Camilla Kronborg

PURPOSE: Adjuvant radiotherapy for node-positive breast cancer (BC) using 50Gy/25fx has been Danish Breast Cancer Group (DBCG) standard. Hypofractionated radiotherapy based on 40Gy/15fx has been increasingly used; however, it is less frequently for locoregional therapy because of concern over more morbidity. DBCG Skagen trial 1 hypothesized that 40Gy/15fx did not cause more lymphedema than 50Gy/25fx 3 years after radiotherapy without compromising the pattern of failure. METHODS: Skagen trial 1 is a phase III, noninferiority trial randomly assigning high-risk BC patients with an indication for locoregional radiotherapy to standard 50Gy/25fx versus experimental 40Gy/15fx. The primary end point was arm lymphedema; assuming a 3-year incidence with 50Gy/25fx of 10%, noninferiority was predefined to maximum 5% excess incidence with 40Gy/15fx. Accrual continued until 3-year estimates were reported in 1,012 patients. RESULTS: Between 2015 and 2021, 2,963 patients consented from 17 centers; the intention-to-treat cohort comprised 2,908 patients: 1,444 had 50Gy (50%), and 1,464 had 40Gy (50%). The median age was 57 years (range, 23-86). At a median follow-up of 4.1 years (IQR, 3.0-5.0), the 3-year rates of lymphedema were 9.4% (50Gy) versus 8.0% (40Gy), odds ratio 0.84 (95% CI, 0.62 to 1.14), and P = .27, thus within the +5-percentage-point noninferiority margin. The median follow-up for cancer outcomes was 5.25 years (IQR, 4.26 to 6.96). Within 8 years, the hazard ratio for locoregional recurrence was 0.96 (95% CI, 0.62 to 1.51), that for distant recurrence was 1.10 (95% CI, 0.89 to 1.37), that for BC mortality was 1.25 (95% CI, 0.93 to 1.66), and that for all-cause mortality was 1.08 (95% CI, 0.85 to 1.36), thus all with no differences by random assignment. CONCLUSION: 40Gy/15fx for locoregional radiotherapy of BC did not result in more lymphedema compared with 50Gy/25fx. There were no differences in locoregional or distant recurrences, breast cancer mortality, nor all-cause mortality between the random assignment arms.

Purpose: Preoperative radiotherapy (pRT) for rectal cancer (RC) reduces local recurrence rates. However, treatment-induced side effects may compromise patient-reported quality of life (QoL). This study aimed to report longitudinal QoL and physician-assessed toxicity in RC patients receiving preoperative intensity modulated radiotherapy (IMRT). Methods: This prospective cohort study included 123 RC patients treated with short-course (SCRT) or long-course chemoradiotherapy (LCRT). Patient-reported outcomes (PRO) were assessed using the EORTC QLQ-C30 and CR29 questionnaires at pretreatment, end of treatment, preoperatively, and at 1-year follow-up. Physician-reported toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE). Longitudinal changes in PROs were analysed using mixed-effects regression modelling. CTCAE grades were reported as frequencies, and symptom transitions illustrated using Sankey diagrams. Results: For EORTC C30 items, pRT-induced transient declines were observed for Global Health, physical, role and social functioning, fatigue, and pain, with scores recovering at preoperative assessment, except for persistent worsening for fatigue. At 1-year, Global Health remained stable; emotional functioning improved; fatigue and social functioning showed minor persistent worsening. Bowel and bladder symptoms peaked during pRT and gradually resolved or improved at 1Y. CTCAE grades were predominantly mild; diarrhoea and rectal bleeding improved over time, while urinary dysfunction and fatigue increased modestly. Sankey plots illustrate symptom transitions. Discrepancies were noted between physician- and patient-reported outcomes. Conclusion: IMRT-based pRT was associated with largely preserved QoL at 1Y. Reported trajectories of PRO and CTCAE scores provide complementary insights to support physician–patient communication, with differences underlining the importance of integrating both perspectives.

Background and purpose: We have previously shown that proton therapy results in considerable reduced doses to abdominal organs at risk (OAR) which likely reduces the patient’s risk of a second malignant tumor, which is vital for this young population with favourable prognosis. Here, we present dosimetric results after implementing intensity modulated proton therapy (IMPT) as a national standard for seminoma. Patient/material and methods: Thirty patients with stage IIA and IIB (< 3 cm) seminoma were treated with five-field robustly multi-field optimised (MFO) proton therapy to 20–24 Gy (relative biological effectiveness [RBE]) to the dog-leg retroperitoneal volume followed by a boost of 10–16 Gy (RBE) to the nodal metastasis. Control CTs were performed routinely, and target coverage evaluated. A standard two cone-beam CT (CBCT) set-up strategy with four match structures was developed, enabling implementation of a standard adaptive scheme. Results: The median clinical target volume (CTV-E) length in the craniocaudal direction was 26.9 cm, with a median volume of 551.4 cm3. Target coverage V95% = 100% for the nominal plan and V95% ≥ 98% for worst-case scenarios were fulfilled for all treatment plans and the 46 recalculated plans on control CTs. Kidney V17Gy was 0–6% and mean kidney dose 0–6 Gy across all plans. Bowel bag V15Gy was 194–698 cm3. All other OAR showed low doses. Four patients had replans (1–2 per patient). The median time for our image guidance (IG) strategy was 14:07 min across all patients with two CBCTs. Interpretation: We have established a robust setup for treatment planning, IG strategy, treatment delivery and adequate response to replanning. Therefore, we suggest considering IMPT for testicular seminoma whenever available.

Background and purpose: Treatment-related diarrhea is a challenge for patients treated with chemo-radiotherapy (CRT) for anal cancer in a curative setting. This study aims to investigate dosimetric and clinical predictors of acute and late diarrhea for patients treated with CRT or radiotherapy (RT) alone for anal cancer. Additionally, to investigate different bowel contouring methods ability to predict diarrhea. Patient/material and methods: Patients treated with CRT or RT alone in the prospective, observational DACG-I Plan-A study (2015–2021) were included. Toxicity endpoints were acute grade ≥2 diarrhea, and late grade ≥1 diarrhea recorded at 1 year after treatment (Common Terminology Criteria of Adverse Events (CTCAE), v4.0). Bowel volumes were contoured on the planning computed tomography (CT) as bowel cavity, bowel bag, individual bowel loops, and terminal ileum. Dosimetric variables included V15Gy, V30Gy, and V45Gy for the different bowel volumes. Clinical variables included tumor size, N-stage, and chemotherapy regimen. Logistic regression was used to evaluate the association between variables and toxicity. Results: Of the 290 patients included in this study, 116 (40%) experienced acute grade ≥2 diarrhea, and 56 of 256 (22%) had late grade ≥1 diarrhea. Patients treated with 5-FU/Capecitabine had a threefold higher risk of acute diarrhea compared to those receiving weekly Cisplatin or RT alone (p < 0.001). A trend indicating an increased risk of acute grade ≥2 diarrhea for patients with larger bowel volumes receiving radiation was observed. This was most pronounced for bowel bag V30Gy (p = 0.09); however, results from the different bowel contouring methods were similar. No parameters were predictive of late diarrhea. Interpretation: No dosimetric or clinical predictors of late diarrhea were found and only a trend was found between higher dose to bowel and risk of acute diarrhea. Treatment with 5-FU/Capecitabine showed a notable association with acute diarrhea. No contouring method was superior in predicting diarrhea.

Background and purpose: Sexual dysfunction is a common consequence of pelvic radiotherapy, influenced by psychological, physical, social, and relational factors. Research has focused on vaginal dose and stenosis in females and penile bulb dose and erectile dysfunction in males, with limited attention to domains, such as arousal, desire, and satisfaction. In the Danish Colorectal Cancer Radiotherapy Group, we aimed to: (1) Develop an atlas of sexual function-related organs at risk and (2) Evaluate if these organs at risk could be spared without compromising target coverage in rectal cancer radiotherapy planning. Patient/material and methods: A multidisciplinary approach was adopted, involving oncology, physics, psychology, surgery, and radiology. MRI-based anatomical definitions were established, and an atlas was created for both males and females, including inferior hypogastric plexus, pudendal vessels/Alcock’s canal, neurovascular bundle, penile bulb, vagina, paracolpium, and bulboclitoris. For comparative planning standard and sexual function-sparing plans were created for each patient. Results: A national consensus atlas for sexual function-related organs at risk was developed. Standard plans (n = 15) and sexual function-sparing plans (n = 15) for seven males and eight females were compared. Sparing of pudendal vessels and bulboclitoris was feasible without compromising the standard plan. For sexual function-related organs at risk in or close to the target, D2% could often be improved. Interpretation: Our consensus-based delineation and planning demonstrate that radiation dose to many sexual function-related organs at risk can be spared or optimized without compromising target coverage or dose to standard organs at risk. Future work includes implementing patient-reported outcomes and integrating these new organs at risk into standard radiotherapy planning.

Background and purpose: Reirradiation is becoming more frequent in clinical practice. However, workflows and practices vary widely between clinics, as general guidelines are scarce or lacking in practical detail. This paper presents comprehensive national Danish consensus recommendations covering all steps of the reirradiation workflow. The aim is to standardise and improve reirradiation treatment quality and provide guidance for much-needed large-scale clinical trials. Methods: An expert panel was formed comprising physicians, clinical physicists, and clinical researchers from all Danish radiotherapy centres. An in-person 2-day workshop was followed by multiple online meetings. Recommendations were based on expert consensus, supported by review of existing literature, and were reviewed by all Danish Multidisciplinary Cancer Groups before publication. Results: Reirradiation cases should be designated clearly as such at each workflow step. Review of patient cases at multidisciplinary reirradiation conferences is encouraged. Immobilisation, positioning, and motion management should resemble that of previous treatment(s) as closely as possible. Information on previous dose should be used in planning and evaluation. The degree of complexity (e.g. summation of dose maxima, rigid/deformable image registration, 3D dose accumulation) should reflect the clinical situation as well as the extent/quality of available information. Dose should always be converted to an equieffective dose before summation. Daily image-guidance and regular evaluation of delivered dose are recommended. We provide guidance on quality assurance of dose mapping and guidelines for clinical reirradiation trials. Interpretation: We present national consensus guidelines for site-independent reirradiation treatment workflows. The guidelines have been approved by the site-specific Danish Multidisciplinary Cancer Groups.