Cyclophosphamide is not associated with clinically relevant late pulmonary dysfunction in Dutch survivors of childhood cancer - the DCCSS-LATER 2 PULM sub-study

R J van Kalsbeek; E A M Feijen; D Bresters; L C M Kremer; S M F Pluijm; O A Asogwa; E van Dulmen-den Broeder; M M van den Heuvel-Eibrink; G O Janssens; W J Tissing; J J Loonen; S J C M M Neggers; H J H van der Pal; C M Ronckers; J C Teepen; A C H de Vries; M Louwerens; M van der Heiden-van der Loo; S M P J Prevaes; A B Versluys

doi:10.1016/j.rmed.2025.107948

Cyclophosphamide is not associated with clinically relevant late pulmonary dysfunction in Dutch survivors of childhood cancer - the DCCSS-LATER 2 PULM sub-study

R J van Kalsbeek, E A M Feijen, D Bresters, L C M Kremer, S M F Pluijm, O A Asogwa, E van Dulmen-den Broeder, M M van den Heuvel-Eibrink, G O Janssens, W J Tissing, J J Loonen, S J C M M Neggers, H J H van der Pal, C M Ronckers, J C Teepen, A C H de Vries, M Louwerens, M van der Heiden-van der Loo, S M P J Prevaes, A B Versluys^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Treatment for childhood cancer may increase the risk of long-term pulmonary complications and dysfunction. Pulmonary surveillance is recommended after established pulmonary toxic exposures, including bleomycin, busulfan, carmustine (BCNU), lomustine (CCNU), radiotherapy to a field exposing the lungs, and pulmonary surgery. However, the role of cyclophosphamide as a pulmonary toxic agent is debated.

AIM: To establish whether cyclophosphamide is associated with late pulmonary dysfunction among survivors of childhood cancer.

METHODS: In this multicenter Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 PULM sub-study, we included 828 survivors with a median follow-up of 26.6 years, treated with cyclophosphamide and/or established pulmonary toxic treatment, or neither. Pulmonary function tests were used to measure the primary outcomes of diffusion impairment (diffusing capacity for carbon monoxide (DLCO) z-score), restriction (total lung capacity (TLC) z-score), and obstruction (forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) z-score. Secondary outcomes comprised chronic cough, recurrent respiratory tract infections, shortness of breath, and supplemental oxygen need.

RESULTS: Diffusion and restrictive abnormalities were highly prevalent among those treated with established pulmonary toxic treatment, with cyclophosphamide (41.0% and 50.4%, respectively) and without (34.3% and 41.9%, respectively), and occurred less frequently in survivors treated with cyclophosphamide only (12.9% and 7.3%, respectively) or in survivor controls (9.9% and 12.4%, respectively). In multivariable analyses, cyclophosphamide did not have a clinically relevant effect on the primary or secondary outcomes.

CONCLUSIONS: This study suggests that cyclophosphamide is not associated with clinically relevant pulmonary dysfunction in long-term childhood cancer survivors.

Original language	English
Article number	107948
Number of pages	13
Journal	Respiratory Medicine
Volume	237
Early online date	8 Jan 2025
DOIs	https://doi.org/10.1016/j.rmed.2025.107948
Publication status	Published - Feb 2025

Keywords

Childhood cancer
Cyclophosphamide
Diffusion
Late effects
Long-term follow-up
Lung disease
Pulmonary dysfunction
Pulmonary toxic treatment
Respiratory symptoms
Restriction
Survivorship

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van Kalsbeek, R. J., Feijen, E. A. M., Bresters, D., Kremer, L. C. M., Pluijm, S. M. F., Asogwa, O. A., Dulmen-den Broeder, E. V., van den Heuvel-Eibrink, M. M., Janssens, G. O., Tissing, W. J., Loonen, J. J., Neggers, S. J. C. M. M., van der Pal, H. J. H., Ronckers, C. M., Teepen, J. C., de Vries, A. C. H., Louwerens, M., van der Heiden-van der Loo, M., Prevaes, S. M. P. J., & Versluys, A. B. (2025). Cyclophosphamide is not associated with clinically relevant late pulmonary dysfunction in Dutch survivors of childhood cancer - the DCCSS-LATER 2 PULM sub-study. Respiratory Medicine, 237, Article 107948. https://doi.org/10.1016/j.rmed.2025.107948

@article{9e8476c7c7b943748cb86c1190e92f11,

title = "Cyclophosphamide is not associated with clinically relevant late pulmonary dysfunction in Dutch survivors of childhood cancer - the DCCSS-LATER 2 PULM sub-study",

abstract = "BACKGROUND: Treatment for childhood cancer may increase the risk of long-term pulmonary complications and dysfunction. Pulmonary surveillance is recommended after established pulmonary toxic exposures, including bleomycin, busulfan, carmustine (BCNU), lomustine (CCNU), radiotherapy to a field exposing the lungs, and pulmonary surgery. However, the role of cyclophosphamide as a pulmonary toxic agent is debated.AIM: To establish whether cyclophosphamide is associated with late pulmonary dysfunction among survivors of childhood cancer.METHODS: In this multicenter Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 PULM sub-study, we included 828 survivors with a median follow-up of 26.6 years, treated with cyclophosphamide and/or established pulmonary toxic treatment, or neither. Pulmonary function tests were used to measure the primary outcomes of diffusion impairment (diffusing capacity for carbon monoxide (DLCO) z-score), restriction (total lung capacity (TLC) z-score), and obstruction (forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) z-score. Secondary outcomes comprised chronic cough, recurrent respiratory tract infections, shortness of breath, and supplemental oxygen need.RESULTS: Diffusion and restrictive abnormalities were highly prevalent among those treated with established pulmonary toxic treatment, with cyclophosphamide (41.0% and 50.4%, respectively) and without (34.3% and 41.9%, respectively), and occurred less frequently in survivors treated with cyclophosphamide only (12.9% and 7.3%, respectively) or in survivor controls (9.9% and 12.4%, respectively). In multivariable analyses, cyclophosphamide did not have a clinically relevant effect on the primary or secondary outcomes.CONCLUSIONS: This study suggests that cyclophosphamide is not associated with clinically relevant pulmonary dysfunction in long-term childhood cancer survivors.",

keywords = "Childhood cancer, Cyclophosphamide, Diffusion, Late effects, Long-term follow-up, Lung disease, Pulmonary dysfunction, Pulmonary toxic treatment, Respiratory symptoms, Restriction, Survivorship",

author = "{van Kalsbeek}, {R J} and Feijen, {E A M} and D Bresters and Kremer, {L C M} and Pluijm, {S M F} and Asogwa, {O A} and {Dulmen-den Broeder}, {E van} and {van den Heuvel-Eibrink}, {M M} and Janssens, {G O} and Tissing, {W J} and Loonen, {J J} and Neggers, {S J C M M} and {van der Pal}, {H J H} and Ronckers, {C M} and Teepen, {J C} and {de Vries}, {A C H} and M Louwerens and {van der Heiden-van der Loo}, M and Prevaes, {S M P J} and Versluys, {A B}",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Ltd",

year = "2025",

month = feb,

doi = "10.1016/j.rmed.2025.107948",

language = "English",

volume = "237",

journal = "Respiratory Medicine",

issn = "0954-6111",

publisher = "W.B. Saunders Ltd",

}

van Kalsbeek, RJ, Feijen, EAM, Bresters, D, Kremer, LCM, Pluijm, SMF, Asogwa, OA, Dulmen-den Broeder, EV, van den Heuvel-Eibrink, MM , Janssens, GO, Tissing, WJ, Loonen, JJ, Neggers, SJCMM, van der Pal, HJH, Ronckers, CM, Teepen, JC, de Vries, ACH, Louwerens, M, van der Heiden-van der Loo, M, Prevaes, SMPJ & Versluys, AB 2025, 'Cyclophosphamide is not associated with clinically relevant late pulmonary dysfunction in Dutch survivors of childhood cancer - the DCCSS-LATER 2 PULM sub-study', Respiratory Medicine, vol. 237, 107948. https://doi.org/10.1016/j.rmed.2025.107948

TY - JOUR

T1 - Cyclophosphamide is not associated with clinically relevant late pulmonary dysfunction in Dutch survivors of childhood cancer - the DCCSS-LATER 2 PULM sub-study

AU - van Kalsbeek, R J

AU - Feijen, E A M

AU - Bresters, D

AU - Kremer, L C M

AU - Pluijm, S M F

AU - Asogwa, O A

AU - Dulmen-den Broeder, E van

AU - van den Heuvel-Eibrink, M M

AU - Janssens, G O

AU - Tissing, W J

AU - Loonen, J J

AU - Neggers, S J C M M

AU - van der Pal, H J H

AU - Ronckers, C M

AU - Teepen, J C

AU - de Vries, A C H

AU - Louwerens, M

AU - van der Heiden-van der Loo, M

AU - Prevaes, S M P J

AU - Versluys, A B

PY - 2025/2

Y1 - 2025/2

N2 - BACKGROUND: Treatment for childhood cancer may increase the risk of long-term pulmonary complications and dysfunction. Pulmonary surveillance is recommended after established pulmonary toxic exposures, including bleomycin, busulfan, carmustine (BCNU), lomustine (CCNU), radiotherapy to a field exposing the lungs, and pulmonary surgery. However, the role of cyclophosphamide as a pulmonary toxic agent is debated.AIM: To establish whether cyclophosphamide is associated with late pulmonary dysfunction among survivors of childhood cancer.METHODS: In this multicenter Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 PULM sub-study, we included 828 survivors with a median follow-up of 26.6 years, treated with cyclophosphamide and/or established pulmonary toxic treatment, or neither. Pulmonary function tests were used to measure the primary outcomes of diffusion impairment (diffusing capacity for carbon monoxide (DLCO) z-score), restriction (total lung capacity (TLC) z-score), and obstruction (forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) z-score. Secondary outcomes comprised chronic cough, recurrent respiratory tract infections, shortness of breath, and supplemental oxygen need.RESULTS: Diffusion and restrictive abnormalities were highly prevalent among those treated with established pulmonary toxic treatment, with cyclophosphamide (41.0% and 50.4%, respectively) and without (34.3% and 41.9%, respectively), and occurred less frequently in survivors treated with cyclophosphamide only (12.9% and 7.3%, respectively) or in survivor controls (9.9% and 12.4%, respectively). In multivariable analyses, cyclophosphamide did not have a clinically relevant effect on the primary or secondary outcomes.CONCLUSIONS: This study suggests that cyclophosphamide is not associated with clinically relevant pulmonary dysfunction in long-term childhood cancer survivors.

AB - BACKGROUND: Treatment for childhood cancer may increase the risk of long-term pulmonary complications and dysfunction. Pulmonary surveillance is recommended after established pulmonary toxic exposures, including bleomycin, busulfan, carmustine (BCNU), lomustine (CCNU), radiotherapy to a field exposing the lungs, and pulmonary surgery. However, the role of cyclophosphamide as a pulmonary toxic agent is debated.AIM: To establish whether cyclophosphamide is associated with late pulmonary dysfunction among survivors of childhood cancer.METHODS: In this multicenter Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 PULM sub-study, we included 828 survivors with a median follow-up of 26.6 years, treated with cyclophosphamide and/or established pulmonary toxic treatment, or neither. Pulmonary function tests were used to measure the primary outcomes of diffusion impairment (diffusing capacity for carbon monoxide (DLCO) z-score), restriction (total lung capacity (TLC) z-score), and obstruction (forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) z-score. Secondary outcomes comprised chronic cough, recurrent respiratory tract infections, shortness of breath, and supplemental oxygen need.RESULTS: Diffusion and restrictive abnormalities were highly prevalent among those treated with established pulmonary toxic treatment, with cyclophosphamide (41.0% and 50.4%, respectively) and without (34.3% and 41.9%, respectively), and occurred less frequently in survivors treated with cyclophosphamide only (12.9% and 7.3%, respectively) or in survivor controls (9.9% and 12.4%, respectively). In multivariable analyses, cyclophosphamide did not have a clinically relevant effect on the primary or secondary outcomes.CONCLUSIONS: This study suggests that cyclophosphamide is not associated with clinically relevant pulmonary dysfunction in long-term childhood cancer survivors.

KW - Childhood cancer

KW - Cyclophosphamide

KW - Diffusion

KW - Late effects

KW - Long-term follow-up

KW - Lung disease

KW - Pulmonary dysfunction

KW - Pulmonary toxic treatment

KW - Respiratory symptoms

KW - Restriction

KW - Survivorship

UR - http://www.scopus.com/inward/record.url?scp=85214825840&partnerID=8YFLogxK

U2 - 10.1016/j.rmed.2025.107948

DO - 10.1016/j.rmed.2025.107948

M3 - Article

C2 - 39793859

SN - 0954-6111

VL - 237

JO - Respiratory Medicine

JF - Respiratory Medicine

M1 - 107948

ER -

Cyclophosphamide is not associated with clinically relevant late pulmonary dysfunction in Dutch survivors of childhood cancer - the DCCSS-LATER 2 PULM sub-study

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