Definitive Concurrent Chemoradiation Therapy Research Articles

Esophageal Cancer Outcomes After Definitive Chemotherapy With Intensity Modulated Proton Therapy

PurposeThe effectiveness of intensity-modulated proton therapy (IMPT) for esophageal cancer treated with definitive concurrent chemoradiation therapy remains inadequately explored. We investigated long-term outcomes and toxicity experienced by patients who received IMPT as part of definitive esophageal cancer treatment. Patients and MethodsWe retrospectively identified and analyzed 34 patients with locally advanced esophageal cancer who received IMPT with concurrent chemotherapy as a definitive treatment regimen at The University of Texas MD Anderson Cancer Center from 2011 to 2021. The median IMPT dose was 50.4 GyRBE in 28 fractions; concurrent chemotherapy consisted of fluorouracil and/or taxane and/or platinum. Survival outcomes were determined by the Kaplan-Meier method, and toxicity was scored according to the Common Terminology Criteria for Adverse Events version 4.0. ResultsThe median age of all patients was 71.5 years. Most patients had stage III (cT3 cM0) adenocarcinoma of the lower esophagus. At a median follow-up time of 39 months, the 5-year overall survival rate was 41.1%; progression-free survival, 34.6%; local regional recurrence-free survival, 78.1%; and distant metastasis-free survival, 65.0%. Common acute chemoradiation therapy-related toxicities included hematologic toxicity, esophagitis (and late-onset), fatigue, weight loss, and nausea (and late-onset); grade 3 toxicity rates were 26.0% for hematologic, 18.0% for esophagitis and 9.0% for nausea. No patient had grade ≥3 wt loss or radiation pneumonitis, and no patients had pulmonary fibrosis or esophageal fistula. No grade ≥4 events were observed except for hematologic toxicity (lymphopenia) in 2 patients. ConclusionLong-term survival and toxicity were excellent after IMPT for locally advanced esophageal cancer treated definitively with concurrent chemoradiation therapy. When available, IMPT should be offered to such patients to minimize treatment-related cardiopulmonary toxicity without sacrificing outcomes.

Quantification of diffuse parenchymal lung disease in non-small cell lung cancer patients with definitive concurrent chemoradiation therapy for predicting radiation pneumonitis.

We sought to quantify diffuse parenchymal lung disease (DPLD) extent using quantitative computed tomography (CT) analysis and to investigate its association with radiation pneumonitis (RP) development in non-small cell lung cancer (NSCLC) patients receiving definitive concurrent chemoradiation therapy (CCRT). A total of 82 NSCLC patients undergoing definitive CCRT were included in this prospective cohort study. Pretreatment CT scans were analyzed using quantitative CT analysis software. Low-attenuation area (LAA) features based on lung density and texture features reflecting interstitial lung disease (ILD) were extracted from the whole lung. Clinical and dosimetric factors were also evaluated. RP development was assessed using the Common Terminology Criteria for Adverse Events version 5.0. Univariable and multivariable logistic regression analyses were performed to identify independent risk factors for grade ≥3 (≥GR3) RP. RP was identified in 68 patients (73.9%), with nine patients (10.9%) experiencing ≥GR3 RP. Univariable logistic regression analysis identified excess kurtosis and high-attenuation area (HAA)_volume (cc) as significantly associated with ≥GR3 RP. Multivariable logistic regression analysis showed that the combined use of imaging features and clinical factors (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and CHEMO regimen) demonstrated the best performance (area under the receiver operating characteristic curve = 0.924) in predicting ≥GR3 RP. Quantified imaging features of DPLD obtained from pretreatment CT scans would predict the occurrence of RP in NSCLC patients undergoing definitive CCRT. Combining imaging features with clinical factors could improve the accuracy of the predictive model for severe RP.

Identification of predictive factors for early relapse in patients with unresectable stage III non-small cell lung cancer receiving consolidation durvalumab after concurrent chemoradiation therapy.

Patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiation therapy (CCRT) benefit from durvalumab consolidation therapy. However, predictive factors for early relapse during durvalumab maintenance have not yet been identified. The present study included the lung cancer cohort of the Catholic Medical Centers at the Catholic University of Korea from January 2018 to December 2021. A total of 51 NSCLC patients treated with durvalumab consolidation therapy after definitive CCRT were included in the analysis. Early relapse was defined as patients experiencing relapse within 6 months of starting initial durvalumab therapy. Among the 51 patients, 15 (29.4%) relapsed during the study period. Median time from initial therapy of durvalumab to progression was 451.00 ± 220.87 days (95% confidence interval [CI]: 18.10-883.90) in overall patients. In multivariate analysis, younger age (adjusted odds ratio [aOR], 0.792; 95% CI: 0.642-0.977; p = 0.030), higher pack-years (aOR, 1.315; 95% CI: 1.058-1.635; p = 0.014), non-COPD (aOR, 0.004; 95% CI: 0.000-0.828; p = 0.004) and anemia (aOR, 234.30; 95% CI: 1.212-45280.24; p = 0.042), were independent predictive factors for early relapse during durvalumab consolidation therapy. Younger age, higher number of pack-years, non-COPD, and anemia were independent predictive factors for early relapse during durvalumab consolidation therapy in patients with unresectable stage III NSCLC after definitive CCRT. Careful patient selection and clinical attention are needed for high-risk individuals.

Tumor Microenvironment Landscape of NSCLC Reveals Resistance Mechanisms for Programmed Death-Ligand 1 Blockade After Chemoradiotherapy: A Multicenter Prospective Biomarker Study (WJOG11518L:SUBMARINE)

IntroductionThe PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE). MethodsA total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers. ResultsThe importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocyte density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17–14.04] for CD8+ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12–20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. ConclusionsOur study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.

Abstract 2173: A multi-institutional prospective biomarker study of durvalumab after concurrent chemoradiation therapy in patients with unresectable stage III non-small cell lung cancer (WJOG11518L/SUBMARINE)

Abstract Background: Programmed cell death-ligand 1 (PD-L1) inhibitor durvalumab has been found to improve disease control in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with definitive concurrent chemoradiation therapy (dCCRT), but approximately a half of patients eventually experience disease progression within one year after the start of durvalumab. The mechanism of this resistance at such an early timing is poorly identified. Therefore, we conducted a prospective biomarker study to explore the resistance mechanisms to durvalumab after CCRT (Trial Identifier: UMIN000035916). Methods: A total of 139 patients with unresectable stage III NSCLC enrolled into this study after dCCRT were treated with durvalumab for up to 1 year. 135 patients who fulfilled the predetermined selection criteria were included for this primary biomarker analysis. Archival tumor tissues collected before the treatment were analyzed by immunohistochemistry for several key biomarkers such as PD-L1, CD8, and CD73, DNA sequencing for tumor-mutation burden (TMB) and genomic profile, as well as gene expression profiling (GEP). Peripheral blood mononuclear cells (PBMC) were also collected before and after durvalumab for flow-cytometry (FCM) analysis where available. Progression-free survival (PFS) was compared based on these biomarkers. Results: Median follow-up time was 14.4 months. Median PFS was 14.9 months (95% confidence interval [CI], 11.3-not reached), and 1-year PFS rate was 56.3% (95% CI, 47.3-64.3). CD8+ tumor-infiltrating lymphocytes (TILs), PD-L1 tumor proportion score (TPS), TMB, and CD73 on tumor cells were associated with PFS (hazard ratios [HRs], 0.40 [95% CI, 0.22-0.73] for CD8+TILs; 0.67 [95% CI, 0.40-1.11] for PD-L1-TPS ≥1%; 0.59 [95% CI, 0.34-1.02] for high TMB; 1.45 [95% CI, 0.86-2.43] for high CD73). Common pathogenic gene alterations such as EGFR, KRAS, and TP53 were not associated with PFS. Multivariable analysis including key clinical factors as covariables indicated that CD8+TILs and the CD73-expressing tumor cells were independently associated with durvalumab outcome (HRs, 0.26 [95% CI, 0.08-0.89] for CD8+TILs; 5.83 [95% CI, 1.33-25.62] for CD73). The significance of CD73-expressing tumor cells as a resistance factor was more obvious in patients with high CD8+TILs (HR, 2.35 [95% CI, 1.14-4.86]). GEP of tumor tissue and FCM of PBMC suggested that CD73-expressing tumor cells prevented effective reinvigoration of antigen-reactive CD8+ T cells by durvalumab due to the immunosuppressive activity. Conclusions: Low preexisting CD8+TILs or high CD73-expressing tumor cells were suggested to be primary resistance mechanism to durvalumab after CCRT in stage III NSCLC. Further development of next treatment approach will be prompted based on these findings. Citation Format: Koji Haratani, Atsushi Nakamura, Nobuaki Mamesaya, Kenji Sawa, Yasuto Yoneshima, Ryota Saito, Tomohiro Ozaki, Kenjiro Tsuruoka, Akito Hata, Kosuke Tsuruno, Tomohiro Sakamoto, Shunsuke Teraoka, Masahide Oki, Hiroshi Watanabe, Tomoyuki Otani, Kazuko Sakai, Shuta Tomida, Yasutaka Chiba, Akihiko Ito, Kazuto Nishio, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Hidetoshi Hayashi. A multi-institutional prospective biomarker study of durvalumab after concurrent chemoradiation therapy in patients with unresectable stage III non-small cell lung cancer (WJOG11518L/SUBMARINE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2173.

A phase Ⅱ prospective trial of photobiomodulation therapy in limiting oral mucositis in the treatment of locally advanced head and neck cancer patients.

This study aimed to compare the historical incidence rate of severe oral mucositis (OM) in head and neck cancer patients undergoing definitive concurrent chemoradiation therapy (CRT) versus a prospective cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with prophylactic photobiomodulation therapy (PBMT). This US-based, institutional, single-arm, phase Ⅱ prospective clinical trial was initiated in 50 patients (age ≥ 18 years, Karnofsky Performance Scale Index > 60, with locally advanced HNSCC (excluding oral cavity) receiving definitive or adjuvant radiation therapy (RT) with concurrent platinum-based chemotherapy (CT). PBMT was delivered three times per week throughout RT utilizing both an intraoral as well extraoral delivery system. Primary outcome measure was incidence of severe OM utilizing both the National Cancer Institute Common Toxicity Criteria, version 4.0 (NCI-CTCAE) Grade ≥3 and the World Health Organization Mucositis Grading Scale (WHO) Grade ≥3 versus historical controls; secondary outcome measures included time to onset of severe OM following therapy initiation. At baseline, all patients included in final analysis (N = 47) had OM Grade 0. Average RT and CT dose was (66.3 ± 5.1) Gy and (486.1 ± 106.8) mg/m2, respectively. Severe OM was observed in 11 of 47 patients (23%, confidence interval: 12, 38). OM toxicity grade trended upward during treatment, reaching a maximum at 7 weeks (WHO: 1.8 vs. NCI-CTCAE: 1.7). Subsequently, OM grade returned to baseline 3 months following completion of RT.The mean time toonset of severe OM was (35 ± 12) days. The mean time to resolution of severe OM was (37 ± 37) days. Compared to historical outcomes, PBMT aides in decreasing severe OM in patients with locally advanced HNSCC. PBMT represents a minimally invasive, prophylactic intervention to decrease OM as a major treatment-related side effect.

The prognostic significance of pretreatment squamous cell carcinoma antigen levels in cervical cancer patients treated by concurrent chemoradiation therapy and a comparison of dosimetric outcomes and clinical toxicities between tomotherapy and volumetric modulated arc therapy

BackgroundTo analyze the prognostic factors associated with stage IB-IVA cervical cancer in patients who underwent concurrent chemoradiation therapy (CCRT) and to compare the clinical toxicities and dosimetric parameters of organs at risk between the different radiotherapy techniques.MethodsThis retrospective study enrolled 93 patients with stage IB-IVA cervical cancer who underwent definitive CCRT between April 2009 and December 2017. Nine patients (9.7%) received 3DCRT, 43 patients (46.2%) underwent VMAT, and 41 patients (44.1%) received tomotherapy, and all of them followed by brachytherapy using a 2D planning technique. The treatment outcomes and related prognostic factors were analyzed. We also compared the clinical toxicities and dosimetric parameters between the different techniques used for the last 30 patients.ResultsWith a median follow-up of 52.0 months, the 5-year overall survival (OS), progression-free survival (PFS), locoregional recurrence–free survival (LRRFS), and distant metastases–free survival (DMFS) were analyzed. In a Cox proportional hazards regression model, pretreatment SCC Ag > 10 ng/mL was a significant prognostic factor for PFS (hazard ratio [HR] 2.20; 95% confidence interval [CI] 1.03–4.70; P = 0.041), LRRFS (HR, 3.48; 95% CI 1.07–11.26; P = 0.038), and DMFS (HR 2.80; 95% CI 1.02–7.67; P = 0.045). Increasing the rectal volume receiving a radiation dose exceeding 30 Gy (V30 of rectum; odds ratio [OR] 1.15; 95% CI 1.10–1.30; P = 0.03) was associated with a higher possibility of ≥ Grade 2 acute radiation therapy (RT)-related diarrhea. The median rectal V30 values were 56.4%, 97.5%, and 86.5% for tomotherapy, 3-dimensional conformal radiation therapy (3DCRT), and volumetric modulated arc therapy (VMAT), respectively (P < 0.001). In addition, the chance of experiencing ≥ Grade 2 acute diarrhea were 10.0%, 66.7%, and 54.5% for tomotherapy, 3DCRT, and VMAT, respectively (P = 0.029).ConclusionsPatients with pretreatment SCC Ag ≤ 10 ng/mL have better PFS, LRRFS, and DMFS than those with pretreatment SCC Ag > 10 ng/mL. The rectal V30 is a significant predictor of severe acute diarrhea. Tomotherapy significantly decreased the rectal V30, reducing the severity of acute RT-related diarrhea during external beam RT.Trial registration This study was approved by the institutional review board at Kaohsiung Medical University Hospital. The registration number is KMUHIRB-E(I)-20190054 and retrospectively registered on 2019/3.

Risk factors for primary site necrosis after definitive concurrent chemoradiotherapy in head and neck cancer.

To identify risk factors of primary site necrosis (PSN) after definitive concurrent chemoradiation therapy (CCRT) in patients with nonoral cavity head and neck cancer (HNC). We retrospectively reviewed the records of 256 patients treated with CCRT for HNC during 2010-2018. Patient-related (age, sex, history of smoking, hypertension, diabetes mellitus, serum hemoglobin and albumin), tumor-related (tumor site, American Joint Committee on Cancer stage), and treatment-related (induction chemotherapy, maximum point dose and mean dose of planning target volume [PTV] of primary site, absolute volumes of the PTV receiving >50-75 Gy [V50-V75]) variables were analyzed. Critical dosimetric parameters of PSN were identified using receiver operating characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analyses were used to select the significant variables for PSN development. After median follow-up of 44 months (range, 5-127), 7 patients (2.7%) developed PSN with a median time to event of 10 months (range, 3-12). V70 ⩾79.8 mL was the most critical dosimetric parameter for PSN (area under the ROC curve 0.873, sensitivity 0.857, specificity 0.747). In univariate analyses, pretreatment serum hemoglobin <11.0 g/dL and V70 ⩾79.8 mL were significantly associated with higher risk of PSN occurrence. V70 ⩾79.8 mL (hazard ratio 5.960, 95% confidence interval 1.289-27.548; p = 0.022) remained significant predictors of PSN in multivariate analyses. V70 ⩾79.8 mL is significantly related to the risk of developing PSN. These findings offer valuable clues for clinicians to minimize PSN incidence in HNC treated with curative CCRT.

Integration of EGFR Inhibition With Radiation-Based Multimodality Treatment in Stage III EGFR Mutant NSCLC

<h3>Purpose/Objective(s)</h3> Patients with stage III epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) treated with concurrent chemoradiation therapy (CRT) may not benefit from consolidation immune checkpoint inhibitors, and adjuvant EGFR tyrosine kinase inhibitor (TKI) treatment with osimertinib is now approved for stage IB-IIIA. Whether and how to integrate TKI into the treatment of unresectable or borderline resectable stage III disease is unclear. <h3>Materials/Methods</h3> Patients with stage III (AJCC 7th ed.) EGFR mutant NSCLC amenable to CRT ± surgery were enrolled onto an IRB-approved Phase II trial (clinicaltrials.gov registered) and received induction afatinib 40 mg QD x 2 months, either definitive or neoadjuvant CRT with cisplatin/pemetrexed, surgery if appropriate, and 2 years of adjuvant afatinib provided there was no primary progression during the induction phase. The trial was closed for slow accrual. The primary endpoint of objective response rate after induction TKI and early survival outcomes have been previously reported. This is a secondary analysis of recurrences and updated outcomes. <h3>Results</h3> Seventeen patients completed induction TKI and CRT ± surgery between 2012 and 2020. There were 74% females. Median age was 56 years (range, 34-75 years). Neoadjuvant and definitive median radiation doses were 54 Gy (range, 45-66 Gy) and 66.6 Gy (range, 63-72 Gy). Ten patients with biopsy confirmed N2 (n = 9) or N3 (n = 1) disease underwent surgery which showed a mediastinal sterilization rate of 60%. Adjuvant TKI was initiated in 14 patients including 1 case of off-protocol erlotinib. Three patients aborted TKI, 7 completed 2 years of TKI, 2 remained on TKI at last follow-up while 2 switched to other treatments after recurrence. Notably, of the 7 patients completing 2 years of TKI, 6 recurred after a median interval of only 3 months (range, 1-55 months) from the completion date. In total there were 11 recurrences. The dominant pattern of recurrence was distant with just 1 isolated local failure in a patient treated with definitive CRT. Five of 11 recurrences were CNS-only, all of which occurred after completion of adjuvant TKI at a median interval of 4 months. Four of these patients had intracranial disease control at last follow-up. No grade 3+ radiation treatment related toxic events were observed. With a median follow-up of 43.3 months for patients alive, median progression-free survival (PFS) and overall survival (OS) times were 32 months and not reached, respectively. 3-year PFS and OS rates were 31% (95% CI, 6-56%) and 69% (43-94%), respectively. <h3>Conclusion</h3> This trial highlights the efficacy of aggressive local therapy and the potential promise of TKI treatment for stage III EGFR mutant NSCLC though interpretations are limited by small sample size. One particular risk for patients was CNS-only recurrence suggesting that better CNS directed treatments and CNS surveillance strategies should be studied to increase cure rates in this unique, genotype-defined NSCLC population.

Deep Learning Analysis of CT Images Reveals High-Grade Pathological Features to Predict Survival in Lung Adenocarcinoma.

Simple SummaryThe high-grade pattern (micropapillary or solid pattern, MPSol) in lung adenocarcinoma affects the patient’s poor prognosis. We aimed to develop a deep learning (DL) model for predicting any high-grade patterns in lung adenocarcinoma and to assess the prognostic performance of model in advanced lung cancer patients who underwent neoadjuvant of definitive concurrent chemoradiation therapy (CCRT). Our model considering both tumor and peri-tumoral area showed area under the curve value of 0.8. DL model worked well in independent validation set of advanced lung cancer, stratifying their survival significantly. The subgroup with a high probability of MPSol estimated by the DL model showed a 1.76-fold higher risk of death. Thus, our DL model can be useful in estimating high-grade histologic patterns in lung adenocarcinomas and predicting clinical outcomes of patients with advanced lung cancer who underwent neoadjuvant or definitive CCRT.We aimed to develop a deep learning (DL) model for predicting high-grade patterns in lung adenocarcinomas (ADC) and to assess the prognostic performance of model in advanced lung cancer patients who underwent neoadjuvant or definitive concurrent chemoradiation therapy (CCRT). We included 275 patients with 290 early lung ADCs from an ongoing prospective clinical trial in the training dataset, which we split into internal–training and internal–validation datasets. We constructed a diagnostic DL model of high-grade patterns of lung ADC considering both morphologic view of the tumor and context view of the area surrounding the tumor (MC3DN; morphologic-view context-view 3D network). Validation was performed on an independent dataset of 417 patients with advanced non-small cell lung cancer who underwent neoadjuvant or definitive CCRT. The area under the curve value of the DL model was 0.8 for the prediction of high-grade histologic patterns such as micropapillary and solid patterns (MPSol). When our model was applied to the validation set, a high probability of MPSol was associated with worse overall survival (probability of MPSol >0.5 vs. <0.5; 5-year OS rate 56.1% vs. 70.7%), indicating that our model could predict the clinical outcomes of advanced lung cancer patients. The subgroup with a high probability of MPSol estimated by the DL model showed a 1.76-fold higher risk of death (HR 1.76, 95% CI 1.16–2.68). Our DL model can be useful in estimating high-grade histologic patterns in lung ADCs and predicting clinical outcomes of patients with advanced lung cancer who underwent neoadjuvant or definitive CCRT.

Abstract 438: Deep learning based radiomic biomarker for predicting the presence of high-grade histologic patterns in lung adenocarcinoma

Abstract Introduction: The presence of high-grade histologic patterns such as micropapillary or solid (MPSol) in patients with lung adenocarcinoma (ADC) is known to have a poor prognosis even if it is not the most predominant subtype. However, since it is difficult to determine the histologic pattern of the entire tumor with a small biopsy sample, there is a growing need for non-invasive biomarkers that can predict the histologic pattern of lung ADC. We developed a deep learning (DL)-based model as a radiomic biomarker that predicts high-grade ADC patterns and validated by applying it to the independent clinical dataset. Methods: A total of 290 early lung ADCs (from 275 patients) underwent curative surgical resection recruited from Samsung Medical Center were retrospectively analyzed as a training dataset. We developed a 3D convolutional DL model called morphologic-view context-view 3D network (MC3DN). Our model was developed to focus on morphologic characteristics of target lesion with contexture information observed around the lesion. Additional information about pathologic size and segmentation were trained together. An independent dataset of 416 patients with advanced lung cancer who underwent neoadjuvant concurrent chemoradiation therapy (CCRT) or definitive CCRT was analyzed to assess the prognostic performance of our model. Results: Of the training set, 54 (18.6%) lesions had MPSol pattern as the most or second predominant histologic pattern in the pathologic specimen. For the prediction of the presence of MPSol pattern, the area under the curve (AUC) value of the baseline MC3DN was 0.77. When training the model with pathologic size and segmentation together through multi-task learning, the AUC value increased to 0.80. When applied to the validation set, a high probability of MPSol estimated by DL model was associated with worse overall survival (probability of MPSol &amp;gt; 0.5 vs ≤ 0.5; 5-year OS rate 59.0% vs 73.6%, p=0.007). The subgroup with a high probability of MPSol showed 1.78 folds high risk for death (95% CI 1.17-2.72, p = 0.008). It was also significantly associated with overall survival after adjusting for other prognostic factors including age, sex, smoking, ECOG, and TNM stage (HR 1.61, 95% CI 1.05-2.47, p=0.029). Conclusion: MC3DN model through CT images could be useful in estimating any high-grade histologic pattern of lung ADCs and predicting clinical outcomes of patients with advanced lung cancer who underwent neoadjuvant or definitive CCRT. This model is also applied to inoperable patients and could be used to establish a treatment plan. Citation Format: Yeonu Choi, Jaehong Aum, Seunghwan Shin, Chan-Young Ock, Se-Hoon Lee, Hong Kwan Kim, Jhingook Kim, Ho Yun Lee. Deep learning based radiomic biomarker for predicting the presence of high-grade histologic patterns in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 438.

Change in Physical Performance Correlates with Decline in Quality of Life and Frailty Status in Head and Neck Cancer Patients Undergoing Radiation with and without Chemotherapy.

Simple SummaryQuality of life (QoL) scores and frailty status are becoming increasingly important criterion with implications on both how patients are treated and survival in head and neck cancer (HNC). Despite this, physicians lack tools to identify patients who are at risk of suffering declines in QoL and becoming frail following treatment. Therefore, we investigated whether functional decline, as measured by a series of physical tests called the Short Physical Performance Battery (SPPB), correlated with a reduction in QoL and increased risk of frailty. In the current study, patients who experienced a decline in SPPB scores were significantly more likely to have changes in physical functioning QoL measures as well as transition to frail status following treatment. In conclusion, the SPPB may be a useful tool to identify patients who may benefit from additional rehabilitation in future studies.Patient-reported quality of life (QoL) metrics, frailty status, and physical functioning are emerging concepts in head and neck cancer (HNC) with implications on both treatment decision-making and prognosis. The impact of treatment-related functional decline on QoL and frailty has not been well-characterized in HNC and was the focus of this investigation. Methods: Patients who underwent radiation therapy for HNC from 2018 to 2020 were evaluated as a prospective observational cohort. Functional decline, QoL, and the frailty phenotype were measured via the Short Physical Performance Battery (SPPB), European Organization for Research and Treatment of Cancer (EORTC) qlq-C30, and Fried Frailty index, respectively. Results: A total of 106 HNC patients were included, 75 of which received concurrent chemoradiation therapy (CCRT) and 31 received radiation alone, both with and without surgery. There was a decrease in SPPB overall (p < 0.001) from the beginning to the end of treatment in the CCRT group but not the radiation group (p = 0.43). Change in overall SPPB points following treatment correlated with the decline in physical QoL for both groups (p < 0.05) as well as transition frail status in the CCRT group (p < 0.001) with a trend in the radiation group (p = 0.08). Conclusions: Change in SPPB correlates with QoL and transition to frailty status in patients undergoing definitive CCRT for HNC with similar trends in those receiving radiation alone. Decline in SPPB could potentially be useful in identification of those who may benefit from rehabilitation in future studies.

Patterns of Care and Barriers to Utilization of Definitive Concurrent Chemoradiation Therapy for Stage III Non-Small Cell Lung Cancer in Russia.

Definitive concurrent chemoradiation (cCRT) is offered to only 3% of Russian patients with stage III NSCLC. To determine the patterns of care and barriers to cCRT utilization in Russia, we conducted a survey of practicing radiation oncologists (ROs). Electronic IRB-approved survey containing 15 questions was distributed to Russian ROs. Fisher's exact test or Cochran-Armitage test of trend was used to assess the associations between clinical experience, practice type, and patterns of care. We analyzed 58 questionnaires completed by ROs-16 respondents from tertiary referral hospitals, and 42 from community or private centers. A total of 88% of respondents formulate treatment recommendations in multi-disciplinary tumor boards. For unresectable stage III NSCLC, the most common recommendation is sequential CRT (50%), followed by concurrent CRT (40%), with an observed higher utilization of cCRT in tertiary centers (9/16, 56% vs 14/42, 33%). Of the respondents, 31% do not offer cCRT to their pts. Among reasons for avoiding cCRT are (1) poor performance of pts (76%); (2) high toxicity of therapy (55%); (3) lack of consensus among tumor board members (33%); and (4) preference for sequential CRT (31%). Only 3% do not irradiate elective LNs. Eighty-six percent of respondents counsel their NSCLC pts regarding smoking cessation. Despite level 1 evidence, cCRT is rarely used in Russia for pts with locally advanced NSCLC, and preference for sequential therapy and concerns over high toxicity are the most common barriers. Education of Russian ROs may increase cCRT utilization, leading to improved survival, notably in the era of maintenance immunotherapy.

Patterns of definitive radiotherapy practice for cervical cancer in South Korea: a survey endorsed by the Korean Radiation Oncology Group (KROG 20-06)

ObjectiveThe Korean Radiation Oncology Group conducted a nationwide questionnaire survey to evaluate the patterns of clinical practice for patients with cervical cancer receiving definitive radiation therapy (RT) in South Korea.MethodsPracticing radiation oncologists from 93 centers in South Korea were administered a questionnaire survey via e-mail. The survey focused on demographic characteristics, diagnostic evaluation, indications for definitive RT, RT techniques, RT field and dose prescription, lymph node (LN) boost RT, brachytherapy, and chemotherapy.ResultsThe response rate was 62.4% (58/93 institutions). Of the 2,134 patients treated at the radiation oncology department in 2019, 48.8% underwent definitive RT. The selection of patients for definitive concurrent chemoradiation therapy and RT field, and RT dose prescription varied greatly. The upper border of the pelvis was commonly used as the bony landmark for external beam RT (81%–88% of respondents). Most (96.6%) centers performed LN boost RT with median total doses of 59 Gy and 59.2 Gy for pelvic and retroperitoneal LN, respectively. With 50% of the centers offering brachytherapy, image-guided brachytherapy and volume-based prescription were applied in 48.3% and 37.9%, respectively. Upfront concurrent chemoradiation therapy with varying prescription doses was considered by 60.4% respondents in cases of supraclavicular LN metastasis.ConclusionMost differences were noted in the indications for treatment, RT field, and prescription dose. This finding can serve as a reference for establishing practical RT guidelines for the management of locally advanced cervical cancer.

Surgery for cervical cancer: consensus & controversies.

Surgery plays an important role in the management of early-stage cervical cancer. Type III radical hysterectomy with bilateral pelvic lymph node dissection using open route is the standard surgical procedure. There is level I evidence against the use of laparoscopic/robotic approach for radical hysterectomy for cervical cancer. Emerging data support the use of sentinel lymph node biopsy and nerve sparing radical hysterectomy in carefully selected patients with early-stage disease. In locally advanced cervical cancer patients, the use of neoadjuvant chemotherapy (NACT) followed by radical surgery yields inferior disease-free survival compared to definitive concurrent chemoradiation therapy. Therefore, definitive concurrent chemoradiation is the standard treatment for locally advanced disease. Fertility preserving surgery is feasible in highly selected young patients. Role of less-radical surgical procedures in patients’ with low-stage disease with good prognostic factors is under evaluation.

Predicting Clinical Outcomes of Patients with Stage III Non-Small-Cell Lung Cancer Treated with Concurrent Chemoradiation with and without PD-1/PD-L1 Inhibitors Using Cone Beam Computed Tomography

Currently, there are no standardized biomarkers that predict response to consolidative therapy with Programmed cell Death receptor -1(PD-1) or Programmed cell Death receptor -Ligand 1 (PD-L1) inhibitors used after concurrent chemoradiation therapy (CCRT) for patients with stage III unresectable locally advanced non-small-cell lung cancer (LA-NSCLC).We hypothesized that tumor volume reduction during CCRT may be predictive of response to consolidative PD-1/PDL-1 inhibitors. We retrospectively reviewed the medical records of patients treated with definitive CCRT, both with and without consolidative PD-1/PD-L1 inhibitors. CCRT consisted of 60Gy in 30 fractions with platinum-based chemotherapy doublet. Primary gross tumor volumes (GTV) of all patients were contoured on set-up cone-beam computed tomography (CBCT) scans acquired on day 1, 15, 29, and 43 of CCRT, as well as on follow-up CT at 1 month. GTV reduction was quantified as the percent difference in volume on each CBCT and follow-up CT, relative to CBCT Day 1. Mid-treatment shrinkage (MTS) and End of Treatment Tumor Shrinkage (ETTS) were defined at day 29 and 43, respectively. Progression-free survival (PFS) was calculated using Kaplan-Meier curves and the log-rank test was used for statistical evaluation. 93 LA-NSCLC patients completed definitive CCRT, of which 24 received consolidative PD-1/PD-L1 inhibitors. For the entire cohort, the median age was 66.5 years (range: 51-84 years) and 54% were males. Adenocarcinoma represented 51%, squamous cell carcinoma 40% and undifferentiated histology 9%. 32% had stage IIIA and 68% had stage IIIB (AJCC 7th edition). Median follow-up was 43 months (range: 36-53 months). Patients who received PD-1/PD-L1 inhibitors achieved significantly longer PFS than CCRT-only group (22.5 vs. 9.5 months, p = 0.014). For the 93 patients, median ETTS was 40.6% (range: 39.3-50.3). Median ETTS was comparable between PD-1/PD-L1 inhibitors and CCRT-only group (41.2% vs. 40%). Patients who received PD-1/PD-L1 inhibitors and achieved ETTS > 35% demonstrated a trend toward improved PFS compared to those who had ETTS ≤ 35% (median PFS was not reached vs. 11.03 months, p = 0.059). Similarly, patients who received PD-1/PD-L1 inhibitors and achieved MTS of > 35% were associated with numerically better PFS compared to patients who did not achieve the same cut off (median PFS was not reached vs. 13.15 months, p = 0.059). Patients who achieved a significant reduction in their tumor volume during CCRT are more likely to benefit from consolidative PD-1/PD-L1 inhibitors. Measuring tumor volume dynamics using the readily available CBCT images acquired during CCRT may serve as a potential biomarker to predict response to PD-1/PD-L1 inhibition therapy.

Comparison of Functional Larynx Preservation in Patients with Locally Advanced Squamous Cell Carcinoma of the Larynx and Hypopharynx Treated with Induction Chemotherapy vs Concurrent Chemoradiation Alone

Functional organ preservation is an important outcome measure in the treatment of squamous cell carcinoma (SCC) of the larynx and hypopharynx (HPX) as laryngectomy is associated with significant morbidity. Numerous studies have established the efficacy of larynx preservation with concurrent chemoradiation therapy (CRT) in the setting of locally advanced disease. However, the role of induction chemotherapy (IC) remains a topic of ongoing investigation. This study aims to compare outcomes of patients with locally advanced SCC of the larynx and HPX who received either IC plus CRT to those who received CRT alone. The primary outcome is to determine whether the addition of IC improves functional larynx-preservation survival (FLPS) in patients treated with definitive CRT for stage III-IV SCC of the larynx and HPX. Secondary outcomes are laryngectomy rate, overall survival (OS), and progression-free survival (PFS). Records of patients with clinical stage III and IV SCC of the larynx and HPX treated non-operatively between 2005 and 2019 were identified. Eligible patients were at least 18 years of age, had pathologically confirmed SCC of the larynx or HPX, and were treated definitively with IC plus CRT or CRT alone. Patients with distant metastases were excluded. FLPS was defined as the time until death, local progression, laryngectomy, or non-functional larynx. Kaplan-Meier curves were generated for FLPS, OS, and PFS. These outcomes were compared using the stratified log-rank test and laryngectomy rates were compared using Fisher’s Exact Test, where a p-value < 0.05 was considered statistically significant. Ninety patients met inclusion criteria: 52 patients had laryngeal SCC; 19 received IC plus CRT and 33 were treated with CRT alone. Thirty-eight patients had SCC of the HPX; 19 received IC plus CRT and 19 were treated with CRT alone. The median follow-up was 24 months. There were no significant differences in T stage between the IC and CRT arms. Patients who underwent IC received a median of 3 cycles (range 1-6). There was no difference in 3-year FLPS (61% vs 67.8%; p = 0.88), OS (73.9% vs 86.2%; p = 0.42) or PFS (53.6% vs 62.6%; p = 0.44) between the IC plus CRT vs CRT, respectively, in the entire cohort. These outcomes were also not statistically different between the two groups when stratified by primary site of larynx or HPX. Laryngectomy rates were not statistically different between those receiving IC compared to CRT alone (18.4 % vs 7.7%; p = 0.19). This result was also seen on subset analysis by site. In this retrospective study of patients with locally advanced SCC of the larynx and HPX, IC did not significantly improve 3-year FLPS, OS, PFS, or laryngectomy rates compared to CRT alone for the entire cohort or on subgroup analysis by site. A large prospective series would provide a more robust understanding of the role of IC in this group of patients.

Parametric Response Mapping of Coregistered Positron Emission Tomography and Dynamic Contrast Enhanced Computed Tomography to Identify Radioresistant Subvolumes in Locally Advanced Cervical Cancer

To identify subvolumes that may predict treatment response to definitive concurrent chemoradiation therapy using parametric response mapping (PRM) of coregistered positron emission tomography (PET) and dynamic contrast-enhanced (DCE) computed tomography (CT) in locally advanced cervical carcinoma. Pre- and midtreatment (after 23 ± 4 days of concurrent chemoradiation therapy) DCE CT and PET imaging were performed on 21 patients with cervical cancer who were enrolled in a pilot study to evaluate the prognostic value of CT perfusion for primary cervical cancer (NCT01805141). Three-dimensional coregistered maps of PET/CT standardized uptake value (SUV) and DCE CT blood flow (BF) were generated. PRM was performed using voxel-wise joint histogram analysis to classify voxels within the tumor as highly metabolic and perfused (SUVhiBFhi), highly metabolic and hypoxic (SUVhiBFlo), low metabolic activity and hypoxic (SUVloBFlo), or low metabolic activity and perfused (SUVloBFhi) tissue based on thresholds determined from population means of pretreatment PET SUV and DCE CT BF. Relationships between baseline pretreatment imaging metrics and relative changes in metabolic tumor volume (ΔMTV), calculated from before treatment and during treatment imaging, were determined using univariable and multivariable linear regression models. The relative volume of three PRM subvolumes significantly changed during treatment (SUVhiBFhi: P = .04; SUVhiBFlo: P = .0008; SUVloBFhi: P = .02), whereas SUVloBFlo did not (P = .9). Pretreatment PET SUVmax (r = -.58, P = .006), PET SUVmean (ρ = -.59, P = .005), DCE CT BFmean (r = -.50, P = .02), tumor volume (ρ = -.65, P = .001) and PRM SUVhiBFhi (ρ = -.59, P = .004) were negatively correlated with ΔMTV, whereas PRM SUVloBFlo was positively related to ΔMTV (r = .77, P < .0001). In a multivariable model that predicted ΔMTV, PRM SUVloBFlo, which combines both PET/CT and DCE CT, was the only significant variable (β = 1.825, P = .03), dominating both imaging modalities independently. PRM was applied in locally advanced cervical carcinoma treated definitively with chemoradiation, and radioresistant subvolumes were identified that correlated with changes in MTV and predicted treatment response. Identification of these subvolumes may assist in clinical decision making to tailor therapies, such as brachytherapy, in an effort to improve patient outcomes.

Clinical Significance of Vulnerability Assessment in Patients with Primary Head and Neck Cancer Undergoing Definitive Concurrent Chemoradiation Therapy

This study aimed to identify vulnerable patients with head and neck cancer undergoing concurrent chemoradiation therapy (CCRT) who are susceptible to higher treatment-related adverse effects and have poorer treatment tolerance. This study also aimed to determine whether comprehensive geriatric assessment, developed in the geriatric population, can predict vulnerability to treatment-related adverse events and survival even in nongeriatric patients with head and neck cancer, as well as the prevalence of vulnerability and its effect on toxicities and survival among these patients. This prospective cohort study examined 461 patients with primary head and neck cancer who underwent definitive CCRT during 2016 to 2017 at 3 medical centers across Taiwan. Vulnerability is defined as susceptibility to cancer- and treatment-related adverse events that result in poor treatment tolerance and unexpected emergent medical needs, such as hospitalization and emergency room visits. Vulnerability was assessed as impairment with ≥2 dimensions on comprehensive geriatric assessment, 7 days before CCRT. The association of vulnerability with treatment-related adverse events and survival was analyzed. The prevalence of vulnerability was 22.2%, 27.3%, 30.2%, and 27.9% among patients aged 20 to 34, 35 to 49, 50 to 64, and >65 years, respectively. Survival was poorer in vulnerable patients than in nonvulnerable patients (hazard ratio, 1.97; 95% confidence interval, 1.26-3.07; P = .003). Vulnerable patients showed a higher tendency toward CCRT incompletion (19.5% vs 6.1%, P < .001), hospitalization (34.6% vs 23.5%, P = .020), need for tubal feeding (29.3% vs 11.8%, P<.001), and longer length of hospital stay (8.1 days vs 4.0 days, P = .004) than nonvulnerable patients. Hematologic and nonhematologic toxicities were more severe in vulnerable patients than in nonvulnerable patients. Vulnerability, which is an urgent concern when it presents among patients with head and neck cancer, was independently associated with poorer survival and severe treatment-related complications. Vulnerability assessment should be routinely evaluated in all patients with primary head and neck cancer who are undergoing definitive CCRT, not only in such patients who are geriatric.

Skeletal muscle deposits from primary oropharyngeal carcinoma: A home away from home

There have been significant improvements in loco-regional control of head and neck squamous cell carcinoma (HNSCC), but distant metastasis remains a clinically important challenge. The incidence of distant metastasis in HNSCC is quite uncommon, varying from 4% - 26%. The most often involved sites being lung, liver and bone. Several factors influencing the incidence of distant metastasis include primary tumour site, grading, nodal involvement, and status of locoregional disease. We report a case of a 59-year old gentleman with oropharyngeal carcinoma treated 6 months back presenting with swelling over the right infra-scapular region and the medial aspect of lower one third of right thigh resulting from metastasis to skeletal muscle. The results of histology and immunohistochemistry were consistent with a metastasis from a squamous cell carcinoma oropharynx. The disease was staged as stage III initially at the time of presentation. The patient received definitive concurrent chemoradiation therapy to the primary and nodal regions. There was no evidence of locoregional disease after 1 year. In the literature, there are reports of HNSCC metastasizing to different parts of the body. However, this is among the few case report of a metastasis to the skeletal muscle. Keywords: Chemoradiotherapy, Immunohistochemistry, Oropharyngeal neoplasm, Skeletal muscle.