Development and comprehensive evaluation of a national DBCG consensus-based auto-segmentation model for lymph node levels in breast cancer radiotherapy.

BACKGROUND AND PURPOSE: This study aimed at training and validating a multi-institutional deep learning (DL) auto segmentation model for nodal clinical target volume (CTVn) in high-risk breast cancer (BC) patients with both training and validation dataset created with multi-institutional participation, with the overall aim of national clinical implementation in Denmark. MATERIALS AND METHODS: A gold standard (GS) dataset and a high-quality training dataset were created by 21 BC delineation experts from all radiotherapy centres in Denmark. The delineations were created according to ESTRO consensus delineation guidelines. Four models were trained: One per laterality and extension of CTVn internal mammary nodes. The DL models were tested quantitatively in their own test-set and in relation to interobserver variation (IOV) in the GS dataset with geometrical metrics, such as the Dice Similarity Coefficient (DSC). A blinded qualitative evaluation was conducted with a national board, presented to both DL and manual delineations. RESULTS: A median DSC > 0.7 was found for all, except the CTVn interpectoral node in one of the models. In the qualitative evaluation 'no corrections needed' were acquired for 297 (36 %) in the DL structures and 286 (34 %) for manual delineations. A higher rate of 'major corrections' and 'easier to start from scratch' was found in the manual delineations. The models performed within the IOV of an expert group, with two exceptions. CONCLUSION: DL models were developed on a national consensus cohort and performed on par with the IOV between BC experts and had a comparable or higher clinical acceptance than expert manual delineations.

Spot-scanning proton therapy for early breast cancer in free breathing versus deep inspiration breath-hold.

BACKGROUND AND PURPOSE: Proton therapy for breast cancer is usually given in free breathing (FB). With the use of deep inspiration breath-hold (DIBH) technique, the location of the heart is displaced inferiorly, away from the internal mammary nodes and, thus, the dose to the heart can potentially be reduced. The aim of this study was to explore the potential benefit of proton therapy in DIBH compared to FB for highly selected patients to reduce exposure of the heart and other organs at risk. We aimed at creating proton plans with delivery times feasible with treatment in DIBH. MATERIAL AND METHODS: Sixteen patients with left-sided breast cancer receiving loco-regional proton therapy were included. The FB and DIBH plans were created for each patient using spot-scanning proton therapy with 2-3 fields, robust and single field optimization. For the DIBH plans, minimum monitor unit per spot and spot spacing were increased to reduce treatment delivery time. RESULTS: All plans complied with target coverage constraints. The median mean heart dose was statistically significant reduced from 1.1 to 0.6 Gy relative biological effectiveness (RBE) by applying DIBH. No statistical significant difference was seen for mean dose and V17Gy RBE to the ipsilateral lung. The median treatment delivery time for the DIBH plans was reduced by 27% compared to the FB plans without compromising the plan quality. INTERPRETATION: The median absolute reduction in dose to the heart was limited. Proton treatment in DIBH may only be relevant for a subset of these patients with the largest reduction in heart exposure.

Plan robustness evaluation strategies in whole-pelvic proton therapy for high-risk prostate cancer patients within a randomised clinical trial.

BACKGROUND: Inter-fractional anatomical changes challenge robust delivery of whole-pelvic proton therapy for high-risk prostate cancer. Pre-treatment robust evaluation (PRE) takes uncertainties in isocenter shifts and distal beam edge in treatment plans into account. Using weekly control computed tomography scans (cCTs), the aim of this study was to evaluate the PRE strategy by comparing to an off-line during-treatment robust evaluation (DRE) while also assessing plan robustness with respect to protocol planning constraints. MATERIAL AND METHODS: Treatment plans and cCTs from ten patients included in the pilot phase of the PROstate PROTON Trial 1 were analysed. Treatment planning followed protocol guidelines with 78 Gy to the primary clinical target volume (CTVp) and 56 Gy to the elective target (CTVe) in 39 fractions. Recalculations of the treatment plans were performed for a total of 64 cCTs and dose/volume measures corresponding to clinical constraints were evaluated for this DRE against the simulated scenario interval from the PRE. RESULTS: Of the 64 cCTs, 59 showed DRE CTVp measures within the robustness range from the PRE; this was also the case for 39 of the cCTs for the CTVe measures. However, DRE CTVe coverage was still within constraints for 57 of the 64 cCTs. DRE dose/volume measures for CTVp fulfilled target coverage constraints in 59 of 64 cCTs. All DRE measures for the rectum, bladder, and bowel were inside the PRE range in 63, 39, and 31 cCTs, respectively. CONCLUSION: The PRE strategy predicted the DRE scenarios for CTVp and rectum. CTVe, bladder, and bowel showed more complex anatomical variations than simulated by the PRE isocenter shift. Both original and recalculated nominal treatment plans showed robust treatment delivery in terms of target coverage.

Proton therapy planning and image-guidance strategies within a randomized controlled trial for high-risk prostate cancer.

The Danish Prostate Cancer Group is launching the randomized trial, PROstate PROTON Trial 1 (NCT05350475), that compares photons and protons to the prostate and pelvic lymph nodes in treatment of high-risk prostate cancer. The aim of the work described in this paper was, in preparation of this trial, to establish a strategy for conventionally fractionated proton therapy of prostate and elective pelvic lymph nodes that is feasible and robust. Proton treatments are image-guided based on gold fiducial markers and on-board imaging systems in line with current practice. Our established proton beam configuration consists of four coplanar fields; two posterior oblique fields and two lateral oblique fields, chosen to minimize range uncertainties associated with penetrating a varying amount of material from both treatment couch and patient body. Proton plans are robustly optimized to ensure target coverage while keeping normal tissue doses as low as is reasonably achievable throughout the course of treatment. Specific focus is on dose to the bowel as a reduction in gastrointestinal toxicity is the primary endpoint of the trial. Strategies have been established using previously treated patients and will be further investigated and evaluated through the ongoing pilot phase of the trial.

Proton therapy for early breast cancer patients in the DBCG proton trial: planning, adaptation, and clinical experience from the first 43 patients.

BACKGROUND: The Danish Breast Cancer Group (DBCG) Proton Trial randomizes breast cancer patients selected on high mean heart dose (MHD) or high lung dose (V20Gy/V17Gy) in the photon plan between photon and proton therapy. This study presents the proton plans and adaptation strategy for the first 43 breast cancer patients treated with protons in Denmark. MATERIAL AND METHODS: Forty-four proton plans (one patient with bilateral cancer) were included; 2 local and 42 loco-regional including internal mammary nodes (IMN). Nineteen patients had a mastectomy and 25 a lumpectomy. The prescribed dose was either 50 Gy in 25 fractions (n = 30) or 40 Gy in 15 fractions (n = 14) wherefrom five received simultaneous integrated boost to the tumor bed. Using 2-3 en face proton fields, single-field optimization, robust optimization and a 5 cm range shifter ensured robustness towards breathing motion, setup- and range uncertainties. An anatomical evaluation was performed by evaluating the dose after adding/removing 3 mm and 5 mm tissue to/from the body-outline and used to define treatment tolerances for anatomical changes. RESULTS: The nominal and robust criteria were met for all patients except two. The median MHD was 1.5 Gy (0.5-3.4 Gy, 50 Gy) and 1.1 Gy (0.0-1.5 Gy, 40 Gy). The anatomical evaluations showed how 5 mm shrinkage approximately doubled the MHD while 5 mm swelling reduced target coverage of the IMN below constraints. Ensuring 3-5 mm robustness toward swelling was prioritized but not always achieved by robust optimization alone emphasizing the need for a distal margin. Twenty-eight patients received plan adaptation, eight patients received two, and one received five. CONCLUSION: This proton planning strategy ensured robust treatment plans within a pre-defined level of acceptable anatomical changes that fulfilled the planning criteria for most of the patients and ensured low MHD.

Androgen Deprivation Therapy Combined With Particle Therapy for Prostate Cancer: A Systematic Review.

PURPOSE: There is high-level evidence for addition of androgen deprivation therapy to photon-based radiotherapy of the prostate in intermediate- and high-risk prostate cancer. Little is known about the value of ADT in particle therapy of prostate cancer. We are conducting a systematic review on biochemical disease-free survival, overall survival, and morbidity after combined particle therapy and ADT for prostate cancer. METHODS: A thorough search in PubMed, Embase, Scopus, and Web of Science databases were conducted, searching for relevant studies. Clinical studies on prostate cancer and the treatment combination of particle therapy and androgen deprivation therapy were included. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on PROSPERO (CRD42021230801). RESULTS: A total of 298 papers were identified. Fifteen papers reporting on 7,202 patients after proton or carbon-ion therapy for localized prostate cancer where a fraction or all patients received ADT were selected for analysis. Three thousand five hundred and nineteen (49%) of the patients had received combined ADT and particle therapy. Primarily high-risk (87%), to a lesser extent intermediate-risk (34%) and low-risk patients (12%) received ADT. There were no comparative studies on the effect of ADT in patients treated with particles and no studies identified ADT as an independent prognostic factor related to survival outcomes. CONCLUSIONS: The review found no evidence to support that the effects on biochemical disease-free survival and morbidity of combining ADT to particle therapy differs from the ADT effects in conventional photon based radiotherapy. The available data on the topic is limited.

Late urinary morbidity and quality of life after radical prostatectomy and salvage radiotherapy for prostate cancer.

OBJECTIVE: There is a paucity of knowledge of long-term urinary morbidity in patients treated for prostate cancer (PCa) with radical prostatectomy (RP) and salvage radiotherapy (SRT). Improved long-term survival calls for heightened awareness of late effects from radiotherapy after RP. The purpose of this study was to assess late urinary morbidity and its potential impact on quality of life (QoL) in patients treated with RP plus SRT compared with patients treated with RP alone. MATERIALS AND METHODS: Long-term morbidity and QoL were evaluated using a cross-sectional design with validated questionnaires in urinary morbidity [Danish Prostatic Symptom Score (DAN-PSS)] and QoL [European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)]. Included were a total of 227 patients treated with SRT and 192 treated with RP in the periods 2006-2010 and 2005-2007, respectively. RESULTS: Weak stream, straining, frequency and nocturia were significantly more prevalent in patients treated with RP + SRT than in patients treated with RP alone. Patients treated with RP + SRT generally suffered from more severe urinary symptoms. The QoL scores of the two treatment groups were not statistically significantly different, but a high level of urinary morbidity was significantly related to decreased QoL (p = 0.000). CONCLUSIONS: Patients treated with SRT have a higher rate of urinary morbidity than do patients treated with RP alone. Severe urinary morbidity was significantly related to decreased QoL, but did not differ between the two treatment groups.

Urinary bladder dose-response relationships for patient-reported genitourinary morbidity domains following prostate cancer radiotherapy.

BACKGROUND AND PURPOSE: Radiotherapy (RT) induced genitourinary (GU) morbidity is typically assessed by physicians as single symptoms or aggregated scores including symptoms from various domains. Here we apply a method to group patient-reported GU symptoms after RT for localized prostate cancer based on their interplay, and study how these relate to urinary bladder dose. MATERIALS AND METHODS: Data were taken from two Scandinavian studies (N=207/276) including men treated with external-beam RT (EBRT) to 78/70Gy (2Gy/fraction; median time-to-follow-up: 3.6-6.4y). Within and across cohorts, bladder dose-volume parameters were tested as predictors for GU symptom domains identified from two study-specific questionnaires (35 questions on frequency, incontinence, obstruction, pain, urgency, and sensory symptoms) using univariate and multivariate logistic regression analysis (MVA) with 10-fold cross-validation. Performance was evaluated using Area Under the Receiver Operating Characteristic Curve (Az). RESULTS: For the identified Incontinence (2-5 symptoms), Obstruction (3-5 symptoms), and Urgency (2-7 symptoms) domains, MVA demonstrated that bladder doses close to the prescription doses were the strongest predictors for Obstruction (Az: 0.53-0.57) and Urgency (Az: 0.60). For Obstruction, performance increased for the across cohort analysis (Az: 0.61-0.64). CONCLUSIONS: Our identified patient-reported GU symptom domains suggest that high urinary bladder doses, and increased focus on both obstruction and urgency is likely to further add to the understanding of GU tract RT responses.

Salvage radiation therapy following radical prostatectomy. A national Danish study.

BACKGROUND: The purpose of this observational cohort study was to evaluate the outcome and prognostic factors following salvage radiotherapy (SRT) in a consecutive national cohort. MATERIAL AND METHODS: Between 2006 and 2010, 259 patients received SRT in Denmark. Patient- and cancer-related characteristics were retrospectively retrieved from patient charts. The primary end point was biochemical progression-free survival (b-PFS). RESULTS: At the end of follow-up, 51% of the patients displayed a prostate-specific antigen (PSA) level <0.1 ng/ml. The three-year b-PFS rate for the total cohort was 57.0%. Nearly half of the patients (44%) received androgen deprivation therapy (ADT) in combination with SRT. Positive surgical tumour margins (p = 0.025) and ADT (p = 0.001) were the only markers independently correlated with b-PFS. In patients who received SRT without ADT, both a pre-SRT PSA level ≤0.5 ng/ml (p = 0.003) and pathological tumour stage T1-T2 (p = 0.036) independently correlated with b-PFS. Moreover, a duration between radical prostatectomy (RP) and SRT ≤29 months (p = 0.035) independently correlated with b-PFS in patients treated with ADT in combination with RT. CONCLUSIONS: In patients treated for biochemical failure after RP, positive surgical tumour margins and PSA levels ≤0.5 ng/mL at the time of SRT were associated with a favourable outcome. Despite less favourable tumour characteristics, patients receiving SRT and ADT demonstrated improved b-PFS, and in particular, patients with PSA levels >0.2 ng/ml benefitted from additional ADT.

Development and validation of a scoring system for late anorectal side-effects in patients treated with radiotherapy for prostate cancer.

PURPOSE: To develop and validate a scoring system for evaluation of long term anorectal dysfunction following radiotherapy for prostate cancer. MATERIALS AND METHODS: Patients treated for prostate cancer with radiotherapy filled in questionnaires on anorectal function and quality of life. Items for the condensed anorectal dysfunction score (RT-ARD) were identified and weighted by binomial regression analysis. The score was tested in a separate patient material by receiver operating characteristic (ROC) analysis and correlations to quality of life domains. RESULTS: A total of 309 patients participated in the study. The items selected were "incontinence for solid stool", "ability to defer defecation", "unproductive call to stool", "clustering of stool", and "mucus in stool." Patients were grouped into three categories according to the RT-ARD score; 0-8 (no RT-ARD), 9-23 (minor RT-ARD), 24-45 (major RT-ARD). ROC analyses revealed high sensitivity (91%) and specificity (85%) for major RT-ARD. The prediction model demonstrated a perfect fit in 60%, moderate fit in 36% and no fit in 4%. There was good correlation between the RT-ARD score and quality of life. CONCLUSIONS: The RT-ARD score is a validated and simple instrument for evaluation of anorectal dysfunction following radiotherapy for prostate cancer, and the RT-ARD score correlates to the patient's quality of life.