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Malignant disease and the lung
PAEDIATRIC RESPIRATORY REVIEWS (2000) 1, 279–286 doi:10.1053/prrv.2000.0060, available online at http://www.idealibrary.com on
RECENT ADVANCES
Malignant disease and the lung M. E. M. Jenney Department of Paediatric Oncology, Llandough Hospital, Penlan Road, Penarth CF 64 2XX, UK KEYWORDS lung; toxicity; childhood cancer
Summary Primary lung tumours in childhood are rare. However, cancer in a child may have an impact on the lung in a number of ways. Chemotherapy and radiotherapy may be directly toxic to the lung. Young children are particularly sensitive to the effects of radiotherapy, which can cause impairment of growth of muscle, skin and bone, in addition to its direct toxic effect on the underlying lung. The lung is vulnerable to infection – particularly protozoal, viral and fungal organisms, as well as bacterial. Children undergoing bone marrow transplantation are at greater risk of lung damage, as they are profoundly immunosuppressed and have received intensive cytotoxic chemotherapy or radiotherapy. The underlying cause of lung damage may be difficult to determine because of the complexity of treatment and the additional risk of infectious complications. In a small number of children, pulmonary complications may be fatal. However, for the many survivors, although abnormalities of lung function are frequently detected, these are rarely clinically significant and, with notable exceptions, do not appear to deteriorate with time. However, data remain scanty; there is a real need for ongoing prospective studies of lung function in survivors of childhood cancer. © 2000 Harcourt Publishers Ltd
INTRODUCTION Primary malignant tumours of the lung are rare in childhood. However, the lung may be exposed to a number of insults in the child with malignant disease, which can lead to pulmonary damage. Chemotherapy itself may be directly toxic to the lung. Children are able to tolerate prolonged, intensive chemotherapy regimens, and as a result the lung becomes susceptible to infections in a profoundly immunocompromised host. Radiotherapy has a direct, toxic effect on lung tissue. It also limits the growth of bones and soft tissues, particularly when used in the young child. Metastases are common in many childhood malignancies. They frequently respond well to chemotherapy, but sequential thoracotomy is used in some tumours as part of a combined modality approach. Perhaps most importantly, these insults to the lung during childhood may have long-term effects as the lung is growing and maturing, especially during early years, ultimately limiting lung capacity and function. Correspondence to: M.E.M. Jenney, Tel: +44 29 2071 5229, Fax: +44 29 2070 8064, email: [email protected] 1526–0550/00/030279 + 08 $35.00/0
Survival rates in childhood cancer have improved dramatically over the past 30 years, now approximately 70% overall, rising to 80–90% for some children with leukaemia, Wilms’ tumour and Hodgkin’s disease. There is therefore a steady increase in the number of children and young adults in the community (approximately 1 in 900) who have survived cancer, some of whom may have longterm complications, including those affecting the lung. Children are robust, and the vast majority will have no pre-morbid conditions. They can therefore tolerate highdose, intensive therapy, usually comprising chemotherapy and, for some solid tumours, surgery with or without radiotherapy. Higher dose strategies are sometimes required, with bone marrow ablation and subsequent rescue using autologous or allogeneic stem cell re-infusion or bone marrow transplant. Therapy is intensive, and although treatment-related mortality is low, there can be significant morbidity which can have an impact on the child’s lung function, both acutely and in the long term. The long-term adverse effects on the lung following treatment result almost entirely from the therapy received. As treatment regimens have been modified © 2000 Harcourt Publishers Ltd
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over the past 30 years there has been a steady reduction in the amount of radiation used, with a corresponding increase in the use and intensity of chemotherapeutic agents. There is a lack of prospective studies evaluating the long-term effects of cancer therapy, particularly on the lung. Most reports are based on cross-sectional data which may reflect very different treatment strategies used over the time period from which the cohorts are recruited. This limits interpretation of the data. However, some important issues relating to the long-term toxicity, including radiation field and dose, the use of 1,3 -bis (2chloroethyl)-1-nitrosurea (BCNU), and other cytotoxic drugs are clearly apparent. The age at which the child is treated, and the combination and duration of therapy all have an impact on the long-term sequelae, particularly as chemotherapeutic treatment protocols intensify.
PRIMARY TUMOURS OF THE LUNG The lung is a common site for metastatic disease in children (Wilms’ tumour, osteogenic sarcoma, soft tissues sarcomas, germ cell tumours). Enlargement of mediastinal lymph nodes may also occur (typically Hodgkin’s lymphoma and T-cell non-Hodgkin’s lymphoma). However, primary tumours of the lung are exceptionally rare in childhood. Two examples are given below.
Pulmonary blastoma Pleural pulmonary blastoma is a dysembryonic neoplasm which occurs almost exclusively in childhood (other examples of dysembryonic tumours are Wilms’ tumour, neuroblastoma and hepatoblastoma). It originates from the thoracopulmonary mesenchyme. The largest series reported to date1 has identified three histiological types. Type 1 is purely cystic, type 2 cystic and solid, and type 3 purely solid. Children present with respiratory difficulty, with or without fever. The age at presentation differs for the three types being 10, 34 and 44 months for types I, II and III, respectively. Overall 5-year survival was 83% for type 1 and 42% for types II and III. Although the tumour is aggressive it responds to chemotherapy, but because of the rarity of the tumour a wide variety of chemotherapeutic regimens have been used (frequently comprising vincristine, actinomycin D and cyclophosphamide).
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LUNG TOXICITY FOLLOWING TREATMENT FOR MALIGNANT DISEASE General issues The treatment of childhood cancer comprises three modalities: surgery, radiotherapy and cytotoxic chemotherapy. All may result in long-term sequelae for the child and all may affect the lung. It is becoming increasingly apparent that many children remain asymptomatic despite identifiable abnormalities of lung function in the long term. Because of the use of multi-modal treatment, the effects of individual components may be difficult to identify. Damage may be a result of the disease process itself, intercurrent infections, or due to therapy received by the child. The age of the child at treatment may also be important; the younger the child, the more physically vulnerable. This may particularly be true for pulmonary damage, as the lung continues to mature in the post-natal period with development not complete for at least 2 years, and possibly beyond. The majority of childhood malignancies occur between 1 and 5 years.
Chemotherapy The effects of cytotoxic agents on the lung may be acute, usually with a clinical syndrome of pneumonitis or acute pulmonary oedema, or a chronic picture of restrictive lung disease or progressive pulmonary fibrosis. The incidence and severity of lung toxicity following treatment for childhood cancer is unknown. Chemotherapeutic agents are rarely given alone and the contribution of individual agents to the development of subsequent lung damage in many cases remains unclear. However, there are clear associations between some toxic agents, clinical settings and subsequent lung damage where pulmonary toxicity is important. Damage to the lung by cytotoxic agents is thought to be caused by several mechanisms; alteration in the normal pulmonary immunological balance, enhancement of the effects of proteinolytic enzymes, alteration of the growth through interference of collagen synthesis and alteration of the body’s normal oxygen systems2.
Nitrosureas
Peripheral neuro-ectodermal tumour of chest wall (Askin’s tumour) Small round cell tumours occurring in the thoracopulmonary region (classically chest wall) are known as Askin’s tumour. They occur predominently in adolescents. The classification of these tumours is poorly defined; they appear to have ‘neural’ characteristics and are thought to be of neuroectodermal origin. They are very aggressive tumours and carry a poor prognosis.
1,3 -bis (2-chloroethyl)-1-nitrosurea-(BCNU). One of the most striking reports of cytotoxic lung damage has been that relating to BCNU. Concern was first raised in 1978 with a report of a death from lung fibrosis in a patient who had received BCNU at the age of 2 years as part of treatment for medulloblastoma. Following this, a series of 31 patients who had received BCNU between 1970 and 1976 were reported. Seventeen children survived their tumour and had been asymptomatic for several years.
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However, six (35%) died of pulmonary fibrosis 1–13 years after completing treatment, and of the eight available for study, a further six had evidence of lung fibrosis on chest radiograph, biopsy or physiological lung function testing.3 These patients were reviewed 3 years later; two further patients had died of pulmonary fibrosis, giving a mortality from lung fibrosis in the survivors of their original tumour of 47%. The eight patients dying of lung fibrosis had a median age at treatment of 2.5 years. The nine long-term survivors have a median age of 10 years at the time of treatment. All five patients treated below the age of 5 years died of lung fibrosis.4 Lung fibrosis has been associated with a similar agent: 1-(2-chloroethyl)-3Cyclohexyl-1-nitrosurea (CCNU). The first report in 1983 described two patients who had received very high doses of the drug, but both had received other agents potentially toxic to the lung. Other patients have been reported to have a restrictive defect following this drug, but the majority have received additional craniospinal radiotherapy. The scatter of the radiation to the lungs may also cause lung damage.
Alkylating agents Busulphan. The alkylating agents cyclophosphamide and busulphan are known to cause lung fibrosis in adults. Busulphan is the treatment of choice in chronic myeloid leukaemia in adults. In children it is increasingly used as part of the conditioning regimen for autologous and allogeneic bone marrow transplants in those too young to receive total body irradiation (0–2 years), and those receiving autologous stem cell rescue as part of a highdose strategy in poor risk tumours. These children will have previously received intensive therapy also containing agents potentially toxic to the lung. In adults the clinical picture of lung toxicity develops insidiously and damage appears to be dose-related. There are no reports of lung toxicity in patients receiving doses of busulphan less than 500 mg in the absence of other potentially toxic factors. In a review of 56 cases the onset of lung disease was at an average cumulative dose of 2900 mg.5 The average time between commencing therapy and the onset of lung damage was greater than 4 years. Symptoms of cough, dyspnoea and fever occurred, and eventually lung fibrosis. Abnormalities on lung function testing show a restrictive defect and a reduction in transfer factor. The extent of damage in children is not known, but there are concerns because of the increasing use of the agent in a high risk (very young) group, many of whom are not yet old enough to have regular lung function testing. Cyclophosphamide. There have been several reports of lung toxicity following treatment with cyclophosphamide in adults and children. The incidence is thought to be around 1%. Cyclophosphamide is used together with busulphan and total body irradiation (TBI) as conditioning
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for bone marrow transplantation. Its role in the aetiology of subsequent lung damage has not been clarified.
Antibiotics Bleomycin. Bleomycin is an anti-tumour antibiotic isolated from Streptomyces verticullus. In children this is used most frequently in the treatment of germ cell tumours, which carry an extremely good prognosis with an overall survival of around 90%. Although bleomycin is well recognized as causing lung damage in adults, data in children remain scanty. In adults the incidence of toxicity is thought to be 10%. Initially pneumonitis may occur with symptoms of dyspnoea, cough and fever. There may be abnormalities on lung function testing without overt clinical disease. The classic radiographic changes are a fine reticulo-nodular shadow at the lung bases. Occasionally the nodules may be large in size and can be mistaken for metastatic disease. Cumulative dose, radiotherapy to the chest and supplemental oxygen therapy may all exacerbate lung damage. The potential toxicity of oxygen therapy is important for children who may require serial anaesthetics for therapy and follow-up. It is not known how long the lungs remain sensitized to oxygen therapy: therefore, care should be taken indefinitely when anaesthetics are administered. A recent review of children treated for germ cell tumours who had received bleomycin demonstrated mild long-term abnormalities. Pulmonary function tests were performed in 13 of 18 patients who had received median and cumulative dose of 120 mg/m.2 There were restrictive (n=5) or diffusion (n=3) abnormalities, but only three patients were clinically symptomatic. Chest radiographs showed mediastinal or pleural fibrosis in survivors treated with bleomycin (n=8), thoracic radiation (n=5) or surgery (n=4), but only two were symptomatic.6 Actinomycin D. Although actinomycin D has not been implicated in the pathogenesis of cytotoxic drug-induced lung damage, it enhances the toxicity of therapeutic irradiation to the lung. It follows that patients receiving irradiation to the lung (whole lung irradiation, total body irradiation, abdominal or flank irradiation), may be more susceptible to radiation induced damage if they have also received actinomycin D.
Antimetabolites Methotrexate. Methotrexate is an agent used widely in children with acute lymphoblastic leukaemia. It was first implicated as a cause of pneumonitis in 1969 with a reported incidence of 30%. However, it has subsequently been recognized that the true incidence of methotrexateinduced pneumonitis is lower, and it is likely that the first reports reflected episodes of pneumonitis caused by Pneumocystis carinii pneumonia (PCP) or other infective agents. The pathogenesis of methotrexate lung toxicity
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remains uncertain, as children rarely receive methotrexate alone. However, a hypersensitivity reaction has been postulated, as demonstrated by an acute alveolar interstitial infiltrate, hypercellularity on bronchoalveolar lavage with an increase in lymphocyte counts (predominantly CD8 suppressor/cytotoxic lymphocytes), and the rapid and complete recovery on withdrawal of the drug.7 Damage does not appear to be dose-related. Lung function tests performed during the lung disease in four children demonstrated a significant decrease in pulmonary compliance (mean 56% predicted, range 61–53%) and decreased lung transfer capacity for carbon monoxide in one child.7 Retinoic acid syndrome. All transretinoic acid (ATRA) is now the initial treatment of choice for adults with acute promyelocytic leukaemia (acute myeloid leukaemia – subtype M3), and is increasingly used in children in addition to chemotherapy. In adults a syndrome occurring 2–21 days after administration has been described, with symptoms of fever and respiratory distress (other findings include weight gain, oedema, pleural and pericardial effusions diffuse alveolar haemorrhage, skin reactions). Bilateral diffuse infiltrates may be present on chest radiograph and on CT scanning peripheral nodules have been described. Therapy comprises dexamethasone and stopping ATRA, but is not always successful. As the use of ATRA in children increases, early identification of the syndrome will be important.
The effects of multiagent chemotherapy on the lung There has been increasing interest in the lung function of two groups of children in whom survival rates are excellent and in whom lung toxicity has been identified; those surviving acute lymphoblastic leukaemia and Hodgkin’s disease. The majority of these are asymptomatic, and because of the complexity of therapy and the wide combination of chemotherapeutic agents used, the identification of specific agents responsible for any long-term damage has been difficult. However, it is important to highlight these groups, as the numbers of children attending for follow-up is increasing and lung toxicity may become important in the future as treatment protocols intensify. The most comprehensive cross-sectional review of pulmonary function after treatment for ALL in childhood is the study of a population-based cohort of 94 survivors in first remission treated without spinal irradiation or bone marrow transplantation.8 Pulmonary function tests were compared to reference values collected at the Research Institution. Children were studied at a median of 8 years after stopping therapy and had slight subclinical restrictive findings with reduced transfer factor and coefficient. Changes in lung function were related to a younger age at treatment and to more dose-intensive treatment protocols.
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A restrictive defect has also been described after therapy for Hodgkin’s disease. Young age was identified as a risk factor. Radiotherapy (mediastinal or mantle fields) is well recognized as causing a restrictive lung defect; however, a similar pattern has also been described in children receiving chemotherapy alone.
Radiotherapy-related lung toxicity In 1975 Bloomer and Hellman categorized the effects of radiation on normal tissue as acute, intermediate and late.9 These effects are thought to depend on the type of cells irradiated, the volume of normal tissue irradiated and the time/dose features (fractionation of the treatment schedule). The acute effects result from the depletion of actively dividing cells, and the extent of this reaction depends on time/dose fractionation and the total dose. Normal tissues typically involved are skin, gut (epithelium of the intestinal tract), bladder and bone marrow. Intermediate effects are also related to both time/dose fractionation and total dose. They are thought to result from injury to cells which slowly proliferate or renew, such as endothelium or connective tissue. Radiation pneumonitis and pericarditis are important intermediate effects. These effects characteristically occur at 2–3 months after treatment. Late effects are related to the total dose of irradiation administered. Almost all cells may be affected, including endothelium, connective tissue and the organ itself. The mechanism is not clearly understood, but may either affect slowly proliferating cell renewal systems or alter the structural integrity of certain macromolecules. Late radiation effects are particularly important in children, as growth of the organ, tissue or limb may be severely affected. Limitation of thoracic growth may result in a restrictive pulmonary deficit in later life, as may pulmonary fibrosis. Damage to the lung is thought to be due to direct effects of the radiation on cell membranes, protein and DNA. An inflammatory response can follow the initial tissue damage and contribute further to tissue injury. In addition, the acute changes can lead to an increased risk of infection, disturbance of immunoglobulin production and altered pulmonary diffusion.10 Radiation damage to the lung depends on a number of factors: the volume of lung irradiated, the dose and fractionation of the dose – for example, 30 Gy with conventional fractionation (1.8–2.0 Gy per fraction) delivered to the whole lung will precipitate a fatal reaction, but is well tolerated if the volume of the radiation is reduced to 25%. Fractionation of the dose permits some repair of damage to occur between fractions and improves the tolerance of the lung tissue to irradiation. Many chemotherapeutic agents interact with radiotherapy, increasing the toxicity of the irradiation. The
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most common of these is actinomycin D, although agents such as adriamycin are also important. The clinical picture of pulmonary damage following irradiation reflects the pathological processes. The clinical syndrome can be divided into two consecutive phases. The acute phase of radiation–induced pneumonitis develops insidiously with non-specific symptoms 1–6 months following completion of treatment (see below). A late “radiation fibrosis” may follow the acute phase. The earlier the onset, the more severe and protracted the illness is likely to be. A patient may be asymptomatic or, if the reaction is severe, suffer acute respiratory distress. Symptoms are usually dry cough, dyspnoea, fever and general malaise. Rarely, there may be chest pain due to pleural involvement. Physical signs are often not present, although consolidation may occur, there may be erythema of overlying skin, and a pleural friction rub may be present. The chest radiograph shows interstitial shadowing, classically with well defined borders restricted to the irradiated lung volume. A fine resolution CT scan may also be helpful in demonstrating localized abnormalities. Infection may be suspected either concurrently or as a differential diagnosis, and bronchoalveolar lavage (BAL) is a valuable tool. Therapy usually comprises steroids with or without antibiotic cover, depending on the clinical picture. In children who have received total body irradiation, graft versus host disease and an atypical intestitial pneumonitis are important differential diagnoses. If true radiation pneumonitis occurs in this setting, it may be fatal. The largest study of whole lung irradiation on the lungs of children is that of Benoist.11 Forty-eight children with pulmonary metastases were studied and followed. The dose of whole lung irradiation was 20 Gy (higher than the currently recommended dose level of 12–14 Gy). In the 11 patients in whom lung function testing was performed, reduction of vital capacity, functional residual capacity and lung compliance were observed. Long-term lung damage can occur following radiation in patients with Hodgkin’s disease who receive mediastinal or mantle radiotherapy as part of their treatment. Doses of up to 30 Gy are given to a limited field, with shielding of the lung. A reduction in total lung capacity and transfer factor has been detected in these patients at follow-up.
Surgery Surgery may be an important part of the management of some childhood tumours, in particular Wilms’ tumour and osteogenic sarcoma. It is has been well documented that for some children long-term remission and even cure can be achieved by the use of sequential thoracotomy for removal of pulmonary metastases. The long-term effect on lung function clearly depends on whether the disease is bilateral and the volume of normal lung tissue removed.
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Bone marrow transplantation (BMT) and the lung The transplant may be allogeneic (from a sibling), a matched unrelated donor (MUD), a haplotype antigen mismatched donor either related (usually parent) or unrelated, or syngeneic (from a twin). If, after marrow ablation, the patient’s own bone marrow is re-infused, the transplant is termed autologous. Autologous ‘rescue’ following marrow ablation is now often achieved using the patient’s own stem cells (rather than bone marrow) which have been harvested following stimulation by the cytokine granulocyte colony stimulating factor (G-CSF). Whilst donor marrow is used almost exclusively in the management of childhood leukaemias, marrow ablation with autologous stem cell rescue is increasingly used in treatment for high risk solid tumours. Lung toxicity following transplantation depends in part on the conditioning therapy used; for leukaemia, usually high dose cyclophosphamide +/–total body irradiation (TBI), or high dose cyclophosphamide with busulphan for the younger child is used. Children undergoing myeloablative therapy for solid tumours could have a number of chemotherapeutic agents in high dose; e.g. carboplatin, cyclophosphamide, busulphan, etoposide alone or in combination. These children have often previously received intensive therapy over a prolonged period, which may have an additional adverse effect on the lung. This is particularly important if the child has had prior lung irradiation with the subsequent use of busulphan or bleomycin. A further risk factor for lung damage is infection in a child who is profoundly immunosuppressed. Whilst the pattern of infection reflects that of other children receiving therapy for malignant disease (see below), there is an increased risk of fungal and viral (particularly CMV) infection. Systemic, oral antifungal (fluconazole, itraconazole) and antiviral (acyclovir) prophylaxis are routinely prescribed throughout the transplant period, and if the child has no evidence of previous infection with CMV, CMVnegative or leucodepleted blood products are used wherever possible to minimize risk. In children who have received allogeneic bone marrow or stem cells, a further complication is graft versus host disease (GVHD). T cells from the donor marrow proliferate and differentiate in response to histocompatability antigens in the host (recipient) tissue and attack recipient cells with resulting signs and symptoms of GVHD. T-cell depletion of the marrow or immunosuppression posttransplant are used in an attempt to avoid/control GVHD. The risk of GVHD is higher in older children (>10 years) and in children who have received marrow from unrelated or ‘mismatched’ donors. Acute GVHD usually affects the skin, gastrointestinal tract and liver. The lung is affected by GVHD in its chronic phase. The pathogenesis of the lung damage remains
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unclear: however, brochiolitis obliterans is known to occur. A longitudinal study of 25 children who had undergone BMT for leukaemia or lymphoma demonstrated a reduction of transfer factor and lung volumes immediately after BMT which initially improved. However, at a median follow-up of 8 years post-transplant, the children had significantly reduced transfer factor, total lung capacity and forced vital capacity. All children were asymptomatic at the time of testing, and none had chronic GVHD.12 A further study of 77 children undergoing BMT assessed pre- and post transplant demonstrated abnormalities both in the pre-transplant (when compared to predicted values) and further deterioration at 100 days post-transplant. The pattern of abnormalities was similar, with a fall in DLCO, vital capacity pre-transplant compared to controls and a further fall in DLCO, VC and TLC when compared to pre-BMT data. There is concern regarding the recent increase in the use of high-dose cyclophosphamide together with highdose busulphan as conditioning therapy for autologous transplant for some poor risk tumours (e.g. neuroblastoma). These procedures are frequently performed in very young children, who may be at increased risk of pulmonary dysfunction.
Infectious complications The colonization of the upper airway is altered by chemotherapy; there is a fall in secretory immunoglobulins and alteration of the normal humoral and mucosal immune mechanisms. These factors lead to an increased risk of infection, and if the child is neutropenic then the likelihood of lower respiratory tract infection is even greater. One particular complication that presents is fever, deteriorating lung function with pulmonary infiltrates on the chest radiograph. The infiltrates may be localized or diffuse, and are a common and sometimes complex diagnostic challenge. The differential diagnosis will depend on whether the child is neutropenic and whether the radiograph abnormality is diffuse or localized. All children presenting with clinical signs and symptoms of pneumonia should be evaluated with a chest radiograph, blood cultures, blood count and measurement of oxygen saturation. Bronchoalveolar lavage (BAL) can be extremely valuable as it carries a relatively low morbidity. However, it may not be helpful if anti-viral or anti fungal agents, or high dose co-trimoxazole, have already been commenced, or if the underlying process is drug- or radiation-induced. Open lung biopsy is the gold standard,12 but is not frequently used because of the associated morbidity in a child who may already potentially require ventilation. Transbronchial biopsy is usually not indicated, in particular if the platelet count is also low. For both neutropenic and non-neutropenic patients, the cause of the ‘pneumonia’ can be bacterial, viral,
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fungal, protozoal, drug-induced or a manifestation of radiation pneumonitis. The organisms will vary according to the immunological state of the child and are listed below:
Non-neutropenic (often lymphopenic) child Protozoa Fungi Viruses Bacteria
P. carinii,T. Gondii Aspergillus, candida, Zygomcetes, cryptococcus RSV, adenovirus, CMV,VZV, HSV, influenza Mycoplasma, Legionella, Chlamydia, Mycobacteria
Cytotoxic chemotherapy Radiation
The aetiology is similar for both neutropenic and nonneutropenic children; bacterial infection is more likely in the neutropenic child and protozoal in the nonneutropenic (but lymphopenic) child. Localized infiltrates are less likely to be caused by protozoal organisms than diffuse infiltrates. The most common infective causes of pneumonitis are discussed below.
Pneumocystis carinii pneumonia (PCP) Pneumocystis carinii infection is one of the commonest infections occurring in the non-neutropenic, immunosuppressed child. The majority of normal children have been exposed to this organism. Infection is thought to occur following reactivation of latent cysts, although patient to patient transmission has also been suggested. Characteristically children with PCP infection present with a dry cough, fever and increasing tachypnoea and hypoxia. Crackles may not be audible in the chest. The chest radiograph classically shows bilateral infiltrates radiating from the hilum, although the appearances may be focal. Children at particular risk of PCP infection are those who have prolonged continuous immunosuppressive therapy, particularly with steroids: for example, those receiving treatment for acute lymphoblastic leukaemia, some lymphomas, Ewing’s sarcoma, and following BMT. In these children, prophylactic antibiotic therapy is mandatory. This usually comprises co-trimoxazole twice daily 2 or 3 days each week. If this is not tolerated, dapsone or nebulized pentamidine may be used.
Aspergillus Aspergillus most commonly occurs in those children profoundly immunosuppressed (with neutropenia) for long periods. For example, those receiving therapy for acute
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non-lymphoblastic leukaemia, some lymphomas, following BMT or following high-dose chemotherapy with autologous stem cell re-infusion. Children who have received prolonged courses of broad spectrum intravenous antibiotic are at particular risk, and for that reason if fever persists after 5 days of antibiotic therapy, empirical antifungal therapy is commenced with amphotericin B or ambisome (liposomal amphotericin). Aspergillus flavus and A. fumigatus are the most common species. There is an increased risk of aspergillus infection where high levels of dust are present (e.g. around building works). Clinical symptoms are indistinguishable from other causes of pneumonitis, although haemoptysis may occur in severe cases. The chest radiography may show localized rounded or even cavitating lesions. Diagnosis usually relies on BAL or, if tolerated, open lung biopsy.
Cytomegalovirus (CMV) Children are at most risk of CMV pneumonitis following BMT. The most common cause is reactivation of the latent virus in children who have evidence of prior CMV infection (IgG antibody positive) at the time of their transplant. Transmission also occurs through blood product transfusion or from the donor marrow. Children with GVHD are at greatest risk of CMV infection. The virus can be isolated from urine, blood (buffy coat and PCR) or from BAL. Clinically, CMV pneumonitis is difficult to distinguish from that caused by other infective agents. The chest radiograph shows bilateral diffuse or nodular infiltrates. Treatment with gancyclovir is often effective, although subsequent reactivation can occur. The use of intravenous immunoglobulin to prevent CMV infection is debated, but it is routine practice is some transplant units.
SUMMARY The paediatric lung can be adversely affected by cancer therapy in a number of ways. However, there is remarkably little long-term damage, except in a minority of patients who have received radiotherapy (particularly at a young age), or who have received agents known to cause long-term damage, e.g. BCNU. Although abnormalities can be detected post-therapy, the majority are asymptomatic. However, it is not known whether these children will develop long-term complications or whether they will be at greater risk of chronic lung disease in adult life. Pulmonary complications are multifactorial. Complications may be due to a combination of chemotherapy, radiotherapy and infection. It remains very difficult to identify individual factors responsible either clinically or pathologically. Documentation of the effects of therapy for childhood cancer on the lung is poor. The majority of studies are
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based on cross-sectional cohorts who have often received very different treatment regimens. Although assessment of lung function in very young children remains a challenge, there is a need for large prospective studies of children treated on current protocols. Cure rates are improving, but often at the cost of more intensive therapy: the impact of such changes on the lung in the long term are unknown.
PRACTICE POINTS • Damage to lung sustained during treatment for childhood cancer is often mild and the child asymptomatic. • A minority of patients are a risk of significant impairment depending on therapy received (e.g. following bone marrow transplantation). • The aetiology of long term damage is multifactorial. • Radiotherapy is toxic to the lung. The extent of damage depends on cumulative dose, volume of lung irradiated and the age of the child at the time of therapy.
RESEARCH DIRECTIONS • Prospective (longitudinal) assessment of lung function in children treated for cancer. • Understanding changes in immune status during therapy for childhood cancer and its relationship with lung disease. • The impact of pneumonitis during treatment on lung function in the long term.
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7. Fauroux V, Meyer-Milsztaim A, Boccon-Givod L et al. Cytotoxic drug induced pulmonary disease in infants and children. Paediat Pulmonol 1994; 18: 347–355. 8. Nysom K, Holm K, Hertz H, Hesse B. Risk factors for reduced pulmonary function after malignant lymphoma in childhood. Med Paediatr Oncol 1998; 30: 240–248. 9. Bloomer WD, Hellman F. Normal tissue responses to radiation therapy. New Engl J Med 1975; 293: 80–83. 10. Gross N. The pathogensis of radiation – induced lung damage. Lung 1981; 159: 115–125.
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11. Benoist MR, Lemerle J, Jean R, Rufin T, Scheinmann P, Pauper J. Effects on pulmonary function of whole lung irradiation for Wilms’ tumour in children. Thorax 1982; 37: 175–180. 12. Nysom K, Holm K, Birger H et al. Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma. Arch Dis Child 1996; 74: 432–436. 13. Browne MJ, Potter D, Gress J et al. A randomised trial of open lung biopsy versus empiric antimicrobial therapy in cancer patients with diffuse pulmonary infiltrates. J Clin Oncol 1990; 8: 222.
RECENT ADVANCES
Malignant disease and the lung M. E. M. Jenney Department of Paediatric Oncology, Llandough Hospital, Penlan Road, Penarth CF 64 2XX, UK KEYWORDS lung; toxicity; childhood cancer
Summary Primary lung tumours in childhood are rare. However, cancer in a child may have an impact on the lung in a number of ways. Chemotherapy and radiotherapy may be directly toxic to the lung. Young children are particularly sensitive to the effects of radiotherapy, which can cause impairment of growth of muscle, skin and bone, in addition to its direct toxic effect on the underlying lung. The lung is vulnerable to infection – particularly protozoal, viral and fungal organisms, as well as bacterial. Children undergoing bone marrow transplantation are at greater risk of lung damage, as they are profoundly immunosuppressed and have received intensive cytotoxic chemotherapy or radiotherapy. The underlying cause of lung damage may be difficult to determine because of the complexity of treatment and the additional risk of infectious complications. In a small number of children, pulmonary complications may be fatal. However, for the many survivors, although abnormalities of lung function are frequently detected, these are rarely clinically significant and, with notable exceptions, do not appear to deteriorate with time. However, data remain scanty; there is a real need for ongoing prospective studies of lung function in survivors of childhood cancer. © 2000 Harcourt Publishers Ltd
INTRODUCTION Primary malignant tumours of the lung are rare in childhood. However, the lung may be exposed to a number of insults in the child with malignant disease, which can lead to pulmonary damage. Chemotherapy itself may be directly toxic to the lung. Children are able to tolerate prolonged, intensive chemotherapy regimens, and as a result the lung becomes susceptible to infections in a profoundly immunocompromised host. Radiotherapy has a direct, toxic effect on lung tissue. It also limits the growth of bones and soft tissues, particularly when used in the young child. Metastases are common in many childhood malignancies. They frequently respond well to chemotherapy, but sequential thoracotomy is used in some tumours as part of a combined modality approach. Perhaps most importantly, these insults to the lung during childhood may have long-term effects as the lung is growing and maturing, especially during early years, ultimately limiting lung capacity and function. Correspondence to: M.E.M. Jenney, Tel: +44 29 2071 5229, Fax: +44 29 2070 8064, email: [email protected] 1526–0550/00/030279 + 08 $35.00/0
Survival rates in childhood cancer have improved dramatically over the past 30 years, now approximately 70% overall, rising to 80–90% for some children with leukaemia, Wilms’ tumour and Hodgkin’s disease. There is therefore a steady increase in the number of children and young adults in the community (approximately 1 in 900) who have survived cancer, some of whom may have longterm complications, including those affecting the lung. Children are robust, and the vast majority will have no pre-morbid conditions. They can therefore tolerate highdose, intensive therapy, usually comprising chemotherapy and, for some solid tumours, surgery with or without radiotherapy. Higher dose strategies are sometimes required, with bone marrow ablation and subsequent rescue using autologous or allogeneic stem cell re-infusion or bone marrow transplant. Therapy is intensive, and although treatment-related mortality is low, there can be significant morbidity which can have an impact on the child’s lung function, both acutely and in the long term. The long-term adverse effects on the lung following treatment result almost entirely from the therapy received. As treatment regimens have been modified © 2000 Harcourt Publishers Ltd
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over the past 30 years there has been a steady reduction in the amount of radiation used, with a corresponding increase in the use and intensity of chemotherapeutic agents. There is a lack of prospective studies evaluating the long-term effects of cancer therapy, particularly on the lung. Most reports are based on cross-sectional data which may reflect very different treatment strategies used over the time period from which the cohorts are recruited. This limits interpretation of the data. However, some important issues relating to the long-term toxicity, including radiation field and dose, the use of 1,3 -bis (2chloroethyl)-1-nitrosurea (BCNU), and other cytotoxic drugs are clearly apparent. The age at which the child is treated, and the combination and duration of therapy all have an impact on the long-term sequelae, particularly as chemotherapeutic treatment protocols intensify.
PRIMARY TUMOURS OF THE LUNG The lung is a common site for metastatic disease in children (Wilms’ tumour, osteogenic sarcoma, soft tissues sarcomas, germ cell tumours). Enlargement of mediastinal lymph nodes may also occur (typically Hodgkin’s lymphoma and T-cell non-Hodgkin’s lymphoma). However, primary tumours of the lung are exceptionally rare in childhood. Two examples are given below.
Pulmonary blastoma Pleural pulmonary blastoma is a dysembryonic neoplasm which occurs almost exclusively in childhood (other examples of dysembryonic tumours are Wilms’ tumour, neuroblastoma and hepatoblastoma). It originates from the thoracopulmonary mesenchyme. The largest series reported to date1 has identified three histiological types. Type 1 is purely cystic, type 2 cystic and solid, and type 3 purely solid. Children present with respiratory difficulty, with or without fever. The age at presentation differs for the three types being 10, 34 and 44 months for types I, II and III, respectively. Overall 5-year survival was 83% for type 1 and 42% for types II and III. Although the tumour is aggressive it responds to chemotherapy, but because of the rarity of the tumour a wide variety of chemotherapeutic regimens have been used (frequently comprising vincristine, actinomycin D and cyclophosphamide).
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LUNG TOXICITY FOLLOWING TREATMENT FOR MALIGNANT DISEASE General issues The treatment of childhood cancer comprises three modalities: surgery, radiotherapy and cytotoxic chemotherapy. All may result in long-term sequelae for the child and all may affect the lung. It is becoming increasingly apparent that many children remain asymptomatic despite identifiable abnormalities of lung function in the long term. Because of the use of multi-modal treatment, the effects of individual components may be difficult to identify. Damage may be a result of the disease process itself, intercurrent infections, or due to therapy received by the child. The age of the child at treatment may also be important; the younger the child, the more physically vulnerable. This may particularly be true for pulmonary damage, as the lung continues to mature in the post-natal period with development not complete for at least 2 years, and possibly beyond. The majority of childhood malignancies occur between 1 and 5 years.
Chemotherapy The effects of cytotoxic agents on the lung may be acute, usually with a clinical syndrome of pneumonitis or acute pulmonary oedema, or a chronic picture of restrictive lung disease or progressive pulmonary fibrosis. The incidence and severity of lung toxicity following treatment for childhood cancer is unknown. Chemotherapeutic agents are rarely given alone and the contribution of individual agents to the development of subsequent lung damage in many cases remains unclear. However, there are clear associations between some toxic agents, clinical settings and subsequent lung damage where pulmonary toxicity is important. Damage to the lung by cytotoxic agents is thought to be caused by several mechanisms; alteration in the normal pulmonary immunological balance, enhancement of the effects of proteinolytic enzymes, alteration of the growth through interference of collagen synthesis and alteration of the body’s normal oxygen systems2.
Nitrosureas
Peripheral neuro-ectodermal tumour of chest wall (Askin’s tumour) Small round cell tumours occurring in the thoracopulmonary region (classically chest wall) are known as Askin’s tumour. They occur predominently in adolescents. The classification of these tumours is poorly defined; they appear to have ‘neural’ characteristics and are thought to be of neuroectodermal origin. They are very aggressive tumours and carry a poor prognosis.
1,3 -bis (2-chloroethyl)-1-nitrosurea-(BCNU). One of the most striking reports of cytotoxic lung damage has been that relating to BCNU. Concern was first raised in 1978 with a report of a death from lung fibrosis in a patient who had received BCNU at the age of 2 years as part of treatment for medulloblastoma. Following this, a series of 31 patients who had received BCNU between 1970 and 1976 were reported. Seventeen children survived their tumour and had been asymptomatic for several years.
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However, six (35%) died of pulmonary fibrosis 1–13 years after completing treatment, and of the eight available for study, a further six had evidence of lung fibrosis on chest radiograph, biopsy or physiological lung function testing.3 These patients were reviewed 3 years later; two further patients had died of pulmonary fibrosis, giving a mortality from lung fibrosis in the survivors of their original tumour of 47%. The eight patients dying of lung fibrosis had a median age at treatment of 2.5 years. The nine long-term survivors have a median age of 10 years at the time of treatment. All five patients treated below the age of 5 years died of lung fibrosis.4 Lung fibrosis has been associated with a similar agent: 1-(2-chloroethyl)-3Cyclohexyl-1-nitrosurea (CCNU). The first report in 1983 described two patients who had received very high doses of the drug, but both had received other agents potentially toxic to the lung. Other patients have been reported to have a restrictive defect following this drug, but the majority have received additional craniospinal radiotherapy. The scatter of the radiation to the lungs may also cause lung damage.
Alkylating agents Busulphan. The alkylating agents cyclophosphamide and busulphan are known to cause lung fibrosis in adults. Busulphan is the treatment of choice in chronic myeloid leukaemia in adults. In children it is increasingly used as part of the conditioning regimen for autologous and allogeneic bone marrow transplants in those too young to receive total body irradiation (0–2 years), and those receiving autologous stem cell rescue as part of a highdose strategy in poor risk tumours. These children will have previously received intensive therapy also containing agents potentially toxic to the lung. In adults the clinical picture of lung toxicity develops insidiously and damage appears to be dose-related. There are no reports of lung toxicity in patients receiving doses of busulphan less than 500 mg in the absence of other potentially toxic factors. In a review of 56 cases the onset of lung disease was at an average cumulative dose of 2900 mg.5 The average time between commencing therapy and the onset of lung damage was greater than 4 years. Symptoms of cough, dyspnoea and fever occurred, and eventually lung fibrosis. Abnormalities on lung function testing show a restrictive defect and a reduction in transfer factor. The extent of damage in children is not known, but there are concerns because of the increasing use of the agent in a high risk (very young) group, many of whom are not yet old enough to have regular lung function testing. Cyclophosphamide. There have been several reports of lung toxicity following treatment with cyclophosphamide in adults and children. The incidence is thought to be around 1%. Cyclophosphamide is used together with busulphan and total body irradiation (TBI) as conditioning
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for bone marrow transplantation. Its role in the aetiology of subsequent lung damage has not been clarified.
Antibiotics Bleomycin. Bleomycin is an anti-tumour antibiotic isolated from Streptomyces verticullus. In children this is used most frequently in the treatment of germ cell tumours, which carry an extremely good prognosis with an overall survival of around 90%. Although bleomycin is well recognized as causing lung damage in adults, data in children remain scanty. In adults the incidence of toxicity is thought to be 10%. Initially pneumonitis may occur with symptoms of dyspnoea, cough and fever. There may be abnormalities on lung function testing without overt clinical disease. The classic radiographic changes are a fine reticulo-nodular shadow at the lung bases. Occasionally the nodules may be large in size and can be mistaken for metastatic disease. Cumulative dose, radiotherapy to the chest and supplemental oxygen therapy may all exacerbate lung damage. The potential toxicity of oxygen therapy is important for children who may require serial anaesthetics for therapy and follow-up. It is not known how long the lungs remain sensitized to oxygen therapy: therefore, care should be taken indefinitely when anaesthetics are administered. A recent review of children treated for germ cell tumours who had received bleomycin demonstrated mild long-term abnormalities. Pulmonary function tests were performed in 13 of 18 patients who had received median and cumulative dose of 120 mg/m.2 There were restrictive (n=5) or diffusion (n=3) abnormalities, but only three patients were clinically symptomatic. Chest radiographs showed mediastinal or pleural fibrosis in survivors treated with bleomycin (n=8), thoracic radiation (n=5) or surgery (n=4), but only two were symptomatic.6 Actinomycin D. Although actinomycin D has not been implicated in the pathogenesis of cytotoxic drug-induced lung damage, it enhances the toxicity of therapeutic irradiation to the lung. It follows that patients receiving irradiation to the lung (whole lung irradiation, total body irradiation, abdominal or flank irradiation), may be more susceptible to radiation induced damage if they have also received actinomycin D.
Antimetabolites Methotrexate. Methotrexate is an agent used widely in children with acute lymphoblastic leukaemia. It was first implicated as a cause of pneumonitis in 1969 with a reported incidence of 30%. However, it has subsequently been recognized that the true incidence of methotrexateinduced pneumonitis is lower, and it is likely that the first reports reflected episodes of pneumonitis caused by Pneumocystis carinii pneumonia (PCP) or other infective agents. The pathogenesis of methotrexate lung toxicity
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remains uncertain, as children rarely receive methotrexate alone. However, a hypersensitivity reaction has been postulated, as demonstrated by an acute alveolar interstitial infiltrate, hypercellularity on bronchoalveolar lavage with an increase in lymphocyte counts (predominantly CD8 suppressor/cytotoxic lymphocytes), and the rapid and complete recovery on withdrawal of the drug.7 Damage does not appear to be dose-related. Lung function tests performed during the lung disease in four children demonstrated a significant decrease in pulmonary compliance (mean 56% predicted, range 61–53%) and decreased lung transfer capacity for carbon monoxide in one child.7 Retinoic acid syndrome. All transretinoic acid (ATRA) is now the initial treatment of choice for adults with acute promyelocytic leukaemia (acute myeloid leukaemia – subtype M3), and is increasingly used in children in addition to chemotherapy. In adults a syndrome occurring 2–21 days after administration has been described, with symptoms of fever and respiratory distress (other findings include weight gain, oedema, pleural and pericardial effusions diffuse alveolar haemorrhage, skin reactions). Bilateral diffuse infiltrates may be present on chest radiograph and on CT scanning peripheral nodules have been described. Therapy comprises dexamethasone and stopping ATRA, but is not always successful. As the use of ATRA in children increases, early identification of the syndrome will be important.
The effects of multiagent chemotherapy on the lung There has been increasing interest in the lung function of two groups of children in whom survival rates are excellent and in whom lung toxicity has been identified; those surviving acute lymphoblastic leukaemia and Hodgkin’s disease. The majority of these are asymptomatic, and because of the complexity of therapy and the wide combination of chemotherapeutic agents used, the identification of specific agents responsible for any long-term damage has been difficult. However, it is important to highlight these groups, as the numbers of children attending for follow-up is increasing and lung toxicity may become important in the future as treatment protocols intensify. The most comprehensive cross-sectional review of pulmonary function after treatment for ALL in childhood is the study of a population-based cohort of 94 survivors in first remission treated without spinal irradiation or bone marrow transplantation.8 Pulmonary function tests were compared to reference values collected at the Research Institution. Children were studied at a median of 8 years after stopping therapy and had slight subclinical restrictive findings with reduced transfer factor and coefficient. Changes in lung function were related to a younger age at treatment and to more dose-intensive treatment protocols.
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A restrictive defect has also been described after therapy for Hodgkin’s disease. Young age was identified as a risk factor. Radiotherapy (mediastinal or mantle fields) is well recognized as causing a restrictive lung defect; however, a similar pattern has also been described in children receiving chemotherapy alone.
Radiotherapy-related lung toxicity In 1975 Bloomer and Hellman categorized the effects of radiation on normal tissue as acute, intermediate and late.9 These effects are thought to depend on the type of cells irradiated, the volume of normal tissue irradiated and the time/dose features (fractionation of the treatment schedule). The acute effects result from the depletion of actively dividing cells, and the extent of this reaction depends on time/dose fractionation and the total dose. Normal tissues typically involved are skin, gut (epithelium of the intestinal tract), bladder and bone marrow. Intermediate effects are also related to both time/dose fractionation and total dose. They are thought to result from injury to cells which slowly proliferate or renew, such as endothelium or connective tissue. Radiation pneumonitis and pericarditis are important intermediate effects. These effects characteristically occur at 2–3 months after treatment. Late effects are related to the total dose of irradiation administered. Almost all cells may be affected, including endothelium, connective tissue and the organ itself. The mechanism is not clearly understood, but may either affect slowly proliferating cell renewal systems or alter the structural integrity of certain macromolecules. Late radiation effects are particularly important in children, as growth of the organ, tissue or limb may be severely affected. Limitation of thoracic growth may result in a restrictive pulmonary deficit in later life, as may pulmonary fibrosis. Damage to the lung is thought to be due to direct effects of the radiation on cell membranes, protein and DNA. An inflammatory response can follow the initial tissue damage and contribute further to tissue injury. In addition, the acute changes can lead to an increased risk of infection, disturbance of immunoglobulin production and altered pulmonary diffusion.10 Radiation damage to the lung depends on a number of factors: the volume of lung irradiated, the dose and fractionation of the dose – for example, 30 Gy with conventional fractionation (1.8–2.0 Gy per fraction) delivered to the whole lung will precipitate a fatal reaction, but is well tolerated if the volume of the radiation is reduced to 25%. Fractionation of the dose permits some repair of damage to occur between fractions and improves the tolerance of the lung tissue to irradiation. Many chemotherapeutic agents interact with radiotherapy, increasing the toxicity of the irradiation. The
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most common of these is actinomycin D, although agents such as adriamycin are also important. The clinical picture of pulmonary damage following irradiation reflects the pathological processes. The clinical syndrome can be divided into two consecutive phases. The acute phase of radiation–induced pneumonitis develops insidiously with non-specific symptoms 1–6 months following completion of treatment (see below). A late “radiation fibrosis” may follow the acute phase. The earlier the onset, the more severe and protracted the illness is likely to be. A patient may be asymptomatic or, if the reaction is severe, suffer acute respiratory distress. Symptoms are usually dry cough, dyspnoea, fever and general malaise. Rarely, there may be chest pain due to pleural involvement. Physical signs are often not present, although consolidation may occur, there may be erythema of overlying skin, and a pleural friction rub may be present. The chest radiograph shows interstitial shadowing, classically with well defined borders restricted to the irradiated lung volume. A fine resolution CT scan may also be helpful in demonstrating localized abnormalities. Infection may be suspected either concurrently or as a differential diagnosis, and bronchoalveolar lavage (BAL) is a valuable tool. Therapy usually comprises steroids with or without antibiotic cover, depending on the clinical picture. In children who have received total body irradiation, graft versus host disease and an atypical intestitial pneumonitis are important differential diagnoses. If true radiation pneumonitis occurs in this setting, it may be fatal. The largest study of whole lung irradiation on the lungs of children is that of Benoist.11 Forty-eight children with pulmonary metastases were studied and followed. The dose of whole lung irradiation was 20 Gy (higher than the currently recommended dose level of 12–14 Gy). In the 11 patients in whom lung function testing was performed, reduction of vital capacity, functional residual capacity and lung compliance were observed. Long-term lung damage can occur following radiation in patients with Hodgkin’s disease who receive mediastinal or mantle radiotherapy as part of their treatment. Doses of up to 30 Gy are given to a limited field, with shielding of the lung. A reduction in total lung capacity and transfer factor has been detected in these patients at follow-up.
Surgery Surgery may be an important part of the management of some childhood tumours, in particular Wilms’ tumour and osteogenic sarcoma. It is has been well documented that for some children long-term remission and even cure can be achieved by the use of sequential thoracotomy for removal of pulmonary metastases. The long-term effect on lung function clearly depends on whether the disease is bilateral and the volume of normal lung tissue removed.
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Bone marrow transplantation (BMT) and the lung The transplant may be allogeneic (from a sibling), a matched unrelated donor (MUD), a haplotype antigen mismatched donor either related (usually parent) or unrelated, or syngeneic (from a twin). If, after marrow ablation, the patient’s own bone marrow is re-infused, the transplant is termed autologous. Autologous ‘rescue’ following marrow ablation is now often achieved using the patient’s own stem cells (rather than bone marrow) which have been harvested following stimulation by the cytokine granulocyte colony stimulating factor (G-CSF). Whilst donor marrow is used almost exclusively in the management of childhood leukaemias, marrow ablation with autologous stem cell rescue is increasingly used in treatment for high risk solid tumours. Lung toxicity following transplantation depends in part on the conditioning therapy used; for leukaemia, usually high dose cyclophosphamide +/–total body irradiation (TBI), or high dose cyclophosphamide with busulphan for the younger child is used. Children undergoing myeloablative therapy for solid tumours could have a number of chemotherapeutic agents in high dose; e.g. carboplatin, cyclophosphamide, busulphan, etoposide alone or in combination. These children have often previously received intensive therapy over a prolonged period, which may have an additional adverse effect on the lung. This is particularly important if the child has had prior lung irradiation with the subsequent use of busulphan or bleomycin. A further risk factor for lung damage is infection in a child who is profoundly immunosuppressed. Whilst the pattern of infection reflects that of other children receiving therapy for malignant disease (see below), there is an increased risk of fungal and viral (particularly CMV) infection. Systemic, oral antifungal (fluconazole, itraconazole) and antiviral (acyclovir) prophylaxis are routinely prescribed throughout the transplant period, and if the child has no evidence of previous infection with CMV, CMVnegative or leucodepleted blood products are used wherever possible to minimize risk. In children who have received allogeneic bone marrow or stem cells, a further complication is graft versus host disease (GVHD). T cells from the donor marrow proliferate and differentiate in response to histocompatability antigens in the host (recipient) tissue and attack recipient cells with resulting signs and symptoms of GVHD. T-cell depletion of the marrow or immunosuppression posttransplant are used in an attempt to avoid/control GVHD. The risk of GVHD is higher in older children (>10 years) and in children who have received marrow from unrelated or ‘mismatched’ donors. Acute GVHD usually affects the skin, gastrointestinal tract and liver. The lung is affected by GVHD in its chronic phase. The pathogenesis of the lung damage remains
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unclear: however, brochiolitis obliterans is known to occur. A longitudinal study of 25 children who had undergone BMT for leukaemia or lymphoma demonstrated a reduction of transfer factor and lung volumes immediately after BMT which initially improved. However, at a median follow-up of 8 years post-transplant, the children had significantly reduced transfer factor, total lung capacity and forced vital capacity. All children were asymptomatic at the time of testing, and none had chronic GVHD.12 A further study of 77 children undergoing BMT assessed pre- and post transplant demonstrated abnormalities both in the pre-transplant (when compared to predicted values) and further deterioration at 100 days post-transplant. The pattern of abnormalities was similar, with a fall in DLCO, vital capacity pre-transplant compared to controls and a further fall in DLCO, VC and TLC when compared to pre-BMT data. There is concern regarding the recent increase in the use of high-dose cyclophosphamide together with highdose busulphan as conditioning therapy for autologous transplant for some poor risk tumours (e.g. neuroblastoma). These procedures are frequently performed in very young children, who may be at increased risk of pulmonary dysfunction.
Infectious complications The colonization of the upper airway is altered by chemotherapy; there is a fall in secretory immunoglobulins and alteration of the normal humoral and mucosal immune mechanisms. These factors lead to an increased risk of infection, and if the child is neutropenic then the likelihood of lower respiratory tract infection is even greater. One particular complication that presents is fever, deteriorating lung function with pulmonary infiltrates on the chest radiograph. The infiltrates may be localized or diffuse, and are a common and sometimes complex diagnostic challenge. The differential diagnosis will depend on whether the child is neutropenic and whether the radiograph abnormality is diffuse or localized. All children presenting with clinical signs and symptoms of pneumonia should be evaluated with a chest radiograph, blood cultures, blood count and measurement of oxygen saturation. Bronchoalveolar lavage (BAL) can be extremely valuable as it carries a relatively low morbidity. However, it may not be helpful if anti-viral or anti fungal agents, or high dose co-trimoxazole, have already been commenced, or if the underlying process is drug- or radiation-induced. Open lung biopsy is the gold standard,12 but is not frequently used because of the associated morbidity in a child who may already potentially require ventilation. Transbronchial biopsy is usually not indicated, in particular if the platelet count is also low. For both neutropenic and non-neutropenic patients, the cause of the ‘pneumonia’ can be bacterial, viral,
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fungal, protozoal, drug-induced or a manifestation of radiation pneumonitis. The organisms will vary according to the immunological state of the child and are listed below:
Non-neutropenic (often lymphopenic) child Protozoa Fungi Viruses Bacteria
P. carinii,T. Gondii Aspergillus, candida, Zygomcetes, cryptococcus RSV, adenovirus, CMV,VZV, HSV, influenza Mycoplasma, Legionella, Chlamydia, Mycobacteria
Cytotoxic chemotherapy Radiation
The aetiology is similar for both neutropenic and nonneutropenic children; bacterial infection is more likely in the neutropenic child and protozoal in the nonneutropenic (but lymphopenic) child. Localized infiltrates are less likely to be caused by protozoal organisms than diffuse infiltrates. The most common infective causes of pneumonitis are discussed below.
Pneumocystis carinii pneumonia (PCP) Pneumocystis carinii infection is one of the commonest infections occurring in the non-neutropenic, immunosuppressed child. The majority of normal children have been exposed to this organism. Infection is thought to occur following reactivation of latent cysts, although patient to patient transmission has also been suggested. Characteristically children with PCP infection present with a dry cough, fever and increasing tachypnoea and hypoxia. Crackles may not be audible in the chest. The chest radiograph classically shows bilateral infiltrates radiating from the hilum, although the appearances may be focal. Children at particular risk of PCP infection are those who have prolonged continuous immunosuppressive therapy, particularly with steroids: for example, those receiving treatment for acute lymphoblastic leukaemia, some lymphomas, Ewing’s sarcoma, and following BMT. In these children, prophylactic antibiotic therapy is mandatory. This usually comprises co-trimoxazole twice daily 2 or 3 days each week. If this is not tolerated, dapsone or nebulized pentamidine may be used.
Aspergillus Aspergillus most commonly occurs in those children profoundly immunosuppressed (with neutropenia) for long periods. For example, those receiving therapy for acute
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non-lymphoblastic leukaemia, some lymphomas, following BMT or following high-dose chemotherapy with autologous stem cell re-infusion. Children who have received prolonged courses of broad spectrum intravenous antibiotic are at particular risk, and for that reason if fever persists after 5 days of antibiotic therapy, empirical antifungal therapy is commenced with amphotericin B or ambisome (liposomal amphotericin). Aspergillus flavus and A. fumigatus are the most common species. There is an increased risk of aspergillus infection where high levels of dust are present (e.g. around building works). Clinical symptoms are indistinguishable from other causes of pneumonitis, although haemoptysis may occur in severe cases. The chest radiography may show localized rounded or even cavitating lesions. Diagnosis usually relies on BAL or, if tolerated, open lung biopsy.
Cytomegalovirus (CMV) Children are at most risk of CMV pneumonitis following BMT. The most common cause is reactivation of the latent virus in children who have evidence of prior CMV infection (IgG antibody positive) at the time of their transplant. Transmission also occurs through blood product transfusion or from the donor marrow. Children with GVHD are at greatest risk of CMV infection. The virus can be isolated from urine, blood (buffy coat and PCR) or from BAL. Clinically, CMV pneumonitis is difficult to distinguish from that caused by other infective agents. The chest radiograph shows bilateral diffuse or nodular infiltrates. Treatment with gancyclovir is often effective, although subsequent reactivation can occur. The use of intravenous immunoglobulin to prevent CMV infection is debated, but it is routine practice is some transplant units.
SUMMARY The paediatric lung can be adversely affected by cancer therapy in a number of ways. However, there is remarkably little long-term damage, except in a minority of patients who have received radiotherapy (particularly at a young age), or who have received agents known to cause long-term damage, e.g. BCNU. Although abnormalities can be detected post-therapy, the majority are asymptomatic. However, it is not known whether these children will develop long-term complications or whether they will be at greater risk of chronic lung disease in adult life. Pulmonary complications are multifactorial. Complications may be due to a combination of chemotherapy, radiotherapy and infection. It remains very difficult to identify individual factors responsible either clinically or pathologically. Documentation of the effects of therapy for childhood cancer on the lung is poor. The majority of studies are
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based on cross-sectional cohorts who have often received very different treatment regimens. Although assessment of lung function in very young children remains a challenge, there is a need for large prospective studies of children treated on current protocols. Cure rates are improving, but often at the cost of more intensive therapy: the impact of such changes on the lung in the long term are unknown.
PRACTICE POINTS • Damage to lung sustained during treatment for childhood cancer is often mild and the child asymptomatic. • A minority of patients are a risk of significant impairment depending on therapy received (e.g. following bone marrow transplantation). • The aetiology of long term damage is multifactorial. • Radiotherapy is toxic to the lung. The extent of damage depends on cumulative dose, volume of lung irradiated and the age of the child at the time of therapy.
RESEARCH DIRECTIONS • Prospective (longitudinal) assessment of lung function in children treated for cancer. • Understanding changes in immune status during therapy for childhood cancer and its relationship with lung disease. • The impact of pneumonitis during treatment on lung function in the long term.
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7. Fauroux V, Meyer-Milsztaim A, Boccon-Givod L et al. Cytotoxic drug induced pulmonary disease in infants and children. Paediat Pulmonol 1994; 18: 347–355. 8. Nysom K, Holm K, Hertz H, Hesse B. Risk factors for reduced pulmonary function after malignant lymphoma in childhood. Med Paediatr Oncol 1998; 30: 240–248. 9. Bloomer WD, Hellman F. Normal tissue responses to radiation therapy. New Engl J Med 1975; 293: 80–83. 10. Gross N. The pathogensis of radiation – induced lung damage. Lung 1981; 159: 115–125.
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11. Benoist MR, Lemerle J, Jean R, Rufin T, Scheinmann P, Pauper J. Effects on pulmonary function of whole lung irradiation for Wilms’ tumour in children. Thorax 1982; 37: 175–180. 12. Nysom K, Holm K, Birger H et al. Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma. Arch Dis Child 1996; 74: 432–436. 13. Browne MJ, Potter D, Gress J et al. A randomised trial of open lung biopsy versus empiric antimicrobial therapy in cancer patients with diffuse pulmonary infiltrates. J Clin Oncol 1990; 8: 222.