Prospective results for 5-year survival and toxicity of moderately hypofractionated radiotherapy with simultaneous integrated boost (SIB) in (very) high-risk prostate cancer.

Purpose: High-risk (HR) prostate cancer patients usually receive high-dose radiotherapy (RT) using a two-phase sequential technique, but data on a simultaneous integrated boost (SIB) technique are lacking. We prospectively evaluated the long-term results of urinary (GU) and digestive (GI) toxicity and survival data for high-dose RT using a SIB technique in HR and very high-risk (VHR) prostate cancer. Methods: Patients were treated using an SIB technique in 34 fractions, at a dose of 54.4 Gy to the pelvis and seminal vesicles and 74.8 Gy to the prostate, combined with 36 months of androgen-depriving therapy in a prospective multicenter study. Acute and late GU and GI toxicity data were collected. Overall survival (OS), biochemical-relapse-free survival (bRFS), loco-regional-relapse-free survival (LRRFS), metastasis-free-survival (MFS) and disease-free-survival (DFS) were assessed. Results: We recruited 114 patients. After a median follow-up of 62 months, very few patients experienced acute (M0-M3) (G3-4 GU = 3.7 %; G3-4 GI = 0.9 %) or late (M6-M60) severe toxicity (G3-4 GU = 5.6 %; G3-4 GI = 2.8 %). The occurrence of acute G2 + GU or GI toxicity was significantly related to the consequential late G2 + toxicity (p < 0.01 for both GU and GI). Medians of OS, bRFS, LRRFS, MFS and DFS were not reached. At 60 months, OS, bRFS, LRRFS, MFS and DFS were 88.2 % [82.1; 94.7], 86.0 % [79.4 %;93.2 %], 95.8 % [91.8 %;99.9 %], 87.2 % [80.9 %;94.0 %] and 84.1 % [77.2 %;91.6 %] respectively. Conclusion: SIB RT at a dose of 54.4 Gy to the pelvis and 74.8 Gy to the prostate is feasible, leading to satisfying tumor control and reasonable toxicity in HR and VHR prostate cancer.

Feasibility study of adaptive radiotherapy with Ethos for breast cancer.

Purpose: The aim of this study was to assess the feasibility of online adaptive radiotherapy with Ethos for breast cancer. Materials and methods: This retrospective study included 20 breast cancer patients previously treated with TrueBeam. All had undergone breast surgery for different indications (right/left, lumpectomy/mastectomy) and were evenly divided between these four cases, with five extended cone beam computed tomography (CBCT) scans per patient. The dataset was used in an Ethos emulator to test the full adaptive workflow. The contours generated by artificial intelligence (AI) for the influencers (left and right breasts and lungs, heart) and elastic or rigid propagation for the target volumes (internal mammary chain (IMC) and clavicular lymph nodes (CLNs)) were compared to the initial contours delineated by the physician using two metrics: Dice similarity coefficient (DICE) and Hausdorff 95% distance (HD95). The repeatability of influencer generation was investigated. The times taken by the emulator to generate contours, optimize plans, and calculate doses were recorded. The quality of the scheduled and adapted plans generated by Ethos was assessed using planning target volume (PTV) coverage, homogeneity indices (HIs), and doses to organs at risk (OARs) via dose-volume histogram (DVH) metrics. Quality assurance (QA) of the treatment plans was performed using an independent portal dosimetry tool (EpiQA) and gamma index. Results: On average, the DICE for the influencers was greater than 0.9. Contours resulting from rigid propagation had a higher DICE and a lower HD95 than those resulting from elastic deformation but remained below the values obtained for the influencers: DICE values were 0.79 ± 0.11 and 0.46 ± 0.17 for the CLN and IMC, respectively. Regarding the repeatability of the influencer segmentation, the DICE was close to 1, and the mean HD95 was strictly less than 0.15 mm. The mean time was 73 ± 4 s for contour generation per AI and 80 ± 9 s for propagations. The average time was 53 ± 3 s for dose calculation and 125 ± 9 s for plan optimization. A dosimetric comparison of scheduled and adapted plans showed a significant difference in PTV coverage: dose received by 95% of the volume (D95%) values were higher and closer to the prescribed doses for adapted plans. Doses to organs at risk were similar. The average gamma index for quality assurance of adapted plans was 99.93 ± 0.38 for a 3%/3mm criterion. Conclusion: This study comprehensively evaluated the Ethos® adaptive workflow for breast cancer and its potential technical limitations. Although the results demonstrated the high accuracy of AI segmentation and the superiority of adapted plans in terms of target volume coverage, a medical assessment is still required.

A multi-centric evaluation of self-learning GAN based pseudo-CT generation software for low field pelvic magnetic resonance imaging.

Purpose/objectives: An artificial intelligence-based pseudo-CT from low-field MR images is proposed and clinically evaluated to unlock the full potential of MRI-guided adaptive radiotherapy for pelvic cancer care. Materials and method: In collaboration with TheraPanacea (TheraPanacea, Paris, France) a pseudo-CT AI-model was generated using end-to-end ensembled self-supervised GANs endowed with cycle consistency using data from 350 pairs of weakly aligned data of pelvis planning CTs and TrueFisp-(0.35T)MRIs. The image accuracy of the generated pCT were evaluated using a retrospective cohort involving 20 test cases coming from eight different institutions (US: 2, EU: 5, AS: 1) and different CT vendors. Reconstruction performance was assessed using the organs at risk used for treatment. Concerning the dosimetric evaluation, twenty-nine prostate cancer patients treated on the low field MR-Linac (ViewRay) at Montpellier Cancer Institute were selected. Planning CTs were non-rigidly registered to the MRIs for each patient. Treatment plans were optimized on the planning CT with a clinical TPS fulfilling all clinical criteria and recalculated on the warped CT (wCT) and the pCT. Three different algorithms were used: AAA, AcurosXB and MonteCarlo. Dose distributions were compared using the global gamma passing rates and dose metrics. Results: The observed average scaled (between maximum and minimum HU values of the CT) difference between the pCT and the planning CT was 33.20 with significant discrepancies across organs. Femoral heads were the most reliably reconstructed (4.51 and 4.77) while anal canal and rectum were the less precise ones (63.08 and 53.13). Mean gamma passing rates for 1%1mm, 2%/2mm, and 3%/3mm tolerance criteria and 10% threshold were greater than 96%, 99% and 99%, respectively, regardless the algorithm used. Dose metrics analysis showed a good agreement between the pCT and the wCT. The mean relative difference were within 1% for the target volumes (CTV and PTV) and 2% for the OARs. Conclusion: This study demonstrated the feasibility of generating clinically acceptable an artificial intelligence-based pseudo CT for low field MR in pelvis with consistent image accuracy and dosimetric results.

Time-Dependent ROC Curve Analysis for Assessing the Capability of Radiation-Induced CD8 T-Lymphocyte Apoptosis to Predict Late Toxicities after Adjuvant Radiotherapy of Breast Cancer Patients.

Late fibrosis can occur in breast cancer patients treated with curative-intent radiotherapy. Predicting this toxicity is of clinical interest in order to adapt the irradiation dose delivered. Radiation-induced CD8 T-lymphocyte apoptosis (RILA) had been proven to be associated with less grade ≥2 late radiation-induced toxicities in patients with miscellaneous cancers. Tobacco smoking status and adjuvant hormonotherapy were also identified as potential factors related to late-breast-fibrosis-free survival. This article evaluates the predictive performance of the RILA using a ROC curve analysis that takes into account the dynamic nature of fibrosis occurrence. This time-dependent ROC curve approach is also applied to evaluate the ability of the RILA combined with the other previously identified factors. Our analysis includes a Monte Carlo cross-validation procedure and the calculation of an expected cost of misclassification, which provides more importance to patients who have no risk of late fibrosis in order to be able to treat them with the maximal irradiation dose. Performance evaluation was assessed at 12, 24, 36 and 50 months. At 36 months, our results were comparable to those obtained in a previous study, thus underlying the predictive power of the RILA. Based on specificity and cost, RILA alone seemed to be the most performant, while its association with the other factors had better negative predictive value results.

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). METHODS: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. RESULTS: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). CONCLUSIONS: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

A prospective registry study of stereotactic magnetic resonance guided radiotherapy (MRgRT) for primary liver tumors.

BACKGROUND AND PURPOSE: Stereotactic body radiation therapy (SBRT) has demonstrated safe and effective results for primary liver tumors. Magnetic Resonance guided Radiotherapy (MRgRT) is an innovative radiotherapy modality for abdominal tumors. The aim of this study is to report on acute and late toxicities and initial oncological results for primary liver tumors treated with MRgRT. MATERIALS AND METHODS: We prospectively included in our cohort all patients treated by MRgRT for a primary liver tumor at the Montpellier Cancer Institute. The primary endpoint was acute and late toxicities assessed according to CTCAE v 5.0. The mean prescribed dose was 50 Gy in 5 fractions. RESULTS: Between October 2019 and April 2022, MRgRT treated 56 patients for 72 primary liver lesions. No acute or late toxicities of CTCAE grade greater than 2 attributable to radiotherapy were noted during follow-up. No cases of radiation-induced liver disease (RILD), either classical or non-classical, occurred. After a median follow-up of 13.2 months (95% CI [8.8; 15.7]), overall survival was 85.1% (95% CI: [70.8; 92.7]) at 1 year and 74.2% at 18 months (95% CI [52.6; 87.0]). Local control was 98.1% (95% CI: [87.4; 99.7]) and 94.7% (95% CI: [79.5; 98.7]) at 12 and 18 months, respectively. Among the HCC subgroup, no local recurrences were observed. CONCLUSION: MRgRT for primary liver tumors is safe without severe adverse events and reach excellent local control. Numerous studies are underway to better assess the value of MRI guidance and adaptive process in these indications.

Contouring variation affects estimates of normal tissue complication probability for breast fibrosis after radiotherapy.

BACKGROUND: Normal tissue complication probability (NTCP) models can be useful to estimate the risk of fibrosis after breast-conserving surgery (BCS) and radiotherapy (RT) to the breast. However, they are subject to uncertainties. We present the impact of contouring variation on the prediction of fibrosis. MATERIALS AND METHODS: 280 breast cancer patients treated BCS-RT were included. Nine Clinical Target Volume (CTV) contours were created for each patient: i) CTV_crop (reference), cropped 5 mm from the skin and ii) CTV_skin, uncropped and including the skin, iii) segmenting the 95% isodose (Iso95%) and iv) 3 different auto-contouring atlases generating uncropped and cropped contours (Atlas_skin/Atlas_crop). To illustrate the impact of contour variation on NTCP estimates, we applied two equations predicting fibrosis grade ≥ 2 at 5 years, based on Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) models, respectively, to each contour. Differences were evaluated using repeated-measures ANOVA. For completeness, the association between observed fibrosis events and NTCP estimates was also evaluated using logistic regression. RESULTS: There were minimal differences between contours when the same contouring approach was followed (cropped and uncropped). CTV_skin and Atlas_skin contours had lower NTCP estimates (-3.92%, IQR 4.00, p < 0.05) compared to CTV_crop. No significant difference was observed for Atlas_crop and Iso95% contours compared to CTV_crop. For the whole cohort, NTCP estimates varied between 5.3% and 49.5% (LKB) or 2.2% and 49.6% (RS) depending on the choice of contours. NTCP estimates for individual patients varied by up to a factor of 4. Estimates from "skin" contours showed higher agreement with observed events. CONCLUSION: Contour variations can lead to significantly different NTCP estimates for breast fibrosis, highlighting the importance of standardising breast contours before developing and/or applying NTCP models.

Comparison of prone and supine positioning for breast cancer radiotherapy using REQUITE data: dosimetry, acute and two years physician and patient-reported outcomes.

OBJECTIVE: Most patients receive whole breast radiotherapy in a supine position. However, two randomised trials showed lower acute toxicity in prone position. Furthermore, in most patients, prone positioning reduced doses to the organs at risk. To confirm these findings, we compared toxicity outcomes, photographic assessment, and dosimetry between both positions using REQUITE data. METHODS: REQUITE is an international multi-centre prospective observational study that recruited 2069 breast cancer patients receiving radiotherapy. Data on toxicity, health-related quality of life (HRQoL), and dosimetry were collected, as well as a photographic assessment. A matched case control analysis compared patients treated prone (n = 268) versus supine (n = 493). Exact matching was performed for the use of intensity-modulated radiotherapy, boost, lymph node irradiation, chemotherapy and fractionation, and the nearest neighbour for breast volume. Primary endpoints were dermatitis at the end of radiotherapy, and atrophy and cosmetic outcome by photographic assessment at two years. RESULTS: At the last treatment fraction, there was no significant difference in dermatitis (p = .28) or any HRQoL domain, but prone positioning increased the risk of breast oedema (p < .001). At 2 years, patients treated in prone position had less atrophy (p = .01), and higher body image (p < .001), and social functioning (p < .001) scores. The photographic assessment showed no difference in cosmesis at 2 years (p = .22). In prone position, mean heart dose (MHD) was significantly lower for left-sided patients (1.29 Gy vs 2.10 Gy, p < .001) and ipsilateral mean lung dose (MLD) was significantly lower for all patients (2.77 Gy vs 5.89 Gy, p < .001). CONCLUSIONS: Prone radiotherapy showed lower MLD and MHD compared to supine position, although the risk of developing breast oedema during radiotherapy was higher. At 2 years the photographic assessment showed no difference in the cosmetic outcome, but less atrophy was seen in prone-treated patients and this seems to have a positive influence on the HRQoL domain of body image.

(Pre)treatment risk factors for late fatigue and fatigue trajectories following radiotherapy for breast cancer.

Fatigue is common in breast-cancer survivors. Our study assessed fatigue longitudinally in breast cancer patients receiving adjuvant radiotherapy (RT) and aimed to identify risk factors associated with long-term fatigue and underlying fatigue trajectories. Fatigue was measured in a prospective multicenter cohort (REQUITE) using the Multidimensional Fatigue Inventory (MFI-20) and analyzed using mixed models. Multivariable logistic models identified factors associated with fatigue dimensions at 2 years post-RT and latent class growth analysis identified individual fatigue trajectories. A total of 1443, 1302, 1203 and 1098 patients completed the MFI-20 at baseline, end of RT, after 1 and 2 years. Overall, levels of fatigue significantly increased from baseline to end of RT for all fatigue dimensions (P < .05) and returned to baseline levels after 2 years. A quarter of patients were assigned to latent trajectory high (23.7%) and moderate (24.8%) fatigue classes, while 46.3% and 5.2% to the low and decreasing fatigue classes, respectively. Factors associated with multiple fatigue dimensions at 2 years include age, BMI, global health status, insomnia, pain, dyspnea and depression. Fatigue present at baseline was consistently associated with all five MFI-20 fatigue dimensions (ORGeneralFatigue = 3.81, P < .001). From latent trajectory analysis, patients with a combination of factors such as pain, insomnia, depression, younger age and endocrine therapy had a particularly high risk of developing early and persistent high fatigue years after treatment. Our results confirmed the multidimensional nature of fatigue and will help clinicians identify breast cancer patients at higher risk of having persistent/late fatigue so that tailored interventions can be delivered.

Implementation of the Calypso system: a commissioning experience.

Background: The aim of this study was to describe the clinical implementation of the Calypso system with its potential impact on the treatment delivery. Materials and methods: The influence of the electromagnetic array was investigated on the kilovoltage cone beam computed tomography (kV-CBCT) image quality using the CATPHAN 504 CBCT images. Then, the QFix kVue Calypso couch top and the array attenuation, and their dosimetric influence on the Volumetric modulated arc therapy (VMAT) treatments of prostate was evaluated. Results: Regarding the image quality, a significant increase of noise (p < 0.01) was detected with the array in place, resulting in a significant decrease in signal noise ratio (SNR) (p < 0.01). No difference in absolute contrast was observed. Finally, there was a significant decrease in contrast noise ratio (CNR) (p < 0.01) even if the deviation was only of 2.5%. For the dosimetric evaluation, the maximum attenuation of the couch was 12.02% and 13.19% for X6 and X6 flattening filter free (FFF), respectively (configuration of rails out). Besides, the mean attenuation of the array was 1.15% and 1.67% for X6 and X6 FFF, respectively. For the VMAT treatment plans, the mean dose was reduced by 0.61% for X6 and by 0.31% for X6 FFF beams when using the electromagnetic array. Conclusions: The Calypso system does not affect significantly the kV-CBCT image quality and the VMAT plan dose distribution.

Genome-wide association study of treatment-related toxicity two years following radiotherapy for breast cancer.

BACKGROUND AND PURPOSE: Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy. MATERIALS AND METHODS: A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure. RESULTS: Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10-5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10-8), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10-10), rs75912034 (p = 1.12 × 10-10), rs145328458 (p = 1.06 × 10-9) and rs61966612 (p = 1.23 × 10-9), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10-8) and rs34063419 (p = 1.21 × 10-8), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10-8). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level. CONCLUSIONS: This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.

Robustness of Breast Margins with Volumetric Modulated Arc Therapy without a Six-Degrees-of-Freedom Couch: A Dosimetric Evaluation.

In our hospital, a TrueBeam linear accelerator and the PerfectPitch 6-degrees-of-freedom (6-DOF) couch (Varian), with 7 mm margins, are used for volumetric modulated arc therapy (VMAT) of breast cancer (BC). This study tested whether a 3-degrees-of-freedom (3-DOF) couch, i.e., without rotation compensation (such as the Halcyon couch), affected dose metrics. A total of 446 daily extended cone beam computed tomography (CBCT) data of 20 patients who received VMAT for BC were used to recalculate the treatment plans with the session registration (6-DOF) and a simulated matching with 3-DOF. The initial plan provided significantly better coverage for internal mammary chain and clavicular lymph node clinical target volumes (CTVs) than the 6-DOF and 3-DOF CBCT plans. The volumes receiving 110% of the prescribed dose (V110%) were increased for all CTVs with the 6-DOF and 3-DOF CBCT plans, but the difference was significant only for the breast/chest wall CTV (p < 0.05; paired samples t-test). Protection of the heart and lungs was comparable among plans. The dose volume histograms based on the 6-DOF and 3-DOF data were similar for CTVs and organs at risk. Therefore, with a 7 mm margin, VMAT and a 3-DOF couch can be used for BC treatment without any compromise in delivery accuracy.

Stereotactic MR-Guided Radiotherapy for Liver Metastases: First Results of the Montpellier Prospective Registry Study.

Liver stereotactic body radiotherapy (SBRT) is a local treatment that provides good local control and low toxicity. We present the first clinical results from our prospective registry of stereotactic MR-guided radiotherapy (MRgRT) for liver metastases. All patients treated for liver metastases were included in this prospective registry study. Stereotactic MRgRT indication was confirmed by multidisciplinary specialized tumor boards. The primary endpoints were acute and late toxicities. The secondary endpoints were survival outcomes (local control, overall survival (OS), disease-free survival, intrahepatic relapse-free survival). Twenty-six consecutive patients were treated for thirty-one liver metastases between October 2019 and April 2022. The median prescribed dose was 50 Gy (40-60) in 5 fractions. No severe acute MRgRT-related toxicity was noted. Acute and late gastrointestinal and liver toxicities were low and mostly unrelated to MRgRT. Only 5 lesions (16.1%) required daily adaptation because of the proximity of organs at risk (OAR). With a median follow-up time of 17.3 months since MRgRT completion, the median OS, 1-year OS and 2-year OS rates were 21.7 months, 83.1% (95% CI: 55.3-94.4%) and 41.6% (95% CI: 13.5-68.1%), respectively, from MRgRT completion. The local control at 6 months, 1 year and 2 years was 90.9% (95% CI: 68.3-97.7%). To our knowledge, we report the largest series of stereotactic MRgRT for liver metastases. The treatment was well-tolerated and achieved a high LC rate. Distant relapse remains a challenge in this population.

Comparing symptom reporting by prostate cancer patients and healthcare professionals in the international multicentre REQUITE study.

INTRODUCTION: Previous studies showed that healthcare professionals and patients had only moderate to low agreement on their assessment of treatment-related symptoms. We aimed to determine the levels of agreement in a large cohort of prostate cancer patients. METHODS: Analyses were made of data from 1,756 prostate cancer patients treated with external beam radiotherapy (RT) and/or brachytherapy in Europe and the USA and recruited into the prospective multicentre observational REQUITE study. Eleven pelvic symptoms at the end of RT were compared after translating patient-reported outcomes (PROs) into CTCAE-based healthcare professional ratings. Gwet's AC2 agreement coefficient and 95% confidence intervals were calculated for each symptom. To compare severity of grading between patients and healthcare professionals, percent agreement and deviations for each symptom were graphically depicted. Stratified and sensitivity analyses were conducted to identify potential influencing factors and to assess heterogeneity and robustness of results. RESULTS: The agreement for the 11 pelvic symptoms varied from very good (AC2 > 0.8: haematuria, rectal bleeding, management of sphincter control) to poor agreement (AC2 ≤ 0.2: proctitis and urinary urgency). Fatigue had a negative impact on the agreement. Patients tended to grade symptoms more severely than healthcare professionals. Information on sexual dysfunction was missing more frequently in healthcare professional assessment than PROs. CONCLUSION: Agreement was better for observable than subjective symptoms, with patients usually grading symptoms more severely than healthcare professionals. Our findings emphasize that PROs should complement symptom assessment by healthcare professionals and be taken into consideration for clinical decision-making to incorporate the patient perspective.

Anti-PD-1 for the treatment of advanced cutaneous squamous cell carcinoma in elderly patients: a French multicenter retrospective survey.

BACKGROUND: Anti-PD1 agents are currently recommended as first-line treatment in advanced cutaneous squamous cell carcinoma (acSCC) by updated European guidelines. Although acSCC frequently affects elderly patients with multiple comorbidities, this subset of patients is often excluded of registration clinical trials. PURPOSE: To assess anti-PD-1 efficacy and safety in elderly acSCC patients in real-life conditions and describe this specific population with oncogeriatric evaluation tools. METHODS: A multicenter retrospective study including acSCC patients at least 70 years old treated with PD-1 inhibitors was conducted in French referral centers. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety data, time to response (TTR), duration of response (DOR), overall survival (OS), and progression-free survival (PFS). RESULTS: 63 patients were included. ORR was 57.1% (95% CI 44.0-69.5), median TTR and DOR were 3 and 5.5 months respectively. Median OS was not reached (95% CI 12.5 months-not reached) at data cut-off after a median follow-up of 8 months while median PFS was 8 months. (95% CI 5 months-not reached). Grade 3-5 adverse effects occurred in 47.6% of patients. 41.3% of patients experienced degradation of ECOG performance status during anti-PD-1 treatment. Nutritional state worsened in 27% of patients and 57.1% lost weight during treatment. CONCLUSION: In this particular subset of acSCC patients PD-1 inhibitors obtain results similar to those obtained in younger populations included in pivotal clinical trials, with acceptable safety. A specific oncogeriatric evaluation at treatment initiation and during follow-up appears important in this setting most notably to help manage toxicity.

Association of polymorphisms in TGFB1, XRCC1, XRCC3 genes and CD8 T-lymphocyte apoptosis with adverse effect of radiotherapy for prostate cancer.

The genetic background of each person might affect the severity of radiotherapy (RT)-induced normal tissue toxicity. The aim of study was to evaluate the influence of TGFB1 C-509T and Leu10Pro, XRCC1 Arg280His and XRCC3 Thr241Met polymorphisms as well as the level of radiation-induced CD8 T-lymphocyte apoptosis (RILA) on adverse effects of RT for prostate cancer (PCa). The study included 88 patients with localized or locally advanced PCa who were treated with RT. The polymorphisms were determined by PCR-RFLP analysis on DNA from peripheral blood mononuclear cells. RILA values were measured by flow cytometry. We found that CT genotype of TGFB1 C-509T could be protective biomarker for acute genitourinary (GU) and gastrointestinal (GI) radiotoxicity, while Thr variant of XRCC3 Thr241Met could predict the risk for acute GU radiotoxicity. Correlation between RILA values and toxicity was not detected. Univariate logistic regression analysis showed that Gleason score and risk group were risk factors for late GU, while for late GI radiotoxicity it was diabetes mellitus type 2. However, in multivariate model those were not proven to be significant and independent risk factors. Identification of assays combination predicting individual radiosensitivity is a crucial step towards personalized RT approach.

High weekly integral dose and larger fraction size increase risk of fatigue and worsening of functional outcomes following radiotherapy for localized prostate cancer.

Introduction: We hypothesized that increasing the pelvic integral dose (ID) and a higher dose per fraction correlate with worsening fatigue and functional outcomes in localized prostate cancer (PCa) patients treated with external beam radiotherapy (EBRT). Methods: The study design was a retrospective analysis of two prospective observational cohorts, REQUITE (development, n=543) and DUE-01 (validation, n=228). Data were available for comorbidities, medication, androgen deprivation therapy, previous surgeries, smoking, age, and body mass index. The ID was calculated as the product of the mean body dose and body volume. The weekly ID accounted for differences in fractionation. The worsening (end of radiotherapy versus baseline) of European Organisation for Research and Treatment of Cancer EORTC) Quality of Life Questionnaire (QLQ)-C30 scores in physical/role/social functioning and fatigue symptom scales were evaluated, and two outcome measures were defined as worsening in ≥2 (WS2) or ≥3 (WS3) scales, respectively. The weekly ID and clinical risk factors were tested in multivariable logistic regression analysis. Results: In REQUITE, WS2 was seen in 28% and WS3 in 16% of patients. The median weekly ID was 13.1 L·Gy/week [interquartile (IQ) range 10.2-19.3]. The weekly ID, diabetes, the use of intensity-modulated radiotherapy, and the dose per fraction were significantly associated with WS2 [AUC (area under the receiver operating characteristics curve) =0.59; 95% CI 0.55-0.63] and WS3 (AUC=0.60; 95% CI 0.55-0.64). The prevalence of WS2 (15.3%) and WS3 (6.1%) was lower in DUE-01, but the median weekly ID was higher (15.8 L·Gy/week; IQ range 13.2-19.3). The model for WS2 was validated with reduced discrimination (AUC=0.52 95% CI 0.47-0.61), The AUC for WS3 was 0.58. Conclusion: Increasing the weekly ID and the dose per fraction lead to the worsening of fatigue and functional outcomes in patients with localized PCa treated with EBRT.

The correlation between pre-treatment symptoms, acute and late toxicity and patient-reported health-related quality of life in non-small cell lung cancer patients: Results of the REQUITE study.

BACKGROUND AND PURPOSE: To investigate the association between clinician-scored toxicities and patient-reported health-related quality of life (HRQoL), in early-stage (ES-) and locally-advanced (LA-) non-small cell lung cancer (NSCLC) patients receiving loco-regional radiotherapy, included in the international real-world REQUITE study. MATERIALS AND METHODS: Clinicians scored eleven radiotherapy-related toxicities (and baseline symptoms) with the Common Terminology Criteria for Adverse Events version 4. HRQoL was assessed with the European Organization for Research and Treatment of Cancer core HRQoL questionnaire (EORTC-QLQ-C30). Statistical analyses used the mixed-model method; statistical significance was set at p = 0.01. Analyses were performed for baseline and subsequent time points up to 2 years after radiotherapy and per treatment modality, radiotherapy technique and disease stage. RESULTS: Data of 435 patients were analysed. Pre-treatment, overall symptoms, dyspnea, chest wall pain, dysphagia and cough impacted overall HRQoL and specific domains. At subsequent time points, cough and dysphagia were overtaken by pericarditis in affecting HRQoL. Toxicities during concurrent chemo-radiotherapy and 3-dimensional radiotherapy had the most impact on HRQoL. Conversely, toxicities in sequential chemo-radiotherapy and SBRT had limited impact on patients' HRQoL. Stage impacts the correlations: LA-NSCLC patients are more adversely affected by toxicity than ES-NSCLC patients, mimicking the results of radiotherapy technique and treatment modality. CONCLUSION: Pre-treatment symptoms and acute/late toxicities variously impact HRQoL of ES- and LA-NSCLC patients undergoing different treatment approaches and radiotherapy techniques. Throughout the disease, dyspnea seems crucial in this association, highlighting the additional effect of co-existing comorbidities. Our data call for optimized radiotherapy limiting toxicities that may affect patients' HRQoL.

Efficacy, safety, and feasibility of volumetric modulated arc therapy for synchronous bilateral breast cancer management.

Purpose: Volumetric Modulated Arc Therapy (VMAT) exhibits potent advantages regarding target volume coverage and protection of organs at risk, notably in the context of anatomical constraints. Nevertheless, reports concerning VMAT for the treatment of synchronous bilateral breast cancers (SBBC) have been scarce to date. As such, we conducted this observational study to assess efficacy, safety and feasibility of VMAT in SBBC. Materials and Methods: From August 2011 to December 2017, 54 consecutive patients with SBBC with or without axillary nodes involvement underwent a treatment protocol containing radiotherapy using VMAT. A total dose (TD) of 52.2Gy in 29 fractions was delivered to breast and internal mammary chain (IMC) nodes Planning Target Volume (PTV) plus, if applicable, a TD of 49.3Gy in 29 fractions to the supra- and infra-clavicular nodes PTV and a TD of 63.22Gy in 29 fractions to tumor boost PTV. Lungs, heart, esophagus, trachea, liver, thyroid and spinal cord were considered as organs at risk. VMAT feasibility and organ at risk sparing were evaluated by treatments planning of the 20 first enrolled patients. Tolerance and patients' outcome were prospectively monitored by acute/late toxicities records and by the analysis of overall survival (OS), locoregional recurrence-free survival (LRFS) and recurrence-free survival (RFS). Results: Breast, supraclavicular nodes and boost PTV coverage was adequate with at least 98% of PTV encompassed by more than 95% of the prescribed dose. Less than 90% of IMC PTV was encompassed by 95% of the prescribed dose. Mean lung dose was 12.3Gy (range: 7.7 - 18.7); mean heart dose was 10.7Gy (range: 6.2 - 22.3). Concerning acute toxicities, only 2 patients experienced grade 3 skin toxicity (3.7%) and only 1 patient developed grade 1 pneumonitis. After a median follow-up of 5.3 years, grade 2 fibrosis and/or shrinking was observed in 5 patients (10%), and grade 3 fibrosis in 1 patients (2%). The 5-year LRFS-rate, RFS-rate and OS were 98% [95% CI= 86.12-99.70%], 96% [95% CI= 84.63-98.96%] and 100%, respectively.