Introduction: The standard of care (SoC) for unresectable stage III non-small-cell lung cancer (NSCLC) is durvalumab maintenance therapy after concurrent chemoradiation in patients with PD-L1 > 1%. However, the concurrent approach is only amenable for about one-third of patients due to co-morbidities. Although sequential regimens are usually not regarded as curative, these schedules applied in a dose-escalated manner may be similarly radical as SoC. As combining high-dose radiation and durvalumab remains a question of debate this retrospective bi-center study aims to evaluate pulmonary toxicity after high-dose chemoradiotherapy beyond 70 Gy compared to SoC. Patients and Methods: Patients with NSCLC stage III received durvalumab after either sequential high-dose chemoradiation or concomitant SoC. Chemotherapy consisted of platinum combined with either pemetrexed, taxotere, vinorelbine, or gemcitabine. The primary endpoint was short-term pulmonary toxicity occurring within six months after the end of radiotherapy (RT). Results: A total of 78 patients were eligible for this analysis. 18F-FDG-PET-CT, cranial MRT, and histological/cytological verification were mandatory in the diagnostic work-up. The high-dose and SoC group included 42/78 (53.8%) and 36/78 (46.2%) patients, respectively, which were matched according to baseline clinical variables. While the interval between the end of RT and the start of durvalumab was equal in both groups (p = 0.841), more courses were administered in the high-dose cohort (p = 0.031). Pulmonary toxicity was similar in both groups (p = 0.599), whereas intrathoracic disease control was better in the high-dose group (local control p = 0.081, regional control p = 0.184). Conclusion: The data of this hypothesis-generating study suggest that sequential high-dose chemoradiation followed by durvalumab might be similar to SoC in terms of pulmonary toxicity and potentially more effective with respect to intra-thoracic disease control. Larger trials with a prospective design are warranted to validate these results.

The treatment of locally recurrent lung cancer is a major challenge for radiation-oncologists, especially with data on high-dose reirradiation being limited to small retrospective studies. The aim of the present study is to assess overall survival (OS) for patients with locally recurrent lung cancer after high-dose thoracic reirradiation. Thirty-nine patients who were re-irradiated for lung cancer relapse between October 2013 and February 2019 were eligible for the current retrospective analysis. All patients were re-irradiated with curative intent for in-field tumor recurrence. The diagnostic work-up included a mandatory ¹⁸F-FDG-PET-CT scan and—if possible—histological verification. The ECOG was ≤2, and the interval between initial and second radiation was at least nine months. Thirty patients (77%) had non-small cell lung cancer (NSCLC), eight (20%) had small cell lung cancer (SCLC), and in one patient (3%) histological confirmation could not be obtained. More than half of the patients (20/39, 51%) received re-treatment with dose differentiated accelerated re-irradiation (DART) at a median interval of 20.5 months (range: 6–145.3 months) after the initial radiation course. A cumulative EQD₂ of 131 Gy (range: 77–211 Gy) in a median PTV of 46 mL (range: 4–541 mL) was delivered. Patients with SCLC had a 3 mL larger median re-irradiation volume (48 mL, range: 9–541) compared to NSCLC patients (45 mL, range: 4–239). The median cumulative EQD2 delivered in SCLC patients was 84 Gy (range: 77–193 Gy), while NSCLC patients received a median cumulative EQD2 of 135 Gy (range: 98–211 Gy). The median OS was 18.4 months (range: 0.6–64 months), with tumor volume being the only predictor (p < 0.000; HR 1.007; 95%-CI: 1.003–1.012). In terms of toxicity, 17.9% acute and 2.6% late side effects were observed, with a toxicity grade >3 occurring in only one patient. Thoracic high dose reirradiation plays a significant role in prolonging survival, especially in patients with small tumor volume at recurrence.

Introduction: Thoracic re-irradiation for recurrent lung cancer dates back four decades, when the first small series on 29 patients receiving palliative doses was published. With 5-year overall survival rates of 57% in PDL-1 positive patients after primary chemo-radio-immunotherapy, the number of patients who experience loco-regional relapse will increase in the near future. In this context, centrally recurring lung tumors pose a major treatment challenge. Hence, the aim of the current review is to compile the available evidence on curatively intended thoracic re-irradiation for this special clinical situation. Methods: A systematic literature search according to the PRISMA guidelines was performed. A study was included when the following criteria were met: (1) 66% of the patients had NSCLC, (2) a total dose of 50 Gy in the second course and/or a biologically effective dose of at least 100 Gy in both treatment courses was administered, (3) re-irradiation was administered with modern radiation techniques, (4) 50% or more of the patients had a centrally located relapse, (5) the minimum cohort size was 30 patients. Results: Of the initial 227 studies, 11 were analyzed, 1 of which was prospective. Median overall survival (OS) was 18.1 months (range 9.3–25.1), median progression free survival (PFS) was nine months (range 4.5–16), and median loco-regional control (LRC) was 12.1 months (range 6.5–20). Treatment-related mortality rates ranged from 2% to 14%. The total dose at re-irradiation correlated with both LRC (p-value = 0.012) and OS (p-value = 0.007) with a close relation between these two clinical endpoints (p-value = 0.006). The occurrence of acute toxicity grade 1 to 4 depended on the PTV size at re-irradiation (p-value = 0.033). Conclusion: The evidence regarding curative re-irradiation for centrally recurrent NSCLC is primarily based on scarce retrospective data, which are characterized by a high degree of heterogeneity. The OS in this clinically challenging situation is expected to be around 1.5 years after re-treatment. Patients with a good performance score, younger age, small tumors, and a longer interval to recurrence potentially benefit most from re-irradiation. In this context, prospective trials are warranted to achieve substantial advances in the field.

Background: Chemoradiotherapy (CRT) is the standard treatment for patients with inoperable stage III non‐small cell lung cancer (NSCLC) stage III. With a median OS beyond 30 months, adequate pulmonary function (PF) is essential to ensure acceptable quality of life after treatment. Forced expiratory volume in 1 second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) are the most widely used parameters to assess lung function. The aim of the current study was to evaluate dose‐volume effects of accelerated high‐dose radiation on PF.Methods: A total of 72 patients were eligible for the current analysis. After induction chemotherapy, all patients received dose‐differentiated accelerated radiotherapy with intensity‐modulated radiotherapy (IMRT‐DART). PF tests were performed six weeks, three and six months after the end of radiotherapy.Results: The median total dose to the tumor was 73.8 Gy (1.8 Gy bid) with a size dependent range between 61.2 and 90 Gy. In the whole cohort, 321 pulmonary function tests were performed. At six months, the median FEV1 relative to baseline was 0.95 (range: 0.56–1.36), and the relative median DLCO decreased to 0.98 (range: 0.64–1.50). The correlation between V20_{total lung} and FEV1 decline was statistically significant (P = 0.023). A total of 13 of 34 (38%) COPD patients had a 4%–21% FEV1 decrease.Conclusion: Patients with a V20_{total lung} < 21% are at a low risk for PF decrease after high dose irradiation treatment. Although overall short term FEV1 and DLCO differ only moderately from baseline these changes may be clinically important, especially in patients with COPD.Key points: Significant findings: Pulmonary function after high dose irradiation decreases only moderately. FEV1 and DLCO decrease depend on V20_{total lung}. Small differences in lung function may be clinically important for COPD patients. KPS predicts minimal clinically important differences (MCID). What this study adds: This study shows that high‐dose irradiation delivered with intensity‐modulated techniques does not impair short‐term lung function even in patients with compromised respiratory capacity before treatment. This is a pre‐requisite for adequate quality of life after thoraco‐oncological therapy.

Background: In order to characterize the various subtypes of breast cancer more precisely and improve patients selection for breast conserving therapy (BCT), molecular profiling has gained importance over the past two decades. MicroRNAs, which are small non-coding RNAs, can potentially regulate numerous downstream target molecules and thereby interfere in carcinogenesis and treatment response via multiple pathways. The aim of the current two-phase study was to investigate whether hsa-miR-375-signaling through RASD1 could predict local control (LC) in early breast cancer. Results: The patient and treatment characteristics of 81 individuals were similarly distributed between relapse (n = 27) and control groups (n = 54). In the pilot phase, the primary tumors of 28 patients were analyzed with microarray technology. Of the more than 70,000 genes on the chip, 104 potential hsa-miR-375 target molecules were found to have a lower expression level in relapse patients compared to controls (p-value < 0.2). For RASD1, a hsa-miR-375 binding site was predicted by an in silico search in five mRNA-miRNA databases and mechanistically proven in previous pre-clinical studies. Its expression levels were markedly lower in relapse patients than in controls (p-value of 0.058). In a second phase, this finding could be validated in an independent set of 53 patients using ddPCR. Patients with enhanced levels of hsa-miR-375 compared to RASD1 had a higher probability of local relapse than those with the inverse expression pattern of the two markers (log-rank test, p-value = 0.069). Conclusion: This two-phase study demonstrates that hsa-miR-375/RASD1 signaling is able to predict local control in early breast cancer patients, which—to our knowledge—is the first clinical report on a miR combined with one of its downstream target proteins predicting LC in breast cancer.