who had been conscious during the last 3 days of life were perceived by their relatives to have had moderate to severe pain for more than half of this time period.39,40
Pain problems at the end of life are certainly complicated by the widely acknowledged problem of under-treatment, a problem that exists despite numerous available approaches to manage pain effectively.41 The commonly accepted approach to cancer pain relief, outlined in the World Health Organization (WHO) cancer pain guidelines, uses a comprehensive pain assessment and a combination of opioid, non-opioid, and adjuvant drugs titrated to the individual needs of the patient according to the severity of the pain.42,43 These guidelines have been tested in numerous studies that have confirmed that this approach can provide adequate pain relief for 70 to 90% of cancer patients who experience pain.41,44-48 Additional strategies are available to address pain that is not responsive to the basic guideline interventions.41 In such instances, pain specialists can be called upon to provide recommendations to help maximize the patient's alertness while providing adequate pain relief. This, as noted, was a major concern expressed by patients in the University of Toronto and Duke University studies that addressed patient preferences at the end of life.17,18 Thus, in the setting of a wealth of data indicating that pain is undertreated,49-51 it is not possible to ascertain the degree to which the high prevalence of pain in advanced disease reflects worsening pathology, undertreatment, or both. Nonetheless, it is apparent that in the setting of care delivery for patients with germ cell tumors (in whom pain could result from bone or visceral metastases, tumor masses adjacent to neural structures, hepatomegaly, or other causes), it is crucial that expertise in pain management be available (see also Chapter 26).
As with pain, there are now specific studies addressing the prevalence of dyspnea at the end of life for patients with germ cell tumors. Dyspnea is, however, a symptom that is commonly reported toward the end of life. Variable prevalence rates have been reported in advanced cancer cases, ranging from 20 to 78%.52-55 Methodologic inconsistencies between studies likely account, at least in part, for this wide variation. Two studies reported that dyspnea increases at the end of life. The National Hos pice Study reported that dyspnea was present in 70% of 1,754 patients during the final 6 weeks of life,52 and a study of 86 cancer patients by Higginson and McCarthy found that in 21% of the patients, dyspnea was a severe symptom near death.53 The SUPPORT study reported dyspnea as moderate to severe for the last few days of life in 70% and 30% of lung and colon cancer patients, respectively. Unfortunately, the methodology of studies of dyspnea has often been less than optimal, and in some studies, judgments about the presence of dyspnea have been made by caregivers (rather than patients) and may have reflected an observation of "heavy breathing" that may or may not have been distressing at the end of life. Dyspnea (when it is subjectively distressing), while not a symptom that has been as intensively studied as pain, is treatable, and there are management guidelines that describe effective strategies for minimizing patients' distress.56 Given that lung metastases are common in the setting of advanced germ cell tumors, attention should be paid to this symptom, and clinicians should be prepared to treat it when it does occur.
Anxiety, worry, nervousness, and sadness have commonly been reported by patients with advanced cancer.2429-33 As with the symptoms discussed above, effective treatment guidelines have been described for these conditions.57 In the setting of germ cell tumors, in which patients may be young and in which death is viewed as occurring at an "unnatural" time of life, these symptoms are likely to be common both in patients and in their care-givers. Many young patients have had no experiences with deaths of relatives or friends, and their fears may be focused on an array of concerns, some of which may occur and some of which are most unlikely. Some concerns may relate to the physical experience of death itself; others may relate to emotional, social, and spiritual losses and fears. Fears can be wide-ranging. For example, never having encountered death, some patients may fear worsening pain or dementia, others may fear dependence on family for long periods and loss of control, others may be focused on losses related to children or parents, and yet others may be concerned about spiritual issues. Young patients may have concerns about children, siblings, parents, finances, and other mat ters that are somewhat different from the concerns of older patients.
It is important for clinicians caring for patients with germ cell tumors to be aware of the spectrum of concerns that trigger anxiety and depression, including both the common concerns and concerns that may be linked to a patient's young age, and to be open to exploring these concerns. Of course, this should be undertaken in a timely manner that is respectful of the patients' culture, preferences for information, and understanding of their disease status. In addition, physicians need to be prepared to explain and implement approaches to symptom management, patient and family support, and other concerns. It is important that clinicians also are able to diagnose states of anxiety and depression that may need specific phar-macologic treatments and that they are aware of the spectrum of treatments available for such problems. In some instances, referral to specialized support may be the optimal approach. There is a risk that those clinicians who provide care for young patients (such as young patients with germ cell tumors) may assume that anxiety and depression are "natural" under such circumstances and may not recognize when such symptoms may be amenable to treatment.*
The level of consciousness near the end of life is influenced by a diverse range of factors, including the extent of disease, coexisting organ failure, and medication use. Specific germ cell tumor data are, again, not available. Clinical experience suggests that it is not uncommon for patients to harbor concerns about the "mode of death" that is likely to occur, and this can contribute to anxiety. One aspect upon which some patients focus relates to level of consciousness. Especially with patients who are young and have not been involved with others who have died, there is a risk that they may worry about losing consciousness
*Editor's note: In this difficult situation, another complicating variable may be the contrast between the success of therapy in other patients being treated at the same time and the failure of therapy to achieve cure in the dying patient; this may lead to an additional complexity of the depression and anxiety that characterize this phase of care of patients with advanced germ cell cancer.
or losing their ability to communicate for long periods. The data that exist for other advanced cancers suggest that the ability to communicate effectively with caregivers begins to decrease for the majority of patients only in the last few days of life. The SUPPORT study described the experiences of patients with lung cancer (n = 409) and documented that 80% were reported by family members to be conscious during the 3 days prior to death, with 55% reported as being able to communicate effectively at this time.40 In the population with colon cancer (n = 148), these figures were 70% and 40%, respectively. A survey of patients with cancer who died at St. Christopher's Hospice in the United Kingdom described 10% of patients as alert, 67% as drowsy or semiconscious, and 23% as unarousable or unconscious during the last 24 hours of life.58 Last, a survey of inpatient and home care cancer deaths found that one-third of patients were able to interact with others 24 hours prior to death; this group decreased to one-fifth of patients 12 hours before death and to one-tenth of patients in the hour before death.59
Delirium, a common condition associated with confusion, has been found to be highly prevalent in the cancer population, particularly in the days immediately prior to death. This symptom is commonly under-diagnosed and, in addition to its well known symptomatic correlates (hallucinations, confusion, and agitation), may be manifest by a myriad of "minor" symptoms, including difficulty in concentrating, anxiety, and tearfulness. As mentioned above, there is a risk that these symptoms can be viewed as normal when present in a young person who is suffering from a life-threatening disease. Without a thorough mental status examination, there is a risk that the condition (which has very specific treatment interventions, including attention to etio-logic factors and specific therapies such as neu-roleptics) may go untreated or may not be treated specifically. Due to the relatively small numbers of patients with germ cell tumors treated at any one institution (among other reasons), studies of prevalence rates of delirium in patients with germ cell tumors have not been reported, and data must be drawn from other more generic cancer studies.
Massie and colleagues reported that 11 (85%) of13 terminally ill patients with cancer developed delirium prior to death and that the early symptoms were often misdiagnosed as anxiety, anger, depression, or psychosis.60 In a survey of 140 patients with cancer who were referred for neurologic assessment of encephalopathy, a multifactorial cause of this problem was found for most patients. A single cause of the altered mental status was found in 33% of patients whereas 67% had multiple causes. Drugs (especially opioids), metabolic abnormalities, infection, and recent surgery were the most common etiologic fac-tors.61 In important work, Bruera and colleagues studied 66 episodes of cognitive failure in 39 patients admitted to a palliative care service and demonstrated that this condition is often reversible during the last weeks of life.62 Drugs, sepsis, and brain metastasis were found to be the most frequently detected etiologic factors, and 22 (33%) of the 66 episodes improved, 10 spontaneously and 12 as a result of treatment. Although delirium is more commonly seen at the end of life, it can occur earlier in the course of cancer, in response to medications and infections or after surgical procedures, and is reversible in most instances. It is crucial for clinicians caring for patients with germ cell tumors to be aware of the manifestations of this important and troublesome condition and to have an understanding of the approach to its treatment.
In summary, these findings indicate that the majority of patients with cancer will be able to communicate in the days immediately prior to their deaths. This finding may be reassuring for patients or family members who harbor specific worries about this issue. Studies of mental status also point to the importance of health care providers and the patients' caregivers being watchful for changes in mental status as many causes of delirium can be remedied quickly.
More research-based data would be optimal to quantify and improve the end-of-life experience for all patients, including those with germ cell tumors. However, it is apparent from both the hospice literature and from the clinical experience of palliative care clinicians and oncologists that even now (although functional deterioration is common at the end of life), comfort can be achieved for almost all patients. Unfortunately, despite the existence of an array of symptom-specific treatment strategies, evidence remains that these are underused and/or not optimally implemented for many symptoms.40'49'50'63,64 Numerous aspects of palliative care could be improved through further research. Among other aspects that could be developed are instruments for the assessment of distress in cases in which self-reporting is not feasible; more effective and faster-acting treatments for delirium and anxiety/depression; interventions to minimize the distress associated with both common and less common symptoms; and approaches to eliminating the barriers to symptom relief and palliative care delivery. Readers with an interest in research in this area may be interested in the US National Institutes of Health (NIH) State-of-the-Science Statement on symptom management in cancer,65 which focuses on pain, depression, and fatigue. This report's conclusions and recommendations, however, are broad in scope and applicability. Another helpful resource that provides a current review of the existing data and that highlights research needs in this field is an Internet-based interactive symptom research textbook recently developed through the NIH.66
As to specific research topics that may be helpful to illuminate and improve the symptomatic experience of the population of patients with germ cell tumors, it is unlikely that many specific studies of this population will be undertaken, due to the rarity of this disease, the small proportion of patients who have chemotherapy-resistant disease, and the fact that these patients are located in a wide array of geographic areas. Nonetheless, if such studies are not undertaken, it would be helpful to have data to illuminate the symptom-based experiences of young patients, in general, who die as a result of cancers and interventions that may be specifically applicable in such settings.
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