Standard Chemoradiation Research Articles

BIOM-26. SURVIVAL OUTCOMES AND PROGNOSTIC FACTORS IN PRIMARY GLIOBLASTOMA FROM A REAL-WORLD RETROSPECTIVE STUDY

Abstract INTRODUCTION Glioblastoma has limited therapeutic options and is associated with a poor prognosis. Treatment, clinical outcomes, and prognostic factors remain poorly characterised outside of the selected population enrolled in clinical trials. METHODS Demographic, tumour molecular profiles, treatment, and survival data was collated for patients who underwent a biopsy or resection diagnostic of de novo glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazards models to examine the association of potential prognostic markers with survival. RESULTS 490 patients were identified: 60% were male with a median age of 59 years. 60% of patients had surgical debulking, and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% non-standard chemo/radio-therapy, and 19% no further treatment; 22% of patients who had adjuvant therapy had surgery at relapse, 37% second-line chemotherapy, and 11% third-line chemotherapy. Median survival was 9.2 months (IQR 7.9-10.3 months), with survival at 12- and 24-months 41% and 13% respectively. In multivariate analysis, longer survival was associated with debulking surgery vs biopsy alone (14.9 vs 8 months) (HR 0.54 [95%CI 0.41-0.70]); subsequent treatment after diagnosis (HR 0.12 [0.08-0.16]) (standard chemoradiotherapy [16.9 months] vs non-standard regimens [9.2 months] vs none [2.0 months]); tumour MGMT promotor methylation (HR 0.71 [0.58-0.87]); and younger age (hazard ratio vs age< 50: 1.70 [1.26-2.30] for ages 50-59; 3.53 [2.65-4.70] for ages 60-69; 4.82 [3.54-6.56] for ages 70+). IDH mutation was associated with longer survival (HR 0.64 [0.66-0.97] in univariate but not multivariate analysis. CONCLUSION Median survival for patients with glioblastoma is less than a year. Younger age, debulking surgery, treatment with chemoradiotherapy, and MGMT promotor methylation are independently associated with longer survival.

Standard 6-week chemoradiation for elderly patients with newly diagnosed glioblastoma

Glioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard 6-week chemoradiation (CRT) in particular, although this is the mainstay for younger patients. All patients with newly diagnosed GBM and age ≥ 70 who were referred to our institution for 6-week CRT were reviewed from 2004 to 2018. MGMT status was not available for treatment decision at that time. The primary endpoint was overall survival (OS). Secondary outcomes were progression-free survival (PFS), early adverse neurological events without neurological progression ≤ 1 month after CRT and temozolomide hematologic toxicity assessed by CTCAE v5. 128 patients were included. The median age was 74.1 (IQR: 72–77). 15% of patients were ≥ 80 years. 62.5% and 37.5% of patients fulfilled the criteria for RPA class I–II and III–IV, respectively. 81% of patients received the entire CRT and 28% completed the maintenance temozolomide. With median follow-up of 11.7 months (IQR: 6.5–17.5), median OS was 11.7 months (CI 95%: 10–13 months). Median PFS was 9.5 months (CI 95%: 9–10.5 months). 8% of patients experienced grade ≥ 3 hematologic events. 52.5% of patients without neurological progression had early adverse neurological events. Post-operative neurological disabilities and age ≥ 80 were not associated with worsened outcomes. 6-week chemoradiation was feasible for “real-life” elderly patients diagnosed with glioblastoma, even in the case of post-operative neurological disabilities. Old does not necessarily mean worse.

NRG Oncology/Alliance LU005: A Phase II/III Randomized Study of Chemoradiation vs. Chemoradiation Plus Atezolizumab in Limited Stage Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Clinical outcomes for limited stage small cell lung cancer (LS-SCLC) remain suboptimal. Standard of care chemoradiation with platinum/etoposide and thoracic radiation to 45 Gy delivered twice daily followed by prophylactic cranial irradiation yields a median overall survival of 30 months. LU005 is a randomized phase II/III trial designed to test the addition of atezolizumab to concurrent chemoradiation. <h3>Materials/Methods</h3> Patients with LS-SCLC (Tx-T4, N0-N3, M0) are randomly assigned in a 1:1 ratio to either standard chemoradiation, consisting of thoracic radiation (45 Gy twice daily or 66 Gy daily) with concurrent platinum/etoposide chemotherapy, or the experimental arm, consisting of the same chemoradiation regimen plus the addition of atezolizumab delivered concurrently with thoracic radiation, every 3 weeks for 12 months duration. Thoracic radiation begins with the second cycle of chemotherapy in both treatment arms. Stratification variables include radiation schedule (once daily vs. twice daily), chemotherapy (cisplatin vs. carboplatin), gender, and performance status (PS 0/1 vs. 2). Prophylactic cranial radiation is recommended for patients who have a response to treatment. The phase II primary endpoint is progression free survival (PFS) and the phase III primary endpoint is overall survival (OS). The overall sample size for phase II/III will be 506. Secondary endpoints include objective response rates, local control, distant metastases free, and quality of life. Correlative studies will include blood and tissue based tumor mutational burden analysis, with the hypothesis that higher mutational burden will predict for improved PFS in the experimental arm. <h3>Results</h3> As of 3/01/2021, 374 sites are approved to enroll patients. Two-hundred patients have been accrued. Current enrollment is ahead of projected accrual. <h3>Conclusion</h3> LU005 is a randomized II/III trial testing the addition of atezolizumab to standard chemoradiation for LS-SCLC. Accrual remains robust in spite of the ongoing COVID 19 pandemic. Funding: This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA180803 (IROC) from the National Cancer Institute (NCI) and Genentech.

Analysis of Pathologic Complete Response Rates Between Different Neoadjuvant Radiation Treatment Regimens for Rectal Cancer

The standard of care for rectal cancer is either long or short course radiation followed by surgery with or without adjuvant chemotherapy. Recently, total neoadjuvant therapy, an approach consisting of giving all chemotherapy and radiotherapy prior to definitive surgery, has been a promising alternative. This study aims to assess the pathologic complete response (pCR) rates among different neoadjuvant treatment regimens and determine if neoadjuvant chemotherapy improves pCR rates.Electronic medical databases were queried to identify rectal cancer patients treated with neoadjuvant therapy at our institution from 2006-2019. Patients were grouped according to neoadjuvant therapy received: long-course chemoradiation (CRT), long-course chemoradiation with chemotherapy (CRT TNT), short-course radiation (SCRT), and short-course radiation with chemotherapy (SCRT TNT). Patients without follow-up data or surgical pathology reports were excluded. pCR was defined as no evidence of disease at surgery. pCR rates were determined and compared using Chi-square analysis.A total of 249 patients were analyzed. Table 1 shows treatment characteristics in each group. There were 200 (80.3%) patients who received CRT, 26 (10.4%) who received CRT TNT, 13 (5.2%) who received SCRT, and 10 (4%) who received SCRT TNT. Initial stage was different between groups, with metastatic patients more likely to receive SCRT TNT (P < 0.001). The median time to surgery were significantly different between groups (P < 0.001). Eleven (42.3%) and 6 (60%) patients received FOLFOX, and 13 (50%) and 4 (40%) of the patients received XELOX for CRT TNT and SCRT TNT, respectively. The remaining patients (7.7%) in the CRT TNT group received Capecitabine. For CRT, 53 (26.5%) patients achieved pCR, 3 (11.5%) in CRT TNT, 1 (7.7%) in SCRT, and 2 (20%) in SCRT TNT. None of these differences were statistically different (P = 0.19). On univariate analysis, age (P = 0.13), clinical T stage (P = 0.13), clinical N stage (P = 0.95), time to surgery (P = 0.82), and presence of chemotherapy in the neoadjuvant regimen (P = 0.22) were not significant predictors for pCR.Total neoadjuvant treatment for rectal cancer did not improve pCR rates over standard chemoradiation or short course radiation alone, which is contrary to what published series suggest. These results maybe be explained in part by the fact that chemotherapy was delivered first and the time from completing radiation to the time of surgery was not significantly different between groups. These data suggest that meaningful gains in pCR rates may be achieve by sequencing chemoradiation earlier in the TNT course. Future studies are needed to investigate this hypothesis.

Prospective Phase I/II Study of Radiation and Chemotherapy With Ipilimumab Followed by Nivolumab for Patients With Stage III Unresectable NSCLC

We hypothesized that the addition of concurrent ipilimumab (IPI) with chemoradiotherapy followed by consolidative nivolumab (NIVO) would be safe and tolerable for patients with unresectable stage III non-small cell lung cancer (NSCLC). We report early outcomes and toxicity associated with this regimen in a phase I/II clinical trial.The study was designed as a prospective, multicenter phase I/II trial. Eligible patients had ECOG 0-1 and unresectable stage III NSCLC. Therapy included a platinum-based chemotherapy doublet with concurrent radiotherapy to 60 Gy in 30 fractions over six weeks and two doses of concurrent IPI (1 mg/kg) given weeks 1 and 4. Maintenance NIVO was initiated 1-3 weeks after completion of chemoradiotherapy/IPI and given every 4 weeks (480 mg) for up to 12 cycles. The primary endpoints were to evaluate the safety and tolerability of the regimen (Phase I) and the 12-month PFS (Phase II). Treatment-related toxicity was assessed according to CTCAE v5.0. Time to event analysis was performed with Kaplan Meier (KM) and Cox proportional hazard (CPH) models. Results are reported with 95% confidence intervals (CI).Nineteen of a planned 55 patients were enrolled in the trial which was discontinued without proceeding to the Phase II component due to exceeding the futility boundary for toxicity. The median follow-up was 21 months by the reverse KM method. The 12-month PFS estimate was 54% (CI 29-78) and the median PFS was 19 months (CI 6-not reached). The 12-month OS estimate was 60% (CI 36-84) while the median OS was not reached. Ten patients (53%, CI 29-76) experienced grade 2 or higher (G2+) pneumonitis. The median time to development of G2+ pneumonitis was 5.5 months and the risk of G2+ pneumonitis at 6- and 12-months was 57% (CI 30-84) and 74% (CI 49-99), respectively. Sixteen patients (84%, CI 68-100) had any G3+ treatment related toxicity. The most common G3+ toxicities were pulmonary (8 patients, 42%, CI 20-67) and cytopenias (7 patients, 37%, CI 16-62). Five patients (26%, CI 6-46) had possible treatment related G5 toxicity, including three patients with possible treatment related G5 pulmonary toxicity (16%, CI 0-32). There was no difference in the mean percent of lung volume receiving 20 Gy (V20) between those with and without G2+ pneumonitis (26%, CI 20-32 vs 21%, CI 16-27, P = 0.18), nor in the mean lung dose (14 Gy, CI 10-17 vs 15 Gy, CI 12-18, P = 0.35). Neither mean lung dose nor lung V20 were associated with time to G2+ pneumonitis on univariable CPH.The combination of concurrent IPI with standard chemoradiation followed by maintenance NIVO for unresectable stage III NSCLC is associated with significant toxicity which may limit opportunities for improved outcomes, although the sample size in this trial is small. Alternative strategies or sequencing should be explored to integrate immunotherapy with cytotoxic chemotherapy and radiation for patients with unresectable stage III NSCLC.

Predictive Capability and Dynamic Characteristic of Tumor Voxel Dose-Response Assessed Using 18F-FDG PET/CT Imaging Feedback

To effectively implement FDG-PET/CT imaging feedback for tumor voxel treatment response assessment and treatment adaptation, this study investigated the predictive capability and the dynamic characteristic of tumor voxel treatment response with respect to the timing of imaging feedback.Serial FDG-PET/CT images were obtained at pretreatment and weekly during the standard chemoradiotherapy with treatment dose of 2Gy × 35 from 33 head and neck cancer patients. Reference of tumor voxel dose-response matrix (DRMref) was constructed for each patient using the average slope of tumor voxel PET intensity change ratio obtained from the first 4 weekly PET feedback images following deformable PET/CT image registration. The predictive capability of tumor voxel DRM assessed using 1 or 2 PET feedback images obtained during the first 4 treatment weeks was evaluated. The evaluation included the tumor voxel DRM correlation and the voxel DRM discrepancy between the predictions and the reference. The dynamic characteristics of DRM were studied by comparing the DRM assessed at different treatment weeks. The dynamic characteristics were also correlated to the tumor volume and tumor voxel location with respect to the human papillomavirus (HPV) status.The correlation coefficient between the DRMref and the DRMs predicted using a single feedback image increased from 0.82±0.2 for DRM2 at the 2nd treatment week to 0.95±0.03 for DRM4 at the 4th treatment week. The deviation between the tumor voxel DRMref and the predicted DRMs was (4.7±53.9)% for DRM2, (-7.3±21.1)% for DRM3, and (6.2±15.6)% for DRM4. The deviation reduced to (4.4±8.4)% or (1.1±7.8)% when using the week 2&4 or 3&4 feedback images. Tumor voxel improved its response significantly after 2nd treatment week in both HPV+ and HPV- tumors. In HPV- tumors, the magnitude of tumor voxel DRM reduction was correlated with the distance from the tumor surface to the voxels with a Spearman correlation coefficient = 1, P = 0.017.Tumor voxel treatment response showed large improvement after the 2nd treatment week with the delivered dose of 2Gy × 10 and got relatively stabilized after 2Gy × 15. FDG-PET/CT imaging acquired in the 3rd treatment week is recommended if single image feedback is selected. Feedback images obtained in the 2nd and 4th treatment weeks will additionally improve predictive capability and provide guidance for early treatment dose adjustment.

Identifying Optimal Neoadjuvant Strategy Based on Pathological Complete Response Rates in Local Advanced Rectal Cancer: A Systematic Review and Network Meta-Analysis

<h3>Purpose/Objective(s)</h3> Patients with locally advanced rectal cancer (LARC) who achieve a pathological complete response (pCR) to neoadjuvant chemoradiation therapy (CRT) have an enhanced prognosis Watch and wait is appropriate treatment strategy after patients achieving clinical complete response, but the proportion is small. We aimed to identify optimal neoadjuvant strategy based on pCR rates in LARC by network meta-analysis. <h3>Materials/Methods</h3> This network meta-analysis (NMA), based on phase II and phase III studies, involving patients with LARC, indirectly compared seven strategies including short course radiotherapy (SCRT) + immediate surgery, SCRT + delayed surgery, SCRT + consolidation chemotherapy + surgery, induction chemotherapy + long course chemoradiotherapy (LCCRT) + surgery, LCCRT + consolidation chemotherapy + surgery, LCCRT + delayed surgery and standard neoadjuvant chemoradiotherapy. Studies were identified through PubMed, EMBASE, the Cochrane Library, and abstracts found in ASTRO and ASCO. The primary endpoint pathological complete response (pCR) with odds risk (OR) were pooled according to frequentist network meta-analytical techniques. <h3>Results</h3> Fifteen trials, involving 4424 patients met our eligibility criteria. For LARC patients, the pCR-NMA was based on all 15 trials. In terms of pCR, all other treatments performed significantly better than SCRT + immediate surgery. SCRT + consolidation chemotherapy + surgery, LCCRT + consolidation chemotherapy + surgery, and LCCRT + delayed surgery performed significantly better than SCRT + delayed surgery. SCRT + delayed surgery performed significantly better than SCRT +immediate surgery (OR 0.07, 95% CI 0.01–0.29). SCRT + consolidation chemotherapy + surgery performed significantly better than standard neoadjuvant LCCRT (OR 2.2, 95% CI 1.1–5.0). Interestingly, SCRT + consolidation chemotherapy + surgery had superior trends to the remaining six treatment models. By direct and indirect comparison, we obtained a ranking of the pCR rates achieved by these treatment modalities:SCRT + consolidation chemotherapy + surgery > LCCRT + consolidation chemotherapy + surgery > LCCRT + delayed surgery > induction chemotherapy +LCCRT + surgery > standard neoadjuvant LCCRT > SCRT + delayed surgery > SCRT + immediate surgery. <h3>Conclusion</h3> Evidence from this study suggests that SCRT + consolidation chemotherapy may yield higher pCR rates compared to other treatment modalities in LARC patients at this stage.

A Phase II Trial of Primary Tumor SBRT Boost Prior to Concurrent Chemoradiation for Locally-Advanced Non-Small Cell Lung Cancer (LA-NSCLC)

Primary tumor failure is common in patients treated with chemoradiation (CRT) for unresectable LA-NSCLC. Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control in Stage I NSCLC. This trial tested an SBRT boost to the primary tumor prior to the start of CRT to improve primary tumor control (PTC).Patients with LA-NSCLC with primary tumor ≤10 cm were enrolled on a prospective phase II trial testing an SBRT boost in 2 fractions (central 6 Gy x 2, peripheral 8 Gy x 2) immediately followed by standard concurrent CRT (60 Gy in 30 fractions). Patients were staged with PET-CT, brain MRI, and underwent 4D-CT simulation for radiation planning using a customized immobilization device that enabled radiation planning for the sequential delivery of the SBRT boost and conventionally-fractionated radiation from the same CT dataset. Chemotherapy was carboplatin/paclitaxel (C/P) or cisplatin/etoposide. For patients receiving C/P, consolidation C/P for 2 cycles was given at the discretion of the medical oncologist. The trial was later amended to allow for consolidation durvalumab. The primary objective was to estimate PTC rate at 1-year with a hypothesis that the 1-year PTC rate is ≥90%. Secondary objectives were to establish the safety, feasibility, objective response rate (ORR; RECISTv1.1), and rates of regional & distant control, disease-free survival (DFS), and overall survival (OS). Exploratory functional MRI (fMRI) scans before and within the first 30 hrs of the first SBRT fraction were performed in 11 patients.The study enrolled 21 patients (10 male, 11 female), with median age 62 years (range 52-78). 16 patients received 6 Gy x 2 SBRT boost, while 5 patients received 8 Gy x 2 SBRT boost. 18 patients received C/P chemotherapy, of whom 9 patients received consolidation C/P. Six patients received consolidation durvalumab. Median pre-treatment primary tumor size was 5.0 cm (range 1.0-8.3). Median and mean follow-up were17.9 and 20.2 months, respectively. The most common toxicities were fatigue, neutropenia, leukopenia, lymphopenia, anemia, pneumonitis, fibrosis, dyspnea and esophagitis. Five grade 4 toxicities related to treatment occurred [lymphopenia (3), neutropenia (1), and leukopenia (1)], but no grade 5 toxicities related to treatment occurred. ORR at 3 and 6 months was 72.7% and 80.0%. The PTC rate was 100% and 92.3% at 1 and 2 years, respectively. The 2-year regional and distant control were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 yrs were 46.1% and 50.3%, respectively. Median survival was 37.8 months. fMRI detected a mean relative decrease in BOLD signal of -87.1% (P = 0.05).Dose escalation to the primary tumor utilizing upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably with the literature. Through the use of 1 CT simulation dataset, accurate calculation of the planned dose through the 2 sequentially-delivered plans is achievable.

Effect of Levetiracetam Use Duration on Overall Survival of Isocitrate Dehydrogenase Wild-Type Glioblastoma in Adults: An Observational Study.

The association between levetiracetam and survival with isocitrate dehydrogenase (IDH) wild-type glioblastomas is controversial. We investigated whether the duration of levetiracetam use during the standard chemoradiation protocol affects overall survival (OS) of patients with IDH wild-type glioblastoma. In this observational single-institution cohort study (2010-2018), inclusion criteria were (1) age ≥18 years; (2) newly diagnosed supratentorial tumor; (3) histomolecular diagnosis of IDH wild-type glioblastoma; and (4) standard chemoradiation protocol. To assess the survival benefit of levetiracetam use during the standard chemoradiation protocol (whole duration, part time, and never subgroups), a Cox proportional hazard model was constructed. We performed a case-matched analysis (1:1) between patients with levetiracetam use during the whole duration of the standard chemoradiation protocol and patients with levetiracetam use part time or never according to the following criteria: sex, age, epileptic seizures at diagnosis, Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) class, tumor location, preoperative volume, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Patients with unavailable O6-methylguanine-DNA methyltransferase promoter methylation status (48.5%) were excluded. A total of 460 patients were included. The median OS was longer in the 116 patients with levetiracetam use during the whole duration of the standard chemoradiation protocol (21.0 months; 95% confidence interval [CI] 17.2-24.0) than in the 126 patients with part-time levetiracetam use (16.8 months; 95% CI 12.4-19.0) and in the 218 patients who never received levetiracetam (16.0 months; 95% CI 15.5-19.4; p = 0.027). Levetiracetam use during the whole duration of the standard chemoradiation protocol (adjusted hazard ratio [aHR] 0.69; 95% CI 0.52-0.93; p = 0.014), MGMT promoter methylation (aHR 0.53; 95% CI 0.39-0.71; p < 0.001), and gross total tumor resection (aHR 0.57; 95% CI 0.44-0.74; p < 0.001) were independent predictors of longer OS. After case matching (n = 54 per group), a longer OS was found for levetiracetam use during the whole duration of the standard chemoradiation protocol (hazard ratio 0.63; 95% CI 0.42-0.94; p = 0.023). Levetiracetam use during the whole standard chemoradiation protocol possibly improves OS of patients with IDH wild-type glioblastoma. It should be considered in the antitumor strategy of future multicentric trials. This study provides Class III evidence that in individuals with IDH wild-type glioblastoma, levetiracetam use throughout the duration of standard chemotherapy is associated with longer median OS.

Differential role of residual metabolic tumor volume in inoperable stage III NSCLC after chemoradiotherapy\u2009\xb1\u2009immune checkpoint inhibition

BackgroundThe PET-derived metabolic tumor volume (MTV) is an independent prognosticator in non-small cell lung cancer (NSCLC) patients. We analyzed the prognostic value of residual MTV (rMTV) after completion of chemoradiotherapy (CRT) in inoperable stage III NSCLC patients with and without immune checkpoint inhibition (ICI).MethodsFifty-six inoperable stage III NSCLC patients (16 female, median 65.0 years) underwent 18F-FDG PET/CT after completion of standard CRT. rMTV was delineated on 18F-FDG PET/CT using a standard threshold (liver SUVmean + 2 × standard deviation). 21/56 patients underwent additional ICI (CRT-IO, 21/56 patients) thereafter. Patients were divided in volumetric subgroups using median split dichotomization (MTV ≤ 4.3 ml vs. > 4.3 ml). rMTV, clinical features, and ICI-application were correlated with clinical outcome parameters (progression-free survival (PFS), local PFS (LPFS), and overall survival (OS).ResultsOverall, median follow-up was 52.0 months. Smaller rMTV was associated with longer median PFS (29.3 vs. 10.5 months, p = 0.015), LPFS (49.9 vs. 13.5 months, p = 0.001), and OS (63.0 vs. 23.0 months, p = 0.003). CRT-IO patients compared to CRT patients showed significantly longer median PFS (29.3 vs. 11.2 months, p = 0.034), LPFS (median not reached vs. 14.0 months, p = 0.016), and OS (median not reached vs. 25.2 months, p = 0.007). In the CRT subgroup, smaller rMTV was associated with longer median PFS (33.5 vs. 8.6 months, p = 0.001), LPFS (49.9 vs. 10.1 months, p = 0.001), and OS (63.0 vs. 16.3 months, p = 0.004). In the CRT-IO subgroup, neither PFS, LPFS, nor OS were associated with MTV (p > 0.05 each). The findings were confirmed in subsequent multivariate analyses.ConclusionIn stage III NSCLC, smaller rMTV is highly associated with superior clinical outcome, especially in patients undergoing CRT without ICI. Patients with CRT-IO show significantly improved outcome compared to CRT patients. Of note, clinical outcome in CRT-IO patients is independent of residual MTV. Hence, even patients with large rMTV might profit from ICI despite extensive tumor load.

Artificial intelligence for early prediction of treatment response in glioblastoma

Abstract Aims Treatment response assessment in glioblastoma is challenging. Patients routinely undergo conventional magnetic resonance imaging (MRI), but it has a low diagnostic accuracy for distinguishing between true progression (tPD) and pseudoprogression (psPD) in the early post-chemoradiotherapy time period due to similar imaging appearances. The aim of this study was to use artificial intelligence (AI) on imaging data, clinical characteristics and molecular information within machine learning models, to distinguish between and predict early tPD from psPD in patients with glioblastoma. Method The study involved retrospective analysis of patients with newly-diagnosed glioblastoma over a 3.5 year period (n=340), undergoing surgery and standard chemoradiotherapy treatment, with an increase in contrast-enhancing disease on the baseline MRI study 4-6 weeks post-chemoradiotherapy. Studies had contrast-enhanced T1-weighted imaging (CE-T1WI), T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) sequences, acquired at 1.5 Tesla with 6-months follow-up to determine the reference standard outcome. 76 patients (mean age 55 years, range 18-76 years, 39% female, 46 tPD, 30 psPD) were included. Machine learning models utilised information from clinical characteristics (age, gender, resection extent, performance status), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and 307 quantitative imaging features; extracted from baseline study CE-T1WI/ADC and T2WI sequences using semi-automatically segmented enhancing disease and perilesional oedema masks respectively. Feature selection was performed within bootstrapped cross-validated recursive feature elimination with a random forest algorithm and Naïve Bayes five-fold cross-validation to validate the final model. Results Treatment response assessment based on the standard-of-care reports by clinical neuroradiologists showed an accuracy of 33% (sensitivity/specificity 52%/3%) to distinguish between tPD and psPD from the early post-treatment MRI study at 4-6 weeks. Machine learning-based models based on clinical and molecular features alone demonstrated an AUC of 0.66 and models using radiomic features alone from the early post-treatment MRI demonstrated an AUC of 0.46-0.69 depending on the feature and mask subset. A combined clinico-radiomic model utilising top common features demonstrated an AUC of 0.80 and an accuracy of 74% (sensitivity/specificity 78%/67%). The features in the final model were age, MGMT promoter methylation status, two shape-based features from the enhancing disease mask (elongation and sphericity), three radiomic features from the enhancing disease mask on ADC (kurtosis, correlation, contrast) and one radiomic feature from the perilesional oedema mask on T2WI (dependence entropy). Conclusion Current standard-of-care glioblastoma treatment response assessment imaging has limitations. In this study, the use of AI through a machine learning-based approach incorporating clinical characteristics and MGMT promoter methylation status with quantitative radiomic features from standard MRI sequences at early 4-6 weeks post-treatment imaging showed the best model performance and a higher accuracy to distinguish between tPD and psPD for early prediction of glioblastoma treatment response.

Impact of Dose-Escalated Chemoradiation on Quality of Life in Patients With Locally Advanced Rectal Cancer: 2-Year Follow-Up of the Randomized RECTAL-BOOST Trial

Dose-escalated chemoradiation (CRT) for locally advanced rectal cancer did not result in higher complete response rates but initiated more tumor regression in the randomized RECTAL-BOOST trial (Clinicaltrials.gov NCT01951521). This study compared patient reported outcomes between patients who received dose-escalated CRT (5×3 gray boost+CRT) or standard CRT for 2 years after randomization. Patients with locally advanced rectal cancer who were participating in the RECTAL-BOOST trial filled out European Organisation for Research and Treatment of Cancer QLQ-C30 and CR29 questionnaires on quality of life (QoL) and symptoms at baseline, 3, 6, 12, 18, and 24 months after start of treatment. Between-group differences in functional QoL domains were estimated using a linear mixed-effects model and expressed as effect size (ES). Symptom scores were compared using Mann-Whitney U test. Patients treated with dose-escalated CRT (boost group, n=51) experienced a significantly stronger decline in global health at 3 and 6 months (ES -0.4 and ES -0.4), physical functioning at 6 months (ES -1.1), role functioning at 3 and 6 months (ES -0.8 and ES -0.6), and social functioning at 6 months (ES -0.6), compared with patients treated with standard CRT (control group, n=64). The boost group reported significantly more fatigue at 3 and 6 months (83% vs 66% respectively 89% vs 76%), pain at 3 and 6 months (67% vs 36% respectively 80% vs 44%), and diarrhea at 3 months (45% vs 29%) compared with the control group. From 12 months onwards, QoL and symptoms were similar between groups, apart from more blood/mucus in stool in the boost group. In patients with locally advanced rectal cancer, dose-escalated CRT resulted in a transient deterioration in global health, physical, role, and social functioning and more pain, fatigue and diarrhea at 3 and 6 months after start of treatment compared with standard CRT. From 12 months onwards, the effect of dose-escalated CRT on QoL largely resolved.

Magnetic Resonance Imaging Mapping of Brain Tumor Burden: Clinical Implications for Neurosurgical Management: Case Report.

ABSTRACTBACKGROUND AND IMPORTANCEDistinction of brain tumor progression from treatment effect on postcontrast magnetic resonance imaging (MRI) is an ongoing challenge in the management of brain tumor patients. A newly emerging MRI biomarker called fractional tumor burden (FTB) has demonstrated the ability to spatially distinguish high-grade brain tumor from treatment effect with important implications for surgical management and pathological diagnosis.CLINICAL PRESENTATIONA 58-yr-old male with glioblastoma was treated with standard concurrent chemoradiotherapy (CRT) after initial resection. Throughout follow-up imaging, the distinction of tumor progression from treatment effect was of concern. The surgical report from a redo resection indicated recurrent glioblastoma, while the tissue sent for pathological diagnosis revealed no tumor. Presurgical FTB maps confirmed the spatial variation of tumor and treatment effect within the contrast-agent enhancing lesion. Unresected lesion, shown to be an active tumor on FTB, was the site of substantial tumor growth postresection.CONCLUSIONThis case report introduces the idea that a newly developed MRI biomarker, FTB, can provide information of tremendous benefit for surgical management, pathological diagnosis as well as subsequent treatment management decisions in high-grade glioma.

Association between circulating CD39+CD8+ T cells pre-chemoradiotherapy and prognosis in patients with nasopharyngeal carcinoma.

BackgroundThe mortality rate among patients with nasopharyngeal carcinoma (NPC) has improved significantly with the advent of chemoradiotherapy strategies. However, distant metastasis remains problematic. Tumor-specific reactivity in cancer patients has been detected exclusively in CD39+ T cells, particularly in CD39+CD103+ T cells. Circulating cancer-specific T cells are important for protecting against metastasis. This study aimed to evaluate the predictive value of circulating CD39+CD8+ T cells for metastasis in patients with NPC.MethodsWe performed a cross-sectional, longitudinal study of 55 patients with newly diagnosed NPC of stage III–IVa. All patients were initially treated with standard combined chemoradiotherapy. Blood samples were obtained from 24 patients before and at 1 month and 6 months after treatment. T cell expression of CD39 and CD103, together with the markers of T cell exhaustion programmed death-1 (PD-1)/T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and markers of cell differentiation CD27/CC-chemokine receptor 7/CD45RA, was examined by flow cytometry. The Wilcoxon rank-sum test analysis was used to analyze the differences between two groups. Kaplan-Meier analysis was used for analysis of progression-free survival (PFS).ResultsThe expression of circulating CD39+CD8+ and CD39+CD103+ CD8+ T cells was significantly higher in patients without distant metastasis (CD39+CD8+: 6.52% [1.24%, 12.58%] vs. 2.41% [0.58%, 5.31%], Z=−2.073, P=0.038 and CD39+CD103+CD8+: 0.72% [0.26%, 2.05%] vs. 0.26% [0.12%, 0.64%], Z=−2.313, P = 0.021). Most CD39+ T cells did not express PD-1 or Tim-3. Patients with high expression of CD39+CD103+CD8+ T cells had better PFS than patients with low expression (log rank value = 4.854, P = 0.028). CD39+CD8+ T cells were significantly elevated at 1-month post-treatment (10.02% [0.98%, 17.42%] vs. 5.91% [0.61%, 10.23%], Z = −2.943, P = 0.003). The percentage of advanced differentiated CD8+ T cells also increased at 1-month post-treatment compared with pre-treatment (33.10% [21.60%, 43.05%] vs. 21.00% [11.65%, 43.00%], Z = −2.155, P = 0.031). There was a significant correlation between elevated CD39+CD8+ T cells and increased effector memory T cells (intermediate stage: r = 0.469, P = 0.031; advanced stage: r = 0.508, P = 0.019).ConclusionsCD39+CD8+ circulating T cells have preserved effector function, contributing to an improved prognosis and a reduced risk of metastasis among NPC patients. These cells may thus be a useful predictive marker for a better prognosis in patients with NPC.

Long-Term Outcomes and Sites of Failure in Locally Advanced, Cervical Cancer Patients Treated by Concurrent Chemoradiation with or without Adjuvant Chemotherapy: ACTLACC Trial.

Objectives:To evaluate sites of failure and long-term survival outcomes of locally advanced stage cervical cancer patients who had standard concurrent chemo-radiation (CCRT) versus those along with adjuvant chemotherapy (ACT) after CCRT. Methods:Patients aged 18–70 years who had FIGO stage IIB-IVA without para-aortic lymph node enlargement (excluding by International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IIIC2r), The Eastern Cooperative Oncology Group (ECOG) scores 0–2, and non-aggressive histopathology were randomized to have CCRT with weekly cisplatin followed by observation (arm A) or ACT with paclitaxel plus carboplatin every 4 weeks for 3 cycles (arm B). Results:From 2015-2017, 259 patients were evaluated. The majority of patients were in stage II and had squamous cell carcinoma with a median tumor size of 5 cm. After the median follow-up of 40.87 months, 17.1% of the patients in arm A and 12.3% of the patients in arm B experienced recurrences (p=0.280). Adding all events of failure (persistence/progression/recurrence), treatment failures tended to be lower in arm A than in arm B: 13.2 versus 21.5 % for loco-regional failure (p = 0.076) and 3.9 versus 6.9% for loco-regional failure and systemic failure (p = 0.278). On the other hand, systemic failure tended to be higher in arm A than in arm B: 13.2% versus 6.9% (p =0.094). The 5-year progression-free survival and 5-year overall survival of patients in both arms were not significantly different. Conclusions:ACT with paclitaxel plus carboplatin after CCRT did not improve response or survival of patients compared to CCRT alone. Although systemic failure tended to be lower in patients who had ACT after CCRT than those who had only CCRT, loco-regional failure with or without systemic failure tended to be higher. However, all of these differences were not statistically significant.

378TiP A phase I/II/IIb study to evaluate the safety and efficacy of the tumor-targeting human antibody-cytokine fusion protein L19TNF plus standard temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma

Glioblastoma is a poorly immunogenic cancer and is inevitably lethal despite a multimodal standard of care treatment comprising surgery followed by radiochemotherapy with temozolomide. Different immunotherapies including peptide vaccination and immune checkpoint inhibition have so far failed to improve survival. The administration of pro-inflammatory cytokines may convert the immunologically “cold” glioblastoma microenvironment into a “hot” one and may trigger potent antitumor immunity. Tumor necrosis factor (TNF) is one of the most potent pro-inflammatory cytokines.

LBA22 Neoadjuvant chemotherapy with oxaliplatin and capecitabine versus chemoradiation with capecitabine for locally advanced rectal cancer with uninvolved mesorectal fascia (CONVERT): Initial results of a multicenter randomised, open-label, phase III trial

Combined chemoradiation therapy is currently the standard practice for locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). The CONVERT study compares neoadjuvant chemotherapy with CapeOx alone to standard chemoradiotherapy (CRT) with Capecitabine for these patients.

Predictors of Pathologic Response After Total Neoadjuvant Therapy in Patients With Rectal Adenocarcinoma: A National Cancer Database Analysis.

Purpose/objectivesInduction chemotherapy followed by chemoradiation and surgical resection in rectal cancer, known as total neoadjuvant therapy (TNT), is associated with improved pathologic complete response (pCR) rates. The National Cancer Database was utilized to identify factors associated with pCR and survival following treatment with TNT compared to standard neoadjuvant chemoradiation (nCRT).Materials/methodsThe National Cancer Database was queried from 2004 to 2015 for patients with locally advanced, non-metastatic rectal cancer. We identified 16,299 patients receiving neoadjuvant chemotherapy and radiation followed by definitive surgical resection. Patients were stratified by treatment received, either TNT (n=350) or nCRT (n=15,949). Multivariate binomial regression analysis and propensity matching were used to evaluate predictors of pCR. Kaplan-Meier and Cox multivariate analysis of survival were performed.ResultsMedian follow-up was 38 months vs 53 months in the TNT vs nCRT groups, respectively. There were more patients with T4 or node-positive disease in the TNT group. There was a trend towards improved pCR in the TNT group (p=0.053). Patients achieving pCR had improved 5-year overall survival (OS) of 85.1%. The 5-year OS was not improved for TNT (76.2%) over nCRT (69.9%) (p=0.19). Pelvic nodal pCR was significantly higher in the TNT group (72%). When stratified by clinical stage, patients with cT3 (p=0.038) or cN1 (p=0.049) disease had improved OS with TNT.ConclusionsCompared to nCRT, TNT is correlated with higher rates of complete pelvic nodal clearance in patients with locally advanced rectal adenocarcinoma. The use of TNT showed improved survival in patients with cT3 and cN1 disease, indicating a potential benefit for patients with less advanced disease.

Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer

Most older patients with esophageal cancer cannot complete the standard concurrent chemoradiotherapy (CCRT). An effective and tolerable chemoradiotherapy regimen for older patients is needed. To evaluate the efficacy and toxic effects of CCRT with S-1 vs radiotherapy (RT) alone in older patients with esophageal cancer. A randomized, open-label, phase 3 clinical trial was conducted at 23 Chinese centers between June 1, 2016, and August 31, 2018. The study enrolled 298 patients aged 70 to 85 years. Eligible participants had histologically confirmed esophageal cancer, stage IB to IVB disease based on the 6th edition of the American Joint Committee on Cancer (stage IVB: only metastasis to the supraclavicular/celiac lymph nodes) and an Eastern Cooperative Oncology Group performance status of 0 to 1. Data analysis was performed from August 1, 2020, to March 10, 2021. Patients were stratified according to age (<80 vs ≥80 years) and tumor length (<5 vs ≥5 cm) and randomly assigned (1:1) to receive either CCRT with S-1 or RT alone. The primary end point was the 2-year overall survival rate using intention-to-treat analysis. Of the 298 patients enrolled, 180 (60.4%) were men. The median age was 77 (interquartile range, 74-79) years in the CCRT group and 77 (interquartile range, 74-80) years in the RT alone group. A total of 151 patients (50.7%) had stage III or IV disease. The CCRT group had a significantly higher complete response rate than the RT group (41.6% vs 26.8%; P = .007). Surviving patients had a median follow-up of 33.9 months (interquartile range: 28.5-38.2 months), and the CCRT group had a significantly higher 2-year overall survival rate (53.2% vs 35.8%; hazard ratio, 0.63; 95% CI, 0.47-0.85; P = .002). There were no significant differences in the incidence of grade 3 or higher toxic effects between the CCRT and RT groups except that grade 3 or higher leukopenia occurred in more patients in the CCRT group (9.5% vs 2.7%; P = .01). Treatment-related deaths were observed in 3 patients (2.0%) in the CCRT group and 4 patients (2.7%) in the RT group. In this phase 3 randomized clinical trial, CCRT with S-1 was tolerable and provided significant benefits over RT alone in older patients with esophageal cancer. ClinicalTrials.gov Identifier: NCT02813967.

Total Neoadjuvant Therapy Versus Standard Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer: A Comparison of Short- and Long-term Oncologic Outcomes.

To evaluate the impact of neoadjuvant multi-agent systemic chemotherapy and radiation (TNT) vs neoadjuvant single-agent chemoradiation (nCRT) and multi-agent adjuvant chemotherapy on overall survival (OS), tumor downstaging, and circumferential resection margin (CRM) status in patients with locally advanced rectal cancer. Outside of clinical trials and small institutional reports, there is a paucity of data regarding the short and long-term oncologic impact of TNT as compared to nCRT. Adult patients with stage II-III rectal adenocarcinoma were identified in the National Cancer Database [2006-2015]. Out of 8,548 patients, 36% received TNT and 64% nCRT. In the cohort, 13% had a pCR and 20% a neoadjuvant rectal (NAR) score <8. In multivariable analysis, as compared to nCRT, TNT demonstrated numerically higher pCR rates ( P = 0.05) but had similar incidence of positive CRM ( P = 0.11). Similar results were observed with NAR scores <8 as the primary endpoint. After adjusting for confounders, OS was comparable between the 2 groups. Additional factors independently associated with lower OS included male gender, uninsured status, low income status, high comorbidity score, poorly differentiated tumors, abdominoperineal resection, and positive surgical margins (all P <0.01). In separate models, both pCR and a NAR score <8 were associated with improved OS. In this national cohort, TNT was not associated with better survival and/or CRM negative status in comparison with nCRT, despite numerically higher downstaging rates. Further refinement of patient selection and treatment regimens are needed to establish effective neoadjuvant platforms to improve outcomes of patients with rectal cancer.