Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer.
OBJECTIVE
In dose-escalation studies of radiotherapy (RT) for non-small-cell lung cancer (NSCLC), radiation pneumonitis (RP) is the most important dose-limiting complication. Transforming growth factor-beta1 (TGF-beta1) has been reported to be associated with the incidence of RP. It has been proposed that serial measurements of plasma TGF-beta1 can be valuable to estimate the risk of RP and to decide whether additional dose-escalation can be safely applied. The aim of this study was to evaluate prospectively the time course of TGF-beta1 levels in patients irradiated for NSCLC in relation to the development of RP and dose-volume parameters.


METHODS
Plasma samples were obtained in 68 patients irradiated for medically inoperable or locally advanced NSCLC (dose range, 60.8-94.5 Gy) before and 4, 6, and 18 weeks after the start of RT. Plasma TGF-beta1 levels were determined using a bioassay on the basis of TGF-beta1-induced plasminogen activator inhibitor-1 expression in mink lung cells. All patients underwent chest computed tomography scans before RT that were repeated at 18 weeks after RT. The computed tomography data were used to calculate the mean lung dose (MLD) and to score the radiation-induced radiologic changes. RP was defined on the basis of the presence of either radiographic changes or clinical symptoms. Symptomatic RP was scored according to the Common Toxicity Criteria (Grade 1 or worse) and the Southwestern Oncology Group criteria (Grade 2 or worse). Multivariate analyses were performed to investigate which factors (pre- or posttreatment TGF-beta1 level, MLD) were associated with the incidence of RP. To improve our understanding of the time course of TGF-beta1 levels, we performed a multivariate analysis to investigate which factors (pre-RT TGF-beta1 level, MLD, RP) were independently associated with the posttreatment TGF-beta1 levels.


RESULTS
The pre-RT TGF-beta1 levels were increased in patients with NSCLC (median 21 ng/mL, range, 5-103 ng/mL) compared with healthy individuals (range, 4-12 ng/mL). On average, the TGF-beta1 levels normalized toward the end of treatment and remained stable until 18 weeks after RT. In 29 patients, however, TGF-beta1 was increased at the end of RT with respect to the pre-RT value. The multivariate analyses revealed that the MLD was the only variable that correlated significantly with the risk of both radiographic RP (p = 0.05) and symptomatic RP, independent of the scoring system used (p = 0.05 and 0.03 for Southwestern Oncology Group and Common Toxicity Criteria systems, respectively). The TGF-beta1 level at the end of RT was significantly associated with the MLD (p <0.001) and pre-RT TGF-beta1 level (p = 0.001).


CONCLUSIONS
The MLD correlated significantly with the incidence of both radiographic and symptomatic RP. The results of our study did not confirm the reports that increased levels of TGF-beta1 at the end of RT are an independent additional risk factor for developing symptomatic RP. However, the TGF-beta1 level at the end of a RT was significantly associated with the MLD and the pre-RT level.
De Jaeger
Katrien
K
Department of Radiotherapy, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. k.d.jaeger@nki.nl
Seppenwoolde
Yvette
Y
Kampinga
Harm H
HH
Boersma
Liesbeth J
LJ
Belderbos
José S A
JS
Lebesque
Joos V
JV
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D008168:Lung / Q000528:radiation effects; D008175:Lung Neoplasms / Q000097:blood* / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D017564:Radiation Pneumonitis / Q000097:blood / Q000209:etiology*; D011879:Radiotherapy Dosage; D012016:Reference Values; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000097:blood*; D053773:Transforming Growth Factor beta1
D015415:Biomarkers; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1