Pediatr Blood Cancer 2014;61:1527–1528
HIGHLIGHT
by Christine N. Duncan,
MD
*
Bleomycin and Pulmonary Screening: Many Questions, Few Answers
T
he number of survivors of childhood cancer continues to expand. The American Cancer Society recently estimated that were over 375,000 survivors of childhood and adolescent cancer living in the United States at the time of most recent assessment [1]. They further estimated that approximately 1 in 530 adults between the ages of 20 years and 39 years is a childhood cancer survivor [1]. The importance of the late effects following pediatric cancer therapy has long been recognized. However, as the survivor population increases so does the appreciation and understanding of the complexity of late effects. Late noninfectious pulmonary toxicities can have a potentially devastating impact on the quality of life and survivors of childhood cancer. The Childhood Cancer Survivor Study (CCSS) found that compared with siblings, survivors of childhood cancer had a statistically significant increased relative risk of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen, exercise-induced shortness of breath, and bronchitis [2]. While the importance of these effects is appreciated by the oncology community, a comprehensive understanding of the prevalence, risk factors, and effective means of prevention of treatment of these disorders is lacking. The spectrum of noninfectious pulmonary late effects is broad and includes interstitial pneumonitis, pulmonary fibrosis, restrictive and obstructive lung disease, ARDS, bronchiolitis obliterans, and bronchiolitis obliterans organizing pneumonia [3]. The risk for each of these late effects depends on the underlying disease, patient age, health behaviors, and concomitant medical conditions, and treatment modalities received. Chemotherapeutic treatment with bleomycin is a wellknown risk factor for pulmonary late effects, particularly pulmonary fibrosis and interstitial pneumonitis [3,4]. In the CCSS, prior bleomycin therapy was significantly associated with the use of supplemental oxygen in patients who lived a minimum of five years following diagnosis [2]. In this issue of Pediatric Blood and Cancer, De et al. [5] report on the respiratory function assessed by clinical history and pulmonary function test (PFT) abnormalities of children who received bleomycin over a 12-year period at a single center. Reports of pulmonary function testing were available from 80 out of the 207 patients who received bleomycin during the study period. The authors limited the analysis to testing done at least 1 year following diagnosis. The clinical value of this manuscript lays both in the data presented as well as the questions that these data raise. Of paramount importance is that pulmonary function abnormalities were present in greater than half of the population studied. Hyperinflation was the most common change followed by obstructive disease, non-uniform distribution of ventilation, and restrictive changes. The high prevalence of abnormalities supports
C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25083 Published online 9 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
recommendations for ongoing pulmonary monitoring of all children following bleomycin therapy. However, the specific composition and duration of pulmonary monitoring is not clear. The Children’s Oncology Group provides guidelines for pulmonary surveillance following bleomycin therapy [6]. The group recommends chest radiograph and PFTs with spirometry and DLCO at entry into long-term follow-up and then only as clinically indicated for those with progressive pulmonary dysfunction or abnormal results. This is clearly appropriate monitoring for a large portion of the survivorship community and PFTs are a cornerstone of pulmonary late effects monitoring [7]. The clear advantages of PFTs are the noninvasive nature of the testing, capacity to follow functional trends at regular intervals, and ability to distinguish categories of defect. A primary disadvantage is that PFTs cannot be easily completed in young children and some with developmental disabilities. The current study found that younger age at diagnosis was a risk factor for PFT abnormalities following bleomycin and the inability to reliably obtain this testing in young survivors is a significant disadvantage. Infantile pulmonary function testing can be performed in those developmentally unable to complete standard PFTs, but requires sedation and results are limited to spirometry. This raises the question of how best to monitor pulmonary function in the youngest survivors. Other mechanisms for pulmonary assessment include thorough medical history taking at each visit, the 6-minute walk or play test, and high-resolution chest computed tomography (CT) with inspiratory and expiratory views. The advantages of each of these methods of assessments are accompanied by significant limitations. Medical history taking and the 6-minute walk test are inexpensive and can be performed at all centers. However, a highlight of the manuscript is that the majority of children with abnormalities have no symptoms as such, medical history taking and walk tests may be unrevealing. Highresolution CT with inspiratory and expiratory views may identify obstructive changes and can be assessed serially. However, CT scans do not provide a functional assessment, may require sedation, and additional radiation exposure for late effects screening is not ideal. Thus, the question of how to monitor young children following bleomycin therapy remains unanswered. It is imperative that improved means of assessing the pulmonary
Dana-Farber Cancer Institute, 450 Brookline Ave., Dana-320, Boston, Massachusetts
Correspondence to: Christine N. Duncan, MD, Dana-Farber Cancer Institute, 450 Brookline Ave., Dana-320, Boston, MA 02115. E-mail: [email protected] Received 1 April 2014; Accepted 1 April 2014
1528 function in young and developmentally disabled children are investigated. The duration of screening remains an open question. It is known that the cumulative incidence of pulmonary complications in childhood cancer survivors increases with increasing time since diagnosis [8]. The median duration of follow-up at the time of pulmonary function testing in the highlighted study was 6.05 years. Both of these facts suggest that screening should continue for a prolonged period after treatment, perhaps indefinitely. For the survivor with no pulmonary symptoms and normal and/or stable PFT results, this may be excessive and unnecessary. De and colleagues reported that despite the high-incidence of PFT abnormalities, only 8.7% had clinical symptoms. There is unfortunately insufficient literature available to guide the duration of monitoring for these patients. It is estimated that 15,780 new cases of cancer will be diagnosed in children and adolescent in 2014 [1]. The majority of these patients will be long-term survivors of their disease. The current
Pediatr Blood Cancer DOI 10.1002/pbc
study draws attention to the risk of pulmonary toxicity in patients who received bleomycin. Prospective studies are needed to adequately answer the questions raised by this and other studies of pulmonary late effects.
REFERENCES 1. Ward E, Desantis C, Robbins A, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014;64:83–103. 2. Hudson MM, Mulrooney DA, Bowers DC, et al. High-risk populations identified in Childhood Cancer Survivor Study investigations: Implications for risk-based surveillance. J Clin Oncol 2009;27:2405– 2414. 3. Huang TT, Hudson MM, Stokes DC, et al. Pulmonary outcomes in survivors of childhood cancer: A systematic review. Chest 2011;140:881–901. 4. Goldiner PL, Carlon GC, Cvitkovic E, et al. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J 1978;1:1664–1667. 5. De A, Guryev I, LaRiviere A, et al. Pulmonary function abnormalities in childhood cancer survivors treated with bleomycin. Pediatr Blood Cancer 2014; in press. 6. American Academy of Pediatrics Section on Hematology/Oncology Children’s Oncology Group. Longterm follow-up care for pediatric cancer survivors. Pediatrics 2009;123:906–915. 7. Mulder RL, Thonissen NM, van der Pal HJ, et al. Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer. Thorax 2011;66:1065–1071. 8. Mertens AC, Yasui Y, Liu Y, et al. Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer 2002;95:2431–2441.
HIGHLIGHT
by Christine N. Duncan,
MD
*
Bleomycin and Pulmonary Screening: Many Questions, Few Answers
T
he number of survivors of childhood cancer continues to expand. The American Cancer Society recently estimated that were over 375,000 survivors of childhood and adolescent cancer living in the United States at the time of most recent assessment [1]. They further estimated that approximately 1 in 530 adults between the ages of 20 years and 39 years is a childhood cancer survivor [1]. The importance of the late effects following pediatric cancer therapy has long been recognized. However, as the survivor population increases so does the appreciation and understanding of the complexity of late effects. Late noninfectious pulmonary toxicities can have a potentially devastating impact on the quality of life and survivors of childhood cancer. The Childhood Cancer Survivor Study (CCSS) found that compared with siblings, survivors of childhood cancer had a statistically significant increased relative risk of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen, exercise-induced shortness of breath, and bronchitis [2]. While the importance of these effects is appreciated by the oncology community, a comprehensive understanding of the prevalence, risk factors, and effective means of prevention of treatment of these disorders is lacking. The spectrum of noninfectious pulmonary late effects is broad and includes interstitial pneumonitis, pulmonary fibrosis, restrictive and obstructive lung disease, ARDS, bronchiolitis obliterans, and bronchiolitis obliterans organizing pneumonia [3]. The risk for each of these late effects depends on the underlying disease, patient age, health behaviors, and concomitant medical conditions, and treatment modalities received. Chemotherapeutic treatment with bleomycin is a wellknown risk factor for pulmonary late effects, particularly pulmonary fibrosis and interstitial pneumonitis [3,4]. In the CCSS, prior bleomycin therapy was significantly associated with the use of supplemental oxygen in patients who lived a minimum of five years following diagnosis [2]. In this issue of Pediatric Blood and Cancer, De et al. [5] report on the respiratory function assessed by clinical history and pulmonary function test (PFT) abnormalities of children who received bleomycin over a 12-year period at a single center. Reports of pulmonary function testing were available from 80 out of the 207 patients who received bleomycin during the study period. The authors limited the analysis to testing done at least 1 year following diagnosis. The clinical value of this manuscript lays both in the data presented as well as the questions that these data raise. Of paramount importance is that pulmonary function abnormalities were present in greater than half of the population studied. Hyperinflation was the most common change followed by obstructive disease, non-uniform distribution of ventilation, and restrictive changes. The high prevalence of abnormalities supports
C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25083 Published online 9 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
recommendations for ongoing pulmonary monitoring of all children following bleomycin therapy. However, the specific composition and duration of pulmonary monitoring is not clear. The Children’s Oncology Group provides guidelines for pulmonary surveillance following bleomycin therapy [6]. The group recommends chest radiograph and PFTs with spirometry and DLCO at entry into long-term follow-up and then only as clinically indicated for those with progressive pulmonary dysfunction or abnormal results. This is clearly appropriate monitoring for a large portion of the survivorship community and PFTs are a cornerstone of pulmonary late effects monitoring [7]. The clear advantages of PFTs are the noninvasive nature of the testing, capacity to follow functional trends at regular intervals, and ability to distinguish categories of defect. A primary disadvantage is that PFTs cannot be easily completed in young children and some with developmental disabilities. The current study found that younger age at diagnosis was a risk factor for PFT abnormalities following bleomycin and the inability to reliably obtain this testing in young survivors is a significant disadvantage. Infantile pulmonary function testing can be performed in those developmentally unable to complete standard PFTs, but requires sedation and results are limited to spirometry. This raises the question of how best to monitor pulmonary function in the youngest survivors. Other mechanisms for pulmonary assessment include thorough medical history taking at each visit, the 6-minute walk or play test, and high-resolution chest computed tomography (CT) with inspiratory and expiratory views. The advantages of each of these methods of assessments are accompanied by significant limitations. Medical history taking and the 6-minute walk test are inexpensive and can be performed at all centers. However, a highlight of the manuscript is that the majority of children with abnormalities have no symptoms as such, medical history taking and walk tests may be unrevealing. Highresolution CT with inspiratory and expiratory views may identify obstructive changes and can be assessed serially. However, CT scans do not provide a functional assessment, may require sedation, and additional radiation exposure for late effects screening is not ideal. Thus, the question of how to monitor young children following bleomycin therapy remains unanswered. It is imperative that improved means of assessing the pulmonary
Dana-Farber Cancer Institute, 450 Brookline Ave., Dana-320, Boston, Massachusetts
Correspondence to: Christine N. Duncan, MD, Dana-Farber Cancer Institute, 450 Brookline Ave., Dana-320, Boston, MA 02115. E-mail: [email protected] Received 1 April 2014; Accepted 1 April 2014
1528 function in young and developmentally disabled children are investigated. The duration of screening remains an open question. It is known that the cumulative incidence of pulmonary complications in childhood cancer survivors increases with increasing time since diagnosis [8]. The median duration of follow-up at the time of pulmonary function testing in the highlighted study was 6.05 years. Both of these facts suggest that screening should continue for a prolonged period after treatment, perhaps indefinitely. For the survivor with no pulmonary symptoms and normal and/or stable PFT results, this may be excessive and unnecessary. De and colleagues reported that despite the high-incidence of PFT abnormalities, only 8.7% had clinical symptoms. There is unfortunately insufficient literature available to guide the duration of monitoring for these patients. It is estimated that 15,780 new cases of cancer will be diagnosed in children and adolescent in 2014 [1]. The majority of these patients will be long-term survivors of their disease. The current
Pediatr Blood Cancer DOI 10.1002/pbc
study draws attention to the risk of pulmonary toxicity in patients who received bleomycin. Prospective studies are needed to adequately answer the questions raised by this and other studies of pulmonary late effects.
REFERENCES 1. Ward E, Desantis C, Robbins A, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014;64:83–103. 2. Hudson MM, Mulrooney DA, Bowers DC, et al. High-risk populations identified in Childhood Cancer Survivor Study investigations: Implications for risk-based surveillance. J Clin Oncol 2009;27:2405– 2414. 3. Huang TT, Hudson MM, Stokes DC, et al. Pulmonary outcomes in survivors of childhood cancer: A systematic review. Chest 2011;140:881–901. 4. Goldiner PL, Carlon GC, Cvitkovic E, et al. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J 1978;1:1664–1667. 5. De A, Guryev I, LaRiviere A, et al. Pulmonary function abnormalities in childhood cancer survivors treated with bleomycin. Pediatr Blood Cancer 2014; in press. 6. American Academy of Pediatrics Section on Hematology/Oncology Children’s Oncology Group. Longterm follow-up care for pediatric cancer survivors. Pediatrics 2009;123:906–915. 7. Mulder RL, Thonissen NM, van der Pal HJ, et al. Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer. Thorax 2011;66:1065–1071. 8. Mertens AC, Yasui Y, Liu Y, et al. Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer 2002;95:2431–2441.
