Immunotherapy in unresectable stage III non-small-cell lung cancer: state of the art and novel therapeutic approaches.

The standard of care for patients with stage III non-small-cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT) followed by 1 year of adjuvant durvalumab. Despite the survival benefit granted by immunotherapy in this setting, only 1/3 of patients are alive and disease free at 5 years. Novel treatment strategies are under development to improve patient outcomes in this setting: different anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] antibodies after CCRT, consolidation immunotherapy after sequential chemoradiotherapy, induction immunotherapy before CCRT and immunotherapy concurrent with CCRT and/or sequential chemoradiotherapy. Cross-trial comparison is particularly challenging in this setting due to the different timing of immunotherapy delivery and different patients' inclusion and exclusion criteria. In this review, we present the results of clinical trials investigating immune therapy in unresectable stage III NSCLC and discuss in-depth their biological rationale, their pitfalls and potential benefits. Particular emphasis is placed on the potential mechanisms of synergism between chemotherapy, radiation therapy and different monoclonal antibodies, and how this affects the tumor immune microenvironment. The designs and questions tackled by ongoing clinical trials are also discussed. Last, we address open questions and unmet clinical needs, such as the necessity for predictive biomarkers (e.g. radiomics and circulating tumor DNA). Identifying distinct subsets of patients to tailor anticancer treatment is a priority, especially in a heterogeneous disease such as stage III NSCLC.

Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade ≥3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer.

Concurrent chemotherapy and radiotherapy (CCRT) followed by durvalumab immune therapy in appropriate patients is considered to be the standard of care in most fit stage III non-small-cell lung cancer (NSCLC) patients. However, CCRT is a toxic treatment that affects all organ systems and may cause acute and permanent side effects, some of which may be lethal. Supportive care is therefore of utmost importance in this clinical setting. A group of experts from the European Society for Therapeutic Radiology and Oncology (ESTRO) and the European Society of Medical Oncology (ESMO) identified the following items of importance for further improvement of supportive care: smoking cessation; nutrition before and during CCRT (including treatment and prevention of anorexia); physical exercise before and during CCRT; prevention and treatment of acute esophagitis and dysphagia; treatment of cough and dyspnea; treatment of skin reactions; treatment of fatigue; prophylaxis of nausea and emesis; prevention, diagnosis, and treatment of cardiac disease and damage; and optimization of radiotherapy techniques and chemotherapy adjustments to reduce toxicity in the era of immune therapy. The resulting recommendations are summarized in this manuscript and knowledge gaps identified, in which future investments are needed to improve supportive care and hence quality of life and survival for our stage III NSCLC patients.

Tumor regression during radiotherapy for non-small cell lung cancer patients using cone-beam computed tomography images.

PURPOSE: Previous literature has reported contradicting results regarding the relationship between tumor volume changes during radiotherapy treatment for non-small cell lung cancer (NSCLC) patients and locoregional recurrence-free rate or overall survival. The aim of this study is to validate the results from a previous study by using a different volume extraction procedure and evaluating an external validation dataset. METHODS: For two datasets of 94 and 141 NSCLC patients, gross tumor volumes were determined manually to investigate the relationship between tumor volume regression and locoregional control using Kaplan-Meier curves. For both datasets, different subgroups of patients based on histology and chemotherapy regimens were also investigated. For the first dataset (n = 94), automatically determined tumor volumes were available from a previously published study to further compare their correlation with updated clinical data. RESULTS: A total of 70 out of 94 patients were classified into the same group as in the previous publication, splitting the dataset based on median tumor regression calculated by the two volume extraction methods. Non-adenocarcinoma patients receiving concurrent chemotherapy with large tumor regression show reduced locoregional recurrence-free rates in both datasets (p < 0.05 in dataset 2). For dataset 2, the opposite behavior is observed for patients not receiving chemotherapy, which was significant for overall survival (p = 0.01) but non-significant for locoregional recurrence-free rate (p = 0.13). CONCLUSION: The tumor regression pattern observed during radiotherapy is not only influenced by irradiation but depends largely on the delivered chemotherapy schedule, so it follows that the relationship between patient outcome and the degree of tumor regression is also largely determined by the chemotherapy schedule. This analysis shows that the relationship between tumor regression and outcome is complex, and indicates factors that could explain previously reported contradicting findings. This, in turn, will help guide future studies to fully understand the relationship between tumor regression and outcome.

Current status of immune checkpoint inhibition in early-stage NSCLC.

Immune checkpoint inhibition (ICI) immunotherapy has revolutionized the approach to metastatic non-small-cell lung cancer (NSCLC). In particular, antibodies blocking the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand (PD-L1) are associated with higher response rates, improved overall survival and better tolerability as compared with conventional cytotoxic chemotherapy. Recently, ICI has moved from the second-line to the first-line setting for many patients with non-oncogene-addicted NSCLC, either alone or in combination with chemotherapy. The next logical step is to examine this therapy in patients with non-metastatic NSCLC to improve long-term overall survival and cure rates. For patients with unresectable stage III NSCLC, ICI with durvalumab after concurrent chemoradiotherapy has brought a major improvement in 2-year progression-free and overall survival, which holds promise for an improved cure rate. As the relapse pattern in patients with completely resected early-stage NSCLC is predominantly systemic, high expectations rest on the integration of ICI therapy in their treatment approach. A large number of studies with adjuvant or neo-adjuvant ICI are ongoing and will be discussed here. The advent of stereotactic ablative radiotherapy has brought a valid alternative treatment of patients unfit for or not willing to undergo surgery. Data on combining systemic therapy and stereotactic ablative radiotherapy are virtually non-existent, but there is a strong biological rationale to combine radiotherapy and ICI therapy. Early findings in small feasibility studies are promising and now need to be explored in well-designed phase III trials.

Multi-center reproducibility of structural, diffusion tensor, and resting state functional magnetic resonance imaging measures.

PURPOSE: The aim of this study is to assess multi-center reproducibility and longitudinal consistency of MRI imaging measurements, as part of a phase III longitudinal multi-center study comparing the neurotoxic effect following prophylactic cranial irradiation with hippocampal avoidance (HA-PCI), in comparison with conventional PCI in patients with small-cell lung cancer. METHODS: Harmonized MRI acquisition protocols from six participating sites and two different vendors were compared using both physical and human phantoms. We assessed variability across sites and time points by evaluating various phantoms and data including hippocampal volume, diffusion metrics, and resting-state fMRI, from two healthy volunteers. RESULTS: We report average coefficients of variation (CV) below 5% for intrascanner, intravendor, and intervendor reproducibility for both structural and diffusion imaging metrics, except for diffusion metrics obtained from tractography with average CVs ranging up to 7.8%. Additionally, resting-state fMRI showed stable temporal SNR and reliable generation of subjects DMN across vendors and time points. CONCLUSION: These findings indicate that the presented multi-site MRI acquisition protocol can be used in a longitudinal study design and that pooling of the acquired data as part of the phase III longitudinal HA-PCI project is possible with careful monitoring of the results of the half-yearly QA assessment to follow-up on potential scanner-related longitudinal changes in image quality.

Does selective pleural irradiation of malignant pleural mesothelioma allow radiation dose escalation? : A planning study.

BACKGROUND: After lung-sparing radiotherapy for malignant pleural mesothelioma (MPM), local failure at sites of previous gross disease represents the dominant form of failure. Our aim is to investigate if selective irradiation of the gross pleural disease only can allow dose escalation. MATERIALS AND METHODS: In all, 12 consecutive stage I-IV MPM patients (6 left-sided and 6 right-sided) were retrospectively identified and included. A magnetic resonance imaging-based pleural gross tumor volume (GTV) was contoured. Two sets of planning target volumes (PTV) were generated for each patient: (1) a "selective" PTV (S-PTV), originating from a 5-mm isotropic expansion from the GTV and (2) an "elective" PTV (E-PTV), originating from a 5-mm isotropic expansion from the whole ipsilateral pleural space. Two sets of volumetric modulated arc therapy (VMAT) treatment plans were generated: a "selective" pleural irradiation plan (SPI plan) and an "elective" pleural irradiation plan (EPI plan, planned with a simultaneous integrated boost technique [SIB]). RESULTS: In the SPI plans, the average median dose to the S­PTV was 53.6 Gy (range 41-63.6 Gy). In 4 of 12 patients, it was possible to escalate the dose to the S­PTV to >58 Gy. In the EPI plans, the average median doses to the E­PTV and to the S­PTV were 48.6 Gy (range 38.5-58.7) and 49 Gy (range 38.6-59.5 Gy), respectively. No significant dose escalation was achievable. CONCLUSION: The omission of the elective irradiation of the whole ipsilateral pleural space allowed dose escalation from 49 Gy to more than 58 Gy in 4 of 12 chemonaive MPM patients. This strategy may form the basis for nonsurgical radical combined modality treatment of MPM.

Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.

BACKGROUND: Chemotherapy (CT) combined with radiotherapy is the standard treatment of 'limited-stage' small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and CT. MATERIALS AND METHODS: We carried out a meta-analysis of individual patient data in randomized trials comparing earlier versus later radiotherapy, or shorter versus longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival. RESULTS: Twelve trials with 2668 patients were eligible. Data from nine trials comprising 2305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, 'earlier or shorter' versus 'later or longer' thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of 'earlier or shorter' radiotherapy among trials with a similar proportion of patients who were compliant with CT (defined as having received 100% or more of the planned CT cycles) in both arms (HR 0.79, 95% CI 0.69-0.91), and in favour of 'later or longer' radiotherapy among trials with different rates of CT compliance (HR 1.19, 1.05-1.34, interaction test, P < 0.0001). The absolute gain between 'earlier or shorter' versus 'later or longer' thoracic radiotherapy in 5-year overall survival for similar and for different CT compliance trials was 7.7% (95% CI 2.6-12.8%) and -2.2% (-5.8% to 1.4%), respectively. However, 'earlier or shorter' thoracic radiotherapy was associated with a higher incidence of severe acute oesophagitis than 'later or longer' radiotherapy. CONCLUSION: 'Earlier or shorter' delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis.

2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on locally advanced disease.

Variation in causes of death in patients with non-small cell lung cancer according to stage and time since diagnosis.

BACKGROUND: Many patients with non-small cell lung cancer (NSCLC) die within the first few years of diagnosis, and considerable excess mortality remains even after 5 years. We investigated the death rate and the distribution of causes of death for NSCLC patients by age and stage at diagnosis during long-term follow-up. PATIENTS AND METHODS: All 72 021 patients aged 45-89 years diagnosed with stage I-III NSCLC between 1989 and 2008 in the Netherlands and who died up till 2011 were derived from the Netherlands Cancer Registry and linked with the database of Statistics Netherlands for underlying causes of death. Mortality ratios and proportional distribution of causes of death were calculated during 5 time periods after diagnosis of NSCLC (up to 15 years). RESULTS: Median follow-up was 9.6 years (range: 0-23 years). Lung cancer was the predominant cause of death in the first 6 years after diagnosis (being 80%-85% and ∼90% up to 3 years for localized and locally advanced disease, respectively, and ∼60%-75% and ∼75%-85% during years 4-6 for both stage groups, respectively). Thereafter, lung cancer as cause of death proportionally decreased with time since diagnosis, but remained over 30%. Hence, cardiovascular diseases and chronic obstructive pulmonary diseases (COPD) became more important causes of death, especially for patients aged >60 years at diagnosis (up to 34% for cardiovascular diseases and up to 19% for COPD). CONCLUSIONS: With time, the relative contribution of cardiovascular and COPD causes of death increased, although the absolute contribution of lung cancer remained high in non-metastatic NSCLC. Therefore, managing morbidity of these diseases remains relevant.

Single-Centre 20-Year Experience with Surgical Treatment of Thymic Tumours.

BACKGROUND: Large single-centre institutional series on thymic tumours are rare. Complete resection remains the mainstay of successful treatment. Characteristics and survival were reviewed in all patients treated between 19932013. METHODS: Hospital databases revealed 134 patients with pathologically-proven thymic tumour. Follow-up (median 63 months) was through patient notes and telephone contact with general practitioner. RESULTS: Patients were classified in Masaoka-Koga stages: I: 50 (37%); Ila: 14 (10%); lib: 14 (10%); III: 27 (20%); IVa: 19 (14%); IVb: 4 (3%); unknown: 6 (5%). According to WHO classification, pathological subtypes were A: 19 (14%); AB: 25 (19%); B1: 21 (16%); B2: 31 (23%); B3: 15 (11%); thymic carcinoma: 23 (17%). Parathymic syndromes were diagnosed in 45 patients: myasthenia gravis (84%); pure red-cell aplasia (4%); hypogammaglobulinemia (2%); and others. 124 patients (93%) underwent surgery with complete resection in 104 (84%). Surgical approach was: sternotomy: 79; thoracotomy: 35; cervicotomy: 2; other/unknown: 8. In 73 patients (59%) no biopsy was taken prior to surgical resection, 25 were treated with induction chemotherapy, 36 received adjuvant radiotherapy. Hospital mortality was 0.81%. 35 patients died during follow-up (13 of tumour or treatment-related causes). Overall and recurrence-free survival at 5, 10, and 15 years were 86%; 64%; 47% and 67%; 49%; and 31%, respectively and were significantly (p < 0.01) different according to Masaoka-Koga stage. There was a significant association between WHO classification and Masaoka-Koga stages I-IIa-IIb versus III-IVa-IVb (p < 0.01). CONCLUSIONS: Operability and complete resectability of thymic tumours in our experience is high resulting in prolonged overall and recurrence-free survival. Masaoka-Koga stage is an important predictor for survival and shows a significant association with WHO classification.

Single-centre 20-year experience with surgical treatment of thymic tumours.

BACKGROUND: Large single-centre institutional series on thymic tumours are rare. Complete resection remains the mainstay of successful treatment. Characteristics and survival were reviewed in all patients treated between 1993-2013. METHODS: Hospital databases revealed 134 patients with pathologically-proven thymic tumour. Follow-up (median 63 months) was through patient notes and telephone contact with general practitioner. RESULTS: Patients were classified in Masaoka-Koga stages: I: 50 (37%); IIa: 14 (10%); IIb: 14 (10%); III: 27 (20%); IVa: 19 (14%); IVb: 4 (3%); unknown: 6 (5%). According to WHO classification, pathological subtypes were A: 19 (14%); AB: 25 (19%); B1: 21 (16%); B2: 31 (23%); B3: 15 (11%); thymic carcinoma: 23 (17%). Parathymic syndromes were diagnosed in 45 patients : myasthenia gravis (84%); pure red-cell aplasia (4%); hypogammaglobulinemia (2%); and others. 124 patients (93%) underwent surgery with complete resection in 104 (84%). Surgical approach was: sternotomy: 79; thoracotomy: 35; cervicotomy: 2; other/unknown: 8. In 73 patients (59%) no biopsy was taken prior to surgical resection, 25 were treated with induction chemotherapy, 36 received adjuvant radiotherapy. Hospital mortality was 0.81%. 35 patients died during follow-up (13 of tumour or treatment-related causes). Overall and recurrence-free survival at 5, 10, and 15 years were 86%; 64%; 47% and 67%; 49%; and 31%, respectively and were significantly (p < 0.01) different according to Masaoka-Koga stage. There was a significant association between WHO classification and Masaoka-Koga stages I-IIa-IIb versus III-IVa-IVb (p < 0.01). CONCLUSIONS: Operability and complete resectability of thymic tumours in our experience is high resulting in prolonged overall and recurrence-free survival. Masaoka-Koga stage is an important predictor for survival and shows a significant association with WHO classification.

Influence of experience and qualification on PET-based target volume delineation. When there is no expert--ask your colleague.

BACKGROUND AND PURPOSE: The integration of positron emission tomography (PET) information for target volume delineation in radiation treatment planning is routine in many centers. In contrast to automatic contouring, research on visual-manual delineation is scarce. The present study investigates the dependency of manual delineation on experience and qualification. PATIENTS AND METHODS: A total of 44 international interdisciplinary observers each defined a [(18)F]fluorodeoxyglucose (FDG)-PET based gross tumor volume (GTV) using the same PET/CT scan from a patient with lung cancer. The observers were "experts" (E; n = 3), "experienced interdisciplinary pairs" (EP; 9 teams of radiation oncologist (RO) + nuclear medicine physician (NP)), "single field specialists" (SFS; n = 13), and "students" (S; n = 10). Five automatic delineation methods (AM) were also included. Volume sizes and concordance indices within the groups (pCI) and relative to the experts (eCI) were calculated. RESULTS: E (pCI = 0.67) and EP (pCI = 0.53) showed a significantly higher agreement within the groups as compared to SFS (pCI = 0.43, p = 0.03, and p = 0.006). In relation to the experts, EP (eCI = 0.55) showed better concordance compared to SFS (eCI = 0.49) or S (eCI = 0.47). The intermethod variability of the AM (pCI = 0.44) was similar to that of SFS and S, showing poorer agreement with the experts (eCI = 0.35). CONCLUSION: The results suggest that interdisciplinary cooperation could be beneficial for consistent contouring. Joint delineation by a radiation oncologist and a nuclear medicine physician showed remarkable agreement and better concordance with the experts compared to other specialists. The relevant intermethod variability of the automatic algorithms underlines the need for further standardization and optimization in this field.

Treatment outcome of patients with synchronous oligometastatic non-small cell lung cancer in the immunotherapy era: Analysis of a real-life intention-to-treat population.

The standard first-line treatment for non-oncogene driven metastatic non-small cell lung cancer (NSCLC) is an immune checkpoint inhibitor (ICI) based strategy. Although guidelines increasingly advise adding local radical treatment (LRT) to patients with synchronous oligometastatic (sOMD) NSCLC responding to systemic therapy, this recommendation is based on the studies without ICI. Furthermore, the majority of published oligometastatic studies were not on an intention-to-treat basis, resulting in selection bias. Moreover, staging Positron Emission Tomography-Computed Tomography (PET-CT) and brain imaging were often not mandatory and definitions of oligometastatic were heterogeneous. Therefore, this study focused on a single centre retrospective series, including all adequately staged patients with sOMD NSCLC according to the European Organisation for Research and Treatment of Cancer definition (maximum of 5 metastases in 3 organs) that were treated with induction (chemo)-ICI and compared outcomes to those treated with chemotherapy only, with and without LRT. The primary end-points were median progression-free survival (PFS) and overall survival (OS) for patients treated with induction (chemo)-ICI versus chemotherapy. Out of 68 included patients, 38 (56%) eventually received LRT. With a median follow-up of 26.7 months, the median PFS was 19.0 months for (chemo)-ICI (n = 18) versus 6.8 for chemotherapy-only (n = 50) (HR 0.5, p = 0.03), the median OS was 19.3 versus 15.7 months, respectively (HR 0.8, p = 0.4). In patients having received LRT, median PFS was 19.0 months for (chemo)-ICI versus 8.3 for chemotherapy-only (HR 0.6, p = 0.2). In conclusion, an ICI-based systemic treatment is feasible and may result in superior survival outcomes. This should be investigated in prospective trials. Strategies to improve response rates to systemic treatment are also needed.

Cost-effectiveness of proton radiotherapy versus photon radiotherapy for non-small cell lung cancer patients: Exploring the model-based approach.

INTRODUCTION: Proton radiotherapy (PT) is a promising but more expensive strategy than photon radiotherapy (XRT) for the treatment of non-small cell lung cancer (NSCLC). PT is probably not cost-effective for all patients. Therefore, patients can be selected using normal tissue complication probability (NTCP) models with predefined criteria. This study aimed to explore the cost-effectiveness of three treatment strategies for patients with stage III NSCLC: 1. photon radiotherapy for all patients (XRTAll); 2. PT for all patients (PTAll); 3. PT for selected patients (PTIndividualized). METHODS: A decision-analytical model was constructed to estimate and compare costs and QALYs of all strategies. Three radiation-related toxicities were included: dyspnea, dysphagia and cardiotoxicity. Costs and QALY's were incorporated for grade 2 and ≥ 3 toxicities separately. Incremental Cost-Effectiven Ratios (ICERs) were calculated and compared to a threshold value of €80,000. Additionally, scenario, sensitivity and value of information analyses were performed. RESULTS: PTAll yielded most QALYs, but was also most expensive. XRTAll was the least effective and least expensive strategy, and the most cost-effective strategy. For thresholds higher than €163,467 per QALY gained, PTIndividualized was cost-effective. When assuming equal minutes per fraction (15 minutes) for PT and XRT, PTIndividualized was considered the most cost-effective strategy (ICER: €76,299). CONCLUSION: Currently, PT is not cost-effective for all patients, nor for patient selected on the current NTCP models used in the Dutch indication protocol. However, with improved clinical experience, personnel and treatment costs of PT can decrease over time, which potentially leads to PTIndividualized, with optimal patient selection, will becoming a cost-effective strategy.

Clinical implementation of standardized neurocognitive assessment before and after radiation to the brain.

Background: Radiotherapy induced impairment of cognitive function can lead to a reduced quality of life. The aim of this study was to describe the implementation and compliance of standardized neurocognitive assessment. In addition, the first results of cognitive changes for patients receiving a radiation dose to the brain are described. Materials and methods: Patients that received radiation dose to the brain (neuro, head and neck and prophylactic cranial irradiation between April-2019 and Dec-2021 were included. Three neuro cognitive tests were performed a verbal learning and memory test, the Hopkins Verbal Learning Test; a verbal fluency test, the Controlled Oral Word Association Test and a speed and cognitive flexibility test, the Trail Making Test A&B. Tests were performed before the start of radiation, 6 months (6 m) and 1 year (1y) after irradiation. The Reliable Change Index (RCI) between baseline and follow-up was calculated using reference data from literature. Results: 644 patients performed the neurocognitive tests at baseline, 346 at 6 months and 205 at 1y after RT, with compliance rates of 90.4%, 85.6%, and 75.3%, respectively. Reasons for non-compliance were: 1. Patient did not attend appointment (49%), 2. Patient was unable to perform the test due to illness (12%), 3. Patient refused the test (8 %), 4. Various causes, (31%). A semi-automated analysis was developed to evaluate the test results. In total, 26% of patients showed a significant decline in at least one of variables at 1y and 11% on at least 2 variables at 1y. However, an increase in cognitive performance was observed in 49% (≥1 variable) and 22% (≥2 variables). Conclusion: Standardized neurocognitive testing within the radiotherapy clinic was successfully implemented, with a high patient compliance. A semi-automatic method to evaluate cognitive changes after treatment was defined. Data collection is ongoing, long term follow-up (up to 5 years after treatment) and dose-effect analysis will be performed.

Radiation-induced oesophagitis in lung cancer patients. Is susceptibility for neutropenia a risk factor?

BACKGROUND: Radiation-induced oesophagitis is a major side effect of concurrent chemotherapy and radiotherapy. A strong association between neutropenia and oesophagitis was previously shown, but external validation and further elucidation of the possible mechanisms are lacking. METHODS AND PATIENTS: A total of 119 patients were included at two institutions. The concurrent group comprised 34 SCLC patients treated with concurrent carboplatin and etoposide, and concurrent chest irradiation, and 36 NSCLC patients with concurrent cisplatin and etoposide, and concurrent radiotherapy, while the sequential group comprised 49 NSCLC patients received sequential cisplatin and gemcitabine, and radiotherapy. RESULTS: Severe neutropenia was very frequent during concurrent chemoradiation (grade: 4 41.4%) and during induction chemotherapy in sequentially treated patients (grade 4: 30.6%), but not during radiotherapy (only 4% grade 1). In the concurrent group, the odds ratios of grade 3 oesophagitis vs. neutropenia were the following: grade 2 vs. grade 0/1: 5.60 (95% CI 1.55-20.26), p = 0.009; grade 3 vs. grade 0/1: 10.40 (95% CI 3.19-33.95); p = 0.0001; grade 4 vs. grade 0/1: 12.60 (95% CI 4.36-36.43); p < 0.00001. There was no correlation between the occurrence of neutropenia during induction chemotherapy and acute oesophagitis during or after radiotherapy alone. In the univariate analysis, total radiation dose (p < 0.001), overall treatment time of radiotherapy (p < 0.001), mean oesophageal dose (p = 0.038) and neutropenia (p < 0.001) were significantly associated with the development of oesophagitis. In a multivariate analysis, only neutropenia remained significant (p = 0.023). CONCLUSION: We confirm that neutropenia is independently correlated with oesophagitis in concurrent chemoradiation, but that the susceptibility for chemotherapy-induced neutropenia is not associated with radiation-induced oesophagitis. Further studies focusing on the underlying mechanisms are thus warranted.