Preserved Long-Term Lung Function in Young Adult Survivors of Common Childhood and Adolescence Malignancies

Abstract

Purpose:

We aimed to evaluate long-term lung function and respiratory outcomes in young adults who survived common pediatric malignancies, treated in a single center.

Methods:

We enrolled young adults who had been treated during their childhood or adolescence for hematological or solid cancer at our Pediatric Oncology Unit, and performed pulmonary function tests (PFT) and clinical evaluation. PFT included spirometry and Diffusing Capacity of Lung for Carbon Monoxide (DLCO).

Results:

We included 121 survivors, mean age 23 years at follow-up, median 15 years from diagnosis. The most common diagnoses were hematological malignancies, mainly acute lymphoblastic leukemia, whereas 31% of the patients were treated for nonhematological cancer, mainly neuroblastoma. Treatments consisted of chemotherapy alone or in combination with radiotherapy and/or hematopoietic stem cell transplantation. Most of the patients denied respiratory symptoms throughout the years. In the whole group only eight patients (6%) had abnormal PFT, consisting mainly in a restrictive pattern and reduced DLCO. PFT abnormalities were of mild degree in most of the cases. Overall, the mean values of forced vital capacity, forced expiratory volume in 1 second, and DLCO were normal, but lower in females, in those who received radiotherapy and in those treated for lymphoma.

Conclusion:

In a group of young adults, surviving the most common childhood malignancies, we found a preserved lung function after a median follow-up of 15 years. The constantly increasing survival in childhood cancer is now associated with a trend toward an improvement in long-term respiratory outcomes.

Introduction

In the last decades, new advanced therapeutic options have significantly improved survival in children affected by malignancies, with a 5-year survival rate approaching 80%.^1,2 Although the goal of the modern antineoplastic treatments is to reduce toxicity to a minimum level using constantly improved protocols, still survival has been associated with adverse treatment-related consequences.^1–3 One recent large survey (5804 survivors) has shown that early-adolescent cancer survivors have a risk of severe and life-threatening chronic health conditions significantly higher than the general population, thus highlighting the need for long-term screening of survivors.⁴

The respiratory system is a main target of the antineoplastic treatment toxicity and can be affected acutely or chronically.⁵ The most common long-term consequence of cytotoxic therapy in the lung is an interstitial disease caused by inflammation and fibrosis of the alveolar wall.

Damage of the capillary endothelium, of the alveolar epithelial lining cells with proliferation of fibroblasts and deposition of collagen are the histological hallmarks of the interstitial lung disease.⁵ Concomitant radiotherapy, generally for mediastinal disease, may cause additional toxicity with a fibrotic effect of radiation starting 2–6 months after completion of the therapy.^5,6 In addition to cytotoxic drugs, other factors can affect lung function over the years in survivors, including thoracic growth deficiency, recurrent infections, and smoking habit.² Hematopoietic stem cell transplantation (HCT) also increases the risk of specific complications.⁷ Functionally, the late effects of the cytotoxic drugs consist in a restrictive pulmonary disease and a reduction of alveolar diffusion capacity.^2,6

In conjunction with the pulmonary functional impairment, as a consequence of the antineoplastic treatment, survivors may complain symptoms, such as cough, due to recurrent chest infections or dyspnea, due to a reduced exercise capacity.^2,6 According to one study, assessing long-term outcomes in a large sample of subjects treated for all kinds of cancers during childhood, respiratory symptoms were three times higher in cancer survivors than in their siblings.⁸ However, it is noteworthy that patients included in this study were treated with chemotherapy more than 30 years ago, while in the last decades new protocols have been developed so that treatment-related toxicity should be reduced. While there has been a great deal of research on short and medium-term changes in lung function in childhood cancer survivors, little is known about long-term respiratory complications.

Therefore, the aim of this study was to evaluate long-term lung function and its determinants in a sample of young adults who survived childhood and adolescence hematological and nonhematological malignancies, treated in a single specialized center.

Patients and Methods

Study population

This prospective single-center study is part of a larger project, performed in the Department of Clinical and Experimental Medicine, University of Catania, with the aim to evaluate long-term organ damage and complications due to cancer treatment in childhood or adolescence. The project has been approved by the Institutional Review Board and signed consent has been obtained for all participants. The subjects enrolled were young adults who had been treated for hematological or solid cancer at our Pediatric Oncology Unit. Chemotherapy protocols used were those of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Drugs more commonly included in the treatment regimens were vincristine, vinblastine, methotrexate, l-asparaginase, doxorubicin, procarbazine, cytarabine, 6-mercaptopurine, and cyclophosphamide.

These cancer survivors, after at least 5 years of discontinuation of the treatment, when the cancer can be considered in remission, were followed up by a multidisciplinary team in our long-term follow-up clinical care program. The program was developed to assess the occurrence of long-term post-treatment complications. All patients eligible for inclusion had to be >18 years. Exclusion criteria were: (i) inability to perform pulmonary function test (PFT); (ii) acute respiratory symptoms in the two previous weeks; (iii) refusal to attend the clinic. Data from consecutive patients attending the follow-up visit in 2019 were collected. Out of 136 patients eligible, we enrolled a total of 121 patients.

Clinical evaluation and pulmonary function

Patients were evaluated at the Respiratory Physiology Laboratory, Pulmonary Unit, by a pulmonary physician. All data on the oncologic diseases and treatment were already available, from clinical records. Data collected at recruitment included demographics, use of tobacco or other additive substances, work exposure, occurrence of respiratory symptoms or diagnosis of a respiratory disease, or any other disease affecting lung function.

After collection of these data, objective examination of the chest was performed and SaO₂ measured. After excluding contraindication, the technician performed PFT consisting in standard spirometry and Diffusing Capacity of Lung for Carbon Monoxide (DLCO). Standard spirometry and single-breath DLCO were performed with a VMAX PFT system (Sensormedics, Italia), calibrated daily, according to standard guidelines.⁹

Predictive values for spirometry were calculated using the equations of Global Lung Function Initiative.¹⁰ Forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁) were considered abnormal when <80% of the predicted values. An obstruction was defined as a FEV₁/FVC% ratio <70, whereas the severity of obstruction was graded on the percentage value of FEV₁. As we did not measure the total lung capacity, a FVC below 80% with an increase in FEV₁/FVC% was considered suggestive of restrictive disease.¹¹ DLCO was considered abnormal when the measured value was <75% of the predicted value.¹² A “PFT abnormality” was defined as the presence of one or more abnormalities.

Statistical analyses

Descriptive statistics was used for demographic and pulmonary functional data presented as mean ± standard deviation. Differences among groups were analyzed using Student's t-test or Mann–Whitney U test, as appropriate. Categorical variables were analyzed using χ² test. p-Value was significant when <0.05. Analyses were performed using SPSS software 14.0.

Results

Study population

In this prospective study, we enrolled a total of 121 Caucasian patients (57% males, age 19–37 years) who had stopped treatments from at least 5 years. A total of 109 patients were diagnosed after or in 2000 and 12 patients were diagnosed from 1983 to 1999. The median follow-up time since diagnosis was 15 years. Demographic data of the study population are shown in Table 1. None of the subjects had work exposure. The most common diagnosis was hematological cancer (51% acute leukemia), whereas 31% were nonhematological malignancies, most commonly neuroblastoma, Wilms tumor, and osteosarcoma (Fig. 1).

FIG. 1.

Distribution of diagnoses.

Table 1.

Demographic and Clinical Data of the Study Group

Number of patients	121
Males, n (%)	69 (57)
Age, years	23 ± 5
BMI, kg/m²	23.7 ± 3
Current smoker, n (%)	5 (4.1)
Period of cancer diagnosis, n
2000–2012	109
Before 1999	12
Pulmonary function
FEV₁%	100.1 ± 14
FVC%	95.8 ± 13
FEV₁/FVC%	88.6 ± 6
FEF_25–75%	99.9 ± 22
DLCO%	98.2 ± 15
Treatment
Chemotherapy only, n	97
Chemotherapy + radiotherapy, n	24
HCT, n (%)	11 (9.0)

Data are expressed as mean ± SD, if not differently indicated.

BMI, body mass index; DLCO, Diffusing Capacity of Lung for Carbon Monoxide; FEF, forced expiratory flow; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; HCT, hematopoietic stem cell transplantation; SD, standard deviation.

Treatments alone or in combination included chemotherapy, radiotherapy, and autologous or allogeneic HCT. Ninety-seven patients received only chemotherapy, 24 in combination with radiotherapy (Table 1). In our group only two patients received busulfan and two bleomycin, drugs with recognized pulmonary toxicity. Details on treatment are shown in Table 2.

Table 2.

Patients Who Presented Abnormal Pulmonary Functional Tests

	Sex	Age, years	Follow-up, years	FEV₁%	FVC%	FEV₁/FVC%	DLCO%	Diagnosis	Treatment
1	M	21	15	77	73	87	34	ALL	Chemotherapy
2	M	22	11	67	86	67	78	NHL	Chemotherapy
3	F	18	14	78	76	98	80	GN	Chemotherapy surgery
4	M	31	18	84	72	91	106	ALL	Chemotherapy
5	M	25	16	73	72	87	76	HL	Chemotherapy radiotherapy
6	F	25	11	82	73	91	74	HL	Chemotherapy radiotherapy
7	F	26	16	68	63	87	72	ALL	Chemotherapy radiotherapy HCT
8	F	21	10	76	72	92	70	OS	Chemotherapy

ALL, acute lymphoblastic leukemia; GN, ganglioneuroblastoma; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; OS, osteogenic sarcoma.

Pulmonary function and risk factors

With the exception of two patients complaining mild exertional dyspnea, most of the patients denied respiratory symptoms through the years after antineoplastic treatments. One patient reported allergic asthma well controlled with topic steroids, one allergic rhinitis. Both had normal PFT. Smoking was reported in 4.1% of cases. In the whole sample, mean values of FEV₁, FVC, and DLCO were within normal range (Table 1).

We found an abnormal PFT only in eight patients (6.6%) (Table 2). One patient had an obstructive disorder and seven patients a restrictive pattern and/or reduced diffusion capacity. PFT abnormalities were mild in five patients and moderate–severe (<70%) in three patients. Three patients with abnormal PFT were in the group treated for Hodgkin and non-Hodgkin lymphoma (15% of all patients in the group with lymphoma), three in the group treated for leukemia (5%), and two in the group treated for nonhematological cancer (5.8%).

Three patients had been treated with radiotherapy in addition to chemotherapy and represented 12% of the total number treated with radiotherapy. One of 11 survivors treated with HCT had abnormal PFT (9%). Patients treated with bleomycin or busulfan had normal PFT. Among patients with abnormal lung function none reported respiratory symptoms. Chest X-rays were normal, except for patient no. 1 who presented at computed tomography scan areas of reticular pattern. The only comorbidities found in this group were hypothyroidism (patient n.4) and severe hypokalemia due to chronic kidney disease (patient n.9).

The low prevalence of cases with abnormal PFT precluded the use a multivariate analysis model to establish risk factors. Therefore, to understand risk factors, we performed a comparison among subgroups. The mean DLCO%, although within normal range, was significantly lower in females than males (96.4 ± 12 vs. 101 ± 12, p < 0.05) and in lymphoma survivors compared with leukemia and nonhematological malignancies to survivors (89.4 ± 13 vs. 106.2 ± 15) (Table 3). We found a lower mean DLCO% in the group treated with combined chemotherapy and radiotherapy compared with the group treated with chemotherapy alone (Table 3). No difference was observed among groups in FVC% and FEV₁% values.

Table 3.

Variables associated with Pulmonary Function

	FEV₁%	FVC%	DLCO%
Sex
Males	98.5 ± 21	101 ± 16	101 ± 12
Females	96.6 ± 17	98.5 ± 21	96.4 ± 12^*
Diagnosis
Lymphoma	94.3 ± 26	96.8 ± 15	89.4 ± 13
Leukemia and nonhematological malignancies	101 ± 14^*	98.3 ± 14	106.2 ± 15^*
Follow-up time, years
>15	99.1 ± 18	95.8 ± 16	96.3 ± 18
<15	102 ± 14	99.7 ± 16	97.2 ± 10
Radiotherapy
Yes	99.2 ± 16	95.1 ± 15	87.4. ± 11
No	98.8 ± 21	93.9 ± 20	102.1 ± 16^*

p < 0.05: males versus females, lymphoma versus leukemia + nonhematological malignancies, lung radiotherapy versus no radiotherapy.

Discussion

Although the target of contemporary antineoplastic treatments is to reduce toxicity, still pulmonary damage is reported as a common medium and long-term complication in childhood and adolescence cancer survivors, and pulmonary function testing is a main stay to monitor this complication.

Our data show that in a sample of adults treated for various common childhood malignancies, mainly after the year 2000, the pulmonary function is generally well preserved. In fact, at a median follow-up time of 15 years, only a small number of patients developed pulmonary functional abnormalities of mild degree. As expected, the dysfunction consisted of restrictive ventilatory disorders and reduced alveolar diffusion capacity, in the absence of respiratory symptoms. Female sex, diagnosis of lymphoma, and radiotherapy were risk factors for lower diffusion capacity, reflecting subclinical alveolar/capillary damage.

The prevalence of pulmonary dysfunction among childhood cancer survivors reported so far ranges from 20% to 100% and respiratory complications vary from a subclinical to a life-threatening condition.¹³ Differences among studies can be attributed generally to small samples and different follow-up time, with most of the studies focusing on the early period after treatment (<5 years).¹³ In addition, most of the research has focused on survivors treated with drugs considered pulmonary toxic, according to the Children's Oncology Group Long-Term Follow-Up Guidelines (COG LTFU).^13,14

Indeed, severe pulmonary dysfunction has been shown by studies including such kind of patients. A notorious study in the 1990s reported pulmonary function impairment at 5 years follow-up in 44% of the patients treated with bleomycin and/or radiotherapy.¹⁵ Armenian et al., among 121 survivors exposed to pulmonary toxic therapy, at 17 years median follow-up, found that 24% of survivors presented restrictive defects and 34% diffusion abnormalities.¹⁶ Two other more recent studies reported, at a median follow-up of 14 and 32 years, pulmonary impairment in 65% of survivors.^17,18

Differently from these studies, focusing on patients exposed to specific pulmonary toxic drugs, we evaluated a more comprehensive sample, including children treated for a variety of malignancies, with acute lymphatic leukemia being the most common diagnosis. To date, little research has been done on long-term changes in lung function, and on the clinical outcomes, in survivors treated for acute leukemia during childhood or adolescence. After a median 6 years follow-up, in a group of 77 survivors treated with chemotherapy for acute lymphoblastic leukemia (ALL), an abnormal DLCO was found in 61% of the cases, whereas 9% presented a restrictive ventilatory deficit.¹⁹ Myrdal et al. have shown that, among 116 ALL survivors, 34% of females and 7% of males had a reduced DLCO during long-term follow-up.²⁰

Likewise, another study including survivors from different type of malignancies showed that 47% had a FVC <80% and 44% a DLCO <75%.²¹ It is clear that, compared with these studies, in our study sample, pulmonary outcomes were definitely better, as in the group with ALL, the overall prevalence of abnormal PFT was 5% and only 3% excluding those survivors who had been treated with radiation and HCT that notoriously worsen lung function. It is interesting that in a sample of children treated in our center with the same protocols used for our adult survivors, the lung clearance index, which detect early subclinical lung damage, was within normal range.²² In our group, although the mean DLCO was within normal range, it was lower in females, confirming previous finding of a greater sensitivity to lung damage in women.^13,16,20

The mechanism by which interstitial lung damage, evidenced early by abnormal DLCO, is more severe in women, has never been explained, although there is suggestion that the smaller size of airways in females may account for the increased susceptibility to toxic agents as compared with males.²³ In addition, it is acknowledged that gender must be considered a risk factor for many other long-term adverse outcomes in cancer survivors.²³ Previous studies have outlined the role of chest radiation, particularly in combination with pulmonary toxic drugs, in determining respiratory dysfunction in childhood cancer survivors.^24,25 One of the earliest studies found that adolescents and young adults treated for childhood lymphoma were at risk for lung function abnormalities, significantly more frequent in patients who received more intense treatment.²⁵

In agreement with previous studies, we also found lower DLCO values in patients treated with radiotherapy.^16,24 However, differently from previous reports, although 12% of our patients treated with radiotherapy had an abnormal PFT, the degree of the dysfunction was very mild.

In our sample, the majority of survivors with altered lung function denied dyspnea or other respiratory symptoms. This might be due to the mild degree of the impairment and likely to the young age of the subjects. Similarly, previous studies reported that changes in lung function often are not associated with respiratory symptoms.^16,18 For this reason, follow-up with PFT is recommended to detect subclinical pulmonary dysfunction.¹⁴

Conclusions

In conclusion, we found that in a group of adult cancer survivors treated for the most common childhood and adolescence malignancies the long-term pulmonary function is generally well preserved, with a lower rate of abnormalities than reported by other studies. Of course, patients included in the study are still quite young, and we cannot exclude that a decline in lung function will occur in the future. In addition, although the sample is inclusive of different kinds of malignancies commonly treated in a specialized center, the number of patients is limited. Multicenter studies are necessary to confirm this trend toward an improvement in pulmonary toxicity of the antineoplastic treatment protocols used in children.

Compliance with Ethical Standards

Informed consent was obtained from all participants included in the study.

Ethics Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional and National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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