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      Radiation dose escalation with modified fractionation schedules for locally advanced NSCLC: A systematic review

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          Abstract

          Concomitant chemo‐radiotherapy (cCRT) with 60 Gy in 30 fractions is the standard of care for stage 111 non‐small cell lung cancer (NSCLC). With a median overall survival of 28.7 months at best and maximum locoregional control rates of 70% at two years, the prognosis for these patients is still dismal. This systematic review summarizes data on dose escalation by alternative fractionation, which has been explored as a primary strategy to improve both local control and overall survival over the past three decades. A Pubmed literature search was performed according to the PRISMA guidelines. Because of the large variety of radiation regimens total doses were converted to EQD 2,T. Only studies using an EQD 2,T of at least 49.5 Gy, which corresponds to the conventional 60 Gy in six weeks, were included. In a total of 3256 patients, the median OS was 17 months (range 7.4–30 months). While OS was better for patients treated after the year 2000 ( P = 0.003) or with a mandatory 18F‐FDG‐PET‐CT in the diagnostic work‐up ( P = 0.001), treatment sequence did not make a difference ( P = 0.106). The most commonly reported toxicity was acute esophagitis (AE) with a median rate of 24% (range 0%–84%). AE increased at a rate of 0.5% per Gy increment in EQD 2,T ( P = 0.016). Dose escalation above the conventional 60 Gy using modified radiation fractionation schedules and shortened OTT yield similar mOS and LRC regardless of treatment sequence with a significant EQD 2,T dependent increase in AE.

          Key points

          Significant findings

          • Modified radiation dose escalation sequentially combined with chemotherapy yields similar outcome as concomitant treatment.

          • OS is better with the mandatory inclusion of FDG‐PET‐CT in the diagnostic work‐up.

          • The risk of acute esophagitis increases with higher EQD 2,T.

          What this study adds

          • Chemo‐radiotherapy (CRT) with modified dose escalation regimens yields OS and LC rates in the range of standard therapy regardless of treatment sequence. This broadens the database of curative options in patients who are not eligible concomitant CRT.

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          Most cited references47

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          Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study.

          We conducted a phase III study to compare the survival impact of concurrent versus sequential treatment with radiotherapy (RT) and chemotherapy (CT) in unresectable stage III non-small-cell lung cancer (NSCLC). Patients were randomly assigned to one of the two treatment arms. In the sequential arm, patients received induction CT with cisplatin (120 mg/m2) on days 1, 29, and 57, and vinorelbine (30 mg/m2/wk) from day 1 to day 78, followed by thoracic RT at a dose of 66 Gy in 33 fractions (2 Gy per fraction and 5 fractions per week). In the concurrent arm, the same RT was started on day 1 with two concurrent cycles of cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d (days 1 to 5 and days 29 to 33); patients then received consolidation therapy with cisplatin 80 mg/m2 on days 78 and 106 and vinorelbine 30 mg/m2/wk from days 78 to 127. Two hundred five patients were randomly assigned. Pretreatment characteristics were well balanced between the two arms. There were six toxic deaths in the sequential arm and 10 in the concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm (log-rank test P = .24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%, respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% v 3%). Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.
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            Hyperfractionated or Accelerated Radiotherapy in Lung Cancer: An Individual Patient Data Meta-Analysis

            Purpose In lung cancer, randomized trials assessing hyperfractionated or accelerated radiotherapy seem to yield conflicting results regarding the effects on overall (OS) or progression-free survival (PFS). The Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group decided to address the role of modified radiotherapy fractionation. Material and Methods We performed an individual patient data meta-analysis in patients with nonmetastatic lung cancer, which included trials comparing modified radiotherapy with conventional radiotherapy. Results In non–small-cell lung cancer (NSCLC; 10 trials, 2,000 patients), modified fractionation improved OS as compared with conventional schedules (hazard ratio [HR] = 0.88, 95% CI, 0.80 to 0.97; P = .009), resulting in an absolute benefit of 2.5% (8.3% to 10.8%) at 5 years. No evidence of heterogeneity between trials was found. There was no evidence of a benefit on PFS (HR = 0.94; 95% CI, 0.86 to 1.03; P = .19). Modified radiotherapy reduced deaths resulting from lung cancer (HR = 0.89; 95% CI, 0.81 to 0.98; P = .02), and there was a nonsignificant reduction of non–lung cancer deaths (HR = 0.87; 95% CI, 0.66 to 1.15; P = .33). In small-cell lung cancer (SCLC; two trials, 685 patients), similar results were found: OS, HR = 0.87, 95% CI, 0.74 to 1.02, P = .08; PFS, HR = 0.88, 95% CI, 0.75 to 1.03, P = .11. In both NSCLC and SCLC, the use of modified radiotherapy increased the risk of acute esophageal toxicity (odds ratio [OR] = 2.44 in NSCLC and OR = 2.41 in SCLC; P < .001) but did not have an impact on the risk of other acute toxicities. Conclusion Patients with nonmetastatic NSCLC derived a significant OS benefit from accelerated or hyperfractionated radiotherapy; a similar but nonsignificant trend was observed for SCLC. As expected, there was increased acute esophageal toxicity.
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              Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study.

              The superiority of chemoradiotherapy (CRT) over radiation alone in locally advanced non-small cell lung cancer (NSCLC) has been proven, but the relative merits of a concurrent schedule versus their sequential administration are less clear. This study compared the safety and efficacy of concurrent and sequential CRT, with chemotherapy (CT) consisting of a cisplatin and vinorelbine regimen, in patients with locally advanced NSCLC. One hundred and two previously untreated patients (aged 42-75 years) with locally advanced, stage IIIA (n = 15) or stage IIIB (n = 87) NSCLC were entered into the study. The CT schedule consisted of up to four cycles of cisplatin 80 mg/m(2) on day 1, and vinorelbine 25 mg/m(2) at the first and fourth cycles (12.5 mg/m(2) during the 2nd/3rd cycles) on days 1, 8, 15 of a 28-day cycle. Radiotherapy (RT) was prescribed at a dose of 60 Gy/30 fractions, given as five fractions per week for 6 weeks. In the concurrent arm (arm A), RT was started on day 4 of cycle 2; whilst in the sequential arm (arm B), RT started within 2 weeks after completion of CT. Fifty-two patients were randomized to concurrent treatment and 50 to the sequential schedule. Overall survival was significantly longer in arm A (median survival 16.6 months) versus arm B (median survival 12.9 months) (P = 0.023 by means of log-rank test; hazard ratio HR = 0.61, 95% CI of HR (0.39-0.93)), and time to progression (TTP) was also significantly longer in arm A (median time to progression 11.9 months) versus arm B (median time to progression 8.5 months) (P = 0.024 by means of log-rank test; HR = 0.62, 95% CI of HR (0.38-0.93)). Ninety-eight patients were evaluable for response and 101 for toxicity. The overall response rate was significantly higher in arm A, 80% (with 21% complete response (CR)) compared with 47% (with 17% CR) in arm B (P = 0.001 by means of chi(2)-test). WHO grade 3 or 4 toxicity was more frequent in arm A than in arm B, with a significantly greater incidence of leucopenia (53% versus 19%, P = 0.009 by means of chi(2) test) and nausea/vomiting (39% versus 15%, P = 0.044 by means of chi(2) test). There were no treatment related deaths. In this study population, concurrent CRT demonstrated significant benefit in terms of response rate, overall survival and time to progression over sequential CRT. The concurrent CRT schedule was associated with higher toxicity; however, the adverse event profile was acceptable in both arms.
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                Author and article information

                Contributors
                f.zehentmayr@salk.at
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                22 April 2020
                June 2020
                : 11
                : 6 ( doiID: 10.1111/tca.v11.6 )
                : 1375-1385
                Affiliations
                [ 1 ] Department of Radiation Oncology Paracelsus Medical University Salzburg Australia
                [ 2 ] Institute for Research and Development on Advanced Radiation Technologies (radART), Paracelsus Medical University Salzburg Australia
                Author notes
                [*] [* ] Correspondence

                Franz Zehentmayr, Müllner Hauptstrasse 48, A‐5020 Salzburg, Australia.

                Tel: +43 57255 58915

                Fax: +43 57255 27298

                Email: f.zehentmayr@ 123456salk.at

                Author information
                https://orcid.org/0000-0001-5931-3907
                Article
                TCA13451
                10.1111/1759-7714.13451
                7262927
                32323484
                cc291f8b-af13-4ba0-b5d0-e8d9849c8c33
                © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 27 February 2020
                : 04 April 2020
                : 05 April 2020
                Page count
                Figures: 4, Tables: 1, Pages: 11, Words: 7043
                Categories
                Invited Review
                Invited Review
                Custom metadata
                2.0
                June, 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:01.06.2020

                acute esophagitis,eqd2,t,modified fractionation,radiation dose escalation,systematic review

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