DÄ internationalArchive50/2015Palliative Care of Adult Patients With Cancer

Clinical Practice Guideline

Palliative Care of Adult Patients With Cancer

Dtsch Arztebl Int 2015; 112: 863-70. DOI: 10.3238/arztebl.2015.0863

Bausewein, C; Simon, S T; Pralong, A; Radbruch, L; Nauck, F; Voltz, R

Background: In Germany, the annual mortality rate from cancer in the year 2011 was 269.9 deaths per 100 000 persons; every fourth death was due to cancer. A central objective of palliative care is to maintain the best possible quality of life for cancer patients right up to the end of their lives.

Methods: The PubMed, Embase, and Cochrane Library databases were systematically searched for pertinent publications, and the ones that were selected were assessed as recommended by the Scottish Intercollegiate Guidelines Network. As part of the German Guideline Program in Oncology, recommendations for the S3 Guideline on Palliative Care concerning seven different topics in the management of adult patients with incurable cancer were developed by a representative expert panel employing a consensus process.

Results: Opioids are the drugs of first choice for severe and moderately severe cancer-related pain, and for breathlessness. No clinically relevant respiratory depression was observed in any study. When opioids are used, accompanying medication to prevent constipation is recommended. Drugs other than opioids are ineffective against breathlessness, but clinical experience has shown that benzodiazepines and opioids can be used in combination in advanced stages of disease, or if the patient suffers from marked anxiety. Depression should be treated even in patients with a short life expectancy; psychotherapy is indicated, and antidepressant medication is indicated as well if depression is at least moderately severe. Communication skills, an essential component of palliative care, play a major role in conversations between the physician and the patient about the diagnosis, the prognosis, and the patient's wish to hasten death. When the dying phase begins, tumor-specific treatments should be stopped.

Conclusion: Palliative care should be offered to cancer patients with incurable disease. Generalist and specialist palliative care constitute a central component of patient care, with the goal of achieving the best possible quality of life for the patient.

LNSLNS

Every fourth man and every fifth woman in Germany dies of cancer (1). In view of this fact, the need for palliative care of those with incurable malignancies is high. Alongside comprehensive oncological management, integration of palliative medicine into the care of these patients plays a vital role in preservation of the best attainable quality of life right up to the time of death.

The quantity and quality of evidence in palliative medicine is constantly improving, with the result that to ensure universal first-class palliative care it has become necessary to formulate guidelines for everyday clinical care and the management of these patients. The guideline development group’s aim was to systematically gather and assess the scientific evidence relating to seven aspects of palliative medicine—breathlessness, cancer pain, constipation, depression, communication, dying phase, and palliative health care structures—and formulate recommendations based on the findings. In accordance with the principles of palliative medicine, the recommendations are intended to help maintain the best possible quality of life for cancer patients (eBox).

Recommendations on basic principles of palliative care
eBox
Recommendations on basic principles of palliative care

Methods

The German S3 Guideline on Palliative Care of Adult Patients With Incurable Cancer was developed under the leadership of the German Association for Palliative Medicine (Deutsche Gesellschaft für Palliativmedizin) within the methodological framework of the German Guideline Program in Oncology (2). The target group comprises all physicians and others involved in the treatment of patients with incurable cancer. Correspondingly, the representative consensus group consisted of elected representatives from 53 medical societies, patients’ organizations, and other institutions (eTable 1). Following agreement on 65 key questions, the group's work began with a search for existing guidelines in the databases of three organizations: (G-I-N: Guidelines International Network; NGC: National Guideline Clearinghouse; AWMF: Association of the Scientific Medical Societies in Germany). Next, systematic reviews and primary studies were sought in the databases PubMed, Embase, and Cochrane Library and by a hand search and selected according to the recommendations of the PRISMA Statement (Figure 1) (e1). On the basis of this body of evidence, seven working groups made up of elected representatives and other experts developed recommendations and explanatory texts (eFigure). Formal agreement on the recommendations was reached at three consensus conferences, where each recommendation was approved by at least 75% of those present.

The PRISMA process, in this instance f or studies on the effectiveness of opiods in the treatment of breathlessness (N = total, n = subtotal)
Figure 1
The PRISMA process, in this instance f or studies on the effectiveness of opiods in the treatment of breathlessness (N = total, n = subtotal)
Grading of evidence (according to SIGN) and recommendations (according to AWMF standards)
Table 1
Grading of evidence (according to SIGN) and recommendations (according to AWMF standards)
Procedure for the development of recommendations (adapted from the guideline report of the German S3 Guideline on Palliative Care of Adult Patients With Incurable Cancer
eFigure
Procedure for the development of recommendations (adapted from the guideline report of the German S3 Guideline on Palliative Care of Adult Patients With Incurable Cancer
Participating medical societies, organizations, professional associations, and experts
eTable 1
Participating medical societies, organizations, professional associations, and experts

Results

The highest study quality was found for the areas breathlessness, pain, and depression. For the areas constipation, communication, and dying phase, the evidence was only moderate or weak. The quality of evidence with regard to palliative health care structures varied depending on structure, with the best results for specialist palliative home care. Overall, the guideline contains 13 statements and 217 recommendations, of which 100 are evidence based (recommendation strength and evidence level according to the Scottish Intercollegiate Guidelines Network (SIGN) (Table 1) are given in parentheses in the following). The remaining 117 recommendations are based on expert consensus (EC). Furthermore, ten quality indicators were agreed.

Breathlessness

Assessment

Breathlessness is “a subjective experience of breathing discomfort” (3) and should thus be assessed by the patient (EC). Management of breathlessness should, if possible and expedient, be preceded or accompanied by treatment of the cause (EC).

General treatment

General measures such as explanation, reassurance, relaxation exercises, and breathing exercises form an important part of the treatment of breathlessness (EC) (4). Two further non-pharmacological treatments showed moderate efficacy in a Cochrane review (5) and two randomized controlled trials (RCTs) (6, 7): a stream of cool air on the face (e.g., from a hand-held fan; Borg mean value 2.6 [standard deviation (SD) 1.48] versus 3.7 [SD 1,83]; p = 0.003 [6]) and walking aids to increase mobility (B/1–).

Drug treatment

Oral or parenteral opioids should be used as drugs of choice for the relief of breathlessness (A/1+). The effectiveness of opioids has been clearly demonstrated (improvement of 9.5 mm on the visual analog scale [VAS], 95% confidence interval [3.0 mm; 16.1 mm]; p = 0.006) (8, 9). No instance of clinically relevant respiratory depression was observed in any of the studies (statement 1+). Particular care is required in the presence of severe renal insufficiency. If the adverse effects worsen, the choice and dose of opioid should be modified accordingly (B/3) (Table 2).

Use of opioids depending on severity of renal insufficiency and advice on choice of opioid
Table 2
Use of opioids depending on severity of renal insufficiency and advice on choice of opioid

Other classes of drugs have shown no demonstrable effect. Nevertheless, an open recommendation was formulated for benzodiazepines owing to positive clinical experience of their use in combination with opioids, particularly in patients who have advanced disease or are in the dying phase (0/1–) and in the presence of severe anxiety. Phenothiazines, antidepressants, buspirone and glucocorticoids are not recommended (B/1–, for glucocorticoids B/1+).

There is high-quality evidence that oxygen is not effective for relief of breathlessness in non-hypoxemic patients (standardized mean difference = –0.09, 95% confidence interval [–0.22; 0.04]; p = 0.16) (10, 11). Oxygen therefore cannot be recommended for this group of patients (B/1+).

Cancer pain

The recommendations in this section are based on a modification of the European Association for Palliative Care (EAPC) guideline on the use of opioids in the treatment of patients with cancer pain, which is based on an extensive review of the literature (12). An additional systematic literature search was carried out for the non-opioid analgesic metamizole (dipyrone), which is widely used in Germany.

Assessment

As for breathlessness, the severity of pain should if possible be assessed by the patient (EC).

Choice of drug

Step-II opioids or, alternatively, low-dose step-III opioids should be used to treat slight to moderate pain and whenever pain is not sufficiently controlled by non-opioid analgesics (B/1−).

The step-III opioids morphine, oxycodone, and hydromorphone can all be used as the drug of choice (0/1−), because three systematic reviews (1315) have shown that none of them is clearly superior to the others in efficacy or side effect profile. In the case of breakthrough pain, oral rapid-release opioids or transmucosal fentanyl should be administered (A/1+). As an alternative to oral opioids, fentanyl or buprenorphine can be given transdermally via delivery systems (0/1−), for instance if the patient suffers from dysphagia or simply prefers this form of drug delivery.

Amitriptyline, gabapentin, or pregabalin are recommended for the treatment of neuropathic cancer pain that cannot be sufficiently controlled with opioid analgesics (A/1+) (16).

The limited evidence for the efficacy of metamizole (17, 18), together with the clinical experience, justifies an open recommendation for the use of metamizole alone to treat slight pain or in combination with opioids for moderate to severe pain (0/1−).

Administration

Either slow-release or immediate-release oral preparations can be used for dose titration when opioid treatment is initiated (0/1−). Opioid switching can be considered if pain control is inadequate or severe adverse effects occur (0/3). Adverse effects may also be reduced by opioid dose reduction. In the case of renal insufficiency, the same precautions should be observed as described above for breathlessness (Table 2).

Constipation

Prophylaxis and treatment

Initiation of opioid treatment should be accompanied by medication to prevent constipation (EC).

Treatment of constipation should follow a stepwise approach (EC). First, osmotic (e.g., macrogol) or stimulating (e.g., bisacodyl, sodium picosulfate) laxatives should be given (A/1−) (19). If the symptoms are not successfully controlled, a combination of these two classes of laxatives should be tried. As a third step, peripheral opioid antagonists (e.g., methylnaltroxone, A/1+ [20]) are administered in addition to the step-2 laxatives in patients who require opioids for pain control. Step 4 involves the use of additional pharmacological (castor oil, erythromycin, amidotrizoate, etc.) or non-pharmacological (enemas, manual evacuation) measures. Any of these steps can be accompanied by physiotherapy treatments such as colonic massage.

Depression

The terms “depression” and “depressive episode” are used interchangeably in the following.

Screening and diagnosis

Because depressed patients often do not spontaneously talk about their mental state, the presence of depression should be actively and regularly assessed (A/4). A screening procedure should be used for this purpose (B/1+), e.g., a simple two-question instrument: “During the past month, have you often been bothered by feeling down, depressed, or hopeless?” and “During the past month, have you often been bothered by little interest or pleasure in doing things?” (21). In the case of a positive response, i.e., if one of the two questions is affirmed, the existence of depression and, if present, its severity according to ICD-10 criteria should be ascertained (EC) and the risk of suicide assessed. The diagnosis of depression in the palliative care setting may not be easy, because the end of life is associated with a normal grieving process that can be very hard to differentiate from depression (eTable 2).

Characteristics of depression versus grieving reaction
eTable 2
Characteristics of depression versus grieving reaction

Treatment

The appropriate treatment for depression depends on the severity of depressive symptoms (guideline recommendations adapted from the S3 Guideline/National Disease Management Guideline “Unipolar Depression” [22]). Psychotherapy should be offered even for mild depression, and certainly for moderate and severe depression (EC); behavioral or depth-psychology techniques should be used (EC). Pharmacological treatment should be offered to patients with moderate or severe depression (EC) and should follow the recommendations of the above-mentioned guideline (EC). The evidence from three systematic reviews confirmed the effectiveness of antidepressants versus placebo in the palliative setting (odds ratio [OR] 2.25, 95% confidence interval [1.38; 3.67]; p = 0.001), but showed no clear superiority of any one antidepressant over others (statement 1−) (2325). In the accompanying text, the guideline specifies three drugs that can be preferentially used in the palliative setting, based on both clinical and pharmacological criteria and the conclusions of a systematic review (23): mirtazapine, sertraline and citalopram.

Psychostimulants are ineffective in depression and should therefore not be used (B/1−).

Patients with a short prognosis

One aspect with particular relevance in the context of palliative medicine is the treatment of patients who have only a short time to live. Even if the life expectancy is just a few weeks, treatment should be initiated (EC). As the end of life approaches, more emphasis should be placed on short-term psychotherapeutic interventions.

Communication

Discussion of profound changes in the course of disease

Breaking bad news about the course of the cancer disease, including recurrence, is a challenging task and should primarily be handled by the treating physician (e.g., the patient's primary care physician or oncologist) (EC). Information should be delivered piece by piece, not all at once, and the patient should be encouraged to ask questions (EC). If at all possible, the patient's relatives should be involved in these conversations about the patient’s situation (EC).

Addressing dying and death

Even if they do not raise the subject unprompted, most patients welcome the opportunity to talk about end of life issues. All those directly involved with patient care should clearly convey their openness to such discussions, and words such as “dying” and “death” should be used in a sensitive way (EC).

If the patient expresses the wish to hasten death, this should be met with empathy and willingness to talk (EC). Such a statement does not automatically mean that the patient actually desires active shortening of life; it may conceal a cry for help and the wish to live (26, 27). Therefore, possible reasons for wanting to die must be discussed (EC).

Advance care planning

Advance care planning (eTable 3) offers patients in palliative care the opportunity to consider and stipulate in advance their preferences regarding the last phase of life. Patients should be given this chance in good time and repeatedly (EC).

Glossary
eTable 3
Glossary

The dying phase

Identification

The guideline defines the dying phase as the last 3 to 7 days of life. The beginning of this phase can be determined using criteria such as breathing changes, alteration in state of consciousness and the emotions expressed (e.g., anxiety), increasing weakness and deterioration in general state, skin changes, confusion, and loss of interest in eating and drinking, together with the intuition of those involved in the patient's care (0/4). These indicators were identified as a result of the findings of two systematic reviews and a Delphi survey (2830). The assessment should be made by an interprofessional team (B/4). There is currently no validated instrument for determining the beginning of the dying phase.

Frequent symptoms

Together with pain and breathlessness, another relatively frequent symptom in the dying phase is delirium. Treatment centers around general measures designed to comfort the patient. Should medication be needed, haloperidol is recommended (B/1−) (31). Death rattle is usually less disturbing for the patient than for the relatives and does not necessarily require treatment. Steps that can be taken if indicated include positioning techniques (0/4) and administration of anticholinergics (0/1−) (32). Tracheal secretions should not be sucked (B/4). Finally, if the patient becomes agitated in the days leading up to death the causes—e.g., pain, constipation, and delirium— should be established. Dying patients suffering from anxiety should be treated with general measures (EC). Benzodiazepines can be added (EC).

Medication and other measures

The decisive criterion for initiation or continuation of drug treatment in the days immediately before death is the goal of best attainable quality of life. With this aim in mind, the principal drug classes that can be used in the presence of treatable symptoms are opioids, antipsychotics, benzodiazepines, and anticholinergics (EC). Tumor-specific treatments should be ended (EC). Equally, measures that will not help to achieve this goal should not be initiated; if already being used, they should be discontinued. This includes, for example, ventilation, dialysis/hemofiltration, intensive care, and repositioning to avoid bed sores or pneumonia (EC). If a defibrillator has been implanted, its cardioverter function should be deactivated (EC). Palliative sedation, administered by experienced and competent physicians and specialist nurses, is the last resort in the case of refractory distress (EC).

The guideline group recommends abstention from artificial nutrition and hydration of the dying patient (B/2), but the decision should be taken on an individual basis and after careful consideration (e.g., relief of hunger and thirst). This recommendation is based on six non-randomized trials (33, 34) and one RCT (35) on the effect of administration of fluids and was extrapolated, as indirect evidence, to parenteral feeding. The RCT showed no superiority of fluid administration over placebo in effect on selected symptoms of dehydration (−3.3 versus –2.8; p = 0.77).

Palliative health care structures

Palliative care should be offered as soon as incurable cancer is diagnosed, although tumor-specific treatment can be given in parallel (EC). The palliative care structures available to patients in Germany with incurable cancer and their relatives as the disease progresses are depicted in Figure 2.

Treatment path for patients and rela tives (source: German S3 Guideline on Palliative Care of Adult Patients With Incurable Cancer
Figure 2
Treatment path for patients and rela tives (source: German S3 Guideline on Palliative Care of Adult Patients With Incurable Cancer

Whether generalist or specialist palliative care (eTable 3) is offered depends on the complexity of the patient's situation. The following criteria are relevant for evaluation of complexity in the palliative setting (36): the needs of the patient and relatives—which have to be assessed in the physical, psychological, social, and spiritual dimensions (EC)—, the patient's functional status, and the phase of disease (EC) (eTable 4). In the case of low to moderate complexity, generalist palliative care usually suffices. Specialist palliative care is indicated in highly complex situations (EC). This is the case, for instance, in the presence of pronounced physical symptoms that are difficult to control, in mentally unstable patients who are not coping with their disease, or in the lack of family support. The high complexity may be expressed in the constant need to adapt the treatment plan to changing circumstances.

Factors influencing the complexity of the patient’s situation and available instruments for assessment
eTable 4
Factors influencing the complexity of the patient’s situation and available instruments for assessment

At the same time, the needs of the relatives must also be considered. Above all, they should be provided with information on support and counseling in grief and bereavement (EC).

General palliative measures can be administered by all those involved in the management of patients with cancer, provided they have basic qualification in palliative care (EC). Alongside recognizing the need for palliative measures and acting accordingly (EC), those concerned with palliative care should, for example, treat and manage symptoms and problems of low to moderate complexity, set treatment goals, and coordinate care, as well as taking steps to initiate specialist palliative care whenever indicated (EC).

A specialist palliative care team should include members from at least three occupational groups (physician, nurse, other occupation), of whom at least one physician and one nurse should possess a qualification in specialist palliative medicine (A/1−) (3740).

Conclusion

Although various factors make it difficult to conduct studies in palliative medicine, relatively good evidence could be identified, particularly with regard to the physical symptoms of cancer patients. With regard to palliative care structures, the findings of the numerous studies from other countries were not always applicable to the situation in Germany.

Acknowledgments
The authors thank all elected representatives and experts for their energetic help in drawing up the guideline. Particular thanks are due to Dr. Markus Follmann, Prof. Ina Kopp, Dr. Monika Nothacker, Thomas Langer, and Dr. Simone Wesselmann of the German Guideline Program in Oncology for their advice on methods and their unwavering support. We are especially grateful to Verena Geffe of the guideline office. We are very thankful to the three bodies that created the German Guideline Program in Oncology and provided financial support: the Association of the Scientific Medical Societies in Germany, the German Cancer Society, and German Cancer Aid.

Conflict of interest statement
Prof. Bausewein has received author royalties for the book “Leitfaden Palliative Care” from Elsevier.

Dr. Simon has received study support (third-party funding) from Teva and Otsuka.

Prof. Nauck has received reimbursement of costs connected with lectures and seminars from Mundipharma, Archimedes, Roche, and Teva.

Prof. Voltz has received consultancy fees (advisory board) from the Allgemeine Ortskrankenkasse (AOK; a large general statutory health insurance provider in Germany) and from Mundipharma, Teva, Archimedes, and Pfizer. He has received author royalties for the book “Leitfaden Palliative Care” from Elsevier. The Koblenz Social Court has paid him a honorarium for acting as an expert advisor. He has received reimbursement of conference attendance fees and travel costs as well as lecture honoraria from the AOK and from Mundipharma, Roche, MDS, Hexal, Archimedes, and MSA. He has been provided with study support by Teva.

The remaining authors declare that no conflict of interest exists.

Translated from the original German by David Roseveare.

Manuscript submitted on 16 September 2015, revised version accepted on
20 October 2015

Corresponding author:
PD Dr. med. Steffen T. Simon
Uniklinik Köln
Zentrum für Palliativmedizin
Kerpener Str. 62
50937 Köln, Germany
steffen.simon@uk-koeln.de

@Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref5015

eBox, eFigure, eTables:
www.aerzteblatt-international.de/15m0863

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Department of Palliative Medicine, University Hospital Munich, Campus Grosshadern: Prof. Bausewein; Department of Palliative Medicine, University Hospital Cologne: PD Dr. Simon, Dr. Pralong, Prof. Dr. Voltz; Department of Palliative Medicine, University Hospital Bonn: Prof. Radbruch; Department of Palliative Medicine, University Medical Center Göttingen: Prof. Nauck
The PRISMA process, in this instance f or studies on the effectiveness of opiods in the treatment of breathlessness (N = total, n = subtotal)
Figure 1
The PRISMA process, in this instance f or studies on the effectiveness of opiods in the treatment of breathlessness (N = total, n = subtotal)
Treatment path for patients and rela tives (source: German S3 Guideline on Palliative Care of Adult Patients With Incurable Cancer
Figure 2
Treatment path for patients and rela tives (source: German S3 Guideline on Palliative Care of Adult Patients With Incurable Cancer
Key messages
Grading of evidence (according to SIGN) and recommendations (according to AWMF standards)
Table 1
Grading of evidence (according to SIGN) and recommendations (according to AWMF standards)
Use of opioids depending on severity of renal insufficiency and advice on choice of opioid
Table 2
Use of opioids depending on severity of renal insufficiency and advice on choice of opioid
Recommendations on basic principles of palliative care
eBox
Recommendations on basic principles of palliative care
Procedure for the development of recommendations (adapted from the guideline report of the German S3 Guideline on Palliative Care of Adult Patients With Incurable Cancer
eFigure
Procedure for the development of recommendations (adapted from the guideline report of the German S3 Guideline on Palliative Care of Adult Patients With Incurable Cancer
Participating medical societies, organizations, professional associations, and experts
eTable 1
Participating medical societies, organizations, professional associations, and experts
Characteristics of depression versus grieving reaction
eTable 2
Characteristics of depression versus grieving reaction
Glossary
eTable 3
Glossary
Factors influencing the complexity of the patient’s situation and available instruments for assessment
eTable 4
Factors influencing the complexity of the patient’s situation and available instruments for assessment
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