Background and purpose:Safe delivery of high-dose reirradiation depends on robust evaluation of previously delivered dose on current patient anatomy. This study aims to assess the variability of 1) rigid (RIR) and deformable (DIR) image registration, and 2) dose-mapping based on RIR or DIR, as part of the pre-trial quality assurance for CURE Lung, a Scandinavian thoracic reirradiation trial. Materials and methods:Seven lung cancer cases, treated with curatively intended reirradiation near a previously irradiated region, were distributed to six Danish centres. Organs-at-risk (OARs) were delineated on CT images of previous (CTprev) and current treatment (CTcurrent). RIR and DIR from CTprev to CTcurrent were performed for all cases at each centre, and doses were mapped from CTprev to CTcurrent using both methods. Mapped and current physical doses were converted to equieffective doses (EQD2), and cumulative EQD2-doses were generated on CTcurrent. Inter-centre variation was assessed using volume coefficients and distance measurements. A linear mixed-effects model tested the effect of registration method on OAR alignment, near-maximum and volumetric EQD2-dose constraints from CURE Lung, and variability in DVH bands. Results:DIR significantly reduced the geometrical variations for all OARs, with mean surface distances <4.4 mm. Near-maximum EQD2-doses overall had less variability with DIR compared to RIR. No significant differences were found for the full DVH bands. Conclusion:DIR provides significantly better consistency in transfer of OAR from CTprev to CTcurrent and reduces variability in EQD2-dose evaluations compared to RIR. This supports preferential use of DIR for reirradiation planning in lung cancer.

BACKGROUND AND PURPOSE:The NIELS trial will examine if inhomogeneous dose-escalated radiotherapy up to a mean dose of 80 Gy in 40 fractions (fx), twice-daily delivered (BID), for patients with limited disease small cell lung cancer can improve overall survival. Because of the inherent risks of dose-escalation, pre-trial QA is particularly important. This study aims to examine the feasibility of the NIELS trial planning approach in a multicenter setting. MATERIALS AND METHODS:The NIELS trial will randomize patients between standard dose radiotherapy (60 Gy/40fx BID) and inhomogeneous dose-escalated radiotherapy (up to 80 Gy/40fx BID). Five representative patient cases were distributed to seven Nordic centers for pre-trial QA planning of a standard and an escalated dose plan. Targets for escalation were primary tumor (GTVp) and involved lymph nodes (GTVn). We evaluated inter-center variation in achievable dose-escalation and doses to organs at risk (OAR). RESULTS:All targets could be escalated beyond the standard dose, with a median mean dose of 79.6 Gy [76.9-81.0] and 75.8 Gy [68.3-81.1] for GTVp and GTVn. Some targets could not be fully escalated due to OAR proximity. Three separate breaches of mandatory OAR constraints were observed in 35 escalated dose plans. There was a statistical difference in mean lung dose between standard and escalated plans, though clinically small, with a median inter-patient difference of 0.3 Gy. There were no differences in mean doses to the heart and esophagus. CONCLUSION:Inhomogeneous dose-escalation as planned in the NIELS trial is feasible, and the dose-escalation can be performed respecting the OAR constraints in a multi-center setting.

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.

PURPOSE:Radiation dose escalation for locally advanced non-small cell lung cancer (LA-NSCLC) has been challenged by toxicity concerns. The Scandinavian phase III multicenter dose-escalation trial NARLAL2 (ClinicalTrials.gov identifier: NCT02354274) used a novel approach to dose escalation: heterogeneous escalation driven by the fluorodeoxyglucose positron emission tomography-avid region, with strict normal tissue dose constraints. We report early toxicity within 6 months of random assignment. MATERIALS AND METHODS:Patients were recruited from seven institutions in Scandinavia. Eligibility criteria included performance status 0-1, NSCLC stage IIB-IIIB, and feasibility of delivering 66 Gy/33 fraction treatment plan. Patients were randomly assigned between standard (66 Gy) and heterogeneously dose-escalated radiotherapy. Two treatment plans were made for each patient before random assignment with matched mean lung dose and V20Gy, and strict dose constraints for all normal tissues. Toxicity was evaluated weekly during radiotherapy, and every 3 months after random assignment. Concurrent chemotherapy was cisplatin/carboplatin and vinorelbine. RESULTS:Between January 2015 and March 2023, 350 patients were randomly assigned. The as-treated analysis included 178 patients in the standard and 172 in dose-escalated (mean tumor dose 88 Gy) arms. Median gross tumor and planning target volumes were, respectively, 54 cm3 and 321 cm3 (standard arm) and 61 cm3 and 339 cm3 (escalated arm). No difference in early toxicity between the two arms was observed. Grade 2 esophagitis during radiotherapy was 28.1% and 25.6%, grade 3 esophagitis 7.3% and 4.1%, grade 2 pneumonitis 15.7% and 20.3%, and grade 3 pneumonitis 3.9% and 5.8% in standard and escalated arms, respectively. For both arms, the maximum grade of early toxicity aggregated over all toxicities was 35% and 1% for grades ≥3 and 5, respectively. Four patients died from potential treatment-related toxicity. CONCLUSION:Heterogeneous dose escalation did not increase early toxicity despite delivery of 88 Gy mean dose to the primary tumor, demonstrating this as an attractive strategy for LA-NSCLC radiotherapy dose escalation.

Purpose: This work examines the dosimetric performance of two algorithms creating a corrected CBCT (corrCBCT) and a virtual CT (vCT) implemented in a commercial treatment planning system. Methods: 60 patients distributed across all patient groups treated with curative intent at Vejle Hospital (breast, lung, prostate and anal/rectal cancer) were selected for the present study. Clinical treatment plans were recalculated on corrCBCT and vCT, as well as a reference CT (refCT) acquired as close in time to the CBCT image as possible. Recalculated doses were compared using gamma analysis, as well as by comparing D98%, D50%, and D2% for all delineated targets and organs at risk.Results: High dosimetric accuracy is demonstrated on both the corrCBCT and vCT. Gamma 2%/2 mm pass rates >98% were found for all patients except two outliers still having >93% pass rates. Equivalence of all evaluated dose metrics within +/- 1 Gy was observed for all patient groups, while the pelvic patients additionally showed equivalence for all metrics within +/- 1% of the refCT dose. For the thoracic patients, equivalence within +/- 2.5% was established for all metrics except median dose to the ipsilateral lung, calculated on corrCBCT for the breast patient group.Conclusion: The corrCBCT and vCT images are shown in excellent dosimetric agreement with refCT images, and show high potential for future use for streamlined adaptive radiotherapy workflows.

Purpose or ObjectiveThe RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating treatment response.Selumetinib (AZD6244/ ARRY-142886) an inhibitor of MEK, has been shown to enhance the effect of radiotherapy (RT) in preclinical studies. Material and MethodsThis single-arm, single-centre, open-label phase I trial, recruited patients with stage III non-small cell lung cancer (NSCLC) unsuitable for concurrent chemoradiotherapy or stage IV with dominant thoracic symptoms.Enrolment to the dose-finding stage used a Fibonacci 3+3 design (maximum number=18) followed by recruitment of an expanded cohort (n=15).Oral selumetinib was administered at a starting dose of 50mg twice daily commencing 7 days before RT, then in combination with thoracic radiotherapy (TRT) for 6-6.5 weeks (60-66Gy in 30-33 fractions).The primary objective was to determine the recommended Phase 2 dose. ResultsFrom 06/10-02/15, 21 patients were enrolled.Median age 63 years (range 50-73).M:F ratio 12(57%):9(43%).ECOG PS 0:1, 7(33%):14(67%).Stage III 16(76%):IV 5(24%).Mean GTV 64cm3 (range 0.8-223.73).In the dose-finding stage, 2 out of a total of 6 patients experienced dose-limiting toxicities (DLT) but only one DLT (G3 diarrhoea) was treatment-related.Despite meeting the pre-defined criteria for escalation, the trial management group elected to treat the expanded cohort (n=15) at the starting dose.All 21 received induction chemotherapy and completed TRT as planned.Compliance to selumetinib was >80%.The most common adverse events are listed in table 1.There were 2 survivors (24 & 26 months) at analysis.The 1-year survival was 38%, stage III 44% vs stage IV 20%, 2-year survival was 24%, stage III 31% vs stage IV 0%.The main cause of disease progression was distant metastases in 10/21 (48%).

Background and Purpose Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy(tumour) and 74Gy(lymph nodes), was pursued and compared to standard 66Gy/33F plans. Material and Methods Dose plans for the first thirty patients enrolled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue.

BACKGROUND AND PURPOSE:Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans.MATERIAL AND METHODS:Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue.RESULTS:The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation.CONCLUSIONS:FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.

Purpose or Objective: Conventionally in radiotherapy, a large beam forming apparatus is rotated around a stationary patient in order to achieve multiple beam angles.However, for a number of emerging and existing treatment modalities such as proton therapy, heavy ion therapy, MRI guided therapy, and synchrotron based therapies, such an approach results in prohibitively expensive and complex treatment systems.At the same time, much of the world has no access whatsoever to even conventional radiation therapy treatments.Replacing the gantry rotation with patient rotation could lead to much simpler and more cost effective treatment units.However, it is often assumed that patient acceptance would be a major barrier to widespread use of such a system.The purpose of this work was to test this assumption by investigating patient tolerance to slow single arc rotation.