title: High dose daily amifostine and hypofractionated intensively accelerated radiotherapy for locally advanced breast cancer. A phase I/II study and report on early and late sequellae.
abstract: Intrinsic radioresistance, tumor hypoxia and ability of cancer cells to undergo rapid repopulation during radiotherapy are associated with failure of radiotherapy. Tumors with low alpha/beta-ratio values or hypoxic tumors unable to undergo re-oxygenation, are unlikely to be eradicated with standard radiotherapy. Although the therapeutic efficacy of accelerated regimens based on low-dose per fraction may be high since they minimize the adverse role of rapid tumor repopulation, the cellular compartment with low alpha/beta-ratio values (i.e. hypoxic cells) remains a limiting factor. Accelerated hypofractionation, which may be more effective in such tumors, cannot be safely applied unless normal tissues are protected. In the present study we assessed the feasibility of hypofractionated and accelerated radiotherapy supported by cytoprotection (HypoARC) with high dose daily amifostine. Fifteen breast cancer patients with locally advanced disease entered radiation-dose escalation protocoL Twelve consecutive fractions of 3.5-4Gy (5 fractions/week) were given to the breast/chest wall, supraclavicular and axillary area, within 17 days. A high dose of amifostine, at 1,000 mg flat dose, was given 20 minutes before each radiotherapy fraction. Amifostine administration was well- tolerated with minor side-effects (vomiting in 6 out of 15 and hypotention in 2 out of 15 patients). Radiation induced acute skin toxicity was negligible (grade 3 in 1 out of 15 patients). Ten out of 15 patients survived more than 12 months and 7 out of 15 more than 18 months following HypoARC. None of these patients showed any signs of late sequellae, such as lung and myoskeletal fibrosis, or brachial plexopathy. Complete and partial responses were obtained in 11 out of 15 (73%) and in 4 out of 15 (27%) patients, respectively. High dose daily amifostine during hypofractionated radiotherapy is feasible. HypoARC regimen is well-tolerated, effective and has minimal acute and late toxicity to normal breast, chest and axillary tissues.
authors.affiliation: Department of Radiotherapy and Oncology, Democritus University of Thrace, Alexandroupolis, Greece. targ@her.forthnet.gr
authors.forename: M I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: D
authors.initials: D
authors.lastname: Yannakakis
mesh_terms: D000328:Adult; D000368:Aged; D004999:Amifostine / Q000008:administration & dosage* / Q000009:adverse effects; D001132:Arm / Q000473:pathology; D001917:Brachial Plexus / Q000528:radiation effects; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D004487:Edema / Q000209:etiology; D005240:Feasibility Studies; D005260:Female; D005355:Fibrosis; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000209:etiology; D011658:Pulmonary Fibrosis / Q000209:etiology; D011832:Radiation Injuries / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000209:etiology; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D011855:Radiodermatitis / Q000209:etiology; D011882:Radiotherapy, High-Energy / Q000009:adverse effects / Q000379:methods*; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D011837:Radiation-Protective Agents; D004999:Amifostine