Search Results (184)

Systemic chemotherapy is a standard treatment for patients with stage IV cancer with distant metastases, and there is little evidence of the effectiveness of local treatments for distant metastatic lesions. However, in recent years, randomized phase II trials targeting oligometastases in lung cancer and solid tumors have reported that local therapy combined with systemic chemotherapy improves clinical outcomes. We reviewed previous clinical trials and demonstrated the efficacy of radiotherapy for oligometastatic disease. Stereotactic body radiotherapy (SBRT) is a promising treatment that achieves high local control rates for oligometastatic disease. Although SBRT generally does not cause severe adverse events, the safety of SBRT combined with systemic chemotherapy needs to be carefully considered. We discussed the efficacy and safety of SBRT and summarized the details of SBRT methods and techniques for each metastatic site. Further research and clinical trials are warranted to improve the efficacy of SBRT combined with systemic chemotherapy for oligometastatic non-small cell lung cancer (NSCLC). Full article

Background/Objectives: The global population of individuals aged ≥ 80 years is rapidly growing, leading to an increasing incidence of cancer diagnoses in this age group. While stereotactic body radiotherapy (SBRT) has proven effective in treating pulmonary oligometastases, patients over 80 remain underrepresented in clinical analyses. This study aimed to evaluate clinical outcomes and toxicity of SBRT for pulmonary oligometastases in octogenarians. Methods: This retrospective, single-centre analysis included 34 patients aged ≥ 80 years treated with SBRT for histologically confirmed pulmonary oligometastases between 2010 and 2024. Results: A total of 46 pulmonary metastases were treated with curative intent using fractionation schemes of 3 × 15 Gy, 6 × 8 Gy, or 10 × 6 Gy. Median biologically effective dose (BED10) was 112.5 Gy. Follow-up included regular CT imaging and toxicity assessment according to CTCAE. With a median follow-up of 22.6 months, 1-, 2-, and 3-year local control (LC) rates were 95.2%, 95.2%, and 90.2%, respectively. Median overall survival (OS) was 46.6 months, with 1-, 2-, and 3-year OS rates of 78.4%, 71.4%, and 59.5%. Progression-free survival (PFS) at 1, 2, and 3 years was 63.4%, 51.6%, and 47.3%, respectively. No grade ≥ 3 toxicities were observed. Grade 2 pneumonitis and dermatitis occurred in 2.9% each and were well managed. Asymptomatic rib fractures were detected in 5.9% of patients. No significant predictors for LC, PFS, or OS were identified in univariate analysis. Conclusions: SBRT for pulmonary oligometastases in patients ≥ 80 years is feasible, safe, and effective. High local control, favourable cancer-specific survival, and minimal toxicity support its use as a curative-intent treatment in this growing patient population. These findings contribute important site- and age-specific evidence and support the inclusion of very elderly patients in future prospective SBRT trials. Full article

Despite advances in surgery, chemotherapy, and radiation treatments for pancreatic ductal adenocarcinoma (PDAC), 5-year survival rates remain at nearly 11%. Cholangiocarcinoma, while not as severe, also possesses similar survival rates. Fewer than 20% of patients are surgical candidates at time of diagnosis; therefore, it is imperative that alternative therapies are effective for non-surgical patients. There are several thermal ablative techniques, including radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), microwave ablation (MWA), alcohol ablation, stereotactic body radiotherapy (SBRT), cryoablation, irreversible electroporation (IRE), biliary intraluminal brachytherapy, and biliary photodynamic therapy (PDT). Emerging literature in animal models and human patients has demonstrated that endoscopic ultrasound (EUS)-guided RFA (EUS-RFA) prevents tumor progression through coagulative necrosis, protein denaturation, and activation of anticancer immunity in local and distant tumor tissue (abscopal effect). RFA treatment has been shown to not only reduce tumor-associated immunosuppressive cells but also increase functional T cells in distant tumor cells not treated with RFA. The remarkable ability to reduce tumor progression and promote tumor microenvironment (TME) remodeling makes RFA a very promising non-surgical therapy technique that has the potential to reduce mortality in this patient population. EUS-RFA offers superior precision and safety compared to other ablation techniques for pancreatic and biliary cancers, due to real-time imaging capabilities and minimally invasive nature. Future research should focus on optimizing RFA protocols, exploring combination therapies with chemotherapy or immunotherapy, and expanding its use in patients with metastatic disease. This review article will explore the current data and underlying pathophysiology of EUS-RFA while also highlighting the role of ablative therapies as a whole in immune activation response. Full article

Purpose/Objective(s): Peritoneal carcinosis can occur in several gastrointestinal or gynecological malignancies and its prognosis is usually poor. With the advent of more effective systemic agents, the overall survival of metastatic patients has been revolutionized and isolated peritoneal or abdominal wall metastases might benefit from local treatments; Stereotactic Body Radiotherapy (SBRT) might be considered in selected patients with oligometastatic presentation. Materials/Methods: Oligometastases were defined according to recent ESTRO/EORTC consensus. Inclusion criteria were as follows: ECOG PS ≤ 2, written informed consent, up to five lesions to be treated at the same time, patients treated with radiotherapy schedules applying minimum 6 Gy per fraction. The primary endpoint of the study was local control (LC); acute and late toxicity, distant progression-free survival (DPFS), time-to-next systemic treatment (TNST), polymetastatic-free survival (PMFS) and overall survival (OS) were secondary endpoints. Toxicity was assessed according to CTCAE criteria v5.0. Statistical associations between clinical variables and outcomes were assessed using Fisher’s exact test, and Kruskal–Wallis test, as appropriate. Survival outcomes were estimated using the Kaplan–Meier method and compared using the log-rank test. Results: Between April 2020 and September 2024 a total of 26 oligometastatic lesions located in the peritoneum or in the abdominal wall detected in 20 patients received SBRT with Helical Tomotherapy. All cases have been assessed by a multidisciplinary team. Only in three patients out of twenty did more than one lesion receive SBRT: two lesions in two patients, and five lesions in a single case of colorectal cancer with ongoing third-line systemic treatment. Median total dose was 30 Gy (27–35 Gy) in five fractions (3–5). The most frequent primary neoplasm was ovarian cancer in 14/20, endometrial in 2/20, while the remaining were colorectal, vaginal, pancreatic and non-small cell lung cancer. Four lesions were located in the abdominal wall, while the remaining twenty-two were located in the peritoneum. Concurrent systemic therapy was administered in 18/20 patients. With a median follow-up of 15 months (range, 6–59), our 1-year LC was 100%, while 1-year DPFS, PMFS, TNTS and OS rates were 54%, 69%, 61% and 83%, respectively. Abdominal wall location and treatment of a subsequent oligometastatic recurrence with a second course of SBRT were both significantly associated with improved OS (p = 0.03 and p = 0.04, respectively). No G ≥ 3 adverse events occurred. Conclusion: Our preliminary data support the use of SBRT in selected cases of oligometastatic disease located in the peritoneum or in the abdominal wall with excellent results in terms of tolerability and promising clinical outcomes. Full article

Stereotactic Body Radiotherapy (SBRT) has emerged as a pivotal treatment modality for early-stage non-small cell lung cancer (NSCLC), offering highly precise, high-dose radiation delivery. However, several clinical challenges remain, particularly in the treatment of central or ultracentral tumors, which are located near critical structures such as the heart, bronchi, and great vessels. The introduction of MRI-guided SBRT has significantly improved targeting precision, allowing for better assessment of tumor motion and adjacent organ structures. Additionally, SBRT has demonstrated efficacy in multifocal NSCLC, providing an effective option for patients with multiple primary tumors. Recent advances also highlight the role of SBRT in locally advanced NSCLC, where it is increasingly used as a complementary approach to concurrent chemotherapy or in cases where surgery is not feasible. Moreover, the combination of SBRT with immunotherapy has shown promising potential, enhancing tumor control and immunological responses. Furthermore, SBRTs application in SCLC is gaining momentum as a palliative and potentially curative option for selected patients. This narrative review explores these evolving clinical scenarios, the technical innovations supporting SBRT, and the integration of immunotherapy, providing an in-depth look at the new frontiers of SBRT in lung cancer treatment. Despite the challenges, the ongoing development of personalized approaches and technological advancements continues to push the boundaries of SBRTs clinical utility in lung cancer. Full article

Background: The management of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with the integration of androgen receptor signaling inhibitors (ARSIs) and metastasis-directed therapies (MDTs). Stereotactic body radiotherapy (SBRT) offers precise local control, yet real-world data on its combination with apalutamide remain limited. Methods: We conducted a multicenter retrospective cohort study including 134 patients with mHSPC treated with apalutamide and SBRT between February 2021 and December 2024. The primary endpoints were progression-free survival (PFS), local control (LC), and treatment safety. PSA kinetics and radiologic response were evaluated, and outcomes were analyzed according to PSA thresholds and treatment timing. Results: Most patients (93.3%) had low-volume disease; 97.1% presented with ≤5 metastases. At a median follow-up of 28 months, LC was 99.3% and 95.5% of patients were progression-free. Complete radiological response was achieved in 87.5% of patients, and 68.4% attained ultralow PSA levels (≤0.02 ng/mL). Undetectable PSA and radiologic complete response were independently associated with improved PFS (p = 0.010 and p = 0.011, respectively). Treatment was well tolerated, with grade ≥3 toxicity occurring in only 2.2% of patients. Conclusions: The combination of apalutamide and SBRT in mHSPC is associated with high local and systemic disease control and minimal toxicity in a real-world setting. This approach may delay systemic treatment intensification and the onset of castration resistance. Prospective studies are warranted to confirm these findings. Full article

Stereotactic body radiotherapy (SBRT) delivers ablative radiation doses with sub-millimeter precision. Radiogenomic studies, meanwhile, provide insights into how tumor-intrinsic genetic factors influence responses to such high-dose treatments. This review explores the radiobiological mechanisms underpinning SBRT efficacy, emphasizing the roles of DNA damage response (DDR) pathways, tumor suppressor gene alterations, and inflammatory signaling in shaping tumor radiosensitivity or resistance. SBRT induces complex DNA double-strand breaks (DSBs) that robustly activate DDR signaling cascades, particularly via the ATM and ATR kinases. Tumors with proficient DNA repair capabilities often resist SBRT, whereas deficiencies in key repair genes can render them more susceptible to radiation-induced cytotoxicity. Mutations in tumor suppressor genes may impair p53-dependent apoptosis and disrupt cell cycle checkpoints, allowing malignant cells to evade radiation-induced cell death. Furthermore, SBRT provokes the release of pro-inflammatory cytokines and activates innate immune pathways, potentially leading to immunogenic cell death and reshaping the tumor microenvironment. Radiogenomic profiling has identified genomic alterations and molecular signatures associated with differential responses to SBRT and immune activation. These insights open avenues for precision radiotherapy approaches, including the use of genomic biomarkers for patient selection, the integration of SBRT with DDR inhibitors or immunotherapies, and the customization of treatment plans based on individual tumor genotypes and immune landscapes. Ultimately, these strategies aim to enhance SBRT efficacy and improve clinical outcomes through biologically tailored treatment. This review provides a comprehensive summary of current knowledge on the genetic determinants of response to stereotactic radiotherapy and discusses their implications for personalized cancer treatment. Full article

Background/Objectives: Non-ablative stereotactic body radiation therapy (SBRT) is commonly employed for locally advanced pancreatic cancer (LAPC) using computed tomography-guided radiotherapy (CTgRT) without online adaptive radiation therapy (oART). The safe delivery of ablative SBRT has been demonstrated using stereotactic magnetic resonance-guided online adaptive radiation therapy (SMART). We performed an in silico comparison of non-adapted CTgRT versus SMART to better understand the potential benefit of oART for ablative pancreatic SBRT. Methods: We retrospectively evaluated original and daily adapted SMART plans that were previously delivered for 20 consecutive LAPC cases (120 total plans across all patients) treated on a 0.35 T MR-linac prescribed to 50 Gy (gross disease) and 33 Gy (elective sites) simultaneously in five fractions. Six comparative CTgRT plans for each patient (one original, five daily treatment) were retrospectively generated with the same prescribed dose and planning parameters as the SMART plans assuming no oART availability. The impact of daily anatomic changes on CTgRT and SMART plans without oART was evaluated across each treatment day MRI scan acquired for SMART. Results: Ninety percent of cases involved the pancreatic head. No statistically significant differences were seen between CTgRT and SMART with respect to target coverage. Nearly all (96%) fractions planned on either CT or MRI platforms exceeded at least one GI organ at risk (OAR) constraint without oART. Significant differences favoring SMART over non-adaptive CTgRT were observed for the duodenum V35 Gy ≤ 0.5 cc (34.2 vs. 41.9 Gy, p = 0.0035) and duodenum V40 Gy ≤ 0.03 cc (37 vs. 52.5 Gy, p = 0.0006) constraints. Stomach V40 Gy trended towards significance favoring SMART (37 vs. 40.3 Gy, p = 0.057) while no significant differences were seen. Conclusions: This is the first study that quantifies the frequency and extent of GI OAR constraint violations that would occur during ablative five-fraction SBRT using SMART vs. CTgRT. GI OAR constraint violations are expected for most fractions without oART whereas all constraints can be achieved with oART. As such, these data suggest that oART should be required for ablative five-fraction pancreatic SBRT. Full article

Background: With rising life expectancy and widespread lung cancer screening, early-stage non-small cell lung cancer (NSCLC) incidence has increased. While surgery is the standard treatment for operable stage I NSCLC, many patients are ineligible due to age or comorbidities. Stereotactic body radiotherapy (SBRT) has achieved good primary tumor control rates and overall survival. This study compares the outcomes of SBRT and surgery for stage I NSCLC using propensity score overlap-weighted dataset. Methods: This retrospective study analyzed clinical stage I NSCLC patients treated at a tertiary hospital from 2012 to 2021. Baseline differences between SBRT and surgery groups were adjusted using overlap weighting. AI-based CT analysis (CT AI-CAD) assessed tumor characteristics, verified by radiologists. Primary outcomes were 5-year cumulative incidence of recurrence and overall survival, with subgroup analyses based on tumor features. Results: Of 1474 patients, 1258 underwent surgery, and 216 received SBRT. After overlap weighting, baseline characteristics were well balanced. The 5-year cumulative incidence of recurrence and OS showed no statistically significant differences between SBRT and surgery groups (recurrence: 16.2% vs. 16.1%; OS: 80.5% vs. 82.9%). Further AI-based CT subgroup analysis showed no significant differences in recurrence rates across tumor features. A solid tumor diameter associated with a significant increase in recurrence was identified as 16.6 mm for SBRT and 18.6 mm for surgery. Conclusions: After overlap weighting, SBRT and surgery showed no statistically significant differences in treatment outcomes in stage I NSCLC. These findings may help guide the timing and selection of safe and effective treatment approaches. Full article

Background/Objectives: The management of localized prostate cancer with regional lymph node involvement (N1M0) presents significant clinical challenges. While once considered indicative of systemic disease, improved imaging and evolving treatment paradigms have redefined node-positive disease as potentially curable. This systematic review aims to assess current evidence regarding treatment modalities and outcomes for patients with localized N1M0 prostate cancer. Methods: A systematic review was conducted to identify studies evaluating therapeutic strategies for N1M0 prostate cancer. Eligible studies included randomized controlled trials, retrospective analyses, and consensus guidelines. Treatment approaches reviewed included radical prostatectomy (RP) with pelvic lymph node dissection (PLND), whole pelvic radiotherapy (WPRT), prostate-only radiotherapy (PORT), androgen deprivation therapy (ADT), and metastasis-directed therapy (MDT), including stereotactic body radiotherapy (SBRT). Key outcomes included overall survival (OS), biochemical recurrence-free survival (bRFS), disease-free survival (DFS), and treatment-related toxicity. Results: Multimodal approaches—particularly the combination of ADT with WPRT or adjuvant radiotherapy following RP—were associated with improved survival outcomes. Patients with limited nodal burden and undetectable postoperative prostate-specific antigen (PSA) levels derived the most benefit. The use of prostate-specific antigen membrane positron-emission tomography/computed tomography (PSMA PET/CT) enhanced detection and guided MDT in oligorecurrent disease. SBRT, simultaneous integrated boost (SIB), and hypofractionated regimens demonstrated promising efficacy with acceptable toxicity profiles. Conclusions: Node-positive localized prostate cancer is optimally managed with individualized, multidisciplinary strategies. Combining systemic and locoregional treatments improves outcomes in selected patients. Ongoing prospective studies are warranted to refine patient selection, optimize treatment sequencing, and integrate novel imaging and systemic agents. Full article

Background and Objectives: Stereotactic radiotherapy enhances local tumor control by delivering high doses directly to the tumor. It is thought to activate the immune system via T-cells, possibly creating a systemic response. This study aims to evaluate stereotactic body radiotherapy’s (SBRT) impact on the immune system by measuring T-cell transcription factors, such as TBX21, GATA-3, FoxP3, and RORɣt. Materials and Methods: Peripheral blood samples were collected from 103 patients before SBRT and from 66 patients two months post-treatment. We measured transcription factors TBX21, GATA-3, FOXP3, and RORγt using ELISA, and performed a complete blood count and C-reactive protein analysis to rule out infections. Statistical analyses included paired t-tests and correlation analyses to assess changes before and after treatment. Results: Post-treatment, significant reductions were observed in TBX21 (Th1), GATA-3 (Th2), and FOXP3 (Treg), while RORɣt (Th17) remained stable but trended higher in lung cancer patients. No correlations were found with demographic factors. However, TBX21 levels were significantly related to the planning target volume (PTV) and biologically effective dose (BED10) in the lung region. Larger PTVs (≥16.5 cc) and higher BED10 doses (≥100 Gy) were linked to smaller reductions in TBX21 (p = 0.008, p = 0.04) and increased RORɣt levels (p = 0.01). Conclusions: Stereotactic radiotherapy reduces immunosuppressive markers like FOXP3 and GATA-3, indicating its potential to boost immune activation by suppressing Treg and Th2 cells. Larger target volumes and higher BED10 values may enhance Th1 responses through TBX21. These findings suggest that SBRT activates the immune system, and its combination with immunotherapy could be promising. Full article

Oligoprogressive disease refers to the setting of a prior or ongoing receipt of systemic therapy, with typically up to three metastatic areas having increased in size and/or avidity compared to the start of the systemic therapy. The role of local ablative therapy (LAT) including radiation has mostly been evaluated in the oligometastatic setting with limited data in oligoprogression. A similar principle of using ablative radiation in the oligometastatic setting may be applied to consolidative therapy for oligoprogressive disease. If systemic therapy can control the majority of the disease, and a few areas of therapy-resistant clones continue to proliferate, then potentially controlling those few resistant clones while maintaining systemic control may be beneficial. Doing so may also extend the duration of benefit of the systemic therapy and reserve next systemic line options at a later point, and potentially improve progression free survival (PFS). Here, we review the current data evaluating the role of radiation in oligoprogressive non-small cell lung cancer (NSCLC) and ongoing trials. Full article

Prostate cancer (PCa) remains the most prevalent cancer among men and the second leading cause of cancer-related deaths worldwide. Early diagnosis is crucial as it opens up various treatment options with curative intent. Recent advancements confirm that radiotherapy (RT), particularly through modern techniques like stereotactic body RT (SBRT) and single-dose RT (SDRT), is a safe and effective treatment for both localized and advanced PCa. This manuscript reviews the evolution and current state of primary prostate SDRT, focusing on its benefits and limitations. SDRT offers advantages such as reduced treatment time and enhanced patient convenience, showing promising efficacy and safety, especially for low- and intermediate-risk PCa. Challenges include controlling intrafraction variability and organ motion, as well as minimizing urethral toxicity. Next-generation imaging and MR-guided RT are improving treatment accuracy. While SDRT shows potential for cost-effective PCa treatment, further research is needed to address its limitations and refine its clinical application. Full article

Goal: This study evaluates the feasibility and outcome of a personalized MRI-based liver SBRT treatment planning platform with the SPION contrast agent Ferumoxytol^® (Sandoz Inc.; Princeton, NJ, USA) to maintain a superior real-time visualization of liver tumors and volumes of functional hepatic parenchyma for radiotherapy planning throughout multi-fractionated liver SBRT with online plan adaptations on an Elekta Unity 1.5 T MR-Linac (Elekta; Stockholm, Sweden). Materials and Methods: Patients underwent SPION-enhanced MRI on the Elekta Unity MR-Linac for improved tumor and functional hepatic parenchyma visualization. An automated contouring algorithm was applied for the delineation and subsequent guided avoidance of functional liver parenchyma volumes (FLVs) on the SPION-enhanced MR-Linac. Radiation dose constraints were adapted exclusively to FLV. Local control, toxicity, and survival were assessed with at least 6-month radiographic follow-up. Pre- and post-transplant outcomes were analyzed in the subset of patients with HCC and hepatic cirrhosis who completed SBRT as a bridge to liver transplant. Model of End-Stage Liver Disease (MELD-Na) was used to score hepatic function before and after SBRT. Results: With a median follow-up of 23 months (range: 3–40 months), 23 HCC patients (26 lesions treated) and 9 patients (14 lesions treated) with hepatic metastases received SBRT (mean dose: 48 Gy, range: 36–54 Gy) in 1–5 fractions. Nearly all patients in this study had pe-existing liver conditions, including hepatic cirrhosis (23), prior TACE (7), prior SBRT (18), or history of hepatic resection (2). Compared to the non-contrast images, SPIONs improved tumor visibility on post-SPION images on the background of negatively enhancing functionally active hepatic parenchyma. Prolonged SPION-contrast retention within hepatic parenchyma enabled per-fraction treatment adaptation throughout the entire multi-fraction treatment course. FLV loss (53%, p < 0.0001) was observed in cirrhotic patients, but functional and anatomic liver volumes remained consistent in non-cirrhotic patients. Mean dose to FLV was maintained within the liver threshold tolerance to radiation in all patients after the optimization of Step-and-Shoot Intensity-Modulated Radiotherapy (SS-IMRT) on the SPION-enhanced MRI-Linac. No radiation-induced liver disease was observed within 6 months post-SBRT, and the MELD-Na score in cirrhotic patients was not significantly elevated at 3-month intervals after SBRT completion. Conclusions: SPION Ferumoxytol^® administered intravenously as an alternative MRI contrast agent on the day of SBRT planning produces a long-lasting contrast effect between tumors and functional hepatic parenchyma for precision targeting and guided avoidance during the entire course of liver SBRT, enabling fast and accurate online plan adaptation on the 1.5 T Elekta Unity MR-Linac. This approach demonstrates a safe and effective bridging therapy for patients with hepatic cirrhosis, leading to low toxicity and favorable transplant outcomes. Full article

Aim: An Early-Stage Non-Small Cell Lung Cancer (ES-NSCLC) patient candidate for stereotactic body radiotherapy (SBRT) may start their treatment without a histopathological assessment, due to relevant comorbidities. The aim of this study is twofold: (i) build prognostic models to test the association between CT-derived radiomic features (RFs) and the outcomes of interest (overall survival (OS), progression-free survival (PFS) and loco-regional progression-free survival (LRPFS)); (ii) quantify whether the combination of clinical and radiomic descriptors yields better prediction than clinical descriptors alone in prognostic modeling for ES-NSCLC patients treated with SBRT. Methods: Simulation CT scans of ES-NSCLC patients treated with curative-intent SBRT at the European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy between 2013 and 2023 were retrospectively retrieved. PyRadiomics v3.0.1 was used for image preprocessing and subsequent RFs extraction and selection. A radiomic score was calculated for each patient, and three prognostic models (clinical model, radiomic model, clinical-radiomic model) for each survival endpoint were built. Relative performances were compared using the C-index. All analyses were considered statistically significant if p < 0.05. The statistical analyses were performed using R Software version 4.1. Results: A total of 100 patients met the inclusion criteria. Median age at diagnosis was 76 (IQR: 70–82) years, with a median Charlson Comorbidity Index (CCI) of 7 (IQR: 6–8). At the last available follow-up, 76 patients were free of disease, 17 were alive with disease, and 7 were deceased. Considering relapses, progression of any kind was diagnosed in 31 cases. Regarding model performances, the radiomic score allowed for excellent prognostic discrimination for all the considered endpoints. Of note, the use of RFs alone proved to be more informative than clinical characteristics alone for the prediction of both OS and LRPFS, but not for PFS, for which the individual predictive performances slightly favored the clinical model. Conclusion: The use of RFs for outcome prediction in this clinical setting is promising, and results seem to be rather consistent across studies, despite some methodological differences that should be acknowledged. Further studies are being planned in our group to externally validate these findings, and to better determine the potential of RFs as non-invasive and reproducible biomarkers in ES-NSCLC. Full article