Androgen deprivation alone versus combined with pelvic radiation for adverse events and quality of life in clinically node-positive prostate cancer.

The COHORT trial was conducted to compare the efficacy of androgen deprivation therapy (ADT) alone versus combined with radiation therapy (ADT + RT) for clinically node-positive prostate cancer. We reported adverse events and quality of life between the two treatment groups. Fifty-nine patients were randomized to receive ADT alone or ADT + RT and analyzed as per-protocol. Patients allocated to the ADT alone arm received ADT for at least 2 years. Patients in the ADT + RT arm received additional pelvic RT. Higher rates of grade ≥ 2 acute genitourinary (0% vs. 7.1%) and late gastrointestinal adverse events (0% vs. 14.3%) were reported in the ADT + RT arm compared with the ADT alone. However, grade ≥ 2 late genitourinary toxicity was more common in the ADT alone than the ADT + RT arm (9.7% vs. 3.6%). No grade ≥ 3 adverse events were reported. There was no statistically significant difference in EPIC scores between two treatment arms. However, the urinary and bowel domains tended to decrease and recover in the ADT + RT arm. In conclusion, ADT + RT demonstrated higher rates of adverse events compared to ADT alone. However, the addition of RT did not significantly impact the quality of life.

Prospective study investigating hypofractionated proton beam therapy in patients with inoperable early stage non-small cell lung cancer.

Purpose: To report the results of hypofractionated proton beam therapy (PBT) for the treatment of early stage lung cancer in patients not suitable for surgical resection. Methods: Data from 27 adult patients, who were diagnosed with inoperable cT1-3N0 non-small cell lung cancer (NSCLC) between March 2018 and August 2020, were analyzed. PBT was prescribed as 64 Cobalt Grey equivalents delivered in 8 fractions (Sumitomo, Japan). The primary endpoint was local control; secondary endpoints included overall survival, quality of life, and grade ≥3 toxicity. Results: The median follow-up was 28.9 months (range, 1.1-62.1 months). During follow-up, 13 (48.1%) patients experienced disease progression, including local progression in 7. Two-year local control rates were 73.5%, 85.7% for T1, and 61.4% for T2-3. The worse local control rate was observed in those with large clinical target volumes (≥ 47.5 cc) and heavy smoking history (≥30 pack-years). The two-year overall survival rate was 76.5%. Grade 3 radiation-related toxicities were observed in 2 (7.4%) patients. In the European Organization for Research and Treatment of Cancer Quality of Life Core 30 results, the global score did not change significantly from baseline. However, dyspnea score increased from 19.8 before PBT to 33.3 at 4 months' post-PBT (p=0.047) and was maintained until 13 months (p=0.028). Conclusion: Hypofractionated PBT was a safe treatment option for inoperable early stage NSCLC and appeared to be appropriate for small tumor volumes. However, local control for larger tumors requires further improvement.

Hypofractionated radiation therapy combined with androgen deprivation therapy for high-risk localized prostate cancer.

INTRODUCTION: This study aimed to analyse the treatment outcomes of moderately hypofractionated radiation therapy (RT) combined with androgen deprivation therapy (ADT) and the prognostic implications of prostate-specific antigen (PSA) kinetics in high-risk localized prostate cancer. METHODS: The medical records of 140 patients who underwent definitive RT (70 Gy in 28 fractions) combined with ADT were retrospectively reviewed. ADT consists of a gonadotropin-releasing hormone agonist and an anti-androgen. Clinical outcomes included the biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS) and prostate cancer-specific survival (PCSS). The BFR and CFR were stratified by the PSA nadir and the time to the PSA nadir, respectively. Acute and late genitourinary and gastrointestinal adverse events were also recorded. RESULTS: The 5-year BFR, CFR, OS and PCSS rates were 9.8%, 4.5%, 90.2% and 98.7%, respectively. Ninety-five (67.9%) patients achieved a PSA nadir of 0.01 ng/mL. Patients with a PSA nadir >0.01 ng/mL had a significantly higher BFR and CFR (BFR, P = 0.001; CFR, P = 0.027), even after adjusting for other prognostic factors [per 0.1 ng/mL; BFR, hazard ratio (HR) 4.440, P < 0.001; CFR, HR 4.338, P = 0.001]. However, the time to the PSA nadir and pre-RT PSA were not significantly associated with the BFR and CFR. Six patients (4.3%) reported grade 3 late adverse events, mostly haematuria and haematochezia. CONCLUSION: Definitive RT with moderate hypofractionation combined with long-term ADT showed good efficacy for high-risk localized prostate cancer. The lowest PSA nadir was significantly associated with a low recurrence rate, indicating the importance of PSA follow-up.

Comparison of radiotherapy techniques in patients with thymic epithelial tumor who underwent postoperative radiotherapy.

PURPOSE: This retrospective study aimed to compare clinical outcomes and dosimetric parameters between radiation therapy (RT) techniques in patients with thymic epithelial tumor (TET). MATERIALS AND METHODS: From January 2016 to December 2020, 101 patients with TET received adjuvant RT (median, 52.8 Gy; range, 48.4 to 66.0). Three different RT techniques were compared: three-dimensional conformal RT (3D-CRT; n = 59, 58.4%), intensity-modulated RT (IMRT; n = 23, 22.8%), and proton beam therapy (PBT; n = 19, 18.8%). RESULTS: The median age of the patients and the follow-up period were 55 years (range, 28 to 79) and 43.4 months (range, 7.7 to 77.2). Patients in the PBT group were of the youngest age (mean age, 45.4 years), while those in IMRT group had the largest clinical target volume (mean volume, 149.6 mL). Patients in the PBT group had a lower mean lung dose (4.4 Gy vs. 7.6 Gy vs. 10.9 Gy, respectively; p < 0.001), lower mean heart dose (5.4 Gy vs. 10.0 Gy vs. 13.1 Gy, respectively; p = 0.003), and lower mean esophageal dose than patients in the 3D-CRT and IMRT groups (6.3 Gy vs. 9.8 Gy vs. 13.5 Gy, respectively; p = 0.011). Twenty patients (19.8%) showed disease recurrence, and seven patients (6.9%) died. The differences in the survival rates between RT groups were not statistically significant. CONCLUSION: In patients with TET who underwent adjuvant RT, PBT resulted in a lower dose of exposure to adjacent organs at risk. Survival outcomes for patients in PBT group were not significantly different from those in other groups.

Neoadjuvant Cisplatin-Based Chemotherapy Followed by Selective Bladder Preservation Chemoradiotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder: Post Hoc Analysis of Two Prospective Studies.

Purpose: Bladder preservation chemoradiotherapy (CRT) in patients with a clinical complete response (cCR) following cisplatin-based neoadjuvant chemotherapy (NAC) is a promising treatment strategy for muscle-invasive bladder urothelial carcinoma (MIBC). A combined analysis of raw data from two prospective phase II studies was performed to better evaluate the feasibility of selective bladder preservation CRT. Materials and Methods: The analysis was based on primary efficacy data from two independent studies, including 76 MIBC patients receiving NAC followed by bladder preservation CRT. The efficacy data included metastasis-free survival (MFS) and disease-free survival (DFS). For the present analysis, starting point of survival was defined as the date of commencing CRT. Results: Among 76 patients, 66 had a cCR following NAC. Sixty-four patients received gemcitabine/cisplatin (GC) combination chemotherapy in neoadjuvant setting, and 12 received nivolumab plus GC. Bladder preservation CRT following NAC was generally well-tolerated, with low urinary tract symptoms being the most common late complication. With a median follow-up of 64 months, recurrence was recorded in 43 patients (57%): intravesical only (n=20), metastatic only (n=16), and both (n=7). In 27 patients with intravesical recurrence, transurethral resection and BCG treatment was given to 17 patients. Salvage cystectomy was performed in 10 patients. Median DFS was 46.3 (95% CI, 25.1-67.5) months, and the median MFS was not reached. Neither DFS nor MFS appeared to be affected by any of the baseline characteristics. However, DFS was significantly longer in patients with a cCR than in those without (HR, 0.465; 95% CI, 0.222-0.976). Conclusion: The strategy of NAC followed by selective bladder preservation CRT based on the cCR is feasible in the treatment of MIBC. A standardized definition of cCR is needed to better assess disease status post-NAC.

Role of invasive mediastinal nodal staging in survival outcomes of patients with non-small cell lung cancer and without radiologic lymph node metastasis: a retrospective cohort study.

Background: Lung cancer diagnostic guidelines advocate for invasive mediastinal nodal staging (IMNS), but the survival benefits of this approach in patients with non-small cell lung cancer (NSCLC) without radiologic evidence of lymph node metastasis (rN0) remain uncertain. We aimed to investigate the impact of IMNS in patients with rN0 NSCLC by comparing the long-term survival between patients who underwent IMNS and those who did not (non-IMNS). Methods: In this retrospective cohort study, we included patients with NSCLC but without radiologic evidence of lymph node metastasis from the Registry for Thoracic Cancer Surgery and the clinical data warehouse at the Samsung Medical Centre, Republic of Korea between January 2, 2008 and December 31, 2016. We compared the 5-year overall survival (OS) rate as the primary outcome after propensity score matching between the IMNS and non-IMNS groups. The age, sex, performance statue, tumor size, centrality, solidity, lung function, FDG uptake in PET-CT, and histological examination of the tumor before surgery were matched. Findings: A total of 4545 patients (887 in the IMNS group and 3658 in the non-IMNS group) who received curative treatment for NSCLC were included in this study. By the mediastinal node dissection, the overall incidence of unforeseen mediastinal node metastasis (N2) was 7.2% (317/4378 patients). Despite the IMNS, 67% of pathological N2 was missed (61/91 patients with unforeseen N2). Based on propensity score matching, 866 patients each for the IMNS and non-IMNS groups were assigned. There was no significant difference in 5-year OS and recurrence-free survival (RFS) between two groups: 5-year OS was 73.9% (95% confidence interval, CI: 71%-77%) for IMNS and 71.7% (95% CI: 68.6%-74.9%; p = 0.23), for non-IMNS (hazard ratio, HR 0.90, 95% CI: 0.77-1.07), while 5-year RFS was 64.7% (95% CI: 61.5%-68.2%) and 67.5% (95% CI: 64.3%-70.9%; p = 0.35 (HR 1.08, 95% CI: 0.92-1.27), respectively. Moreover, the timing and locations of recurrence were similar in both groups. Interpretation: IMNS might not be required before surgery for patients with NSCLC without LN suspicious of metastasis. Further randomised trials are required to validate the findings of the present study. Funding: None.

Long-term findings of rectal endoscopy and rectal bleeding after moderately hypofractionated, intensity-modulated radiotherapy for prostate cancer.

To present rectal endoscopic findings and toxicity after definitive moderately hypofractionated, intensity-modulated radiotherapy (IMRT) for prostate cancer. We retrospectively reviewed patients who underwent IMRT for prostate cancer and underwent post-radiotherapy endoscopies between 2008 and 2018. Endoscopic findings were reviewed and graded using Vienna Rectoscopy Score (VRS). We have analyzed the association between endoscopic findings and rectal bleeding, and investigated risk factors for rectal bleeding. Total 162 patients met the inclusion criteria of this study. There was a trend of VRS worsening during the initial 3 years after radiotherapy followed by recovery. Rectal bleeding was highest at 1 year after radiotherapy and improved thereafter. The 5-year cumulative incidence of grade ≥ 2 rectal bleeding was 14.8%. In the multivariable Cox regression analysis, cardiovascular disease (hazard ratio [HR] 2.732, P = 0.037), rectal wall V65 (HR 1.158, P = 0.027), and VRS ≥ 3 in first post-radiotherapy endoscopy (HR 2.573, P = 0.031) were significant risk factors for rectal bleeding. After IMRT for prostate cancer, VRS and rectal bleeding worsened over 1-3 years after radiotherapy and recovered. Cardiovascular disease, rectal wall V65, and VRS ≥ 3 in first post-radiotherapy endoscopy were significant risk factors for rectal bleeding.

Prostate-specific antigen kinetics in hypofractionated radiation therapy alone for intermediate- and high-risk localized prostate cancer.

Background: This study aimed to evaluate the treatment outcomes and define the prostate-specific antigen (PSA) kinetics as potential prognostic factors in patients with intermediate- or high-risk localized prostate cancer (PCa) who underwent moderately hypofractionated radiation therapy. Methods: The study retrospectively reviewed the medical records of 149 patients with intermediate- or high-risk localized PCa who underwent definitive radiation therapy (70 Gy in 28 fractions) without androgen deprivation therapy. Clinical outcomes were analyzed based on risk stratification (favorable-intermediate, unfavorable-intermediate, and high-risk). The biochemical failure rate (BFR) and clinical failure rate (CFR) were stratified based on the PSA nadir and the time to the PSA nadir to identify the prognostic effect of PSA kinetics. Acute and late genitourinary and gastrointestinal adverse events were analyzed. Results: Significant differences were observed in the BFR and CFR according to risk stratification. No recurrence was observed in the favorable intermediate-risk group. The 7-year BFR and CFR for the unfavorable intermediate-risk and high-risk groups were 19.2% and 9.8%, and 31.1% and 25.3%, respectively. Patients with a PSA nadir >0.33 ng/mL or a time to the PSA nadir <36 months had a significantly greater BFR and CFR. The crude rate of grade 3 late adverse events was 3.4% (genitourinary: 0.7%; gastrointestinal: 2.7%). No grade 4-5 adverse event was reported. Conclusion: A significant difference in clinical outcomes was observed according to risk stratification. The PSA nadir and time to the PSA nadir were strongly associated with the BFR and CFR. Therefore, PSA kinetics during follow-up are important for predicting prognosis.

Radiomics Analysis of 18F-FDG PET/CT for Prognosis Prediction in Patients with Stage III Non-Small Cell Lung Cancer Undergoing Neoadjuvant Chemoradiation Therapy Followed by Surgery.

We investigated the prognostic significance of radiomic features from 18F-FDG PET/CT to predict overall survival (OS) in patients with stage III NSCLC undergoing neoadjuvant chemoradiation therapy followed by surgery. We enrolled 300 patients with stage III NSCLC who underwent PET/CT at the initial work-up (PET1) and after neoadjuvant concurrent chemoradiotherapy (PET2). Radiomic primary tumor features were subjected to LASSO regression to select the most useful prognostic features of OS. The prognostic significance of the LASSO score and conventional PET parameters was assessed by Cox proportional hazards regression analysis. In conventional PET parameters, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of each PET1 and PET2 were significantly associated with OS. In addition, both the PET1-LASSO score and the PET2-LASSO score were significantly associated with OS. In multivariate Cox regression analysis, only the PET2-LASSO score was an independently significant factor for OS. The LASSO score showed better predictive performance for OS regarding the time-dependent receiver operating characteristic curve and decision curve analysis than conventional PET parameters. Radiomic features from PET/CT were an independent prognostic factor for the estimation of OS in stage III NSCLC. The newly developed LASSO score using radiomic features showed better prognostic results for individualized OS estimation than conventional PET parameters.

Whole-Section Landscape Analysis of Molecular Subtypes in Curatively Resected Small Cell Lung Cancer: Clinicopathologic Features and Prognostic Significance.

Despite the recognition of various molecular subtypes in small cell lung cancer (SCLC), most information has been derived from tissue microarrays or biopsy samples. Using whole sections of curatively resected SCLCs, we aimed to elucidate the clinicopathologic relevance and prognostic significance of the molecular subtypes. Whole-section immunohistochemistry was conducted for 73 resected SCLC samples using antibodies representative of molecular subtypes: ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1. Furthermore, multiplexed immunofluorescence was performed to evaluate the spatial relationship of YAP1 expression with other markers. The molecular subtype was correlated with clinical and histomorphologic features, and its prognostic role was explored in this cohort and validated in a previously published surgical cohort. Overall, the molecular subtypes were SCLC-A (54.8%), SCLC-N (31.5%), SCLC-P (6.8%), and SCLC-TN (triple negative, 6.8%). We found significant enrichment of SCLC-N (48.0%; P = .004) among combined SCLCs. Although a distinct subtype with high YAP1 expression was not found, YAP1 expression was reciprocal with ASCL1/NEUROD1 at the cellular level within tumors and was increased in areas with non-small cell-like morphology. Furthermore, the YAP1-positive SCLCs showed significantly increased recurrence at mediastinal lymph nodes (P = .047) and are an independent poor prognostic factor after surgery (adjusted hazard ratio, 2.87; 95% CI, 1.20-6.86; P = .017). The poor prognostic impact of YAP1 was also validated in the external surgical cohort. Our whole-section analysis in resected SCLCs reveals the highly heterogeneous nature of the molecular subtype and its clinicopathologic relevance. Although YAP1 is not a subtype delineator, YAP1 relates to the phenotypic plasticity of SCLC and may serve as a poor prognostic factor in resected SCLC.

Reduced radiation exposure to circulating blood cells in proton therapy compared with X-ray therapy in locally advanced lung cancer: Computational simulation based on circulating blood cells.

Background: We estimated the dose of circulating blood cells (CBCs) in patients with locally advanced non-small cell lung cancer for predicting severe radiation-induced lymphopenia (SRIL) and compared pencil-beam scanning proton therapy (PBSPT) and intensity-modulated (photon) radiotherapy (IMRT). Materials and methods: After reviewing 325 patients who received definitive chemoradiotherapy with PBSPT (n = 37) or IMRT (n = 164). SRIL was diagnosed when two or more events of an absolute lymphocyte count < 200 µL occurred during the treatment course. Dose information for the heart and lungs was utilized for the time-dependent computational dose calculation of CBCs. Results: The dose distribution of CBCs was significantly lesser in the PBSPT group than that in the IMRT group. Overall, 75 (37.3%) patients experienced SRIL during the treatment course; 72 and 3 patients were treated with IMRT and PBSPT, respectively. SRIL was associated with poor progression-free and overall survival outcomes. Upon incorporating the dose information of CBCs for predicting SRIL, CBC D90% > 2.6 GyE was associated with the development of SRIL with the baseline lymphocyte count and target volume. Furthermore, PBSPT significantly reduced the dose of CBC D90% (odds ratio = 0.11; p = 0.004) compared with IMRT. Conclusion: The results of this study demonstrate the significance of the dose distribution of CBCs in predicting SRIL. Furthermore, reducing the dose of CBCs after PBSPT minimized the risk of SRIL. Lymphocyte-sparing radiotherapy in PBSPT could improve outcomes, particularly in the setting of maintenance immunotherapy.

The Incidence and Risk Factors of Chronic Pulmonary Infection after Radiotherapy in Patients with Lung Cancer.

PURPOSE: This study aimed to investigate cumulative incidence and risk factors associated with chronic pulmonary infection (CPI) development after radiotherapy for lung cancer. Materials and Methods: We retrospectively analyzed 1,872 patients with lung cancer who received radiotherapy for lung cancer from 2010-2014, had a follow-up period of ≥ 3 months after radiotherapy, and did not have CPI at the time of radiotherapy. CPI was defined as pulmonary tuberculosis, non-tuberculous mycobacterial pulmonary disease, chronic pulmonary aspergillosis, or pulmonary actinomycosis. The cumulative incidence of CPI and overall survival (OS) were estimated using the Kaplan-Meier method, and a multivariable Cox proportional hazards analysis was performed to identify risk factors associated with CPI development. RESULTS: The median follow-up period was 2.3 years with OS rates of 55.6% and 37.6% at 2 and 5 years, respectively. CPI developed in 59 patients at a median of 1.8 years after radiotherapy, with cumulative incidence rates of 1.1%, 3.4%, 5.0%, and 6.8% at 1, 3, 5, and 7 years, respectively. A lower body mass index, interstitial lung disease, prior pulmonary tuberculosis, larger clinical target volume, history of lung cancer surgery or radiation pneumonitis, and use of inhaled corticosteroids were independent risk factors for CPI development. CONCLUSION: The long-term survival rate of lung cancer patients receiving radiotherapy was not low, but the cumulative incidence of CPI gradually increased to 6.8% at 7 years after radiotherapy. Therefore, close monitoring of CPI development is required in surviving patients with risk factors.

Association of T Cell Senescence with Radiation Pneumonitis in Patients with Non-small Cell Lung Cancer.

PURPOSE: Associations between immunosenescence and radiation pneumonitis (RP) are largely unknown. We aimed to identify a peripheral blood T cell senescence biomarker to predict RP in patients with non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Patients with locally advanced NSCLC who received definitive concurrent chemoradiotherapy (dCRT) were prospectively registered (cohort 1, n=23; cohort 2, n=31). Peripheral blood was collected at baseline, during dCRT, and at 1 month post-dCRT. Patients were dichotomized to grade ≥2 (G2+) RP and grade 0-1 (G0-1) RP. Flow cytometry was performed to assess phenotypes and functional properties of T cell subsets. RP incidence was estimated via competing risk analysis. RESULTS: Five and six patients exhibited G2+ RP following dCRT in cohorts 1 and 2, respectively. Patients with G2+ RP exhibited a more aged T cell pool and higher frequencies of senescent CD57+CD28-CD8+ T cells than patients with G0-1 RP at baseline, during dCRT, and at 1 month post-dCRT. These senescent cells exhibited increased granzyme B, IFN-γ, and TNF-α production. Higher baseline frequency of CD57+CD28-CD8+ T cells was an independent predictor of G2+ RP (hazard ratio, 8.42; 95% confidence interval, 2.58-27.45; P<0.001). Recursive partitioning analysis revealed three distinct risk groups stratified by baseline CD57+CD28-CD8+ T cell frequency and lung V20 Gy, with 1-year cumulative G2+ RP incidences of 50.0%, 16.7%, and 0% for high-, intermediate-, and low-risk groups, respectively (P=0.002). CONCLUSIONS: Higher baseline frequencies of CD57+CD28-CD8+ T cells correlated with increased G2+ RP risks. Our results suggest the need for further investigation of the role of T cell senescence on radiation-induced organ damage.

Neoadjuvant Nivolumab Plus Gemcitabine/Cisplatin Chemotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder.

PURPOSE: The activity and safety of neoadjuvant nivolumab plus gemcitabine/cisplatin (N+GC) were tested in patients with muscle-invasive bladder urothelial carcinoma (MIBC). Materials and Methods: In a prospective phase II trial, patients with cT2-T4a N0 MIBC who were eligible for cisplatin and medically appropriate to undergo radical cystectomy (RC) were enrolled. Treatment with nivolumab 3 mg/kg on days 1 and 15 plus GC (cisplatin 70 mg/m2 on day 1, and gemcitabine 1,000 mg/m2 on days 1, 8, and 15) was repeated every 28 days up to 3 or 4 cycles, depending on the surgery schedules. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging (≤ ypT1), disease-free survival (DFS), and safety. RESULTS: Between September 2019 and October 2020, 51 patients were enrolled. Neoadjuvant N+GC was well tolerated. Among 49 patients who completed neoadjuvant N+GC, clinical complete response (cCR) was achieved in 59% of intent-to-treat (ITT) population. RC was performed in 34 (69%) patients. pCR was achieved in 24% (12/49) of ITT population and 35% (12/34) of RC patients. Median DFS was not reached. Over a median follow-up of 24 months, 12 patients experienced disease recurrence and were treated with palliative therapy or surgery. Although 12 patients declined surgery and were treated with concurrent chemoradiotherapy, DFS was longer in patients with cCR after neoadjuvant therapy than those without. Preoperative programmed death-ligand 1 (PD-L1) did not correlate with pCR or pathologic downstaging rates. CONCLUSION: Neoadjuvant N+GC was feasible and provided meaningful pathologic responses in patients with MIBC, regardless of baseline PD-L1 expression (ONO-4538-X41; CRIS.nih.go.kr, KCT0003804).

Pulmonary function and toxicities of proton versus photon for limited-stage small cell lung cancer.

PURPOSE: We aimed to compare the oncological outcomes and toxicities of definitive proton beam therapy (PBT) and photon beam therapy in patients with limited-stage small cell lung cancer (LS-SCLC). MATERIALS AND METHODS: We retrospectively reviewed 262 patients with newly diagnosed LS-SCLC who underwent definitive PBT (n = 20; proton group) or photon beam therapy (n = 242; photon group) with concurrent chemotherapy between January 2016 and February 2021 and compared overall survival (OS), progression-free survival (PFS), dose-volume parameters, and toxicities between the groups. RESULTS: The median follow-up duration was 24.5 months (range, 3.7 to 78.7). Baseline lung function was significantly worse and clinical target volume (CTV) was larger in the proton group (CTV: 296.6 vs. 215.3 mL; p = 0.080). The mean lung V10 was 37.7% ± 16.8% and 51.6% ± 24.5% in the proton and photon groups, respectively (p = 0.002). Two-year OS and PFS rates were 57.2% and 35.7% in the proton group and 65.3% and 40.8% in the photon group, respectively (p = 0.542 and 0.748, respectively). Grade ≥2 radiation pneumonitis and esophagitis occurred in 5 (25.0%) and 7 (35.0%) PBT-treated patients and 66 (27.3%) and 40 (16.5%) photon beam therapy-treated patients, respectively (p = 0.826 and 0.062, respectively). CONCLUSION: Although the proton group had poorer lung function and a larger CTV than that in the photon group, both groups exhibited comparable treatment outcomes and radiation-related toxicities in LS-SCLC. PBT may be a valuable therapeutic modality in patients with poor pulmonary function or extensive disease burden owing to its lung-sparing ability.

Clinical Outcomes Following Proton and Photon Stereotactic Body Radiation Therapy for Early-Stage Lung Cancer.

We aimed to report the clinical outcomes following stereotactic body radiation therapy (SBRT) using photon or proton equipment in early-stage lung cancer. We retrospectively reviewed 202 cT1-2N0M0 lung cancer patients who underwent SBRT with 60 Gy in four consecutive fractions between 2010 and 2019 at our institution: 168 photon SBRT and 34 proton SBRT. Patients who underwent proton SBRT had relatively poor baseline lung condition compared to those who underwent photon SBRT. Clinical outcomes were comparable between treatment modalities: 5-year local control (90.8% vs. 83.6%, p = 0.602); progression-free survival (61.6% vs. 57.8%, p = 0.370); overall survival (51.7% vs. 51.9%, p = 0.475); and cause-specific survival (70.3% vs. 62.6%, p = 0.618). There was no statistically significant difference in grade ≥ 2 toxicities: radiation pneumonitis (19.6% vs. 26.4%, p = 0.371); musculoskeletal (13.7% vs. 5.9%, p = 0.264); and skin (3.6% vs. 0.0%, p = 0.604). In the binary logistic regression analysis of grade ≥3 radiation pneumonitis, poor performance status and poor baseline diffusion capacity of lung for carbon monoxide were significant. To summarize, though patients with high risk of developing lung toxicity underwent proton SBRT more frequently, the SBRT techniques resulted in comparable oncologic outcomes with similar toxicity profiles. Proton SBRT could be considered for patients at high risk of radiation pneumonitis.

Proton Beam Therapy versus Photon Radiotherapy for Stage I Non-Small Cell Lung Cancer.

Proton beam therapy (PBT) and photon radiotherapy for stage I non-small cell lung cancer (NSCLC) were compared in terms of clinical outcomes and dosimetry. Data were obtained from patients who underwent PBT or photon radiotherapy at two institutions-the only two facilities where PBT is available in the Republic of Korea. Multivariate Cox proportional hazards models and propensity score-matched analyses were used to compare local progression-free survival (PFS) and overall survival (OS). Survival and radiation exposure to the lungs were compared in the matched population. Of 289 patients included in the analyses, 112 and 177 underwent PBT and photon radiotherapy, respectively. With a median follow-up duration of 27 months, the 2-year local PFS and OS rates were 94.0% and 83.0%, respectively. In the multivariate analysis, a biologically effective dose (BED10, using α/ß = 10 Gy) of ≥125 cobalt gray equivalents was significantly associated with improved local PFS and OS. In the matched analyses, the local PFS and OS did not differ between groups. However, PBT showed significantly lower lung and heart radiation exposure in the mean dose, V5, and V10 than photon radiotherapy. PBT significantly reduced radiation exposure to the heart and lungs without worsening disease control in stage I NSCLC patients.

Prospective Study of Proton Therapy for Lung Cancer Patients with Poor Lung Function or Pulmonary Fibrosis.

PBT has a unique depth-dose curve with a Bragg peak that enables one to reduce the dose to normal lung tissue. We prospectively enrolled 54 patients with non-small cell lung cancer treated with definitive PBT. The inclusion criteria were forced expiratory volume in 1 s (FEV1) ≤ 1.0 L or FEV1 ≤ 50% of predicted or diffusing capacity of the lungs for carbon monoxide (DLco) ≤ 50%, or pulmonary fibrosis. The primary endpoint was grade ≥ 3 pulmonary toxicity, and secondary endpoints were changes in pulmonary function and quality of life. The median age was 71.5 years (range, 57-87). Fifteen (27.8%) and fourteen (25.9%) patients had IPF and combined pulmonary fibrosis and emphysema, respectively. The median predicted forced vital capacity (FVC), FEV1, and DLco were 77% (range, 42-104%), 66% (range, 31-117%), and 46% (range, 23-94%), respectively. During the follow-up (median, 14.7 months), seven (13.0%) patients experienced grade ≥ 3 pulmonary toxicity. Seven months after the completion of PBT, patients with IPF or non-IPF interstitial lung disease (ILD) experienced a decrease in the FVC but the decrease in DLco was not significant. Under careful monitoring by pulmonologists, PBT could be a useful treatment modality for lung cancer patients with poor lung function or pulmonary fibrosis.

Toxicity of Proton Therapy versus Photon Therapy on Salvage Re-Irradiation for Non-Small Cell Lung Cancer.

This study evaluated the toxicity associated with radiation techniques on curative re-irradiation (re-RT) in patients with thoracic recurrence of non-small cell lung cancer (NSCLC). From 2011 to 2019, we retrospectively reviewed the data of 63 patients with salvage re-RT for in-field or marginal recurrence of NSCLC at two independent institutions. Re-RT techniques using X-ray beams and proton beam therapy (PBT) were also included. Re-RT had a 2-year overall survival (OS) and local progression-free survival of 48.0% and 52.0%, respectively. Fifteen patients experienced grade 3 or higher toxicity after re-RT. The complication rates were 18.2% (4/22) and 26.8% (11/41) in PBT patients and X-ray patients, respectively. Airway or esophageal fistulas occurred in seven patients (11.1%). Fistulas or severe airway obstruction occurred in patients with tumors adjacent to the proximal bronchial tree and esophagus, who underwent hypofractionated radiotherapy (RT) or concurrent chemotherapy, and with a higher dose exposure to the esophagus. In conclusion, salvage re-RT was feasible even in patients with local recurrence within the previous RT field. PBT showed similar survival outcomes and toxicity to those of other techniques. However, thoracic re-RT should be performed carefully considering tumor location and RT regimens such as the fraction size and concurrent chemotherapy.

Dynamics of Circulating Immune Cells During Chemoradiotherapy in Patients with Non-Small Cell Lung Cancer Support Earlier Administration of Anti-PD-1/PD-L1 Therapy.

PURPOSE: Chemoradiotherapy (CRT) followed by consolidation immune checkpoint inhibitors significantly improves survival in unresectable locally advanced non-small cell lung cancer. However, the optimal sequence for CRT and immune checkpoint inhibitors has not yet been established. We investigated the dynamics of peripheral blood immune cells during CRT to determine the best sequence for treatment. METHODS AND MATERIALS: Peripheral blood samples were prospectively collected pretreatment, weekly during CRT for 6 weeks, and 1 month posttreatment in 24 patients with locally advanced non-small cell lung cancer who received definitive CRT. Immune cell analysis was performed by flow cytometry. Ex vivo PD-1 blockade assays were performed by IFN-γ intracellular cytokine staining. RESULTS: Lymphopenia was prominently observed during CRT and mostly recovered 1 month post-CRT. Robust proliferation of CD8+ T cells was induced, peaking in the last week during CRT and decreasing post-CRT. The robust proliferation of CD8+ T cells led to an increase in the frequency of CD28-CD57+ replicative senescent and terminally differentiated cells post-CRT. Tumor-reactive CD8+ T cells increased during CRT and peaked in the last week. One month post-CRT, the frequency of tumor-reactive CD8+ T cells decreased and TOXhiTCF1lo terminally exhausted CD8+ T cells significantly increased. Anti-PD-1-induced functional restoration of PD-1+CD8+ T cells was maximized in the last week of CRT and significantly decreased post-CRT. CONCLUSIONS: The findings suggest that earlier administration of PD-1 blockade may be associated with superior efficacy compared with delayed administration after completion of CRT. These findings provide an immunologic rationale for optimal timing of combining immune checkpoint inhibitors with CRT in clinical trials.