Acute toxicities followed by management of locally advanced non-small cell lung cancer – TGF-β1 as a predictor of radiation pneumonitis.

Purpose Locally advanced non-small cell lung cancer (LA NSCLC) represents a disease with poor prognosis. The use of more aggressive chemoradiation regimens have yielded conflicting results. This management can be limited by acute and late toxicities, especially radiation pneumonitis (RP) and acute esophagitis (AE). Cytokine Transforming Growth Faktor Beta 1 (TGF-β₁) is high sensitive predictor of radiation-induced pneumonitis. Radioprotector amifostine could reduce the incidence of radio-chemotherapy-induced acute and late toxicities.

Descriptions Between 2000 and 2005, a total of 30 patients with LA NSCLC stage IIIA and IIIB were treated. Patients were randomized to treatment with chemotherapy (CT) – neoadjuvant (4 cycles) followed by concurrent radiochemotherapy (2 cycles) plus amifostine i.v. infusion 500 mg daily – group A (n=15) or neoadjuvant CT (4 cycles) and concurrent radiochemotherapy (2 cycles) alone – group B (n=15). Neoadjuvant chemotherapy consisted of paclitaxel 175 mg/m² i.v. infusion day 1 and cisplatin 75 mg/m² i.v. infusion day 1 (during the concurrent radiochemotherapy day 2), administred every 3 weeks. All patients were treated using 3D conformal radiotherapy (3D-CRT) with planning doses to the ICRU reference point ranging from 63,8 to 72,8 Gy. All patients were assessed at each follow-up visit for signs and symptoms of RP and AE according to CTC, v. 2.0. Lung tissue for histopathologic evaluation had been sampled from two different sites. In both patient groups, the first sample came from the area of PTV 2 (Amax, Bmax) while the second sample was taken from the intact lung outside the PTV 1 (Aref, Bref). Changes in plasma TGF-β₁ levels were obtained before CT, before 3D-CRT, in the middle of course 3D-CRT, and after 3D-CRT.

Summary RP grade 3/4 and AE grade 3 occurred in 5 and 3 patients in group A vs 9 and 8 patients in group B. The median dose of 3D-CRT to GTV was 67,4 Gy. The median of gross tumor mass was 166,13 cm³ (range 63,40-284,26) at the beginning treatment. Plasma level TGF-β₁ were statistically significant elevated (p=0,001) in the middle of course RT in group A (14,9 ng/ml) vs group B (31,3 ng/ml), respectively. Histological examination of lung tissue (Fig. 1-8) showed major differences between groups A and B in terms of the thickening of the alveolocapilary space. The difference between Amax and Bmax samples was statistically significant (p=0,0001).

Conclusions The incidence of pneumonitis and esophagitis was lower for patients receiving amifostine than for patients receiving radiochemotherapy alone. These results suggest that plasma TGF-β₁ levels during treatment may be useful to prediction which patients are at high risk of developing radiation pneumonitis.

References:

1. ANSCHER, MS., KONG, F-M., ANDREWS, K., et al., Plasma transforming growth factor Beta1 as a predictor of radiation pneumonitis, Int J Radiat Oncol Biol Phys, 1998, 41, p. 1029-1036
2. ANTONADOU, D., PETRIDIS, A., SYNODINOU, M., et al., Amifostine reduces radiochemotherapy-induced toxicities in patients with locally advanced non-small cell lung cancer, Semin Oncol, 2003, 30, 6, Supp 18, p. 2-9
3. DeJAEGER, K., SEPPENWOOLDE, Y., KAMPINGA, HH., et al., Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer, Int J Radiat Oncol Biol Phys, 2004, 58, 5, p. 1378-1387
4. KOMAKI, R., LEE, JS., MILAS, L., et al., Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: Report of a randomized comparative trial, Int J Radiat Oncol Biol Phys, 2004, 58, 5, p. 1369-1377
5. NOVAKOVA-JIRESOVA, A., Van GAMEREN, MM., COPPES, RP., et al., Transforming growth factor-β plasma dynamics and post-irradiation lung injury in lung cancer patients, Radiother Oncol, 2004, 71, 2, p. 183-189
6. ÖSTERREICHER, J., PEJCHAL, J., ŠKOPEK, J., et al., Role of type II pneumocytes in pathogenesis of radiation pneumonitis: dose response of radiation-induced lung changes in the transient high vascular permeability period, Experimental and Toxicologic Pathology, 2004, 56, 3, p. 181-187
7. THROUVALAS, N., ANTONADOU, D., PETRIDIS, A., at al., Reduction of Toxicities Associated with Radiochemotherapy in Patients with Locally Advanced Non-Small Cell Lung Cancer Using Amifostine, Int J Radiat Oncol Biol Phys, 2002, 54, 2, p. 106-107
8. TRAVIS, EL., PARKINS, CS., HOLMES, SJ., et al., WR-2721 protection of pneumonitis and fibrosis in mouse lung after single doses of X rays, Int J Radiat Oncol Biol Phys, 1984, 10, p. 243-251
9. ZATLOUKAL, P., PETRUZELKA, L., ZEMANOVA, M., et al., Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study, Lung Cancer, 2004, 46, p. 87-98

MUDr. Jan Stejskal, Ph.D., Department of Radiation Oncology Regional Hospital Pardubice, Kyjevská 44, 532 03 Pradubice, Czech Republic, janstejk@seznam.cz