Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.

Lymphocyte infiltration is a common feature of radiation-induced pneumonitis and fibrosis, but their contribution to the pathogenic processes is still unclear. Here, we addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg).

Radiation therapy is an essential component of present-day cancer management, utilizing ionizing radiation (IR) of different modalities to mitigate cancer progression. IR functions by generating ionizations in cells that induce a plethora of DNA lesions. The most detrimental among them are the DNA double strand breaks (DSBs). In the course of evolution, cells of higher eukaryotes have evolved four major DSB repair pathways: classical non-homologous end joining (c-NHEJ), homologous recombination (HR), alternative end-joining (alt-EJ), and single strand annealing (SSA). These mechanistically distinct repair pathways have different cell cycle- and homology-dependencies but, surprisingly, they operate with widely different fidelity and kinetics and therefore contribute unequally to cell survival and genome maintenance. It is therefore reasonable to anticipate tight regulation and coordination in the engagement of these DSB repair pathway to achieve the maximum possible genomic stability. Here, we provide a state-of-the-art review of the accumulated knowledge on the molecular mechanisms underpinning these repair pathways, with emphasis on c-NHEJ and HR. We discuss factors and processes that have recently come to the fore. We outline mechanisms steering DSB repair pathway choice throughout the cell cycle, and highlight the critical role of DNA end resection in this process. Most importantly, however, we point out the strong preference for HR at low DSB loads, and thus low IR doses, for cells irradiated in the G₂-phase of the cell cycle. We further explore the molecular underpinnings of transitions from high fidelity to low fidelity error-prone repair pathways and analyze the coordination and consequences of this transition on cell viability and genomic stability. Finally, we elaborate on how these advances may help in the development of improved cancer treatment protocols in radiation therapy.

Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33–74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995–1.015), P = 0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986–1.012), P = 0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death. Z5 - 22461/2 - 2002-017 (German Federal Office for Radiation Protection).

Purpose: A confirmatory analysis was performed to determine the prognostic value of metabolic response during induction chemotherapy followed by bimodality/trimodality treatment of patients with operable locally advanced non–small-cell lung cancer. Patients and Methods: Patients with potentially operable stage IIIA(N2) or selected stage IIIB non–small-cell lung cancer received three cycles of cisplatin/paclitaxel (induction chemotherapy) followed by neoadjuvant radiochemotherapy (RCT) to 45 Gy (1.5 Gy twice per day concurrent cisplatin/vinorelbine) within the ESPATUE (Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA[N2] and Selected IIIB Non–Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy) trial. Positron emission tomography scans were recommended before (t₀) and after (t₂) induction chemotherapy. Patients who were eligible for surgery after neoadjuvant RCT were randomly assigned to definitive RCT or surgery. The prognostic value of percentage of maximum standardized uptake value (%SUV_max) remaining in the primary tumor after induction chemotherapy—%SUV_remaining = SUV_max(t₂)/SUV_max(t₀)—was assessed by proportional hazard analysis and receiver operating characteristic analysis. Results: Overall, 161 patients were randomly assigned (155 from the Essen and Tübingen centers), and 124 of these received positron emission tomography scans at t₀ and t₂. %SUV_remaining as a continuous variable was prognostic for the three end points of overall survival, progression-free survival, and freedom from extracerebral progression in univariable and multivariable analysis (P < .016). The respective hazard ratios per 50% increase in %SUV_remaining from multivariable analysis were 2.3 (95% CI, 1.5 to 3.4; P < .001), 1.8 (95% CI, 1.3 to 2.5; P < .001), and 1.8 (95% CI, 1.2 to 2.7; P = .006) for the three end points. %SUV_remaining dichotomized at a cut point of maximum sum of sensitivity and specificity from receiver operating characteristic analysis at 36 months was also prognostic. Exploratory analysis revealed that %SUV_remaining was likewise prognostic for overall survival in both treatment arms and was more closely associated with extracerebral distant metastases (P = .016) than with isolated locoregional relapses (P = .97). Conclusion: %SUV_remaining is a predictor for survival and other end points after multimodality treatment and can serve as a parameter for treatment stratification after induction chemotherapy or for evaluation of adjuvant new systemic treatment options for high-risk patients.

In a previous report, we compared the conformity of robust intensity-modulated proton therapy (IMPT) plans with that of helical tomotherapy plans for re-irradiations of head and neck carcinomas using a fixed set-up error of 2 mm. Here, we varied the maximum set-up errors between 0 and 5 mm and compared the robust IMPT-plans with planning target volume (PTV) based intensity-modulated photon therapy (IMRT).