Interim analysis of patient-reported outcome compliance and dosimetry in a phase 3 randomized clinical trial of oesophagus-sparing spinal radiotherapy.

BACKGROUND: The randomized clinical trial ESO-SPARE investigates if oesophagus-sparing radiotherapy (RT) can reduce dysphagia in patients with metastatic spinal cord compression (MSCC). Patient-reported outcome (PRO) is the only follow-up measure. Due to the fragile patient population, low respondent compliance was anticipated. We performed a planned interim analysis of dosimetry and respondent compliance, to ensure that the protocol requirements were met. METHODS: Patients >18 years referred for cervical/thoracic MSCC radiotherapy in 1-10 fractions were included from two centres. Patients were randomized (1:1) to standard RT or oesophagus-sparing RT, where predefined oesophageal dose constraints were prioritized over target coverage. Patients completed a trial diary with daily reports of dysphagia for 5 weeks (PRO-CTC-AE) and weekly quality of life reports for 9 weeks (QLQ-C30, EQ-5D-5L). According to power calculation, 124 patients are needed for primary endpoint analysis. The sample size was inflated to 200 patients to account for the fragile patient population. The co-primary endpoints, peak patient-reported dysphagia, and preserved ability to walk (EQ-5D-5L), are analysed at 5 and 9 weeks, respectively. The interim analysis was conducted 90 days after the inclusion of patient no 100. Respondent compliance was assessed at 5 and 9 weeks. In all RT plans, oesophagus and target doses were evaluated regarding adherence to protocol constraints. RESULTS: From May 2021 to November 2022, 100 patients were included. Fifty-two were randomized to oesophagus-sparing RT. In 23% of these plans, oesophagus constraints were violated. Overall, the dose to both target and oesophagus was significantly lower in the oesophagus-sparing plans. Only 51% and 41% of the patients were evaluable for co-primary endpoint analysis at five and nine weeks, respectively. Mortality and hospitalization rates were significantly larger in patients who completed <4 days PRO questionnaires. CONCLUSION: Compliance was lower than anticipated and interventions to maintain study power are needed.

Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study.

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.

The advantage of deep-inspiration breath-hold and cone-beam CT based soft-tissue registration for locally advanced lung cancer radiotherapy.

BACKGROUND AND PURPOSE: Three cone-beam computed tomography (CBCT) registration strategies combined with deep-inspiration breath-hold (DIBH) and free-breathing (FB) were explored, in terms of obtaining the smallest planning target volume (PTV). MATERIAL AND METHODS: CBCT images were acquired pre- and post-treatment in FB and DIBH, for 17 locally advanced lung cancer patients. Bony registration on the spine, and soft-tissue registrations on the primary gross tumor volume (GTV-T) and GTV-Total, including malignant lymph nodes (GTV-N), were retrospectively analyzed. Setup-margins and resulting PTVs were calculated. RESULTS: For the spine, the smallest residual misalignments were observed in FB, independently of registration method. For GTV-T and GTV-N, soft-tissue registrations were superior to bony registration, independently of FB or DIBH. Compared to FB, PTV-Totals were during DIBH reduced by 13% and 8% for the soft-tissue and bony registrations, respectively. If intra-fractional motion was included, the corresponding gain of DIBH was reduced to 9% and 7%, respectively. Superiority of DIBH was mainly due to larger clinical target volumes in FB. CONCLUSIONS: Despite larger setup uncertainties compared to FB, DIBH resulted in smaller PTV-Totals for all registration methods. Soft-tissue registrations were superior to bony registration, independently of FB and DIBH. During DIBH, undesirable arching of the back was identified. Daily CBCT pre-treatment target verification is advised.

Monte Carlo calculations support organ sparing in Deep-Inspiration Breath-Hold intensity-modulated radiotherapy for locally advanced lung cancer.

BACKGROUND AND PURPOSE: Studies indicate that Deep-Inspiration Breath-Hold (DIBH) is advantageous over Free-Breathing (FB) for locally advanced lung cancer radiotherapy. However, these studies were based on simplified dose calculation algorithms, potentially critical due to the heterogeneous nature of the lung region. Using detailed Monte-Carlo (MC) calculations, a comparative study of DIBH vs. FB was therefore designed. MATERIAL AND METHODS: Eighteen locally advanced lung cancer patients underwent FB and DIBH CT imaging and treatment planning with the Anisotropic-Analytical-Algorithm (AAA) for intensity-modulated-radiotherapy or volumetric-modulated-arc-therapy using 66Gy in 33 fractions. All plans were re-calculated with MC. RESULTS: Relative to FB, the total lung volume increased 86.8% in DIBH, while the gross tumor volume decreased 14.8%. MC revealed equally under- and over-dosage of the target for FB and DIBH, compared to AAA. For the Organs-At-Risk (OARs), DIBH reduced the mean heart dose by 25.5% (AAA) vs. 12.6% (MC), the total lung V5Gy/V20Gy by 9.0/20.0% (AAA) vs. 11.6/19.9% (MC). CONCLUSIONS: MC calculations revealed (i) that DIBH compared with FB can significantly reduce the dose to the OARs even if the treatment planning is carried out with AAA, and (ii) inferior target dose coverage compared to AAA, irrespectively of FB and DIBH. The dose deviations were similar for FB and DIBH. The observed inferior target dose coverage relates therefore to the treatment planning algorithm rather than breathing technique.

Adaptation requirements due to anatomical changes in free-breathing and deep-inspiration breath-hold for standard and dose-escalated radiotherapy of lung cancer patients.

BACKGROUND: Radiotherapy of lung cancer patients is subject to uncertainties related to heterogeneities, anatomical changes and breathing motion. Use of deep-inspiration breath-hold (DIBH) can reduce the treated volume, potentially enabling dose-escalated (DE) treatments. This study was designed to investigate the need for adaptation due to anatomical changes, for both standard (ST) and DE plans in free-breathing (FB) and DIBH. MATERIAL AND METHODS: The effect of tumor shrinkage (TS), pleural effusion (PE) and atelectasis was investigated for patients and for a CIRS thorax phantom. Sixteen patients were computed tomography (CT) imaged both in FB and DIBH. Anatomical changes were simulated by CT information editing and re-calculations, of both ST and DE plans, in the treatment planning system. PE was systematically simulated by adding fluid in the dorsal region of the lung and TS by reduction of the tumor volume. RESULTS: Phantom simulations resulted in maximum deviations in mean dose to the GTV-T (GTV-T) of -1% for 3 cm PE and centrally located tumor, and + 3% for TS from 5 cm to 1 cm diameter for an anterior tumor location. For the majority of the patients, simulated PE resulted in a decreasing GTV-T with increasing amount of fluid and increasing GTV-T for decreasing tumor volume. Maximum change in GTV-T of -3% (3 cm PE in FB for both ST and DE plans) and + 10% (2 cm TS in FB for DE plan) was observed. Large atelectasis reduction increased the GTV-T with 2% for FB and had no effect for DIBH. CONCLUSION: Phantom simulations provided potential adaptation action levels for PE and TS. For the more complex patient geometry, individual assessment of the dosimetric impact is recommended for both ST and DE plans in DIBH as well as in FB. However, DIBH was found to be superior over FB for DE plans, regarding robustness of GTV-T to TS.

Evaluation of setup accuracy for NSCLC patients; studying the impact of different types of cone-beam CT matches based on whole thorax, columna vertebralis, and GTV.

PURPOSE: The aim of this study is to evaluate the patient setup accuracy by investigating the impact of different types of CBCT matches, performed with 3 (translations only) or 6 (including rotations) degrees-of-freedom (DOF). The purpose is also to calculate and compare CTV to PTV margins based on the various CBCT matches, setups using 2D kV planar imaging or setups using skin markers only (non-IGRT). MATERIAL AND METHODS: Setup images from 16 NSCLC patients with weekly CBCT and daily 2D kV planar imaging were analyzed retrospectively. The CBCT matches were based on the columna vertebralis (CV), the whole thorax (WT) and the soft tissue (ST) delineated GTV, where the ST match was chosen as reference. Thus the translational and rotational shifts in three dimensions were assessed. Finally, setup margins were calculated using van Herk's margin recipe. RESULTS: For 80% of the investigated 3 DOF/2D kV CV setups, the translational shifts were within [-3, 2] mm for all three directions. Corresponding values for the 6 DOF/non-IGRT CV and the 6 DOF/non-IGRT ST matches were [-5, 8] mm. Furthermore, 80% of all setups were within ± 2° for pitch-, roll- and yaw-rotations, and none exceeded 5°. The calculated margins for non-IGRT, about 10 mm, were reduced to approximately 4 mm, regardless of using IGRT setup by CBCT or 2D kV imaging on CV. However, if using WT CBCT setup, the margin in LNG direction was slightly larger, approximately 6 mm. CONCLUSION: IGRT for NSCLC is an essential tool for margin reduction, since patient setups based on IGRT leads to approximately half the margin sizes compared to non-IGRT setups. Both CBCT and 2D kV planar imaging yields approximately the same margins for CV/ST matches. The magnitudes of the patient rotations were <5°.

A beam-matching concept for medical linear accelerators.

The flexibility in radiotherapy can be improved if a patient can be moved between any one of the department's medical linear accelerators without the need to change anything in the patient's treatment plan. For this to be possible, the dosimetric characteristics of the various accelerators must be the same, or nearly the same i.e. the accelerators must be beam-matched. During a period of nine months, eight Varian iX accelerators with 6 and 15 MV photon beams and 6-18 MeV electron beams (only four of the eight) were installed at our clinic. All accelerators fulfilled the vendor-defined "fine beam-match" criteria, and a more extensive set of measurements was carried out during commissioning. The measured absorbed dose data for each accelerator were compared with the first accelerator, chosen as reference, and the TPS calculations. Two of the eight accelerators showed a larger discrepancy for the 15 MV beam not revealed by the vendor-defined acceptance criteria, whereas the other six accelerators were satisfactorily matched. The beam-matching acceptance criteria defined by the vendor are not strict enough to guarantee optimal beam-match. Deviations related to dose calculations and to beam-matched accelerators may add up. The safest and most practical way to ensure that all accelerators are within clinical acceptable accuracy is to include TPS calculations in the evaluation. Further, comparisons between measurements and calculations should be done in absolute dose terms.