Targeting serine/glycine metabolism improves radiotherapy response in non-small cell lung cancer.

BACKGROUND: Lung cancer is the most lethal cancer, and 85% of cases are classified as non-small cell lung cancer (NSCLC). Metabolic rewiring is a cancer hallmark that causes treatment resistance, and lacks insights into serine/glycine pathway adaptations upon radiotherapy. METHODS: We analyzed radiotherapy responses using mass-spectrometry-based metabolomics in NSCLC patient's plasma and cell lines. Efficacy of serine/glycine conversion inhibitor sertraline with radiotherapy was investigated by proliferation, clonogenic and spheroid assays, and in vivo using a serine/glycine dependent NSCLC mouse model by assessment of tumor growth, metabolite and cytokine levels, and immune signatures. RESULTS: Serine/glycine pathway metabolites were significantly consumed in response to radiotherapy in NSCLC patients and cell models. Combining sertraline with radiotherapy impaired NSCLC proliferation, clonogenicity and stem cell self-renewal capacity. In vivo, NSCLC tumor growth was reduced solely in the sertraline plus radiotherapy combination treatment group. Tumor weights linked to systemic serine/glycine pathway metabolite levels, and were inhibited in the combination therapy group. Interestingly, combination therapy reshaped the tumor microenvironment via cytokines associated with natural killer cells, supported by eradication of immune checkpoint galectin-1 and elevated granzyme B levels. CONCLUSION: Our findings highlight that targeting serine/glycine metabolism using sertraline restricts cancer cell recovery from radiotherapy and provides tumor control through immunomodulation in NSCLC.

Measured Steps: Navigating the Path of Oligoprogressive Lung Cancer with Targeted and Immunotherapies.

PURPOSE OF REVIEW: This review discusses the definitions, treatment modalities, management, future directions, and ongoing clinical trials of oligoprogressive disease in oncogene-driven and non-oncogene-driven NSCLC. RECENT FINDINGS: During the last decades, diagnostic and treatment modalities for oligometastatic NSCLC have advanced significantly, leading to improved survival. Additionally, our understanding of the tumor biology of oligoprogressive disease has expanded. However, despite the efforts of organizations, such as EORTC, ESTRO, and ASTRO proposing definitions for oligometastatic and oligoprogressive disease, heterogeneity in definitions persists in (ongoing) trials. Recognizing the significance of subclassification within oligoprogressive disease in NSCLC and the varying risks associated with subsequent metastatic spread, there is a call for tailored management strategies. A consensus on standardized criteria for the definition of oligoprogressive disease is urgently needed and will not only facilitate meaningful comparisons between studies but also pave the way for the development of personalized treatment plans that take into account the heterogeneous nature of oligoprogressive disease.

Visually guided inspiration breath-hold facilitated with nasal high flow therapy in locally advanced lung cancer.

BACKGROUND AND PURPOSE: Reducing breathing motion in radiotherapy (RT) is an attractive strategy to reduce margins and better spare normal tissues. The objective of this prospective study (NCT03729661) was to investigate the feasibility of irradiation of non-small cell lung cancer (NSCLC) with visually guided moderate deep inspiration breath-hold (IBH) using nasal high-flow therapy (NHFT). MATERIAL AND METHODS: Locally advanced NSCLC patients undergoing photon RT were given NHFT with heated humidified air (flow: 40 L/min with 80% oxygen) through a nasal cannula. IBH was monitored by optical surface tracking (OST) with visual feedback. At a training session, patients had to hold their breath as long as possible, without and with NHFT. For the daily cone beam CT (CBCT) and RT treatment in IBH, patients were instructed to keep their BH as long as it felt comfortable. OST was used to analyze stability and reproducibility of the BH, and CBCT to analyze daily tumor position. Subjective tolerance was measured with a questionnaire at 3 time points. RESULTS: Of 10 included patients, 9 were treated with RT. Seven (78%) completed the treatment with NHFT as planned. At the training session, the mean BH length without NHFT was 39 s (range 15-86 s), and with NHFT 78 s (range 29-223 s) (p = .005). NHFT prolonged the BH duration by a mean factor of 2.1 (range 1.1-3.9s). The mean overall stability and reproducibility were within 1 mm. Subjective tolerance was very good with the majority of patients having no or minor discomfort caused by the devices. The mean inter-fraction tumor position variability was 1.8 mm (-1.1-8.1 mm;SD 2.4 mm). CONCLUSION: NHFT for RT treatment of NSCLC in BH is feasible, well tolerated and significantly increases the breath-hold duration. Visually guided BH with OST is stable and reproducible. We therefore consider this an attractive patient-friendly approach to treat lung cancer patients with RT in BH.

ERS statement on harmonised standards for lung cancer registration and lung cancer services in Europe.

The European Respiratory Society (ERS) task force for harmonised standards for lung cancer registration and lung cancer services in Europe recognised the need to create a single dataset for use in pan-European data collection and a manual of standards for European lung cancer services.The multidisciplinary task force considered evidence from two different sources, reviewing existing national and international datasets alongside the results of a survey of clinical data collection on lung cancer in 35 European countries. A similar process was followed for the manual of lung cancer services, with the task force using existing guidelines and national or international recommendations for lung cancer services to develop a manual of standards for services in Europe.The task force developed essential and minimum datasets for lung cancer registration to enable all countries to collect the same essential data and some to collect data with greater detail. The task force also developed a manual specifying standards for lung cancer services in Europe.Despite the wide variation in the sociopolitical landscape across Europe, the ERS is determined to encourage the delivery of high-quality lung cancer care. Both the manual of lung cancer services and the minimum dataset for lung cancer registration will support this aspiration.

Cachexia and Sarcopenia in Oligometastatic Non-Small Cell Lung Cancer: Making a Potential Curable Disease Incurable?

Among patients with advanced NSCLC, there is a group of patients with synchronous oligometastatic disease (sOMD), defined as a limited number of metastases detected at the time of diagnosis. As cachexia and sarcopenia are linked to poor survival, incorporating this information could assist clinicians in determining whether a radical treatment should be administered. In a retrospective multicenter study, including all patients with adequately staged (FDG-PET, brain imaging) sOMD according to the EORTC definition, we aimed to assess the relationship between cachexia and/or sarcopenia and survival. Of the 439 patients that were identified between 2015 and 2021, 234 met the criteria for inclusion and were included. The median age of the cohort was 67, 52.6% were male, and the median number of metastasis was 1. Forty-six (19.7%) patients had cachexia, thirty-four (14.5%) had sarcopenia and twenty-one (9.0%) had both. With a median follow-up of 49.7 months, median PFS and OS were 8.6 and 17.3 months, respectively. Moreover, a trend toward longer PFS was found in patients without cachexia and sarcopenia compared to those with cachexia and/or sarcopenia. In multivariate analysis, cachexia and sarcopenia were not associated with an inferior survival, irrespective of receiving radical treatment. High CRP was associated with inferior survival and could be a prognostic factor, helping the decision of clinicians in selecting patients who may benefit from the addition of LRT. However, despite the homogeneous definition of oligometastatic disease and the adequate staging, our subgroups were small. Therefore, further studies are needed to better understand our hypothesis and generating findings.

Survival of patients with KRAS G12C mutated stage IV non-small cell lung cancer with and without brain metastases treated with immune checkpoint inhibitors.

INTRODUCTION: Few data is available on whether brain metastases (BM) influence survival in patients with stage IV KRAS G12C mutated (KRAS G12C+ ) non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitor (ICI) +/- chemotherapy ([chemo]-ICI). METHODS: Data was retrospectively collected from the population-based Netherlands Cancer Registry. The cumulative incidence of intracranial progression, overall survival (OS) and progression free survival (PFS) was determined for patients with KRAS G12C+ stage IV NSCLC diagnosed January 1 - June 30, 2019, treated with first-line (chemo)-ICI. OS and PFS were estimated using Kaplan-Meier methods and BM+ and BM- groups were compared using log-rank tests. RESULTS: Of 2489 patients with stage IV NSCLC, 153 patients had KRAS G12C+ and received first-line (chemo)-ICI. Of those patients, 35% (54/153) underwent brain imaging (CT and/or MRI), of which 85% (46/54) MRI. Half of the patients with brain imaging (56%; 30/54) had BM, concerning one-fifth (20%; 30/153) of all patients, of which 67% was symptomatic. Compared to BM-, patients with BM+ were younger and had more organs affected with metastasis. Around one-third (30%) of patients with BM+ had ≥5 BM at diagnosis. Three quarters of patients with BM+ received cranial radiotherapy prior to start of (chemo)-ICI. The 1-year cumulative incidence of intracranial progression was 33% for patients with known baseline BM and 7% for those without (p = 0.0001). Median PFS was 6.6 (95% CI 3.0-15.9) and 6.7 (95% CI 5.1-8.5) months for BM+ and BM- (p = 0.80), respectively. Median OS was 15.7 (95% CI 6.2-27.3) and 17.8 (95% CI 13.4-22.0) months for BM+ and BM- (p = 0.77), respectively. CONCLUSION: Baseline BM are common in patients with metastatic KRAS G12C+ NSCLC. During (chemo)-ICI treatment, intracranial progression was more frequent in patients with known baseline BM, justifying regular imaging during treatment. In our study, presence of known baseline BM did not influence OS or PFS.

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).

Self-Reported Cognitive Function and Quality of Life in Patients With SCLC in the Hippocampal Avoidance Prophylactic Cranial Irradiation Versus Prophylactic Cranial Irradiation Randomized Phase 3 Trial (NCT01780675).

Introduction: In the randomized controlled trial in patients with SCLC comparing standard prophylactic cranial irradiation (PCI) with hippocampal avoidance PCI (HA-PCI), we did not observe beneficial effects of HA-PCI on tested cognition. Here, we report findings on self-reported cognitive functioning (SRCF) and quality of life (QoL). Methods: Patients with SCLC were randomized to receive PCI with or without HA (NCT01780675) and assessed at baseline (82 HA-PCI and 79 PCI patients) and at 4, 8, 12, 18, and 24 months of follow-up, using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EORTC QLQ-brain cancer module (BN20). SRCF was assessed with the cognitive functioning scale of the EORTC QLQ-C30 and the Medical Outcomes Study questionnaire. A change of 10 points was used for minimal clinically important differences. Percentages of patients classified with having improved, stable, or deteriorated SRCF were compared between groups using chi-square tests. Changes in mean scores were analyzed using linear mixed models. Results: There was no significant difference in the percentage of patients with deteriorated, stable, or improved SRCF between the treatment arms. Depending on the evaluated time point, 31% to 46% and 29% to 43% of patients in the HA-PCI and PCI arm, respectively, reported a deteriorated SRCF on the basis of the EORTC QLQ-C30 and Medical Outcomes Study. QoL outcomes were not significantly different between the study arms, except for physical functioning at 12 months (p = 0.019) and motor dysfunction at 24 months (p = 0.020). Conclusions: Our trial did not find beneficial effects of HA-PCI over PCI on SRCF and QoL. The cognitive benefit of sparing the hippocampus in the context of PCI is still a subject of debate.

The Association of Gross Tumor Volume and Its Radiomics Features with Brain Metastases Development in Patients with Radically Treated Stage III Non-Small Cell Lung Cancer.

PURPOSE: To identify clinical risk factors, including gross tumor volume (GTV) and radiomics features, for developing brain metastases (BM) in patients with radically treated stage III non-small cell lung cancer (NSCLC). METHODS: Clinical data and planning CT scans for thoracic radiotherapy were retrieved from patients with radically treated stage III NSCLC. Radiomics features were extracted from the GTV, primary lung tumor (GTVp), and involved lymph nodes (GTVn), separately. Competing risk analysis was used to develop models (clinical, radiomics, and combined model). LASSO regression was performed to select radiomics features and train models. Area under the receiver operating characteristic curves (AUC-ROC) and calibration were performed to assess the models' performance. RESULTS: Three-hundred-ten patients were eligible and 52 (16.8%) developed BM. Three clinical variables (age, NSCLC subtype, and GTVn) and five radiomics features from each radiomics model were significantly associated with BM. Radiomic features measuring tumor heterogeneity were the most relevant. The AUCs and calibration curves of the models showed that the GTVn radiomics model had the best performance (AUC: 0.74; 95% CI: 0.71-0.86; sensitivity: 84%; specificity: 61%; positive predictive value [PPV]: 29%; negative predictive value [NPV]: 95%; accuracy: 65%). CONCLUSION: Age, NSCLC subtype, and GTVn were significant risk factors for BM. GTVn radiomics features provided higher predictive value than GTVp and GTV for BM development. GTVp and GTVn should be separated in clinical and research practice.

Small-cell lung cancer.

The incidence and mortality of small-cell lung cancer worldwide make this disease a notable health-care issue. Diagnosis relies on histology, with the use of immunohistochemical studies to confirm difficult cases. Typical patients are men older than 70 years who are current or past heavy smokers and who have pulmonary and cardiovascular comorbidities. Patients often present with rapid-onset symptoms due to local intrathoracic tumour growth, extrapulmonary distant spread, paraneoplastic syndromes, or a combination of these features. Staging aims ultimately to define disease as metastatic or non-metastatic. Combination chemotherapy, generally platinum-based plus etoposide or irinotecan, is the mainstay first-line treatment for metastatic small-cell lung cancer. For non-metastatic disease, evidence supports early concurrent thoracic radiotherapy. Prophylactic cranial irradiation should be considered for patients with or without metastases whose disease does not progress after induction chemotherapy and radiotherapy. Despite high initial response rates, most patients eventually relapse. Except for topotecan, few treatment options then remain. Signalling pathways have been identified that might yield new drug targets.

Radiotherapy for small cell lung cancer in current clinical practice guidelines.

Several guidelines including radiotherapy recommendations exist worldwide for the treatment of small cell lung cancer (SCLC). To evaluate the differences in radiotherapy recommendations we conducted a systematic review. PubMed and the sites of medical societies were searched for SCLC guidelines published in either English, Chinese, or Dutch. This was limited to January 2018 till February 2021 to only include up-to-date recommendations. Data was extracted and compared regarding the guideline's development method and radiotherapy recommendations. Eleven guidelines were identified (PubMed n=4, societies n=7) from Spain (n=1), Canada (n=1), America (n=3), United Kingdom (n=1), the Netherlands (n=1), and China (n=3), respectively. Nine guidelines assessed the strength of evidence (SOE) and specified the strength of recommendation (SOR), although methods were different. The major radiotherapy recommendations are similar although differences exist in thoracic radiotherapy (TRT) dose, time, and volume. Controversial areas are TRT in resected stage I-IIA (pN1), prophylactic cranial irradiation (PCI) in resected as well as unresected stage I-IIA, stereotactic body radiation therapy (SBRT) in unresected stage I-IIA, PCI time, and PCI versus magnetic resonance imaging (MRI) surveillance in stage IV. The existence of several overlapping guidelines for SCLC treatment indicates that guideline development is (unnecessarily) repeated by different organizations or societies. Improvement could be made by better international collaboration to avoid duplicating unnecessary work, which would spare a lot of time and resources. Efforts should be made to work together on controversial or unknown fields.

Risk Factors for Brain Metastases in Patients With Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

The use of prophylactic cranial irradiation (PCI) for small cell lung cancer (SCLC) patients is controversial. Risk factors for brain metastasis (BM) development are largely lacking, hampering personalized treatment strategies. This study aimed to identify the possible risk factors for BM in SCLC.We systematically searched the Pubmed database (1 January 1995 to 18 January 2021) according to the PRISMA guidelines. Eligibility criteria: studies reporting detailed BM data with an adequate sample size (randomized clinical trials [RCTs]: N ≥50; non-RCTs: N ≥100) in patients with SCLC. We summarized the reported risk factors and performed meta-analysis to estimate the pooled hazard ratios (HR) if enough qualified data (i.e., two or more studies; the same study type; the same analysis method; and HRs retrievable) were available. In total, 61/536 records were eligible (18 RCTs and 39 non-RCTs comprising 13,188 patients), in which 57 factors were reported. Ten factors qualified BM data for meta-analysis: Limited stage disease (LD) (HR = 0.34, 95% CI: 0.17-0.67; P = 0.002) and older age (≥65) (HR = 0.70, 95% CI: 0.54-0.92; P = 0.01) were associated with less BM; A higher T stage (≥T3) (HR = 1.72, 95% CI: 1.16-2.56; P = 0.007) was a significant risk factor for BM. Male sex (HR = 1.24, 95% CI: 0.99-1.54; P = 0.06) tended to be a risk factor, and better PS (0-1) (HR = 0.66, 95% CI: 0.42-1.02; P = 0.06) tended to have less BM. Smoking, thoracic radiotherapy dose were not significant (P >0.05). PCI significantly decreased BM (P <0.001), but did not improve OS in ED-SCLC (P = 0.81). A higher PCI dose did not improve OS (P = 0.11). The impact on BM was conflicting between Cox regression data (HR = 0.59, 95% CI: 0.26-1.31; P = 0.20) and competing risk regression data (HR = 0.74, 95% CI: 0.55-0.99; P = 0.04). Compared to M0-M1a, M1b was a risk factor for OS (P = 0.01) in ED-SCLC, but not for BM (P = 0.19). As regular brain imaging is rarely performed, high-quality data is lacking. Other factors such as N-stage and blood biomarkers had no qualified data to perform meta-analysis. In conclusion, younger age, higher T stage, and ED are risk factors for BM, suggesting that PCI should be especially discussed in such cases. Individual patient data (IPD) meta-analysis and well-designed RCTs are needed to better identify more risk factors and further confirm our findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021228391, identifier CRD42021228391.

The overall survival impact of prophylactic cranial irradiation in limited-stage small-cell lung cancer: A systematic review and meta-analysis.

BACKGROUND: Prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (LS-SCLC) patients has become more controversial. Since the publication of the systematic review by Aupérin et al. in 1999, no randomized controlled trials regarding PCI in LS-SCLC have been completed. The aim of this study was to systematically review and meta-analyze the effect of PCI on overall survival (OS) in patients with LS-SCLC. METHODS: A systematic search was conducted in the databases of MEDLINE (PubMed), Embase and the Cochrane library. Only studies that reported an adjusted hazard ratio (aHR), indicating the effect of PCI versus no PCI on OS (adjusted for confounders) in patients with LS-SCLC were included for critical appraisal and meta-analysis. A pooled aHR estimate was calculated using a random-effects model. RESULTS: Pooling of 28 retrospective studies including a total of 18,575 patients demonstrated a significant beneficial effect of PCI versus no PCI on OS with a pooled aHR of 0.62 (95% CI: 0.57-0.69). Substantial heterogeneity of reported aHRs among studies was observed (I2 = 65.9%). Subgroup analyses revealed that this heterogeneity could partly be explained by study sample size. The pooled aHR among 7 versus 21 studies with a sample size of > 300 versus ≤ 300 patients was 0.79 (95% CI: 0.64-0.97) versus 0.56 (95% CI: 0.46-0.69; p < 0.001), respectively. CONCLUSIONS: This meta-analysis demonstrates a significant beneficial effect of PCI on OS in patients with LS-SCLC. Larger studies reported a milder beneficial effect, possibly due to a decreased risk of model overfitting. Serious risk of selection and confounding bias were of concern due to the lack of prospective trials. These results support the role of PCI in standard clinical practice in patients with LS-SCLC while awaiting results of prospective trials on alternative strategies.

Cost-effectiveness of prophylactic cranial irradiation in stage III non-small cell lung cancer.

INTRODUCTION: In stage III non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduces the brain metastases incidence and prolongs the progression-free survival without improving overall survival. PCI increases the risk of toxicity and is currently not adopted in routine care. Our objective was to assess the cost-effectiveness of PCI compared with no PCI in stage III NSCLC from a Dutch societal perspective. METHODS: A cohort partitioned survival model was developed based on individual patient data from three randomized phase III trials (N = 670). Quality-adjusted life years (QALYs) and costs were estimated over a lifetime time horizon. A willingness-to-pay (WTP) threshold of €80,000 per QALY was adopted. Sensitivity and scenario analyses were performed to address parameter uncertainty and to explore what parameters had the greatest impact on the cost-effectiveness results. RESULTS: PCI was more effective and costly (0.443 QALYs, €10,123) than no PCI, resulting in an incremental cost-effectiveness ratio (ICER) of €22,843 per QALY gained. The probability of PCI being cost-effective at a WTP threshold of €80,000 per QALY was 93%. The probability of PCI gaining three and six additional months of life were 76% and 56%. The scenario analysis adding durvalumab increased the ICER to €35,159 per QALY gained. Using alternative survival distributions had little impact on the ICER. Assuming fewer PCI fractions and excluding indirect costs decreased the ICER to €18,263 and €5554 per QALY gained. CONCLUSION: PCI is cost-effective compared to no PCI in stage III NSCLC, and could therefore, from a cost-effectiveness perspective, be considered in routine care.

How to optimize the incorporation of immunotherapy in trials for oligometastatic non-small cell lung cancer: a narrative review.

Patients with oligometastatic disease (OMD) non-small cell lung cancer (NSCLC) are considered as a subgroup of metastatic NSCLC that can obtain long-term survival or even cure. Oligometastatic refers to a state of a limited number of metastases in a limited number of organs. In clinical guidelines it is stated that patients with oligometastatic NSCLC can benefit from the addition of local radical therapy (LRT) to systemic therapy. With the introduction of minimally invasive surgery, advances in interventional radiology and stereotactic radiotherapy (SRT), LRT is becoming feasible for more and more patients. Furthermore, the introduction of immune checkpoint inhibitors (ICI) in the treatment landscape of advanced NSCLC has improved the survival of these patients. Importantly, the use of ICI in combination with LRT is also of interest in the subgroup of NSCLC patients with OMD. For example, it has been suggested that SRT may synergize with ICI as several preclinical studies reported an increased tumor antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumors. In this narrative review, we describe the current evidence of immunotherapy treatment in OMD NSCLC, with a focus on future trial design and problems that need to be addressed.

Immunotherapy in small cell lung cancer: one step at a time: a narrative review.

Chemotherapy with or without radiotherapy has been the standard of care for many years for patients with small cell lung cancer (SCLC). Despite exceptionally high responses (up to 80%) with chemotherapy, the majority of patients relapse rapidly within weeks to months after treatment completion. Therefore, new and better treatment options are necessary. Recently, synergistic activity has been reported for the addition of immune checkpoint inhibitors (ICI) to standard platinum-based chemotherapy in the therapeutic strategy of advanced SCLC. For the first time after several decades, a significant survival improvement was achieved for this population. However, the overwhelming majority of patients do not respond to ICI, or relapse rapidly. There is need for better knowledge about the biology, histopathologic features, and molecular pathways of SCLC. This can probably help to identify the optimal predictive biomarkers, which are warranted to develop an individual therapeutic strategy including the rational use of a combination of immunotherapeutic agents. Here, we provide an overview of the rationale for and clinical results of the completed and ongoing trials using different strategies of immunotherapy in SCLC. In addition, opportunities for further improvement of therapies will be discussed, including the addition of radiotherapy, co-stimulatory antibodies, and other immune modifying agents.

Prophylactic cranial irradiation in patients with small cell lung cancer in The Netherlands: A population-based study.

INTRODUCTION: Controversy has arisen regarding the benefit of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC), particularly since the 2017 Takahashi trial publication that supports MRI surveillance in extensive-stage (ES-)SCLC. The primary aim of this study was to assess trends and determinants in PCI use over the years 2010-2018. A secondary aim was to determine contemporary practice considerations among radiation oncologists (ROs). METHODS: A nationwide population-based cohort study was conducted using the Netherlands Cancer Registry data on all newly diagnosed SCLC patients (2010-2018). The change in PCI frequency over the years and determinants for PCI were analyzed using logistic regression models. Second, an online survey was performed among Dutch lung cancer ROs in 2020. RESULTS: Among 10,264 eligible patients, 4,894 (47%) received PCI. Compared to 2010-2014, PCI use significantly decreased in 2017-2018 in ES-SCLC (OR 0.68, 95%CI 0.60-0.77) and LS-SCLC (OR 0.56, 95%CI 0.47-0.67). Incidence year, age, performance status, and thoracic radiotherapy were independent determinants for PCI. Among 41 survey participants, PCI was recommended always/sometimes/never by 22%/71%/7% in ES-SCLC and 54%/44%/2% in LS-SCLC. For ES-SCLC and LS-SCLC, 63% and 25% of ROs, respectively, confirmed influence of the Takahashi trial on PCI recommendations. Denial of such influence was associated with insufficient institutional MRI capacity. CONCLUSIONS: A significant declining trend of PCI use in both ES-SCLC and LS-SCLC was observed in The Netherlands since 2017. The Takahashi trial seems an explanation for this trend even in LS-SCLC, with differential influence of the trial depending on institutional MRI capacity. An alarming increase in practice variation regarding PCI was found which stresses the importance of ongoing trials.

Association of different fractionation schedules for prophylactic cranial irradiation with toxicity and brain metastases-free survival in stage III non-small cell lung cancer: A pooled analysis of individual patient data from three randomized trials.

We assessed the impact of different PCI fractionation schedules (30 Gy in 10 versus 15 fractions) on brain metastases-free survival (BMFS) and toxicity in stage III NSCLC. Our results suggest that 30 Gy in 10 fractions is associated with increased toxicity, while no conclusive evidence of improving BMFS was seen with this schedule.