Cancer in Children: Clinical Management, 5th Edition

Chapter 8. Supportive care during treatment

Marianne van de Wetering

Introduction

Supportive care of the paediatric cancer patient has played an increasingly important role in the management of these critically ill patients. As intensity of primary treatment has escalated so have the side effects such as myelosuppression and infection.1

Supportive care has become more than supportive in the role that it has come to play to improve the survival of children and adolescents with cancer. Surgery, radiotherapy, and chemotherapy have led to improvement in survival, but this could not have happened without adequate supportive care.2

Prevention of infection

Children receiving treatment for cancer are at increased risk of infection from bacterial, viral, protozoal, and fungal agents. A number of strategies can be applied to reduce the risk of infections.

The environment

If the patient is neutropenic [absolute neutrophil count (ANC) < 500 cells/mm3] there is an increased risk of acquiring nosocomial infections; it is best to stay away from the hospital-environment. One tries to encourage a normal lifestyle where children continue their school life and hobbies. Teachers should be informed of the situation and asked to tell the parents when contact with viral infections such as varicella or measles has taken place.

The hospital environment

If hospital admission is necessary in a neutropenic phase, these patients will be cared for in single rooms. Handwashing is the most essential preventative measure (in the literature handwashing has consistently been shown to prevent the spread of infection). Contact with people with an active infection should be avoided.

Nutrition and diet

There is no proof of the utility of special measures concerning food products during neutropenia (ANC < 500 cells/mm3), but it is recommended not to eat raw food, soft cheeses, and ‘snack foods’. A healthy diet is important for normal growth of the child and to maintain a healthy immune system.

Invasive procedures

During neutropenia any procedure that can disrupt the normal mucosa or skin barriers (such as dental procedures) should be avoided. Inserting a central venous catheter in children with neutropenia is best done under antibiotic cover.2

Selective gut decontamination

Oral non-absorbable and absorbable antibiotics are used to preserve beneficial anaerobic organisms while preventing colonization of the gut by pathogenic aerobic organisms. Usually the combination trimethoprim–sulfamethoxazole (TMP–SMZ) is used. A systematic review pooling data from 56 articles3 has clearly shown that selective decontamination of the gut is effective in preventing bacteraemia (mainly Gram-negative bacteraemia) during neutropenic episodes. Quinolones are slightly more effective than TMP–SMZ. Newer studies combining quinolones or TMP–SMZ with erythromycin or roxithromycin to decrease Gram-positive bacteraemias have not been shown to give a significant reduction. Based on this systematic review and two other published systematic reviews4,5 it is recommended that selective gut decontamination should be started 5 days before the expected neutropenia and continued until ANC > 500/mm3.

Fungal prophylaxis

Trials of antifungal prophylaxis have yielded mixed results.6,7 Evidence was found that oral candidiasis is reduced using drugs that are partially or fully absorbed from the intestinal tract. The partially absorbed drugs (miconazole and clotrimazole) have a better effect than the fully absorbed drugs (fluconazole, itroconazole, ketoconazole) or those that are not absorbed (nystatin, amphotericin, nystatin plus chlorhexidene). Bow et al5 performed a meta-analysis which included study regimens using azoles (fluconazole, itraconazole, ketoconazole, and miconazole) or polyenes (intravenous low-dose amphotericin B or the lipid-based formula of amphotericin B), and control regimens. Prophylaxis reduced the use of parenteral antifungal therapy (number needed to treat (NNT = 10). Furthermore, there was a reduction of superficial fungal infection (NNT= 12) and mortality related to fungal infection (NNT = 52). Overall mortality and the incidence of aspergillosis were unaffected. Antifungal prophylaxis has measurable benefits for patients receiving high-dose chemotherapy, patients undergoing induction therapy for haematologic malignancies, and patients who areexpected to have prolonged episodes of neutropenia.

Prevention of Pneumocystis carinii pneumonia

Studies by Hughes et al8 have clearly demonstrated that TMP–SMZ is highly effective in preventing Pneumocystis carinii pneumonia (PCP). All patients with leukaemia, lymphoma, or BMT (allogeneic or autologous) receive prophylaxis. Children with solid tumours who are expected to have prolonged episodes of neutropenia are also advised to use TMP–SMZ as prophylaxis. An alternative to this prophylaxis is aerosolized pentamidine. This has been shown to be effective within the group of HIV patients, but no large studies have been done in oncology patients. Aerosolized pentamidine must be given every 4 weeks.9,10

Treatment of infection in children with cancer

The frequency and severity of infection that occurs in the cancer patient depends on a complex interaction of a number of factors of which granulocytopenia is the most important. This is defined as ANC < 500 cells/mm3. The frequency and severity of infections increase as ANC drops below 100 cells/mm3. The duration of neutropenia influences the outcome of the infectious episode. Patients with neutropenia for <7 days had a 95 per cent response rate to initial antibiotic therapy compared with a 35 per cent response rate in patients with neutropenia for >15 days.11,12,13 Incidence of infection in neutropenic patients is about 10–15 per cent.

The management of febrile neutropenic children with cancer differs because of institutional variations in the spectrum of infections, antimicrobial susceptibility patterns of pathogenic microorganisms, and the underlying aetiology of the neutropenia. The pattern of infective pathogens has changed significantly over time.

Gram-positive organisms are isolated in 15 per cent of febrile episodes and cause 60 per cent of proven bacteraemia, while fungal infections are documented in 2 per cent of all bloodstream infections. Poor outcome has been reported in 7–10 per cent of patients.11,14 The coagulase-negative staphylococci are the most common Gram-positive organisms, and enterococcal and viridans group streptococcal species are becoming problematic because of increasing antibiotic resistance. The most common Gram-negative organisms are Escherichia coliKlebsiella spp, Serratia spp, Proteus spp, and Pseudomonas aeruginosa. Other serious infections emerge with more intensive chemotherapeutic protocols and bone marrow transplantation because of the prolonged severe neutropenia. Infections with fungal organisms such as Candida species, Aspergillus species, or other opportunistic fungi occur.

In these patients fever is defined as a single temperature >38.3°C, or a temperature >38°C for >1 h. In the management the clinician is directed to careful and repeated evaluation of specific signs and symptoms of a focus or type of infection. Lack of neutrophils leads to minimal signs of inflammation at the site of infection. A thorough physical examination is needed, including emphasis on the mucosal membranes, the lungs, the soft tissues, and the central venous catheter.

Laboratory evaluation should include a complete blood count, liver enzymes, renal function, and blood culture (if a central venous catheter is present, a culture should be taken from this). Urine culture, stool culture, and testing for Clostridium toxin should only be done if indicated. Routine culture of the cerebrospinal fluid is not recommended unless signs or symptoms of meningitis are present. Chest radiography will only be performed when signs are present which lead to the suspicion that there will be changes on the chest radiograph.

Initial antibiotic therapy

Because the progression of infection in neutropenic patients can be rapid and such patients with early bacterial infections cannot be reliably distinguished from non-infected patients at presentation, empirical antibiotic therapy should be started promptly. The initial goal is to provide broad-spectrum antimicrobial cover for both Gram-negative and Gram-positive organisms. This has generally been achieved by offering a combination of antibiotics, such as a cephalosporin and an aminoglycoside. Monotherapy in the form of carbapenem or meropenem is a reasonable alternative.

Modification of treatment

The therapeutic plan should be reassessed after 3–5 days. If the patient has become afebrile within this period and has a positive blood culture, optimal cover should be provided for that organism but broad-spectrum antibiotic cover should be maintained to prevent breakthrough bacteraemia. Antibiotic treatment should be continued for a minimum of 7 days or until the organism is eradicated. It is not necessary to continue until the neutrophils recover. A group of children can be defined who lack signs of infection, who are afebrile for >48 h, who have ANC > 100 cells/mm3, absolute monocyte count > 100 cells/mm3, and C-reactive protein (CRP) < 90 ng/l, and who are at low risk for complications; these children can have their intravenous treatment stopped after 3 days and oral antibiotics continued (oral cefixime) until day 7.15 Riskbased therapy has not yet been validated for children. If the patient has persistent fever after 3–5 days of treatment, a careful reassessment should be performed with additional diagnostic tests such as an abdominal ultrasound scan and chest radiograph looking for a focus. If neutrophils are recovering and the child is not septic, the same antibiotics can be continued despite the continuing fever. The second option is to change antibiotics to target anaerobes, P.aeruginosa, or other organisms not covered by the original protocol. The third option is to add antifungal agents, especially if one expects neutropenia to be prolonged. The fourth option of stopping all antibiotics on the grounds that fever may be due to the medication as such is not recommended by the CDC guidelines. A summary is given in Figure 8.1.

Treatment of central venous catheter infections

Complications related to the long-term use of central venous catheters are minimized by recommended protocols for catheter placement, dressing, care, administration of solutions, and monitoring.16Infectious complications are those that result in infection of the blood-stream and/or device, the subcutaneous pocket, the tunnel, or the exit site. The overall incidence of catheter-related infections is approximately 2 per 1000 catheter days.17 Treatment of the infected catheter can be successful in more than 80 per cent of documented catheter-related infections. Usually these infections are caused by Gram-positive organisms (mainly coagulase-negative staphylococci). Cover for Gram-negative organisms is necessary until an organism is identified. Treatment failures result from infections with multiple organisms, fungi, P. aeruginosa, resistant Gram-negative organisms, and tunnel infections.

In the case of a Staphylococcus aureus infection, the treatment should be administered for at least 2–3 weeks if the catheter is left in place as S.aureus is associated with a late complication rate of 6.1 per cent. If the catheter is left in place, systemic antibiotics should be administered through the catheter. Cycling antibiotics through each lumen or placing concentrated antibiotics within the locked catheter hub (antibiotic-lock technique)18 are not widely validated yet, and so cannot be recommended. If antibiotic-lock therapy is given, systemic therapy should be used as well.18

Treatment of fever without neutropenia

Good evaluation and physical examination is an absolute necessity. Laboratory evaluation will include a blood count, CRP, and blood culture from the central venous catheter. If there is no central venous catheter, one can wait for the blood culture result before starting antibiotics. If a central venous catheter is present, antibiotics (e.g. amoxicillin or augmentin) can be given orally until the blood culture result is known.

Antiviral drugs

Because of the increased use of high-dose chemotherapy, cellular immunity can be depressed and therefore the chance of acquiring viral infections is increased. The most common viral pathogens affecting the immunocompromised child are the herpesviruses including herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), and Epstein–Barr virus (EBV).

Fig. 8.1 Treatment of fever in neutropenia.

Herpesviruses can result in mucosal lesions, skin lesions, and neurologic symptoms. Systemic treatment with aciclovir is needed at a dose of 750 mg/m2/day divided in three doses intravenously for at least 5 days.

Primary infection with VZV results in chickenpox. In the immunocompromised, severe complications can be seen leading to a fulminating illness with visceral dissemination of the virus. Untreated VZV pneumonitis can be fatal in up to 7 per cent of affected children. Treatment should be systemic with aciclovir or the newer oral drugs such as famciclovir or valaciclovir which show a better oral absorption than aciclovir.

Cytomegalovirus (CMV) can result in fever, rash, hepatosplenomegaly, pneumonia, neurologic symptoms, and retinitis. Treatment is with ganciclovir 10 mg/kg/day in two divided doses intravenously or foscarnet. Prolonged courses of therapy are necessary to eradicate the infection.

Respiratory syncytial virus may have a prolonged and more complicated course. Ribavarin may offer therapeutic benefit. Adenovirus is a particular cause of morbidity and sometimes mortality in patients undergoing bone marrow or stem cell transplantation. Therapy is largely supportive.

Haematopoietic colony-stimulating factors

To determine the need for primary administration of colony-stimulating factors (CSFs), it is necessary to decide whether the risk of neutropenia associated with a particular chemotherapy regimen warrants their use.20 Primary use of CSFs should be reserved for patients expected to have a risk of >40 per cent of experiencing febrile neutropenia. Most children are enrolled in international protocols and the use of CSF will be embedded in the protocol. Secondary prophylactic CSF administration is allowed if previous episodes of neutropenia have led to severe infections or delay or dose reduction of chemotherapy. Again, this is delineated in most paediatric protocols. The recommended CSF dose is 5µg/kg/day either subcutaneously or intravenously, although pharmacokinetic analysis favours subcutaneous administration. The available data suggest that rounding the dose to the nearest vial size may enhance patient convenience and reduce costs without clinical detriment. Clinical data suggest that CSF should be started 24–72 h after chemotherapy and continued until the neutrophil count is > 1000/mm3 on two occasions. A higher dose of granulocyte colony-stimulating factor has not been recommended because it has not been associated with improved clinical benefit. One exception is in the setting of peripheral blood progenitor cell mobilization where a dose of 10µg/kg/day has resulted in improved mobilization.21 Generally, children do not have any side effects from these CSFs. Occasionally a influenza-like illness can be seen, with fever, bone pain, and malaise. Laboratory investigations may show a rise in uric acid, lactate dehydrogenase, and alkaline phosphatase.

Anti-emetics

Nausea and vomiting remain an important concern in cancer treatment. In addition to an adequate pharmacological approach, other techniques, such as relaxation, distraction, and explanation of the procedures, should not be forgotten. Adequate control is usually achieved with the treatment given nowadays. Chemotherapeutic agents are grouped in three classes: low emetogenic (<10 per cent of patients experience nausea and vomiting), moderately emetogenic (50 per cent of patients experience nausea and vomiting), and highly emetogenic (100 per cent of patients experience nausea and vomiting). Medication isadjusted to the degree of emetogenecity.

In low emetogenic chemotherapy, no anti-emetic therapy is needed. Occasionally, agents such as metoclopromide, domperidone, or promethazine can be used. In moderately emetogenic chemotherapy, a serotonin receptor antagonist (usually ondansetron) should be used. If this is not effective alone, corticosteroids should be added. Both drugs will work synergistically. In highly emetogenic chemotherapy, the combination of a serotonin receptor antagonist plus steroids should be used. In this group it is recommended that one of the antiemetics is continued for 72 h after stopping the chemotherapy (to prevent delayed emesis). A summary of anti-emetics is given in Table 8.1.

It is very important to attempt an aggressive plan at the start of therapy to avoid or minimize the initial experience of nausea, since there is a greater chance of preventing the development of anticipatory nausea and vomiting. If anticipatory vomiting does occur, benzodiazepines are usually effective.

Table 8.1. Anti-emetic agents

Emetogenic potential

Drug

Anti-emetic therapy

Delayed emesis

Low

Bleomycin
Busulfan oral
Steroids
Fludarabine
Hydroxyurea
Interferon
Melfalan oral
Mercaptopurine
Methotrexate < 50 mg/m2
Thioguanine
Vinblastine
Vincristine

None
OR
Domperidone 0.3 mg/kg
oral 4 times daily
OR
Promethazine
0.5 mg/kg 4 times daily

None

Moderate

Asparaginase
Cytarabine < 1 g/m2
Doxorubicin
Etoposide
Fluouracil < 1000 mg/m2
Gemcitabine
Methotrexate < 1 g/m2
Thiotepa
Topotecan
Cyclofosfamide < 750 mg/m2
Actinomycin
Epirubicin
Idarubicin
Mitoxantrone < 15 mg/m2

Ondansetron
15 mg/m2
3 times daily
OR
Dexamethasone
5mg/m2
3 times daily

None

High

Carboplatin
Carmustine
Cisplatin
Cyclofosfamide < 750 mg/m
Cytarabine < 1 g/m2
Actinomycin
Doxorubicin < 60 mg/m2
Irinotecan
Melfalan (i.v.)
Methotrexate < 1 g/m2
Mitoxantrone < 15 mg/m2
Procarbazine

Ondansetron plus dexamethasone

Continue ondansetron for 72 h after stopping chemotherapy

Newer agents have led to revised anti-emetic guidelines for adults. New serotonin antagonists (palanosetron) and NK-1 antagonists (aprepitant) have improved the effect on both acute and delayed emesis, which is of importance in the high emetogenic group of cytotoxic agents. To date no randomized trials in children have been performed with these new agents.

Radiotherapy can also lead to nausea and vomiting. Therefore it is recommended that a serotonin-receptor antagonist is given about 30 min before the start of radiotherapy.

Obviously the above guidelines are based on the best available evidence. However, discomfort associated with nausea and vomiting is a very subjective experience and therefore treatment should be individualized, allowing the opinions of patients and parents to influence anti-emetic regimens with subsequent courses.22

Pain management

Pain in children with cancer may be associated with the diagnosis itself (e.g. bone metastases in children with stage IV neuroblastoma), the treatment (e.g. mucositis during neutropenic episodes), or the procedures that have to be performed (e.g. lumbar puncture, bone marrow aspiration).

The first step in managing pain is to assess its presence accurately. In children <4 years old, the assessment relies on behavioural pain scales, where crying, posture, and facial expression are used to assess pain. Different validated scales are used for children >4 years of age; these include the faces pain rating scale and the word graphic rating scale. It is extremely important that the pain is assessed at regular intervals over the day by parents or nursing staff and the score found is acted on.

Treatment of pain caused by the disease itself or the treatment

The World Health Organization stepladder23,24 is used as a guideline for adequate treatment of pain (Table 8.2). Its recommendations are as follows

·  Step 1: acetominophen.

·  Step 2: mild opioid (tramadol) combined with step 1.

·  Step 3: opioids (morphine 10µg/kg/h continuous i.v. or s.c.) 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 with the above stepwise approach, adjuvant therapy should be considered (Table 8.3).

Treatment of pain associated with diagnostic procedures

The main goal during paediatric procedures is to make the child comfortable so that the child and parents will not dread the subsequent procedures. Both pain and anxiety have to be managed to achieve adequate control. In general one must achieve a situation in the treatment room where adequate staff will create a calm environment so that the procedure can be performed rapidly and efficiently.

Sedation is performed in many different ways. The American Academy of Pediatrics25 and the American Society of Anesthesiology26 have published guidelines, but these must be individualized to the particular situation for that specific child.

1.   For minor procedures such as venepuntures or access to subcutaneous reservoirs, topical anaesthetic cream (Emla1) can be used an hour before the procedure.

 

2.   For procedures such as bone marrow puncture, conscious sedation can be given. Usually this will consist of midazolam (Versed1) 0.15–0.03 mg/kg rectally 15 min before the procedure or 0.05 mg/kg/i.v. slowly. If the i.v. route is followed, trained anaesthetic personnel should be available as midazolam can produce respiratory depression.

3.   Procedures such as bone marrow trephine are always performed under general anaesthesia where airway patency, breathing, and circulation can be assured.

Table 8.2. Pain management

Medication

Dose

Remarks

Step 1

Acetaminophen (paracetamol)

Oral 15 mg/kg 4–6times daily
Supplementary 20–30 mg/kg
2–4 times daily

Maximum 4000 mg/day

Naproxen (NSAID)
Diclofenac

5 mg/kg 2–3 times daily
1–2 mg/kg 3 times daily

Beware of thrombocytopathy

Step 2
Continue step 1

Tramadol

>1 year: 1–2 mg/kg
3–4 times daily

Maximum 400 mg/day
Weak opioid

Step 3
Continue step 1

Morphine solution

0.1–0.3 mg/kg 4–6 times daily

Antagonist: naloxon

Morphine supplement

0.2–0.4 mg/kg 4–6 times daily

0.1 mg/kg i.v. or i.m.

Morphine i.v.

Starting dose 0.01–0.03 mg/kg/h or 0.25 mg/kg/24 h

 

Morphine i.v. (PCA)

Bolus: 0.02 mg/kg/10 min
Infusion: 0.005 mg/kg/h

 

Fentanyl patch: 25, 50,
75 and 100 µg/h

Transdermal, change every 72 h
Dose: morphine 90 mg oral
equivalent to fentanyl 25 µg/h

Need immediate effect medication first

NSAID, non-steroidal anti-inflammatory drug; PCA, patient-controlled analgesia.
Care has been taken to ensure that the doses are accurate, but the reader should check these carefully.
Readers should also refer to other texts and experienced paediatric pharmacists for further drugs, indications and side
effects.

Table 8.3. Adjuvant pharmacological therapy

Drug group

Examples

Dose

Indication

Anxiolytics

Diazepam
Oxazepam

0.1–0.2 mg/kg 3–4 times daily
< 6 years 2.5–10 mg 3–4 times daily
> 6 years 2.5–15 mg 3–4 times daily

Muscle relaxant

Sedatives

Nitrazepam
Temazepam

1-6 years 2.5-5 mg once daily
>6 years 5 mg once daily
10–20 mg once daily

 

Antidepressants

Amitriptyline

Start does 0.2-0.5 mg/kg in
2 divided doses; dose can
be increased to 3 mg/kg/day

Neuropathic pain

Antiepileptics

Carbamazepine
Rivotril

1.5–3 mg/kg; increase to
2.5–5 mg/kg 2–4 times daily

Neuropathic pain and
phantom pain

Steroids

Prednisone
Dexamethasone

1 mg/kg/day
10 mg/m2/day

Raised intracranial pressure,
brain tumours, severe
end-stage tumours

Blood product transfusion

Not only neutropenia but also anaemia and thrombocytopenia can occur as a consequence of chemotherapy or the oncological disorder itself.

Red cell transfusion

It is not necessary to increase the haemoglobin concentration to normal levels. There is no evidence-based level at which transfusion should be carried out, but most centers choose a level of < 4.0 mmol/l (6.5 g/dl) at which to administer red blood cells. If the child is septic or has cardiopulmonary problems, a level of <6.0 mmol/l (9.5 g/dl) is used, and with radiotherapy an even higher level of 7.0 mmol/l (11.5 g/dl) is maintained because of the need for adequate oxygenation during radiotherapy.1,27 The amount given is 10–15 ml/kg packed red cells in 4–6 h. The product used is leucodepleted (7-log depletion of the number of leucocytes). In this way the chance of HLA sensitization and of infection with prions and cytomegalovirus decreases. The risk of transfusion-related graft-versus-host disease from donor lymphocytes is so small that there is no need to irradiate blood products. The use of irradiated products is only necessary before and after bone marrow transplant until lymphocyte immunity has recovered (6 months after transplant) in the case of severe combined immunodeficiencies and in neonates.28

To decrease the need for red blood cell transfusions, erythropoetin (erythropoetic stem cell factor) has been used in trials but is not yet registered for use in children with cancer. First results from randomized controlled trials show that erythropoetin reduces the number of red blood cell transfusions and keeps the mean haemoglobin at a higher level, especially in haematological malignancies.29

Platelet transfusions

As a general rule platelet transfusions are indicated if the patient is actively bleeding. Prophylactic platelet transfusions are indicated in septic patients, patients with a known bleeding disorder, and patients undergoing an invasive procedure such as placement of a central venous catheter or lumbar puncture. There is little evidence about the appropriate level for transfusion. In patients with sepsis platelets are kept > 15 109/liter and for placement of a catheter or lumbar puncture the level will be kept > 50 109/liter.30,31 The quantity of platelets transfused is 1 unit/10 kg. Repeated transfusions may lead to allo-immunization, reducing the therapeutic effect of transfused platelets. One can then use single-donor transfusions.

Tumour lysis syndrome

Tumour lysis syndrome (TLS) is a set of complications that can arise from treatment of rapidly proliferating and drug-sensitive neoplasms, mostly haematologic malignancies although it has also been shown in solid tumours. Chemotherapy causes rapid destruction of tumour cells leading to release of intracellular substances into the bloodstream. Metabolic disturbances include hyperuricaemia, hyperphosphataemia, hypocalcaemia, and hyperkalaemia. As a consequence both uric acid crystals and calcium phosphate salts can be formed, precipitating renal failure for which dialysis may be necessary. The primary treatment so far has been allopurinol combined with alkaline hyperhydration. By administering sodium bicarbonate, uric acid can be kept ionized to prevent crystallization in the renal tubules. Allopurinol decreases uric acid production and increases hypoxanthine and xanthine, precursors of uric acid which have a higher solubility in alkaline urine. Since there is pre-existing uric acid and allopurinol cannot break down uric acid, 2–3 days are generally necessary for uric acid levels to decrease after initiation of allopurinol treatment. Clinical trials have now been completed using urate oxidase Uricozyme1 or the recombinant form rasburicase (Fasturtec1 in Europe and Elitek1 in the USA). The primary function of urate oxidase is to catalyse conversion of uric acid to allantoin which is water soluble. Alkalinization is then not necessary, thus facilitating phosphorus excretion. It has been shown that urate oxidase decreased uric acid levels to a greater extent than allopurinol, and the drop in uric acid occurred within 4 h of administration. It is advisable to administer urate oxidase to those patients in whom the risk of TLS is high (Burkitt lymphoma, B-cell leukaemia and haematologic malignancies with a high white cell count). In a randomized prospective multicenter trial it was shown that the risk of developing renal complications requiring dialysis in patients treated with rasburicase was 0.4 per cent. Therefore this is the drug of choice for high-risk groups32 (Fig. 8.2).

Vaccinations

Recommendations on vaccination during chemotherapy33 state that killed or inactivated vaccines do not represent a danger to the immunocompromised host, and as a general rule live attenuated vaccines should be administered at least 6 months after stopping chemotherapy. However, it is well known that the immunogenic response to vaccinations is decreased during chemotherapy. This immunogenic response is not zero, which makes it possible to vaccinate with certain vaccines, especially in areas where herd immunity is low. Certain conditions should be met and these include an adequate number of lymphocytes (> 1000 109/liter), an adequate number of granulocytes (> 1000 109/liter), and no use of dexamethasone 14 days before and 1 week after vaccination.

Fig. 8.2 Products of tumour lysis and their disposal.

Measles–mumps–rubella (MMR) vaccine should not be administered to severely immunocompromised patients, but if herd immunity for measles is low, single-antigen measles vaccine should be given with the understanding that this should be repeated after stopping chemotherapy. Oral polio vaccine (OPV) should be avoided in immunocompromised patients and even in household contacts. Enhanced inactivated polio vaccine (eIPV) is recommended in these household contacts and can be given to the immunocompromised patient. It is safe and can confer some degree of protection. Diphtheria–tetanus–pertussis (DTP) can be administered to the immunocompromised, including the use of acellular pertussis containing vaccines (DtaP). Haemophilus influenzae b conjugate vaccine (Hib) should be administered in those situations where the risk of H.influenzae type b is high and in persons with anatomical or functional asplenia or additional sickle cell anaemia. Hepatitis B vaccination should ideally be given after stopping chemotherapy, but in high-risk groups or areas it can be given to the immunocompromised with a lesser immunogenic response. The vaccine advised under these conditions is Recombivax HB 40µg/ml. Periodic booster doses are usually necessary following successful immunization, with the timing determined by serologic testing at 12-month intervals.

Special vaccinations during chemotherapy

1.   Influenza vaccination. A systematic review emphasizing the paucity of data on this vaccine has been published.34 Serological responses are generally lower than expected in healthy controls. Antibody levels considered protective in healthy individuals may not prevent clinical infection in those with malignant disease. There are no data on protection from clinical infection. The vaccine is well tolerated and therefore it is not contraindicated, but there is no evidence that an adequate degree of protection is achieved.

2.   Varicella zoster vaccination. As more complications of varicella zoster infection are seen in immunocompromised patients, it would be of great benefit if oncological patients with no detectable antibodies to VZV could receive the vaccine and seroconvert. In the USA, 575 children with leukaemia in remission were immunized in the Varicella Vaccine Collaborative Study.35 All children were in continuous remission for >1 year and had > 700/mm3 circulating lymphocytes. Most children stopped chemotherapy for 1 week before and after immunization. It was recommended that steroids were not given for 2 weeks after the immunization. The varicella vaccine was safe, immunogenic, and effective. The major adverse reaction was a varicelliform rash, which in most cases could be treated with oral aciclovir. Seroconversion to VZV occurred in 82 per cent of vaccinees after one dose and in 95 per cent after two doses. In addition, the incidence of clinical reactivation in vaccinated children was lower than in unvaccinated leukaemic children. Varicella vaccine administered under these conditions is extremely beneficial to the leukaemic patient.

3.   Pneumococcal vaccine. This is recommended for use in patients >2 years of age with increased risk of pneumococcal disease, such as those with splenic dysfunction, anatomical asplenia, or Hodgkin disease, or after radiotherapy to the spleen.

It must be realized that the above are recommendations for vaccination during chemotherapy (Table 8.4). Those patients who have undergone an allogeneic or autologous bone marrow transplant need to be revaccinated with DTP, HiB, and MMR. This must be started 1 year after transplant and the immunogenic response should be measured.

Table 8.4. Vaccination recommendations during and after chemotherapy

Time related to chemotherapy

Vaccination

Recommendation

During chemotherapy

MMR

Low herd immunity then single Ag–measles vaccine

OPV

Not allowed; if needed use eIPV

DTP

Preferable to wait until after stopping chemotherapy

Hepatitis B

If needed, DTaP; high-risk areas, Recombivax HB

Special vaccinations

Influenza vaccine

Not contraindicated during chemotherapy
Degree of protection low
No evidence-based recommendation

Varicella zoster

Safe and immunogenic in maintenance chemotherapy
Not registered yet for use in children with cancer

Pneumococcal vaccine

Splenic dysfunction, Hodgkin, post-radiotherapy
(radiation spleen)

After chemotherapy

DTP, MMR, HiB

Restart schedule 6 months after stopping chemotherapy

MMR, measles–mumps–rubella vaccine; OPV, oral polio vaccine; eIPV, enhanced inactivated polio vaccine; DTP, diph–
theria–tetanus–pertussis vaccine; DTaP, diphtheria–tetanus–acellular-pertussis vaccine; HiB, Haemophilus influenzae B
conjugate vaccine.
*Table does not apply to children undergoing an autologous or allogenic BMT

References

1. Ritchey AK (1996) The Pediatric Oncology Group: Supportive Care Manual. London: SmithKline Beecham.

2. van de Wetering MD, van Woensel JBM (2003). Prophylactic antibiotics for preventing early central venous catheter Gram positive infections in oncology patients. Cochrane Database Syst Rev (2), CD003295.

3. van de Wetering M, Dewitte M, Kremer L, Offringer M, Scholten R, Caron H (2005). Efficacy of profylactic oral antibiotics in neutropenic afebrile oncology patients: Systematic review of randomised controlled trials. Eur J of Cancer (in press).

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