Purpose/Objective(s) In the phase II ARTFORCE PET-Boost trial, two individualized dose escalation strategies, utilizing hypofractionation and functional imaging, were tested aiming to improve local control in patients with locally advanced non-small cell lung cancer (LA-NSCLC). Before randomization, plans for both arms were optimized and normalized to the mean lung dose, approximating isotoxicity. The purpose of this study is to assess the isotoxicity of the two treatment plans for each patient, by comparing planned dose to organs at risk (OAR). Materials/Methods The PET-Boost trial included patients with stage II-III NSCLC, with a large primary tumor >4cm. Patients received an escalated dose either to the primary tumor as a whole (arm A), or the FDG-avid areas within the primary tumor (>50% SUVmax) (arm B). Before randomization, two treatment plans were created for each patient, one for each arm, with equal mean lung dose (max 20 Gy). In both arms, the escalated dose was delivered in 24 fractions of 3.0-5.4 Gy, defined by OAR constraints. As the PET-subvolume is smaller than the whole tumor, the dose per fraction could be escalated further. Involved lymph nodes received 66 Gy (24 × 2.75 Gy) in both arms. In this analysis, dose metrics were compared for OARs in the whole tumor vs PET-subvolume arm for each patient. Difference was calculated as metricarmB – metricarmA. Wilcoxon sign rank tests were applied to assess intrapatient differences. Results Between 2010 and 2017, 107 patients were randomized in seven European centers. For 87 patients, data from both treatment plans was available for current analysis. The median (+IQR) differences in dose to OARs between arm A and B were as follows: lung Dmean EQD2α/β=3 -0.3 Gy (-0.5 – 0; p<0.005), lung V5physical +1.1% (0.2 - 2.7; p < 0.005), lung V20physical +0.5% (0.1 – 1.3; p<0.005), esophagus Dmean EQD2α/β=10 +0.1 Gy (-0.9 – 0.6; p = 0.76), esophagus V36physical +0.1% (-0.7 – 1.2; p = 0.45), esophagus Dmax EQD2α/β=10 -0.2 Gy (-2.85 – 0.8; p = 0.05), heart Dmax -0.5 Gy EQD2α/β=3 (-2.1 – 0.6; p = 0.04), heart Dmean -0.1 Gy EQD2α/β=3 (-1.5 – 0.1; p < 0.005), brachial plexus Dmaxphysical -0.3 Gy (-2.1 – 0.1; p=0.01), and spinal cord Dmaxphysical -0.4 Gy (-2.1 – 0.8; p=0.03). We found that outliers with larger differences tended to have either very large primary tumors, or relatively small (≤ 70 cm3) tumor volumes. Conclusion An international trial was performed which randomized LA-NSCLC patients between two dose-escalation strategies that aimed to be isotoxic. Though most statistically significance, we found generally small differences in dose to OAR between the two plans. Our results confirm by aiming at an equal mean lung dose, doses to heart, esophagus, brachial plexus and spinal cord were also to a large extent kept isotoxic. Analyses of dose volume histograms in relation to adverse events reported in the trial is ongoing. This study has the ClinicalTrials.gov identifier NCT01024829.

The standard of care for patients with stage III non-small-cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT) followed by 1 year of adjuvant durvalumab. Despite the survival benefit granted by immunotherapy in this setting, only 1/3 of patients are alive and disease free at 5 years. Novel treatment strategies are under development to improve patient outcomes in this setting: different anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] antibodies after CCRT, consolidation immunotherapy after sequential chemoradiotherapy, induction immunotherapy before CCRT and immunotherapy concurrent with CCRT and/or sequential chemoradiotherapy. Cross-trial comparison is particularly challenging in this setting due to the different timing of immunotherapy delivery and different patients' inclusion and exclusion criteria. In this review, we present the results of clinical trials investigating immune therapy in unresectable stage III NSCLC and discuss in-depth their biological rationale, their pitfalls and potential benefits. Particular emphasis is placed on the potential mechanisms of synergism between chemotherapy, radiation therapy and different monoclonal antibodies, and how this affects the tumor immune microenvironment. The designs and questions tackled by ongoing clinical trials are also discussed. Last, we address open questions and unmet clinical needs, such as the necessity for predictive biomarkers (e.g. radiomics and circulating tumor DNA). Identifying distinct subsets of patients to tailor anticancer treatment is a priority, especially in a heterogeneous disease such as stage III NSCLC.

While high local control rates were achieved in this phase II trial of hypofractionated dose escalation in patients with stage II-III NSCLC, distant metastases were frequently seen in this patient cohort with large primary tumors.

Since the introduction of Stereotactic Body Radiotherapy (SBRT), it has firmly established its place in the management of stage I non-small cell lung cancer (NSCLC), showing better overall survival than conventional radiotherapy. In the Netherlands, the first SBRT for lung cancer was performed in 2003. For patients, real-world data is essential to balance treatment toxicity and treatment outcome. This study aims to audit SBRT in patients with stage I NSCLC in the Netherlands.

In the phase II PET-Boost trial (NCT01024829), patients with stage II-III non-small cell lung cancer (NSCLC) were treated with hypofractionated dose escalation to either the primary tumour (PT) as a whole (armA) or the high FDG-uptake region inside the PT (>50%SUVmax) (armB). Results on Freedom From Local Failure at 1-year (primary endpoint), and overall survival (a secondary endpoint) were reported previously (Cooke et al,ESTRO,2020). Here we report on local and regional failure.

Around 9,500 patients are yearly diagnosed with non-small cell lung cancer (NSCLC) in the Netherlands. The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R) is a national registry for lung cancer patients irradiated with curative/radical intent. The standard treatment for inoperable stage III NSCLC (III-NSCLC) is concurrent chemoradiation and adjuvant immunotherapy in responders. In some cases, chemotherapy is withheld for several reasons. The aim of this study is to describe the real-world data of radical radiotherapy only in patients with III-NSCLC and to analyse toxicity and mortality within 3 months post radiation in patients ≤75 years and >75 years of age.

Purpose Previous literature has reported contradicting results regarding the relationship between tumor volume changes during radiotherapy treatment for non-small cell lung cancer (NSCLC) patients and locoregional recurrence-free rate or overall survival. The aim of this study is to validate the results from a previous study by using a different volume extraction procedure and evaluating an external validation dataset. Methods For two datasets of 94 and 141 NSCLC patients, gross tumor volumes were determined manually to investigate the relationship between tumor volume regression and locoregional control using Kaplan–Meier curves. For both datasets, different subgroups of patients based on histology and chemotherapy regimens were also investigated. For the first dataset ( n = 94), automatically determined tumor volumes were available from a previously published study to further compare their correlation with updated clinical data. Results A total of 70 out of 94 patients were classified into the same group as in the previous publication, splitting the dataset based on median tumor regression calculated by the two volume extraction methods. Non-adenocarcinoma patients receiving concurrent chemotherapy with large tumor regression show reduced locoregional recurrence-free rates in both datasets ( p < 0.05 in dataset 2). For dataset 2, the opposite behavior is observed for patients not receiving chemotherapy, which was significant for overall survival ( p = 0.01) but non-significant for locoregional recurrence-free rate ( p = 0.13). Conclusion The tumor regression pattern observed during radiotherapy is not only influenced by irradiation but depends largely on the delivered chemotherapy schedule, so it follows that the relationship between patient outcome and the degree of tumor regression is also largely determined by the chemotherapy schedule. This analysis shows that the relationship between tumor regression and outcome is complex, and indicates factors that could explain previously reported contradicting findings. This, in turn, will help guide future studies to fully understand the relationship between tumor regression and outcome.

Purpose: In selected breast cancer (BC) patients, proton therapy (PrTh) has the potential to lower radiation doses to heart, lung and contralateral breast (CLB) compared to photon therapy. However, higher skin toxicity using PrTh has been reported in literature. We prospectively evaluated acute toxicity in breast cancer patients treated with robust intensity modulated proton therapy (IMPT).

Immune checkpoint inhibition (ICI) immunotherapy has revolutionized the approach to metastatic non-small-cell lung cancer (NSCLC). In particular, antibodies blocking the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand (PD-L1) are associated with higher response rates, improved overall survival and better tolerability as compared with conventional cytotoxic chemotherapy. Recently, ICI has moved from the second-line to the first-line setting for many patients with non-oncogene-addicted NSCLC, either alone or in combination with chemotherapy. The next logical step is to examine this therapy in patients with non-metastatic NSCLC to improve long-term overall survival and cure rates. For patients with unresectable stage III NSCLC, ICI with durvalumab after concurrent chemoradiotherapy has brought a major improvement in 2-year progression-free and overall survival, which holds promise for an improved cure rate. As the relapse pattern in patients with completely resected early-stage NSCLC is predominantly systemic, high expectations rest on the integration of ICI therapy in their treatment approach. A large number of studies with adjuvant or neo-adjuvant ICI are ongoing and will be discussed here. The advent of stereotactic ablative radiotherapy has brought a valid alternative treatment of patients unfit for or not willing to undergo surgery. Data on combining systemic therapy and stereotactic ablative radiotherapy are virtually non-existent, but there is a strong biological rationale to combine radiotherapy and ICI therapy. Early findings in small feasibility studies are promising and now need to be explored in well-designed phase III trials.

Material and MethodsComplete data of 65 patients (pts), including overall, locoregional relapse and distant metastasis-free survival (OS, LRFS, DMFS) information were available.Pts received 41.4Gy in 18 fr (2.3 Gy/fr) delivering ART concomitant boost on the residual GTV in the last 6 fr (3 Gy/fr, GTV Dmean: 45.6Gy).Chemotherapy consisted of oxaliplatin (OXA) 100 mg/m 2 on days -14, 0 (start of RT), and +14, and 5-fluorouracil (5-FU) 200 mg/m 2 /d from day -14 to the end of RT.Uni-and multi-variable Cox regression models for OS, LRFS and DMFS were assessed considering several clinical (age, sex, OXA dose, 5-FU dose, time to surgery, stage) and histological (pCR, pCR or clinical complete response (cCR) followed by surgery refusal (pCR/cCR), Tumor regression grade, Residual vital cells<5%,<10%) variables.High resolution T2-weighted MRI taken before RT (MRIpre) and at half RT (MRIhalf) were available and GTVs were contoured by a single clinician (Vpre, Vhalf).The parameter ERITCP = -ln[(1 -(Vhalf/ Vpre)) Vpre ], previously introduced to quantify early response, was considered.Models including/not including ERITCP (CONV_model and REGR_model respectively) were assessed and their ability in discriminating relapsing pts compared.

Purpose or ObjectiveThe esophagus is an organ at risk in stereotactic radiotherapy for central lung tumors.We studied the correlation between esophagus toxicity and dosimetric/volumetric parameters in order to assess risks, and to derive a Normal Tissue Complication Probability (NTCP) model. Material and MethodsPatients with a central lung tumor from 2 centers who received stereotactic or hypofractionated radiotherapy (≤ 12 fractions) were retrospectively analyzed.Doses were recalculated to an equivalent dose of 2 Gy (EQD2) with an α/β ratio of 10 for acute toxicity (within 3 months).The esophagus was manually delineated and dose-volume histogram (DVH) parameters (Dmax, D1cc, D2cc, D5cc) were evaluated.The primary endpoint was esophagus toxicity as scored by CTCAE version 4.0.NTCP was calculated based on a logistic regression model and significant parameters (p-value < 0.05) were plotted into the logistic model curve.Overall survival was calculated using Kaplan-Meier analysis and groups were compared with the log-rank test. ResultsTwo-hundred-and-thirty-one patients (with 252 tumors) were eligible with median follow-up of 16 months (range 0.3 -84.3).No acute or late grade 3-5 esophagus toxicity was reported.Acute grade 1-2 toxicity was recorded in 38 patients (16.5%).All DVH parameters differed significantly between patients with toxicity versus those without toxicity; median Dmax of 62.2 Gy10 versus 31.6 Gy10, median D1cc of 40.8 Gy10 versus 18.8 Gy10, median D2cc of 35.6 Gy10 versus 16.3 Gy10 and median D5cc of 24.1 Gy10 versus 11.1 Gy10, respectively (p < 0.001 for all parameters, based on Mann-Whitney U test).Out of 27 patients who received a Dmax ≥ 54.7 Gy10 (equivalent of 5 x 7.5 Gy), 37% suffered from grade 1-2 esophagus toxicity.A Dmax ≥ 60.0 (equivalent of 5 x 8 Gy) resulted in toxicity in 1 out of 14 patients.A D1cc ≥ 44.7 Gy10 (equivalent of 5 x 6.5 Gy) resulted in toxicity in 6 out of 12 patients.A D1cc ≥ 49.6 Gy10 (equivalent of 5 x 7 Gy) resulted in toxicity in 5 out of 8 patients.Logistic regression showed significant correlations between all analyzed DVH parameters and toxicity, therefore NTCP-curves were calculated for all parameters (Figure 1 a-b).A 50% probability of acute grade 1-2 esophagus toxicity was found at a Dmax of 67 Gy10, D1cc of 42 Gy10, D2cc of 38 Gy10 and D5cc of 30 Gy10.No significant differences in overall survival were found between patients with and without toxicity: 2-year survival rate was 44% versus 51%, respectively (p = 0.428).Figure 1 a-b: NTCP models for the probability of grade 1-2 acute toxicity in the esophagus ConclusionAs no grades 3-5 esophagus toxicity were observed in our cohort, we conclude that a Dmax of 60.0 Gy10 (5 x 8 Gy) and a D1cc of 49.6 Gy10 (5 x 7 Gy) can be safely delivered using stereotactic radiotherapy.The NTCP-curves derived may serve as guidelines for central lung cancer undergoing stereotactic treatment.