Supportive Care for Children With Cancer Marianne D. van de Wetering and Netteke Y.N. Schouten-van Meeteren In developed countries the survival rate of children with cancer exceeds 75%. Optimal supportive care is necessary to deliver the burdensome treatment protocols. As the intensity of primary treatment has escalated, so have the side effects like myelosuppression and infection. Children who receive aggressive chemotherapy have an approximately 40% chance of experiencing a febrile episode during neutropenia. Patients should be treated with intravenous broad-spectrum antibiotics even if they have been assessed as low risk. There is no proof of the usefulness of special measures concerning food products during neutropenia. In contrast to adults, most children who receive chemotherapy will have a central venous catheter inserted (ⱖ80 –90%). The two most important complications are infections and thrombosis. The Multinational Association of Supportive Care in Cancer (MASCC) guideline in adult oncology is available to prevent and treat nausea and vomiting. In highly emetogenic chemotherapy, the combination of a serotonin receptor antagonist plus a corticosteroid should be used. Pain in children with cancer is mainly therapy- or procedurerelated. As in adults, the stepladder of the World Health Organization (WHO) is used as a guideline for adequate treatment of pain. It is of utmost importance that children receive optimal pain management during the initial procedures. Sedation is performed in many different ways. Palliative care starts with information about the incurability of the disease for parents, the patient, and the professionals involved. Children in palliative care for progressive cancer should be at home as much as possible, even in the terminal phase. The organization of health care and the facilities differ at a national level, so the requirements and choices for optimal care vary by country. Palliative care has to be incorporated into the structural base in the training of pediatricians and pediatric nurses. The first goal of palliative care is to reduce distressing symptoms. During the whole period of palliative care stepwise withdrawal and withholding of treatment options are important issues. The multidisciplinary approach should also span the broad field of psychosocial issues covering both the child’s and the caregiver’s specific psychosocial needs. Continuity of care is also depicted by contacts afterwards during family bereavement. Semin Oncol 38:374-379 © 2011 Elsevier Inc. All rights reserved.
n developed countries the survival rate of children with cancer exceeds 75%. Children can tolerate more intense therapy than adults. Combination chemotherapy, surgery, and/or radiotherapy have improved survival rates. Optimal supportive care is necessary to deliver the burdensome treatment protocols. Eventually 25% of children in developed countries will enter the palliative phase and ultimately die from their disease, while this rate exceeds 70% in developing countries.1,2
Emma Children’s Hospital, Amsterdam, The Netherlands. Address correspondence to Marianne D. van de Wetering, PhD, MMed, FCP(SA), Paediatric Oncologist, Emma Children’s Hospital Amsterdam, Academic Medical Centre, F8-245, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: [email protected]
amc.uva.nl 0270-9295/ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2011.03.006
SUPPORTIVE CARE Infection and Febrile Neutropenia As the intensity of primary treatment has escalated, so have the side effects like myelosuppression and infection. Children who receive aggressive chemotherapy (induction phase of leukemia or lymphoma treatment or any stem cell transplant) have an approximately 40% chance of experiencing a febrile episode during neutropenia. This translates to one episode per 30 days at risk. Approximately 10% to 15% of patients will have a proven bacteremia. Gram-positive organisms now cause up to 70% of proven bacteremias, gram-negative organisms 28%, and fungal infections 2%. Death has been reported in 1% to 3% of febrile neutropenia (FN) episodes in children.3,4 Based on the patient history and initial clinical findings, patients may be assessed as at low or high risk of complications of FN. As yet there is no validated multicenter, multinational risk assessment tool.5 Patients Seminars in Oncology, Vol 38, No 3, June 2011, pp 374-379
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should be treated with intravenous broad spectrum antibiotics even if they have been assessed as low risk. The therapeutic plan should be modified according to clinical response and microbiological findings. Children who are clinically well, lack a significant clinical focus of infection other than upper airway infections, have no positive cultures, and whose fever and neutropenia settle quickly can discontinue antibiotics once they are afebrile for 24 to 48 hours.6 If the child is deteriorating clinically, changing antibiotics and/or adding anerobic cover may be beneficial. Antifungal therapy should be added after 4 to 5 days of persistent fever if there is no other explanation for the elevated temperature. Additional diagnostic evaluations such as early computed tomography of the chest and sinuses, abdominal ultrasound scans, and ophthalmological examination for retinal candidiasis should be considered.7 Careful daily assessment of the neutropenic child is essential.
Prevention of Infection During neutropenia (absolute neutrophil count [ANC] ⬍500 cells/L) one encourages a normal lifestyle where children continue their school life and hobbies. Teachers should be informed about the situation and asked to notify parents when contact with viral infections has taken place (especially varicella or measles in nonimmunized children). There is no proof of the usefulness of special measures concerning food products during neutropenia. It is recommended to avoid raw food, soft cheeses, and “snack foods.” A comparison of cooked and noncooked diets during remission induction therapy for acute myeloid leukemia showed no difference in the two groups in infection severity, time to major infection, or mortality from infection.8 A Cochrane review summarizes the evidence concerning these observations.9 Another way to possibly prevent infection is selective gut decontamination. Oral nonabsorbable and absorbable antibiotics are used to preserve beneficial anaerobic organisms while preventing gut colonization by pathogenic aerobic organisms. Antibiotics are given orally before and during neutropenia if neutropenia is expected to exceed 7 to 10 days duration and to be severe (ANC ⬍100 ⫻ 106/L). Systematic reviews confirm that antibiotic prophylaxis significantly decreases the risk for death from infection compared with placebo or no intervention (relative risk, 0.66 [95% confidence interval, 0.54 – 0.81]).10,11 During intensive chemotherapy in children, antibiotic prophylaxis is recommended before the onset of neutropenia until the ANC is greater than 500 ⫻ 106 /L. Drugs include quinolones or sulfamethaxazole and antifungal agents like flucanozole or liquid itraconazole if the risk for aspergillosis is high.
Central Venous Catheters In contrast to adults, most children who receive chemotherapy will have a central venous catheter inserted (⬎80%–90%) Internal long-term catheters, called port-a-caths, or external long-term catheters, such as the Broviac or Hickmann catheter, are most frequently used. These catheters offer many advantages for administering chemotherapy, blood products, and fluids. Complications related to the long-term use of central venous catheters are minimized by following appropriate protocols for catheter placement, dressing, care, administration of solutions, and monitoring.12 The two most important complications are infections and thrombosis. Infections in central venous catheters occur in approximately 30% of children or in about 2 per 1,000 catheter-days for port-a-caths. In those at high risk (bone marrow transplant patients), these numbers will be larger. Treatment of the infection is successful in more than 80% of documented catheter-related infections. Usually these infections are caused by gram-positive organisms (mainly coagulasenegative staphylococci). Cover for gram-negative organisms is necessary until an organism is identified. Treatment failures result from infections with multiple organisms, fungi, Pseudomonas aeruginosae, resistant gram-negative organisms, and tunnel infections. Thrombosis is less well documented, but it is thought that at least 50% of children experience an episode of occlusion for which an intervention is needed during the duration of the catheter. In this subgroup of children, the catheter should be removed as soon as it is no longer needed. Otherwise, in children with central venous catheters with a proven thrombus, daily subcutaneous low molecular weight heparin should be administered for at least 3 months and anti-Xa levels measured until an adequate value is reached (0.6 –1.0 U/mL).13 Prophylactic anticoagulation in children with central venous catheters is currently not recommended.13
Nausea and Vomiting The Multinational Association of Supportive Care in Cancer (MASCC) guideline in adult oncology is available to prevent and treat nausea and vomiting.14 –16 This guideline cannot automatically be adjusted for children, as no adequate pharmacokinetic trials have been performed. It is important to assess severity with a validated nausea and vomiting tool, such as the Pediatric Nausea Assessment Tool (PENAT) score,17 which is comparable to the Face Pain Rating Scale. In low emetogenic chemotherapy, no antiemetic therapy is needed. Occasionally, agents such as metoclopromide, domperidone, or promethazine can be used. In moderately emetogenic chemotherapy, a serotonin receptor antagonist should be given. If this is ineffective, a cor-
ticosteroid should be added, since the two will work synergistically. In highly emetogenic chemotherapy, the combination of a serotonin receptor antagonist plus a corticosteroid is preferred. In this group of patients, especially those receiving cisplatin, it is recommended to continue to administer one of the antiemetics 72 hours after stopping chemotherapy to prevent delayed emesis.18 It is important to have an aggressive plan at the start of chemotherapy to avoid or minimize initial nausea, and to prevent development of anticipatory nausea and vomiting. If anticipatory vomiting does occur, benzodiazepines are usually effective. Newer agents used in adults such as the 5HT3 receptor antagonists (eg, palanosetron) and NK1 antagonists (eg, aprepitant) offer benefit in both acute and delayed emesis, which is of importance when using highly emetogenic cytotoxic agents. To date, no randomized trials in children have been performed with these new agents, so they are not used routinely.
Pain Pain in children with cancer is mainly therapy- or procedure-related, in contrast to adults, where pain is mainly tumor-related. The first step in managing pain is to accurately assess the pain. In children less than 4 years old, behavioral pain scales—scoring crying, posture, and facial expression—are used. For children over 4 years of age, different validated scales are used, eg, the Faces Pain Rating Scale or the Word Graphic Rating Scale.19,20 It is important that the pain be assessed and documented at regular intervals during the day by child and/or parents or nursing staff, and that appropriate actions are taken based on the score found. As in adults, the stepladder of the World Health Organization (WHO) is used as a guideline for adequate treatment of pain: step 1—paracetamol, acetominophen (oral 15 mg/kg/dose 4 – 6 times per day); step 2—mild opioid (tramadol 1–2 mg/kg/dose 3 times per day) combined with step 1; step 3— opioids (morphine 10 g/kg/h continuous intravenous or subcutaneous administration) combined with step 1. The dose of morphine must be increased until adequate pain control is achieved. If the patient does not achieve adequate pain control, adjuvant therapy should be considered. In pediatric oncology, pain is mostly due to adverse effects of chemotherapy and/or invasive procedures. Children in-hospital most often need continuous strong opioids for less than 1 week, a duration much shorter than that in adults. Adults in out patient care setting receive more pain medication for tumor progression. Children should not suffer, so it is preferred to start too high on the WHO stepladder than to allow the child to endure pain while treatment progresses up the ladder. Since pediatric oncology patients frequently require
M.D. van de Wetering and N.Y.N. Schouten-van Meeteren
invasive, painful procedures, it is of utmost importance that the child receives optimal pain management during the initial procedures. Both pain and anxiety have to be managed to achieve adequate control. In general, one must achieve a relaxed situation in the treatment room where adequate staff will create a calm environment in which the procedure can be performed rapidly and efficiently. Sedation is performed in many different ways. For minor procedures such as venepunctures or access to subcutaneous reservoirs, topical anesthetic cream can be used 1 hour before the procedure. Bone marrow aspirations, trephines, and lumbar punctures are best performed under general anesthetic so that airway patency, breathing, and circulation can be assured. Beyond pharmacologic and medical care one needs to consider nonpharmacologic adjunctive therapy. It is well known that hypnosis, fantasy, art therapy, etc can help relieve anxiety and stress and thus dull the experience of pain.21 Since post-traumatic stress is described in 9% of childhood cancer survivors, especially after more intensive treatment regimens, major efforts should be put into pain management.22
Palliative Care When supportive care for a life-threatening disease like cancer extends into incurable disease, palliative care takes over from supportive care. The WHO definition helps guide the diversity of this care in children: “Palliative care for children is the active total care of the child’s body, mind and spirit, and also involves giving support to the family. It begins when illness is diagnosed, and continues regardless of whether or not a child receives treatment directed at the disease. Health providers must evaluate and alleviate a child’s physical, psychological, and social distress. Effective palliative care requires a broad multidisciplinary approach that includes the family and makes use of available community resources; it can be successfully implemented even if resources are limited. It can be provided in tertiary care facilities, in community health centres and even in children’s homes.”23 This broad vision of palliative care requires sophisticated knowledge, skills, communication, education, and the organization of palliative care in the hospital and beyond.24,25
INFORMATION AND COMMUNICATION Palliative care starts with information about the incurability of the disease for parents, patients, and the professionals involved. The loss of a child is unacceptable for every parent. Honesty about the fatal condition
Supportive care for children with cancer
is important.26 Careful sensitive communication, with the child and parents, and honest information about end-of-life in the palliative phase are considered helpful by parents.27 For parents the process of letting go is strengthened if they perceive the situation of their child realistically. Certainty of death enables them to redefine their parental role, looking primarily at the needs of the child.28 If applicable, parents should be encouraged to communicate with their child about death. Many (27%) regret having avoided the issue, while no regret is seen in those who dealt with it.29
Location of Death and Transmural Teamwork Children in palliative care for progressive cancer should be at home as much as possible, even in the terminal phase. This enables the sick child and the family member to participate in normal life as much as possible. A home care team is a primary prerequisite to fulfil this task.30 Adequate and complete information for the caretakers in the home or hospice situation is crucial. The pediatric oncology team should guarantee continuity of care and knowledge This should be done partly by anticipation of the symptoms and course of disease. The oncologist should provide the home care team with extensive clear anticipatory information at hospital discharge for which standardized formats are advisable.31 This enables the team to be proactive, and think two steps ahead, especially regarding medication management for pain and nausea. The death of a child in home care is an exception for a family physician. Close guidance and contacts from the oncologic specialists should be available constantly. With a well-prepared multidisciplinary approach, most parents become comfortable in the home situation for the final phase of life of their child.32 The organization of health care and the facilities differ at a national level, so the requirements and choices for optimal care vary by country. If the home situation is inadequate, a children’s hospice should be considered.33 In specific circumstances, neither the child nor family benefits from staying at home, so short or even prolonged hospital stays might be preferred. In these cases the hospital room should mimic the home situation as much as possible, and can be prepared with the help of a child life specialist. Private belongings, pictures, bed clothing, curtains, etc should decorate the environment. Pets should be welcomed to the hospital, while more space and liberty for family visits has to be granted.
training in pain management and communication skills, eg, in discussing prognosis, bringing bad news, providing information about code status, and talking with children about end-of-life.34 Palliative care deserves more attention in the training of fellows in pediatric oncology so that they may become adequate coaches for the home care team and parents.35 Structural education in palliative care at a national level is available for nurses to a broader extent via the End-of-Life Nursing Education Consortium–Pediatric Palliative Care (ELNEC-PPC) in the United States, enabling nurses to make a difference in palliative care in their hospital.36 Comprehensive courses for professionals dealing with bereaved parents can educate on important issues such as relations with families, pain and symptom management, ethics, bereavement, and communication issues, and can improve the multidisciplinary approach.37 Comprehensive knowledge is made available worldwide via websites produced and supervised by professionals such as the Association for Children’s Palliative Care (ACT; www.act.org.uk;) in the United Kingdom and the European Association for Palliative Care (EAPC; www.eapcnet.org).
Symptom Management The first goal of palliative care is to reduce distressing symptoms. Minimizing suffering maximizes the possibility of participating in (aspects of) normal life. Common symptoms in terminal cancer are pain, nausea, fatigue, loss of appetite, sleeping disorders, and neurologic symptoms.24,38,39 Differences in underlying diseases (ie, leukemia, bone tumor, or brain tumor) lead to a different spectrum of symptoms in the palliative phase. The treatment might also differ based on individual characteristics of the child, eg, earlier experience of symptoms, age of the child, adverse drug reactions, availability of oral and/or intravenous routes of administration, stage of disease, etc. Each child’s disease has its unique course, requiring professional creativeness to address symptoms and complaints. Many care providers (including parents) are involved in the care process of one child. Well-defined assessments and scales, especially for pain, are mandatory in the treatment of symptoms. Extensive knowledge and experience in palliative care are important in a systematic approach for symptom management. Additional knowledge can best be found in extensive and specialized handbooks.40 Research in palliative care is increasing. It is recommended to work actively with parents and professionals accompanying the dying, with benefit from participatory research.41
Education Palliative care has to be incorporated in the structural base in the training of pediatricians and pediatric nurses. A lack of knowledge of palliative care is reflected by pediatric residents wishing to receive more
Restrictions in Treatment During the whole period of palliative care stepwise withdrawal or withholding of treatment options are important issues. This is especially true when the burden of
the intervention for the child exceeds its benefit.42 The limits of treatment and the inevitability of death should be completely clear. It is important to guide parents (and sometimes children) in these discussions and decisions and prevent avoidance.28 Treatment restrictions that might be discussed concern discontinuation of regular anticancer treatment, participation in phase I/II trials, omission of diagnostic interventions, stopping transfusions or antibiotics, avoiding admittance to the intensive care unit, and no resuscitation orders. These treatment restrictions are most difficult for the parents over the course of disease.43 Parents and/or care providers may consider withholding fluids and nutrition in terminal illness. When artificial fluids and/or nutrition do not serve the goal of promoting comfort, they might prolong suffering and the dying process. The option of withdrawal of fluids should be considered and explained carefully to the parents. The multidisciplinary approach should also span the broad field of psychosocial issues covering both the child’s and caregiver’s specific psychosocial needs. This is described (for all ages) in the recent MASCC position statement.44 In the unique situation of each child and family, different cultures and religions deserve specific attention when discussing end-of-life issues with the child and parents, since habits and spiritual needs differ from among religions.45
After the Death of a Child Although the responsibility for adequate care for the child has finished with the child’s death, continuity of care is also depicted by contacts afterwards during family bereavement. Examples are letters, telephone contacts, visiting the memorial service or the funeral, meeting with parents, sending remembrance cards at the birthday and day of death of the child, and many other possibilities. This part of palliative care is appreciated by parents and professionals.46,47 Ultimately, this type of aftercare is a reflection of the attention to the family system in pediatric palliative care.
SUMMARY Optimal care for children with cancer and their families is a challenge. It deserves a holistic, multidisciplinary approach from dedicated, creative professionals in the hospital and in home care.48
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