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Symptom management during chemotherapy
SYMPOSIUM: ONCOLOGY
Symptom management during chemotherapy
Some child and parent reported symptoms appear to be relatively consistent whether they are highlighted by checklists such as the Therapy-Related Symptom Checklist or by meaningassigned symptoms reported by children, and concur with those highlighted by professionals. These symptoms are nausea and vomiting, fatigue and pain (especially from sore mouth) and these will be discussed in this review. However Woodgate et al recorded numerous symptoms reported by care givers using the Therapy-Related Symptom Checklist, Table 1, which highlights areas for future research programmes.
Dilini Rajapakse
Abstract Improvements in overall childhood cancer survival over the last four decades have been due to improved multimodal therapeutic regimes and supportive care. Symptoms are related to disease, procedures, treatments such as chemotherapy regimens and the overall experience of cancer. These symptoms are viewed as subjective indicators of distress which impact on the child’s quality of life and therefore require a rational approach to management. This review explores the reasons why symptom management during chemotherapy is necessary, assessment of symptoms in children and young people and current approaches to management of common symptoms which are reported by children and professionals as being distressing. These are nausea and vomiting, pain, mucositis and fatigue.
Why is symptom management important? Current thinking recognises the symptom experience as subjective and variable over the cancer trajectory. It is a reflection of the disease state, environmental and psychosocial influences. In addition, a child’s symptom experience has a reciprocal effect on their family and the family’s ethno cultural heritage will impact on this. Parents’ reporting of their child’s symptoms has previously been discounted by physicians as unhelpful and occasionally inaccurate, but research indicates that parents’ knowledge and insight, particularly in younger children, may provide information that is unavailable to physicians. Therefore, in adopting a childcentred overall approach to symptom management it is helpful to acknowledge and utilise the expertise of parents. Woodgate et al report that children’s cancer symptoms are experienced as overall feeling states with assigned meanings. Each symptom experience is therefore a singular, personalised situation in the context of that child, rather than a physiological or psychological state, conceptualized according to the normal experience of professionals. Woodgate et al hypothesise that this explains challenges to symptom management such as: Inadequate symptom reporting due to the belief and expectation that although some symptoms are distressing they are a necessary part of ‘‘beating ‘‘ cancer and so should be endured. Inadequate symptom reporting due to the belief that professionals do not understand the nature of patients’ suffering so would not be able to alleviate it. The child’s difficulty in deconstructing overall feeling states and establishing individual symptoms from them, which then have to be presented accurately in another context, on self report scales.
Keywords chemotherapy; fatigue; mucositis; nausea and vomiting; pain; symptoms; symptom management
Introduction There are 80 to 160 new cases per year of childhood cancer per million children aged under 15 years, worldwide. Survival rates in the U.K. have increased dramatically, largely due to improved therapeutic regimes and supportive care. Symptoms may be related to disease, procedures, treatments such as chemotherapy regimens and the overall experience of cancer. Collins et al demonstrated a high prevalence of children’s reporting of physical and psychological symptoms, suggesting that symptom management during their cancer journey is still inadequate. As such, the science of symptom management deserves the same rational and methodical approach as the science of cure, if it is to achieve the same success. Symptoms during chemotherapy are no longer viewed as manifestations of the side effects of treatments but as subjective indicators of distress, which impact on a child’s quality of life. Longitudinal, qualitative studies are acknowledged to be essential to understand the experience of children and young people undergoing chemotherapy and research programmes are increasingly focussing on patient reported symptoms and outcomes. This review will explore the importance of symptom management during chemotherapy, assessment of symptoms in children and review the current approaches to the management of specific symptoms during chemotherapy.
Reported symptoms by parents and caregivers Symptoms reported by parents and caregivers of children and young people using the Therapy-Related Symptom Checklist Loss of appetite Taste change Nausea and vomiting Weight loss Sore mouth Cough Sore throat
Dilini Rajapakse MBBS MRCPCH MSc DipPallMed Consultant in Paediatric Palliative Medicine, Great Ormond Street hospital. Address: Level 4, Portacabins,Nurses Home, Great Ormond Street hospital, Great Ormond Street, London WC1N 3JH, UK.
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Shortness of breath Numbness of fingers and toes Feeling sluggish Fever Bleeding Hair loss Skin changes
Difficulty sleeping Pain Constipation Stomach cramps Headaches
Table 1
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Incomplete symptom reporting due to professionals not accessing the expertise of the family. Woodgate and colleagues explored the concept of symptom distress in children.This can be defined as the ‘‘physical and mental suffering that results from the experience of symptom occurrence and/or the perception of feeling states.’’. Put simply by a school aged child with acute lymphoblastic leukaemia (ALL), contributing to Ross et al’s study in 1989, ‘‘there are a lot of things about ALL that hurt a lot, not just the needles and medicine and stuff.’’ Acknowledgement of this overall suffering by children and families when symptoms are not adequately managed, has led to an interest in symptom assessment, as part of quality of life assessment in childhood cancer. Despite challenges to symptom assessment and quality of life research in children, understanding the nature and characteristics of symptoms and adopting a meaning-centred approach to management will be beneficial to the child and family.
Woodgate et al reported that many symptom assessment tools although shown to be reliable and valid, are conceptualised as tools for adults and may lack essential aspects of children’s symptom experience. Therefore adult assessment tools are utilised for older children (Symptom Distress Scale, Hinds et al), modified for children (Memorial Symptom Assessment Scale, validated by Collins et al) or new tools are developed specifically for children (Childhood Cancer Stressors Inventory). Lauri and Linder highlighted the limitations of assessment tools for the younger age groups. They reported that self assessment tools are of no value in infants and young children and therefore direct observational techniques or parent proxyreport is necessary to determine symptoms. Younger children have difficulty in responding to items on assessment questionnaires and there was greater variance in responses. This suggests that these tools did not reach acceptable internal consistency for components in that age group. Sometimes younger children required assistance in completing the questions or left more items unanswered suggesting that the feasibility of these tools in this study group was poor. Parent proxy-reports demonstrate varied correlation with patient report depending on the symptom. However several studies have demonstrated significant correlation between parent proxy report and children’s report and are therefore, a valuable resource of information in young children. Assessment instruments which report the multidimensional aspect of symptoms,(frequency, severity, degree of distress) are more useful measures as they reflect the associated distress which documentation of the frequency alone cannot demonstrate. Similarly multiple symptom measurement tools (About My Illness Scale, Hockenbury-Eaton et al) are able to demonstrate interrelationships between symptoms. Finally, Lauri and Linder report that since symptom experience changes during the child’s treatment journey, the overall impact of this requires evaluating. Quality of life measurement instruments (PedQL, Varni et al) are able to provide a temporal document of physical symptoms and therefore contribute to data about the overall experience of the child during and after treatment.
Assessment of symptoms in children and young people Challenges to assessing symptoms experienced by children and young people can be due to intrinsic issues of childhood. These are developmental diversity, the vulnerability of adolescents to symptom distress, variation of the symptom experience in different environmental settings and the recognition of the child as part of a family. In addition, measuring symptoms in children and young people using appropriate assessment tools and engaging children and young people in the reporting of symptoms pose specific issues which are unique to this study group. Developmental diversity research recognises that children of different ages and developmental stages appraise and respond to the illness experience differently. Younger, non-verbal children who lack the ability to express themselves and have fewer coping strategies, are vulnerable. However current research suggests that adolescents have an increased vulnerability to symptom distress, perhaps because they are better able to articulate their distress. This group may choose to ‘‘fight the treatment’’ rather than the cancer, leading to challenges in assessment and management of symptoms. If developmental diversity is not addressed there is the potential for disparities in the health outcomes for children and adolescents of different developmental stages even if the therapies are similar. Therefore it is important to identify age-appropriate assessment tools and interventions. However even if the appropriate tools are available, lack of engagement of children and young people in the process of reporting symptoms may be a barrier. Gibson et al refer to the two way process of successful symptom management whereby health professionals describe and inform young people of the possible side effects of therapies and in turn, the young people report back to the professionals information about the symptoms that they are experiencing. This continued dialogue will enable an individualised plan to be devised. In order to engage children and young people instruments familiar to them should be utilised, such as mobile phone and internet technology as demonstrated by the ASyMS (advanced symptom management system) currently being evaluated by Gibson and colleagues.
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Principles of symptom management Each child or young person requires an individualised symptom management plan, which includes a systematic approach to assessment, identification of a reversible cause for the symptom if possible, treatment options and plans to re-evaluate management strategies. When formulating a management plan it is important to identify an appropriate place of care (ward,daycare,home,local hospital or hospice), anticipate symptoms before their onset, providing information to the child and family about them and to balance the risks and benefits of the treatment for the individual, at their stage of the illness. Pharmacological strategies have their own risks of side effects which must not outweigh the discomfort of the symptom that they are addressing. Non-pharmacological measures include advanced care planning administration of hot and cold packs, massage, play therapy, distraction therapy, hypnotherapy, physiotherapy, occupational therapy and complementary therapies.
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Pain Woodgate et al’s study of meaning assigned symptoms reported by children and young people described pain as a sign which reinforced the suffering nature of cancer. A 10 year old with Acute Lymphoblastic leukaemia reported, ’’What I know about cancer, I know you start with a pain. I know that you get headaches, I know that you get stomach aches, I know that your hair falls out, I know that you have to have pokes, they hurt, that’s all I know.’’ Elliott et al reported a prevalence of 17.5% for reported pain by children with a cancer diagnosis. This includes pain related to the cancer itself, treatment related pain and procedure related pain. Of these, cancer related pain is most common in adult patients but treatment and procedure related pain is most common in children. This reflects the aggressiveness of paediatric treatment protocols and the high long term disease free survival rates in children. Miser et al and Elliott et al found that pain reported by children whose disease had relapsed and therefore researchers had expected to report more pain, only accounted for less than half of the pain reports. This suggested that children whose disease was in remission or who were on first treatment protocols were experiencing pain. There was no significant difference between reports of pain by children with localised disease and children with metastatic disease or leukaemias.
It is important that health professionals understand how children view their symptoms and acknowledge their meaning to children if rational approaches to management are to succeed. Nausea and vomiting In Woodgate et al’s study of meaning assigned symptoms reported by children and young people this symptom was acknowledged as a sign that the cancer is being beaten. A 4 year old girl with neuroblastoma explained ‘‘Take your medicine, even though if you get sick or you get sicker. In one way it’ll make you, help you get better in another way.’’ Chemotherapy induced nausea and vomiting are probably the most reported symptom for children with cancer. Despite knowledge about the emetogenic potential of chemotherapeutic agents, use of improved antiemetic agents and behavioural modification techniques, this symptom remains difficult to treat. It is generally accepted that inadequately controlled nausea and vomiting can lead to anticipatory fear of chemotherapy and poor treatment compliance. The potential to induce vomiting is due to a combination of the chemotherapeutic regime, method of administration and the child’s response and experience. Vomiting is believed to be controlled by the vomiting centre, located in the reticular formation of the medulla oblongata. Vomiting can be triggered by several pathway, Figure 1. Theories of chemotherapy induced vomiting include stimulation of the chemoreceptor trigger zone and release of 5-HT (serotonin) from the gut mucosa, which activate vagal afferents to stimulate the vomiting centre. Anticipatory nausea and vomiting is thought to result from stimulation of the cerebral cortex and limbic system. There is likely to be several processes involved which need to be addressed in order to completely relieve this symptom. Table 2. Etoposide,cytarabine,ifosfamide and cyclophosphamide have a dose related increasing effect on nausea and vomiting. Cyclophosphamide may also have a delayed emesis effect. Therefore antiemetics agents need to be continued for a period after the drug administration has ceased. See Table 3. Non-pharmacological techniques such as hypnosis, progressive muscle relaxation, guide imagery and systemic desensitisation have been effective. Distraction and engaging the younger child’s imagination with play has also been beneficial.
Anxiety Sensory stimuli
Motion sickness
Drugs Uraemia Hypercalcaemia
Gastrointestinal tract stimulation
Cerebral Cortex
Vestibular apparatus
Chemoreceptor trigger zone CTZ
Vagal and sympathetic afferents
The most common chemotherapy related pain episodes reported were Oral mucositis Neuropathic pain due to vincristine treatment. Abdominal pain due to dyspepsia or protracted vomiting during chemotherapy. Febrile infective episodes due to chemotherapy induced neutropenia. Visual analogue scales, picture face scales and verbal descriptor scales have been used to assess pain reported by children and investigators and several groups reported good correlation between children’s reports and those of the investigators suggesting that this was a feasible methodology. Overall intensive or severe pain which rendered the child bedridden, was infrequent, occurring in less than 7% of children in a study by Ljungman et al. Mild or moderate pain (interfering with sleep and daily life) was reported in 22% of children in this study. Pain was scored as being of lower intensity on visual analogue scales than on verbal descriptor scales. None of the studies investigating pain reporting in paediatric oncology have highlighted differences in pain management due to type of cancer pain or treatment related pain. Elliott et al report that in their study investigating 160 children with different types of cancer, of different age groups and different types of cancer pain, 28 children reported pain. Of these 19 children received analgesic medications. Nine of these were receiving paracetamol (acetaminophen), 7 received acetaminophen and codeine phosphate and 3 children were receiving either a strong opioid analgesic alone or in combination with acetaminophen. Adjuvant analgesics (usually for treatment of neuropathic pain) were lorazepam and amitryptline which was being received by one patient each. In this same study, it was suggested that pain reporting by the child and investigator did not correlate with the degree of pain gauged by the health professionals treating the child, as reflected
Vomiting centre
Figure 1 Diagram to illustrate pathways which trigger the vomiting centre in the brain.
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Mechanism of action of some antiemetic medications Type of Agent
Mechanism of action
Example
5HT3 antagonists
Reduce the 5HT receptor activation in the gut mucosa and CTZ.
Antidopaminergic agents
Reduces the Dopamine D2 receptors in the CTZ.
Corticosteroids
?antiprostaglandin activity and changes in cell permeability. Enhances the activity of other antiemetics (5HT3antagonists, metoclopramide) Anxiolytic sedative and amnesic agent. Useful for anticipatory vomiting.
Ondansetron Tropisetron Phenothiazines (prochloperazine, chlorpromazine) Butyrophenones (haloperidol, domperidone) Dexamethasone
Benzodiazepines
Lorazepam
Table 2
in the pain management regime which the child was having. For example of the 9 children receiving no analgesia, although all complained of mild pain, the investigator assessed 1 as having moderate pain. Of the 9 children receiving acetaminophen alone, 3 children reported no pain, 2 mild pain, 2 moderate pain, 1 severe pain and 1 very severe pain. Four patients also reported analgesia toxicity including hallucinations, sleepiness, dizziness, nausea, vomiting and euphoria. In general, assessment and management of chemotherapy related pain directs analgesia regimes according to the World Health Organisation analgesic ladder, Figure 2. This regime is recommended by the clock (regular analegesia), by the ladder (adjuvant analgesic agents may be added at any step of the ladder, and by the mouth (oral route is preferred). When prescribing analgesia, in most situations pain is constant and therefore regular analgesia should be given as a background with short acting preparations for sudden onset pain or incident pain (due to anticipated increases in pain severity). If the child is requiring multiple doses of breakthrough analgesia then the background regime should be increased in increments based on the amount of breakthrough required in the preceding 24 hours. The preferred route of administration is oral but other routes are transdermal as patches, parenteral via central venous catheters or subcutaneous administration or rarely epidural administration. The oral route may be avoided if
enteral absorption is in question due to complications such as mucositis. Neuropathic pain such as jaw pain and lower limb pain associated with administration of vinca alkaloids is treated by reducing the dose of vinca alkaloids or omitting the dose and the pain (and neuropathy) diminishes usually. However adjuvant agents may be used to treat this. The pain is typically characterised by altered sensation, and sometimes colour and temperature changes in the overlying skin. There may be paraesthesia, allodynia and hyperalgesia. Adjuvant therapy includes: Tricyclic antidepressants (TCAs) There is wide experience in the use of TCAs including amitriptyline.They may require several weeks to see any benefit and have anti-muscarinic, sympathomimetic side-effects. They should be used with caution in cardiac disease and renal or hepatic impairment. Anticonvulsants Drugs used include gabapentin and carbamazepine. They may be sedating at first and therefore should be started at a low-dose and increased to achieve therapeutic levels. Again these should be used with caution in renal and cardiac impairment. NMDA receptor antagonists
Opioid e.g. Morphine sulphate + or – non-opioid
The emetic potential of common cytotoxic agents LOW
MODERATE
HIGH
Bleomycin Busulphan Etoposide 5-fluorouracil Methotrxate Mercaptopurine Thioguanine vincristine
Amsacrine Carboplatin Cytarabine Daunorubicin Doxorubicin Mitozantrone Ifosfamide
Cisplatin Cyclophosphamide Dactinomycin melphalan
STEP 3 Severe pain Mild opioid e.g. codeine phosphate + or – non-opioid STEP 2 Moderate pain Non-opioid agents e.g. Paracetamol, NSAIDS STEP 1 Mild pain
Table 3
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Figure 2 The World Health Organisation (WHO) analgesic ladder.
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Drugs used include methadone and ketamine.The effects of ketamine are seen more rapidly after administration than with other adjuvants. Ketamine may cause psychomimetic effects such as dreams, hallucinations, delirium. However, this is less likely at lower doses and slow administration. They should be used with caution in cardiac disease. It is recommended that these regimens should be administered with expert advice and support from a pain management team.
taking naps, having distractions like visitors and activities, physical therapy, going outside, keeping busy and blood transfusions as ways of alleviating their fatigue. To successfully manage this symptom a multidisciplinary approach to the recognition, assessment and treatment of fatigue is therefore necessary, addressing the environment where chemotherapy is given, the daily life of the child and minimising other symptoms that may contribute.
Mucositis Ulceration of the oral mucosa (and that of the entire gastrointestinal tract) can cause pain, infection, dysphagia and alteration of nutritional status. Chemotherapy not only affects the rapidly dividing cells of oral mucosa, it also alters the volume of saliva, microbial flora, composition and integrity of the mucosa.It is thought that children have a higher mitotic index of the oral mucosa than adults and therefore there is a greater chance of this side effect from certain chemotherapeutic agents. It is consistently a high ranking issue for children and young people’s reporting of cancer related symptoms. Clinical features include swelling, dry mouth, desquamation of mucosa of gums and palate and dry and cracked lips. Management involves maintenance of meticulous oral hygiene, maintenance of mucosal integrity for as long as possible, prevention of infection, maintenance of oral function and to keep the child as comfortable as possible. Providing information to the child and family about oral hygiene regimes, regular oral assessments and instituting supportive care, analgesia and infection control regimens is vital to minimising this distressing symptom. The nursing team will educate and support the child and family in these tasks and encourage the family to continue with mouthcare regimens after discharge.
Discussion There has been an important change in the perception of symptoms in children, in the last 25 years from being objective indicators of disease state and side effects of treatment, to their being a subjective experience, varying over the cancer journey of the individual. An individual’s symptom experience reflects the impact of the disease and treatment on them and contributes to their quality of life. As such, symptoms not only affect the child for the duration of the illness and treatment, but may be powerful indicators of their expectations and ability to cope. Therefore inadequately managed symptoms may contribute to the perceived negativity of the cancer experience and contribute to overall morbidity. Challenges to effective symptom management include barriers to patients reporting symptoms, inadequate assessment tools for children of all ages, invalid parent proxy reporting and under recognition of symptoms by professionals. However, it is acknowledged that children grow and develop physically, psychologically, cognitively and spiritually even during periods of illness. Therefore symptom management should reflect this developmental diversity in childhood and adolescence. Symptom management requires a systematic approach of assessment, treatment with multidisciplinary management strategies and re-evaluation. Educating the child and family about their illness and providing information about symptoms and self care strategies will help to empower the individuals and encourage partnership in management. This approach may be useful in managing previously under-recognised symptoms such as cancer related fatigue. Management strategies may be pharmacological or nonpharmacological. The risk of side effects with medications should not outweigh their benefits and patients and carers need to be informed prior to commencing the therapy. Although there is limited research to support the benefits of these strategies the advantages of non-pharmacological strategies such as physiotherapy, massage, guided imagery are that they have no side effects of their own and run concurrently with medication management. With expert guidance, the child, family and local professionals can continue these techniques at home. Finally, it is acknowledged that symptoms in childhood cancer will be disease-specific, therapy specific and child specific. Therefore management strategies should reflect all these elements with the aggressive, evidence based approach that there is to curative management. A
Fatigue Woodgate et al’s study of meaning assigned symptoms by children and young people highlighted the graphic nature by which children describe this symptom and equate their life with living in limbo. A 14 year old boy with Hodgkins disease reported ’’There are days when I wake up when I feel like I’ve been hit by a truck.’’ A 10 year old with acute lymphoblastic leukaemia reported, ‘‘You can fall asleep right on the floor, you get in the door and just fall down and sleep.’’ Cancer-related fatigue has been defined by the National Comprehensive Cancer Network as persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning, and can be described in terms or perceived energy, mental capacity and psychological status. There is a developing evidence base for this previously under recognised symptom in children and adolescents. Hockenberry et al’s original study group described fatigue in terms of reducing their level of functioning and feeling ‘‘sad or mad.’’ Gibson et al reported that 56% of health care professionals thought that most or all of their patients experienced moderate cancer related fatigue and 57% of parents reported that their children expressed fatigue at least once a week. Children and adolescents reported treatments such as chemotherapy, being active, pain, sleep patterns and disruptions, having ‘‘low counts,’’ being in a hospital environment and being anxious and fearful as causes for their fatigue. They described
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FURTHER READING Collins JJ, Devine TD, Dick GS, et al. The measurement of symptoms in young children with cancer: the validation of the memorial symptom
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assessment scale in children aged 7e12. J Pain and Symptom Management 2002; 23: 10e6. Gibson F, Mulhall AB, Richardson A et al. A Phenomenologic study of fatigue in adolescents receiving treatment for cancer. Oncology Nursing Forum, 32: 651e660. Lowis SP, Oakhill A. Management of acute complications of therapy. In: Pinkerton CR, Plowman PN, eds. Paediatric oncology. 2nd edn, 1997. Rajapakse CD. Paediatric pain. MIMS Handbook of Pain Management. 5th edn, 2009. Selwood K, Gibson F, Evans M. Side effects of chemotherapy. In: Gibson F, Evans M, eds. Paediatric oncology: acute nursing care, 1999. Williams PD, Schmideskamp J, Ridder EL, et al. Symptom monitoring and dependant care during cancer treatment in children. Cancer Nursing 2006; 29: 188e97.
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Acknowledgements
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I thank Professor Faith Gibson, (Great Ormond Street hospital and Institute of Child health) for critically reviewing the manuscript.
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Cancer symptoms may be related to disease, procedures, treatments such as chemotherapy and the overall experience of cancer. Symptoms during chemotherapy are subjective experiences which are variable over the cancer trajectory and multifactorial, not merely related to side effects of medications. Symptom assessment tools need to be reliable and validated to be appropriate for use in children and young people and parent-proxy reporting should not be disregarded as inaccurate. Symptom management involves anticipation and education of the children and families about symptoms to expect, evaluating the symptom by history-taking, examination and use of appropriate assessment tools, balancing the risks and benefits of treatment to devise a treatment plan and re-evaluation of the plan. Management strategies should include both pharmacological and non-pharmacological techniques. Commonly reported symptoms are nausea and vomiting, fatigue, pain and mucositis.
Ó 2009 Published by Elsevier Ltd.
Symptom management during chemotherapy
Some child and parent reported symptoms appear to be relatively consistent whether they are highlighted by checklists such as the Therapy-Related Symptom Checklist or by meaningassigned symptoms reported by children, and concur with those highlighted by professionals. These symptoms are nausea and vomiting, fatigue and pain (especially from sore mouth) and these will be discussed in this review. However Woodgate et al recorded numerous symptoms reported by care givers using the Therapy-Related Symptom Checklist, Table 1, which highlights areas for future research programmes.
Dilini Rajapakse
Abstract Improvements in overall childhood cancer survival over the last four decades have been due to improved multimodal therapeutic regimes and supportive care. Symptoms are related to disease, procedures, treatments such as chemotherapy regimens and the overall experience of cancer. These symptoms are viewed as subjective indicators of distress which impact on the child’s quality of life and therefore require a rational approach to management. This review explores the reasons why symptom management during chemotherapy is necessary, assessment of symptoms in children and young people and current approaches to management of common symptoms which are reported by children and professionals as being distressing. These are nausea and vomiting, pain, mucositis and fatigue.
Why is symptom management important? Current thinking recognises the symptom experience as subjective and variable over the cancer trajectory. It is a reflection of the disease state, environmental and psychosocial influences. In addition, a child’s symptom experience has a reciprocal effect on their family and the family’s ethno cultural heritage will impact on this. Parents’ reporting of their child’s symptoms has previously been discounted by physicians as unhelpful and occasionally inaccurate, but research indicates that parents’ knowledge and insight, particularly in younger children, may provide information that is unavailable to physicians. Therefore, in adopting a childcentred overall approach to symptom management it is helpful to acknowledge and utilise the expertise of parents. Woodgate et al report that children’s cancer symptoms are experienced as overall feeling states with assigned meanings. Each symptom experience is therefore a singular, personalised situation in the context of that child, rather than a physiological or psychological state, conceptualized according to the normal experience of professionals. Woodgate et al hypothesise that this explains challenges to symptom management such as: Inadequate symptom reporting due to the belief and expectation that although some symptoms are distressing they are a necessary part of ‘‘beating ‘‘ cancer and so should be endured. Inadequate symptom reporting due to the belief that professionals do not understand the nature of patients’ suffering so would not be able to alleviate it. The child’s difficulty in deconstructing overall feeling states and establishing individual symptoms from them, which then have to be presented accurately in another context, on self report scales.
Keywords chemotherapy; fatigue; mucositis; nausea and vomiting; pain; symptoms; symptom management
Introduction There are 80 to 160 new cases per year of childhood cancer per million children aged under 15 years, worldwide. Survival rates in the U.K. have increased dramatically, largely due to improved therapeutic regimes and supportive care. Symptoms may be related to disease, procedures, treatments such as chemotherapy regimens and the overall experience of cancer. Collins et al demonstrated a high prevalence of children’s reporting of physical and psychological symptoms, suggesting that symptom management during their cancer journey is still inadequate. As such, the science of symptom management deserves the same rational and methodical approach as the science of cure, if it is to achieve the same success. Symptoms during chemotherapy are no longer viewed as manifestations of the side effects of treatments but as subjective indicators of distress, which impact on a child’s quality of life. Longitudinal, qualitative studies are acknowledged to be essential to understand the experience of children and young people undergoing chemotherapy and research programmes are increasingly focussing on patient reported symptoms and outcomes. This review will explore the importance of symptom management during chemotherapy, assessment of symptoms in children and review the current approaches to the management of specific symptoms during chemotherapy.
Reported symptoms by parents and caregivers Symptoms reported by parents and caregivers of children and young people using the Therapy-Related Symptom Checklist Loss of appetite Taste change Nausea and vomiting Weight loss Sore mouth Cough Sore throat
Dilini Rajapakse MBBS MRCPCH MSc DipPallMed Consultant in Paediatric Palliative Medicine, Great Ormond Street hospital. Address: Level 4, Portacabins,Nurses Home, Great Ormond Street hospital, Great Ormond Street, London WC1N 3JH, UK.
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Shortness of breath Numbness of fingers and toes Feeling sluggish Fever Bleeding Hair loss Skin changes
Difficulty sleeping Pain Constipation Stomach cramps Headaches
Table 1
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Ó 2009 Published by Elsevier Ltd.
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Incomplete symptom reporting due to professionals not accessing the expertise of the family. Woodgate and colleagues explored the concept of symptom distress in children.This can be defined as the ‘‘physical and mental suffering that results from the experience of symptom occurrence and/or the perception of feeling states.’’. Put simply by a school aged child with acute lymphoblastic leukaemia (ALL), contributing to Ross et al’s study in 1989, ‘‘there are a lot of things about ALL that hurt a lot, not just the needles and medicine and stuff.’’ Acknowledgement of this overall suffering by children and families when symptoms are not adequately managed, has led to an interest in symptom assessment, as part of quality of life assessment in childhood cancer. Despite challenges to symptom assessment and quality of life research in children, understanding the nature and characteristics of symptoms and adopting a meaning-centred approach to management will be beneficial to the child and family.
Woodgate et al reported that many symptom assessment tools although shown to be reliable and valid, are conceptualised as tools for adults and may lack essential aspects of children’s symptom experience. Therefore adult assessment tools are utilised for older children (Symptom Distress Scale, Hinds et al), modified for children (Memorial Symptom Assessment Scale, validated by Collins et al) or new tools are developed specifically for children (Childhood Cancer Stressors Inventory). Lauri and Linder highlighted the limitations of assessment tools for the younger age groups. They reported that self assessment tools are of no value in infants and young children and therefore direct observational techniques or parent proxyreport is necessary to determine symptoms. Younger children have difficulty in responding to items on assessment questionnaires and there was greater variance in responses. This suggests that these tools did not reach acceptable internal consistency for components in that age group. Sometimes younger children required assistance in completing the questions or left more items unanswered suggesting that the feasibility of these tools in this study group was poor. Parent proxy-reports demonstrate varied correlation with patient report depending on the symptom. However several studies have demonstrated significant correlation between parent proxy report and children’s report and are therefore, a valuable resource of information in young children. Assessment instruments which report the multidimensional aspect of symptoms,(frequency, severity, degree of distress) are more useful measures as they reflect the associated distress which documentation of the frequency alone cannot demonstrate. Similarly multiple symptom measurement tools (About My Illness Scale, Hockenbury-Eaton et al) are able to demonstrate interrelationships between symptoms. Finally, Lauri and Linder report that since symptom experience changes during the child’s treatment journey, the overall impact of this requires evaluating. Quality of life measurement instruments (PedQL, Varni et al) are able to provide a temporal document of physical symptoms and therefore contribute to data about the overall experience of the child during and after treatment.
Assessment of symptoms in children and young people Challenges to assessing symptoms experienced by children and young people can be due to intrinsic issues of childhood. These are developmental diversity, the vulnerability of adolescents to symptom distress, variation of the symptom experience in different environmental settings and the recognition of the child as part of a family. In addition, measuring symptoms in children and young people using appropriate assessment tools and engaging children and young people in the reporting of symptoms pose specific issues which are unique to this study group. Developmental diversity research recognises that children of different ages and developmental stages appraise and respond to the illness experience differently. Younger, non-verbal children who lack the ability to express themselves and have fewer coping strategies, are vulnerable. However current research suggests that adolescents have an increased vulnerability to symptom distress, perhaps because they are better able to articulate their distress. This group may choose to ‘‘fight the treatment’’ rather than the cancer, leading to challenges in assessment and management of symptoms. If developmental diversity is not addressed there is the potential for disparities in the health outcomes for children and adolescents of different developmental stages even if the therapies are similar. Therefore it is important to identify age-appropriate assessment tools and interventions. However even if the appropriate tools are available, lack of engagement of children and young people in the process of reporting symptoms may be a barrier. Gibson et al refer to the two way process of successful symptom management whereby health professionals describe and inform young people of the possible side effects of therapies and in turn, the young people report back to the professionals information about the symptoms that they are experiencing. This continued dialogue will enable an individualised plan to be devised. In order to engage children and young people instruments familiar to them should be utilised, such as mobile phone and internet technology as demonstrated by the ASyMS (advanced symptom management system) currently being evaluated by Gibson and colleagues.
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Principles of symptom management Each child or young person requires an individualised symptom management plan, which includes a systematic approach to assessment, identification of a reversible cause for the symptom if possible, treatment options and plans to re-evaluate management strategies. When formulating a management plan it is important to identify an appropriate place of care (ward,daycare,home,local hospital or hospice), anticipate symptoms before their onset, providing information to the child and family about them and to balance the risks and benefits of the treatment for the individual, at their stage of the illness. Pharmacological strategies have their own risks of side effects which must not outweigh the discomfort of the symptom that they are addressing. Non-pharmacological measures include advanced care planning administration of hot and cold packs, massage, play therapy, distraction therapy, hypnotherapy, physiotherapy, occupational therapy and complementary therapies.
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Pain Woodgate et al’s study of meaning assigned symptoms reported by children and young people described pain as a sign which reinforced the suffering nature of cancer. A 10 year old with Acute Lymphoblastic leukaemia reported, ’’What I know about cancer, I know you start with a pain. I know that you get headaches, I know that you get stomach aches, I know that your hair falls out, I know that you have to have pokes, they hurt, that’s all I know.’’ Elliott et al reported a prevalence of 17.5% for reported pain by children with a cancer diagnosis. This includes pain related to the cancer itself, treatment related pain and procedure related pain. Of these, cancer related pain is most common in adult patients but treatment and procedure related pain is most common in children. This reflects the aggressiveness of paediatric treatment protocols and the high long term disease free survival rates in children. Miser et al and Elliott et al found that pain reported by children whose disease had relapsed and therefore researchers had expected to report more pain, only accounted for less than half of the pain reports. This suggested that children whose disease was in remission or who were on first treatment protocols were experiencing pain. There was no significant difference between reports of pain by children with localised disease and children with metastatic disease or leukaemias.
It is important that health professionals understand how children view their symptoms and acknowledge their meaning to children if rational approaches to management are to succeed. Nausea and vomiting In Woodgate et al’s study of meaning assigned symptoms reported by children and young people this symptom was acknowledged as a sign that the cancer is being beaten. A 4 year old girl with neuroblastoma explained ‘‘Take your medicine, even though if you get sick or you get sicker. In one way it’ll make you, help you get better in another way.’’ Chemotherapy induced nausea and vomiting are probably the most reported symptom for children with cancer. Despite knowledge about the emetogenic potential of chemotherapeutic agents, use of improved antiemetic agents and behavioural modification techniques, this symptom remains difficult to treat. It is generally accepted that inadequately controlled nausea and vomiting can lead to anticipatory fear of chemotherapy and poor treatment compliance. The potential to induce vomiting is due to a combination of the chemotherapeutic regime, method of administration and the child’s response and experience. Vomiting is believed to be controlled by the vomiting centre, located in the reticular formation of the medulla oblongata. Vomiting can be triggered by several pathway, Figure 1. Theories of chemotherapy induced vomiting include stimulation of the chemoreceptor trigger zone and release of 5-HT (serotonin) from the gut mucosa, which activate vagal afferents to stimulate the vomiting centre. Anticipatory nausea and vomiting is thought to result from stimulation of the cerebral cortex and limbic system. There is likely to be several processes involved which need to be addressed in order to completely relieve this symptom. Table 2. Etoposide,cytarabine,ifosfamide and cyclophosphamide have a dose related increasing effect on nausea and vomiting. Cyclophosphamide may also have a delayed emesis effect. Therefore antiemetics agents need to be continued for a period after the drug administration has ceased. See Table 3. Non-pharmacological techniques such as hypnosis, progressive muscle relaxation, guide imagery and systemic desensitisation have been effective. Distraction and engaging the younger child’s imagination with play has also been beneficial.
Anxiety Sensory stimuli
Motion sickness
Drugs Uraemia Hypercalcaemia
Gastrointestinal tract stimulation
Cerebral Cortex
Vestibular apparatus
Chemoreceptor trigger zone CTZ
Vagal and sympathetic afferents
The most common chemotherapy related pain episodes reported were Oral mucositis Neuropathic pain due to vincristine treatment. Abdominal pain due to dyspepsia or protracted vomiting during chemotherapy. Febrile infective episodes due to chemotherapy induced neutropenia. Visual analogue scales, picture face scales and verbal descriptor scales have been used to assess pain reported by children and investigators and several groups reported good correlation between children’s reports and those of the investigators suggesting that this was a feasible methodology. Overall intensive or severe pain which rendered the child bedridden, was infrequent, occurring in less than 7% of children in a study by Ljungman et al. Mild or moderate pain (interfering with sleep and daily life) was reported in 22% of children in this study. Pain was scored as being of lower intensity on visual analogue scales than on verbal descriptor scales. None of the studies investigating pain reporting in paediatric oncology have highlighted differences in pain management due to type of cancer pain or treatment related pain. Elliott et al report that in their study investigating 160 children with different types of cancer, of different age groups and different types of cancer pain, 28 children reported pain. Of these 19 children received analgesic medications. Nine of these were receiving paracetamol (acetaminophen), 7 received acetaminophen and codeine phosphate and 3 children were receiving either a strong opioid analgesic alone or in combination with acetaminophen. Adjuvant analgesics (usually for treatment of neuropathic pain) were lorazepam and amitryptline which was being received by one patient each. In this same study, it was suggested that pain reporting by the child and investigator did not correlate with the degree of pain gauged by the health professionals treating the child, as reflected
Vomiting centre
Figure 1 Diagram to illustrate pathways which trigger the vomiting centre in the brain.
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Mechanism of action of some antiemetic medications Type of Agent
Mechanism of action
Example
5HT3 antagonists
Reduce the 5HT receptor activation in the gut mucosa and CTZ.
Antidopaminergic agents
Reduces the Dopamine D2 receptors in the CTZ.
Corticosteroids
?antiprostaglandin activity and changes in cell permeability. Enhances the activity of other antiemetics (5HT3antagonists, metoclopramide) Anxiolytic sedative and amnesic agent. Useful for anticipatory vomiting.
Ondansetron Tropisetron Phenothiazines (prochloperazine, chlorpromazine) Butyrophenones (haloperidol, domperidone) Dexamethasone
Benzodiazepines
Lorazepam
Table 2
in the pain management regime which the child was having. For example of the 9 children receiving no analgesia, although all complained of mild pain, the investigator assessed 1 as having moderate pain. Of the 9 children receiving acetaminophen alone, 3 children reported no pain, 2 mild pain, 2 moderate pain, 1 severe pain and 1 very severe pain. Four patients also reported analgesia toxicity including hallucinations, sleepiness, dizziness, nausea, vomiting and euphoria. In general, assessment and management of chemotherapy related pain directs analgesia regimes according to the World Health Organisation analgesic ladder, Figure 2. This regime is recommended by the clock (regular analegesia), by the ladder (adjuvant analgesic agents may be added at any step of the ladder, and by the mouth (oral route is preferred). When prescribing analgesia, in most situations pain is constant and therefore regular analgesia should be given as a background with short acting preparations for sudden onset pain or incident pain (due to anticipated increases in pain severity). If the child is requiring multiple doses of breakthrough analgesia then the background regime should be increased in increments based on the amount of breakthrough required in the preceding 24 hours. The preferred route of administration is oral but other routes are transdermal as patches, parenteral via central venous catheters or subcutaneous administration or rarely epidural administration. The oral route may be avoided if
enteral absorption is in question due to complications such as mucositis. Neuropathic pain such as jaw pain and lower limb pain associated with administration of vinca alkaloids is treated by reducing the dose of vinca alkaloids or omitting the dose and the pain (and neuropathy) diminishes usually. However adjuvant agents may be used to treat this. The pain is typically characterised by altered sensation, and sometimes colour and temperature changes in the overlying skin. There may be paraesthesia, allodynia and hyperalgesia. Adjuvant therapy includes: Tricyclic antidepressants (TCAs) There is wide experience in the use of TCAs including amitriptyline.They may require several weeks to see any benefit and have anti-muscarinic, sympathomimetic side-effects. They should be used with caution in cardiac disease and renal or hepatic impairment. Anticonvulsants Drugs used include gabapentin and carbamazepine. They may be sedating at first and therefore should be started at a low-dose and increased to achieve therapeutic levels. Again these should be used with caution in renal and cardiac impairment. NMDA receptor antagonists
Opioid e.g. Morphine sulphate + or – non-opioid
The emetic potential of common cytotoxic agents LOW
MODERATE
HIGH
Bleomycin Busulphan Etoposide 5-fluorouracil Methotrxate Mercaptopurine Thioguanine vincristine
Amsacrine Carboplatin Cytarabine Daunorubicin Doxorubicin Mitozantrone Ifosfamide
Cisplatin Cyclophosphamide Dactinomycin melphalan
STEP 3 Severe pain Mild opioid e.g. codeine phosphate + or – non-opioid STEP 2 Moderate pain Non-opioid agents e.g. Paracetamol, NSAIDS STEP 1 Mild pain
Table 3
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Figure 2 The World Health Organisation (WHO) analgesic ladder.
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Drugs used include methadone and ketamine.The effects of ketamine are seen more rapidly after administration than with other adjuvants. Ketamine may cause psychomimetic effects such as dreams, hallucinations, delirium. However, this is less likely at lower doses and slow administration. They should be used with caution in cardiac disease. It is recommended that these regimens should be administered with expert advice and support from a pain management team.
taking naps, having distractions like visitors and activities, physical therapy, going outside, keeping busy and blood transfusions as ways of alleviating their fatigue. To successfully manage this symptom a multidisciplinary approach to the recognition, assessment and treatment of fatigue is therefore necessary, addressing the environment where chemotherapy is given, the daily life of the child and minimising other symptoms that may contribute.
Mucositis Ulceration of the oral mucosa (and that of the entire gastrointestinal tract) can cause pain, infection, dysphagia and alteration of nutritional status. Chemotherapy not only affects the rapidly dividing cells of oral mucosa, it also alters the volume of saliva, microbial flora, composition and integrity of the mucosa.It is thought that children have a higher mitotic index of the oral mucosa than adults and therefore there is a greater chance of this side effect from certain chemotherapeutic agents. It is consistently a high ranking issue for children and young people’s reporting of cancer related symptoms. Clinical features include swelling, dry mouth, desquamation of mucosa of gums and palate and dry and cracked lips. Management involves maintenance of meticulous oral hygiene, maintenance of mucosal integrity for as long as possible, prevention of infection, maintenance of oral function and to keep the child as comfortable as possible. Providing information to the child and family about oral hygiene regimes, regular oral assessments and instituting supportive care, analgesia and infection control regimens is vital to minimising this distressing symptom. The nursing team will educate and support the child and family in these tasks and encourage the family to continue with mouthcare regimens after discharge.
Discussion There has been an important change in the perception of symptoms in children, in the last 25 years from being objective indicators of disease state and side effects of treatment, to their being a subjective experience, varying over the cancer journey of the individual. An individual’s symptom experience reflects the impact of the disease and treatment on them and contributes to their quality of life. As such, symptoms not only affect the child for the duration of the illness and treatment, but may be powerful indicators of their expectations and ability to cope. Therefore inadequately managed symptoms may contribute to the perceived negativity of the cancer experience and contribute to overall morbidity. Challenges to effective symptom management include barriers to patients reporting symptoms, inadequate assessment tools for children of all ages, invalid parent proxy reporting and under recognition of symptoms by professionals. However, it is acknowledged that children grow and develop physically, psychologically, cognitively and spiritually even during periods of illness. Therefore symptom management should reflect this developmental diversity in childhood and adolescence. Symptom management requires a systematic approach of assessment, treatment with multidisciplinary management strategies and re-evaluation. Educating the child and family about their illness and providing information about symptoms and self care strategies will help to empower the individuals and encourage partnership in management. This approach may be useful in managing previously under-recognised symptoms such as cancer related fatigue. Management strategies may be pharmacological or nonpharmacological. The risk of side effects with medications should not outweigh their benefits and patients and carers need to be informed prior to commencing the therapy. Although there is limited research to support the benefits of these strategies the advantages of non-pharmacological strategies such as physiotherapy, massage, guided imagery are that they have no side effects of their own and run concurrently with medication management. With expert guidance, the child, family and local professionals can continue these techniques at home. Finally, it is acknowledged that symptoms in childhood cancer will be disease-specific, therapy specific and child specific. Therefore management strategies should reflect all these elements with the aggressive, evidence based approach that there is to curative management. A
Fatigue Woodgate et al’s study of meaning assigned symptoms by children and young people highlighted the graphic nature by which children describe this symptom and equate their life with living in limbo. A 14 year old boy with Hodgkins disease reported ’’There are days when I wake up when I feel like I’ve been hit by a truck.’’ A 10 year old with acute lymphoblastic leukaemia reported, ‘‘You can fall asleep right on the floor, you get in the door and just fall down and sleep.’’ Cancer-related fatigue has been defined by the National Comprehensive Cancer Network as persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning, and can be described in terms or perceived energy, mental capacity and psychological status. There is a developing evidence base for this previously under recognised symptom in children and adolescents. Hockenberry et al’s original study group described fatigue in terms of reducing their level of functioning and feeling ‘‘sad or mad.’’ Gibson et al reported that 56% of health care professionals thought that most or all of their patients experienced moderate cancer related fatigue and 57% of parents reported that their children expressed fatigue at least once a week. Children and adolescents reported treatments such as chemotherapy, being active, pain, sleep patterns and disruptions, having ‘‘low counts,’’ being in a hospital environment and being anxious and fearful as causes for their fatigue. They described
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FURTHER READING Collins JJ, Devine TD, Dick GS, et al. The measurement of symptoms in young children with cancer: the validation of the memorial symptom
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assessment scale in children aged 7e12. J Pain and Symptom Management 2002; 23: 10e6. Gibson F, Mulhall AB, Richardson A et al. A Phenomenologic study of fatigue in adolescents receiving treatment for cancer. Oncology Nursing Forum, 32: 651e660. Lowis SP, Oakhill A. Management of acute complications of therapy. In: Pinkerton CR, Plowman PN, eds. Paediatric oncology. 2nd edn, 1997. Rajapakse CD. Paediatric pain. MIMS Handbook of Pain Management. 5th edn, 2009. Selwood K, Gibson F, Evans M. Side effects of chemotherapy. In: Gibson F, Evans M, eds. Paediatric oncology: acute nursing care, 1999. Williams PD, Schmideskamp J, Ridder EL, et al. Symptom monitoring and dependant care during cancer treatment in children. Cancer Nursing 2006; 29: 188e97.
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Acknowledgements
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I thank Professor Faith Gibson, (Great Ormond Street hospital and Institute of Child health) for critically reviewing the manuscript.
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Cancer symptoms may be related to disease, procedures, treatments such as chemotherapy and the overall experience of cancer. Symptoms during chemotherapy are subjective experiences which are variable over the cancer trajectory and multifactorial, not merely related to side effects of medications. Symptom assessment tools need to be reliable and validated to be appropriate for use in children and young people and parent-proxy reporting should not be disregarded as inaccurate. Symptom management involves anticipation and education of the children and families about symptoms to expect, evaluating the symptom by history-taking, examination and use of appropriate assessment tools, balancing the risks and benefits of treatment to devise a treatment plan and re-evaluation of the plan. Management strategies should include both pharmacological and non-pharmacological techniques. Commonly reported symptoms are nausea and vomiting, fatigue, pain and mucositis.
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