Deterioration in health-related quality of life (HRQOL) is frequently observed after surgery for stage I non–small-cell lung cancer. As stereotactic ablative radiotherapy (SABR) can result in local ...control percentages exceeding 90%, we studied baseline and post-treatment HRQOL in SABR patients.
HRQOL data were collected prospectively using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire in 382 consecutive patients treated with SABR. Patients were referred from 68 Dutch centers, with 86% judged unfit for surgery, and 14% declining surgery. An SABR dose of 60 Gy was delivered in three-, five-, or eight treatment fractions, depending on tumor diameter and location. HRQOL data were available for 382 patients at baseline (pre-SABR), and for 282, 212, 144, 56, and 43 patients at 3, 6, 12, 18, and 24 months post-SABR, respectively.
Median survival was 40 months, with a 2-year survival of 66%. Local, regional, and distant failure percentages at 2 years were 6%, 13%, and 22%, respectively. Mean baseline global HRQOL and physical functioning scores were 62.9 ± 1.1 and 61.7 ± 1.1, respectively. Baseline symptom scores were highest for dyspnea (47.1 ± 1.7) and fatigue (37.4 ± 1.3). Except for a nonsignificant decrease in 2 to 3 points per year in physical functioning, no statistically or clinically significant worsening of any of the HRQOL functioning or symptom scores at any follow-up time point was observed.
Patients referred for SABR have substantially worse baseline HRQOL scores than those reported in the surgical literature. Clinically relevant deteriorations in HRQOL subscale scores were not observed after SABR.
Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal ...tissue is the cornerstone of reducing toxicity. Advances in physical targeting and dose-shaping technology have helped to achieve this. FLASH RT is a promising, novel treatment technique that seeks to exploit a potential normal tissue-sparing effect of ultra-high dose rate irradiation. A significant body of in vitro and in vivo data has highlighted a decrease in acute and late radiation toxicities, while preserving the radiation effect in tumor cells. The underlying biological mechanisms of FLASH RT, however, remain unclear. Three main mechanisms have been hypothesized to account for this differential FLASH RT effect between the tumor and healthy tissue: the oxygen depletion, the DNA damage, and the immune-mediated hypothesis. These hypotheses and molecular mechanisms have been evaluated both in vitro and in vivo. Furthermore, the effect of ultra-high dose rate radiation with extremely short delivery times on the dynamic tumor microenvironment involving circulating blood cells and immune cells in humans is essentially unknown. Therefore, while there is great interest in FLASH RT as a means of targeting tumors with the promise of an increased therapeutic ratio, evidence of a generalized FLASH effect in humans and data to show that FLASH in humans is safe and at least effective against tumors as standard photon RT is currently lacking. FLASH RT needs further preclinical investigation and well-designed in-human studies before it can be introduced into clinical practice.
Stereotactic ablative radiotherapy (SABR) is currently not the guideline-recommended treatment for lung tumors measuring more than 5 cm. However, improvements in radiotherapy techniques have led to ...increasing use of SABR for larger tumors.
We analyzed the clinical outcomes in patients with a primary or recurrent NSCLC measuring more than 5 cm and treated with five or eight fractions of SABR at our center. Patients who had prior thoracic radiotherapy were excluded.
A total of 63 consecutive patients with a median tumor diameter of 5.8 cm (range 5.1–10.4) were identified; 81% had T2N0 disease and 18% had T3N0 disease. The median Charlson comorbidity index was 2 (range 0–6). After a median follow-up of 54.7 months, median survival was 28.3 months. Disease-free survival at 2 years was 82.1%, and the local, regional, and distant control rates at 2 years were 95.8%, 93.7%, and 83.6%, respectively. An out-of-field distant recurrence at one or more sites was the most common pattern of failure (10%). Grade 3 or higher toxicity was recorded in 30% of patients, with radiation pneumonitis being the most common toxicity (19%). A likely (n = 4) or possible (n = 8) treatment-related death was scored in 19% of patients. There was preexisting interstitial lung disease in eight patients (13%), with fatal toxicity developing in five of them (63%).
Lung SABR in tumors larger than 5 cm resulted in high local control rates and acceptable survival outcomes in a patient population with appreciable comorbidity. Patients with interstitial lung disease should be considered a very high-risk population for SABR.
Stereotactic ablative radiotherapy is a guideline-recommended treatment for early stage non–small-cell lung cancer. We report on incidence and salvage of local recurrences (LR) and second primary ...lung cancers (SPLC) in a large series of patients with long-term follow-up, to generate data for evidence-based follow-up regimens.
We excluded all patients with double tumors, TNM-stages other than T1-T2N0M0, biologically effective dose less than 100 Gy10 and previous treatment for the index tumor from our institutional database. LR was defined as recurrence in/adjacent to the planning target volume. A diagnosis of SPLC was determined using criteria described by Martini et al.
The 855 patients included had a median follow-up of 52 months. Forty-six patients developed LR after a median of 22 months (range 7–87 months). Actuarial local control rates at 3 and 5 years were 92.4% and 90.9%, respectively. Fifty-four percent had isolated LR and 13% had LR in combination with regional recurrences. Ten patients underwent radical salvage treatment; surgery (N = 6), high-dose radiotherapy (N = 3), or chemoradiation (N = 1). Median overall survival following LR was 13 months, but it was 36 months in patients who underwent radical salvage. A SPLC was diagnosed in 79 patients, after a median interval of 34 months. Actuarial cumulative incidences of SPLC at 3 and 5 years were 11.7% and 16.7%, respectively. Radical salvage for SPLC was performed in 63 patients (80%).
Both the timing of LR and persistent risk of SPLC serve as rationale for long-term follow-up using computed tomography scans in patients fit enough to undergo any radical treatment.
Purpose
A three-dimensional deep generative adversarial network (GAN) was used to predict dose distributions for locally advanced head and neck cancer radiotherapy. Given the labor- and ...time-intensive nature of manual planning target volume (PTV) and organ-at-risk (OAR) segmentation, we investigated whether dose distributions could be predicted without the need for fully segmented datasets.
Materials and methods
GANs were trained/validated/tested using 320/30/35 previously segmented CT datasets and treatment plans. The following input combinations were used to train and test the models: CT-scan only (C); CT+PTVboost/elective (CP); CT+PTVs+OARs+body structure (CPOB); PTVs+OARs+body structure (POB); PTVs+body structure (PB). Mean absolute errors (MAEs) for the predicted dose distribution and mean doses to individual OARs (individual salivary glands, individual swallowing structures) were analyzed.
Results
For the five models listed, MAEs were 7.3 Gy, 3.5 Gy, 3.4 Gy, 3.4 Gy, and 3.5 Gy, respectively, without significant differences among CP-CPOB, CP-POB, CP-PB, among CPOB-POB. Dose volume histograms showed that all four models that included PTV contours predicted dose distributions that had a high level of agreement with clinical treatment plans. The best model CPOB and the worst model PB (except model C) predicted mean dose to within ±3 Gy of the clinical dose, for 82.6%/88.6%/82.9% and 71.4%/67.1%/72.2% of all OARs, parotid glands (PG), and submandibular glands (SMG), respectively. The R
2
values (0.17/0.96/0.97/0.95/0.95) of OAR mean doses for each model also indicated that except for model C, the predictions correlated highly with the clinical dose distributions. Interestingly model C could reasonably predict the dose in eight patients, but on average, it performed inadequately.
Conclusion
We demonstrated the influence of the CT scan, and PTV and OAR contours on dose prediction. Model CP was not statistically different from model CPOB and represents the minimum data statistically required to adequately predict the clinical dose distribution in a group of patients.
•MR-guided radiotherapy was performed in locally advanced pancreatic cancer (LAPC).•Plan re-optimization for LAPC is found to be beneficial in half of fractions.•Adaptation is mainly relevant if ...distance between tumor and organs-at-risk is ≤3 mm.
MR-guided radiation therapy (MRgRT) with daily plan adaptation is a novel but time- and resource-intensive treatment for locally advanced pancreatic cancer (LAPC). We analyzed the benefit in target coverage and organ-at-risk (OAR) sparing of daily plan adaptation in 36 consecutive LAPC patients treated with MRgRT to 40 Gy in 5 fractions.
Adaptive planning was assessed for 180 fractions by comparing non-adapted plans with re-optimized plans using (a) GTV coverage and OAR high-doses, and (b) compliance with institutional objectives for GTV coverage and high-dose OAR constraints. Using these criteria, plan adaptation for each fraction was characterized as “not needed”, “beneficial”, or “no benefit”. Decision-tree analysis was performed to identify subgroups most likely or not to benefit from routine plan adaptation.
The percentage of plans fulfilling institutional constraints increased from 43.9% (non-adapted plans) to 83.3% after online plan adaptation, with significant improvements in GTV coverage and lower V33Gy OAR doses. Adaptive re-optimization was found to be “not needed” in 80 fractions (44.4%), “beneficial” in 95 fractions (52.8%) and of “no benefit” in 5 fractions (2.8%). Decision-tree analysis identified a grouping based on distance from tumor to OAR of ≤3 mm and GTV size, respectively, to be the major determinants for the benefit of daily plan adaptation.
MRgRT with daily plan adaptation for LAPC was of benefit in approximately half of fractions, improving target coverage and OAR sparing. Plan adaptation appeared to be relevant mainly in cases where the GTV to adjacent OAR distance was ≤3 mm.
Spine stereotactic body radiation therapy (SBRT) requires high positioning accuracy and a stable patient to maximize target coverage and reduce excessive irradiation to organs at risk. Positional ...verification during spine SBRT delivery helps to ensure accurate positioning for all patients. We report our experience with noninvasive 3-dimensional target position monitoring during volumetric modulated arc therapy of spine metastases in nonimmobilized patients positioned using only a thin mattress and simple arm and knee supports.
Fluoroscopic planar kV images were acquired at 7 frames/s using the on-board imaging system during volumetric modulated arc therapy spine SBRT. Template matching and triangulation were used to track the target in vertical, longitudinal, and lateral directions. If the tracking trace deviated >1 mm from the planned position in ≥1 direction, treatment was manually interrupted and 6-dimensional cone beam computed tomography (CBCT)-based couch correction was performed. Tracking data were used to retrospectively analyze the target position. Positional data, agreement with CBCT, correlation between position of the couch and direction of any positional correction, and treatment times were analyzed.
In total, 175 fractions were analyzed. Delivery was interrupted 83 times in 66 fractions for a deviation >1 mm. In 97% of cases the difference between tracking data and subsequent clinical shift performed after the CBCT match was ≤0.5 mm. Lateral/longitudinal shift performed after intervention correlated with the couch roll/pitch at the start of treatment (correlation coefficient, -0.63/0.53). Mean (SD; range) time between start of first imaging and end of the last arc was 15.2 minutes (5.1; 7.6-36.3).
Spine tracking during irradiation can be used to prompt an intervention CBCT scan and repositioning so that a spine SBRT target deviates by ≤1 mm from the planned position, even in nonimmobilized patients. kV tracking and CBCT are in good agreement. The data support verification CBCT after all 6 degrees-of-freedom positional corrections in nonimmobilized spine SBRT patients.
Glioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has ...been associated with increased survival and resistance to therapy. The aim of this study is to investigate the effects of AKT inhibition in combination with the current standard of care which consists of irradiation and temozolomide (TMZ) on human malignant glioma cells growing adherent and as multicellular spheroids in vitro.
The effects of the allosteric inhibitor MK2206 combined with irradiation and TMZ were assessed on glioma cells growing adherent and as multicellular 3D spheroids. The interaction was studied on proliferation, clonogenic cell survival, cell invasion, -migration and on expression of key proteins in the PI3K-AKT pathway by western blot.
A differential effect was found at low- (1 μM) and high dose (10 μM) MK2206. At 1 μM, the inhibitor reduced phosphorylation of Thr308 and Ser473 residues of AKT in both adherent cells and spheroids. Low dose MK2206 delayed spheroid growth and sensitized spheroids to both irradiation and TMZ in a synergistic way (Combination index <0.35). In contrast, neither low nor high dose MK2206 did enhance therapy sensitivity in adherent growing cells. Effective inhibition of invasion and migration was observed only at higher doses of MK2206 (>5 μM).
The data show that a 3D spheroid model show different sensitivity to irradiation when combined with AKT inhibition. Thereby we show that MK2206 has potential synergistic efficacy to the current standard of care for glioma patients.
Abstract Purpose To study the dosimetric predictors of early clinical toxicity following SBRT in patients with lung tumors and planning target volumes (PTV) exceeding 80 cm3. Methods Eighteen ...consecutive patients who were treated using volumetric modulated arc therapy (RapidArc™) were assessed. All were either unfit or refused to undergo surgery or chemoradiotherapy. PTV planning objectives were as used in the ROSEL study protocol. Clinical toxicity was scored using Common Toxicity Criteria AE4.0. Lung volumes receiving 5, 10, 15, and 20 Gy ( V5 , V10 , V15 and V20 ) and mean lung dose were assessed and correlated to symptomatic radiation pneumonitis (RP). Results Median age, age-adjusted Charlson-comorbidity score and PTV size were 74, 7.5 and 137 cm3 , respectively. At a median follow-up of 12.8 months, 8 deaths were recorded: 5 arising from comorbidity, 2 were potentially treatment-related and 1 had local recurrence. RP was reported in 5 patients (grade 2 in 3 and grade 3 in 2). All RP occurred in plans without a high priority optimization objective on contralateral lung. Acute RP was best predicted by contralateral lung V5 ( p < 0.0001). Conclusion After SBRT using RapidArc in lung tumors >80 cm3 , the contralateral lung V5 best predicts RP. Limiting contralateral lung V5 to <26% may reduce acute toxicity.
Considering the dismal survival rate, novel therapeutic strategies are warranted to improve the outcome of pancreatic ductal adenocarcinoma (PDAC). Combining nanotechnology for delivery of ...chemotherapeutics—preferably radiosensitizing agents—is a promising approach to enhance the therapeutic efficacy of chemoradiation. We assessed the effect of biodegradable ultrasmall-in-nano architectures (NAs) containing gold ultra-small nanoparticles (USNPs) enclosed in silica shells loaded with cisplatin prodrug (NAs-cisPt) combined with ionizing radiation (IR). The cytotoxic effects and DNA damage induction were evaluated in PDAC cell lines (MIA PaCa2, SUIT2-028) and primary culture (PDAC3) in vitro and in the chorioallantoic membrane (CAM) in ovo model. Unlike NAs, NAs-cisPt affected the cell viability in MIA PaCa2 and SUIT2-028 cells. Furthermore, NAs-cisPt showed increased γH2AX expression up to 24 h post-IR and reduced β-globin amplifications resulting in apoptosis induction at DNA and protein levels. Similarly, combined treatment of NAs-cisPt + IR in PDAC3 and SUIT2-028 CAM models showed enhanced DNA damage and apoptosis leading to tumor growth delay. Our results demonstrate an increased cytotoxic effect of NAs-cisPt, particularly through its release of the cisplatin prodrug. As cisplatin is a well-known radiosensitizer, administration of cisplatin prodrug in a controlled fashion through encapsulation is a promising new treatment approach which merits further investigation in combination with other radiosensitizing agents.
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