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Motivation and Objective State-of-the-art Linac-based photon beam irradiation achieves highly conformal target volume coverage in glioma patients, but is also known to cause side-effects to surrounding tissues and organs. Apart from subjective measures (e.g., questionnaires, function tests) objective means to quantify tissue damage, e.g., anatomical or functional magnetic resonance imaging (MRI) are urgently needed to compare different treatment techniques and beam qualities (e.g., protons vs. photons) and to develop predictive measures for optimal sparing of normal brain tissue. As initial part of our program for dose-dependent spatial mapping of structural and functional radiation induced brain damage, we assessed here a retrospectively collected MRI-dataset in order to potentially detect volumetric changes of the healthy brain tissue (gray and white matter) in the non-affected hemisphere of glioma patients treated with photon irradiation. Material and Methods Structural MRI-scans (T1-weighted) from 18 glioma patients (grade II and III), who underwent high dose radio(chemo)therapy (54-60 Gy) with curative intent have been analyzed. MRIs were acquired before treatment and at several time intervals thereafter. Because of the individual characteristics of these data e.g., voxel size (0.5…6 mm³) and the field strength (1…3 T) a standardized image processing approach was developed. For bias field correction, registration with atlas data, resampling, and segmentation of different tissue types, image processing methods from the ANTs-, FSL- and SPM-toolbox were used, respectively. Based on these images the volumes of white matter and gray matter have been longitudinally analyzed. Results Figure 1 shows the changes of brain tissue volume depicted as box plots with the median values highlighted in red. While the entire brain volume on average remains constant over two years after therapy, in the same time period the volume of gray matter and white matter varies conversely i

Retrospective evaluation of 188 advanced stage non-small cell lung cancer patients treated with IMRT or VMAT revealed a limited increase of moderate to severe acute esophageal toxicity after VMAT. Acute pulmonary toxicity and severe late toxicity were low. Overall survival did not differ between the IMRT and VMAT groups.

Background: Proton beam therapy is promising for the treatment of head and neck cancer (HNC), but it is sensitive to uncertainties in patient positioning and particle range. Studies have shown that the planning target volume (PTV) concept may not be sufficient to ensure robustness of the target coverage. A few planning studies have considered irradiation of unilateral HNC targets with protons, but they have only taken into account the dose on the nominal plan, without considering anatomy changes occurring during the treatment course. Methods: Four pencil beam scanning (PBS) proton therapy plans were calculated for 8 HNC patients with unilateral target volumes: single-field (SFO) and multi-field optimized (MFO) plans, either using the PTV concept or clinical target volume (CTV)-based robust optimization. The dose was recalculated on computed tomography (CT) scans acquired during the treatment course. Doses to target volumes and organs at risk (OARs) were compared for the nominal plans, cumulative doses considering anatomical changes, and additional setup and range errors in each fraction. If required, the treatment plan was adapted, and the dose was compared with the non-adapted plan. Results: All nominal plans fulfilled the clinical specifications for target coverage, but significantly higher doses on the ipsilateral parotid gland were found for both SFO approaches. MFO PTV-based plans had the lowest robustness against range and setup errors. During the treatment course, the influence of the anatomical variation on the dose has shown to be patient specific, mostly independent of the chosen planning approach. Nine plans in four patients required adaptation, which led to a significant improvement of the target coverage and a slight reduction in the OAR dose in comparison to the cumulative dose without adaptation. Conclusions: The use of robust MFO optimization is recommended for ensuring plan robustness and reduced doses in the ipsilateral parotid gland. Anatomical ch

Introduction: Concurrent radiochemotherapy (RCHT) is standard treatment in locally advanced small cell lung cancer (SCLC) patients. Due to conflicting results on elective nodal irradiation (ENI) or selective node irradiation (SNI) there is no clear evidence on optimal target volumes. Therefore, the purposes of this study were to assess the sites of recurrent disease in SCLC and to evaluate the feasibility of SNI versus ENI. Methods: A retrospective single-institution study of 54 consecutive patients treated with RCHT was performed. After state-of-the-art staging, all patients underwent three-dimensional conformal radiotherapy to a total dose of 45 Gy in twice-daily fractions of 1.5 Gy starting concurrently with the first or second chemotherapy cycle. All sites of loco-regional recurrences were correlated to the initial tumor and dose delivered. The impact of potential prognostic variables on outcome was evaluated using the Cox-regression model. Results: After a median time of 11.1 months, 17 patients (31.5%) relapsed locally or regionally: six within the initial primary tumor volume, five within the initially affected lymph nodes, three metachronously within primary tumor and initially affected lymph nodes, and three both inside and outside of the initial nodal disease. All sites of loco-regional recurrence had received 92%-106% of the prescribed dose. Among all investigated co-factors only total GTV revealed a significant correlation with patient outcome. Conclusion: In our study most recurrences occurred within the primary tumor or initially affected lymph nodes, or distantly. We did not register any case of isolated nodal failure, supporting the use of selective nodal irradiation, possibly with the addition of supraclavicular irradiation in patients with nodal disease in the upper mediastinum.

BACKGROUND: Hypoxia is a well recognised parameter of tumour resistance to radiotherapy, a number of anticancer drugs and potentially immunotherapy. In a previously published exploration cohort of 25 head and neck squamous cell carcinoma (HNSCC) patients on [18F]fluoromisonidazole positron emission tomography (FMISO-PET) we identified residual tumour hypoxia during radiochemotherapy, not before start of treatment, as the driving mechanism of hypoxia-mediated therapy resistance. Several quantitative FMISO-PET parameters were identified as potential prognostic biomarkers. Here we present the results of the prospective validation cohort, and the overall results of the study. METHODS: FMISO-PET/CT images of further 25 HNSCC patients were acquired at four time-points before and during radiochemotherapy (RCHT). Peak standardised uptake value, tumour-to-background ratio, and hypoxic volume were analysed. The impact of the potential prognostic parameters on loco-regional tumour control (LRC) was validated by the concordance index (ci) using univariable and multivariable Cox models based on the exploration cohort. Log-rank tests were employed to compare the endpoint between risk groups. RESULTS: The two cohorts differed significantly in several baseline parameters, e.g., tumour volume, hypoxic volume, HPV status, and intercurrent death. Validation was successful for several FMISO-PET parameters and showed the highest performance (ci=0.77-0.81) after weeks 1 and 2 of treatment. Cut-off values for the FMISO-PET parameters could be validated after week 2 of RCHT. Median values for the residual hypoxic volume, defined as the ratio of the hypoxic volume in week 2 of RCHT and at baseline, stratified patients into groups of significantly different LRC when applied to the respective other cohort. CONCLUSION: Our study validates that residual tumour hypoxia during radiochemotherapy is a major driver of therapy resistance of HNSCC, and that hypoxia after the second week of treatment m

Stereotactic body radiotherapy (SBRT) is an alternative to surgery for patients with early stage non-small cell lung cancer (NSCLC) who are inoperable due to comorbid disease or who refuse surgery. SBRT results in an excellent local control rate of more than 90%, which is comparable to surgery, while short and long-term overall toxicity is low. Surgically treated patients are often more extensively staged pre-operatively, e.g. with EBUS, and undergo intra-operative lymph node dissection or sampling. Occult nodal metastases (ONM) detected by lymph node dissection have been shown to increase the incidence of regional recurrence (RR) after surgery, which is associated with poor outcome. In patients undergoing SBRT, however, definite pathological nodal staging is lacking. Therefore, other ways to identify patients at high risk for ONM and RR might be thought for. The aim of this systematic review is to summarize the incidence of and risk factors for RR after SBRT and compare these to those after surgery.

Purpose: To evaluate if inclusion of incidental radiation dose to the cardiac atria and ventricles improves the prediction of Grade ≥3 radiation pneumonitis (RP) in advanced stage non-small cell lung cancer (AS-NSCLC) patients treated with intensity-modulated radiation therapy or volumetric-modulated arc therapy. Material and methods: Using a bootstrap modelling approach, clinical parameters and dose-volume histogram (DVH) parameters of lungs and heart (assessing atria and ventricles separately and combined) were evaluated for RP prediction in 188 AS-NSCLC patients. Results: After a median follow-up of 18.4 months, 26 patients (13.8%) developed RP. Only the median mean lung dose (MLD) differed between groups (15.3 Gy vs 13.7 Gy for the RP and non-RP group, respectively; p=0.004). The MLD showed the highest Spearman correlation coefficient (Rs) for RP (Rs=0.21; p<0.01). Most Rs of the lung DVH parameters exceeded those of the heart DVH parameters. After bootstrap modelling, the heart DVH parameters were seldom included in the model predicting Grade ≥3 RP. The optimal model for RP consisted of the parameters: MLD and cardiac comorbidity (area under the curve: 0.71). Conclusion: Incidental dose to the cardiac atria and ventricles did not improve RP risk prediction in our cohort of AS-NSCLC patients.

Purpose: Tumour hypoxia is well known to increase radio-resistance of tumours. In a recent prospective biomarker imaging trial, hypoxia has been measured by [18F]fluoromisonidazole positron emission tomography (FMISO-PET) scans [1,2]. Here, we compared hypoxia imaging with the expression of hypoxia-associated gene signatures for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated by primary radiochemotherapy (RCHT). Material and methods: FMISO-PET imaging and gene expression analyses were performed on the cohort of 50 HNSCC patients [1,2]. For this study, the FMISO-PET parameters tumour-to-background ratio (TBPpeak) and hypoxic tumour volume (HV1.6) analysed before RCHT were considered. Expressions of 15-, 26- and 30-gene hypoxia-associated signatures [3-5] were analysed from formalin-fixed paraffin-embedded (FFPE) tumour biopsies obtained before RCHT using the GeneChip® Human Transcriptome Array 2.0 (Affymetrix) and nanoString analysis. Gene expressions were compared between the two methods using the Pearson correlation coefficient. Linear regression was applied to relate TBRpeak and HV1.6 to the mean expression of the gene signatures, including the interaction with tumour volume which was assessed on the planning CT by an experienced radiation oncologist. The association of FMISO-PET parameters and gene expressions to loco-regional control (LRC) and progression-free survival (PFS) was assessed by Cox regression. Results: The mean expressions of all hypoxia-associated gene signatures were highly correlated between Affymetrix and nanoString analyses (R>0.5). While TBRpeak and HV1.6 were weakly correlated with the expression of hypoxia-associated genes alone, significant correlations were observed if the interaction term of gene expression and tumour volume was included (R>0.5). Both FMISO-PET parameters were significantly correlated with LRC and PFS (p<0.01), while the combination of hypoxia-associated gene expressions and their inte

BACKGROUND AND PURPOSE: The aim was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome. MATERIAL AND METHODS: A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients). All received cCRT in one of three participating radiation oncology departments in the Netherlands between January 2008 and January 2013. Primary endpoint was locoregional recurrence free survival (LRFS), secondary endpoints were overall survival (OS), progression-free survival (PFS) and distant metastasis free survival (DMFS). RESULTS: No significant differences in LRFS or OS were found. Metformin use was associated with an improved DMFS (74% versus 53% at 2years; p=0.01) and PFS (58% versus 37% at 2years and a median PFS of 41months versus 15months; p=0.01). In a multivariate cox-regression analysis, the use of metformin was a statistically significant independent variable for DMFS and PFS (p=0.02 and 0.03). CONCLUSIONS: Metformin use during cCRT is associated with an improved DMFS and PFS for locally advanced NSCLC patients, suggesting that metformin may be a valuable treatment addition in these patients. Evidently, our results merit to be verified in a prospective trial.

Background and Purpose In this multicentric in silico trial we compared photon, proton, and carbon-ion radiotherapy plans for re-irradiation of patients with squamous cell carcinoma of the head and neck (HNSCC) regarding dose to tumour and doses to surrounding organs at risk (OARs). Material and Methods Twenty-five HNSCC patients with a second new or recurrent cancer after previous irradiation (70 Gy) were included. Intensity-modulated proton therapy (IMPT) and ion therapy (IMIT) re-irradiation plans to a second subsequent dose of 70 Gy were compared to photon therapy delivered with volumetric modulated arc therapy (VMAT). Results When comparing IMIT and IMPT to VMAT, the mean dose to all investigated 22 OARs was statistically significantly reduced for IMIT and to 15 out of 22 OARs (68%) using IMPT. The maximum dose to 2% volume (D2) of the brainstem and spinal cord were statistically significantly reduced using IMPT and IMIT compared to VMAT. The data are available on www.cancerdata.org. Conclusions In this ROCOCO in silico trial, a reduction in mean dose to OARs was achieved using particle therapy compared to photons in the re-irradiation of HNSCC. There was a dosimetric benefit favouring carbon-ions above proton therapy. These dose reductions may potentially translate into lower severe complication rates related to the re-irradiation.

Background and purpose: Isolated nodal failures (INF) are rare after 3D-conformal radiotherapy (3D-CRT) for stage III non-small cell lung cancer (NSCLC). Since incidental nodal irradiation doses are lower with Intensity Modulated Radiation Therapy (IMRT) than with 3D-CRT, INF may be higher after IMRT. We therefore investigated the incidence of INF after IMRT in stage III NSCLC patients. Materials and Methods: Stage III NSCLC patients undergoing radical radiotherapy using IMRT in the period January 2010 till March 2012 were included. The primary endpoint was the rate of INF, secondary endpoints included patterns of failure, progression free survival (PFS), overall survival (OS) and toxicity. Results: 183 stage III NSCLC patients were enrolled. With a median follow-up of 58.0 months 2.2 % of patients had an INF. The median PFS was 15.0 months, the median OS 19.5 months. Patterns of recurrence: 2.2 % INF, 11.5% local and 2.7% loco-regional recurrence, 26.8% distant metastases only, 18.0% a combination of local/loco-regional and distant metastases, and 38.3% patients without recurrence. One INF was out of field, in adjacent lymph nodes. Acute toxicity was limited. Discussion: Selective nodal irradiation using IMRT in stage III NSCLC patients results in a low in-field incidence of INF (2.2%), similar to 3D-CRT, and may thus be considered safe.

Purpose: To analyse the prognostic impact on overall survival (OS) of single versus multiple organ metastases, organ affected, and local disease status in a population based stage IV non-small cell lung cancer (NSCLC) cohort. Methods: In this observational study, data were analysed of all histologically confirmed stage IV NSCLC patients diagnosed between 1 January 2006 and 31 December 2012 registered in the Netherlands Cancer Registry. Location of metastases before treatment was registered. Multivariable survival analyses [age, gender, histology, M-status, local disease status, number of involved organs, actual organ affected] were performed for all patients and for an (18)fluorodeoxyglucose-positron emission tomography ((18)FDG-PET)-staged subgroup. Results: 11,094 patients were selected: 60% male, mean age 65 years, 73% adenocarcinoma. Median OS for 1 (N = 5676), 2 (N = 3280), and >= 3 (N = 2138) metastatically affected organs was 6.7, 4.3, 2.8 months, respectively (p <0.001). Hazard ratio (HR) for 2 versus 1 organ(s) was 1.33 (p <0.001), for >= 3 versus 1 organ(s) 1.91 (p <0.001). Results were confirmed in the (18)FDG-PET-staged cohort (N = 1517): patients with single organ versus 2 and >= 3 organ metastases had higher OS (8.6, 5.7, 3.8 months, HR 1.40 and 2.17, respectively, p <0.001). In single organ metastases, OS for low versus high TN-status was 8.5 versus 6.5 months [HR 1.40 (p <0.001)]. (18)FDG-PET-staged single organ metastases patients with low TN-status had a superior OS than those with high TN-status (11.6 versus 8.2 months, HR 1.62, p <0.001). Conclusion: Patients with single organ metastases stage IV NSCLC have a favourable prognosis, especially in combination with low TN status. They have to be regarded as a separate subgroup of stage IV disease.

PURPOSE: We tested therapeutic efficacy of two dose painting strategies of applying higher radiation dose to tumor subvolumes with high FDG uptake (biologic target volume, BTV): dose escalation and dose redistribution. We also investigated whether tumor response was determined by the highest dose in BTV or the lowest dose in gross tumor volume (GTV). EXPERIMENTAL DESIGN: FDG uptake was evaluated in rat rhabdomyosarcomas prior to irradiation. BTV was defined as 30% of GTV with the highest (BTVhot) or lowest (BTVcold) uptake. To test efficacy of dose escalation, tumor response (time to reach two times starting tumor volume, TGTV2) to Hot Boost irradiation (40% higher dose to BTVhot) was compared with Cold Boost (40% higher dose to BTVcold), while mean dose to GTV remained 12 Gy. To test efficacy of dose redistribution, TGTV2 after Hot Boost was compared with uniform irradiation with the same mean dose (8 or 12 Gy). RESULTS: TGTV2 after 12 Gy delivered heterogeneously (Hot and Cold Boost) or uniformly were not significantly different: 20.2, 19.5, and 20.6 days, respectively. Dose redistribution (Hot Boost) with 8 Gy resulted in faster tumor regrowth as compared with uniform irradiation (13.3 vs. 17.1 days; P = 0.026). Further increase in dose gradient to 60% led to a more pronounced decrease in TGTV2 (10.9 days; P < 0.0001). CONCLUSIONS: Dose escalation effect was independent of FDG uptake in target tumor volume, while dose redistribution was detrimental in this tumor model for dose levels applied here. Our data are consistent with the hypothesis that tumor response depends on the minimum intratumoral dose. Clin Cancer Res; 21(24); 5511-8. ©2015 AACR.

Radiotherapy is along with surgery and chemotherapy one of the prime treatment modalities in cancer. It is applied in the primary, neoadjuvant as well as the adjuvant setting. Radiation techniques have rapidly evolved during the past decade enabling the delivery of high radiation doses, reducing side-effects in tumour-adjacent normal tissues. While increasing local tumour control, current and future efforts ought to deal with microscopic disease at a distance of the primary tumour, ultimately responsible for disease-progression. This review explores the possibility of bimodal treatment combining radiotherapy with immunotherapy.