title: Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support.
abstract: We closely followed the pulmonary function of 150 consecutive high-risk breast cancer patients who underwent standard induction CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) chemotherapy, followed by randomization to either standard-dose CPB (cyclophosphamide, cisplatin, bischloroethylnitrosourea [BCNU]) chemotherapy (SDC) or to high-dose CPB chemotherapy (HDC) with autologous bone marrow transplantation (ABMT) and peripheral blood progenitor cell support (PBPCS). Previously, we have described a delayed pulmonary toxicity syndrome (DPTS) which characterizes the pulmonary dysfunction after HDC and ABMT in this patient population. However, little is known concerning the role induction chemotherapy plays in its development. We found that after three cycles of induction CAF, the mean diffusing capacity of the lungs for carbon monoxide (DL(CO)) significantly decreased by 12.6%. Additionally, in patients receiving HDC, the mean DL(CO) further decreased to a nadir of 55.2 +/- 14.1% which was significantly lower than those receiving SDC (nadir: 80.7 +/- 12.3%). DPTS occurred in 72% of patients receiving HDC as compared with only 4% of patients receiving SDC. All individuals diagnosed with DPTS were treated with prednisone and the 2-yr follow-up of pulmonary function revealed a gradual improvement in mean DL(CO) such that there were no differences between HDC and SDC groups at the end of the study. No mortality was attributable to pulmonary toxicity in either group. After induction chemotherapy, but before HDC, bronchoalveolar lavage (BAL) demonstrated significant elevations in interleukin-6 (IL-6), IL-8, neutrophils, and lymphocytes. We conclude that induction CAF produces asymptomatic pulmonary dysfunction and inflammation which may prime the lungs for further injury by HDC and predispose to the development of DPTS. Fortunately, in this specific ABMT patient population, the early and judicious use of prednisone appears to improve pulmonary function in patients who develop DPTS.
authors.affiliation: Duke University Medical Center, Departments of Medicine and Cell Biology, Divisions of Pulmonary and Critical Care Medicine and Hematology/Oncology, Durham, North Carolina 27710, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Bhalla
authors.forename: S W
authors.initials: SW
authors.lastname: Wilczynski
authors.forename: A M
authors.initials: AM
authors.lastname: Abushamaa
authors.forename: W P
authors.initials: WP
authors.lastname: Petros
authors.forename: C S
authors.initials: CS
authors.lastname: McDonald
authors.forename: J S
authors.initials: JS
authors.lastname: Loftis
authors.forename: N J
authors.initials: NJ
authors.lastname: Chao
authors.forename: J J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: R J
authors.initials: RJ
authors.lastname: Folz
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy*; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000628:therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D001999:Bronchoscopy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011241:Prednisone / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D012128:Respiratory Distress Syndrome / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D012129:Respiratory Function Tests; D012189:Retrospective Studies; D014182:Transplantation, Autologous
chemical_list: D015703:Antigens, CD; D005938:Glucocorticoids; D015850:Interleukin-6; D016209:Interleukin-8; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011241:Prednisone