Safety and Efficacy of HL301 In Radiation Pneumonitis in Patients With Unresectable Non-Small Cell Lung Cancer Receiving Curative Concurrent Chemoradiotherapy: A Multicenter, Randomized, Double-Blinded, Placebo-Controlled, Phase 2a Clinical Trial.

PURPOSE: We aimed to investigate the safety and efficacy of HL301, a standardized combination product of 7 medicinal plants, in radiation pneumonitis in patients with unresectable non-small cell lung cancer undergoing curative concurrent chemoradiotherapy. METHODS AND MATERIALS: The target accrual was 87 and a total of 63 patients were enrolled due to poor accrual rate. We randomly assigned the 63 patients to receive a placebo (arm A), or 1200 mg HL301 (arm B), or 1800 mg HL301 (arm C). Patients received weekly paclitaxel and carboplatin concurrently with intensity-modulated radiation therapy at 60 to 66 Gy in conventional fractionation. Durvalumab was administered as a maintenance treatment according to standard clinical practice. HL301 was administered orally, daily for 12 weeks. The primary endpoint was incidence of grade ≥2 radiation pneumonitis at 24 weeks postchemoradiotherapy. RESULTS: The baseline characteristics of the patients were well balanced. The drug was tolerable with a compliance rate of 86.6%, 86.2%, and 88.8% in arms A, B, and C, respectively (P = .874). None of the patients experienced severe drug-related adverse events. No significant difference in the rate of adverse events were observed between the treatment arms. The incidence of grade ≥2 radiation pneumonitis at 24 weeks postchemoradiotherapy was 37.5% (95% CI, 18.5%-61.4%), 55.6% (95% CI, 33.7%-75.4%), and 52.4% (95% CI, 32.4%-71.7%) in arms A, B, and C, respectively (P = .535). CONCLUSIONS: This is the first exploratory clinical trial to test the safety and efficacy of HL301 in patients with non-small cell lung cancer. Safety and feasibility of HL301 were established but no signals of efficacy in reducing radiation pneumonitis was observed in this dose level.

Treatment of Fanconi anemia patient with synchronous esophageal and tongue cancer in COVID-19 era: a case report.

Although Fanconi anemia patients accompany a high risk of multiple cancers, radiation therapy on these patients has been carried out only in limited cases due to the concern for radiation toxicity that stems from their susceptibility to radiation. We report a case of a 28-year-old female patient diagnosed as synchronous esophageal and tongue cancer, and underwent two cycles of radiation therapy, inevitably in the condition of coronavirus disease 2019 infection. She received radiation therapy of 30 Gy to esophageal mass with neoadjuvant aim in her first-round radiation therapy, and later received 27 Gy to tongue cancer surgical bed with adjuvant aim in her second-round radiation therapy. With no further treatment, she has been maintaining no evidence of disease state for 7 months. Managing Fanconi anemia patients with multiple cancers using radiation therapy is feasible, in which cases a dose de-escalation may be important considering the radiation toxicity and possible future re-treatment.

Effect of Lactobacillus Rhamnosus GG for Regulation of Inflammatory Response in Radiation-Induced Enteritis.

The purpose of this study was to investigate the role of Lactobacillus rhamnosus GG (LGG) probiotics in radiation enteritis using in vivo mice. A total of 40 mice were randomly assigned to four groups: control, probiotics, radiotherapy (RT), and RT + probiotics. For the group of probiotics, 0.2 mL of solution that contained 1.0 × 108 colony-forming units (CFU) of LGG was used and orally administered daily until sacrifice. For RT, a single dose of 14 Gy was administered using a 6 mega-voltage photon beam to the abdominopelvic area. Mice were sacrifice at day 4 (S1) and day 7 (S2) after RT. Their jejunum, colon, and stool were collected. A multiplex cytokine assay and 16 s ribosomal RNA amplicon sequencing were then performed. Regarding cytokine concentrations in tissues, pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6 and monocyte chemotactic protein-1, showed significantly decreased protein levels in colon tissues of the RT + probiotics group than in the RT alone group (all p < 0.05). As for comparing microbial abundance through alpha-diversity and beta-diversity, no significant differences were observed between the RT + probiotics and RT alone groups, except for an increase in alpha-diversity in the stool of the RT + probiotics group. Upon analysis of differential microbes based on treatment, the dominance of anti-inflammatory-related microbes, such as Porphyromonadaceae, Bacteroides acidifaciens, and Ruminococcus, was observed in the jejunum, colon, and stool of the RT + probiotics group. With regard to predicted metabolic pathway abundances, the pathways associated with anti-inflammatory processes, such as biosynthesis of pyrimidine nucleotides, peptidoglycans, tryptophan, adenosylcobalamin, and propionate, were differentially identified in the RT + probiotics group compared to the RT alone group. Protective effects of probiotics on radiation enteritis were potentially derived from dominant anti-inflammation-related microbes and metabolites.

Intrathoracic Progression Is Still the Most Dominant Failure Pattern after First-Line Chemo-immunotherapy in Extensive-Stage Small-Cell Lung Cancer: Implications for Thoracic Radiotherapy.

PURPOSE: This study aimed to compare the failure patterns before and after the introduction of immunotherapy and to determine the role of thoracic radiotherapy (TRT) in extensive-stage small-cell lung cancer (ES-SCLC) treatment. MATERIALS AND METHODS: We retrospectively reviewed 294 patients with ES-SCLC, of which 62.2% underwent chemotherapy alone, 13.3% underwent chemotherapy followed by consolidative TRT (TRT group), and 24.5% underwent chemotherapy with immune checkpoint inhibitor (ICI group). We performed propensity-score matching (PSM) to compare each treatment group. RESULTS: The median follow-up duration was 10.4 months. At the first relapse, in the cohort showing objective response, the proportion of cases showing intrathoracic progression was significantly lower in the TRT group (37.8%) than in the chemotherapy-alone (77.2%, p < 0.001) and the ICI (60.3%, p=0.03) groups. Furthermore, in the subgroup analysis, TRT showed benefits related to intrathoracic progression-free survival (PFS) in comparison with ICI in patients with less than two involved extrathoracic sites (p=0.008) or without liver metastasis (p=0.02) or pleural metastasis (p=0.005) at diagnosis. After PSM, the TRT group showed significantly better intrathoracic PFS than both chemotherapy-alone and ICI groups (p < 0.001 and p=0.04, respectively), but showed no significant benefit in terms of PFS and overall survival in comparison with the ICI group (p=0.17 and p=0.31, respectively). CONCLUSION: In ES-SCLC, intrathoracic progression was the most dominant failure pattern after immunotherapy. In the era of chemoimmunotherapy, consolidative TRT can still be considered a useful treatment strategy for locoregional control.

Definitive radiotherapy in patients with clinical T1N0M0 esophageal squamous cell carcinoma: A multicenter retrospective study (KROG 21-10).

PURPOSE: To assess the failure pattern and analyze the treatment scheme of definitive radiation therapy (RT) for T1N0M0 esophageal squamous cell carcinoma (ESCC). METHODS: We performed a multi-institutional retrospective analysis in T1N0M0 ESCC patients who underwent definitive RT from 2010 to 2019. Patterns of failure were demonstrated as in-, and out-field locoregional, and distant metastasis. In the analysis, freedom-from locoregional recurrence (FFLRR) and their association with clinicopathologic factors were evaluated. Propensity score matching in cT1b patients was done. RESULTS: 168 patients were included with a median follow-up of 34.0 months, and 26 cT1a, 116 cT1b disease. The rates of 3-year all and locoregional recurrence for cT1a were 30.5% and 24.1% and those for cT1b were 27.1% and 25.9%, respectively. Among 116 cT1b patients, 69 patients received elective nodal irradiation (ENI) and 47 received involved field irradiation (IFI). After propensity score matching, the 3-year FFLRR rate was 84.5%. There was no difference between ENI and IFI in FFLRR (P = 0.831) and OS (P = 0.525). The 3-year FFLRR was 83.8% (95% Confidence interval (CI), 61.8-93.8%) in IFI group and 85.3% (95% CI, 65.1-94.3%) in ENI group. In multivariate analysis, concurrent chemotherapy use was marginally associated with FFLRR (Hazard ratio, 0.16; P = 0.064). CONCLUSION: cT1a patients who cannot receive endoscopic resection showed similar failure rates as cT1b patients, questioning the staging accuracy and raised the need for thorough treatment like chemoradiotherapy. In cT1b patients, IFI with 50 to 60 Gy and concurrent chemotherapy could be reasonable.

Exploring the past, present, and future of postoperative radiotherapy for N2 stage non-small cell lung cancer.

Despite conventionally applied postoperative radiotherapy (PORT) in pathological N2 (pN2) stage non-small cell lung cancer (NSCLC) considering high locoregional recurrence, its survival benefit has been a continuous topic of debate. Although several randomized clinical trials have been conducted, many of them have been withdrawn or analyzed without statistical significance due to slow accrual, making it difficult to determine the efficacy of PORT. Recently, the results of large-scale randomized clinical trials have been published, which showed some improvement in disease-free survival with PORT, but finally had no impact on overall survival. Based on these results, it was expected that the debate over PORT in pN2 patients with NSCLC would come to an end. However, since pN2 patients have different clinicopathologic features, it has become more important to carefully select the patient population who will benefit from PORT. In addition, given the development of systemic treatments such as molecular-targeted therapy and immunotherapy, it is crucial to evaluate whether there is any benefit to PORT in the midst of these recent changes. Therefore, determining the optimal treatment approach for NSCLC pN2 patients remains a complex issue that requires further research and evaluation.

Clinical outcomes of radical radiotherapy for pulmonary sarcomatoid carcinoma.

PURPOSE: Pulmonary sarcomatoid carcinoma (PSC) is recognized for its aggressiveness and poor prognosis. The role of radical radiotherapy in PSC remains uncertain due to its scarcity and limited data. In the absence of an effective systemic agent, this study aims to explore the possibility of cure and to investigate potential prognostic factors and treatment outcomes. MATERIALS AND METHODS: From January 2005 to December 2021, 149 PSC patients were identified. Among 62 patients who received radiotherapy for lung lesions, 25 who underwent palliative radiotherapy and 16 who underwent surgery were excluded. RESULTS: The median patient age was 71 years. The majority were male, and 17 patients (81.0%) were diagnosed at an advanced stage. After radical radiotherapy, distant metastasis (47.6%) was the most common site of failure, while the local recurrence rate was quite low (9.5%). Eventually, five patients (26.3%) demonstrated either a partial response or complete remission, including three complete remissions with durable responses. The median progression-free survival (PFS) and overall survival were 4.6 months and 7.9 months, respectively. Univariate and multivariate analyses revealed that a tumor size >5 cm was associated with a worse prognosis (p = 0.045), while a radiation dose >58 GyEQD2 was significantly associated with better PFS (p = 0.038). CONCLUSION: This study demonstrates clinical outcomes after radical radiotherapy in managing PSC, suggesting tumor size and radiation dose could be a predictor of a systemic response. Given the known bad prognosis but complete remission could be achieved in certain subgroups, future research should explore the potential strategies using radical radiotherapy for this challenging patient population.

Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a biomarker in locally advanced unresectable thymic epithelial neoplasm: A single-center, retrospective, longitudinal cohort study.

BACKGROUND: Thymic epithelial tumors (TET) are rare malignancies and lack well-defined biomarkers for neoadjuvant therapy. This study aimed to evaluate the clinical utility of artificial intelligence (AI)-powered tumor-infiltrating lymphocyte (TIL) analysis in TET. METHODS: Patients initially diagnosed with unresectable thymoma or thymic carcinoma who underwent neoadjuvant therapy between January 2004 and December 2021 formed our study population. Hematoxylin and eosin-stained sections from the initial biopsy and surgery were analyzed using an AI-powered spatial TIL analyzer. Intratumoral TIL (iTIL) and stromal TIL (sTIL) were quantified and their immune phenotype (IP) was identified. RESULTS: Thirty-five patients were included in this study. The proportion of patients with partial response to neoadjuvant therapy was higher in the group with nondesert IP in preneoadjuvant biopsy (63.6% vs. 17.6%, p = 0.038). A significant increase in both iTIL (median 22.18/mm2 vs. 340.69/mm2 , p < 0.001) and sTIL (median 175.19/mm2 vs. 531.02/mm2 , p = 0.004) was observed after neoadjuvant therapy. Patients with higher iTIL (>147/mm2 ) exhibited longer disease-free survival (median, 29 months vs. 12 months, p = 0.009) and overall survival (OS) (median, 62 months vs. 45 months, p = 0.002). Patients with higher sTIL (>232.1/mm2 ) exhibited longer OS (median 62 months vs. 30 months, p = 0.021). CONCLUSIONS: Nondesert IP in initial biopsy was associated with a better response to neoadjuvant therapy. Increased infiltration of both iTIL and sTIL in surgical specimens were associated with longer OS in patients with TET who underwent resection followed by neoadjuvant therapy.

Treatment patterns and results of salvage treatment for regional recurrences after stereotactic ablative radiotherapy for primary non-small cell lung cancer.

PURPOSE: Stereotactic ablative radiotherapy (SABR) for early-stage lung cancer has shown promising results; however, regional recurrence (RR) development is not uncommon, and salvage treatment strategies have not been established. We aimed to investigate treatment patterns, prognostic factors, and survival outcomes. MATERIALS AND METHODS: A retrospective analysis of 391 patients who underwent SABR for primary lung cancer from 2012 to 2019 was performed. Among these patients, 90 patients showed recurrence, including local recurrence (n = 9), RR (n = 33), distant metastasis (DM) (n = 57), and RR with simultaneous DM (n = 8). The median follow-up duration was 17.3 months. RESULTS: The median age was 75 years, and most patients underwent primary SABR due to poor lung function (69.7%). Various salvage treatments were performed in cases of RR, including chemotherapy (n = 15), radiotherapy (n = 7), concurrent chemoradiotherapy (n = 2), and best supportive care (n = 9). The median overall survival (OS) and post-recurrence OS (PR-OS) were 22.9 and 11.2 months, respectively. In multivariate analysis, age ≤75 years (HR = 0.36, p = 0.040), isolated recurrence (HR = 0.34, p = 0.037), and radiotherapy without chemotherapy (HR = 0.25, p = 0.024) were significant prognostic factors for PR-OS. CONCLUSIONS: Despite various salvage treatments, PR-OS was less than 1 year after RR in our frail patients group who underwent primary SABR. The toxicities of salvage chemotherapy could be quite severe; thus, careful patient selection is required. Further research is needed to validate our findings.

No survival benefit with early incorporation of thoracic radiotherapy using daily fractionation in patients with limited-stage small cell lung cancer undergoing chemoradiotherapy in the modern era: A systematic review and meta-analysis.

BACKGROUND: When concurrent chemoradiotherapy (CCRT) is administered for limited-stage small cell lung cancer (LS-SCLC), the early incorporation of thoracic radiotherapy (TRT) is generally recommended. However, it is controversial if this approach is really beneficial with most commonly used daily fractionated TRT in the modern era. METHODS: A systematic literature search was performed using several databases following the PRISMA guidelines from Jan 2000 to Nov 2022. We excluded twice-daily TRT-based studies. The hazard ratio (HR) for survival following late TRT as a primary effect size was pooled from comparisons within individual studies according to the timing of daily fractionated TRT (early vs. late). RESULTS: A total of 10 studies including 10,164 analyzable patients met all inclusion criteria. 'Early' timing usually referred to TRT within 1-2 cycles of concurrent chemotherapy. The pooled results demonstrated that the risk of death was not significantly increased following late TRT compared with early TRT (HR 1.01, 95% CI 0.84-1.20, p = 0.94). All sensitivity analysis and planned subgroup analyses showed similar results. In comparison with early TRT, late TRT did not significantly increase the risk of progression (HR 0.94, 95% CI 0.80-1.11, p = 0.48). Furthermore, late TRT was beneficial in alleviating grade 3 or higher esophagitis (OR 0.42, p = 0.01), but no significant differences was found in pneumonitis (OR 0.62, p = 0.38), and neutropenia (OR 0.57, p = 0.11). No evidence of publication bias was found. CONCLUSIONS: This is the first meta-analysis to support the late incorporation of TRT in managing patients with LS-SCLC undergoing daily fractionated CCRT in the modern era. This approach may not compromise survival and can prevent severe acute toxicities. Further prospective studies of the daily fractionated TRT timing are warranted.

Treatment outcomes of stereotactic body radiation therapy for pulmonary metastasis from sarcoma: a multicenter, retrospective study.

PURPOSE: The aim of this study was to evaluate the treatment outcomes and potential dose-response relationship of stereotactic body radiation therapy (SBRT) for pulmonary metastasis of sarcoma. MATERIALS AND METHODS: A retrospective review of 39 patients and 71 lesions treated with SBRT from two institutions was performed. The patients had oligometastatic or oligoprogressive disease, or were receiving palliation. Doses of 20-60 Gy were delivered in 1-5 fractions. The local control per tumor (LCpT) was evaluated according to the biologically effective dose with an α/ß ratio of 10 (BED10) of the prescribed dose (BED10 ≥ 100 Gy vs. BED10 < 100 Gy). Clinical outcomes per patient, including local control per patient (LCpP), pulmonary progression-free rate (PPFR), any progression-free rate (APFR), and overall survival (OS) were investigated. RESULTS: The median follow-up period was 27.2 months. The 1-, 2-, and 3-year LCpT rates for the entire cohort were 100.0%, 88.3%, and 73.6%, respectively. There was no observed difference in LCpT between the two BED10 groups (p = 0.180). The 3-year LCpP, PPFR, APFR, and OS rates were 78.1%, 22.7%, 12.9%, and 83.7%, respectively. Five (12.8%) patients with oligometastasis had long-term disease-free intervals, with a median survival period of 40.7 months. Factors that were associated with a worse prognosis were oligoprogression (vs. oligometastasis), multiple pulmonary metastases, and simultaneous extrathoracic metastasis. CONCLUSION: SBRT for pulmonary metastasis of sarcoma is effective. Some selected patients may achieve durable response. Considerations of SBRT indication and disease extent may be needed as they may influence the prognosis.

Efficacy of Prophylactic Cranial Irradiation According to the Risk of Extracranial Recurrence in Limited-Stage Small Cell Lung Cancer.

PURPOSE: We aimed to evaluate the effectiveness of prophylactic cranial irradiation (PCI) for "early brain metastasis", which occurs before extracranial recurrence (ECR), and "late brain metastasis", which occurs after ECR, in limited-stage small cell lung cancer (LS-SCLC). Materials and Methods: We retrospectively analyzed 271 LS-SCLC patients who underwent definitive chemoradiation. All patients were initially staged with brain magnetic resonance imaging and positron emission tomography. Intracranial recurrence (ICR), ECR, progression-free rate (PFR), and overall survival (OS) were analyzed as clinical endpoints. The competing risk of the first recurrence with ICR (ICRfirst) was evaluated. Significantly associated variables in multivariate analysis of ECR were considered as ECR risk factors. Patients were stratified according to the number of ECR risk factors. RESULTS: The application of PCI was associated with higher PFR (p=0.008) and OS (p=0.045). However, PCI was not associated with any of the clinical endpoints in multivariate analysis. The competing risk of ICRfirst was significantly decreased with the application of PCI (hazard ratio, 0.476; 95% confidence interval, 0.243 to 0.931; p=0.030). Stage III disease, sequential, and stable disease after thoracic radiation were selected as ECR risk factors. For patients without these risk factors, the application of PCI was significantly associated with increased OS (p=0.048) and a decreased risk of ICRfirst (p=0.026). CONCLUSION: PCI may play a role in preventing early brain metastasis rather than late brain metastasis after ECR, suggesting that only patients with a low risk of ECR may currently benefit from PCI.

Low-dose RaDiation therapy for patients with KNee osteoArthritis (LoRD-KNeA): a protocol for a sham-controlled randomised trial.

INTRODUCTION: Low-dose radiation therapy (LDRT) for osteoarthritis (OA) has been performed for several decades. However, supporting evidence from randomised studies using modern methodologies is lacking, and a recently published randomised study failed to show the significant benefit of LDRT. The presented trial aims to evaluate the efficacy and safety of LDRT for patients with knee OA. METHODS AND ANALYSIS: This prospective, multicentre, randomised trial will be conducted in the Republic of Korea. A total of 114 participants will be randomly assigned (1:1:1) to receive sham irradiation, 0.3 Gy/6 fractions of LDRT or 3 Gy/6 fractions of LDRT. Key inclusion criteria are primary knee OA with Kellgren-Lawrence grade 2-3 and visual analogue scale 50-90 when walking at the baseline. The primary endpoint is the rate of responders at 4 months after LDRT according to the OARSI-OMERACT criteria. Concomitant use of analgesics is prohibited until the primary efficacy evaluation is scheduled. ETHICS AND DISSEMINATION: Currently, approval from the Ministry of Food and Drug Safety of the Republic of Korea and the institutional review board of each participating hospital has been obtained. Patient enrolment began in October 2022 and is ongoing at three participating sites. The results will be disseminated to academic audiences and the public via publication in an international peer-reviewed journal and presentation at conferences. This trial will provide valuable information on the safety and efficacy of LDRT for patients with knee OA. TRIAL REGISTRATION NUMBER: NCT05562271.

Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways.

Radiation-induced sarcoma (RIS) is a rare but serious late complication arising from radiotherapy. Despite unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic alterations in them. We analyzed whole-genome sequencing in 11 RIS genomes matched with normal genomes to identify somatic alterations potentially associated with RIS development. Furthermore, the abundance of mutations, mutation signatures, and structural variants in RIS were compared with those in radiation-naïve spontaneous sarcomas. The mutation abundance in RIS genomes, including one hypermutated genome, was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations. The genomic footprints of nonhomologous end joining are prevalent at indels of RIS genomes compared with those in spontaneous sarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis was identified along with predisposing germline variants in the DNA-damage-repair pathways in RIS genomes. The characterization of RIS genomes on a whole-genome sequencing scale highlighted that the nonhomologous end joining pathway was associated with tumorigenesis, and it might pave the way for the development of advanced diagnostic and therapeutic strategies for RIS.

Regional lymph node recurrence after stereotactic body radiation therapy for lung cancer: Patterns of recurrence, treatment approaches, and clinical outcomes (KROG 21-09).

PURPOSE: To present the multi-institutional data on patterns of recurrence, treatment approaches, and clinical outcomes for regional lymph node (LN) recurrence after stereotactic body radiation therapy (SBRT) for primary lung cancer. MATERIALS AND METHODS: The medical records of 114 patients who experienced regional LN recurrence as the first recurrence after lung SBRT were retrospectively reviewed. Patterns of recurrence were classified as local recurrence, regional recurrence, and distant metastasis. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: Half of the patients had regional LN recurrence only. The most common simultaneous recurrence was distant metastasis (38.6 %). Common sites of regional recurrence were ipsilateral hilar (47.2 %), ipsilateral upper mediastinal (40.6 %), and subcarinal (42.5 %) LN stations. 24 (21.1 %) patients underwent salvage radiation therapy (RT), and 44 (38.6 %) patients underwent palliative treatment. Better OS was observed in the salvage RT group (p = 0.025). The 1-year PFS and OS rates were 27.7 % and 55.2 %, respectively, with salvage RT, 14.0 % and 39.9 %, respectively, with palliative treatment, and 22.8 % and 26.8 %, respectively, with no additional treatment. Multivariate analysis showed that salvage RT (PFS, HR 0.463, p = 0.050; OS, HR 0.312, p = 0.002), palliative treatment (PFS, HR 0.436, p = 0.013; OS, HR 0.553, p = 0.050), and simultaneous distant metastasis (PFS, HR 2.335, p = 0.005; OS, HR 1.726, p = 0.054) affected clinical outcomes. CONCLUSION: Many cases of regional LN recurrence are confined to the locoregional area of patients, and appropriate treatment can improve the prognosis of these patients.

Predictors of Post-chemoradiotherapy Pulmonary Complication in Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: We investigated the clinical effects and predictive factors of severe post-chemoradiotherapy pulmonary complications (PCPC) in locally advanced non-small cell lung cancer (LA-NSCLC). Materials and Methods: Medical records of 317 patients who underwent definitive concurrent chemoradiation (CCRT) for LA-NSCLC were reviewed retrospectively. PCPC was defined as an event of admission or emergency department visit for acute or subacute pulmonary inflammatory complications, including pneumonitis and pneumonia, within 6 months after CCRT initiation. Patient characteristics, baseline lung function tests, radiation dosimetric parameters, and laboratory tests were analyzed to investigate their association with PCPC. Prognostic endpoints were disease progression rate (DPR) and overall survival (OS). RESULTS: PCPC was reported in 53 patients (16.7%). The OS of patients with PCPC was significantly worse (35.0% in 2 years) than that of patients without PCPC (67.0% in 2 years, p < 0.001). However, 2-year DPRs were 77.0% and 70.7% in patients with and without PCPC, respectively, which were not significantly different (p=0.087). In multivariate logistic regression, PCPC was independently associated with grade ≥ 1 hypoalbuminemia during CCRT (odds ratio [OR], 5.670; 95% confidence interval [CI], 2.487 to 13.40; p < 0.001), lower diffusing capacity of carbon monoxide (DLCO) (per mL/min/mmHg; OR, 0.855; 95% CI, 0.743 to 0.974; p=0.022), and higher lung V5 (per 10%; OR, 1.872; 95% CI, 1.336 to 2.699; p < 0.001). CONCLUSION: PCPC might be a clinical endpoint to evaluate complications and predict the survival of patients subjected to CCRT for LA-NSCLC. Hypoalbuminaemia, DLCO, and lung V5 might predict PCPC in LA-NSCLC.

Image-Guided Versus Conventional Brachytherapy for Locally Advanced Cervical Cancer: Experience of Single Institution with the Same Practitioner and Time Period.

PURPOSE: This study aimed to compare treatment outcomes and toxicity profile between imaged-guided brachytherapy (IGBT) versus conventional brachytherapy (CBT) performed by the same practitioner during the same time period. MATERIALS AND METHODS: Medical records of 104 eligible patients who underwent brachytherapy for locally advanced cervical cancer were retrospectively reviewed. Fifty patients (48.1%) underwent IGBT, and 54 (51.9%) patients underwent CBT. All patients underwent concurrent chemoradiation with cisplatin. High-dose-rate intracavitary brachytherapy with dose prescription of 25-30 Gy in 4-6 fractions was performed for all patients. Late lower gastrointestinal (GI) and urinary toxicities occurred more than 3 months after the end of brachytherapy were included for comparative and dosimetric analyses. RESULTS: The median follow-up period was 18.33 months (range, 3.25 to 38.43 months). There were no differences in oncologic outcomes between the two groups. The IGBT group had lower rate of actuarial grade ≥ 3 toxicity than the CBT group (2-year, 4.5% vs. 25.7%; p=0.030). Cumulative equieffective D2cc of sigmoid colon was significantly correlated with grade ≥ 2 lower GI toxicity (p=0.033), while equieffective D2cc of rectum (p=0.055) and bladder (p=0.069) showed marginal significance with corresponding grade ≥ 2 toxicities in the IGBT group. Half of grade ≥ 3 lower GI toxicities impacted GI tract above the rectum. Optimal thresholds of cumulative D2cc of sigmoid colon and rectum were 69.7 Gy and 70.8 Gy, respectively, for grade ≥ 2 lower GI toxicity. CONCLUSION: IGBT showed superior toxicity profile to CBT. Evaluating the dose to the GI tract above rectum by IGBT might prevent some toxicities.

Analysis of Once-Daily Thoracic Radiotherapy Dose According to the Underlying Lung Disease in Patients with Limited-Stage Small Cell Lung Cancer Undergoing Concurrent Chemoradiotherapy.

PURPOSE: In the treatment of concurrent chemoradiotherapy (CCRT) in limited-stage small cell lung cancer, the optimal once-daily radiotherapy (RT) dose/fractionation remain unclear although it is the most frequently used. Therefore, this study aimed to compare the treatment outcomes and toxicities of modest dose RT (≤ 54 Gy) with those of standard dose RT (> 54 Gy) and investigate the benefit of the high dose based on patient factors. MATERIALS AND METHODS: Since 2004, our institution has gradually increased the thoracic RT dose. Among the 225 patients who underwent CCRT, 84 patients (37.3%) received > 54 Gy. Because the patients treated with RT > 54 Gy were not randomly assigned, propensity score matching (PSM) was performed. RESULTS: The proportion of patients treated with > 54 Gy increased over time (p=0.014). Multivariate analysis revealed that the overall tumor stage and dose > 54 Gy (hazard ratio, 0.65; p=0.029) were independent prognostic factors for overall survival (OS). PSM confirmed that thoracic RT doses of > 54 Gy showed significantly improved progression-free survival (3-year, 42.7% vs. 24.0%; p < 0.001) and OS (3-year, 56.2% vs. 38.5%; p=0.003). Sensitivity analysis also showed that 60 Gy resulted in better survival than 54 Gy. However, in patients with underlying lung disease, OS benefit from > 54 Gy was not observed but considerable rates of severe pulmonary toxicities were observed (p=0.001). CONCLUSION: Our analysis supports that the 60 Gy RT dose should be considered in the once-daily regimen of CCRT for limited-stage small cell lung cancer without underlying lung disease, but RT dose > 54 Gy did not seem to benefit for patients with chronic obstructive pulmonary disease or interstitial lung disease. Further study is needed to validate these results.

Prediction and clinical impact of delayed lymphopenia after chemoradiotherapy in locally advanced non-small cell lung cancer.

Introduction: The dosimetric factors of radiotherapy have an acute impact on the host immune system during chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (NSCLC). However, even after CRT, a substantial number of patients remain immunosuppressed with delayed lymphopenia. Therefore, we aimed to evaluate clinical and dose-volumetric predictors of delayed lymphopenia after CRT in locally advanced NSCLC. Materials and methods: We retrospectively reviewed 272 patients with locally advanced NSCLC who received definitive CRT from January 2012 to August 2020. Differential blood count data, including serum albumin values, were obtained at baseline, during and at first follow up after CRT. Acute and delayed lymphopenia events were defined as grade III/IV lymphopenia developed during or 4-12 weeks after CRT completion, which accounted for 84% and 10% of cases, respectively. Dose-volume histogram parameters for planned target volume, whole body, heart, lung, great vessels, spleen, esophagus and thoracic vertebral bodies were evaluated. Results: Multivariate analysis revealed that patients with delayed lymphopenia were associated with inferior overall survival (HR 2.53, P = 0.001) and progression-free survival (HR 1.98, P = 0.006). However, there was no significant survival difference between groups stratified by acute lymphopenia. On multivariable logistic regression models, lung V5, baseline ALC, during-CRT ALC, and albumin nadir were significant predictors for delayed lymphopenia. Furthermore, the nomogram for delayed lymphopenia based on these variables had good discrimination (area under the curve, 0.905). Conclusions: In this study, we investigated the prognostic significance of delayed lymphopenia and identified clinico-dosimetric parameters to predict delayed lymphopenia.

Comparable Clinical Outcome Using Small or Large Gross Tumor Volume-to-Clinical Target Volume Margin Expansion in Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma.

The purpose of this study was to evaluate the feasibility of small primary gross tumor volume (GTV)-to-clinical target volume (CTV) margin expansion in neoadjuvant chemoradiation for esophageal squamous cell carcinoma. Medical records of 139 patients with locally advanced esophageal squamous cell carcinoma who underwent neoadjuvant chemoradiation and radical esophagectomy were retrospectively reviewed. Patients treated with longitudinal primary GTV-to-CTV margin expansion of 2 cm and no additional expansion of the CTV through the esophagus were classified into a small margin (SM) group (37 patients). The remaining 102 patients were classified as a large margin (LM) group. Patterns of recurrence including local and out-field regional recurrence rates were compared between the two groups. Clinical outcomes including rates of local control, regional control, failure-free survival, and overall survival were also compared. More patients in the SM group underwent paclitaxel + carboplatin, Mckeown esophagectomy, and intensity-modulated radiation therapy than in the LM group. With a median follow-up of 25.6 months, there was no significant difference in the crude rate of local recurrence (10.8% vs. 6.9%, P=0.694), out-field regional recurrence (27.0% vs. 19.6%, P=0.480), or out-field regional recurrence without in-field recurrence (10.8% vs. 12.7%, P=0.988) between the two groups. There was no significant difference in failure-free survival (5-year, 34.4% vs. 30.6%, P=0.652) or overall survival (44.1% vs. 38.5%, P=1.000), either. Esophageal fistula was not reported in the SM group (0.0% vs. 7.9%, P=0.176). In conclusion, a radiation field with 2 cm of longitudinal primary GTV-to-CTV was feasible in the neoadjuvant setting for esophageal squamous cell carcinoma treatment.