Acute hospitalizations after proton therapy versus intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in the durvalumab era.

INTRODUCTION: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity-modulated radiotherapy (IMRT). METHODS: Patients with locally advanced non-small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90-day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan-Meier method was used for progression-free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. RESULTS: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p < .001) and had higher Charlson Comorbidity Index scores (p = .02). The PBT group received a lower mean heart dose (p < .0001), left anterior descending artery V15 Gy (p = .001), mean lung dose (p = .008), and effective dose to immune circulating cells (p < .001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38-0.81; p = .002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37-0.81; p = .003). There was no difference in other G3+ toxicities, progression-free survival, or overall survival. CONCLUSIONS: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed.

Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation.

PURPOSE: We assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. METHODS AND MATERIALS: This single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). RESULTS: Median age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0-22) and median heart mean dose was 8.7 Gy (IQR 4.6-14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. CONCLUSIONS: With modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

Early Cardiac Effects of Contemporary Radiation Therapy in Patients With Breast Cancer.

PURPOSE: To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD). METHODS AND MATERIALS: In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function. RESULTS: The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], -0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, -0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function. CONCLUSIONS: With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease.

Techniques for and uncertainties of MRI-based reconstruction of titanium tandem and ring brachytherapy applicators.

PURPOSE: Eliminating patient computed tomography (CT) scans for tandem and ring (T&R) brachytherapy can reduce overall procedure time and eliminates imaging dose. However, reconstructing titanium applicators in magnetic resonance imaging (MRI) is challenging. We evaluated the uncertainty of different applicator reconstruction workflows in MR-guided brachytherapy, and assessed the clinical impact of reconstruction uncertainties. METHODS AND MATERIALS: Titanium MRI-compatible T&Rs with aqueous gel in the buildup cap were reconstructed on CTs and MRIs to assess the uncertainties of four different workflows. Reconstruction was performed using (1) proton density-weighted MRIs with solid applicator from a library, (2) applicator-only reference CT fused with MRIs, (3) T2-weighted (T2W) MRIs following GEC-ESTRO guidelines, and (4) patient CTs fused with patient MRIs with in situ applicators. We evaluated dwell positions and plan quality differences using high-risk clinical target volume coverage, and EQD2 D2cc of rectum, sigmoid, bladder, and small bowel. RESULTS: The 2σ uncertainty for dwell positions for each workflow were (1) 2.7 mm for both ring and tandem, (2) 1.4 mm ring and 0.8 mm tandem, (3) 0.2 mm ring and 0.8 mm tandem, and (4) 1.9 mm ring and 0.4 mm tandem. Reconstruction uncertainties resulted in dose variations within acceptable levels (below 10%) except for (1) which resulted in larger dose to the rectum (20%). Dose uncertainties were similar between reference CT and patient CT. CONCLUSIONS: Reconstruction with a reference CT results in similar uncertainty to a patient CT. T2W MRI plans have acceptable uncertainty levels for the applicator reconstruction and resulting dose distributions.

Current State of Image Guidance in Radiation Oncology: Implications for PTV Margin Expansion and Adaptive Therapy.

Image guidance technology has evolved and seen widespread application in the past several decades. Advancements in the diagnostic imaging field have found new applications in radiation oncology and promoted the development of therapeutic devices with advanced imaging capabilities. A recent example is the development of linear accelerators that offer magnetic resonance imaging for real-time imaging and online adaptive planning. Volumetric imaging, in particular, offers more precise localization of soft tissue targets and critical organs which reduces setup uncertainty and permit the use of smaller setup margins. We present a review of the status of current imaging modalities available for radiation oncology and its impact on target margins and use for adaptive therapy.

Inter-centre variability of CT-based stopping-power prediction in particle therapy: Survey-based evaluation.

BACKGROUND AND PURPOSE: Stopping-power ratios (SPRs) are used in particle therapy to calculate particle range in patients. The heuristic CT-to-SPR conversion (Hounsfield Look-Up-Table, HLUT), needed for treatment planning, depends on CT-scan and reconstruction parameters as well as the specific HLUT definition. To assess inter-centre differences in these parameters, we performed a survey-based qualitative evaluation, as a first step towards better standardisation of CT-based SPR derivation. MATERIALS AND METHODS: A questionnaire was sent to twelve particle therapy centres (ten from Europe and two from USA). It asked for details on CT scanners, image acquisition and reconstruction, definition of the HLUT, body-region specific HLUT selection, investigations of beam-hardening and experimental validations of the HLUT. Technological improvements were rated regarding their potential to improve SPR accuracy. RESULTS: Scan parameters and HLUT definition varied widely. Either the stoichiometric method (eight centres) or a tissue-substitute-only HLUT definition (three centres) was used. One centre combined both methods. The number of HLUT line segments varied widely between two and eleven. Nine centres had investigated influence of beam-hardening, often including patient-size dependence. Ten centres had validated their HLUT experimentally, with very different validation schemes. Most centres deemed dual-energy CT promising for improving SPR accuracy. CONCLUSIONS: Large inter-centre variability was found in implementation of CT scans, image reconstruction and especially in specification of the CT-to-SPR conversion. A future standardisation would reduce time-intensive institution-specific efforts and variations in treatment quality. Due to the interdependency of multiple parameters, no conclusion can be drawn on the derived SPR accuracy and its inter-centre variability.

A Single-institution Comparison of Cetuximab, Carboplatin, and Paclitaxel Induction Chemotherapy Followed by Chemoradiation (CRT) Versus CRT for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (LA-SCCHN).

OBJECTIVES: Comparisons of induction chemotherapy (IC) against upfront chemoradiation (CRT) for locally advanced head and neck cancer (LA-HNSCC) have demonstrated no differences except greater toxicity with IC. Effective induction regimens that are less toxic are therefore warranted. To inform future efforts with IC, we present our institutional experience comparing a less toxic IC regimen to CRT. METHODS: We included patients with LA-HNSCC treated with organ-preservation CRT (+/-induction) between 2008 and 2011. Patients were of age above 18 years, ECOG performance status 0-1, and had minimum 6 months follow-up. IC consisted of 8 weekly cycles of cetuximab, carboplatin, and paclitaxel followed by CRT. The CRT regimen was platinum based, with cetuximab reserved for patients contraindicated to receive platinum. RESULTS: Of 118 patients, 24 (20%) received IC and 94 (80%) received CRT. Median follow-up was 17 (IC) and 19 (CRT) months (P=0.05). There were no differences in toxicity between the groups. IC patients were more likely male, with more advanced tumor and nodal stage. Even when controlling for these factors, IC was still associated with worse locoregional control (HR=3.6, P=0.02), distant metastasis-free survival (HR=5.3, P=0.02), and overall survival (HR=5.1, P<0.01). CONCLUSIONS: IC patients had greater disease burden than those receiving CRT. IC was well tolerated, but with significant rates of locoregional and systemic failures. Given the retrospective nature of the study, our findings are not meant to be definitive or conclusive, but rather suggestive in directing future efforts with IC. For now, we favor CRT as the standard option for treatment of inoperable LA-HNSCC.

First Clinical Investigation of Cone Beam Computed Tomography and Deformable Registration for Adaptive Proton Therapy for Lung Cancer.

PURPOSE: An adaptive proton therapy workflow using cone beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT) scan. This can be followed by more accurate offline dose recalculation on the vCT scan, which can trigger a rescan CT (rCT) for replanning. METHODS AND MATERIALS: The workflow was tested retrospectively for 20 consecutive lung cancer patients. A diffeomorphic Morphon algorithm was used to generate the lung vCT by deforming the average planning CT onto the CBCT scan. An additional correction step was applied to account for anatomic modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated according to the water equivalent thickness (WET) and dose statistics and compared with those obtained on the rCT scan. The fast dose approximation consisted of warping the initial planned dose onto the vCT scan according to the changes in WET. The potential under- and over-ranges were assessed as a variation in WET at the target's distal surface. RESULTS: The range-corrected dose from the vCT scan reproduced clinical indicators similar to those of the rCT scan. The workflow performed well under different clinical scenarios, including atelectasis, lung reinflation, and different types of tumor response. Between the vCT and rCT scans, we found a difference in the measured 95% percentile of the over-range distribution of 3.4 ± 2.7 mm. The limitations of the technique consisted of inherent uncertainties in deformable registration and the drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomic or density changes in tumors with complex topology. CONCLUSIONS: A proton therapy workflow based on CBCT provided clinical indicators similar to those using rCT for patients with lung cancer with considerable anatomic changes.

Dosimetric impact of interfraction catheter movement and organ motion on MRI/CT guided HDR interstitial brachytherapy for gynecologic cancer.

PURPOSE: To determine the dosimetric impact of catheter movement for MRI/CT image guided high dose rate (HDR) interstitial brachytherapy (ISBT) for gynecologic cancers. MATERIALS AND METHODS: Ten patients were treated with HDR ISBT. The CTV and organs at risk were contoured using a postimplant MRI and CT. 5 fractions were delivered twice daily on 3 consecutive days. The first fraction was delivered on day 1 (d1), fraction 2-3 on d2 and fraction 4-5 on d3. MRI/CT was acquired prior to the second and fourth fractions. Four scenarios were modeled. (1) The d1 plan was applied to the d2 and d3 CT, using the updated catheter positions. (2) Replanning was performed for d2 and d3. (3) We applied the dwell positions/times from the d2 replan over the d3 CT and compared with a d3 CT replan. (4) Based on daily MRI, target volumes were recontoured and replanned. Dosimetry was analyzed for each plan and compared to the d1 dose distribution. RESULTS: (1) When using the d1 plan on the d2 and d3 CT with the updated catheter positions, the mean CTV D90 was reduced from 93.4% on d1 to 89.3% (p=0.08) on d2 and to 87.7% (p=0.005) on d3. (2) Replanning on d2 and d3 compensated for catheter movement, mean CTV D90 of 95.4% on d2 and 94.6% (p=0.36) on d3. (3) When compared to the replan of d2 applied on the d3 CT vs the d3 replan, there was no significant difference in coverage, mean CTV D90 of 90.9% (p=0.09). (4) Reoptimization based on daily MRI, significantly improved the CTV coverage for each day. The mean D2cc for the rectum was significantly higher with model 1 vs model 3 59.1±4.7 vs 60.9±4.8 (p=0.04) Gy EQD2. There were no significant differences in D2cc of bladder and sigmoid between models. CONCLUSIONS: Interfraction dosimetric changes significantly decreased the CTV coverage of the third day. Rather than replanning on each day, replanning on the day 2 CT before the second or third fraction would give an optimal solution that would compensate for interfraction catheter displacement.