Amifostine as a radioprotector in the management of advanced non-small cell lung cancer – histopathological features

Background and purpose

Locally advanced, surgically unresectable non-small cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens included dose escalation and the addition of cytotoxic chemotherapy to radiotherapy have yielded confl icting results. This management can be limited by acute and late toxicities, especially pneumonitis and esophagitis. Radioprotector – amifostine could reduce the incidence of radio-chemotherapy-induced acute and late toxicities.

Patients and methods

Between 2000 and 2005, a total of 30 patients with locally advanced non-small cell lung cancer stage IIIA and IIIB were treated. After registration, patients were randomized to treatment with neoadjuvant chemotherapy (4 cycles) followed by concurrent radiochemotherapy (2 cycles) plus amifostine i.v. infusion 500 mg daily – group A (n=15) or neoadjuvant chemotherapy (4 cycles) and concurrent radiochemotherapy (2 cycles) alone – group B (n=15). Both neoadjuvant and concurrent chemotherapy consisted of paclitaxel 175 mg/ m² i.v. infusion day 1 and cisplatin 75 mg/m² i.v. infusion day 1 (during with 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 radiation pneumonitis and acute esophagitis according to Common Toxicity Criteria, version 2.0. Histopathologic evaluation was made after necropsy. Lung tissue 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 ). Biopsy material had been fixed in 10% formalin and processed in paraffin. Hematoxylin and eosin-stained, van Gieson-stained, Masson-trichrome-stained and Weigert´s resorcin fuchsin-stained slides were reviewed with light microscopy.

Results

All patients received four cycles of neoadjuvant chemotherapy and received at least one cycle of concurrent radiochemotherapy. The median of gross tumor mass was 166.13 cm3 (range 63.40 – 284.26) at the begining radiochemotherapy. The median 3D-CRT dose was 67.4 Gy (63.8 – 72.8 Gy). Acute esophagitis grade 3 occured in 3 patients in group A vs 8 patients in group B. Radiation pneumonitis grade 1/2 occurred in 10 patients in group A vs 6 patients in group B. Radiation pneumonitis grade 3/4 occurred in 5 patients in group A vs 9 patients in group B. Histological examination of lung tissue showed major differences between groups A and B in terms of the thickening of the alveolocapilary space. The median thickness of the alveolocapillary space was 8.8 μm (range 2.1 – 11.2) and 3.1 μm (range 0.9 – 4.2) for the Amax and Aref samples compared to 49.8 μm (range 10.2 – 71.4) and 2.7 μm (range 1.1 – 3.8) for the Bmax and Bref samples, respectively. The difference between Amax and Bmax samples was statistically significant (p = 0.0001).

Conclusions

The incidence of radiation pneumonitis and acute esophagitis was lower for patients receiving amifostine than for patients receiving radiochemotherapy alone. Significant differences of the thickness of alveolocapillary space may represent the eff ect of amifostine as a protector of the alveolocapillary integrity.

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. STEJSKAL, J., KUBECOVÁ, M., DVOŘÁKOVÁ, D., et al., Acute toxicities followed by management of locally advanced non-small cell lung cancer – TGF-B1 as a predictor and role of amifostine, Journal of Thoracic Oncology, 2008, 3, 4, p. S75
8. 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
9. 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
10. 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