Since the original study by Nguyen et al. , our institution has been using 45 Gy in 15 fractions for unresectable NSCLC who otherwise cannot tolerate the conventional regimen. In that original report, and presently in this updated study with a much larger study cohort, patients receiving accelerated radiotherapy had comparable local and distant recurrence rates with no difference in overall survival compared to conventionally fractionated radiotherapy for all stages combined, even though these patients initially presented with worse prognostic factors. Our study showed no difference in cumulative incidence of locoregional or distant failures between the RT groups in the presence of competing factors. There was some difference in relapse free survival in the 60-63 Gy arm with no difference in overall survival after adjusting for other variables. Lastly, we found treatment to be well tolerated in the ACRT cohort, even though these patients presented with worse prognostic factors (weight loss > 5%, KPS < 70). Overall, our study demonstrates that accelerated radiation therapy with 45 Gy in 15 fractions is an acceptable treatment option with comparable outcomes for patients with inoperable tumors treated with conventional radiotherapy without chemotherapy.
Radiation treatment using daily accelerated hypofractionation for the treatment of locally advanced lung cancers has been reported in other studies. Slotman et al.  retrospectively compared three hypofractionated schemes for the treatment of unresectable NSCLC (stage IIIA-IV) (40 Gy split course, 30-32 Gy in 6 fractions, or 24 Gy in 3 fractions) demonstrated that a split course treatment regimen of 40 Gy had improved overall survival and lower local relapse rates in stage IIIA NSCLC patients, but not in patients with stage IIIB-IV disease. Kepka et al.  performed a dose escalation study in which patients were initially treated with a 4 week course (21 days) at 56.7 Gy (2.7 Gy per fraction), and gradually escalated to a MTD of 60.9 Gy in 21 days (2.9 Gy per fraction). Fit patients received induction chemotherapy for 2-3 cycles. The median survival was 17 months, and the 2- and 3-year overall survival rates were 32 and 19%, respectively.
There are several biological benefits of the 45 Gy in 15 fraction treatment regimen. Applying α/β ratio of 10, this regimen has a biological equivalent dose (BED10) of 58.5 Gy. Although this is lower than the BED10 for patients treated with conventionally fractionated radiation to 60-70 Gy (72-84 Gy), our preliminary data published by Nguyen et al.  and this updated experience seem to indicate that control rates seem similar between the two treatment schemes. The benefit may come in the shortened treatment time, which can counteract tumor repopulation. Many studies have stressed the importance of maintaining radiation treatment duration within a shortened period, to prevent tumor repopulation, which often contains more resistant cells that are much more difficult to treat. The biological benefit of accelerated radiotherapy can best be seen as a negative influence factor against rapid tumor cell proliferation. Cox et al.  showed a significant difference in OS in patients with treatment delays which were noted to be more frequent in patients receiving higher total doses (≥ 69.6 Gy). Other studies looking at lung cancer patients also noted potentially worse outcomes with prolonged radiation treatment times, due in part to repopulation [12, 13].
Our study is limited by its retrospective nature, and apparent imbalances in the treatment groups that are inherent in observational studies. Some of our patients had poor follow-up, and therefore disease recurrence may have been more common than reported. However, the merits of our study are that this is a review of a fairly large group of patients (> 100) of a regimen of hypofractionated accelerated radiotherapy for a group of patients that would not have otherwise tolerated a longer course of therapy. The comparison groups were patients who received > 60 Gy without concurrent chemotherapy, which we believe, despite the inherent limitations, better answered the issue of dose and removed the confounding factor of patient selection for the receipt of concurrent chemotherapy.
We believe our reported experience demonstrated the tolerability and relative effectiveness of this treatment regimen. Currently concurrent chemoradiation is the standard therapy for the management of locally advanced NSCLC, based on the recently published phase III trial RTOG 9410 . This regimen improved the median survival by about 3 months over induction chemotherapy and conventionally fractionated radiotherapy. However, this treatment regimen carries substantially higher grade 3 or higher non-hematologic acute toxicities, such as esophagitis and mucositis. Limiting concurrent chemotherapy with radiotherapy would minimize this additive toxicity. Since distant metastatic disease is still the major pattern of failure for locally advanced NSCLC, treatment using a regimen of high dose systemic chemotherapy sandwiched with a short course of effective local therapy may improve disease outcomes while reducing treatment related toxicities.
Building upon our experience is the basis of an ongoing dose escalation radiotherapy trial at our institution using proton beam therapy in advanced lung cancer patients (45 Gy to 52.5 Gy to 60 Gy in 15 fractions), as well as a proposed phase II trial using sequential high dose chemotherapy and the sandwiched hypofractionated radiotherapy using the MTD (from the above dose escalation trial) in 15 fractions using protons or IMRT for locally advanced NSCLC. We believe this approach for the treatment of unresectable lung cancers can become a standard in the future, by minimizing both the toxicity of concurrent chemotherapy and the delay of long course radiotherapy. By shortening the overall treatment time and allowing full dose systemic therapy to be delivered sequentially with effective local radiotherapy may improve the distant metastatic rate and accelerated repopulation potential.