Meriel E. M. Jenney
Introduction and history
The best protection against the development of late effects following therapy for childhood cancer is to avoid or minimize any damage by therapy in the first place. Where possible, therapy should be reduced by lowering doses of chemotherapeutic agents known to be associated with late adverse effects, or by reducing the dose or field of radiation, minimizing exposure to normal and sensitive tissues, to limit injury. Cure remains paramount, even where concerns of adverse late effects exist. However, as the understanding of the biology of tumours and the risk that individual patients face from their tumours improves, treatment can be delivered with greater confidence to optimize cure rate and at the same time reduce therapy, where possible, to minimize late adverse sequelae.
Some children will inevitably require intensive therapy with predictable late effects, and for them protection means the early identification of problems, prompt intervention, and optimal coordination of ongoing care, often through multidisciplinary support.
This chapter is not an exhaustive list of late effects that occur in different groups of patients. For details of the late effects of therapy the reader can refer to recent texts including that by Wallace and Green.1 Another important study is the Childhood Cancer Survivors Study (CCSS),2 which has generated a large body of evidence. This is an epidemiologic study of over 14 000 survivors of childhood cancer in the USA. It provides detailed information relating to the treatment the patients had received and their current health status. Although many of the treatment strategies have changed since the patients within that cohort were treated, it is nonetheless a comprehensive study and the size of the population allows detailed exploration of the long-term impact of different therapies.
Another important group of survivors are those who have undergone bone marrow transplantation. The issues affecting these patients will not be fully discussed in this chapter, and the reader is referred to a recent series of comprehensive reviews of the impact of bone marrow transplantation on both the endocrine3 and non-endocrine4,5 late effects that can occur following this procedure.
When considering the evidence base relating to the late effects of therapy for childhood cancer the difficulty in obtaining reliable data systematically must be recognized. Crosssectional clinical studies of patients can provide important information about the late effects of therapy and have been the backbone of research in this area. However, they are limited by the variation in therapy that many of the patients have received. Other demographic differences such as age at diagnosis, stage of disease, and changes in approach to therapy and provision of supportive care over time may also have an impact on the spectrum and severity of problems seen. Patients treated in a similar way within individual clinical trials are the most valuable source of accurate information about important late effects. There is a need for prospective studies of late effects to be built into ongoing clinical studies, but the late sequelae of therapy can take a long time to develop and follow-up is challenging but costly. Therefore these studies lag behind those of acute clinical therapy.
Protection against late effects is about prevention and intervention. This chapter will explore two themes. First, we consider how the impact of late effects can be minimized through early recognition and, where possible, the use of interventions and additional therapy. Secondly, we explore specific areas where late effects have been recognized and how strategies have been introduced within the treatment setting and clinical trials to minimize long-term toxicity. The importance of coordinating the follow-up of patients in order to optimize ongoing care in a cost-effective way will also be considered. With the steady rise in the numbers of survivors, there is a need to rationalize follow-up strategies and identify how patients can realistically receive ongoing care into the long term.
Predictable late effects: what can be done?
Cardiac complications
If a patient survives >5 years without tumour recurrence, one important cause of late mortality is treatment-related cardiac disease.6,7 Radiotherapy and anthracycline chemotherapy cause late cardiac dysfunction and have been and continue to be widely used in the treatment of childhood cancer. Many survivors are at some degree of risk. But at how much risk? As echocardiographic and other techniques used to identify abnormalities of cardiac dysfunction improve, many of which may be subclinical, the interpretation and clinical significance of some of these findings, may be debated. Robust evidence relating to the real need for, the frequency, and the appropriate method of follow-up remains elusive.
Cardiac disease is an important cause of morbidity in the general population regardless of prior cancer therapy. Several factors may interact with radiation or anthracycline-related cardiac disease; these include hyperlipidaemia, hypertension, smoking, and obesity, particularly as the age of the population of survivors increases. Appropriate health education is an important aspect of ongoing care and must not be overlooked.
Anthracyclines
Exposure to anthracycline chemotherapy and the use of radiotherapy to the mediastinum, chest, thoracic spine, or whole body are the most important risk factors for the development of cardiac disease in the long term. Exposure to both treatment modalities significantly increases long-term risk, but either therapy alone can lead to late complications. The impact of radiotherapy will be discussed below.
There has been considerable debate about the regimens used for the administration of anthracyclines, in particular the length of infusion (e.g. bolus, 48 h) and the use of cardioprotective agents. There is evidence from a randomized trial that dexrazoxane (cardioxane) has a protective effect against acute injuries.8 There has been recent reassuring evidence, based on a cohort of patients treated for leukaemia in the UK, demonstrating no association between length of infusion time and later cardiac dysfunction.9
Guidelines for follow-up have been based on large retrospective studies of patients and there is a need for prospective assessment of risk factors and the frequency and methods used for followup. Those risk factors currently recognized as important are cumulative anthracycline dose, young age at therapy, female gender, and additional radiotherapy (Table 11.1). Subclinical abnormalities of cardiac function have been identified, using echocardiography, in patients following relatively low cumulative doses of anthracyclines. All patients exposed to the agent should have some assessment of cardiac function following therapy. A fractional shortening of <28 per cent is generally regarded as significant in the long term, although other findings such as septal dyskinesia and dysrhythmias may also be important. If significant abnormalities are identified, formal advice regarding limitation of activities should be sought from a cardiologist with an interest in this area. Although aerobic exercise is generally safe and indeed encouraged, there are concerns about patients with known abnormalities undertaking isometric exercise (e.g. weightlifting) and generally this should be avoided in this situation. There are reports of cardiac decompensation during pregnancy, and it is imperative that those girls who have received a higher dose of anthracyclines, particularly at a young age, or who have had additional radiation to the chest are monitored during pregnancy and, if necessary, labour.
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Table 11.1. Patients at higher risk of cardiotoxicity who may warrant more frequent surveillance |
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The frequency of cardiac evaluation has been difficult to define and varies between international groups, particularly as access to appropriate paediatric or adult cardiology services may also vary. In general, the younger the age at time of therapy and the higher the cumulative dose received, the more frequent is the follow-up. Most cardiologists would reassess patients, even with normal cardiac function, during or at the end of puberty and if clinically significant abnormalities are identified, follow-up would then be more frequent. Cardiac impairment following anthracycline chemotherapy can continue to deteriorate over time. The awareness of potential deterioration during puberty, pregnancy, and isometric exercise is important. Patients and their parents should be fully informed of the risks, and coordination of cardiac follow-up in these settings is essential.
Does early therapy improve outcome?
If there is symptomatic cardiac dysfunction, patients will usually receive appropriate therapy with ACE inhibitors and diuretics with or without digoxin. However, whether early therapy for subclinical dysfunction leads to an improved long-term outcome is unclear. Whether the use of ACE inhibitors in asymptomatic patients with subclinical anthracycline cardiotoxicity is of value remains unproven, although there has been considerable interest in this area. Other measures of cardiac function such as the serum measurement of natriuretic peptides [N-terminal of the propeptide atrial natriuretic peptide (NT-proANP)] are also currently being explored, but their use remains experimental at present.
Radiotherapy
The heart is exposed to radiation within any field involving the mediastinum. However, lung, abdominal, left chest wall, spinal, and total body irradiation may also directly affect the heart and result in late complications. Patients receiving doses 40 Gy are at greatest risk, as are those who have also received cardiotoxic chemotherapy, such as anthracyclines or high-dose cyclophosphamide, or who were young at the time of radiotherapy. Radiation-induced cardiac disease, particularly coronary vascular disease, has been most commonly reported in survivors of Hodgkin disease. In one large cohort of patients, the relative risk of death due to acute myocardial infarction was 41.5 (95 per cent confidence interval, 18.1–82.1).10 Cardiomyopathy and valvular disease can also occur. Many patients will be asymptomatic, with symptoms reported to occur 7–39 years following radiotherapy.
Regular clinical evaluation with specific relevance to cardiac complications is clearly very important. Frequency of screening depends on risk factor; the higher the radiation dose and the younger the age at therapy, the greater will be the frequency. Early referral to a cardiologist is strongly recommended if any subclinical abnormality occurs (e.g. prolonged QT interval, cardiac dysfunction, or dysrhythmias). Other factors that predispose to cardiac disease, such as obesity, hyperlipidaemia, and a strong family history, should also be considered and intervention for patients with these additional risk factors may be particularly important. Additional evaluation during pregnancy is also recommended.
Pulmonary complications
Chemotherapy
The frequency of lung complications appears to have fallen over recent years, largely because of a greater understanding of which chemotherapeutic agents cause significant long-term damage and of the impact of radiotherapy which has led to the avoidance of pulmonary complications.
Many patients will have mild abnormalities of pulmonary function; they will be asymptomatic, although on closer questioning some will admit to some exercise intolerance. Formal lung function testing will demonstrate a mild restrictive abnormality (e.g. patients following treatment for acute lymphoblastic leukaemia, Hodgkin disease), but there is no evidence to date that the lung function in these patients deteriorates over time. The pathogenesis of these abnormalities is probably multifactorial, with multi-agent chemotherapy and previous chest infections both playing a part.
However, other patients may be susceptible to significant pulmonary dysfunction (Table 11.2). This may be due to exposure to agents known to lead to significant pulmonary damage, including fibrosis, or radiotherapy, or a combination of chemotherapy and radiotherapy. The recognition of significant interactions may be critical in the avoidance of major lung toxicity or even death (e.g. the use of busulphan in patients who may receive radiotherapy to the lung).
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Table 11.2. Chemotherapy and late lung toxicity |
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There is a clear relationship between radiation dose, volume, and risk of radiation pneumonitis with subsequent fibrosis. It is generally accepted that a dose of 14 Gy to one whole lung is safe in the acute setting, but higher doses can only be delivered to part of the lung, as fibrosis is likely to follow. Regular review of pulmonary function is important for patients who have received radiotherapy as there may be a restrictive lung abnormality with or without fibrosis, although there is little therapy available.
Exercise should be encouraged and smoking avoided. The assessment of cardiac function is also important for those with evidence of pulmonary fibrosis who may be at risk of pulmonary hypertension.
Endocrine issues
Bone mineral density
Osteopenia in survivors of childhood cancer is likely to be multifactorial. It has been reported most frequently in survivors of acute lymphoblastic leukaemia but has also been identified in other patients, including those previously treated for brain tumours. The causes of osteopenia are thought to include prior cranial irradiation or direct radiation (spine, total body irradiation), the direct effect of certain chemotherapeutic agents (e.g. chemotherapy for acute lymphoblastic leukaemia, ifosfamide), and steroids. A general reduction in activity both during therapy and even following completion of active treatment (this has been particularly noted in survivors of childhood leukaemia) may also be implicated. It is possible that there is also suboptimal mineralization of bone at critical times such as during puberty. This is an area where intervention may be important.
The treatment of osteopenia (>2.5 SD below mean for age and pubertal status) should be supervised by a clinician with expertise in this area. The use of bisphosphonates is controversial. However, physical activity and regular exercise will help to improve bone mineral density and should be encouraged. Other reasons to encourage exercise include the higher incidence of obesity now recognized in some of these survivors. Nutritional supplementation (e.g. calcium) may confer some benefit.
The assessment of bone mineral density in patients with clinical fractures is clearly important. However, whether survivors of leukaemia should have routine dual-energy X-ray absorptiometry (DEXA) scanning or other imaging is currently a matter of active research interest. It is important to note that the interpretation of DEXA scanning requires correction for size and pubertal status in children in the clinic setting. As osteopenia and osteoporosis become increasingly recognized as an important issue for women in later years, the long-term impact of early osteopenia is as yet unknown and will need careful ongoing evaluation.
Fertility
Perhaps the single most important strategy for preservation of fertility in boys is the facilitation of sperm banking at the time of diagnosis. For many, the impact of therapy on fertility may be unclear, and unless there is an urgent indication for immediate therapy, sperm storage should be encouraged for peripubertal and postpubertal boys.
There are several aspects of therapy for childhood cancer that can lead to impairment of fertility in the long term. In general, boys are more susceptible to late sequelae than girls. They have a greater sensitivity to chemotherapy, particularly alkylating agents. Leydig cell function is preserved to a greater extent than Sertoli cell function. Therefore boys may progress appropriately through puberty, but may nonetheless have inadequate sperm production, with impaired fertility, requiring more detailed investigation. Girls are born with a pool of primordial follicles which potentially can develop, with appropriate hormonal stimulation, into mature oocytes. This pool steadily depletes during childhood and puberty, under normal circumstances to approximately 400 000 by the time of menarche. Cytotoxic chemotherapy and radiotherapy will further deplete this pool and can result in loss of hormone production, lack of ovulation, uterine dysfunction, and a premature menopause. With girls in puberty one can think of harvesting ova from the ovaries before the start of chemotherapy with alkylating agents or before radiotherapy when the ovaries are positioned in the radiotherapy field. Ova banking, as with with sperm banking in boys, may be considered before treatment starts.
Cytotoxic chemotherapy Several chemotherapeutic agents can potentially impair fertility (Table 11.3). There is considerable individual variation in sensitivity to these agents. Most importantly, girls appear to be relatively resistant to the adverse impact of chemotherapy alone, with the exception of alkylating agents, particularly cyclophosphamide in high doses or in combination with other agents known to impair fertility.
Many studies have specifically studied the effects of cyclophosphamide. Interpretation is often difficult, as the impact of other potentially gonadotoxic chemotherapy that may have been received and the age and pubertal status at the time of therapy may also influence longterm fertility potential. Nonetheless it is generally agreed that a cumulative dose of cyclophosphamide > 7.5g/m2 will lead to infertility for boys, but lower doses could also be implicated.
The impact of ifosfamide is less clear. It is similar to cyclophosphamide in its activity but the impact on fertility may be less severe. There are anecdotal reports of pregnancies fathered by boys who have received significant cumulative doses of the agent, but these are not sufficient to be reassuring. It is used with increasing frequency in the treatment of many solid tumours and further definitive information about its impact on fertility is urgently required.
There is evidence that girls receiving alkykating agents (chlorambucil and procarbazine or mustine) as part of a therapeutic regimen for Hodgkin disease will be at risk of early menopause. It is important to inform them of this risk at an appropriate time in terms of their family planning.
Abdominal, pelvic, or total body irradiation is likely to result in impairment of ovarian or testicular function. Furthermore, radiotherapy to the uterus (high-dose pelvic or abdominal irradiation) in childhood may affect uterine distensibility and blood flow and its subsequent potential to accommodate a viable pregnancy. Girls with Wilms tumour or other pelvic sarcomas are at most risk of this problem, and flank irradiation (extending into the pelvis) is particularly associated with low birth weight in subsequent offspring. Limitation of uterine distensibility is also an important consideration in the light of new techniques such as embryo transfer which are now becoming available.
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Table 11.3. Chemotherapeutic agents that can have an adverse impact on fertility |
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Radiotherapy to the brain can also affect fertility indirectly through its effect on the pituitary. High dose (>24 Gy) radiotherapy to the hypothalamus/pituitary (e.g. for brain tumours) may result in delayed puberty, whereas lower doses (>24 Gy) may be associated with precocious puberty, especially in young girls.
Clinical implications A history of primary or secondary amenorrhoea is important, and boys should be asked about potency and nocturnal emissions. Pubertal development should be closely monitored in all patients at risk of late endocrinopathy, particularly in girls who have received radiotherapy to the brain as young children. Where problems are suspected, measurement of FSH and LH, and possibly inhibin, may be helpful, with additional measurement of testosterone in boys and oestradiol in girls. Semen analysis will determine fertile potential for male survivors, although many do not wish to know their fertility status for some time.
The vast majority of patients, particularly girls, need reassurance that they are fertile and indeed should be given or encouraged to seek appropriate contraceptive advice.
Close liaison with, and access to, clinical specialists in fertility is vital to provide appropriate information and access to therapeutic interventions whenever possible. This is also an example where patients of an appropriate age may benefit from attending the clinic without their parents to allow open and honest discussion about important, but sometimes uncomfortable, issues. The timing of these discussions is important and the need for confidentiality must be recognized.
The breast
A field of radiation that includes prepubertal breast tissue may result in significant breast hypoplasia and asymmetry. Girls receiving this therapy are also at an increased risk of second malignancy, which is particularly well recognized in younger women <25 years treated for Hodgkin disease. All female survivors of childhood cancer should be taught breast selfexamination and this should be emphasized for those previously exposed to radiotherapy.
Careful monitoring, with appropriate use of mammography or MRI scanning is advised. These examinations are of prime importance in addition to breast self-examination.
The impact of previous radiotherapy on a mother's ability to breast-feed remains unknown, although lactation may be impaired.
Second malignancy
At some stage following completion of therapy, patients need to be informed that they may be at an increased risk of a second cancer. For many this risk is small, although it remains an important cause of late deaths in survivors.7,11 The greatest risk occurs in those with previous exposure to radiotherapy, when a second malignancy may occur within or on the edge of the radiation field. Exposure to the epipodophyllotoxins (topoisomerase II inhibitors such as VP16 and VM26) and alkylating agents also increases the risk of a second cancer.
Other patients and their families may be at risk if they have a condition known to be associated with an increased risk of malignancy (e.g. Li–Fraumeni syndrome, familial retinoblastoma, or neurofibromatsis type I) (see Chapter 2) These families will need referral for genetic counselling and, for some, ongoing cancer screening.
Patients should be encouraged to take part in any national screening programmes that are available (e.g. cervical or testicular). Breast cancer screening is particularly important, where in addition to breast self-examination and formal clinical breast examination, patients should be advised regarding early mammography. It has been suggested that mammography should commence 8–10 years after radiotherapy to the chest and be undertaken every 1–3 years thereafter (once the patient is >25 years old) depending on risk. Because of the denser breast tissue in younger patients, mammograms may be difficult to interpret. Local policies vary and advice should be taken for patients on an individual basis. Other imaging modalities (e.g. ultrasound and MRI) are currently under evaluation as assessment tools for screening in highrisk patients.
Survivors of childhood cancer should be encouraged to take responsibility for their own health, and advice regarding a healthy lifestyle is important for all survivors. The following should be specifically encouraged:
· avoiding excessive exposure to the sun
· avoid smoking
· healthy diet
· active lifestyle.
Dental issues
The recognition of dental problems is important. They are common following radiotherapy, particularly if it was received at a young age, or given to a relatively high dose (>30 Gy). The development of the tooth or its root may be impaired, with an increase in malocclusion or dental decay. Good oral hygiene and regular dental review should be encouraged, with orthodontic intervention as appropriate. Intensive chemotherapy given at a time of critical development in dentition may also result in the impairment of root development and increased caries.
Hearing
Those at risk of hearing loss will have been exposed to cisplatin or carboplatin (the risk is greater with cisplatin and with higher cumulative doses); the most common impairment is high-tone loss. The risk is increased if the patient has had a high exposure to aminoglycosides. Radiotherapy, particularly to the posterior fossa, can also lead to loss of hearing. If abnormalities are identified, ongoing review is important.
For those at risk of hearing impairment, a pure tone audiogram should be performed at regular intervals throughout treatment, so that the balance of risk and benefit of the chemotherapy can be adequately assessed, and at the end of therapy. For younger children, formal paediatric ENT or audiology assessments should be provided. As children are reviewed in clinic, parents should be specifically questioned about the hearing and speech development of their child with early referral for speech therapy where necessary.
Transfusion-related sequelae
The risk of transfusion-related infection depends on the country where the patient was treated and the screening that was in place at the time of therapy. The screening programmes for hepatitis B, hepatitis C, and HIV vary within Europe and across other countries. Patients should be offered screening whenever appropriate, with referral to specialist care if infection is confirmed.
Splenectomy
Some patients will lose their spleen as a direct result of involvement by the primary tumour (usually lymphoma) and subsequent removal. A greater number will lose splenic function as a result of radiotherapy either to the spleen itself, or following total body irradiation and highdose conditioning therapy for bone marrow transplant (functional splenectomy). Immunization is often not possible prior to loss of splenic function, as the patient will have been immunosuppressed at the time of active therapy. Immunization following immune recovery is essential and patients should receive the following:
· pneumococcal vaccine with re-immunization every 5 years
· Haemophilus influenzae type b vaccine
· influenza vaccine annually
· new conjugated meningococcal C vaccine.
Long-term antibiotic prophylaxis (penicillin or erythromycin) is strongly recommended, with additional antibiotics available to be used whenever infective symptoms occur or when the patient is travelling. It should be noted that these patients are particularly susceptible to malaria. Care should be taken when travelling to areas endemic for malaria and appropriate chemoprophylaxis should be provided.
Psychosocial issues
Reports of long-term psychologic or adjustment problems in survivors of childhood cancer are conflicting. Many patients adapt extremely well to normal life following therapy, and adjust psychologically and socially as they move through childhood and adolescence into adulthood. However, it is well recognized that some patients are at risk of anxiety and depression in the long term with evidence of post-traumatic stress in some. All patients are at risk of psychologic problems and should be given the opportunity to express their concerns in the clinic setting. More formal consideration of these issues is appropriate for those survivors at greater risk of late adverse psychosocial issues.
A large comparative study of psychosocial outcomes in long-term survivors of acute lymphoblastic leukaemia and Wilms tumour suggested no increase in rates of psychiatric disorders when compared with a control peer group.12 However, there was evidence of poorer functioning in the area of relationships and friendships in the survivors when compared with the control subjects. Poorer coping was associated with lower intellectual ability scores. This is of note, as it mirrors findings in other studies. Although patient selection and study designs vary, some themes persist in the literature relating to the risk factors for problems with long-term psychologic adjustment. Other studies have also suggested that those who have received cranial radiotherapy, particularly at a young age, are at a significantly increased risk of psychologic problems and learning difficulties, and are less likely to marry or be in a long-term relationship.
The diagnosis and its treatment are clearly not the only factors influencing psychologic outcome, and other issues such as family functioning, coping mechanisms, length of follow-up, and premorbid psychologic state may be important.
The complexity of this area should be recognized, and the discussion of issues such as adaptation and coping mechanisms is beyond the scope of this chapter. Nonetheless these issues may be important and the reader is referred to the recent text by Eiser13 for further details.
Interventions for psychologic sequelae
There is, rightly, a strong focus on the physical late effects of therapy in the clinic setting. However, psychosocial issues and problems should not be overlooked as they may be very amenable to therapy. Timely intervention may make a real difference to long-term outcome, and formal neurologic or psychologic assessment is vital for some. The causes of behavioural problems seen in survivors of childhood cancer are likely to be multifactorial and appropriate supportive therapy should be offered if at all possible.
Educational issues
Ongoing close liaison with education services will also be very important for some patients. Certain specific learning difficulties are known to be associated with previous cranial radiotherapy, and this is recognized as the most important risk factor for educational problems in the long term. Such problems include concentration, visual and spatial awareness, mathematics, and language processing, although any aspect of cognitive functioning may be affected. Prolonged school absence or prolonged hospitalization may adversely affect educational ability in others, again raising the need for formal educational assessment or support.
Early formal assessment for patients with risk factors such as prior cranial radiotherapy, prolonged absence from school, and hearing or visual deficits following therapy is imperative, as subtle problems may be difficult to recognize in the busy classroom setting. It is of particular concern as these patients may be embarrassed and seek to cover up their difficulties; furthermore, children may respond well to additional help with specific learning difficulties. Deficits in educational attainment, social competence, and behaviour can be difficult to predict even when cognitive, sensorimotor, endocrine, and emotional impairments have been documented.
Strategies for minimizing late effects
Minimizing therapy
Significant achievements have been made in the treatment of childhood cancer over the past two decades, despite a remarkable lack of new chemotherapeutic agents or the development of other novel techniques. Much of the progress has been a result of the better understanding of the biology of the disease and, through collaboration and sharing data, analysis of risk factors has led to an ability to stratify patients more appropriately. Those patients who are at a greater risk of relapse can be treated more intensively (with improved supportive care), whilst those with a better prognosis may receive less intensive therapy with fewer late adverse effects. There are a number of examples where a systematic change in therapy has led to a significant fall in the frequency or severity of late effects, such as the omission of cranial radiotherapy as central nervous system prophylaxis in the treatment of acute lymphoblastic leukaemia. Problems with cognitive development and hormonal dysfunction (growth hormone secretion) have been significantly reduced as a result of the change in therapy, although it is possible that the more intensive chemotherapy now used may lead to other late effects.
However, in other situations the balance, or choices, in therapy may be less clear and debate continues about optimizing cure rates whilst limiting late adverse sequelae. Two examples are given below.
Hodgkin disease
Hodgkin disease is one of the clearest examples where the prognosis for the majority of patients with the disease is excellent, yet where there are well-recognized and important late effects of therapy. Chemotherapy and involved field radiotherapy have been the mainstay of treatment for decades. However as the late effects of radiotherapy and the excellent results with chemotherapy alone have been recognized, so the number of patients requiring radiotherapy has fallen and the size of fields used reduced.
The impact of radiotherapy is particularly important for girls, and a dramatic increase in the number with breast cancers was largely responsible for the high incidence of second cancers in survivors of Hodgkin disease (standardized incidence ratio 18.1 [95 per cent confidence interval (CI) 14.3–22.3]), where the estimated actuarial incidence of breast cancer in female survivors with Hodgkin's disease was 35 per cent (CI 17.4–52.6).14
Even if radiotherapy can be avoided, other important late effects for patients with Hodgkin disease must be considered, and minimizing the long-term impact of chemotherapy has been also challenging. As previously described, alkylating agents are known to be associated with infertility in boys and early menopause in girls.
Therefore treatment strategies have been developed which attempt to minimize these late effects in a cohort of patients with an excellent prognosis. Radiotherapy is still used for some, but many patients can be treated with chemotherapy alone. In an attempt to reduce the impact of alkylating agents on fertility, new regimens have been introduced which include anthracyclines and avoid some of the alkylating agents. Therefore a different pattern of late effects can be anticipated, with a potentially greater impact on the heart, particularly if radiotherapy for mediastinal disease cannot be avoided.
Whether therapy should be gender based is a matter of debate, and a study in the UK has attempted to give choice to some patients and their families. For example, patients with stage I (neck) disease can be offered a choice of radiotherapy or chemotherapy. This is an interesting question, but whether the families have adequate information to make such a choice, or whether they actually wish to do so, remains to be seen.
Rhabdomyosarcoma
Radiotherapy has been a cornerstone of the treatment of soft tissue sarcomas, including rhabdomyosarcomas, and has been used systematically as a strategy for local disease control, often with surgery. It was then recognized that some patients could be cured without radiotherapy, not just at the very ‘good risk’ sites (e.g. paratesticular), but also at other sites where the late effects of radiotherapy (e.g. orbit or pelvis) may cause significant morbidity. Different strategies have been developed within different international collaborative groups, and a workshop was convened between these groups to evaluate the relative outcome following the different treatment strategies for one site with a high survival rate, the orbit. The treatment of orbital rhabdomyosarcoma highlights the issue of the philosophical differences in the approach to therapy and the importance of careful risk stratification. The results demonstrated a comparable overall survival for the four international groups participating.15 However, the event-free survival of those patients who had not received systematic radiotherapy was significantly lower than that of the other groups. These patients went on to receive further chemotherapy and radiotherapy. Nonetheless, this strategy (radiotherapy for selected patients) also demonstrated that approximately 40 per cent of patients could be cured without radiotherapy and its associated late effects.
These examples demonstrate the importance of choices in therapy. Cure remains paramount, but there are some patients currently being overtreated who may be saved late sequelae from both radiotherapy and chemotherapy. Minimizing the numbers that relapse will also be important, as additional chemotherapy and radiotherapy will further increase the burden of late effects.
New strategies
Surgical approaches
Surgery was an important part of cancer therapy long before the introduction of chemotherapy and radiotherapy. It remains a critical part of the management of some malignancies, particularly tumours of the bone, brain, eye, and soft tissues. Surgical techniques have become increasingly sophisticated, and even when major potentially deforming surgery is required, the long-term cosmetic and functional results have dramatically improved. Examples are the endoprosthetic replacement of bone, most commonly used as part of the treatment for osteogenic sarcoma, and laser surgery for retinoblastoma. Reconstructive surgery following surgery or radiotherapy to sites such as the face, bladder, or perineum (vagina) may dramatically improve a patient's quality of life. However, assumptions about the patient's views should not be made. Some will choose to live with their deformity, adapting well even to major facial disfigurement. Others may rate function more highly than the cosmetic result (e.g. amputation versus endoprosthetic replacement). Understanding coping mechanisms and influences on body image are also an important part of optimizing outcome.
Radiotherapy approaches
The avoidance of radiotherapy wherever possible for children >3–5 years of age is the most important strategy in preventing potentially devastating late effects in this age group, as the limitation of the growth of bones and soft tissues and the impact of radiation on the brain is particularly severe in the very young. It is hoped that the use of CT and MRI planning for the treatment of many childhood tumours has dramatically improved the clinician's ability to limit the volume and dose of radiation delivered to normal tissues and therefore minimize long-term damage.
Conformal radiotherapy (i.e. shaping the beam to allow the selective avoidance of important radiosensitive structures) is becoming more sophisticated with intensity-modulated radiotherapy (IMRT), which is a further development in this area. The use of brachytherapy (e.g. for pelvic tumours) is of value in a selected population.
The late effects of radiotherapy are well described elsewhere16 and relate to the organ exposed to the treatment. Toxicity is related to size (volume) of field and cumulative dose, and the younger the child, the greater the toxicity. Direct tissue damage, inflammation, and fibrosis are most commonly seen. There is also a relationship between radiotherapy exposure and the risk of late second cancers. However, it is important to recognize that as the routine use of radiotherapy for many solid tumours and leukaemias has reduced, so the late effects of more intensive chemotherapeutic regimens may be identified in years to come. Although the avoidance of late effects is important, local control of the disease remains critical and should not be compromised.
Chemotherapy
The acute adverse effects of chemotherapy are well recognized and many strategies are in place to minimize them. This is not the case for late effects, and research in this area has centered on the reduction of late cardiotoxicty. Two strategies have been tried: the use of a cardioprotective agent, cardioxane, and the use of liposomal anthracyclines. Work is ongoing in children at present and data are currently preliminary, although there may be a place for these agents in the future.
The role of the late-effects clinic
For many patients, the model of follow-up in the paediatric oncology clinic by the physicians who originally treated the child is the ideal setting. They are seen in familiar surroundings by medical and nursing staff who have cared for them over a long period of time. However, for others, even if the frequency of follow-up is only on an annual or even biannual basis, hospital attendance may not be necessary or indeed optimal. It can be hard for a child (or the family) to consider themselves ‘cured’ if they are asked to attend hospital on a regular basis. The attendance itself can perpetuate the perception of an ongoing illness and prevent a full return to normal life. It can be very stressful, even years after therapy has been completed. It may also not be necessary.
The need for some ongoing contact with survivors is clearly very important. If they are not followed up, information about serious late effects, long-term adjustment, and future morbidity will be lost. However, much of this information could be obtained through other models of care and contact between the patient and clinical staff. Work is currently under way exploring different strategies of follow-up. For some, contact with a clinic nurse or the primary care physician, or even a telephone call or questionnaire, may be entirely adequate and less intrusive in the long term.17 There will be situations where important late effects are newly recognized, and where some asymptomatic patients may benefit from further evaluation. Future access to these patients is clearly important.
The long-term follow-up clinic has a crucial role in a number of ways (Table 11.4):
· ongoing care of those survivors with a high risk of developing late adverse effects of therapy
· monitoring of progression through puberty, particularly if there is a high risk of endocrinopathy
· coordination with other speciality clinics (e.g. cardiology, endocrinology, or neurology)
· provision of information to survivors relating to their own risks and advice regarding lifestyle and responsibility for their own care.
The majority of patients will stay on active follow-up for at least 10 years after diagnosis or until they have completed puberty, whichever is the longer. It is important to remember that the child, not his or her parents, is the patient. There may be very sensitive issues previously unknown to the child (e.g. infertility, second cancer risk) and these should be discussed at an appropriate time, when the patient is ready to receive such information, and in a confidential manner. The transition to caring for an adult can be challenging for paediatric doctors and nurses, but the correct handling of this, sometimes difficult, stage can help the survivor to move on to greater independence.
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Table 11.4. The role of the clinic in long term follow-up |
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Conclusion
The number of survivors of childhood cancer will continue to rise as survival rates improve. Whilst many important late effects of therapy are recognized and strategies are in place to address them, reliable evidence about the causes of problems and the best way to address them remains scarce. It is even unclear how many of these patients should be reviewed, how frequently, and by whom. However, national and international collaborative groups are currently developing guidelines for the follow-up of survivors. These will be based on available evidence, expert opinion, and good clinical practice in an attempt to provide practical advice and resource for clinicians responsible for these often complex patients. It will always be challenging to undertake clinical research in this area; patients move on not just psychologically, but also physically, and collecting data from cohorts is both costly and time consuming for patients and their carers alike. Nonetheless, we need to learn from these patients as they grow older, and only by following them on into the future will we understand the very-long-term effects of the treatment of childhood cancer, whether risks increase further with age, and what truly are the most cost-effective strategies for their ongoing health care.
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