Oncology

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Chapter 14 Oncology

Long Case

Oncology

The oncology long case provides an opportunity for a general paediatrician to display competence in assessing and managing a child with cancer, and his or her family, both within multiple contexts: the domestic situation, schooling requirements, wider social relationships and within the medical framework. The medical needs reflect the multi-layered levels of care required for the patient and delivered by the general practitioner, the general paediatrician, the paediatric oncologist and other consultants whose help may be required from time to time.

The general paediatrician (the candidate) should be able to demonstrate that he or she can competently handle the medical aspects of a child with cancer as well as the complex professional interrelationships that are involved in coordinating care. The candidate should also be familiar with any recent advances that could affect the management of the patient, which requires a close relationship with the treating oncologist.

The last few years have seen many advances in most areas of paediatric oncology, including a more detailed understanding of the genetic basis of cancer, the development of disease specific investigations and an expansion of disease classifications. For example, acute myeloid leukaemia (AML) is now regarded as a group of related but biologically distinct diseases. This has led to specific treatments being developed for specific subtypes of AML. Advances in paediatric oncology have led to the recognition that prognosis and relapse risk for patients can be better defined by use of multiple molecular biology techniques, such as the use of very sensitive methods to detect cancer-specific genetic changes, which are used to detect minimal residual disease (MRD) burden after therapy. In addition, advances have led to a better understanding of the interacting abnormal genetic and mechanisms that are responsible at a molecular level for the pathogenesis of neoplasms.

Haematopoietic stem cell transplantation (HSCT) now has an expanded set of indications for malignant diseases, including various subgroups of patients with acute lymphoblastic leukaemia (ALL), AML and myelodysplasia.

Of great importance is the role of medical practitioners to provide long-term sensitive surveillance and follow-up. A web-based comprehensive set of guidelines for management of such survivors, the Children’s Oncology Group (COG) Long-term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, can be found at www.survivorshipguidelines.org. Both these initiatives have expanded the literature significantly and are very useful to many candidates.

In Australia and New Zealand, all major paediatric centres are members of the US-based Children’s Oncology Group (COG), a consortium of childhood cancer centres that promotes clinical and laboratory research trials in paediatric oncology.

The general principles of care are similar for patients with haematological malignancies, solid tumours or brain tumours.

An approach to any oncology long case could potentially fit into the following scheme.

History: an overview

At the outset of the interview, it is important to identify clearly the primary and secondary diagnoses, as well as important historical landmarks such as the date of diagnosis, the date of completion of therapy, the history of relapse, or major secondary events such as significant sequelae of therapy (e.g. endocrinopathies or second tumours). Spend your time wisely and carefully in the interview. Limit yourself to about 1–3 minutes to synthesise an overview of the child’s condition and focus on gathering data relevant to the presentation. Parents of oncology patients have frequently had sustained and prolonged medical contact, and could fill hours recounting ‘what the doctor said’. This approach is very time-consuming and often unhelpful.

Before diagnosis

1. Initial symptoms (with particular reference to the usual non-specific nature of oncology symptoms). A notable difference from adult presentation is the paucity of these symptoms. Unlike adults with cancer, it is very unusual for a child to present with weight loss, haemoptysis or haematemesis and melaena. Symptoms that may present in children include a mass, and the eight ‘Ps’: Pyrexia, Pain, Pallor, Purpura, Persistent squint, Personality change, Posterior fossa symptoms, and do not forget the Pretenders (i.e. ALL or neuroblastoma impersonating arthritis, or mediastinal lymph nodes impersonating asthma).

2. Symptom duration (may give a guide to disease ‘tempo’). For example, patients with B-cell lymphoma may present as extremely ill, with a history of illness spanning a few days, compared to a patient with a brain tumour or other solid tumour, who may have experienced symptoms for many months.

3. Parental guilt about acts of commission or omission may have contributed to their child developing cancer.

4. An enquiry about the parent’s feeling towards the diagnosis is often revealing. Most parents are initially very angry, an anger that may be self-directed and related to guilt, or directed at doctors or others who they perceive as having failed in their duty to provide an early diagnosis—although, at the time, the non-specific symptoms may not have suggested malignancy as a likely possibility.

Factors 3 and 4 (above) will impact on the family’s approach to their sick child and possibly bias the relationships that they establish subsequently with people entrusted with the care of their children, particularly as the care and follow-up of a child with cancer nowadays can be expected to span in excess of 10 years for long-term survivors (over 70% of cases) whom we expect will survive.

Post-diagnosis phase

Important aspects in the history include an appreciation of the parents’ understanding of the details and significance of the diagnosis, or even whether the family is aware of the precise diagnosis. The candidate should enquire about the level of knowledge of treatment-related details that the family has acquired in the interval from diagnosis. The examinee should determine the family’s understanding of the prognosis, which falls into two broad categories: what they have been told by their doctor, and what they believe. The level of parental awareness and understanding of the condition is important, as this affects the parents’ level of care for the child and compliance with medication requirements and appointments. It also influences whether they strive to maintain a near-normal lifestyle for the child, or withdraw him or her from social interaction in anticipation of early death, perceived needs of additional protection and suchlike. The candidate should enquire about the impact of the diagnosis on siblings, the marital relationship, the financial situation for the family and job stresses. Parents may respond inappropriately in the post-diagnosis phase, by selling their house to relocate closer to the hospital, resigning from stable employment, or moving away from familiar and supportive communities, because they believe they are acting in the best interests of the child.

Current status of the patient

The details of the therapy received in the specific treatment protocol for that patient should be sought. The details should be general. Is most medication oral, IV or IM? Is there a central line? How many visits to the hospital for treatment? Can the local doctor or local hospital give any chemotherapy? No candidate will be expected to be familiar with all protocols. Be sure to ask about the complementary therapies.

Enquire about problems such as infections (especially pulmonary), marrow suppression and complications arising from this (such as febrile neutropenic episodes, anaemia and thrombocytopenia), compliance with oral chemotherapy and pneumocystis prophylaxis with cotrimoxazole (or a similar drug), and any other side effects from therapy, including nausea, vomiting and rashes. Then concentrate on the current status, particularly the immediate (rather than late) effects of treatment and their consequences, such as: lethargy and easy fatiguability from anaemia; nausea, vomiting and anorexia, resulting in weight loss; alopecia; limitation of activities (e.g. swimming) because of the presence of central lines, or ostomies involving the gastrointestinal or genitourinary tracts.

Other

The impact on daily activity of amputation of a lower extremity for bone tumour should be explored (and secondary consequences such as kyphoscoliosis sought during physical examination). Growth and development should be explored with the families. Social issues and schooling can then be discussed in the light of the foregoing information.

Finally, details of late effects of treatment and underlying illness should be sought.

Any family history of conditions associated with a predisposition to malignancy should be noted (e.g. immunodeficiencies, neurofibromatosis type 1).

From the above, the candidate should be able to formulate a comprehensive problem list, picking up items from each of the sections, prioritising these and being ready to discuss them.

Examination

See the short-case section in this chapter on late effects of oncology treatment.

Management plan

The following is an outline of the major issues that the general paediatrician may need to address, divided into general and specific problem areas.

Discussion points

1. Relapse of primary disease.

2. Growth and development.

3. Development of second tumour.

4. Social issues.

5. Schooling.

6. Infection.

7. Immunisation.

8. Issues of ongoing chemotherapy (crisis intervention for bone marrow suppression).

9. Supportive care.

10. Haematopoietic stem cell transplantation (HSCT)

11. Therapeutic modifications: risk-adapted therapy.

12. The dying child.

Relapse of primary disease

Note that patients who relapse are unlikely to be selected for an examination. However, this does not diminish the importance of properly assessing the issues regarding relapse.

In seeking symptoms from the parents or patient, the candidate ought to enquire whether any new symptoms resemble those present before the diagnosis, and determine the level of anxiety that these new symptoms are causing. Progressive symptoms such as weight loss, unexplained anorexia, nausea, fever or the appearance of lymphadenopathy, organomegaly, excessive bruising, bleeding, gum oozing, knotty palpable masses or painful bony masses all warrant further investigation.

Growth and development

Irradiation is the single most important factor in determining long-term growth and development. The candidate should know which structures were within the treatment portal, and the total dose used. Patients treated with craniospinal irradiation will be at the combined risk of hypopituitarism and relative shortening of the vertebral column. In addition, even if the pituitary is spared, the thyroid gland may well receive sufficient radiotherapy to result in biochemical hypothyroidism that requires intervention (because if it is untreated, the risk of thyroid cancer is enhanced). Any irradiated area may demonstrate relative soft-tissue atrophy.

In the past, cranial radiotherapy was used for CNS prophylaxis in a majority of patients with ALL. Modern treatment regimens now restrict the use of cranial radiation to 10% or less of patients with ALL. Up to 50% of children treated for acute leukaemia with cranial radiotherapy can have decreased growth hormone secretion. Loss of final height can also be influenced by early (rarely precocious) onset of puberty, or (too) early institution of testosterone therapy for hypogonadism in boys. The management usually comprises growth hormone, delaying treatment with testosterone. There have been reports in the literature linking use of growth hormone with subsequent brain tumour development. However, most investigators do not believe currently that the risk is enhanced.

If there has been a bone marrow transplant, the eyes should be checked by a paediatric ophthalmologist regularly (say, 12–24 monthly) for cataracts from total body irradiation (or from steroids). Hearing may be impaired by drugs such as cisplatin or aminoglycosides, and requires regular review and audiological assessment. Ideally, a formal psychological assessment should be carried out before any cranial irradiation. After treatment, psychological assessment may be repeated on a regular basis, in conjunction with neurological examination, MRI scanning and assessment of school performance, to monitor neuropsychological outcome and provide early rehabilitative intervention if needed. The spectrum of central nervous system damage varies from decreased performance at school, to frank leukoencephalopathy, spasticity and significant intellectual impairment. Intravenous methotrexate may result in leuko-encephalopathy in children with ALL, especially after irradiation. Pubertal development may be early (rarely precocious); however, delayed puberty is more common, with high gonadotropin levels from end-organ gonadal damage.

The one issue to address in adolescent patients is future reproductive potential. In boys with tumours such as Hodgkin’s disease, sperm storage should be considered before irradiation and chemotherapy. In girls, ovarian tissue storage is now available.

Development of second tumour

The risk of developing a second malignancy may approach 15–20% at 20 years in long-term survivors of childhood cancer, and appears to be related to the original diagnosis and treatment modalities. In ALL, children who have received cranial irradiation when under 6 years of age are susceptible to brain tumours, and children who have had extensive treatment with epipodophyllotoxins (teniposide and etoposide) are at greater risk of developing acute myeloid leukaemia (AML).

Social issues

Some long-time survivors have trouble adjusting to the stress of normal life. This can be assessed by simple interview and psychometric testing. Potential problems include diminished school performance, behavioural problems, impaired attainment of social skills, ongoing anxiety regarding relapse and the financial burden of the child’s treatment on the family. These areas should be explored so that appropriate intervention can be made.

Schooling

Survivors of ALL in particular are at risk of school-related problems, including repeating grades and a need for special education. This may relate to neurological damage from CNS prophylactic therapy. Assessment of school performance allows evaluation of problems with memory, concentration and attention span: all well-recognised sequelae. The amount of schooling that a child missed during treatment should be noted. Has the trend of school absence continued after therapy was completed? If so, determine the reasons. Is it excessive concern about infections such as varicella or measles (exposures to which are not relevant more than 6 months from the end of treatment)? The school situation must always be explored at follow-up.

Infection

The child on chemotherapy

Common childhood infections occur in children receiving therapy for cancer just as in normal children, and many can be managed in the usual way, provided that the child does not appear toxic, there is an identifiable localised infection, the neutrophil count is greater than 1.0 × 109/L and regular follow-up is provided. Often chemotherapy may be continued, after consultation, through the course of mild infections, be they bacterial or viral. If a child is unwell at home, with a fever and rhinorrhoea, the parents should be advised to contact the paediatrician. If the temperature is above a previously agreed level (e.g. 38°C), then the child should be seen either in hospital.

All children on therapy who are febrile need prompt assessment, and in most cases antibiotics should be started early (without waiting for result of blood count). Blood cultures should be collected before antibiotics.

If the neutrophil count is low (below 0.5 × 109/L), the child should be admitted to hospital. The management of febrile neutropenia should include broad-spectrum parenteral antibiotic therapy (e.g. ceftriaxone, tobramycin, teicoplanin). Antibiotics ideally should be commenced within 1–2 hours of the child reaching the emergency room. It is inappropriate to wait for the results of the blood count before starting therapy with antibiotics, especially if there is any delay in processing the sample in the laboratory. In such circumstances, antibiotics should be started. If the count is normal, there is less cause for concern. Remember, however, that many patients have central venous access devices in place, which can be the cause of serious infections despite normal neutrophil numbers. Always remind the family that fevers occurring within 6–8 hours of flushing a central line may be due to the introduction of bacteria into the patient from an infected CVL. For more details, see below.

Granulocyte colony stimulating factor (G-CSF) can decrease duration of hospitalisation for prolonged febrile neutropenia after intensive remission induction chemotherapy. G-CSF can be started 24 hours after cytotoxics and is given subcutaneously daily for 10 days. G-CSF may be ceased when the neutrophil count is greater than 1.0 × 109/L, and beyond the nadir. A new long-lasting form of G-CSF is now available: Peg-G-CSF, which is administered as a single dose 24 hours after completing the chemotherapy course.

Exposure to certain viruses requires specific intervention. In the case of varicella contacts, varicella zoster immune globulin should be given within 96 hours of exposure, and is more efficacious the earlier it is given. With measles contacts, standard immunoglobulin is recommended. In patients who are at risk of significant infection with herpes simplex virus (HSV), valacyclovir can be used (this has a longer half-life than aciclovir). Ganciclovir is often used for CMV prophylaxis in the setting of stem cell transplantation.

For prophylaxis against oral candidiasis, oral nystatin or amphotericin B lozenges can be given. In patients with prolonged neutropenia and/or lymphopenia, fluconazole may be used (covers Candida but not Aspergillus), or itraconazole (covers aspergillosis, e.g. post-transplant). Cotrimoxazole is recommended as prophylaxis against Pneumocystis carinii, particularly in patients with prolonged lymphopenia (lymphocytes less than 1.0 × 109/L or CD4 count below 400). In patients where cotrimoxazole causes neutropenia, or there are unacceptable side effects, pentamidine may be considered.

Mouth care is important in children with mouth ulceration or mucositis, or in those at risk of these if they are neutropenic (<1.0 × 109/L). Chlorhexidine mouthwash may be useful, as it is bacteriocidal.

The child off chemotherapy

For the first 3–6 months after completion of chemotherapy, there is a continued susceptibility to infection, although this is quite small. This risk is much greater for patients who continue to receive immunosuppressive therapy; for example, post-BMT for chronic graft-versus-host disease (GVHD). Children with chronic GVHD are immunosuppressed, as they are generally receiving steroids and anti-T-cell medications (cyclosporine or mycophenolate). They are often relatively neutropenic. Patients with active GVHD should not attend school. It is advisable for the schoolteacher to notify the parents, within the first 6 months of ceasing chemotherapy, of any outbreaks of chickenpox or measles in the class.

Immunisation

Susceptibility to live vaccines is maximal during chemotherapy and for the first 6 months after chemotherapy. Thus avoidance of live vaccines is recommended, with the exception of live varicella vaccine, which can be given safely during the maintenance therapy for ALL (but not during the early intensive phases—the first 6 months of treatment). This, however, is not routine practice in Australia. Killed virus vaccines (e.g. Salk vaccine) can be given.

Some authorities avoid administering live measles and mumps vaccine to siblings, as there is a small risk of transmission. Others consider this risk minimal and the vaccine safe. Influenza vaccine is safe and may have a place in patients with chronic chest symptoms. Hepatitis B recombinant vaccine is safe, but as these patients are immunosuppressed, adding a further booster dose is recommended. Titres may be checked 12 months later to assess efficacy. There are now recommendations regarding immunisation in two distinct groups: those who receive standard therapy and those who require stem cell therapy.

Immunisation with standard dose chemotherapy

There is a decrease in the concentrations of vaccine-antigen specific antibodies after completing chemotherapy. During chemotherapy, children are immunosuppressed and so cannot have live vaccines such as measles–mumps–rubella (MMR). Non-live vaccines can still be given according to the routine immunisation schedule. After completion of chemotherapy, it is wise to re-immunise children, following the routine immunisation schedule of the child’s country of residence, starting 3–6 months after the cessation of treatment. Immune function recovery can occur as early as 3 months post-treatment.

Immunisation with HSCT

HSCT recipients are significantly immunosuppressed for months after transplantation. Immune reconstitution occurs faster with autologous than with allogeneic transplantation. They have extensive alterations in their immune function and are especially susceptible to infection with polysaccharide-encapsulated organisms. For autologous HSCT, the immunosuppression is mainly due to pretransplant treatment. For allogeneic HSCT, the immunosuppression is due to a combination of pretransplant conditioning, GVHD and immunosuppressive therapy following HSCT. B-lymphocyte reconstitution occurs 3–6 months after transplant, and immunoglobulin isotypes start normalising 6 months after transplant, but there is an IgG subclass imbalance, with low IgG2 levels for 18 months or more after transplant. T-lymphocyte reconstitution starts at 1–2 months, peaks at 3–6 months and reaches normal levels by 1–2 years after transplant. It is important that these children receive the full immunisation schedule of their country of residence, usually 18 months after cessation of therapy, and this should include immunisation against Streptococcus pneumoniae with the seven-valent pneumococcal conjugate vaccine 7vPCV and the 23-valent-pneumococcal polysaccharide vaccine 23vPPV, and against Neisseria meningitidis with the meningococcal C conjugate vaccines MenCCV and the tetravalent meningococcal polysaccharide vaccines 4vMenPV. The current Australian Immunisation Handbook outlines the schedule post-HSCT.

Issues related to ongoing chemotherapy

For oncology patients receiving chemotherapy, there are misconceptions about how best to ‘protect’ children. The following advice is standard in Paediatric Oncology Centres:

1. Check that relatives are well before visits.

2. Patients can swim in swimming pools (even with central lines, but they require prompt cleaning after the swim). Swimming policy varies between units—generally advise against swimming if there is an external central line.

3. Children can go shopping in supermarkets and attend group gatherings (e.g. church, birthday parties).

4. Prophylactic cotrimoxazole is essential.

Crisis intervention

The candidate should be familiar with medical practices in his or her own teaching hospital’s oncology unit. For example, prophylactic platelet transfusions for severe thrombocytopenia (platelet count below 10 × 109/L) is not standard practice in all units.

Drug toxicities

The paediatrician must be aware of the various side effects of the many drugs used in the treatment of the malignancy, and be cognisant of a confusing complaint—for example, ataxia in a child with leukaemia—being possibly due to drug toxicity (e.g. vincristine neuropathy) rather than necessarily meaning CNS relapse.

Thrombocytopenia is one of the more common drug side effects. If the platelet count is below 20 × 109/L, spontaneous bleeding can occur. If the platelet count is below 50 × 109/L, minor trauma can result in bleeding. If there is no overt bleeding, then simple precautions suffice, such as avoiding injurious activities or invasive procedures (unless essential, which may require them to be covered by platelet transfusion), body-contact sports, strenuous exercise or hard-bristled toothbrushes. Note that severe headaches may indicate CNS haemorrhage. Avoidance of drugs such as aspirin or antihistamines (which can interfere with normal platelet function) is important.

Febrile neutropenic episodes

Neutropenia means a neutrophil count of below 1.0 × 109/L, but most infections occur with a level below 0.5 × 109/L, and most of those are below 0.2 × 109/L. Clinically, the problem can be very difficult to assess, as there are no classic signs or symptoms. Particular areas on which to focus include the skin, mucous membranes (ulceration, candida, herpes), chest, central-line site and perianal region (ischiorectal abscesses can be very subtle).

Management usually includes admission to hospital, culture of the potential sites outlined, blood cultures and administration of broad-spectrum parenteral antibiotic therapy. Most units withhold chemotherapy until the child is afebrile for more than a day and the neutrophil count has returned to above 1.0 × 109/L.

Pulmonary infections

These are among the most common form of severe infection seen in oncology patients, and there are many possible pathogens. The neutrophil count plus the chest X-ray may be a useful guides in management. Note that in the presence of neutropenia, pulmonary markings may not be prominent, despite significant infection. Approximately 50% of bacterial infections are due to Gram-positive bacteria and the remainder are due to Gram-negative organisms: thus broad-spectrum antibiotic therapy cover is advisable. Opportunistic infections can occur, such as Pneumocystis carinii (although most patients are on cotrimoxazole prophylaxis for this), opportunistic viruses (e.g. cytomegalovirus), fungi, Mycobacterium or Mycoplasma. Note that radiological findings may be due to non-infectious causes (e.g. leukaemic infiltration or toxicity from chemotherapy or radiotherapy).

Central venous access devices

These may be central lines or totally implantable venous access devices, such as Port-a-Cath and Infuse-A-Port. These devices are routinely used in most conditions encountered in oncology. They require regular heparin flushes to avoid clots forming, and may on occasion become infected, particularly with Staphylococcus species.

Supportive care

Mouth care

Mouth care is important in children with mouth ulceration or mucositis, or in those at risk of these if they are neutropenic (<1.0 × 109/L). Chlorhexidine mouthwash is useful, as it is bactericidal. In very young patients, chlorhexidine gel is appropriate, and before meals xylocaine viscous is useful.

Antiemetics

All chemotherapy protocols include the use of 5-HT3 antagonists such as ondansetron, as vomiting occurs predictably after many specific chemotherapeutic agents. Ondansetron can be given intravenously or orally, the latter being significantly cheaper and available in the form of wafers or syrup. If ondansetron is not enough, meto-clopramide or dexamethasone provide additional antiemetic effect.

Many of the drugs used in solid tumour protocols are very emetogenic. These include adriamycin, carboplatin, cisplatin, cyclophosphamide (CPA) and ifosphamide. Ondansetron is usually given before, during and after each chemotherapy infusion.

Haematopoietic stem cell transplantation (HSCT)

In allogeneic HSCT, healthy haematopoietic stem cells are harvested from a separate donor, related or unrelated, though clearly human leukocyte antigen (HLA) matched cells would be ideal, and used to replace the patient’s abnormal cells; in autologous HSCT, the patient is his or her own donor, where healthy haematopoietic stem cells are harvested stored and reinfused after cytoreduction. Allogeneic donors for SCT in children can be of several types: these include cells from bone marrow, umbilical cord blood, mobilised peripheral blood, unmanipulated or T-cell depleted, or CD34 or CD133 selected grafts. (The use of T-cell depletion and high-dose infusions of CD34+ cells can reduce the rate of severe GVHD, and can improve the rate of engraftment.) The selection of donors depends on underlying diagnosis, risk for relapse, availability, age of patient (younger preferred), size of patient, cytomegalovirus (CMV) status (negative preferred), sex of donor (male preferred; female donors, especially those with high parity, have association with a higher rate of GVHD); but the most important consideration is high-resolution HLA matching; identification of an HLA donor at the DNA level is prioritised. Matching at 10 out of 10 alleles would be ideal; a low mortality rate is reported in SCT in children 7 out of 10 or 8 out of 10 HLA allele matched unrelated donors with the use of antithymocyte globulin. Even the availability of a matched sibling, or a 10 out of 10 allele matched unrelated donor, does not prevent transplant related complications including GVHD.

Autologous HSCT can be used in the treatment of neuroblastoma, AML, and Hodgkin’s and non-Hodgkin’s lymphoma. Allogeneic HSCT can be used in the treatment of ALL, AML, CML, and Hodgkin’s and non-Hodgkin’s lymphoma.

Allogeneic stem cell transplantation: selected haematological malignancies

Acute lymphoblastic leukaemia: Certain patients who relapse after initial treatment, plus subgroups of patients with high-risk features of relapse, will proceed to an allogeneic SCT; in the latter, this can occur while in the first remission. SCT may be the only curative therapy for the former. Relapsed ALL is the fourth-commonest malignant disease in childhood (with a higher incidence than many newly diagnosed paediatric tumours). Outcomes for SCT are best when performed during first or second complete remission.

Acute myeloid leukaemia: The best therapy during first remission is controversial; SCT is preferred for patients with less favourable prognoses, such as those with complex karyotypes (e.g. -5, del(5q), -7, 3q abnormalities) or hyperleucocytosis. Allogeneic SCT during the second remission is associated with better outcome after relapse.

High-grade myelodysplastic syndrome: Allogeneic SCT is the treatment of choice.

Therapy-related myelodysplastic (MDS) syndrome and AML are clonal malignant disorders occurring after exposure to cytotoxic agents; these tend to be more aggressive than the de novo disorders, and SCT may be the only curative therapy available.

Chronic myeloid leukaemia (CML): Allogeneic transplantation from a matched related family donor is the only curative approach.

HSCT: bone marrow transplantation (BMTx)

In the weeks leading up to BMTx, especially in late autumn/early winter, isolating the children is a good idea, because if they get RSV, parainfluenza, adenovirus or influenza, this will delay the BMTx.

Candidates should know that pre-transplant preparative regimens usually combine very high dose cytotoxic agents and immunosuppressive agents (e.g. CPA, melphalan, cytosine arabinoside [ara C], etoposide, thiotepa, busulphan, fludarabine) with various doses (e.g. 12 grey to 15.75 grey before allogeneic transplantation for leukaemia) of fractionated total body irradiation (TBI). Non-TBI-based regimens usually use busulphan or CPA, with or without melphalan, etoposide, thiotepa and fludarabine. The preparative regimen should have sufficient cytotoxic anti-leukaemic effect combined with adequate immunosuppression to ensure engraftment.

After BMTx/HSCT

All recipients of allogeneic marrow are at risk of GVHD post-engraftment. Agents used to prevent this occurring include methotrexate (MTX), cyclosporine (CSA), prednisolone, tacrolimus and mycophenylate mofetil. The main target organs of acute GVHD are the skin (maculopapular rash), liver (cholestatic jaundice) and gut (anorexia/diarrhoea).

Acute GVHD may require treatment with prednisolone, antithymocyte globulin, tacrolimus, psoralin plus ultraviolet light (PUVA).

In the first 6 months after transplant, the child should not attend school, and social contacts should be limited (especially with GVHD). There are no firm recommendations regarding the use of live viral vaccines for these patients. If the child is well, and has no GVHD, then after 12 months live viral vaccines are safe.

Late effects post-BMTx/HSCT

Chronic GVHD appears around 80 days post-BMTx. The main target organs are the skin (epidermal atrophy, focal dermal fibrosis, scleroderma, loss of hair and nails), liver (cholestatic jaundice), eyes (keratoconjunctivitis sicca) and mouth (erythema, lichenoid lesions of buccal mucosa). Less often, the lungs, gut and neuromuscular system may be involved. If GVHD is extensive, treatment may involve the use of prednisolone with CPA, prednisolone with tacrolimus, azathioprine or PUVA.

Other effects related to the BMTx process include graft rejection and immunological dysfunction (short-lasting, donor-derived T- and B-lymphocyte immunity (TBI); reimmunisation of patients should occur 12 months post-BMTx).

Complications of the preparative regimen include lung disease (both restrictive and obstructive defects can occur long term), development of second malignancies (at 15 years, around 6% if no TBI, but 20% if received TBI), endocrine dysfunction (growth hormone deficiency, gonadal dysfunction, hypothyroidism) and neuropsychological problems.

Alternative transplantations: umbilical cord blood transplantation (UCBT) and haploidentical transplantation

Umbilical cord blood (UCB) is an alternative source for transplantable stem and progenitor cells. CB can be collected from the placenta via the umbilical vein after the baby is delivered. GVHD occurs at lower rates than matched-sibling BMTx. Cord blood is available at short notice. Disadvantages include the potential for unknowing transmission of genetic diseases (e.g. immune deficiency and storage diseases), and the limitation of volume and cell content of what is collected (i.e. the finite number of stem cells in the CB unit). CBT may be very useful for those without a matched donor for BMTx. Predictors of success after UCBT include the number of cells in the UCB graft, and the degree of HLA disparity; a cell dose of 3 × 107 per kg have a much higher survival rate.

Haploidentical transplantation with T-cell depletion using CD 34+ positive selection from mobilised peripheral stem cells can be successful, without GVHD, with outcomes comparable to matched unrelated donor transplantation.

With the addition of matched or partially matched UCB and haploidentical donors to the pool of available donors, most children with high-risk haematological malignancies should be able to have a donor found for them, and then have an allogeneic transplantation if the risk/benefit ratio is favourable.

Therapeutic modifications: risk-adapted therapy

As the number of survivors has increased, so there has been heightened awareness of the potential consequences of treatment. This has led to modifications to therapy to enhance the quality of life for survivors. The following brief summary outlines risk-adapted therapies aimed at diminishing complications, the latter grouped according to the organ system involved.

Cardiopulmonary

Decreased dose of radiation; improved shielding of heart and lungs; decreased doses of anthracyclines (cardiotoxic) and bleomycin (pulmonary toxicity); newer anthracyclines with decreased cardiotoxicity; the use of cardioprotective agents (dexrazoxane); routine monitoring (e.g. echocardiography, pulmonary function tests).

Endocrine

Lower doses and volumes of radiotherapy; routine oophoropexy during pelvic radiotherapy; reducing doses of alkylating agents in patients with good prognoses; routine testing for deficiencies of various hormones (e.g. growth hormone, oestrogen, thyroid hormone) and replacement thereof; ovarian tissue and sperm storage.

Genitourinary

The use of mesna, a uroprotectant drug that binds to toxic metabolites in the urine, after CPA or ifosfamide, and decreases haemorrhagic cystitis; new analogues with less renal toxicity (e.g. carboplatin compared with cisplatin); routine monitoring (e.g. blood testing for electrolytes, including phosphorus, and magnesium).

Neurological

Elimination of intrathecal and intravenous methotrexate after cranial irradiation has decreased leukoencephalopathy; delaying therapeutic radiation until older (aiming for over 3 years) by utilising systemic chemotherapy; routine monitoring of neuropsychological status.

Second malignancy

Decreased exposure to alkylating agents, plus limiting volume of radiation in Hodgkin’s lymphoma; greatly diminished use of epipodophyllotoxins in leukaemia; increased education of survivors about potential of late effects of their specific therapy.

The dying child

There are many issues that need to be addressed in a child for whom no further beneficial therapy is possible. Most children nowadays die at home. Palliative treatment involves issues of control of pain, nutrition and appreciation of the psychosocial dynamics of the family. These children may show an inability to cope by features such as denial of their illness, withdrawal or unwarranted anger.

The family’s mourning can include, again, denial, anger and depression, and very often seeking further opinions or considering alternative forms of therapy. These processes should be understood and accepted by the paediatrician. For the child who dies in hospital, the major objective is ensuring maximum comfort. This can be aided by surrounding the child with familiar possessions from home and having no restriction on visitors. Invariably, other children on the ward become aware of the change in the management of these patients, and frank discussion should be encouraged, as well as permitting interaction with the dying child.

The death of the child invariably is associated with confusion and shock, irrespective of the degree of expectation and preparation. Prior discussions regarding issues of post-mortem examination and, if the child dies at home, transport of the body to the hospital, are usually beneficial to the family. The role of the paediatrician extends beyond the death of the child to helping the family cope with caring for siblings, discussing unresolved issues and intervening, by appropriate referral, where an abnormal grief reaction is apparent, such as acting out by siblings, or severe depression and contemplation of suicide in the parents. As the most severe grief may occur some months after the child’s death, follow-up should be for many months rather than weeks.

Short Case

Late effects of oncology treatment

Later effects of oncology treatment plus common signs of disease relapse (in particular, acute leukaemia) are outlined in Table 14.1. This is incomplete, of course, due to the nature of the wide range of tumours and their individual modes of relapse. Some of the findings mentioned will be relevant only to children still on chemotherapy. This approach may be found useful in assessing children in follow-up clinics. Several of the findings can only be ascertained fully by involving other specialised areas, such as neuropsychology and audiology. Neurocognitive dysfunction is the area that worries survivors of cancer and their parents the most. Survivors of (especially) ALL and central nervous system (CNS) tumours, head and neck tumours requiring radiation therapy and patients treated with HSCT are most at risk. Cranial radiotherapy is the main risk factor for adverse neurocognitive outcome. In ALL patients, exposure to chemotherapy alone will still be associated with neurocognitive decline in two thirds of patients. These children tend to have problems with executive function, memory, attention and concentration, processing speed and visual perceptual skills, which translates to inattention in class, inconsistent academic performance, not finishing homework, incomplete assignments, careless errors, and trouble with planning and organisation, with specific problems in the areas of mathematics, reading and spelling. It is usually in the later years of school that these sorts of problems become apparent, when rote learning is replaced with reasoning, and organisational skills and time management skills become of paramount importance. Simple educational accommodations may help (sitting at the front of the class, being allowed extra time to complete exams). These features cannot be assessed in a short-case setting, but the examiners will appreciate the candidate mentioning the importance of these areas, after the physical examination is complete.

Table 14.1 Late effects of oncology treatment

General observations
Introduce yourself: ask name, age, school; assess intelligence (is child alert, conversant?) (leukoencephalopathy secondary to treatment [XRT,MTX]; subnormal IQ with intracranial tumours); note hearing aids, glasses, glass eye, deformities, amputations, prostheses
Parameters

• Height (short stature: growth hormone deficiency, panhypopituitarism [cranial XRT, MTX], hypothyroidism [thyroid XRT or MIBG], steroid therapy, skeletal changes from spinal XRT)

• Upper segment:lower segment (US:LS) ratio (skeletal changes from radiation of spine)

• Weight

• Head circumference

• Percentile charts, noting trend since treatment, look at growth velocity

Tanner staging (delay: alkylating agents, radiation to gonads, cisplatin, carboplatin) Cushingoid features (steroid therapy) Tachypnoea, cyanosis or cough (radiation- or chemotherapy-induced pneumonitis, or pulmonary infection) Skin

• Pallor: anaemia from marrow suppression (most agents), or bone marrow relapse of leukaemia (or development of secondary leukaemia)

• Bruises: thrombocytopenia from marrow suppression (most agents) or (rare) coagulopathy from L-asparaginase, or bone marrow relapse of leukaemia

• Dermatitis (MTX, 6-MP, 6-TG)

• Hyperpigmentation (chronic GVHD from BMT)

• Desquamation (bleomycin)

• Jaundice (MTX, 6-MP, 6-TG, bleomycin, radiation to liver)

• Pigmented naevi (increased by most agents)

Manoeuvres Stand with hands and feet together (asymmetry from XRT to limbs or hemihypertrophy with Wilms’ tumour—do not confuse the two) Gait: full examination for evidence of neuropathy (VCR), spasticity (leukoencephalopathy), cerebellar ataxia (L-asparaginase), antalgic limp (marrow relapse of leukaemia), or proximal myopathy (steroids); also may detect evidence of cerebral tumour (second malignancy) Romberg’s test (neuropathy from VCR) Back Effects on bony skeleton (XRT, steroids, GVHD, MTX, BMT, endocrinopathy; poor mineral density, growth anomalies, avascular necrosis); effects on paraspinal soft tissues (XRT, steroids, GVHD; muscle weakness, hypoplasia, impaired mobility) Inspect; look for scars, any vertebral masses (secondary malignancy) Bend forward and touch toes (to assess for scoliosis or kyphosis from spinal irradiation, particularly if unilateral) Palpate for tenderness (steroids; rickets from ifosfamide) Upper limbs Effects on bony skeleton (XRT, steroids, GVHD, MTX, BMT, endocrinopathy; poor mineral density, growth anomalies, avascular necrosis; effects especially on large joints); effects on soft tissues (XRT, steroids, GVHD; muscle weakness, hypoplasia, impaired mobility) Inspect; look for scars (previous diagnostic or curative surgery) Asymmetry (limb radiation, hemihypertrophy) Contractures (limb XRT, chronic GVHD) Peripheral stigmata of chronic liver disease (MTX, 6-MP, radiation to abdomen) Palmar crease pallor (marrow suppression) Pulse (bradycardia; untreated hypothyroidism from XRT to thyroid, or busulphan, BMT, MIBG) Neurological examination: Peripheral neuropathy (vinca alkaloids, usually reversible; test reflexes and sensation to document this) Functional assessment if:

• any asymmetry or contractures suggestive of radiation to limb, or

• scars from resection of tumour with potential neurological or vascular complications, or

• amputation—examine function with prosthesis; check how well fits, any loosening or infection

Blood pressure (elevated from steroids, bleomycin, MTX nephrotoxicity, radiation nephritis, renal damage from GVHD; low from adrenal insufficiency from XRT to adrenal area, BMT) Head and neck Alopecia (reversible: ADR, bleomycin, CPA, daunorubicin, VCR; irreversible: post-BMTx; busulfan; cranial XRT + anthracycline given close together) Scars (previous diagnostic, curative or debulking surgery) Midfacial hypoplasia, small nose, chin (XRT to head and neck → altered growth bone/soft tissue) Eyes (XRT, busulphan, steroids, GVHD)

• Aniridia (association with Wilms’ tumour, not a late effect)

• Conjunctival pallor (marrow suppression, various agents)

• Scleral icterus (bleomycin, MTX, 6-MP, 6-TG, radiation to liver)

• External ocular movements for evidence of cranial nerve palsy (CNS relapse of leukaemia, VCR neuropathy)

• Cataracts (corticosteroids, radiation to eyes)

• Papilloedema (CNS relapse of leukaemia)

Hearing impairment/hearing aid (XRT, cisplatin, carboplatin, antibiotics)

Mouth

• Dry (salivary gland dysfunction from XRT)

• Mucositis (MTX, 6-MP, 6-TG, actinomycin D)

Temporomandibular joint: note interdental distance (normally should be able to fit three fingers lined up vertically, between lower and upper teeth); limited range of movement (XRT) Teeth (XRT, BMT; tooth/root agenesis, root thinning/shortening, enamel dysplasia)

• Microdontia; poor enamel and root formation (radiation to head)

• Dental caries (most agents)

Thyroid: look and palpate for nodules (thyroid carcinoma from craniospinal XRT) Chest Scars (previous diagnostic, curative or debulking surgery) Praecordial assessment for cardiomegaly (cardiomyopathy) from anthracyclines (the ‘rubicins’) or radiation (mediastinal XRT), pericarditis (reversible—from mediastinal XRT), evidence of congestive cardiac failure (from cardiomyopathy), abnormal rhythms Full respiratory examination for tachypnoea, cough or crackles due to interstitial pneumonitis or pulmonary fibrosis (bleomycin, busulphan, MTX, CPA, XRT, GVHD), pulmonary infection (opportunistic viruses, bacteria/fungi if still on chemotherapy) Assess bony tenderness at sternum, clavicles, spine (marrow relapse: leukaemia, secondary leukaemia) Abdomen Scars (previous diagnostic, curative or debulking surgery) Prominent veins (chronic liver disease from MTX, 6-MP or XRT to abdomen) Hepatomegaly (MTX, 6-MP or relapse of leukaemia or Iymphoma) Splenomegaly (relapse of leukaemia or Iymphoma) Genitals: Tanner staging (delay from alkylating agents or gonadal XRT); ambiguous genitalia with Denys–Drash syndrome (association with Wilms’, not a late effect) Testicular enlargement (relapse of leukaemia) Undescended testes (association with Wilms’, not a late effect) Lower limbs Effects on bony skeleton (XRT, steroids, GVHD, MTX, BMT, endocrinopathy; poor mineral density, growth anomalies, avascular necrosis; effects on large joints); effects on soft tissues (XRT, steroids, GVHD; muscle weakness, hypoplasia, impaired mobility) Asymmetry (limb radiation, hemihypertrophy) Contractures (limb XRT, chronic GVHD from BMT) Ankle oedema (from cardiac, liver or renal disease; see above) Bony (tibial) tenderness (marrow relapse of leukaemia) Neurological examination: Peripheral neuropathy (vinca alkaloids; usually reversible; test ankle and knee jerks and sensation to document this) Delayed relaxation of ankle jerks (hypothyroidism from thyroid radiation, busulphan, BMT) Functional assessment if:

• any asymmetry or contractures suggestive of radiation to limb, or

• scars from resection of tumour with potential neurological or vascular complications, or

• amputation: examine function with prosthesis; check how well it fits, any loosening, or infection

Other Temperature chart: fever with intercurrent infection (myelosuppression with various agents) or (rare) radiation pneumonitis Urinalysis

• Blood (CPA-induced cystitis)

• Proteinuria (radiation nephritis)

• Glucose (corticosteroids)

ADR = adriamycin; BMT = bone marrow transplantation; CNS = central nervous system; CPA = cyclophosphamide; GVHD = graft-versus-host disease; MIBG = radioactive iodine metaidobenzoguanidine; MTX = methotrexate; 6-MP = 6-mercaptopurine; 6-TG = 6-thioguanine; VCR = vincristine; XRT = radiotherapy.

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