Risk factors for cognitive impairment in radically treated stage III NSCLC: Secondary findings of the NVALT-11 study.

AIM: To identify risk factors for self-reported cognitive impairment in radically treated stage III non-small cell lung cancer (NSCLC). METHODS: Cognitive functioning was assessed using the EORTC-QLQ-C30 at seven pre-specified time points in the phase III NVALT-11 trial (observation versus prophylactic cranial irradiation [PCI] in stage III NSCLC treated with chemo-radiotherapy ± surgery). Cognition was analyzed as binary (impairment or not) and continuous outcome, respectively, using generalized estimating equation (GEE) before and after multiple imputation. A score < 75 was defined as cognitive impairment. A mean difference by < 10, 10-<20, ≥ 20 points was regarded as of no, moderate, and large clinical effect, respectively. We categorized the cognitive impairment into four types based on changes over time: sustained, reversible, recurring, and alternating. RESULTS: In the no-PCI arm, 43/84 [51.2%] reported cognitive impairment at least once, of which 31.4% were sustained, 25.7% reversible, 28.6% recurring, and 14.3% alternating. Results were similar in the PCI arm. Cognitive functioning at baseline was comparable in two arms and a score < 75 was a significant risk factor with large effect for subsequent cognitive impairment (no-PCI: ß = -23.30, p < 0.001; PCI arm: ß = -22.34, p < 0.001; All: ß = -23.47, p < 0.001). Younger age (≤60y), squamous histology, and PCI were risk factors without clinical relevance (ß > -10, p < 0.05). Cognitive functioning declined over time (ß = -0.26, p = 0.001) except for patients with cognitive impairment at baseline (ß = 0.141, p = 0.33). CONCLUSION: Cognitive impairment is dynamic over time with four types. Baseline cognitive impairment (score < 75) is the most important risk factor for subsequent cognitive impairment in stage III NSCLC. Note: This work has been partly reported as an oral presentation at the ESTRO 2021 meeting (OC-0176).

Investigation of the added value of CT-based radiomics in predicting the development of brain metastases in patients with radically treated stage III NSCLC.

Introduction: Despite radical intent therapy for patients with stage III non-small-cell lung cancer (NSCLC), cumulative incidence of brain metastases (BM) reaches 30%. Current risk stratification methods fail to accurately identify these patients. As radiomics features have been shown to have predictive value, this study aims to develop a model combining clinical risk factors with radiomics features for BM development in patients with radically treated stage III NSCLC. Methods: Retrospective analysis of two prospective multicentre studies. Inclusion criteria: adequately staged [18F-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT), contrast-enhanced chest CT, contrast-enhanced brain magnetic resonance imaging/CT] and radically treated stage III NSCLC, exclusion criteria: second primary within 2 years of NSCLC diagnosis and prior prophylactic cranial irradiation. Primary endpoint was BM development any time during follow-up (FU). CT-based radiomics features (N = 530) were extracted from the primary lung tumour on 18-FDG-PET-CT images, and a list of clinical features (N = 8) was collected. Univariate feature selection based on the area under the curve (AUC) of the receiver operating characteristic was performed to identify relevant features. Generalized linear models were trained using the selected features, and multivariate predictive performance was assessed through the AUC. Results: In total, 219 patients were eligible for analysis. Median FU was 59.4 months for the training cohort and 67.3 months for the validation cohort; 21 (15%) and 17 (22%) patients developed BM in the training and validation cohort, respectively. Two relevant clinical features (age and adenocarcinoma histology) and four relevant radiomics features were identified as predictive. The clinical model yielded the highest AUC value of 0.71 (95% CI: 0.58-0.84), better than radiomics or a combination of clinical parameters and radiomics (both an AUC of 0.62, 95% CIs of 0.47-076 and 0.48-0.76, respectively). Conclusion: CT-based radiomics features of primary NSCLC in the current setup could not improve on a model based on clinical predictors (age and adenocarcinoma histology) of BM development in radically treated stage III NSCLC patients.

Optimal delineation of the clinical target volume for thymomas in the post-resection setting: A multi-center study.

BACKGROUND: The definition of the clinical target volume (CTV) for post-operative radiotherapy (PORT) for thymoma is largely unexplored. The aim of this study was to analyze the difference in CTV delineation between radiation oncologists (RTO) and surgeons. METHODS: This retrospective multi-center study enrolled 31 patients who underwent PORT for a thymoma from five hospitals. Three CTVs were delineated per patient: one CTV by the RTO, one CTV by the surgeon (blinded to the results of the RTO) and a joint CTV after collaboration. Volumes (cm3), Hausdorff distances (HD) and Dice similarity coefficients (DSC) were analyzed. RESULTS: RTO delineated significantly bigger CTVs than surgeons (mean: 93.9 ± 63.1, versus 57.9 ± 61.3 cm3, p = 0.003). Agreement was poor between RO and surgeons, with a low mean DSC (0.34 ± 0.21) and high mean HD of 4.5 (±2.2) cm. Collaborative delineation resulted in significantly smaller volumes compared to RTO (mean 57.1 ± 58.6 cm3, p < 0.001). A mean volume of 18.9 (±38.1) cm3 was included in joint contours, but missed by RTO. Conversely, a mean volume of 55.7 (±39.9) cm3 was included in RTO's delineations, but not in the joint delineations. CONCLUSIONS: To the best of our knowledge, this is the first study investigating CTV definition in thymoma. We demonstrated a significant variability between RTO and surgeons. Joint delineation prompted revisions in smaller CTV as well as favoring the surgeons' judgement, suggesting that surgeons provided relevant insight into other risk areas than RTO. We recommend a multidisciplinary approach to PORT for thymomas in clinical practice.

Development and external validation of a nomogram to predict overall survival following stereotactic body radiotherapy for early-stage lung cancer.

BACKGROUND: Prognostication tools for early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT) are currently lacking. The purpose of this study was to develop and externally validate a nomogram to predict overall survival in individual patients with peripheral early-stage disease. METHODS: A total of 587 NSCLC patients treated with biologically effective dose > 100 Gy10 were eligible. A Cox proportional hazards model was used to build a nomogram to predict 6-month, 1-year, 3-year and 5-year overall survival. Internal validation was performed using bootstrap sampling. External validation was performed in a separate cohort of 124 NSCLC patients with central tumors treated with SBRT. Discriminatory ability was measured by the concordance index (C-index) while predictive accuracy was assessed with calibration slope and plots. RESULTS: The resulting nomogram was based on six prognostic factors: age, sex, Karnofsky Performance Status, operability, Charlson Comorbidity Index, and tumor diameter. The slope of the calibration curve for nomogram-predicted versus Kaplan-Meier-estimated overall survival was 0.77. The C-index of the nomogram (corrected for optimism) was moderate at 0.64. In the external validation cohort, the model yielded a C-index of 0.62. CONCLUSIONS: We established and validated a nomogram which can provide individual survival predictions for patients with early stage lung cancer treated with SBRT. The nomogram may assist patients and clinicians with treatment decision-making.

Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study.

Purpose The purpose of the current study was to investigate whether prophylactic cranial irradiation (PCI) reduces the incidence of symptomatic brain metastases in patients with stage III non-small-cell lung cancer (NSCLC) treated with curative intention. Patients and Methods Patients with stage III NSCLC-staged with a contrast-enhanced brain computed tomography or magnetic resonance imaging-were randomly assigned to either observation or PCI after concurrent/sequential chemoradiotherapy with or without surgery. The primary end point-development of symptomatic brain metastases at 24 months-was defined as one or a combination of key symptoms that suggest brain metastases-signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms-and magnetic resonance imaging or computed tomography demonstrating the existence of brain metastasis. Adverse effects, survival, quality of life, quality-adjusted survival, and health care costs were secondary end points. Results Between 2009 and 2015, 175 patients were randomly assigned: 87 received PCI and 88 underwent observation only. Median follow-up was 48.5 months (95% CI, 39 to 54 months). Six (7.0%) of 86 patients in the PCI group and 24 (27.2%) of 88 patients in the control group had symptomatic brain metastases ( P = .001). PCI significantly increased the time to develop symptomatic brain metastases (hazard ratio, 0.23; [95% CI, 0.09 to 0.56]; P = .0012). Median time to develop brain metastases was not reached in either arm. Overall survival was not significantly different between both arms. Grade 1 and 2 memory impairment (26 of 86 v seven of 88 patients) and cognitive disturbance (16 of 86 v three of 88 patients) were significantly increased in the PCI arm. Quality of life was only decreased 3 months post-PCI and was similar to the observation arm thereafter. Conclusion PCI significantly decreased the proportion of patients who developed symptomatic brain metastases with an increase of low-grade toxicity.

Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial.

INTRODUCTION: In ES-SCLC patients with residual intrathoracic disease after first-line chemotherapy, the addition of thoracic radiotherapy reduces the risk of intrathoracic recurrence, and improves 2-year survival. To identify patient subgroups for future trials investigating higher dose (extra)thoracic radiotherapy, we investigated the prognostic importance of number and sites of metastases in patients included in the CREST trial. MATERIALS/ METHODS: Additional data on sites and numbers of metastases were collected from individual records of 260 patients from the top 9 recruiting centers in the randomized CREST trial (53% of 495 study patients), which compared thoracic radiotherapy (TRT) to no TRT in ES-SCLC patients after any response to chemotherapy. All patients received prophylactic cranial irradiation. RESULTS: The clinical characteristics and outcomes of the 260 patients analyzed here did not differ significantly from that of the other 235 patients included in the CREST trial, except that fewer patients had a WHO=0 performance status (24% vs 45%), and a higher proportion had WHO=2 (15% vs 5%; p<0.0001). No distant metastases were recorded in 5%, 39% had metastases confined to one organ, 34% to two, and 22% to three or more organ sites. Metastases were present in the liver (47%), bone (40%), lung (28%), extrathoracic (non-supraclavicular) lymph nodes (19%), supraclavicular nodes (18%), adrenals (17%) and other sites (12%). The OS (p=0.02) and PFS (p=0.04) were significantly better in patients with 2 or fewer metastases, with OS significantly worse if liver (p=0.03) and/or bone metastases (p=0.04) were present. DISCUSSION: This analysis of patients recruited from the top 9 accruing centers in the CREST trial suggests that future studies evaluating more intensive thoracic and extra-thoracic radiotherapy in ES-SCLC should focus on patients with fewer than 3 distant metastases.

Toxicity and quality of life after high-dose-rate brachytherapy as monotherapy for low- and intermediate-risk prostate cancer.

BACKGROUND AND PURPOSE: The use of HDR brachytherapy (HDR-BT) as monotherapy for prostate cancer (PC) is increasing worldwide with good tumour control rates and acceptable toxicity. We report our results on toxicity and quality of life (QoL) after HDR-BT monotherapy for PC patients. MATERIALS AND METHODS: 166 low- and intermediate-risk localized PC patients were treated with HDR-BT to a total dose of 38Gy in four fractions. Genitourinary (GU) and gastrointestinal (GI) toxicities were prospectively assessed using EORTC-RTOG questionnaires and physicians charts. QoL was evaluated using EORTC QLQ-PR25 questionnaires. RESULTS: Three months after treatment, acute GU and GI toxicities were reported in 10.8% and 7.2%. Acute toxicity resolved within two months in the majority of patients (61%). Late grade ⩾ 2 GU and GI toxicity were reported in 19.7% and 3.3% of patients 12 months after HDR-BT. Mean QLQ-PR25 scores showed clinically relevant changes from baseline for urinary symptoms and sexual functioning. With a mean follow-up of 35 months, biochemical failure was observed in 2.4%. Overall survival at 60 months was 93.6% and cancer-specific survival was 100%. CONCLUSIONS: HDR-BT monotherapy for localized PC showed excellent clinical outcome and acceptable acute and late toxicity. Urinary symptoms and sexual function QoL decreased after treatment.

Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial.

BACKGROUND: Most patients with extensive stage small-cell lung cancer (ES-SCLC) who undergo chemotherapy, and prophylactic cranial irradiation, have persistent intrathoracic disease. We assessed thoracic radiotherapy for treatment of this patient group. METHODS: We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. We enrolled patients with WHO performance score 0-2 and confirmed ES-SCLC who responded to chemotherapy. They were randomly assigned (1:1) to receive either thoracic radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy. All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Secondary endpoints included progression-free survival. This study is registered with the Nederlands Trial Register, number NTR1527. FINDINGS: We randomly assigned 498 patients between Feb 18, 2009, and Dec 21, 2012. Three withdrew informed consent, leaving 247 patients in the thoracic radiotherapy group and 248 in the control group. Mean interval between diagnosis and randomisation was 17 weeks. Median follow-up was 24 months. Overall survival at 1 year was not significantly different between groups: 33% (95% CI 27-39) for the thoracic radiotherapy group versus 28% (95% CI 22-34) for the control group (hazard ratio [HR] 0.84, 95% CI 0.69-1.01; p=0.066). However, in a secondary analysis, 2-year overall survival was 13% (95% CI 9-19) versus 3% (95% CI 2-8; p=0.004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0.73, 95% CI 0.61-0.87; p=0.001). At 6 months, progression-free survival was 24% (95% CI 19-30) versus 7% (95% CI 4-11; p=0.001). We recorded no severe toxic effects. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (three vs four). INTERPRETATION: Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. FUNDING: Dutch Cancer Society (CKTO), Dutch Lung Cancer Research Group, Cancer Research UK, Manchester Academic Health Science Centre Trials Coordination Unit, and the UK National Cancer Research Network.

High-dose-rate brachytherapy and external-beam radiotherapy for hormone-naïve low- and intermediate-risk prostate cancer: a 7-year experience.

PURPOSE: To report clinical outcomes and early and late complications in 264 hormone-naïve patients with low- and intermediate-risk prostate cancer treated with high-dose-rate brachytherapy (HDR-BT) in combination with external-beam radiotherapy (EBRT). METHODS AND MATERIALS: Between February 2000 and July 2007, 264 patients underwent HDR-BT in combination with EBRT as a treatment for their low- to intermediate-risk prostate cancer. The HDR-BT was performed using ultrasound-based implantation. The total HDR-BT dose was 18 Gy in 3 fractions within 24 h, with a 6-h minimum interval. The EBRT started 2 weeks after HDR-BT and was delivered in 25 fractions of 1.8 Gy to 45 Gy within 5 weeks. RESULTS: After a mean follow-up of 74.5 months, 4 patients (1.5%) showed prostate-specific antigen progression according to the American Society for Radiation Oncology definition and 8 patients (3%) according to the Phoenix definition. A biopsy-proven local recurrence was registered in 1 patient (0.4%), and clinical progression (bone metastases) was documented in 2 patients (0.7%). Seven-year actuarial freedom from biochemical failure was 97%, and 7-year disease-specific survival and overall survival were 100% and 91%, respectively. Toxicities were comparable to other series. CONCLUSIONS: Treatment with interstitial HDR-BT plus EBRT shows a low incidence of late complications and a favorable oncologic outcome after 7 years follow-up.

Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors.

PURPOSE: To assess local control, overall survival, and toxicity of four-dimensional, risk-adapted stereotactic body radiotherapy (SBRT) delivered while tracking respiratory motion in patients with primary and metastatic lung cancer located in the central chest. METHODS: Fifty-eight central lesions of 56 patients (39 with primary, 17 with metastatic tumors) were treated. Fifteen tumors located near the esophagus were treated with 6 fractions of 8 Gy. Other tumors were treated according to the following dose escalation scheme: 5 fractions of 9 Gy (n = 6), then 5 fractions of 10 Gy (n = 15), and finally 5 fractions of 12 Gy (n = 22). RESULTS: Dose constraints for critical structures were generally achieved; in 21 patients the coverage of the PTV was reduced below 95% to protect adjacent organs at risk. At a median follow-up of 23 months, the actuarial 2-years local tumor control was 85% for tumors treated with a BED >100 Gy compared to 60% for tumors treated with a BED ≤ 100 Gy. No grade 4 or 5 toxicity was observed. Acute grade 1-2 esophagitis was observed in 11% of patients. CONCLUSION: SBRT of central lung lesions can be safely delivered, with promising early tumor control in patients many of whom have severe comorbid conditions.

Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: clinical outcome.

PURPOSE: To report the clinical outcome of treatment using real-time tumor tracking for 70 patients with inoperable stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Seventy inoperable patients with peripherally located early-stage NSCLC were treated with 45 or 60 Gy in three fractions using CyberKnife. Pathology was available in 51% of patients. Thirty-nine patients had a T1-tumor and 31 had a T2-tumor. Markers were placed using the vascular, percutaneous intra-, or extra-pulmonary approach, depending on the risk of pneumothorax. RESULTS: The actuarial 2-year local control rate for patients treated with 60 Gy was 96%, compared to 78% for patients treated with a total dose of 45 Gy (p=0.197). All local recurrences (n=4) occurred in patients with T2-tumors. Overall survival for the whole group at two years was 62% and the cause specific survival was 85%. The median follow-up was 15 months. Grade 3 toxicity occurred in two patients (3%) after marker placement. Treatment-related late grade 3 toxicity occurred in 7 patients (10%). No grade > or = 4 toxicity occurred. CONCLUSION: Excellent local control of 96% at 1- and 2-years was achieved using 60 Gy in three fractions for NSCLC patients treated with the real-time tumor tracking. Toxicity was low.

HDR prostate monotherapy: dosimetric effects of implant deformation due to posture change between TRUS- and CT-imaging.

HDR monotherapy for prostate cancer consists of four fractions. The first fraction is delivered with online TRUS-based treatment planning. For the last three fractions the treatment plan is based on a CT-scan acquired in between fractions 1 and 2. The patient position (high lithotomy, rectal US probe) during TRUS-guided catheter implantation and first fraction differs from the patient position in the CT-scan and the remaining three fractions (lowered legs, no TRUS probe). This study describes the effect of posture changes on dose distributions when a plan designed for the TRUS anatomy is applied to the CT-scan anatomy. The aim is to quantify dosimetrical errors that would result from skipping the use of a planning CT-scan, and rely for all fractions on the TRUS plan. Such a procedure would substantially reduce the involved workload, and would increase patient comfort. For three prostate cancer patients, images were acquired during TRUS-guided catheter implantation. Furthermore, a CT-scan (no US probe in rectum, different position of legs) was acquired and matched with the TRUS set. On both TRUS and CT, prostate, urethra and rectum were delineated and all catheters were traced. For each patient, an optimized treatment plan was designed using TRUS images and contours. Catheters with obtained dwell positions of the TRUS plan were transferred individually to the catheter positions in the CT. Changes in dose distribution due to relocation of catheters were evaluated using DVHs. For all patients the dose distributions changed significantly due to rearrangement of the catheters, having most impact on the urethra (maximum observed change: 32% volume receiving > or = 120% of the prescribed dose) and a reduction of PTV coverage (6-28%). Implant deformation when changing from TRUS patient set-up to CT set-up affected negatively the quality of optimized treatment plans. Inclusion of more patients in this study was planned, but because of the observed strong negative effects it is already concluded that the TRUS plan cannot be used for the last three fractions with a deviating patient set-up.