Purpose: Local failure rates after radiation therapy (RT) for locally advanced non–small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. Patients and Methods: Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity. Results: No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. Conclusion: Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.

The development of advanced radiation technologies, including intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT) and proton therapy, has resulted in increasingly conformal radiation treatments. Recent evidence for the importance of minimizing dose to normal critical structures including the heart and lungs has led to incorporation of these advanced treatment modalities into radiation therapy (RT) for non-small cell lung cancer (NSCLC). While such technologies have allowed for improved dose delivery, implementation requires improved target accuracy with treatments, placing increasing importance on evaluating tumor motion at the time of planning and verifying tumor position at the time of treatment. In this review article, we describe issues and updates related both to motion management and image guidance in the treatment of NSCLC.

Locally advanced rectal cancers are treated with neoadjuvant chemoradiation therapy followed by surgery. In a minority (~20%) of patients, no tumor is present at the time of surgery; these patients with a complete pathologic response (pathCR) to neoadjuvant therapy have better treatment outcomes. Unfortunately, the inherent radioresistance of colorectal cancer (CRC) cells dictates that the majority of patients do not achieve a pathCR. Efforts to improve these odds have fueled the search for novel, relatively less‐toxic radiosensitizers with distinct molecular mechanism(s) and broad‐spectrum anticancer activities. Here, we use zerumbone, a sesquiterpene from the edible ginger (Zingiber zerumbet Smith), to enhance radiosensitivity of CRC cells. Short exposure to zerumbone (7 h) profoundly sensitized CRC cells, independent of their p53 or k‐RAS status. Zerumbone enhanced radiation‐induced cell cycle arrest (G2/M), increased radiation‐induced apoptosis, but induced little apoptosis by itself. Zerumbone significantly enhanced radiation‐induced DNA damage, as evident by delayed resolution of post‐irradiation nuclear γH2AX foci, whereas zerumbone treatment alone did not induce γH2AX foci formation. Zerumbone pretreatment inhibited radiation‐induced nuclear expression of DNA repair proteins ataxia‐telangiectasia mutated (ATM) and DNA‐PKcs. Interestingly, zerumbone‐mediated radiosensitization did not involve reactive oxygen species (ROS), but was mediated through depletion of cellular glutathione (GSH). Ability of only thiol‐based antioxidants to abrogate zerumbone‐mediated radiosensitization further corroborated this hypothesis. The α,β‐unsaturated carbonyl group in zerumbone was found to be essential for its bioactivity as zerumbone analog α‐Humulene that lacks this functional group, could neither radiosensitize CRC cells, nor deplete cellular GSH. Our studies elucidate novel mechanism(s) of zerumbone's ability to enhance CRC radiosensitivity.