Local-regional Failure Research Articles

Wind-induced collapse mode and mechanism of super-large hyperbolic steel reticulated shell cooling tower with stiffening rings

With advancement of dry-air cooling technology, it has become feasible to use steel reticulated shell structures in design and construction of industrial cooling towers. Steel reticulated shell cooling towers (SRSCTs) with light weight, high strength, and rapid construction have development potential. Wind-induced collapse accidents in cooling towers frequently occur, characterized by pronounced nonlinear behavior involving significant deformation and material failure. Nevertheless, current stability and collapse analyses of cooling towers based on linear theory and elastic deformation are inadequate and unsafe. Thus, the wind-resistant stability of SRSCTs must be evaluated considering their inherent high flexibility and low damping levels. Considering a 220 m high hyperbolic SRSCT as a case study, a wind-induced collapse FEM simulation and analysis were performed. The average and fluctuating wind loads were measured in a reduced-scale model during wind tunnel tests and used as the time-variant wind pressure in a structural finite-element model. The dynamic performance and buckling collapse analyses of the cooling tower were conducted considering geometric and material nonlinearities. The entire wind-induced failure process of the SRSCT in extreme winds was systematically investigated. The weaknesses in the structural stiffness and the failure process were quantified, with five failure stages and four failure modes. The failure stages included linear elasticity, local member failure, local regional failure, overall structural failure, and collapse. The failure modes included circumferential plastic buckling zone failure, windward buckling failure of the shell, crosswind failure of the stiffening ring (hinged curved-beam mechanism), and windward failure of the stiffening ring (triangular arch-like mechanism). This study confirms that development of plastic buckling zones and formation of plastic hinges, considering geometric and material nonlinearity, are the dominant factor in wind-induced failure and collapse of SRSCTs.

Effect analysis of 847 nasopharyngeal carcinoma cases treated with intensity modulated radiation: Experience and suggestions

ObjectivesTo identify the failure patterns and prognostic factors of nonmetastatic nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. MethodsData on 847 patients with newly diagnosed, non-disseminated NPC treated by IMRT between 2012 and 2016 were retrospectively reviewed. Survival outcome, failure patterns and prognosis factors were analyzed. ResultsThe 5-year local relapse-free survival, nodal relapse-free survival, distant metastasis-free survival, disease-free survival, and overall survival rates were 94.3%, 95.3%, 84.8%, 76.5% and 85.7%, respectively. The major local recurrence sites were the nasopharynx (91.5%, 43/47) and skull base (68.1%, 32/47); 39 patients had in-field failures, four had marginal failures, and four had out-field failures. Level IIb (62.2%, 23/37) was the most frequent regional recurrence site, followed by IIa (35.1%, 13/37) and retropharyngeal region (32.4%, 12/37); 35 cases had in-field failure alone, one had out-field failure alone, and one had both in- and out-field failure. TNM stage was the most significant factor for prognosis prediction. 402 (47.5%) patients had acute adverse events of grade 3 or 4; leukopenia (31.5%) and mucositis (26.7%) was the most common hematological and non-hematological event, respectively. Late complications were slight or moderate damages; xerostomia (647/847, 76.4%) and hearing impairment (422/847, 49.8%) remained the most troublesome. ConclusionNPC patients treated with IMRT obtained satisfactory survival outcomes. The key failure pattern was distant metastasis. The main pattern of local–regional failure was in-field failure. Screening high risk patients with distant metastases and optimizing radiotherapy targets should be studied.

Contact x-ray brachytherapy for the treatment of rectal cancer: A systematic review and meta-analysis.

e15628 Background: Rectal cancer is a highly prevalent disease, particularly among the elderly and frail populations. While surgical resection has traditionally been the primary management approach, it carries inherent risks, including operative mortality, morbidity, and poor long-term functional outcomes. These risks are particularly pronounced in older, co-morbid individuals. Evidence presented in the 2023 phase III OPERA randomised trial suggests that Contact X-ray Brachytherapy (CXB) is a viable organ-preserving alternative to radical surgery. We conducted a systematic review and meta-analysis to assess the clinical effectiveness of CXB in the treatment of rectal cancer. Methods: This systematic review was prospectively registered (CRD42021284969) and reported in accordance with PRISMA guidelines. PubMed, EMBASE, SCOPUS and Cochrane CENTRAL Libraries were interrogated using the search terms “Rectal cancer”, “Contact Brachytherapy”, and synonym terms. Literature search and data extraction were conducted by two reviewers, with recourse to a senior author for resolution of conflicts. Clinical complete response (cCR) was the primary outcome. Secondary outcomes include local regrowth, regional recurrence, salvage surgery rates, long-term disease control post-salvage surgery and survival outcomes. Proportional meta-analyses were conducted and presented as forest plots with summary proportions and 95% confidence intervals. The Higgins I2 statistic was used to assess for heterogeneity. The random effects model was employed in studies reporting substantial heterogeneity (I2> 50%). Results: The literature search identified 973 studies, of which 48 studies encompassing 5,447 patients were included in the meta-analysis. Pooled estimates of outcomes were as follows: cCR rate = 80% (95% CI 76-88%), local regrowth = 15% (95% CI 12-18%), regional failure rate = 3% (95% CI 2-4%), salvage surgery rate = 14% (95% CI 11-18%), long-term disease control post-salvage surgery rate = 88% (95% CI 78-96%) and organ preservation 82% (95% CI 75-88%). A subgroup analysis was conducted and stratified by concomitant therapy (CXB alone, CXB & EBRT, CXB & EBCRT). CXB, in conjunction with EBCRT, leads to a statistically significant reduction in both local regrowth and regional failure. The local regrowth rates were 16% (95% CI 11-21%), 17% (95% CI 11-23%), and 10% (95% CI 8-13%) respectively, with a p-value of 0.05. The regional failure rates were 4% (95% CI 2-8%), 4% (95% CI 2-5%), and 1% (95% CI 0-2%), p = 0.02. Conclusions: CXB, combined with EBCRT, in the appropriately selected patient can achieve long-term disease control whilst avoiding major surgery. Salvage surgery is a viable option for patients who experience disease regrowth, with excellent long-term disease control. CXB may be considered a safe alternative to surgery in the appropriately selected patient.

Intra-treatment hypoxia directed major radiation de-escalation as definitive treatment for human papillomavirus-related oropharyngeal cancer.

6007 Background: We previously reported that surgery to the primary site with hypoxia-directed de-escalated radiation to the neck for human papillomavirus associated oropharyngeal carcinoma (HPV+ OPC) can lead to excellent oncologic outcomes. We now report the results of a successor multi-center phase II trial of hypoxia-directed de-escalated chemoradiotherapy without surgery for HPV+OPC. Methods: HPV+ OPC (T0-2/N1-N2c/AJCC 7th) patients were eligible for enrollment. Tumors without evidence of hypoxia on 18F-FMISO (fluoromisonidazole) PET received de-escalated chemoradiation to 30Gy while those with hypoxia received chemoradiation to 70Gy. The primary objective was achieving a 2-year locoregional control (LRC) of 95% (failure was locoregional recurrence where surgical salvage was unfeasible) with a 7% non-inferiority margin. We enrolled a total of 158 subjects upfront to account for a 5% loss due to death (of reasons other than cancer) or follow-up. Secondary objectives were local failure (LF), regional failure (RF), distant metastasis (DM), overall survival (OS), toxicities, and patient-reported MD Anderson Dysphagia Inventory (MDADI) scores. LF, RF, and DM were estimated using the Cumulative Incidence Function, and OS was estimated using the Kaplan-Meier method. Results were reported up to 1/31/2024. Results: From 4/28/20-4/17/23, 158 HPV+ OPC patients were enrolled where150 patients were eligible for analyses. Patient characteristics: Tonsil (43%); Base of Tongue (47%); unknown primary (10%); >/=10 pack years (22%); T0 (9%), T1 (44%), T2 (47%); N1 (14%), N2a (11%), N2b (59%), N2c (16%). 111 (74%) received 30Gy; 95% cisplatin. With 24 months (8-43) of median follow-up, the 2-year LF, RF, DM rates were 4.2%, 6.9%, 2.0%, respectively. The 2-year overall survival probability was 99%. Only 2 patients could not undergo salvage surgery [one 30Gy (second recurrence); one 70Gy (M1)], both received systemic therapy with durable response. Acute grade 3-4 toxicities were 32% (67% neutropenia). Mean MDADI scores: 92.93 (baseline); 68.24 (3 weeks), 91.45 (4 months) after chemoradiation. Conclusions: These early data indicate that major de-escalation to 30Gy based on hypoxia status achieved significant toxicity reduction without compromise in survival for HPV+ OPC treated with chemoradiation without surgery. Clinical trial information: NCT03323463 .

Systematic evaluation and meta-analysis of the prognosis of down-staging human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma using cetuximab combined with radiotherapy instead of cisplatin combined with radiotherapy.

To evaluate the efficacy and safety of cetuximab instead of cisplatin in combination with downstaging radiotherapy for papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC). Meta-analysis and systematic evaluation. The PubMed, Embase, Web of Science, and Cochrane library databases were searched up to June 8, 2023, as well as Clinicaltrials.gov Clinical Trials Registry, China Knowledge Network, Wanfang Data Knowledge Service Platform, and Wiprojournal.com. Randomized controlled trials reporting results of standard regimens of cetuximab + radiotherapy vs cisplatin + radiotherapy in treating HPV+ OPSCC were included. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), local regional failure rate (LRF), distant metastasis rate (DM), and adverse events (AE). Two reviewers independently extracted data and assessed the risk of bias of the included studies. The HR and its 95% CI were used as the effect analysis statistic for survival analysis, while the OR and its 95% CI were used as the effect analysis statistic for dichotomous variables. These statistics were extracted by the reviewers and aggregated using a fixed-effects model to synthesise the data. A total of 874 relevant papers were obtained from the initial search, and five papers that met the inclusion criteria were included; a total of 1,617 patients with HPV+ OPSCC were enrolled in these studies. Meta-analysis showed that OS and PFS were significantly shorter in the cetuximab + radiotherapy group of patients with HPV+ OPSCC compared with those in the conventional cisplatin + radiotherapy group (HR = 2.10, 95% CI [1.39-3.15], P = 0.0004; HR = 1.79, 95% CI [1.40-2.29], P < 0.0001); LRF and DM were significantly increased (HR = 2.22, 95% CI [1.58-3.11], P < 0.0001; HR = 1.66, 95% CI [1.07-2.58], P = 0.02), but there was no significant difference in overall grade 3 to 4, acute and late AE overall (OR = 0.86, 95% CI [0.65-1.13], P = 0.28). Cisplatin + radiotherapy remains the standard treatment for HPV+ OPSCC. According to the 7th edition AJCC/UICC criteria, low-risk HPV+ OPSCC patients with a smoking history of ≤ 10 packs/year and non-pharyngeal tumors not involved in lymphatic metastasis had similar survival outcomes with cetuximab/cisplatin + radiotherapy. However, further clinical trials are necessary to determine whether cetuximab + radiotherapy can replace cisplatin + radiotherapy for degraded treatment in individuals who meet the aforementioned characteristics, particularly those with platinum drug allergies. CRD42023445619.

Platinum-based adjuvant chemoradiotherapy versus adjuvant radiotherapy in patients with head and neck adenoid cystic carcinoma

PurposeThe objective of the study was to assess the effectiveness and toxicity of platinum-based adjuvant chemoradiotherapy (POCRT) in comparison to postoperative radiotherapy (PORT) in patients with head and neck adenoid cystic carcinoma (HNACC).Materials and methodsThis retrospective study analyzed patients diagnosed with HNACC at our center between January 2010 and April 2020. A 1:1 propensity score matching method was used to create a matched cohort.ResultsIn this study, 206 patients were analyzed, with 147 patients (71.4%) receiving postoperative radiotherapy (PORT) and 59 patients (28.6%) receiving POCRT. Twenty-one patients experienced local–regional failure. The 3-, 5-, and 10-yr local–regional control (LRC) rate for the cohort were 92.0%, 90.6%, and 86.9%, respectively. In both the entire cohort and the matched cohort, the POCRT group exhibited superior LRC compared to the PORT group (Gray's test, all P < 0.05*). Multivariate analysis identified adjuvant concurrent chemotherapy as an independent prognostic factor for LRC (Competing risks regression, HR = 0.144, 95% CI 0.026–0.802, P = 0.027*). In addition, the POCRT group had higher incidences of upper gastrointestinal toxicity and hematologic toxicities, including leukopenia, neutropenia, and anemia (all P < 0.05*).ConclusionIn terms of reducing locoregional failures in HNACC patients, POCRT may potentially offer a more effective therapeutic approach than using PORT alone, although it also entails an augmented burden of treatment-related toxicity.

Oncologic Outcomes of Conventionally Fractionated, Hypofractionated, and Stereotactic Body Spot-Scanned Proton Radiation Therapy for Prostate Cancer: The Mayo Clinic Experience.

Spot/pencil beam scanned proton therapy is a relatively new technology with fundamental differences from double scattered or IMRT. We aimed to report the long-term oncologic outcomes of a contemporary prospective series of patients treated with spot-scanned proton therapy (SSPT). An IRB-approved prospective registry identified patients with prostate cancer treated with proton therapy between January 2016 and December 2018. Descriptive statistics were calculated for all patients. Clinical, demographic, and treatment characteristics were gathered and analyzed. Kaplan-Meier curves were generated to estimate survival and recurrence rates. Outcomes assessed included 5-year overall survival (OS), 5-year local control (LC), biochemical failure (BF), regional and distant failures, and physician-reported adverse events (AEs). Biochemical failure was defined as rise in PSA ≥ 2.0 ng/mL above nadir PSA. Acute and chronic gastrointestinal (GI) and genitourinary (GU) grade 2+ and grade 3+ baseline-adjusted AEs were assigned using CTCAE v5.0. All failures were re-staged with PET C-11 or PSMA. With a median follow up of 4.4 years (IQR 3.7 - 5), two hundred and eighty-six prostate cancer patients with a median age of 72 (IQR 67.5 - 77) were treated with spot-scanned proton radiation. The median Gleason grade group was 3 (IQR 2 - 4). The median pre-RT PSA was 6.9 ng/mL (IQR 4.3 - 10.5). Median T-stage was T1c. Nearly 64% of all patients were on androgen deprivation therapy at the time of initiating radiation treatment. The median total radiation dose was 79.2 Gy delivered over 44 fractions, 70 Gy over 28 fractions, and 38 Gy over 5 fractions for CF, HF, and SBRT regimens, respectively. The BF rate for all patients was 8.4%. The 5-year LC rates for CF, HF, and SBRT were 100% (95% CI: 100 - 100), 100% (95% CI: 100 - 100), and 97.3% (95% CI: 92.2 - 100), respectively (p = 0.07). Regional recurrences occurred in 12 (4.2%) patients: 8 (5.6%) treated with CF, 2 (2.1%) with HF, and 2 (4.3%) with SBRT (p = 0.62). Distant metastatic failures occurred in 12 patients (4.2%): 5 (3.5%) treated with CF, 7 (7.4%) with HF, and none with SBRT (0%) (p = 0.052). The 5-year OS for patients treated with CF, HF, and SBRT SSPT were 88.2% (95% CI: 81.8 - 95), 86.2% (95% CI: 77.6 - 95.6), and 97.2% (95% CI: 92 - 100), respectively (p = 0.1). Acute and chronic grade 2+ GI baseline-adjusted AEs occurred in 8 (2.8%) and 51 (17.8%) patients, respectively. Acute and chronic grade 3+ GI baseline-adjusted AEs occurred in 3 (1%) and 4 (1.4%) patients, respectively. Acute and chronic grade 2+ GU-related AEs were observed in 72 (25.2%) and 63 (22%) patients, respectively. Acute and chronic grade 3+ GU toxicity was observed in 3 (1%) and 6 (2.1%) patients, respectively. Spot-scanned proton radiation therapy provides high local control rates and excellent oncologic outcomes across different fractionation schedules with low long-term AE rates.

The Role of Radiation Therapy for Metastatic Cervical Cancer

Survival rates for women with metastatic cervical cancer (CC) are low, with limited management options. Radiation therapy (RT) for metastatic disease has led to prolonged survival in other malignancies, however, the data are scarce in CC. Herein, we evaluated the effect of RT for metastatic CC. A total of 58 patients with metastatic CC between September 2019 and January 2023 were retrospectively analyzed. All the patients were treated with platinum-based chemotherapy combined with targeted therapy or immunotherapy followed with or without RT (NRT). The recent efficacy, survival status and prognostic factors were analyzed statistically. Objective response rate (ORR) was 63.6% with one complete and twenty partial responses in RT group (n = 33) and 40.0% with two complete and eight partial responses in NRT group (n = 25), respectively (p = 0.074). Disease control rate (DCR) of the RT and NRT groups were 79.4% vs 80.0%, respectively (p = 0.861). Median follow-up time was 17 months (3-39months). In RT group, 11(33.3%) patients experienced local regional or distant failure and 9 (27.3%) patients were dead. In NRT group, 15(60%) patients had progression and 8 (32%) patients dead. There was no significant difference between the two groups in overall survival (OS); however, RT group displayed superior progression-free survival (PFS) (1-year OS: 72.7% vs. 68.0%, p = 0.460; 1-year PFS: 66.7% vs. 40.0%, p = 0.039). The multivariate analysis showed that RT, immunotherapy, lymph node metastasis only relevant predictor of superior PFS but not OS. In subgroup analysis, patients treated with RT appeared to have a better PFS in some specific cohorts, such as age>45 years (72.0% vs 36.4% P = 0.015), squamous carcinoma histology (71.0% vs 40.9% P = 0.017), metastatic at diagnosis (75.0% vs 47.6% P = 0.012), non-targeted therapy (72.4% vs 43.8% P = 0.040). No significant increase in treatment-related toxicity was observed in the RT group compared with the NRT group. RT provided superior PFS in metastatic CC patients compared to NRT, and well tolerated. Moreover, RT, immunotherapy, lymph node metastasis only were independent significant prognostic factors for PFS. Subgroup analysis showed that combination of RT and chemotherapy obtained favorable PFS in metastatic CC patients with age>45 years, squamous carcinoma histology, metastatic at diagnosis, non-targeted therapy. Studies with a larger sample size and longer follow-up are warranted.

Pre-Brachytherapy Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) Response as Predictor of Local Control in the Definitive Treatment of Cervical Cancer

Chemoradiation consisting of external beam radiotherapy (EBRT) followed by brachytherapy (BT) is the standard of care for Stage IB2-IVA cervical cancer (CC). Multi-parametric MRI (mpMRI) is a valuable tool for initial staging, treatment planning and response assessment. In this study, we aim to explore the potential of mpMRI, in particular DW-MRI, to predict overall tumor control following chemoradiation in CC. We identified 78 consecutive patients treated with chemoradiation for FIGO IB2-IVA CC between 2012-2020, who had an MRI at baseline (MRb) and post-EBRT prior to brachytherapy boost (MRpb) that included DW-MRI (b-value = 0 and 800 s/mm2). Median age was 53 years, most patients had squamous cell carcinoma (76.9%) and advanced-stage disease (56.4% stage IIIA-IVA). Median time from completion of EBRT to MRpb was 3 days. Regions of interest (ROI) in primary tumor were delineated on DW image (b = 0 s/mm2) using ITK-SNAP software. DW-MRI data were fitted to a monoexponential model to calculate apparent diffusion coefficient (ADC) values using in-house software platform (MRI-QAMPER). MRpb mean ADC values (n = 78) and relative changes (%) in mean ADC values between MRb and MRpb (n = 64) were correlated with outcomes, including local failure (LF), regional or distant failure (RDF), and failure at any site (FAS), with death without failure as a competing risk. Median follow-up time was 45 months (95% CI 38, 53). At first post treatment assessment, 72 patients (92.3%) had a complete response (CR) in the cervix and 68 patients (87.2%) had CR in all disease sites. Of patients who had CR in the cervix (n = 72), only 1 patient had local recurrence. Of patients who had CR in all disease sites, 10 later recurred (1 LF only, 1 LF&RDF, 8 RDF only). Overall, 7 patients (9%) had LF, and 19 patients (24.4%) had FAS. A higher mean ADC value in MRpb was associated with LF (HR 4.3, 95% CI 1.32, 14.6; P = 0.016), but not with RDF (P = 0.4) or FAS (P = 0.5). A higher relative change in the mean ADC value between MRb and MRpb was associated with a lower risk of LF (HR 0.94, 95% CI 0.90, 0.98; P = 0.002), but not with RDF (P = 0.8) or FAS (P = 0.4). Treatment response as measured on prebrachytherapy DW-MRI is a significant predictor of local control in patients undergoing chemoradiation for stage IB2-IVA CC. ADC values, a quantitative imaging biomarker on MRpb may be instrumental in dose intensification/de-escalation efforts in CC.

Predicting cancer relapse following lung stereotactic radiotherapy: an external validation study using real-world evidence.

For patients receiving lung stereotactic ablative radiotherapy (SABR), evidence suggests that high peritumor density predicts an increased risk of microscopic disease (MDE) and local-regional failure, but only if there is low or heterogenous incidental dose surrounding the tumor (GTV). A data-mining method (Cox-per-radius) has been developed to investigate this dose-density interaction. We apply the method to predict local relapse (LR) and regional failure (RF) in patients with non-small cell lung cancer. 199 patients treated in a routine setting were collated from a single institution for training, and 76 patients from an external institution for validation. Three density metrics (mean, 90th percentile, standard deviation (SD)) were studied in 1mm annuli between 0.5cm inside and 2cm outside the GTV boundary. Dose SD and fraction of volume receiving less than 30Gy were studied in annuli 0.5-2cm outside the GTV to describe incidental MDE dosage. Heat-maps were created that correlate with changes in LR and RF rates due to the interaction between dose heterogeneity and density at each distance combination. Regions of significant improvement were studied in Cox proportional hazards models, and explored with and without re-fitting in external data. Correlations between the dose component of the interaction and common dose metrics were reported. Local relapse occurred at a rate of 6.5% in the training cohort, and 18% in the validation cohort, which included larger and more centrally located tumors. High peritumor density in combination with high dose variability (0.5 - 1.6cm) predicts LR. No interactions predicted RF. The LR interaction improved the predictive ability compared to using clinical variables alone (optimism-adjusted C-index; 0.82 vs 0.76). Re-fitting model coefficients in external data confirmed the importance of this interaction (C-index; 0.86 vs 0.76). Dose variability in the 0.5-1.6cm annular region strongly correlates with heterogeneity inside the target volume (SD; ρ = 0.53 training, ρ = 0.65 validation). In these real-world cohorts, the combination of relatively high peritumor density and high dose variability predicts increase in LR, but not RF, following lung SABR. This external validation justifies potential use of the model to increase low-dose CTV margins for high-risk patients.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials

For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

Final Report of NRG Oncology RTOG 0022: A Phase 1/2 Study of Conformal and Intensity Modulated Radiation for Oropharyngeal Cancer

XXXX XXXX XXXX XXXX (XXXX) XXXX was the first clinical trial evaluating multi-institution feasibility of IMRT for head and neck cancer. The primary endpoints of 2-year local-regional failure and reduction in acute xerostomia were reported previously. This report provides secondary endpoints with long-term follow-up. Eligibility included patients diagnosed with T1-2, N0-1 oropharyngeal cancer. Secondary endpoints included disease control and overall survival. Local-regional failure rates were estimated by the cumulative incidence method, and disease-free and overall survival rates were estimated by the Kaplan-Meier method. Late toxicities were graded by XXXX/EORTC criteria and are reported with descriptive statistics. Sixty-seven of 69 enrolled patients were analyzed. Fifty patients (75%) had T2 disease and 38 (57%) were node negative (N0). Median follow-up was 11.9 years. Estimated 10-year local-regional failure, disease-free survival and overall survival rates were 15% (95%CI 8-25), 50% (95%CI 38-62) and 67% (95%CI 55-78), respectively. Highest reported late toxicities were: grade 5: 0%, grade 4: 9%, grade 3: 13%, and grade 2: 63%. Grade 3-4 late toxicities involved mucous membranes (7%), bone (4%), esophagus (4%), salivary gland (4%), pain (3%), weight loss (1%), and hemorrhage (1%). Grade 2-3 salivary gland toxicity was reported in 70% but improved over time. Forty-one (74.5%) and 17 (42.5%) of surviving patients had a toxicity assessment at > 5 years and >10 years, respectively. This report of XXXX/XXXX XXXX, based on an early, prospectively collected dataset of head and neck IMRT treatments, provides benchmark long-term outcomes of this early version of the technology. At 10 years, 2/3 of patients were alive, with an acceptable level of grade 3-4 late toxicities.

Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patents with Locally Advanced Non–Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab

The addition of consolidative durvalumab to chemoradiation has improved disease control and survival in locally advanced non-small cell lung cancer (NSCLC). However, there remains a need to identify biomarkers for response to this therapy to allow for risk adaptation and personalization. To evaluate whether TMB or other variants associated with radiation response are also associated with outcomes following definitive chemoradiation and adjuvant durvalumab among patients with locally advanced unresectable NSCLC. This cohort study included consecutive patients with unresectable locally advanced NSCLC treated with chemoradiation and adjuvant durvalumab between November 2013 and March 2020 who had prospective comprehensive genomic profiling. This study was completed at a multisite tertiary cancer center. The median (IQR) follow-up time was 26 (21-36) months. Statistical analysis was conducted from April to October 2022. Patients were grouped into TMB-high (≥10 mutations/megabase [mt/Mb]) and TMB-low (<10 mt/Mb) groups and were additionally evaluated by the presence of somatic alterations associated with radiation resistance (KEAP1/NFE2L2) or radiation sensitivity (DNA damage repair pathway). The primary outcomes were 24-month local-regional failure (LRF) and progression-free survival (PFS). In this cohort study of 81 patients (46 [57%] male patients; median [range] age, 67 [45-85] years), 36 patients (44%) had TMB-high tumors (≥10 mt/Mb). Patients with TMB-high vs TMB-low tumors had markedly lower 24-month LRF (9% [95% CI, 0%-46%] vs 51% [95% CI, 36%-71%]; P = .001) and improved 24-month PFS (66% [95% CI, 54%-84%] vs 27% [95% CI, 13%-40%]; P = .003). The 24-month LRF was 52% (95% CI, 25%-84%) among patients with KEAP1/NFE2L2-altered tumors compared with 27% (95% CI, 17%-42%) among patients with KEAP1/NFE2L2-wildtype tumors (P = .05). On Cox analysis, only TMB status was associated with LRF (hazard ratio [HR], 0.17; 95% CI, 0.03-0.64; P = .02) and PFS (HR, 0.45; 95% CI, 0.21-0.90; P = .03). Histology, disease stage, Eastern Cooperative Oncology Group status, programmed cell death ligand 1 expression, and pathogenic KEAP1/NFE2L2, KRAS, and DNA damage repair pathway alterations were not significantly associated with LRF or PFS. In this cohort study, TMB-high status was associated with improved local-regional control and PFS after definitive chemoradiation and adjuvant durvalumab. TMB status may facilitate risk-adaptive radiation strategies in unresectable locally advanced NSCLC.

Accelerated Hypofractionated Radiotherapy for Centrally Located Lung Tumours Not Suitable for Stereotactic Body Radiotherapy or Chemoradiotherapy

AimsAccelerated hypofractionated radiotherapy is used at our institution for non-small cell lung cancer (NSCLC) patients not eligible for stereotactic body radiotherapy or chemoradiotherapy. The purpose of this study was to report clinical outcomes of delivering 60 Gy in 15 fractions for these patients. Materials and MethodsAll NSCLC patients who received 60 Gy in 15 fractions were reviewed. Outcomes of interest were local failure, regional failure, distant progression, overall survival and treatment-associated toxicities. ResultsIn total, 111 patients were included. The median age was 78.8 years and most tumours were adenocarcinoma (n = 55, 49.6%). Sixty-five patients (58.6%) were N0. The cumulative incidence of local failure at 12 and 24 months in the N0 cohort was 5.2% and 14.2%, respectively, compared with 11.5% and 14.8% for N+ patients. Tumour size >35 mm predicted for local failure (hazard ratio 2.706, 95% confidence interval 1.002–7.307, P = 0.0494). Distant progression at 12 and 24 months in N0 patients was 13.7% and 24.3% compared with 24.6% and 33.5% in N+ patients. In N0 patients, larger tumour size was associated with increased risk of distant progression. The median overall survival was 38.1 months in N0 patients versus 31.7 months in N+ patients. The most common toxicity was radiation pneumonitis (n = 6, 6.4%). The incidence of any grade 3 toxicity was 10.3% at ≥1 year. There were no deaths or hospitalisations attributed to treatment. ConclusionsAccelerated hypofractionated radiotherapy is well tolerated and resulted in favourable clinical outcomes in various stages of NSCLC patients.

Primary radiation therapy for advanced-stage laryngeal cancer: A laryngo-esophageal dysfunction disease-free survival.

To evaluate the outcomes of advanced-stage laryngeal squamous cell carcinoma (SCC) patients treated with functional-preservation strategy with a specific focus on laryngo-esophageal dysfunction disease-free survival (LEDDFS). A retrospective review was conducted of stage III-IVB laryngeal SCC patients who were treated with curative-intent radiotherapy (RT) (2007-2018). Patients were preferentially managed with upfront chemoradiation (CCRT); except for those with cN2-3, cT4, or large volume cT3 (induction chemotherapy followed by RT or CCRT is an option), and those who were unfit or declined chemotherapy (received altered RT). The primary endpoint was 3-year LEDDFS, and secondary endpoints were 3-year local failure (LF), regional failure (RF), distant metastasis (DM), overall survival (OS), disease-free survival (DFS), and acute and late toxicities. Cox proportional hazard tests were used for multivariable analysis (MVA). A total of 213 cases were included. With a median follow-up of 37 months, the 3-year LEDDFS was 50%, while the 3-year OS, DFS, LF, RF, and DM were 81%, 74%, 9%, 5%, and 7%, respectively. On MVA, cT4-category was the only predictor of inferior LEDDFS (HR: 0.47, [95% CI: 0.29-0.74], p < .01). The most common grade ≥ 3 acute and late radiation therapy oncology group (RTOG) toxicity were esophageal toxicity: 16.7% and 29.6%, respectively. Primary RT resulted in favorable oncologic and functional outcomes in only half of the advanced-stage laryngeal cancer patients. Future clinical trials are required to investigate further treatment options aiming to improve the oncologic and maintain functional outcomes with utilization of LEDDFS as the primary endpoint. 4.

Non-Operative Management is Feasible and Safe in Patients with Rectal Cancer Who Achieve Clinical Complete Response to Short-Course Radiation Therapy and Consolidation Chemotherapy

<h3>Purpose/Objective(s)</h3> The purpose of this study was to report on patients with localized rectal adenocarcinoma followed with non-operative management (NOM) with a watch-and-wait (W&W) strategy after achieving clinical complete response (cCR) to short-course radiation therapy (SCRT) and consolidation chemotherapy. <h3>Materials/Methods</h3> Patients with rectal adenocarcinoma who achieved cCR to SCRT and consolidation chemotherapy and were subsequently managed with NOM were included in this study. Endpoints included overall survival (OS), freedom from local failure (FFLF), freedom from distant metastasis (FFDM), and disease-free survival (DFS). cCR was defined by absence of residual tumor, nodularity, and ulceration on endoscopic evaluation. FFLF was defined as time from achieving cCR to development of intraluminal recurrence on endoscopic evaluation. DFS was defined as time from completion of SCRT to death, local-regional failure, or distant failure. Local failures that were successfully salvaged were not considered disease progression. Patients with sustained cCR were given surveys to assess general and bowel quality of life: 1. EORTC Quality of Life Questionnaire Core 30, 2. EORTC Quality of Life Questionnaire-Colorectal Cancer 29, and 3. Low anterior resection syndrome (LARS) score. <h3>Results</h3> A total of 87 patients were treated with SCRT and chemotherapy, of which 33 had cCR. Of the 33 with cCR, 26 patients were managed with NOM. Median age was 63 years (range, 44-79 years). Median follow-up was 20.4 months (range, 7.2-46.2 months). All patients were treated with SCRT to 25 Gy in 5 fractions. Chemotherapy regimens included mFOLFOX (n=20), CAPOX (n=3), mFOLFOX and CAPOX (n=1), mFOLFOX and FLOX (n=1), CAPOX and capecitabine (n=1), for a median of 4.5 months (range, 2.0-9.0 months). Median FFLF was not reached, with 6-month, 1-year, and 2-year FFLF rates of 85.7%, 68.0%, and 68.0%, respectively. Seven (26.9%) patients developed local failure at a median of 6.8 months (range, 3.4-30.2 months) after achieving cCR, of which 5 (71.4%) were successfully salvaged. Median OS was not reached with 6-month, 1-year, and 2-year OS rates of 100%. Median FFDM was not reached, with 6-month, 1-year, and 2-year FFDM rates of 100%, 94.7%, and 89.2%, respectively. Median DFS was not reached, with 6-month, 1-year, and 2-year DFS rates of 100%, 95.0%, and 89.4%, respectively. Survey response rate was 83.3%. Median LARS score was 27 (range, 0-37) and mean LARS score was 20.9. Major LARS, minor LARS, and no LARS occurred in 3 patients (20%), 6 patients (40%), and 6 patients (40%), respectively. There were no differences in EORTC and LARS survey scores between patients who had > 50% of their anal sphincter region included in the prescription-dose radiation volume and those who did not. <h3>Conclusion</h3> Non-operative management with W&W strategy may be an appropriate option for patients with rectal adenocarcinoma who achieve cCR to SCRT and consolidation chemotherapy. Furthermore, anorectal function appears to be adequate with this approach.

Reply to Letter to the Editor regarding "Oncological outcomes of squamous cell carcinoma of the cervical esophagus treated with definitive (chemo-)radiotherapy: a systematic review and meta-analysis".

In a previous study, we performed a meta-analysis of the oncological outcomes of patients suffering from cervical esophageal squamous cell carcinoma treated with definitive chemoradiotherapy. Further analysis was performed, and a random effect modeling showed a pooled local-regional failure rate of 41.4% (95% CI 32.2-50.8), and a pooled distant failure rate of 21.6% (95% CI 17.0-26.5). The included studies used a median radiotherapy (RT) dose of 61.2Gy (95% CI 60.0-62.0, range 56.0-66.0), but we measured a non-significant impact of the RT dose on the pooled overall survival (OS), suggesting that an increased RT dose might not be related to an improved OS (p = 0.23). Further research should be conducted to define predictors and prognostic categories that may select the best treatment option for each patient.

Tumor Mutational Burden Predicts Progression-Free Survival and Local-Regional Control in Locally Advanced Non-Small Cell Lung Cancer Patients Treated with Chemoradiation and Durvalumab

<h3>Purpose/Objective(s)</h3> The impact of tumor genomics on disease outcomes in locally advanced non-small cell lung cancers (NSCLC) treated with concurrent chemoradiation (cCRT) and durvalumab remains unclear. We assessed if tumor mutational burden (TMB) and mutations in genes associated with radiation sensitivity can predict for disease control. <h3>Materials/Methods</h3> Consecutive patients treated with cCRT and durvalumab who underwent tumor genomic profiling were included. Genomic characteristics including TMB and 26 genes from three radio-sensitizing DNA damage and repair (DDR) pathways (DNA checkpoints, Fanconi Anemia and homologous recombination) and genes associated with radiation resistance (KEAP1, NFE2L2, STK11, PIK3CA) were examined. Cox modeling was used to assess associations between clinical features, TMB, and pathogenic mutations in DDR or radiation resistance genes with disease outcomes. Kaplan-Meier analysis was used to estimate overall survival (OS), progression-free survival (PFS) and local-regional failure (LRF) and compare PFS and LRF between patients with high-TMB (≥ 10 mt/Mb) and low-TMB. A p-value <0.05 was considered significant. <h3>Results</h3> Eighty-one patients with median follow-up of 26 months were assessed. Median age was 67 years, 71% (n=57) had stage IIIB/IIIC disease and PD-L1 expression was available for 67 (83%) patients, of whom 42 (63%) had PD-L1 ≥1%. Median TMB was 8.8 mt/Mb. In total, 17% (n=14) and 35% (n=28) of patients had pathogenic mutations in DDR and radiation resistance genes, respectively (Table 1). Among all patients, the 24-month OS, PFS and LRF estimates were 72% (95% CI: 62-82), 45% (34-56%) and 31% (1-43%), respectively. On Cox analysis, only TMB associated with PFS [HR: 0.95 (0.92-0.98), p=0.009] and LRF [HR: 0.89 (0.83-0.97, p=0.009]. Neither PDL1 expression, DDR or radiation resistance mutations, histology, stage nor ECOG associated with PFS or LRF. Compared to patients with low-TMB, patients with high-TMB had improved PFS and less LRF: 24-month PFS: 66% vs 27% (p=0.003) and 24-month LRF: 9% vs 52% (p=0.001). <h3>Conclusion</h3> In patients with locally advanced NSCLC treated with cCRT and durvalumab, high-TMB predicts for improved progression-free survival and local-regional control. Potential underlying mechanisms include increased genomic instability and tumor immunogenicity enhancing sensitivity to this multimodal treatment.

Intensified Radiation Therapy for Laryngeal Cancer: Oncologic and Functional Outcomes

<h3>Purpose/Objective(s)</h3> To evaluate the outcomes of advanced-stage laryngeal squamous cell carcinoma (SCC) patients (pts) treated with functional-preservation strategy at a tertiary cancer center with a specific focus on laryngo-esophageal dysfunction disease free survival (LDDFS). <h3>Materials/Methods</h3> Retrospective review was conducted of stage III-IVB laryngeal SCC pts who were treated with curative-intent radiotherapy (RT) (2007-2018). Pts were preferentially managed with upfront chemoradiation (CRT); except for those with cN2-3, cT4, or large volume cT3 (induction chemotherapy followed by RT or CRT is an option), and those who were unfit or declined chemotherapy (received accelerated RT). The primary endpoint was 3-yr LDDFS, and secondary endpoints were 3-yr local failure (LF), regional failure (RF), distant metastasis (DM), overall survival (OS), disease-free survival (DFS) and acute and late toxicities. Events for LDDFS included death, tumor relapse (i.e., LF, RF, DM), and late laryngo-esophageal dysfunction (defined by feeding tube dependence, tracheostomy or aspiration pneumonia >6 months post-RT), whichever occurred first. Cox proportional hazard test were used for multivariable analysis (MVA). <h3>Results</h3> A total of 213 cases were included (table 1). With a median follow-up of 37 months, the 3-yr LDDFS was 50%, while the 3-yr OS, DFS, LF, RF, and DM were 81%, 74%, 9%, 5% and 7%, respectively. On MVA, cT4- category was the only predictor of inferior LDDFS (HR: 0.47, [95%CI: 0.29-0.74], p<0.01). The most common grade ≥ 3 acute and late RTOG toxicity were esophageal toxicity: 16.7% and 29.6%, respectively. <h3>Conclusion</h3> Intensified RT resulted in favorable oncologic and functional outcome in only half of the advanced stage laryngeal cancer pts. Future clinical trials are required to investigate further treatment intensification particularly in T4-primary tumors aiming to improve the oncologic and maintain functional outcomes with utilization of LDDFS as the primary endpoint.

Evaluation of risk-tailored individualized selection of radiation therapy target volume for head and neck carcinoma of unknown primary.

Intensity-modulated radiation therapy (IMRT) has enabled risk-tailored approach to elective mucosal and nodal clinical target volumes (CTVs) in treatment of head and neck carcinoma of unknown primary (HNCUP). This study report outcomes following such approach. HNCUP patients treated with definitive IMRT between 2005 and 2018 were reviewed. Local failure (LF), regional failure (RF), distant metastasis (DM), overall survival (OS) and grade ≥3 late toxicity (LT) were analyzed. Multivariable analysis (MVA) was used to identify OS predictors for entire cohort and cN2-3 subgroup. A total of 203 patients were eligible: cN1 (7%), cN2a (14%), cN2b (46%), cN2c (14%) and cN3 (19%). Among 118 patients with known HPV status (by p16 staining), 81 (68%) were positive. IMRT target volume spared contralateral tonsil (55%), bilateral or contralateral sides of hypopharynx (72%), nasopharynx (72%), larynx (87%) and contralateral uninvolved neck (21%). Median follow-up was 5years. Five-year LF, RF, DM, OS, and LT were 3%, 14%, 10%, 79%, and 7% respectively. Four patients developed mucosal recurrence: 3 within and 1 at the margin of the elective mucosal CTV. None of ipsilateral neck irradiation patients failed in the contralateral uninvolved neck. MVA identified cN2c-N3, HPV-negative status and older age as predictors for inferior OS. Within cN2-3 subgroup (n=189): cN2c-N3, HPV-negative status and older age predicted lower OS, while concurrent chemotherapy was associated with better OS. Definitive IMRT with risk-adaptive radiation volume de-escalation for HNCUP resulted in high probability of tumor control with acceptable rate of late toxicity.