Ultrahypofractionated Radiation Therapy for Prostate Cancer Including Seminal Vesicles in the Target Volume: A Treatment-planning Study Based on the HYPO-RT-PC Fractionation Schedule.

Purpose: Ultrahypofractionated (UHF) radiation therapy (RT) has become a treatment alternative for patients with localized prostate cancer. In more advanced cases, seminal vesicles (SVs) are routinely included in the target volume. The Scandinavian HYPO-RT-PC trial, which compared 42.7 Gy in 7 fractions (fr) to conventional fractionation (CF), did not include SVs in the clinical target volume. The primary objective of the present work was to implement a ultrahypofractionated-simultaneous integrated boost (UHF-SIB) for prostate cancer RT, incorporating SVs into the target volume based on this fractionation schedule. A secondary objective was to analyze the unintentional dose coverage of SVs from state-of-the-art volumetric modulated arc therapy treatments to the prostate gland only. Methods and Materials: Two different equieffective UHF-SIB treatment schedules to SVs were derived based on the CF clinical schedule (50.0 Gy/25 fr to elective SVs and 70.0 Gy/35 fr to verified SV-invasion (SVI)) using the linear quadric model with α/ß = 2 Gy and 3 Gy. The dose to the prostate was 42.7 Gy/7 fr in both schedules, with 31.2 Gy/37.8 Gy (α/ß = 2 Gy) and 32.7 Gy/40.1 Gy (α/ß = 3 Gy) to elective SV/verified SVI. Volumetric modulated arc therapy plans to the proximal 10 mm and 20 mm were optimized, and dose-volume metrics for target volumes and organs at risk were evaluated. Results: Dose metrics were overall lower for UHF-SIB compared with CF. QUANTEC-based volume criteria were 2% to 7% lower for the rectum and 2% to 4% lower for the bladder in the UHF-SIB. The D98% to elective SV was 7 to 12 Gy3 lower with UHF-SIB, and the corresponding data for verified SVI were approximately 2 to 3 Gy3. The SV(10 mm) V90%/(29.5 Gy) for prostate-only treatments (42.7 Gy) were as follows: median (IQR), 99% (87-100) and 78% (58-99) for the clinical target volume and planning target volume, respectively. Conclusions: UHF RT based on the HYPO-RT-PC fractionation schedule, with a SIB technique, to the prostate and the base of the SV can be planned with lower doses (EQD2) to organs at risk, compared with CF. The unintentional dose to the proximal parts of SVs in prostate-only treatment can be substantial.

Dose-volume relationships of planned versus estimated delivered radiation doses to pelvic organs at risk and side effects in patients treated with salvage radiotherapy for recurrent prostate cancer.

Purpose: To investigate estimated delivered dose distributions using weekly cone-beam computed tomography (CBCT) scans for pelvic organs at risk (OARs) in salvage radiotherapy (SRT) after radical prostatectomy. Furthermore, to compare them with the originally planned dose distributions and analyse associations with gastrointestinal (GI) and genitourinary (GU) side effects. Methods: This study is part of a phase II trial involving SRT for recurrent prostate cancer. Treatment was personalised based on PSA response during SRT, classifying patients as PSA responders or non-responders. Estimated radiation dose distributions were obtained using deformable image registration from weekly CBCT scans. GI and GU toxicities were assessed using the RTOG toxicity scale, while patient-reported symptoms were monitored through self-assessment questionnaires. Results: The study included 100 patients, with similar treatment-related side effects observed in both responders and non-responders. Differences in dose-volume metrics between the planned and estimated delivered doses for the examined OARs were mostly modest, although generally statistically significant. We identified statistically significant associations between QUANTEC-recommended dose-volume constraints and acute bowel toxicity, as well as late urinary patient-reported symptoms, for both the estimated delivered and planned dose distributions. Conclusion: We found small but statistically significant differences between estimated delivered and planned doses to OARs. These differences showed trends toward improved associations for estimated delivered dose distributions with side effects. Enhanced registration methods and imaging techniques could potentially further enhance the assessment of truly delivered doses and yield more reliable dose-volume constraints for future therapies.

A prospective phase II study of prostate-specific antigen-guided salvage radiotherapy and 68Ga-PSMA-PET for biochemical relapse after radical prostatectomy - The PROPER 1 trial.

Background and purpose: The treatment of biochemical recurrence (BCR) after prostatectomy is challenging as the site of the recurrence is often undetectable. Our aim was to test a personalised treatment concept for BCR based on PSA kinetics during salvage radiotherapy (SRT) combined with prostate-specific membrane antigen positron emission tomography (PSMA-PET). Materials and methods: This phase II trial included 100 patients with BCR. PSMA-PET was performed at baseline. PSA was measured weekly during SRT. Initially, 70 Gy in 35 fractions was prescribed to the prostate bed. Radiotherapy was adapted after 50 Gy. Non-responders (PSA still ≥ 0.15 ng/mL) received sequential lymph node irradiation with a boost to PSMA-PET positive lesions, while responders (PSA < 0.15 ng/mL) continued SRT as planned. PET-findings were only taken into consideration for treatment planning in case of PSA non-response after 50 Gy. Results: Data from 97 patients were eligible for analysis. Thirty-four patients were classified as responders and 63 as non-responders. PSMA-PET was positive in 3 patients (9%) in the responder group and in 22 (35%) in the non-responder group (p = 0.007). The three-year failure-free survival was 94% for responders and 68% for non-responders (median follow-up 38 months). There were no significant differences in physician-reported urinary and bowel toxicity. Patient-reported diarrhoea at end of SRT was more common among non-responders. Conclusion: This new personalised treatment concept with intensified SRT based on PSA response demonstrated a high tumour control rate in both responders and non-responders. These results suggest a clinically significant effect with moderate side effects in a patient group with otherwise poor prognosis. PSMA-PET added limited value. The treatment approach is now being evaluated in a phase III trial.Clinical trial registration numbers: NCT02699424&ISRCTN45905321.

Primary tumor volume and prognosis for patients with p16-positive and p16-negative oropharyngeal squamous cell carcinoma treated with radiation therapy.

BACKGROUND: The prescribed radiation dose to patients with oropharyngeal squamous cell carcinoma (OPSCC) is standardized, even if the prognosis for individual patients may differ. Easy-at-hand pre-treatment risk stratification methods are valuable to individualize therapy. In the current study we assessed the prognostic impact of primary tumor volume for p16-positive and p16-negative tumors and in relationship to other prognostic factors for outcome in patients with OPSCC treated with primary radiation therapy (RT). METHODS: Five hundred twenty-three OPSCC patients with p16-status treated with primary RT (68.0 Gy to 73.1 Gy in 7 weeks, or 68.0 Gy in 4.5 weeks), with or without concurrent chemotherapy, within three prospective trials were included in the study. Local failure (LF), progression free survival (PFS) and overall survival (OS) in relationship to the size of the primary gross tumor volume (GTV-T) and other prognostic factors were investigated. Efficiency of intensified RT (RT with total dose 73.1 Gy or given within 4.5 weeks) was analyzed in relationship to tumor volume. RESULTS: The volume of GTV-T and p16-status were found to be the strongest prognostic markers for LF, PFS and OS. For p16-positive tumors, an increase in tumor volume had a significantly higher negative prognostic impact compared with p16-negative tumors. Within a T-classification, patients with a smaller tumor, compared with a larger tumor, had a better prognosis. The importance of tumor volume remained after adjusting for nodal status, age, performance status, smoking status, sex, and hemoglobin-level. The adjusted hazard ratio for OS per cm3 increase in tumor volume was 2.3% (95% CI 0-4.9) for p16-positive and 1.3% (95% 0.3-2.2) for p16-negative. Exploratory analyses suggested that intensified RT could mitigate the negative impact of a large tumor volume. CONCLUSIONS: Outcome for patients with OPSCC treated with RT is largely determined by tumor volume, even when adjusting for other established prognostic factors. Tumor volume is significantly more influential for patients with p16-positive tumors. Patients with large tumor volumes might benefit by intensified RT to improve survival.

Results from a prospective, randomised study on (accelerated) preoperative versus (conventional) postoperative radiotherapy in treatment of patients with resectable squamous cell carcinoma of the oral cavity - The ARTSCAN 2 study.

BACKGROUND AND PURPOSE: An earlier prospective randomised multicentre study (ARTSCAN) in head and neck cancer patients that compared conventionally fractionated radiotherapy (CF) with accelerated radiotherapy (AF) was inconclusive. In the subgroup of oral cavity squamous cell cancer (OCSCC) a large absolute, but not statistically significant, difference in local control was seen in favour of AF. This difference was more pronounced in resectable tumours. The finding raised the hypothesis that AF could be beneficial for OCSCC patients. In addition, the longstanding controversy on pre- or postoperative radiotherapy was addressed. MATERIALS AND METHODS: Patients with OCSCC, judged to withstand and likely benefit from combined therapy, were recruited. Subjects were randomised to either preoperative AF with 43 fractions given as a concomitant boost with two fractions/day to the tumour bearing volume to a total dose of 68 Gy in 4.5 weeks followed by surgery, or primary surgery with postoperative CF, total dose 60 or 66 Gy in 6-7 weeks. For patients whose tumours had high-risk features, 66 Gy and concomitant cisplatin was prescribed. RESULTS: 250 patients were randomised. Median follow-up was 5 years for locoregional control (LRC) and 9 years for overall survival (OS). There were no statistically significant differences between the two treatment arms regarding LRC and OS. LRC at five years was 73% (95% CI, 65-82) in preoperative AF and 78% (95% CI, 70-85) in postoperative CF. Toxicity was more pronounced in preoperative AF. CONCLUSION: This study does not support that AF prior to surgery improves outcome in oral cavity cancer compared with postoperative CF.

Adaptive sequential plan-on-plan optimization during prostate-specific antigen response guided radiotherapy of recurrent prostate cancer.

BACKGROUND: Treatment adaptation based on tumour biomarker response during radiotherapy of prostate cancer, could be used for both escalation and de-escalation of radiation doses and volumes. To execute an adaptation involving extension of treatment volumes during radiation can however be restricted by the doses already delivered. The aim of this work was to develop a treatment planning method that addresses this challenge. MATERIAL AND METHODS: A volumetric-modulated-arc-therapy (VMAT) planning method with sequential plan-on-plan optimization was developed for a prospective phase II trial including 100 patients on salvage radiotherapy (SRT) for prostate cancer recurrence. A treatment adaptation was performed after five weeks of SRT based on prostate-specific antigen response during this phase of the treatment. This involved extension of treatment volumes for non-responders (n = 64) to include pelvic lymph nodes and boost to 68Gallium-Prostate-Specific-Membrane-Antigen-Positron-Emission-Tomography positive lesions. This method was evolved by introducing an EQD2 (equivalent dose in 2.0 Gy fractions) correction of the base plan for improved dose coverage. RESULTS: All dose-volume criteria for target coverage were met for the non-responders when based on physical dose. An EQD2 correction of the base plan for non-responders, implemented for the final 29 patients, led to a statistically significant improvement in dose coverage as compared to the 35 patients treated without EQD2 correction. CONCLUSIONS: This is to our knowledge the only study presented on biomarker-guided sequential VMAT radiotherapy using a plan-on-plan technique in the pelvis. By using a biologically adapted technique an improved target coverage was achieved without compromising doses to organs at risk.

Long-Term Risk of Hip Complications After Radiation Therapy for Prostate Cancer: A Dose-Response Study.

PURPOSE: The aim of the present study was to analyze the long-term incidence of hip complications after external beam radiation therapy compared with age-matched controls from the general population. We also investigated whether there were any dose-response associations. METHODS AND MATERIALS: A total of 349 patients with prostate cancer treated to curative dose with external beam radiation therapy between 1997 and 2002 were included in the study. Physical and fractionation-corrected dose-volume descriptors were derived for the femoral heads, pubic bone, and sacrum. Information on skeletal events was collected for the patients and 1661 matched controls through the Prostate Cancer database Sweden. Uni- and multivariable Cox proportional hazard regressions were used to analyze the time to event. RESULTS: Data from 346 patients were available for analysis. The median mean physical dose and corresponding equivalent 2-Gy/fraction dose (EQD2) to the femoral heads were 35.5 Gy and 28.7 Gy, respectively. The median follow-up time was 16.0 years. During the follow up, 12 hip fractures occurred. Hip osteoarthritis was diagnosed in 36 cases, with 29 cases leading to replacement surgery. No increased risk of hip fractures was found. Hip osteoarthritis was the only event for which a statistically significant difference was found between the irradiated cohort and the controls (cause-specific hazard ratio: 1.56; 95% confidence interval, 1.07-2.26; P = .02). The cumulative incidence of osteoarthritis at 10 years was 8.1% and 4.9% in the irradiated cohort and the controls, respectively. A significant relationship between osteoarthritis and the volume of the femoral head receiving ≥40 Gy (ie, EQD2) was found. CONCLUSIONS: In this study of 346 patients treated with conventional radiation therapy, we found no increased risk of hip fracture but an increased risk of clinically relevant osteoarthritis at long-term follow up. Our results indicate a dose-response relationship between osteoarthritis and the volume of the femoral head receiving an EQD2 dose of ≥40 Gy.

Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.

BACKGROUND: The HYPO-RT-PC trial compared conventionally fractionated radiotherapy with ultra-hypofractionated radiotherapy in patients with localised prostate cancer. Ultra-hypofractionation was non-inferior to conventional fractionation regarding 5-year failure-free survival and toxicity. We aimed to assess whether patient-reported quality of life (QOL) differs between conventional fractionation and ultra-hypofractionation up to 6 years after treatment in the HYPO-RT-PC trial. METHODS: HYPO-RT-PC is a multicentre, open-label, randomised, controlled, non-inferiority, phase 3 trial done in 12 centres (seven university hospitals and five county hospitals) in Sweden and Denmark. Inclusion criteria were histologically verified intermediate-to-high-risk prostate cancer (defined as T1c-T3a with one or two of the following risk factors: stage T3a; Gleason score ≥7; and prostate-specific antigen 10-20 ng/mL with no evidence of lymph node involvement or distant metastases), age up to 75 years, and WHO performance status 0-2. Participants were randomly assigned (1:1) to conventional fractionation (78·0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) via a minimisation algorithm with stratification by trial centre, T-stage, Gleason score, and prostate-specific antigen. QOL was measured using the validated Prostate Cancer Symptom Scale (PCSS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline, the end of radiotherapy, months 3, 6, 12, and 24 after radiotherapy, every other year thereafter up to 10 years, and at 15 years. The primary endpoint (failure-free survival) has been reported elsewhere. Here we report QOL, a secondary endpoint analysed in the per-protocol population, up to 6 years after radiotherapy. The HYPO-RT-PC trial is registered with the ISRCTN registry, ISRCTN45905321. FINDINGS: Between July 1, 2005, and Nov 4, 2015, 1200 patients were enrolled and 1180 were randomly assigned (conventional fractionation n=591, ultra-hypofractionation n=589); 1165 patients (conventional fractionation n=582, ultra-hypofractionation n=583) were included in this QOL analysis. 158 (71%) of 223 patients in the conventional fractionation group and 146 (66%) of 220 in the ultra-hypofractionation group completed questionnaires at 6 years. The median follow-up was 48 months (IQR 25-72). In seven of ten bowel symptoms or problems the proportion of patients with clinically relevant deteriorations at the end of radiotherapy was significantly higher in the ultra-hypofractionation group than in the conventional fractionation group (stool frequency [p<0·0001], rush to toilet [p=0·0013], flatulence [p=0·0013], bowel cramp [p<0·0001], mucus [p=0·0014], blood in stool [p<0·0001], and limitation in daily activity [p=0·0014]). There were no statistically significant differences in the proportions of patients with clinically relevant acute urinary symptoms or problems (total 14 items) and sexual functioning between the two treatment groups at end of radiotherapy. Thereafter, there were no clinically relevant differences in urinary, bowel, or sexual functioning between the groups. At the 6-year follow-up there was no difference in the incidence of clinically relevant deterioration between the groups for overall urinary bother (43 [33%] of 132 for conventional fractionation vs 33 [28%] of 120 for ultra-hypofractionation; mean difference 5·1% [95% CI -4·4 to 14·6]; p=0·38), overall bowel bother (43 [33%] of 129 vs 34 [28%] of 123; 5·7% [-3·8 to 15·2]; p=0·33), overall sexual bother (75 [60%] of 126 vs 59 [50%] of 117; 9·1% [-1·4 to 19·6]; p=0·15), or global health/QOL (56 [42%] of 134 vs 46 [37%] of 125; 5·0% [-5·0 to 15·0]; p=0·41). INTERPRETATION: Although acute toxicity was higher for ultra-hypofractionation than conventional fractionation, this long-term patient-reported QOL analysis shows that ultra-hypofractionation was as well tolerated as conventional fractionation up to 6 years after completion of treatment. These findings support the use of ultra-hypofractionation radiotherapy for intermediate-to-high-risk prostate cancer. FUNDING: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.

COVID-19 Concerns Among Old Age Psychiatric In- and Out-Patients and the Employees Caring for Them, a Preliminary Study.

A questionnaire was administered to 14 patients admitted at the Department of Old Age Psychiatric 24-h unit at Oslo University Hospital with questions about experiences and fears regarding COVID-19. A similar adjusted questionnaire was administered to 19 outpatients. The purpose was to investigate if the patients had fears, anxieties, and quality of life issues related to COVID-19 that could affect their treatment. A quest back questionnaire with similar questions about patient care and work conditions was sent to the personnel working with these patients, and 46 of 81 responded. Most patients welcomed the strict measures that were applied, including a visitation ban for inpatients and a reduction in consultations for the outpatients. Most patients reported that they were not very scared of getting COVID-19, nor did many believe that they would die if they were infected. A minority of patients reported being very worried. The patients also differed on other issues related to the COVID-19 situation. A minority were negative to the interventions, rules, and regulations, and/or considered the risk of infection to be elevated at the clinic, and/or that the quality of their daily life was negatively impacted. Employees more often than patients were concerned about the COVID-19 influence on their health. They were also concerned about being at work amid the crisis. About half of their comments were related to the fear of inadvertently infecting patients with COVID-19. Also, a majority complained about aspects related to the implemented COVID-19 guidelines. This study is explorative in nature, mainly due to its small sample size, which makes it difficult to draw conclusions from the results. However, the results imply a need for addressing the COVID-19 concerns of both patients and employees, to prevent potential negative effects on treatment and overall life quality. Future research should investigate the self-reported effects of the pandemic situation on a larger sample size of elderly psychiatric patients.

PSA decay during salvage radiotherapy for prostate cancer as a predictor of disease outcome - 5 year follow-up of a prospective observational study.

BACKGROUND AND PURPOSE: Biochemical recurrence after prostatectomy is commonly treated with salvage radiotherapy (SRT). In this prospective observational study we investigated the PSA decay rate, determined by predefined serial PSA measurements during SRT, as a predictor for treatment outcome. MATERIALS AND METHODS: Between 2013 and 2016, 214 patients were included in the study. The prescribed dose to the prostate bed was 70 Gy in 35 fractions (7 weeks) without hormonal treatment. PSA was measured weekly during SRT. Assuming first order kinetics, a PSA decay-rate constant (k) was calculated for 196 eligible patients. The ability of k to predict disease progression was compared with known clinical prediction parameters using Cox regression, logistic regression and ROC analyses. Disease progression was defined as continuously rising PSA after SRT, PSA increase by ≥0.2 ng/ml above nadir after SRT, hormonal treatment or clinical progression. RESULTS: After a median follow up of 4.7 years the estimated failure-free survival at 5 years was 56%. The PSA decay-rate constant (k) was found to be the strongest predictor of disease progression in both uni-and multivariable analyses. CONCLUSION: The addition of k to established clinical variables significantly improves the possibility to predict treatment outcome after SRT and could be used to personalize future therapies.

No Increased Cardiac Mortality or Morbidity of Radiation Therapy in Breast Cancer Patients After Breast-Conserving Surgery: 20-Year Follow-up of the Randomized SweBCGRT Trial.

PURPOSE: Radiation therapy (RT) after breast-conserving surgery reduces locoregional recurrences and improves survival but may cause late side effects. The main purpose of this paper was to investigate long-term side effects after whole breast RT in a randomized clinical trial initiated in 1991 and to report dose-volume data based on individual 3-dimensional treatment plans for organs at risk. METHODS AND MATERIALS: The trial included 1187 patients with T1-2 N0 breast cancer randomized to postoperative tangential whole breast RT or no further treatment. The prescription dose to the clinical target volume was 48 to 54 Gy. We present 20-year follow-up on survival, cause of death, morbidity, and later malignancies. For a cohort of patients (n = 157) with accessible computed tomography-based 3-dimensional treatment plans in Dicom-RT format, dose-volume descriptors for organs at risk were derived. In addition, these were compared with dose-volume data for a cohort of patients treated with contemporary RT techniques. RESULTS: The cumulative incidence of cardiac mortality was 12.4% in the control group and 13.0% in the RT group (P = .8). There was an increase in stroke mortality: 3.4% in the control group versus 6.7% in the RT group (P = .018). Incidences of contralateral breast cancer and lung cancer were similar between groups. The median Dmean (range) heart dose for left-sided treatments was 3.0 Gy (1.1-8.1), and the corresponding value for patients treated in 2017 was 1.5 Gy (0.4-6.0). CONCLUSIONS: In this trial, serious late side effects of whole breast RT were limited and less than previously reported in large meta-analyses. We observed no increase in cardiac mortality in irradiated patients. Doses to the heart were a median Dmean of 3.0 Gy for left-sided RT. The observed increase in stroke mortality may partly be secondary to cardiac side effects, complications to anticoagulant treatment, or to chance, rather than a direct side effect of tangential whole breast irradiation.

Altered fractionation diminishes importance of tumor volume in oropharyngeal cancer: Subgroup analysis of ARTSCAN-trial.

BACKGROUND: A large tumor volume negatively impacts the outcome of radiation therapy (RT). Altered fractionation (AF) can improve local control (LC) compared with conventional fractionation (CF). The aim of the present study was to investigate if response to AF differs with tumor volume in oropharyngeal cancer. METHODS: Three hundred and twenty four patients with oropharyngeal cancer treated in a randomized, phase III trial comparing CF (2 Gy/d, 5 d/wk, 7 weeks, total dose 68 Gy) to AF (1.1 Gy + 2 Gy/d, 5 d/wk, 4.5 weeks, total dose 68 Gy) were analyzed. RESULTS: Tumor volume had less impact on LC for patients treated with AF. There was an interaction between tumor volume and fractionation schedule (P = .039). This differential response was in favor of CF for small tumors and of AF for large tumors. CONCLUSION: AF diminishes the importance of tumor volume for local tumor control in oropharyngeal cancer.

Erectile Dysfunction and Absorbed Dose to Penile Base Structures in a Randomized Trial Comparing Ultrahypofractionated and Conventionally Fractionated Radiation Therapy for Prostate Cancer.

PURPOSE: To study the relationships between absorbed dose to penile base structures and erectile dysfunction (ED) in patients treated with ultrahypofractionated (UHF) radiation therapy (RT) or conventionally fractionated (CF) RT for prostate cancer. METHODS AND MATERIALS: This dose-response study comprises 673 patients (57%) of the 1180 per-protocol patients included in the HYPO-RT-PC trial (median follow-up 5, years), where patients were randomized to CF (39 × 2.0 Gy, 8 weeks) or UHF (7 × 6.1 Gy, 2.5 weeks). No androgen deprivation therapy was allowed. Only patients with erectile function sufficient for intercourse at baseline and complete RT data were included in this study. Erectile function was assessed by physician at regular follow-ups. The main endpoint was severe ED (EDs). The penile bulb (PB) and crus were retrospectively delineated on the treatment planning computed tomography scans. Dose-volume descriptors were derived from EQD2 converted dose matrices (α/ß = 3 Gy). Univariable and multivariable Cox proportional hazard regression and logistic regression were used to find predictors for EDS. RESULTS: No significant difference in EDs was found between CF and UHF. During the follow-up period, EDs occurred in 27% of the patients in both treatment groups. Average (median) PB mean dose, Dmean, was 24.5 (20.2) in CF and 18.7 (13.1) Gy3 in UHF. Age was the only significant predictor for EDs in Cox analyses. All dose-volume variables contributed significantly in univariable logistic regression at 2-year follow-up. Age and near maximum dose (D2%) were significant predictors for EDs in multivariable logistic regression analyses at both 1 and 2 years. CONCLUSIONS: The frequency of EDS was similar in the CF and UHF treatment groups. Age at radiation therapy was the strongest predictor for EDs, followed by dose to PB, and was most evident for younger patients. We propose D2 % <50 Gy3 and Dmean <20 Gy3 to the PB as the primary objectives to be applied in the treatment planning process.

Substantial intrinsic variability in chemoradiosensitivity of newly established anaplastic thyroid cancer cell-lines.

Background: Well characterized human cell lines are needed for preclinical treatment studies of anaplastic thyroid cancer (ATC).Aims/Objectives: The aim was to establish, verify and characterize a panel of ATC cell lines.Material and methods: Cell lines were established from ATC fine-needle aspiration biopsies and characterized genetically and functionally regarding treatment sensitivities.Results: Eight cell lines were established in vitro and the anaplastic thyroid origin was verified. Seven of the cell lines were also grown as xenografts. The cell lines harboured complex karyotypes with modal numbers in hyperdiploid to near-pentaploid range. Five were TP53 mutated and three carried the BRAFV600E mutation. None had rearrangements of RET. For doxorubicin, IC50 ranged from 0.42 to 46 nmol/L and for paclitaxel from 1.6 to 196 nmol/L. Radiation sensitivity varied between 2.6 and 6.3 Gy. Two of the BRAF mutated cell lines displayed high sensitivity to vemurafenib, while the third was similar to the wild-type ones.Conclusions and significance: We describe a series of new ATC cell lines demonstrating large heterogeneity in the response to cytostatic drugs and the BRAF inhibitor vemurafenib. The observations are relevant to future attempts to optimize treatment combinations for ATC.

Palliative short-course hypofractionated radiotherapy followed by chemotherapy in esophageal adenocarcinoma: the phase II PALAESTRA trial.

Background: The majority of patients with incurable esophageal adenocarcinoma suffer from dysphagia. We assessed a novel treatment strategy with initial short-course radiotherapy followed by chemotherapy with the primary aim to achieve long-term relief of dysphagia.Methods: This phase II trial included treatment-naîve patients with dysphagia due to esophageal adenocarcinoma not eligible for curative treatment. External beam radiotherapy with 20 Gy in five fractions to the primary tumor was followed by four cycles of chemotherapy (FOLFOX regimen). Dysphagia was assessed using a five-grade scale.Results: From October 2014 to May 2018 a total of 29 patients were enrolled. The rate of dysphagia improvement was 79%, median duration of improvement 6.7 months (12.2 months for responders) and median overall survival 9.9 months. In the pre-specified per protocol analysis (23 patients) the rate of dysphagia improvement was 91%, median duration of improvement 12.2 months (14.0 months for responders) and median overall survival 16.0 months. The most common grade 3-4 adverse events were neutropenia (29%), infection (25%), anorexia (11%), esophagitis (11%) and fatigue (11%).Conclusion: Initial palliative short-course radiotherapy followed by chemotherapy is a promising treatment strategy that can provide long-lasting relief of dysphagia in patients with esophageal adenocarcinoma.

Distribution of Locoregional Breast Cancer Recurrence in Relation to Postoperative Radiation Fields and Biological Subtypes.

PURPOSE: To investigate incidence and location of locoregional recurrence (LRR) in patients who have received postoperative locoregional radiation therapy (LRRT) for primary breast cancer. LRR-position in relation to applied radiotherapy and the primary tumor biological subtype were analyzed with the aim of evaluating current target guidelines and radiation therapy techniques in relation to tumor biology. METHODS AND MATERIALS: Medical records were reviewed for all patients who received postoperative LRRT for primary breast cancer in southwestern Sweden from 2004 to 2008 (N = 923). Patients with LRR as a first event were identified (n = 57; distant failure and death were considered competing risks). Computed tomographic images identifying LRR were used to compare LRR locations with postoperative LRRT fields. LRR risk and distribution were then related to the primary breast cancer biologic subtype and to current target guidelines. RESULTS: Cumulative LRR incidence after 10 years was 7.1% (95% confidence interval [CI], 5.5-9.1). Fifty-seven of the 923 patients in the cohort developed LRR (30 local recurrences and 30 regional recurrences, of which 3 cases were simultaneous local and regional recurrence). Most cases of LRR developed fully (56%) or partially (26%) within postoperatively irradiated areas. The most common location for out-of-field regional recurrence was cranial to radiation therapy fields in the supraclavicular fossa. Patients with an estrogen receptor negative (ER-) (hazard ratio [HR], 4.6; P < .001; 95% CI, 2.5-8.4) or HER2+ (HR, 2.4; P = .007; 95% CI, 1.3-4.7) primary breast cancer presented higher risks of LRR compared with those with ER+ tumors. ER-/HER2+ tumors more frequently recurred in-field (68%) rather than marginally or out-of-field (32%). In addition, 75% of in-field recurrences derived from an ER- or HER+ tumor, compared with 45% of marginal or out-of-field recurrences. A complete pathologic response in the axilla after neoadjuvant treatment was associated with a lower degree of LRR risk (P = .022). CONCLUSIONS: Incidence and location of LRR seem to be related to the primary breast cancer biologic subtype. Individualized LRRT according to tumor biology may be applied to improve outcomes.

Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.

BACKGROUND: Hypofractionated radiotherapy for prostate cancer has gained increased attention due to its proposed high radiation-fraction sensitivity. Recent reports from studies comparing moderately hypofractionated and conventionally fractionated radiotherapy support the clinical use of moderate hypofractionation. To date, there are no published randomised studies on ultra-hypofractionated radiotherapy. Here, we report the outcomes of the Scandinavian HYPO-RT-PC phase 3 trial with the aim to show non-inferiority of ultra-hypofractionation compared with conventional fractionation. METHODS: In this open-label, randomised, phase 3 non-inferiority trial done in 12 centres in Sweden and Denmark, we recruited men up to 75 years of age with intermediate-to-high-risk prostate cancer and a WHO performance status between 0 and 2. Patients were randomly assigned to ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) or conventional fractionated radiotherapy (78·0 Gy in 39 fractions, 5 days per week for 8 weeks). No androgen deprivation therapy was allowed. The primary endpoint was time to biochemical or clinical failure, analysed in the per-protocol population. The prespecified non-inferiority margin was 4% at 5 years, corresponding to a critical hazard ratio (HR) limit of 1·338. Physician-recorded toxicity was measured according to the Radiation Therapy Oncology Group (RTOG) morbidity scale and patient-reported outcome measurements with the Prostate Cancer Symptom Scale (PCSS) questionnaire. This trial is registered with the ISRCTN registry, number ISRCTN45905321. FINDINGS: Between July 1, 2005, and Nov 4, 2015, 1200 patients were randomly assigned to conventional fractionation (n=602) or ultra-hypofractionation (n=598), of whom 1180 (591 conventional fractionation and 589 ultra-hypofractionation) constituted the per-protocol population. 1054 (89%) participants were intermediate risk and 126 (11%) were high risk. Median follow-up time was 5·0 years (IQR 3·1-7·0). The estimated failure-free survival at 5 years was 84% (95% CI 80-87) in both treatment groups, with an adjusted HR of 1·002 (95% CI 0·758-1·325; log-rank p=0·99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0·057). There were no significant differences in grade 2 or worse urinary or bowel late toxicity between the two treatment groups at any point after radiotherapy, except for an increase in urinary toxicity in the ultra-hypofractionation group compared to the conventional fractionation group at 1-year follow-up (32 [6%] of 528 patients vs 13 [2%] of 529 patients; (p=0·0037). We observed no differences between groups in frequencies at 5 years of RTOG grade 2 or worse urinary toxicity (11 [5%] of 243 patients for the ultra-hypofractionation group vs 12 [5%] of 249 for the conventional fractionation group; p=1·00) and bowel toxicity (three [1%] of 244 patients vs nine [4%] of 249 patients; p=0·14). Patient-reported outcomes revealed significantly higher levels of acute urinary and bowel symptoms in the ultra-hypofractionation group compared with the conventional fractionation group but no significant increases in late symptoms were found, except for increased urinary symptoms at 1-year follow-up, consistent with the physician-evaluated toxicity. INTERPRETATION: Ultra-hypofractionated radiotherapy is non-inferior to conventionally fractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival. Early side-effects are more pronounced with ultra-hypofractionation compared with conventional fractionation whereas late toxicity is similar in both treatment groups. The results support the use of ultra-hypofractionation for radiotherapy of prostate cancer. FUNDING: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.

Target definition in radiotherapy of prostate cancer using magnetic resonance imaging only workflow.

In magnetic resonance (MR) only radiotherapy, the target delineation needs to be performed without computed tomography (CT). We investigated in thirteen patients with prostate cancer, how the clinical target volume (CTV) was affected, when the target delineation procedure was changed from using both CT and MR images to using MR images only. The mean volume of the CTVCT/MR was 61.0 cm3 as compared to 49.9 cm3 from MR-only based target delineation, corresponding to an average decrease of 18%. Our results show that CTVMR-only was consistently smaller than CTVCT/MR, which has to be taken into consideration before clinical commissioning of MR-only radiotherapy.

Comparative treatment planning study for mediastinal Hodgkin's lymphoma: impact on normal tissue dose using deep inspiration breath hold proton and photon therapy.

BACKGROUND: Late effects induced by radiotherapy (RT) are of great concern for mediastinal Hodgkin's lymphoma (HL) patients and it is therefore important to reduce normal tissue dose. The aim of this study was to investigate the impact on the normal tissue dose and target coverage, using various combinations of intensity modulated proton therapy (IMPT), volumetric modulated arc therapy (VMAT) and 3-dimensional conformal RT (3D-CRT), planned in both deep inspiration breath hold (DIBH) and free breathing (FB). MATERIAL AND METHODS: Eighteen patients were enrolled in this study and planned with involved site RT. Two computed tomography images were acquired for each patient, one during DIBH and one during FB. Six treatment plans were created for each patient; 3D-CRT in FB, 3D-CRT in DIBH, VMAT in FB, VMAT in DIBH, IMPT in FB and IMPT in DIBH. Dosimetric impact on the heart, left anterior descending (LAD) coronary artery, lungs, female breasts, target coverage, and also conformity index and integral dose (ID), was compared between the different treatment techniques. RESULTS: The use of DIBH significantly reduced the lung dose for all three treatment techniques, however, no significant difference in the dose to the female breasts was observed. Regarding the heart and LAD doses, large individual variations were observed. For VMAT, the mean heart and LAD doses were significantly reduced using DIBH, but no significant difference was observed for 3D-CRT and IMPT. Both IMPT and VMAT resulted in improved target coverage and more conform dose distributions compared to 3D-CRT. IMPT generally showed the lowest organs at risk (OAR) doses and significantly reduced the ID compared to both 3D-CRT and VMAT. CONCLUSIONS: The majority of patients benefited from treatment in DIBH, however, the impact on the normal tissue dose was highly individual and therefore comparative treatment planning is encouraged. The lowest OAR doses were generally observed for IMPT in combination with DIBH.

MR and CT data with multiobserver delineations of organs in the pelvic area-Part of the Gold Atlas project.

PURPOSE: We describe a public dataset with MR and CT images of patients performed in the same position with both multiobserver and expert consensus delineations of relevant organs in the male pelvic region. The purpose was to provide means for training and validation of segmentation algorithms and methods to convert MR to CT like data, i.e., so called synthetic CT (sCT). ACQUISITION AND VALIDATION METHODS: T1- and T2-weighted MR images as well as CT data were collected for 19 patients at three different departments. Five experts delineated nine organs for each patient based on the T2-weighted MR images. An automatic method was used to fuse the delineations. Starting from each fused delineation, a consensus delineation was agreed upon by the five experts for each organ and patient. Segmentation overlap between user delineations with respect to the consensus delineations was measured to describe the spread of the collected data. Finally, an open-source software was used to create deformation vector fields describing the relation between MR and CT images to further increase the usability of the dataset. DATA FORMAT AND USAGE NOTES: The dataset has been made publically available to be used for academic purposes, and can be accessed from https://zenodo.org/record/583096. POTENTIAL APPLICATIONS: The dataset provides a useful source for training and validation of segmentation algorithms as well as methods to convert MR to CT-like data (sCT). To give some examples: The T2-weighted MR images with their consensus delineations can directly be used as a template in an existing atlas-based segmentation engine; the expert delineations are useful to validate the performance of a segmentation algorithm as they provide a way to measure variability among users which can be compared with the result of an automatic segmentation; and the pairwise deformably registered MR and CT images can be a source for an atlas-based sCT algorithm or for validation of sCT algorithm.