br Corresponding authors br tion techniques such as intensit
⇑ Corresponding authors.
tion techniques, such as intensity modulated radiotherapy, are used to prevent ARIE by excluding the JNJ-42153605 from the radia-tion field. This approach is often not feasible when the esophagus is located close to the involved lymph nodes in the mediastinum.
The drugs including adrenocorticotropic hormone and certain antibiotics, such as a mixture of lidocaine, dexamethasone and gentamycin (mLDG), are the main treatments used for ARIE in China , although the effectiveness of mLDG has not been confirmed in clinical trials. Particular attention has been paid to the development of radioprotective agents, which are capable of preserving normal tissues without compromising anti-tumor effect . EGCG has been extensively investigated in order to ameliorate radiation-induced damage [7–10]. An experiment showed that EGCG exerted protective effects against radiation-induced normal cell death in vitro . It had the ability to scavenge superoxide anion, hydroxyl radical and hydrogen peroxide. In addition, EGCG
was also able to intercalate into the DNA, protecting against radiation-induced DNA strand breaks .
Our previous phase I study preliminarily showed oral adminis-tration of EGCG was feasible and safe in patients with locally advanced lung cancer receiving radiotherapy . The recom-mended concentration was 440 lmol/L. A prospective, single-arm, phase II study was subsequently conducted to assess the effectiveness and safety of EGCG in addressing ARIE . Then, we launched this prospective randomized controlled study to clin-ically validate the preventive and therapeutic value of EGCG in patients with ARIE.
Material and methods
This was a 3-arm, prospective, randomized, controlled clinical study designed to assess the efficacy of EGCG in the prevention and treatment of ARIE in patients receiving sequential or concur-rent chemoradiotherapy. The research design was approved by the local study review and its registration number was NCT02577393 (www.clinicaltrials.gov). And an informed consent was obtained from all the subjects.
Eligible patients were required to meet the following inclusion criteria: pathologically documented LC; considered medically inoperable stage IIIA or stage IIIB or limited stage small cell lung cancer; age 18 years; Karnofsky’s score 70; adequate hemato-logic, hepatic and renal function; FEV1 >800 cc; mean esophagus dose >20 Gy. Exclusion criteria were as follows: a known allergy or hypersensitivity to EGCG; pregnancy or lactation; prior radia-tion to the thorax [11,12].
All patients underwent three-dimensional conformal radiother-apy or intensity modulation radiation therapy. A repeat-fixation mask or vacuum bag was used for the CT-simulation scan. Eclipse treatment planning system (Eclipse 8.6, Varian Medical Systems) was used for radiotherapy (RT) planning. Planning target volume included gross tumor volume and margins of 0.5–1.5 cm for meta-static regional lymph nodes, 0.8–1.5 cm for primary tumor. The total radiation dose was 50–66 Gy (1.8–2 Gy fractions once daily) or 45 Gy (1.5 Gy twice daily) for 5 days per week. The prescribed
target dose was prescribed to the isocenter with a minimum target dose of 95% and a maximum dose of 107% covering 95% of PTV. For the purpose of consistency, the tissues were contoured by a team consisting of three radiation oncologist in all patients. The entire esophagus was identified and contoured on each axial plane of the planning CT scan from the inferior border of the cricoid carti-lage to the gastroesophageal junction. The radiation dose limits were exactly the same as before: mean lung dose 18 Gy, the max-imum spinal cord 50 Gy, total heart 35 Gy.
Study design and treatment
EGCG (440 lmol/L, purity 95% by HPLC; from NINGBO HEP Biotech Co., Ltd) or mLDG (lidocaine 0.16 mg/mL, dexamethasone 0.02 mg/mL, and gentamycin 0.16 mg/mL) dissolved in 0.9% saline solution was administered three times a day. For applications, repeated swallowing of 10 ml of the two solutions was indispens-able to assure the prolonged presence of drug in the esophageal wall.