Symptoms During Outpatient Cancer Treatment and Options for their Management

Abstract

Background

Cancer patients account for a large segment of the German healthcare system, with a 5-year prevalence of around 1.7 million persons. Advances in oncological treatment, now frequently performed on an outpatient basis, are granting many of these individuals a longer life span. At the same time, cancer patients often suffer disease-related symptoms and adverse effects from their tumor treatment, which may strongly impair their quality of life despite the improved techniques for management of side effects.

Methods

This review is based on a selective literature search of the PubMed and Cochrane Library databases carried out in December 2019 and January 2020. Special attention was paid to guidelines, expert opinions, and recommendations from professional societies.

Results

Alongside decreased well-being, cancer patients often suffer from fatigue (70–100%), loss of appetite (6–53%), pain (30–80 %), and dyspnea (10–70%). The prevalence and severity of the symptoms varies depending on the tumor entity and the patient’s sex. A meta-analysis showed that besides causal treatment, physical activity achieves moderately strong effects in tumor-associated fatigue syndrome (Cohen’s d = 0.30 [0.25; 0.36]). The WHO recommends early use of opioids in tumor-associated pain. A meta-analysis of randomized trials described symptom relief by means of opioids also in dyspnea (standardized mean difference: -0.32 [-0.53; -0.10]). Increasingly, guidelines are recommending regular palliative medical symptom screening.

Conclusion

Regular documentation of symptoms in outpatients offers the opportunity for targeted management of symptoms during treatment with the involvement of various disciplines such as palliative medicine, exercise therapy, and psychotherapy.

cme plus

This article has been certified by the North Rhine Academy for Continuing Medical Education. Participation in the CME certification program is possible only over the internet: cme.aerzteblatt.de. The deadline for submission is 29 April 2022.

With an incidence of around 492 000 and a 5-year prevalence of around 1.7 million people in 2016, patients with cancer represent a large treatment group in the Germany healthcare system (1). The oncological services network consists of hospitals and individual practices (1). Advances in oncological therapies have led to longer life span, even for patients with metastatic or locally advanced cancer; nonetheless, despite improved management of adverse effects, having advanced disease or metastastis can lead to increased rates of hospitalization and a poorer quality of life (e1, 2, e2, e3).

According to a survey of oncologists in the USA, the involvement of palliative (medical) care teams often takes place late in the course of disease (e4). The need for treatment due to certain symptoms is often not adequately met, for example for pain (25%), emotional needs (10–84%), and fatigue (18–74%) (3, e4, e5). A method of documentation of symptoms that is integrated into the clinical treatment context can help improve communication between doctor and patient (4, e6, e7) and align treatment more closely to needs, thereby increase patient wellbeing (4– 6).

This article describes the symptoms of cancer patients who have received outpatient cancer therapy and the evidence-based treatment options for the four main symptoms.

Methods

This narrative review is based on a selective literature search in the PubMed and Cochrane Library databases using relevant keywords (such as “patient-reported outcome”, “outpatient”, “symptoms”, “cancer patients”, and “palliative care”) and supplemented with guidelines, expert opinions, and recommendations from specialist societies. The survey was carried out until October 2020.

Results

Symptoms of cancer patients in an outpatient setting

Patients with cancer can experience various symptoms due to their disease and/or the therapy itself. In the literature, the prevalence of symptoms is presented differently in the order of precedence and in the percentages. In addition to a poor general condition, fatigue (70%–100%), loss of appetite (6%–53%), pain (30%–80%), and dyspnea (10%–70%) are described as the main symptoms of patients with cancer in an outpatient setting. Monocentric data are shown as an example in Figure 1 (e6, 7, 8, e7, e8). In particular, symptoms in the last six months of life include a decreased well-being, lack of appetite, and increased tiredness (9).

The severity of the symptoms depends on the cancer type and patient‘s sex (e7, e9, e10). While pain and fatigue are prevalent in patients with cancer of the central nervous system or head-and-neck area, loss of appetite and a poor general condition are more likely to occur in patients with cancer of the gastrointestinal tract, lungs, breasts, or genital area (e7, 10, e11). While these symptoms vary with the distinct types of cancer, fatigue, anxiety, and depression seem to occur regardless of the type of cancer. Differences between the sexes are also described. While dysphagia (22%–28% versus 14%–16%; male versus female) and insomnia (52%–61% versus 45%–56%) occur more frequently in male patients, nausea (34%–42% versus 22%–31%), vomiting (24%–28% versus 17%–22%), and anxiety (29%–60% versus 20%–51%) play a larger role for female patients (e7, e12– e14).

The following sections describe the most common symptoms in cancer patients.

Cancer-related fatigue syndrome

The cancer-related fatigue syndrome is the most dominant symptom (70%–100%) in patients with cancer (e15). The symptoms of cancer-related fatigue syndrome range from excessive exhaustion that is not proportional to prior activities or the subsequent recovery phases, to impaired concentration and memory. This syndrome is often associated with numerous symptoms, including pain (effect size d = 0.6; U = 83.31; p = 0.00), dyspnea (d = 0.45; U = 25.91; p = 0.00), nausea/vomiting (d = 0.82; U = 119.76; p = 0.00), loss of appetite (d = 0.65; U = 63.47; p = 0.00), and psychological stress, especially depression (d = 1.49, U = 297.80, p = 0.00) and anxiety (d = 1.11; U = 227.79; p = 0.00) (11).

In the case of pronounced fatigue or weakness during patient screening, specialist societies and expert working groups (12– 14) recommend carrying out a fatigue assessment once other comorbidities (including anemia, infection, dehydration, and cachexia) have been excluded. In Germany, this assessment can use various validated German-language questionnaires (e.g., BFI, FACT-F, CFS, MFI-20, FSI) (e16). Indications of depression in the differential diagnosis include history of depression, pronounced listlessness, sustained feelings of worthlessness, thoughts of suicide, insomnia, and daily mood swings, while the main indication of cancer-related fatigue is exhaustion that is not proportional to recent activity (e17– e19).

Discussing this syndrome in detail with patients can help them to better understand it. Treatment strategies can then be developed together. This process can be aided by The Blue Guide “Fatigue: Chronic Fatigue in Cancer” from the German Cancer Aid (Deutschen Krebshilfe) (15) or by special patient seminars.

In addition to cause-specific therapies, symptom-oriented therapies should also be used (figure 2). According to meta-analyses, physical activity plays a major role in the treatment of cancer-related fatigue syndrome (weighted effect size, Cohen’s d: 0.30; 95% confidence interval [0.25; 0.36]), as does psychotherapeutic interventions (16, e20– e22).

Figure 2.

Interventions for cancer-related fatigue syndrome according to Cuhls et al. (12)

Pain

About 30% of patients undergoing curative therapy (e23), and 60% to 80% of patients with incurable cancer, experience pain (e24, 17). Therefore, these patients should be regularly recorded as part of a symptom screening; in Germany, this can be done for example using the Minimal Documentation System (MIDOS 2) (18) or the German Integrated Palliative Care Outcome Scale (IPOS) (19), in order to initiate adequate pain therapy at an early stage. Corresponding questionnaires are available for free download on the website of the German Society for Palliative Medicine (Deutschen Gesellschaft für Palliativmedizin) (20).

A distinction should be made between nociceptive (visceral or somatic) and neuropathic pain. In addition to the pain characteristics, the extent, dynamics, and intensity of pain at the beginning and during the treatment course should be recorded using a verbal rating scale (VRS; no pain, or mild, moderate, or severe pain) or a numeric rating scale (NRS; 0–10). The World Health Organization (WHO) recommends a 3-step ladder in which the use of opioids is recommended for moderate and severe cancer pain (21). If possible, medication should be administered orally and at a specified interval. The dose should be increased gradually until the patient is pain-free. At the beginning of pain control, an assessment should be carried out, for example with the help of the McGill Pain Questionnaire (e25) or the German Pain Questionnaire (DSF, Deutschen Schmerz-Fragebogens; [22]), in order to determine the type of pain, the cause of pain, and the appropriate pain management. Observation sheets in German, such as the “Observation Tool for Pain Assessment in Elderly People with Dementia” (BISAD, Beobachtungsinstrument für die Schmerzerfassung bei alten Menschen mit Demenz; [e26]) or the questionnaire “Assessment of Pain in Dementia” (BeSD, Beurteilung von Schmerzen bei Demenz), can help with assessment if a self-assessment is not possible (e27).

In 2018, the WHO made the following important updates to the recommendation for the treatment of cancer-related pain symptoms (21):

1. Patients with cancer pain should receive nonsteroidal anti-inflammatory drugs (NSAIDs, for example ibuprofen or paracetamol) and opioids. The pain intensity should decide whether this is initiated as a monotherapy or a combination therapy (high level of recommendation, low level of evidence). Thirteen studies were able to show evidence of pain reduction with the combination of NSAIDs and strong opioids (21).

2. For pain control, any opioid can be considered, with regular monitoring of the severity of the pain, alone or in combination with an NSAID (strong recommendation, low level of evidence; see also the German Guideline on Palliative Medicine [23]). Phase IV studies (e28), a meta-analysis (e29), and reviews (e30, e31) have shown comparable results in the efficacy of morphine, hydromorphone, oxycodone, fentanyl, and buprenorphine.

3. To achieve good pain control, opiates (slow- or immediate-release) should be taken orally, if possible. If oral or transdermal delivery is not an option, subcutaneous delivery is preferred (strong recommendation, moderate level of evidence). A total of seven studies have shown that subcutaneous administration is comparable to intravenous opioid administration in terms of effects and tolerance (24).

4. Supplementary steroids can be used for better pain control if indicated (high level of recommendation, moderate level of evidence). Steroids were found (in four trials for methylprednisolone, two trials for dexamethasone, and one trial for prednisolone) to reduce pain as compared to placebo (net difference of -9.9 [16.0; -3.8]) (21).

5. For bone metastases, bisphosphonates should be used to prevent and treat bone pain (strong recommendation, moderate level of evidence). Bisphosphonates showed a significant improvement in pain control as compared to placebo (net difference of -11.8 [-17.6; -6.1]) (21). Despite an equivalent reduction in pain, the WHO does not recommend RANK ligand antibodies (such as denosumab) for the management of pain related to bone metastases, due to the cost–benefit ratio (21). However, these drugs can prevent the occurrence of skeletal events and are recommended for preventive use by the German Clinical Practice Guideline for Supportive Therapy, as are bisphosphonates (25).

6. In the case of pain related to bone metastases, a single-dose (SD) radiation therapy should be carried out (strong recommendation, high level of evidence). Irradiation with a low-fractionated dose or SD (8–15 Gy) as well as with a high-fractionated dose or multiple dose (MD; 20–30 Gy over several fractions) showed comparable results with a complete reduction in pain (SD 25%; MD 26%). Due to the significantly lower costs (SD, $998 versus MD, $2 316) and the more efficient use of resources (more patients in the same time with comparable pain reduction), the WHO recommends single-fraction radiotherapy for pain treatment (21).

For pain that is difficult or impossible to control, it is advisable to involve a pain therapist or palliative care specialist in pain management at an early stage.

Lack of appetite and cachexia

Cancer therapy–specific adverse effects, such as changes in taste, mucositis, nausea, or constipation, often lead to loss of appetite, malnutrition (cachexia), and muscle wasting (sarcopenia). These symptoms are often associated with a greater risk of hospitalization and higher costs, as well as a negative prognosis and increased mortality (e32, e33).

According to the definition, cancer cachexia is defined by an unintended weight loss of more than 5% over the past six months, weight loss of more than 2% with a body mass index <20, or a muscle mass index compatible with sarcopenia (26). According to this definition, weight loss over the past six months, the body mass index, or a measurement of muscle mass using a radiological density measurement (dual-energy X-ray absorptiometry, DXA) should therefore be monitored during the screening procedures (26). Useful German-language screening tools include the Nutritional Risk Screening (NRS 2002 [27]) or the Malnutrition Universal Screening Tool (MUST [e34]), which can be found on the website of the German Society for Nutritional Medicine e.V. (e35).

The therapy of cancer cachexia is based on the stage. A distinction is made between pre-cachexia, cachexia, and refractory cachexia (table). For pre-cachexia (mild weight loss [≤ 5%] and metabolic changes, such as anorexia and reduced glucose tolerance), monitoring and preventive interventions (such as nutritional advice and appropriate exercise) should be continued in addition to cause-specific treatment (28). If cachexia is diagnosed, multimodal management should be followed, consisting of the following elements:

Table. Management of cancer cachexia based on Fearon et al. (26).

	Pre-cachexia	Cachexia	Refractory cachexia
Definition	– Weight loss ≤ 5 % – Metabolic changes	– Weight loss >5% or – BMI <20 + weight loss >2% Often associated with reduced food intake/systemic inflammation	– All symptoms of cachexia – Progressive cancer that does not respond to anticancer therapy – Poor performance status – Life expectancy <3 months
Measures	– Monitoring – Preventive interventions (nutritional advice, exercise options)	Cause-specific, multimodal management with: – N utritional advice and therapy – Oral/parenteral nutrition (25–30 kcal/kg BW/day) with protein supplements (1.0–1.5 g/kg BW/day) – Exercise therapy (to increase muscle and strength) – Psycho-oncological support	– Symptom management – Psycho-oncological support – Establish a set of common goals with respect to nutritional advice for patients and family

BMI, body-mass index; BW, body weight

• Adequate nutrition (oral/parenteral, 25–30kcal/kg body weight/day);

• Protein supplementation (1.0–1.5g/kg body weight/day)

• Psychotherapeutic support;

• Targeted muscle and strength building (26, 29).

Currently, there is only a weak recommendation for a continual use of corticosteroids. For refractory cachexia (progressive cancer, poor state of well-being, and short life expectancy [<3 months]), exercise therapies are of less interest. In this phase, psycho-oncological support is particularly important, in order to avoid conflict situations between the patient, relatives, and caregivers (for example, eating-related distress) (e36, e37). Initial studies suggest that patients, relatives, and caregivers benefit from receiving, and agreeing on, family-centered nutritional advice (e38, e39).

Dyspnea

Dyspnea is also a frequent symptom (10–70% [e40]) in patients with cancer treated in an outpatient setting, and it increases in frequency and severity at end of life (e41, 9). Treatment of dyspnea should not only be symptom-oriented but also should consider a cause-specific diagnosis (with appropriate therapy). Pulmonary (e.g., pneumonia, pneumonitis, pulmonary embolism, tumor-related obstruction, pleural effusion), cardiac (e.g., heart failure, arrhythmia, pericardial effusion) and hematological (e.g., anemia) causes are frequent causes of dyspnea in patients with a cancer (30, e42).

As shortness of breath has a pronounced affective component, general and non-drug interventions alone or in combination with medicines play a major role in the treatment of dyspnea (box 1). In particular, patients can be helped by general measures, such as patient training with instructions of how to establish a body-friendly, adapted mobility, adjust the daily rhythm, keep the face area cool, and involve relatives; patients can then use emergency measures for an emergency respiratory attack. Despite only a moderate evidence level, using fans has proven itself in practice and is recommended in the guidelines for palliative medicine (23). Walking aids, such as rollators or walking sticks, also promote mobility. Due to the lack of evidence (31), continuous oxygen administration should only be prescribed in hypoxic patients for whom long-term oxygen therapy is indicated.

BOX 1. Symptom-oriented therapy of dyspnea according to Bausewein et al. (e42) and Rosenbruch et al. (30).

• General interventions

  • Remain calm

  • Provide reassurance and information to the patient

  • Open windows, cool the room

  • Have the patient sit upright /sit leaning forward

  • Request that the patient:

    • concentrates on exhalation

    • relaxes his/her shoulders

    • loosens his/her lower jaw

  • Prepare a dyspnea emergency plan

  • If relief is insufficient, a palliative care specialist should be consulted

• Non-pharmacological interventions

  • Fan/handheld fan moving air directly to face

  • Walking aids, rollator

  • Movement and breathing therapy

  • Stimulate breathing by massage

  • Air humidification

  • Use of essential oils (lemon, cedar)

  • Psychological interventions (imagination, relaxation exercises)

• Pharmacological interventions

  • Opioids (such as morphine*)

    • opioid naïve: starting dose of morphine: 2.5 mg p.o. or 1.25 mg s.c.

    • pre-existing opioid therapy: dose increase by 25%

  • Benzodiazepines* only if there are accompanying symptoms of anxiety

    • lorazepam 0.5–1.0 mg p.o. every 6–8 hours

    • midazolam 2.5–5 mg s.c. every 4 hours

  • Oxygen

    • only indicated for hypoxia and long-term therapy

    • mostly dispensable with symptomatic therapy

* Off-label use; p.o., per oral; s.c., subcutaneous

In symptom-oriented drug therapy of dyspnea, opioids are the only drug group to have sufficient evidence in the treatment of dyspnea based on advanced lung diseases (meta-analysis of randomized studies: standardized mean difference -0.32 [-0.53; -0.10], p = 0.004]) (32). The informative value of observational and pilot studies is not yet sufficient for transnasal and transmucosal delivery. For this reason, opiates should be used orally or parenterally for symptomatic relief of dyspnea (23). In opioid-naïve patients, symptom relief has been described as early as 10–30 mg orally (p.o.) (e43). Therefore, a morphine dose of 2.5–5 mg p.o. or 1–2.5 mg subcutaneously (s.c.) every four hours is recommended (off-label use). With previous opioid therapy, an effect can be achieved by increasing the dose by 25% (e44; Box 1).

There is no evidence for the use of benzodiazepines. Only one study showed an effect for midazolam (33). Despite the lack of evidence, the use of benzodiazepines is recommended in the German Clinical Practice Guideline on Palliative Medicine (23) based on the good clinical experience, especially if there is anxiety or panic.

Palliative care needs

An early integration of specialized palliative care into the oncological setting can help to improve the symptoms that accompany palliative cancer care (standardized mean difference [SMD] -0.23 [-0.35; -0.10]) and thus improve the quality of life of patients (SMD 0.27 [0.15; 0.38]) (e45, 34, – 36).

The timely involvement of specialized palliative care is recommended by the specialist societies, as the effects are classified as clinically relevant (despite the statistically low effect size) (23, e46, e47). The early involvement of an in-hospital palliative care service promotes patient orientation and effectively supports the treating oncologist in controlling symptoms (e48).

An international committee of experts recommended several criteria for referral, including two time-based and nine needs-based criteria (37), which record the following information: one or more severe physical symptoms, severe emotional distress, request for hastened death, spiritual crisis, the need for advance planning, patient request for referral, delirium, brain or leptomeningeal metastases, and spinal canal compression (Box 2).

BOX 2. Referral criteria for specialized palliative care according to Hui et al. (37).

• Time-based

  • Within three months of the diagnosis of an advanced incurable cancer with a life expectancy of less than 1 year

  • Second-line of palliative systemic therapy

• Need-based

  • Severe symptoms

  • Emotional distress

  • Request for hastened death

  • Spiritual crisis

  • Need for advance planning

  • Patient request

  • Delirium

  • Brain or leptomeningeal metastases

  • Spinal canal compression

As the outpatient care of oncological patients increases, palliative medical care and advice for home will also become necessary. The outpatient palliative care structure includes (e49, e50):

• Visiting hours for specialized palliative medicine in oncological centers;

• General care by general practitioners and specialists, as well as outpatient nursing services with basic palliative care qualifications;

• Specialized care (general outpatient palliative care [AAPV, allgemeine ambulante Palliativversorgung] and specialized outpatient palliative care [SAPV, spezialisierte ambulante Palliativversorgung]).

Psycho-oncological and palliative care screening

Regular self-assessment of the symptoms and needs of patients with cancer (Patient Reported Outcome Measurement, PROM) enables a patient’s experiences to be recorded in a structured manner (38, e51). Early and repeated monitoring of symptoms in routine outpatient care correlates with an improved quality of life for patients (34% versus 18%), with a extended phase in which chemotherapy can be carried out (8.2 versus 6.3 months, p = 0.002) as well as reduced emergency room visits (34% versus 41%, p = 0.02), lower hospitalization rates (45% versus 49%, p = 0.08), and longer survival times (31.5 months versus 26.0 months, p = 0.03; hazard ratio [HR] 0.83, p = 0.04) (6, 39).

Psycho-oncological and palliative care screening is increasingly required by specialist societies and is firmly anchored in the oncological guidelines (e52). In German-language countries, symptom screening for palliative care is predominantly carried out using MIDOS_2 (18) or IPOS (19). Psychosocial stress can be assessed with the Hornheider Screening Instrument (HSI) (e53), while the questionnaires PHQ9 (e54) and GAD7 (e55) can document depression and anxiety in patients. This makes it possible for the oncological treatment team to monitor the symptoms of patients with cancer in an interdisciplinary manner based on oncological guidelines in an outpatient setting, and to treat them in an evidence-based and targeted manner.

Overview

Already the frequency of the most common symptoms, such as fatigue, pain, lack of appetite, and dyspnea, make it clear that psycho-oncological, supportive therapy, and palliative care expertise should be included within the outpatient cancer therapy, based on symptoms and needs. This can be achieved with psycho-oncological–palliative care screening.

Figure 1.

Prevalence of symptoms in outpatient oncological patients* – Percentage of moderate and severe symptoms (7)

* Results of a self-assessment using MIDOS 2 of 705 patients with cancer in an oncological outpatient clinic at a university hospital in Germany, during treatment in a curative and palliative setting

Key Messages.

• Outpatients with cancer predominantly suffer from fatigue, pain, loss of appetite, and dyspnea.

• An especially high-level or complex burden of symptoms makes specialist care necessary.

• Early integration of a movement therapy can help to alleviate a large number of symptoms in patients with cancer.

• In patients with metastasis or a locally advanced cancer, early involvement of palliative medical care services should also be established.

Questions on the article in the issue 17/2021:

Symptoms During Outpatient Cancer Treatment and Options for their Management

CME credit for this unit can be obtained via cme.aerzteblatt.de until 29 April 2022. Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1

What is the approximate 5-year prevalence of patients with cancer in Germany

1. around 0.5 million persons

2. around 0.9 million persons

3. around 1.7 million persons

4. around 2.3 million persons

5. around 3.2 million persons

Question 2

According to a self-assessment of 705 patients in an oncological outpatient department, what are the most frequently reported moderate and severe symptoms during outpatient cancer therapy?

1. Constipation, dyspnea, and loss of appetite

2. Pain, vomiting, and fear

3. Nausea, vomiting, and dyspnea

4. Fatigue, weakness, and pain

5. Loss of appetite, constipation, and vomiting

Question 3

What is the name of a proven documentation system that should be used regularly as part of symptom screening in patients with cancer?

1. MIDOS_2

2. PICOS_2

3. IPAS

4. MIPOS

5. SIDOS_2

Question 4

Which unintended weight loss defines cancer cachexia in patients with a body mass index of ≥?

1. > 2% over the past six months

2. > 5 kg over the past eight weeks

3. > 5% iover the past ten months

4. > 2 kg over the past six months

5. > 5% over the past six months

Question 5

Which questionnaires can be used to measure depression and anxiety in patients?

1. HSI and VAS

2. PHQ9 and GAD7

3. ZUF-8 and WIRK

4. BSA and HSI

5. VAS and ZUF-8

Question 6

Which are the main measures to use for refractory cachexia in patients with a short life expectancy, according to Fearon et al. (2011)?

1. Oral/parenteral nutrition with protein intake

2. Exercise therapy to build muscle and strength

3. Self-help group for malnutrition

4. Symptom management and psycho-oncological support

5. Continuous use of corticosteroids

Question 7

Which pharmacological measure has sufficient evidence for symptom-oriented therapy of dyspnea in advanced lung diseases?

1. Taking pregabalin

2. Taking cineol

3. Taking opioids

4. Taking corticosteroids

5. Taking NSAIDs

Question 8

For which type of metastasis should bisphosphonates be used to reduce pain?

1. Bone metastases

2. Liver metastases

3. Lung metastases

4. Brain metastases

5. Adrenal metastases

Question 9

Which symptoms of patients with cancer should be treated with methylphenidate?

1. Constipation

2. Nausea

3. Fear

4. Fatigue

5. Dyspnea

Question 10

You can find out more about symptom-oriented therapy (among other things) in brochures from the German Cancer Aid. What are these called?

1. Green Guides

2. Red Guides

3. White Guides

4. Yellow Guides

5. Blue Guides