Although this is a retrospective study, HypoFXSRT with a BED of less than 180 Gy was almost safe for stage I NSCLC, and the local control and overall survival rates in 5 years with a BED of 100 Gy or more were superior to the reported results for conventional radiotherapy. For all treatment methods and schedules, the local control and survival rates were better with a BED of 100 Gy or more compared with less than 100 Gy. HypoFXSRT is feasible for curative treatment of patients with stage I NSCLC.

BACKGROUND Stereotactic irradiation (STI) has been actively performed using various methods to achieve better local control of Stage I nonsmall cell lung carcinoma (NSCLC) in Japan. The authors retrospectively evaluated results from a Japanese multiinstitutional study. METHODS Patients with Stage I NSCLC (n = 245; median age, 76 years; T1N0M0, n=155; T2N0M0, n=90) were treated with hypofractionated high‐dose STI in 13 institutions. Stereotactic three‐dimensional treatment was performed using noncoplanar dynamic arcs or multiple static ports. A total dose of 18–75 gray (Gy) at the isocenter was administered in 1–22 fractions. The median calculated biologic effective dose (BED) was 108 Gy (range, 57–180 Gy). RESULTS During follow‐up (median, 24 months; range, 7–78 months), pulmonary complications of National Cancer Institute‐Common Toxicity Criteria Grade > 2 were observed in only 6 patients (2.4%). Local progression occurred in 33 patients (14.5%), and the local recurrence rate was 8.1% for BED ≥ 100 Gy compared with 26.4% for < 100 Gy (P < 0.05). The 3‐year overall survival rate of medically operable patients was 88.4% for BED ≥ 100 Gy compared with 69.4% for < 100 Gy (P < 0.05). CONCLUSIONS Hypofractionated high‐dose STI with BED < 150 Gy was feasible and beneficial for curative treatment of patients with Stage I NSCLC. For all treatment methods and schedules, local control and survival rates were better with BED ≥ 100 Gy compared with < 100 Gy. Survival rates in selected patients (medically operable, BED ≥ 100 Gy) were excellent, and were potentially comparable to those of surgery. Cancer 2004. © 2004 American Cancer Society.

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Recurrence is frequently associated with the acquisition of radioresistance by tumors and resulting failures in radiotherapy. We report, in this study, that long-term fractionated radiation (FR) exposures conferred radioresistance to the human tumor cells, HepG2 and HeLa with cyclin D1 overexpression. A positive feedback loop was responsible for the cyclin D1 overexpression in which constitutively active AKT was involved. AKT is known to inactivate glycogen synthase kinase-3b (GSK3b), which is essential for the proteasomal degradation of cyclin D1. The resulting cyclin D1 overexpression led to the forced progression of S-phase with the induction of DNA double strand breaks. Cyclin D1-dependent DNA damage activated DNA-dependent protein kinase (DNA-PK), which in turn activated AKT and inactivated GSK3b, thus completing a positive feedback loop of cyclin D1 overproduction. Cyclin D1 overexpression led to the activation of DNA damage response (DDR) consisted of ataxia telangiectasia mutated (ATM)-and Chk1-dependent DNA damage checkpoint and homologous recombination repair (HRR). Long-term FR cells repaired radiation-induced DNA damage faster than non-FR cells. Thus, acquired radioresistance of long-term FR cells was the result of alterations in DDR mediated by cyclin D1 overexpression. Inhibition of the AKT/GSK3b/cyclin D1/ Cdk4 pathway by the AKT inhibitor, Cdk4 inhibitor or cyclin D1 targeting small interfering RNA (siRNA) suppressed the radioresistance. Present observations give a mechanistic insight for acquired radioresistance of tumor cells by cyclin D1 overexpression, and provide novel therapeutic targets for recurrent radioresistant tumors.