Standard Chemoradiation Therapy Research Articles

Impact of facility volume on outcomes in patients with pancreatic cancer treated with radiotherapy.

644 Background: The impact of facility volume on overall survival (OS) outcomes in patients with pancreatic cancer (PC) treated with radiotherapy (RT), both standard chemoradiation (CRT) and stereotactic body radiation therapy (SBRT) is not well-defined. Methods: This retrospective study analyzed 16,315 patients with locally advanced (LA) or borderline resectable (BR) PC from the National Cancer Database (2004-2019) who received neoadjuvant RT or RT without surgery across RT facilities with low- (<10 cases/yr), intermediate- (10-20 cases/yr), and high-volumes (>20 cases/yr) of PC cases. Log rank and cox regression were used for univariable and multivariable survival analysis, and Kaplan-Meier curves were generated. Results: Patients were largely treated at low (n=8055) volume centers, followed by intermediate (n=3783), and high (n=4477). Approximately half of the cohort were male (51.4%), and predominantly white (82.5%), and non-Hispanic (92%). On univariable analysis (Table), high-volume centers had improved survival outcomes in the overall population, as well as in both SBRT and CRT subsets (p<0.0001). On multivariable analysis, treatment during the most recent time period: 2016-2019 (HR 0.646, p<0.001), receiving care at a high-volume center (HR 0.844, p<0.001), use of SBRT (HR 0.915, p<0.001), administration of multiagent chemotherapy (HR 0.706, p<0.001) and undergone surgical resection (HR 0.405, p<0.001) were associated with improved OS. In a subgroup analysis of patients receiving SBRT, median OS was 22.6 months for high-volume, 20.0 for intermediate-volume and 18.4 months at low-volume centers (p<0.001). Conclusions: Patients receiving RT for LAPC or BRPC at high-volume centers had longer OS compared to those receiving radiation at intermediate- or low-volume centers. In those undergoing SBRT, treatment at high-volume centers had improved OS compared to intermediate- and low-volume centers. These findings suggest that radiation oncologists’ expertise is critical for providing high-quality RT in PC, especially for SBRT.[Table: see text]

Linking tumor immune infiltrate and systemic immune mediators to treatment response and prognosis in advanced cervical cancer

Cervical cancer (CC) poses a significant burden on individuals in developing regions, exhibiting heterogeneous responses to standard chemoradiation therapy, and contributing to substantial mortality rates. Unraveling host immune dynamics holds promise for innovative therapies and discovery of clinically relevant biomarkers. We studied prospectively locally advanced CC patients pre-treatment, stratifying them as responders (R) or non-responders (NR). R patients had increased tumor-infiltrating lymphocytes (TILs), while NR patients showed elevated PD-1 scores, CD8+ and PD-L2+ TILs, and PD-L1 immune reactivity. NR patients exhibited higher systemic soluble mediators correlating with TIL immune markers. R patients demonstrated functional polarization of CD4 T cells (Th1, Th2, Th17, and Treg), while CD8+ T cells and CD68+ macrophages predominated in the NR group. Receiver operating characteristic analysis identified potential CC response predictors, including PD-L1-immunoreactive (IR) area, PD-L2, CD8, FGF-basic, IL-7, IL-8, IL-12p40, IL-15, and TNF-alpha. Dysfunctional TILs and imbalanced immune mediators contribute to therapeutic insufficiency, shedding light on local and systemic immune interplay. Our study informs immunological signatures for treatment prediction and CC prognosis.

NIMG-46. MULTI-PARAMETRIC MRI RADIOMIC ANALYSIS USING DEEP LEARNING PREDICTS PERITUMORAL GLIOBLASTOMA INFILTRATION AND SUBSEQUENT RECURRENCE

Abstract PURPOSE Glioblastoma (GBM) is the most aggressive and infiltrative brain tumor with a very poor prognosis which hasn’t significantly improved in over 20 years. The almost 100% recurrence rate is due to cancer infiltration beyond the tumor margins currently being targeted by standard of care. Prior studies used traditional supervised machine learning have shown great promise in predicting tumor infiltration beyond these margins. We hypothesize that deep learning methods can further improve such predictive maps and guide intensive, yet targeted and personalized therapies. METHODS MRIs from a cohort of 109 de novo GBM patients were collected from Hospital of the University of Pennsylvania. All the patients incorporated in this study had pre-operative multi-parametric MRI scans including T1, T1Gd, T2, T2-FLAIR, ADC, and underwent surgical resection followed by standard chemoradiation therapy and had pathologically confirmed recurrence. A novel, automated deep learning method, informed by results of prior studies using support vector machines, was constructed to train a patch-based ensemble CNN to identify regions of peri-tumoral cancer infiltration. Leave-one-out was used to evaluate the predictive value of this method, against pathology-proven subsequent recurrence. RESULTS Probability maps, representing the likelihood of tumor infiltration and eventual recurrence, were binarized using threshold of 50% cutoff, compared with actual recurrence on post-recurrence MRI scans. The average cross-validated accuracy was 92%, specificity was 93%, patient-based sensitivity was 78%, and odds-ratio among all patients was 12.95 (Estimated “hot spots” were 12.95 times more likely to present recurrence in the future). CONCLUSIONS This study demonstrates that Multi-parametric MRI pattern analysis using CNN based network can successfully predict tumor infiltration in peritumoral region for Glioblastoma patients. These suggest that new intensive, yet precisely targeted treatments can be developed, guided by AI-driven predictive maps of infiltration.

A Phase II Trial Evaluating Rapid Mid-Treatment Nodal Shrinkage to Select for Adaptive Deescalation in p16+ Oropharyngeal Cancer Patients Undergoing Definitive Chemoradiation

The purpose of this study is to determine if rapid mid-treatment nodal shrinkage (RMNS) can identify patients with p16+ oropharyngeal cancer (OPC) who can be safely deescalated with reduced dose chemoradiation therapy (CRT). The primary endpoint was 2-year progression free survival (PFS). Inclusion criteria were as follows: T1-3, N1, M0 (AJCC 8th edition) p16+ OPC with <10 pack-year smoking history. All patients were initially planned for standard dose CRT (70 Gy) and weekly cisplatin. Patients were evaluated with a CT scan at week 4 for RMNS, defined as >40% nodal volumetric reduction from baseline. If RMNS was achieved, they proceeded to deescalated CRT (60 Gy). If not, they received standard CRT. Biomarker correlates were collected at baseline and week 4 of CRT including plasma TTMV (tumor tissue modified viral) HPV DNA and MRI diffusion weighted imaging (DWI). Univariate logistic regression analyses (UVA) were performed to evaluate predictors of RMNS. Odds ratios with 95% CI are reported, using a p<0.05 for statistical significance with a two-sided test. Wilcoxon rank sum tests were used to evaluate differences between the two groups using p < 0.05, 2-sided) for statistical significance. All statistical procedures were performed using R () with no adjustments for multiple testing. Thirty-six patients were enrolled: median age: 60 years; 81% male; primary site: 36% base of tongue, 53% tonsil, 11% both; T-stage: 39% T1, 50% T2, 11% T3; N-stage: 100% N1; any smoking history: 58% yes, 42% no; 67% (n = 24) had RMNS and received deescalated CRT while the remaining proceeded to standard CRT. At a median follow-up of 32.4 months, 2-year PFS between the standard and deescalated groups were 91.7% vs 90.9%, respectively (p = 0.97). All patients with recurrence underwent successful salvage treatment with 2-year OS 100% for all patients. On UVA, rapid TTMV HPV DNA clearance (baseline to week 4) (OR 12.0 [1.65-250], p = 0.034), lower MRI diffusivity (ADC) at baseline (OR 0.79 [0.61-0.97], p = 0.042) and week 4 (OR 0.76 [0.60-0.91], p = 0.009), and higher MRI diffusional kurtosis at baseline (OR 1.09 [1.01-1.21], p = 0.051) and week 4 (OR 1.24 [1.09-1.52], p = 0.009) were significantly associated with RMNS. When comparing the deescalated and standard cohorts, the mean baseline and week 4 MRI ADC were significantly lower and week 4 MRI diffusional kurtosis was significantly higher in the deescalated group. In this phase II study, rapid mid-treatment nodal shrinkage appeared to select favorable risk p16+ oropharynx cancer patients for treatment de-escalation. Rapid clearance of TTMV HPV DNA at week 4 as well as MRI DWI biomarkers of low ADC and high diffusional kurtosis values were correlated with RMNS. A larger study is planned to incorporate RMNS and biomarkers for further treatment de-escalation. Additional trial information is available at ClinicalTrials.gov (Identifier: NCT03215719).

Circulating Growth Differentiation Factor 15 as a Biomarker in Patients with Unresected Locally Advanced Non-Small Cell Lung Cancer Treated with Chemo-Radiotherapy with or without Metformin

Growth differentiation factor 15 (GDF15) is a member of the TGFβ family suggested to have prognostic value in cancer. Plasma GDF15 levels are elevated in humans during cellular stress, chronic diseases, and cancer and in response to cytotoxic (chemotherapy and radiation) or metabolic (metformin) therapies. Currently, the effect of combined metformin and cytotoxic treatment on circulating GDF15 is not known, and it is unclear whether GDF15 can serve as a biomarker in patients receiving such therapy. To examine this question, we analyzed circulating GDF15 levels in stage IIIA or IIIB NSCLC patients that participated in the randomized phase II clinical trial OCOG-ALMERA (NCT02115464). In OCOG-ALMERA patients were randomized to treatment with concurrent platinum-based chemotherapy and chest radiotherapy (60-66 Gy), with or without consolidation chemotherapy (CRT) or the same treatment plus metformin (2000mg/d). Dosimetric parameters and survival outcomes were collected by the trial. EDTA Plasma was collected from patients at baseline, 2 weeks into CRT treatment, at completion of CRT and 6 months after treatment initiation and assayed for GDF15 using an ELISA method. Statistical analyses were conducted to explore potential associations between plasma GDF15 with survival and dosimetric parameters. Fifteen patients from the metformin arm and 18 from the control arms provided EDTA plasma for this analysis. Average baseline GDF15 levels for all participants were elevated compared to those reported for healthy individuals. Baseline plasma GDF15 was statistically prognostic for RFS and OS (hazard ratio = 1.19, 95% CI = 1.06 to 1.34, p = 0.005). GDF15 levels increased during CRT treatment reaching the highest value at the end of cytotoxic therapy. Addition of metformin to CRT treatment was associated with further increase in circulating GDF15 (p<0.001). Plasma GDF15 levels at 2 weeks of CRT were positively correlated with size of the radiotherapy clinical target volume and volumes of esophagus and heart receiving high dose radiotherapy. This work suggests that GDF15 may be a promising prognostic marker to predict response to standard chemoradiation therapy in NSCLC. Future studies should aim to validate these results in larger datasets and examine whether GDF15 may have value as early biomarker of radiation toxicity in lung cancer patients.

A random graph-based neural network approach to assess glioblastoma progression from perfusion MRI

The identification of glioblastoma progression from the non-contrast enhancing areas is critically challenging to clinicians. This leads to poor prognosis and a very high local progression rate even after surgical resection and chemo-radiotherapy. Deep learning methods have been aiding in tracking tumor segmentation and progression. However, feature-based learning from these methods requires large datasets, multiple annotations, and measurements, resulting in complex, time-consuming networks. This work introduces a random Graph Neural Network (GNN) approach using two 16 × 16 random graph convolution layers to perform pixel-wise classification and predict glioblastoma progression from advanced perfusion MRI. A total of 17 patients, newly diagnosed with glioblastoma and treated with surgery and standard concomitant chemo-radiation therapy (CRT), were examined from The Cancer Imaging Archive Brain-Tumor-Progression dataset. Dynamic susceptibility contrast (DSC) MRI exams generated within 90 days following CRT completion and at clinically determined progression were evaluated for each patient. Three DSC modalities, such as normalized cerebral blood flow, normalized relative cerebral blood volume, and standardized relative cerebral blood volume were considered for the study. The proposed model provided an overall competitive accuracy of 99.76% with a training time of 6 minutes and a test time of 7.36 seconds. The proposed random GNN model demonstrates promising potential to predict final ground-truth maps accurately.

Intraoperative computed tomography perfusion navigation for maximal resection of high grade gliomas: a prospective non-randomized trial

Background: The main purpose of surgery for glioblastoma is to ensure the maximally possible cytoreduction. Computed tomography perfusion imaging has non-invasive tools for assessment of tumor blood flow and allows for visualization of the tumor borders and its most malignant zones.&#x0D; Aim: To evaluate the efficacy of intraoperative computed tomography perfusion navigation (ICTPN) during surgery for high grade gliomas.&#x0D; Materials and methods: This prospective non-randomized study included 142 patients (76 men and 66 women) with morphologically verified diagnosis of glioblastoma or diffuse astrocytoma grade 4 (World Health Organization 2021 criteria), who had surgery from 2016 to 2022. The ICTPN-based procedures were performed in 94 patients, with 55 with gross total and 39 with subtotal tumor resection. The control group included 48 patients with non-ICTPN-based surgical procedures. All patients were treated with standard adjuvant chemoradiation therapy. The efficacy of surgery was assessed every 3 months. The study endpoint was any tumor progression. The duration of the follow-up was 15 months. Baseline and contrast-enhanced preoperative imaging and postoperative follow-up assessments were performed with a 3T magnetic resonance imaging scanner (General Electric Discovery W750). ICTPN was done with a 32 slice computed tomography scanner (Toshiba Aquilion LB).&#x0D; Results: In the totally resected ICTPN group, the mean duration of the relapse-free period was 13.05 months; the relapse-free survival at 6 and 12 months was 92 and 55%, respectively (p 0.001). These results were significantly better than those in the subtotally resected ICTPN patients (8.98 months, 66 and 9%, respectively; log rank test for Kaplan-Meier curves, p 0.001) and in non-ICTPN patients (5.81 months, 23 and 0%, respectively, log rank test, p 0.001).&#x0D; Conclusion: ICTPN enables a more objective assessment of the tumor borders and the extent of its resection, as well as relapse-free survival benefits for the patients.

In situ immune impact of nivolumab + ipilimumab combination before standard chemoradiation therapy (RTCT) for FIGO IB3-IVA in patients (pts) with cervical squamous carcinoma: COLIBRI trial, a GINECO study.

5501 Background: We report the results of a window-of-opportunity phase 2 trial using neoadjuvant nivolumab + ipilimumab followed by standard chemoradiation therapy (RTCT) in cervical squamous cell carcinoma pts using the CD8+/FOXP3+ ratio as a surrogate marker of immune checkpoint blockade (ICB) in situ effect. Association with better clinical outcome after neoadjuvant chemotherapy and higher CD8+/FOXP3+ ratio was described in cervical cancer pts. However, immune modulation after ICB and correlation with treatment response needs to be characterized. Methods: The primary objective was to explore the changes in the ratio of CD8+/FOXP3+ in tumor biopsies performed before and after ICB (prior to standard RTCT) by multiplex-immunofluorescence (mIF) analyzing densities of CD8 effector T cells (CD8+: CD3+CD8+FOXP3-) and CD4 regulatory T cells (FOXP3+: CD3+CD8-FOXP3+). To normalize the distribution of the values, mIF data were log-transformed (log10). Targeted gene expression profiling of 2,549 genes using HTG technology allowed us to evaluate the 27-gene based ‘HOT’ score reported to be associated with immunologically active tumors (Foy J-P. et al., 2022, Eur J Can). Results: Pts received 1 cycle of nivolumab 3 mg/kg (D1D15) + ipilimumab 1 mg/kg (D1) before starting RTCT + brachytherapy. After RTCT, pts could continue nivolumab in maintenance 480 mg total dose every 28 days for 6 months. Forty pts were treated (including 50% FIGO III-IV). There were no new or unexpected toxicity. Grade≥3 AEs related to ICB occurred in 3 pts. mIF data of the 28 evaluable pts revealed an increase of total CD8+ cells (Wilcoxon, p=0.009), proliferating CD8+ cells (p=0.002) and CD8+/FOXP3+ ratio (p=0.03) between baseline and before RTCT. In the 37 pts evaluable by HTG, a significant increase of expression of the CD8A gene (paired t-test, p=2.2e-05) and the ‘HOT’ score (paired t-test, p=3.1e-06) was observed after ICB. The Objective Response Rate on primary tumor before, after, at the end of treatment (EOT) is reported in table. Correlation between CD8+/FOXP3+ ratio, the ‘HOT’ score and response to treatment will be presented. Conclusions: These data indicate that neoadjuvant nivolumab + ipilimumab is safe and orchestrates de novo immune responses in cervical squamous cell carcinoma. The 82.5% CR rate on primary tumor 6 months post RTCT suggests favorable clinical outcomes. Clinical trial information: NCT04256213 . [Table: see text]

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines, anti-PD-1 and poly I:C

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.

Clinical Effects of Immuno-Oncology Therapy on Glioblastoma Patients: A Systematic Review

The most prevalent and deadly primary malignant glioma in adults is glioblastoma (GBM), which has a median survival time of about 15 months. Despite the standard of care for glioblastoma, which includes gross total resection, high-dose radiation, and temozolomide chemotherapy, this tumor is still one of the most aggressive and difficult to treat. So, it is critical to find more potent therapies that can help glioblastoma patients have better clinical outcomes. Additionally, the prognosis for recurring malignant gliomas is poor, necessitating the need for innovative therapeutics. Immunotherapy is a rather new treatment for glioblastoma and its effects are not well studied when it is combined with standard chemoradiation therapy. We conducted this study to evaluate different glioblastoma immunotherapy approaches in terms of feasibility, efficacy, and safety. We conducted a computer-assisted literature search of electronic databases for essays that are unique, involve either prospective or retrospective research, and are entirely written and published in English. We examined both observational data and randomized clinical trials. Eighteen studies met the criteria for inclusion. In conclusion, combining immunotherapy with radiochemotherapy and tumor removal is generally possible and safe, and rather effective in the prolongation of survival measures.

Individualized Treatment Responsiveness as Quantified by Dynamic Changes in Cell Free HPV DNA in Patients Receiving Induction Chemotherapy and Definitive Chemoradiation for HPV-Related Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> Studies have shown that induction chemotherapy (IC) is a viable pathway to chemoradiation therapy (CRT) de-intensification in HPV-related head and neck cancer (HNC). However, reliance on imaging alone for eligibility may incorrectly exclude cases where radiographic response lags or otherwise confounds biological response. We report serial cell free HPV DNA (cfHPV DNA) dynamics as a quantitative measure of early treatment responsiveness for HPV-related HNC patients receiving IC followed by CRT. <h3>Materials/Methods</h3> Starting Sept 26, 2021, we enrolled patients with locally advanced, high-risk HPV positive HNC who received 1-2 cycles of platinum/taxane IC followed by standard definitive CRT. Peripheral blood was collected biweekly during IC and weekly during CRT to measure cfHPV DNA levels using HPV-SEQ, a CLIA-certified assay that uses SafeSEQ technology to sensitively detect and quantify HPV16 and HPV18 DNA in plasma (Sysmex Inostics). The treating radiation oncologist delineated tumor volumes on pre- and post-IC CT simulation scans. <h3>Results</h3> At present, 86 plasma samples have been examined across 12 enrolled patients. The median age was 65 years (range: 35-79). The primary disease sites included 8 oropharynx (OPX), 2 nasopharynx, 1 sinonasal, and 1 larynx, with all tumors being high-risk HPV positive by in-situ hybridization. All patients had at least cT3 disease or cN3 disease by AJCC 8 criteria, with 7 patients having cT4 disease. Half of the patients have a >10 pack-year smoking history. Tumor volume measurements and cfHPV DNA levels at key time-points for the 8 patients who have completed IC are summarized in Table 1 below. <h3>Conclusion</h3> Serial cfHPV DNA may provide an earlier and more quantitative readout of individualized treatment responsiveness compared with imaging assessment alone in HPV-related HNC. We identify a group of patients with locally advanced disease who had complete or near-complete cfHPV DNA clearance during IC. Rapid and effective clearance of cfHPV DNA may ultimately serve as a preferred metric for identifying "exceptional responders" who are ideal biological candidates for short-course CRT after IC. Our granular cfHPV DNA dataset with biweekly measurements during IC and weekly measurements during CRT should lead to a more precise evaluation of cfHPV DNA clearance velocity and tumor response kinetics with this paradigm.

Progression of Disease with Neo-Adjuvant Chemotherapy in Locally Advanced Cervical Cancer: Case Reports and Literature Review

Background: Optimal treatment for locally advanced cervical cancer is still a controversial issue as the current standard therapy is associated with radiation toxicity. Neo-adjuvant chemotherapy followed by surgery is an alternative treatment modality which has promising outcomes. Cases: Two cases of cervical carcinoma, aged 33 and 40 years old, stage 1b2 and 1b3, given neoadjuvant chemotherapy (NACT) with combination of platinum-based agents and Taxane, and planned for radical surgery after completion of chemotherapy. Result: Progression of disease observed in both cases after 3rd cycle of chemotherapy required change of treatment modalities to standard chemoradiation therapy (CCRT). Conclusion: NACT followed by surgery has promising outcomes as it gives advantages in lower long-term complication, targeted in younger-aged group and sexually active women for better quality of life, besides offering similar survival rates compared with CCRT. Estimation of response rate to chemotherapy plays a major role in patient selection in order to have successful outcomes.

Immune checkpoint inhibitors in head and neck squamous cell carcinoma: A systematic review of phase-3 clinical trials

BACKGROUNDThe outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal. A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors (ICIs). The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field.AIMTo evaluate the evidence on the effectiveness of ICIs in HNSCC, based on published phase-3 clinical trials.METHODSWe searched PubMed, Cochrane Library, Embase, and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC). We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-3 clinical trial. A sensitive search filter was used to limit our results to randomized controlled trials.RESULTSFive phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: Four in R/M HNSCC and one in LAHNSCC. In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care (standard single-agent systemic therapy). While the net gain in overall survival (OS) with nivolumab was 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01], that with pembrolizumab was 1.5 mo (HR = 0.80 nominal P = 0.0161). The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes. In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME. In LAHNSCC, immunotherapy using avelumab (an anti-PD-L1 agent) along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.CONCLUSIONAnti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings, with acceptable toxicity profiles compared to standard therapy. There is no proven efficacy in the curative setting to date.

NEXT: A single-arm, phase 2, open-label study of adjuvant nivolumab after completion of chemo-radiation therapy in patients with localized muscle-invasive bladder cancer.

506 Background: Nivolumab has known efficacy as adjuvant therapy after radical cystectomy in localized muscle invasive bladder cancer (MIBC). We are evaluating the efficacy of nivolumab adjuvant to definitive chemo-radiation therapy (CRT) in MIBC. Methods: In the NEXT study, we are currently enrolling patients with localized MIBC undergoing standard CRT. Participants are started on nivolumab 480 mg IV every 4 weeks (up to 12 doses) within 90 days of completion of CRT. Cystoscopic and scan-based assessments are done every 3 months for the first two years (yrs). The primary endpoint is failure-free survival (FFS) at 2 yrs from the start of CRT, with failure defined as local or systemic disease recurrence. Secondary endpoints include toxicity and quality of life (QOL) assessments. We have planned correlative studies on peripheral blood and tumor tissue. We performed a protocol-defined interim safety and efficacy analysis to assess the 6-month FFS rate with CRT and adjuvant nivolumab. Results: From 8/03/2017 to 9/28/2021, 20 patients were enrolled at two centers; median age is 76 yrs, clinical stage range is T2-T4b, N0-N+, M0; the median number of nivolumab cycles is 6.5, and the median follow-up is 8.9 months. The estimated 6-month FFS rate is 88.2% (95% CI 74.2% - 100%). Disease has progressed in 9 patients, of which 4 have local bladder recurrence (T1 in 3/4) and 5 have distant metastases. The estimated median FFS is 17.1 months (95% CI 8.71 months - infinity). Grade ≥3 treatment-related adverse events (AEs) are noted in 3/20 patients (15%): elevated transaminases, diarrhea, and polymyalgia rheumatica. Grade 3 radiation therapy oncology group (RTOG) AEs occurred in 2 patients. QOL measures are serially evaluable in 13 patients for the first 3 months of adjuvant nivolumab, and are stable in the domains of disease-related physical symptoms, treatment side effects, and function/well-being, while are significantly improved (p=0.023) in the domain of disease-related emotional symptoms. Conclusions: In this first report of the role of immunotherapy adjuvant to CRT for localized bladder cancer, adjuvant nivolumab is well tolerated and has promising efficacy. Clinical trial information: NCT03171025.

BIRC2\u2013BIRC3 amplification: a potentially druggable feature of a subset of head and neck cancers in patients with Fanconi anemia

Head-and-neck squamous cell carcinomas (HNSCCs) are relatively common in patients with Fanconi anemia (FA), a hereditary chromosomal instability disorder. Standard chemo-radiation therapy is not tolerated in FA due to an overall somatic hypersensitivity to such treatment. The question is how to find a suitable alternative treatment. We used whole-exome and whole genome mRNA sequencing to identify major genomic and transcriptomic events associated with FA-HNSCC. CRISPR-engineered FA-knockout models were used to validate a number of top hits that were likely to be druggable. We identified deletion of 18q21.2 and amplification of 11q22.2 as prevailing copy-number alterations in FA HNSCCs, the latter of which was associated with strong overexpression of the cancer-related genes YAP1, BIRC2, BIRC3 (at 11q22.1-2). We then found the drug AZD5582, a known small molecule inhibitor of BIRC2-3, to selectively kill FA tumor cells that overexpressed BIRC2-3. This occurred at drug concentrations that did not affect the viability of untransformed FA cells. Our data indicate that 11q22.2 amplifications are relatively common oncogenic events in FA-HNSCCs, as holds for non FA-HNSCC. Therefore, chemotherapeutic inhibition of overexpressed BIRC2-3 may provide the basis for an approach to develop a clinically realistic treatment of FA-HNSCCs that carry 11q22.2 amplifications.

Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation.

Brain parenchyma infiltration with glioblastoma (GB) cannot be entirely visualized by conventional magnetic resonance imaging (MRI). The aim of this study was to investigate changes in the energy and membrane metabolism measured with phosphorous MR spectroscopy (31P-MRS) in the presumably “normal-appearing” brain following chemoradiation therapy (CRT) in GB patients in comparison to healthy controls. Twenty (seven female, thirteen male) GB patients underwent a 31P-MRS scan prior to surgery (baseline) and after three months of standard CRT (follow-up examination. The regions of interest “contrast-enhancing (CE) tumor” (if present), “adjacent to the (former) tumor”, “ipsilateral distant” hemisphere, and “contralateral” hemisphere were compared, differentiating between patients with stable (SD) and progressive disease (PD). Metabolite ratios PCr/ATP, Pi/ATP, PCr/Pi, PME/PDE, PME/PCr, and PDE/ATP were investigated. In PD, energy and membrane metabolism in CE tumor areas have a tendency to “normalize” under therapy. In different “normal-appearing” brain areas of GB patients, the energy and membrane metabolism either “normalized” or were “disturbed”, in comparison to baseline or controls. Differences were also detected between patients with SD and PD. 31P-MRS might contribute as an additional imaging biomarker for outcome measurement, which remains to be investigated in a larger cohort.

Combination ozone therapy as an effective method of radiomodification in chemoradiation treatment of patients with cervical cancer.

e17515 Background: The purpose of the study was to evaluate advantages of combination ozone therapy as an effective factor of radiomodification and radioprotection in the treatment of patients with cervical cancer. Methods: The study included 20 patients with stage IIIb cervical cancer T3бNхM0, the mean age 52 years. Controls (n = 10) received standard chemoradiation therapy; the main group (n = 10) received combination ozone therapy in addition to chemoradiation therapy. Systemic ozone therapy involved intravenous administration of 250 ml ozonized solution of 0.9% sodium chloride, 15 sessions during external beam radiotherapy. Local ozone therapy involved 15-minute instillations into the vagina during brachytherapy. All patients received standard chemoradiation therapy, total irradiation dose to the primary focus 80 Gy, plus weekly cisplatin 40 mg/m2. Results: In the main group, pain and discomfort in the lower abdomen were managed in 20% patients by the 5th session of ozone therapy; 30% - on the 10th day; in 50% - on the 14th day. In the control group, such symptoms in 40% of patients were reduced after 20 days. The main group showed a more rapid regression of tumor infiltration, disappearance of purulent discharge, relief of intoxication syndrome. Manifestations of gastrointestinal toxicity were observed in 10% of the main group and in 100% controls; leukopenia developed in 7 patients in the control group and was not registered in the main group. MRI showed complete clinical regression in 90% in the main group and in 65% in the control group. The treatment was completed within 7 weeks in the main group and 8.5 weeks in the control group. Conclusions: Combination ozone therapy causes a more pronounced antitumor effect, and its radioprotective effects significantly reduce the severity of chemotherapy-induced disorders. It does not aggravate concomitant pathology and shortens the treatment period.

Trimodality Therapy With or Without Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer.

Bladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown. We identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias. We identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P=.19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P=.921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation. These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials.

Consolidation chemotherapy might improve pathological complete response for locally advanced rectal cancer after neoadjuvant chemoradiation therapy: a meta‐analysis

AbstractPatients with locally advanced rectal cancer who achieve a pathological complete response (pCR) to neoadjuvant chemoradiation therapy (CRT) have an improved prognosis. The need for surgery in these patients has been questioned; however, the proportion of patients who achieve pCR and receive a wait‐and‐watch strategy is small. This meta‐analysis aimed to evaluate whether neoadjuvant consolidation chemotherapy leads to a higher rate of pCR than standard CRT alone in patients with locally advanced rectal cancer. To this end, we carried out a meta‐analysis of three clinical controlled trials, consisting of 466 patients who were divided into the CRT group (n = 211) and the consolidation chemotherapy group (n = 255). The results showed that consolidation chemotherapy could significantly improve the pCR rate compared with neoadjuvant CRT alone (pooled odds ratio for pCR 2.02, 95% confidence interval 1.09–3.57, P = 0.03) and did not increase the adverse events (odds ratio 1.38, 95% confidence interval 0.77–2.50, P = 0.28 for grades 1–2; odds ratio 0.92, 95% confidence interval 0.14–6.13, P = 0.93 for grades 3–4). The findings of our study showed that adding consolidation chemotherapy after CRT is a safe approach that could lead to a higher pCR rate in patients with locally advanced rectal cancer.