Standard Chemoradiation Research Articles

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

PurposeTumor voxel dose–response matrix (DRM) can be quantified using feedback from serial FDG-PET/CT imaging acquired during radiotherapy. This study investigated the dynamic characteristics and the predictive capability of DRM.MethodsFDG-PET/CT images were acquired before and weekly during standard chemoradiotherapy with the treatment dose 2 Gy × 35 from 31 head and neck cancer patients. For each patient, deformable image registration was performed between the pretreatment/baseline PET/CT image and each weekly PET/CT image. Tumor voxel DRM was derived using linear regression on the logarithm of the weekly standard uptake value (SUV) ratios for each tumor voxel, such as SUV measured at a dose level normalized to the baseline SUV0. The dynamic characteristics were evaluated by comparing the DRMi estimated using a single feedback image acquired at the ith treatment week (i = 1, 2, 3, or 4) to the DRM estimated using the last feedback image for each patient. The predictive capability of the DRM estimated using 1 or 2 feedback images was evaluated using the receiver operating characteristic test with respect to the treatment outcome of tumor local–regional control or failure.ResultsThe mean ± SD of tumor voxel SUV measured at the pretreatment and the 1st, 2nd, 3rd, 4th, and last treatment weeks was 6.76 ± 3.69, 5.72 ± 3.43, 3.85 ± 2.22, 3.27 ± 2.25, 2.5 ± 1.79, and 2.23 ± 1.27, respectively. The deviations between the DRMi estimated using the single feedback image obtained at the ith week and the last feedback image were 0.86 ± 4.87, −0.06 ± 0.3, −0.09 ± 0.17, and −0.09 ± 0.12 for DRM1, DRM2, DRM3, and DRM4, respectively. The predictive capability of DRM3 and DRM4 was significant (p < 0.001). The area under the curve (AUC) was increased with the increase in treatment dose level. The DRMs constructed using the single feedback image achieved an AUC of 0.86~1. The AUC was slightly improved to 0.94~1 for the DRMs estimated using 2 feedback images.ConclusionTumor voxel metabolic activity measured using FDG-PET/CT fluctuated noticeably during the first 2 treatment weeks and obtained a stabilized reduction rate thereafter. Tumor voxel DRM constructed using a single FDG-PET/CT feedback image after the 2nd treatment week (>20 Gy) has a good predictive capability. The predictive capability improved continuously using a later feedback image and marginally improved when two feedback images were applied.

Necrosis onstaging 18F FDG PET/CT is associated with worse progression-free survival in patients with stage IIIB non-small cell lung cancer.

The presence of pathological necrosis in the tumor is known to be a factor indicating worse survival. Our study defined necrosis in staging 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with stage IIIB non-small-cell lung cancer (NSCLC) to investigate whether this is a poor prognostic marker. A total of 77 patients with NSCLC were evaluated. To evaluate necrosis on 18F FDG PET/CT, we drew a region of interest (ROI) in the area showing visually very low/or no FDG uptake on PET and PET/CT fusion images. If SUVmax was less than blood pool SUVmax and showed significantly less attenuation [10 to 30 Hounsfield units (HUs)] than surrounding tissue on low-dose correlative CT with non-intravenous contrast, we defined it as necrotic (PETNECROSIS). We evaluated the relationship of SUVmax, tumor size, and PETNECROSIS with progression-free survival (PFS) using a Cox proportional hazard regression model. A PFS analysis was performed on 16 patients treated with standard chemoradiotherapy (CRT) regimen. Tumor size ≤42 mm versus >42 mm (P = 0.044, HR: 6.103, 95 CI%: 1.053-35.358) and PETNECROSİS presence/absence (P = 0.027, HR: 6.719, 95 CI%: 1.245-36.264) were independent predictors for PFS. Patients with tumor size ≤42 mm and PETNECROSİS absence were associated with higher 1-year PFS rate than patients with tumor size >42 mm and PETNECROSİS presence (86% vs. 63.5% P = 0.005 and 87.5% vs. 29%, P = 0.001, respectively). PETNECROSİS is helpful to distinguish the patients who would suffer worse survival in stage IIIB NSCLC.

Survival Outcomes and Prognostic Factors in Glioblastoma.

Simple SummaryGlioblastoma is the most common tumour that originates in the brain in adults. Most of the published data on glioblastoma are from patients in clinical trials who tend to be younger and fitter than the average patient. We therefore looked at patient demographic, tumour characteristics, and treatments received in a group of 490 real-world patients with glioblastoma to evaluate their survival, and to investigate whether we could find any factors that were associated with longer survival. Overall, the average survival of patients was 9 months. Patients tended to live longer if they were younger, had surgery, if they had further treatment after surgery (chemo- or radio-therapy), or if they had a tumour marker called MGMT promotor methylation.Background: IDH-wildtype glioblastoma is the most common malignant primary brain tumour in adults. As there is limited information on prognostic factors outside of clinical trials; thus, we conducted a retrospective study to characterise the glioblastoma population at our centre. Methods: Demographic, tumour molecular profiles, treatment, and survival data were collated for patients diagnosed with glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazard model associations with survival. Results: 490 patients were included; 60% had debulking surgery and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% had non-standard chemo/radio-therapy, and 19% had no further treatment. Overall survival was 9.2 months. In the 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+). Conclusions: The 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.

PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer

BackgroundNeoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer.MethodsWe initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.ResultsA total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.ConclusionsMismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.)

Abstract CT569: Combination of reovirus (pelareorep) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alongside standard chemoradiotherapy and adjuvant chemotherapy (temozolomide) for patients with glioblastoma multiforme (GBM): Long term follow up results of the ReoGlio phase Ib trial

Abstract Background: Oncolytic viruses are of increasing interest as an immunologic approach to treating glioma. We previously reported safety data from a phase Ib, open-label study of intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in newly diagnosed glioblastoma and confirmed that the combination is tolerable. Following agreement from the relevant ethics authorities we have now completed long term follow up data on all patients treated in the study to investigate whether there is a signal of impact on survival. METHODS: 15 patients with newly diagnosed GBM were treated with GM-CSF 50μg subcutaneously on days 1-3 and pelareorep on days 4-5 in weeks 1 and 4 of chemoradiotherapy, and subsequently in week 1 of each adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Following end of study patients were followed up as per institutional practice. Ethical approval was granted to collect survival data in all patients who survived beyond study closure up to June 2021. Results: We showed that using intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in patients with GBM was tolerable with 87% of patients completing treatment as planned. Survival data analysis showed that median OS was 12.6 months for patients in dose level 1 and 16.1 months in dose level 2, giving median OS for all patients 13.1 months. It was notable however that a small number of patients survived beyond 24 months. The 24-month survival estimate for all patients was 33%, 16.7% for dose level 1 and 50% for dose level 2. One patient in dose level 2 remains alive at 42 months. Conclusion: We previously reported that intravenous delivery of pelareorep with standard chemoradiotherapy is tolerable in newly diagnosed GBM. Although based on small numbers, these long-term follow up data suggest that this may be an active combination in a subset of GBM patients and further randomized studies are warranted. Citation Format: Susan C. Short, Jessica Kendall, Anthony Chalmers, Catherine McBain, Alan Melcher, Adel Samson, Rachel Phillip, Sarah Brown. Combination of reovirus (pelareorep) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alongside standard chemoradiotherapy and adjuvant chemotherapy (temozolomide) for patients with glioblastoma multiforme (GBM): Long term follow up results of the ReoGlio phase Ib trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT569.

Abstract 1173: Maintenance-phase Temozolomide as a lymphodepletion platform for intracranialadoptiveγδ T cell-basedtherapy in primary high-grade gliomas

Abstract Introduction: Lymphodepletion is a key factor for responses in both autologous and allogeneic cell therapies. We are currently evaluating in a Phase I trial, the combination of Temozolomide (TMZ) chemotherapy with methylguanine-DNA methyltransferase (MGMT) modified γδ T cells (Drug Resistant Immunotherapy, or DRI) during maintenance TMZ in patients receiving the Stupp protocol. In this report, we examine both DRI graft and circulating lymphocyte phenotype and function during the treatment phase. Methods: Patients meeting enrollment criteria undergo tumor resection, placement of a Rickham catheter in the tumor cavity, and an apheresis collection immediately prior to standard chemoradiotherapy (CRT). DRI follows TMZ on Day 1 of maintenance and consists of 150mg/m2 IV TMZ and concurrent intracranial injection of 1.0 x 107 DRI γδT cells. Peripheral blood (PB) was collected at apheresis and immediately prior to the start of each 28-day maintenance cycle. Flow cytometric (FACS) analysis of PB and DRI grafts using antibodies to CD3, CD4, CD8, CD16/56, CD19, TCR-γδ, Vδ1, Vδ2, CD197, CD27, CD28, CD57, CD45RA, Th1/Th2/Th17 PB serum cytokines, and DRI cytotoxic graft function were obtained. When applicable, FFPE sections of recurrent resected GBM tissues were examined for immune infiltration. Results: DRI grafts contained 74-93% activated γδ T cells with 0.3-0.5 MGMT copies/cell. Cytotoxicity against K562 ranged from 30% to 75% at 40:1 (E:T). Peripheral lymphodepletion was evident throughout TMZ treatment in the Stupp protocol. T cell counts fell precipitously after CRT and cycle 1 (1647+774 vs 609+214 cells/mL) and remained low throughout maintenance phase (range 214-1450 T cells/mL). NK counts remained normal and showed uneven recovery through the first three cycles but failed to recover for the remainder of maintenance phase. γδ T cells also recovered modestly through the first two cycles but failed to recover after additional cycles. Interestingly, CD45RA+CD27- effector T cells showed only slight increases for each patient throughout TMZ maintenance. Cytokine analysis did not show a clear trend except for consistent T cell expression of perforin and IP-10. One patient with recurrent GBM was successfully resected 110d following DRI. Histopathology revealed widespread necrosis with significant infiltration of CD4+ and CD8+ T cells and γδ T cells in the tumor parenchyma. Conclusions: Standard of care TMZ is lymphodepleting and DRI therapy can be conducted in an environment favorable to T cell persistence and sustained immune response. One treated patient demonstrated infiltration of both αβ and γδ T cells 110 days following a single dose of DRI γδ T cells. TMZ maintenance during the Stupp regimen prolongs lymphodepletion, thereby presenting a favorable setting for adoptive cell therapy. Citation Format: Lawrence S. Lamb, Lei Ding, Ryan C. Miller, Mariska ter Haak, Caitlyn Lucas, Becca Weekley, Samantha Youngblood, Cathy Langford, Guoling Chen, Louis B. Nabors. Maintenance-phase Temozolomide as a lymphodepletion platform for intracranialadoptiveγδ T cell-basedtherapy in primary high-grade gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1173.

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.

Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer.

LBA5 Background: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is mismatch repair deficient. Since mismatch repair deficient colorectal cancer is responsive to PD-1 blockade in the metastatic setting, we hypothesized that locally advanced mismatch repair deficient rectal cancer is sensitive to checkpoint blockade and may alter the requirements for chemoradiotherapy and surgery. Methods: We conducted a prospective phase II study in which single agent dostarlimab, an anti PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair deficient stage II and III rectal adenocarcinoma, to be followed by standard chemoradiation and surgery. Patients who achieved a clinical complete response were eligible for omission of chemoradiation and surgery. Results: Twelve patients initiated treatment and have at least 6 months of follow up. All 12 (100%, 95% CI:74%-100%) achieved a clinical complete response with no evidence of tumor on MRI, FDG-PET, endoscopic visualization, digital rectal exam, or biopsy, which satisfied the study’s co-primary endpoint. To date, no patients have required chemoradiation or surgery, and no cases of progression or recurrence have been noted during follow up (range 6-25 months). No serious adverse events &gt; grade 3 were observed. Conclusions: Mismatch repair deficient locally advanced rectal cancer is exceptionally sensitive to single agent PD-1 blockade. Longer follow up is needed to assess response duration. Clinical trial information: NCT04165772.

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

We read with interest the article by Pallud et al.1 in which patients with isocitrate dehydrogenase wild-type glioma who took levetiracetam during the whole standard chemoradiation protocol experienced relevant improvement in survival.

LGG-41. The clinical and molecular landscape of gliomas in adolescents and young adults

OBJECTIVE: Gliomas in adolescents and young adults (AYA) are commonly treated with a standard chemo-radiation approach based on data from adults. The clinical impact of paediatric-type alterations in these tumours is unknown. METHODS: We compiled a multi-institutional cohort of patients diagnosed with glioma between 15-39.9 years over 20 years. Complete molecular analysis, therapeutic data and outcome was collected. For specific alterations, analysis included patients aged 0-39.9 years. RESULTS: A total of 1900 patients with 876 AYA gliomas were included. Ongoing analysis reveals genetic alterations in 95% of available tumours. IDH-mutant tumours account for only 53%, while paediatric-type mutations were found in 35% of AYA tumours with IDH-WT GBM accounting for the remaining 12%. The most common paediatric alterations in AYAs included BRAF p.V600E (11%) and FGFR alterations (6%) while BRAF fusions, H3 p.K27M and H3.3 p.G34R were rarely observed (4%, 4% and 1% respectively). BRAF fused tumours with non-canonical binding partners were enriched in AYAs. Analysis of BRAF-V600E gliomas between ages 0-40 revealed increased tendency for malignant tumours in patients >20 years suggesting malignant transformation possibly due to higher rate of secondary hits including TP53, CDKN2A and ATRX mutations. This resulted in worse overall-survival for AYA patients with BRAF-V600E glioma when compared to children under 20 years (p=0.0032). Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma respectively, compared to 14% and 25% for BRAF-V600E and FGFR-altered high grade glioma. In contrast, continuous decline was observed in the IDH-mutant gliomas with 10-year OS of 50% which declined to 29% at 15 years. CONCLUSIONS: Gliomas in AYA are enriched for paediatric-type alterations with distinct molecularly-based outcomes. As these tumours carry different outcomes than childhood glioma and may respond to targeted inhibitors, AYA gliomas would benefit from comprehensive diagnostic and therapeutic approaches.

Comparison of survival outcomes of patients with newly diagnosed glioblastoma treated with standard chemoradiation in and outside of clinical trials.

2051 Background: Randomized clinical trials use stringent eligibility criteria to select patients which can raise concerns about generalizability of study results. Recent interest in external controls and new trial designs has increasingly focused on the possible use of real-world data sources. We examined potential differences of survival outcomes in clinical trial and real-world datasets in newly diagnosed glioblastoma. Methods: Patient-level data from 4 independent datasets were analyzed. Non-trial data were derived from an institutional dataset of 453 patients with newly diagnosed glioblastoma treated outside of a clinical trial with standard radiation therapy with concurrent and adjuvant temozolomide at a large academic center. Trial patients included patients on the control arm of several multi-institutional trials (NCT00689221, n = 273; NCT00813943, n = 89; NCT00943826; n = 459) and patients treated on trial at our institution (n = 210). Non-trial patients were compared with each of the 4 clinical trial datasets in pairwise comparisons with Cox regression with adjustments for age, sex, extent of resection, KPS and MGMT status. Results: Patient-level data from 1,484 patients were analyzed. Non-trial patients were older compared to patients in the multi-institutional trials (mean 58.6 vs. 56.1 years (NCT00943826), 53.9 years (NCT00813943), 55.7 years (NCT00689221); p &lt; = 0.001). The non-trial cohort had fewer women (43.5% vs. 35.9%, p = 0.02), greater proportion of lower KPS patients (47% KPS &lt;90 vs. 31% KPS &lt;90, p &lt; 0.001) and greater proportion of MGMT methylated patients (49% vs. 33%, p &lt; 0.001) compared to NCT00943826 patients. There were no other significant differences between patient characteristics of non-trial patients and the 4 trial datasets. Trial participation was not associated with improved survival in multivariable analysis after adjustments for clinical covariates (non-trial patients vs. each trial dataset; Table, P &gt; 0.05). Conclusions: Glioblastoma patients treated on multi-institutional clinical trials that were included in our analysis did not have statistically significant differences in survival compared to patients treated outside of a clinical trial at a large academic center after adjustment for relevant variables. Our findings support the possible use of real-world data in the development of external control arms for future trials in newly diagnosed glioblastoma. [Table: see text]

Selective treatment de-intensification with reduced-dose radiation and omitted concurrent chemotherapy guided by response to induction chemotherapy in HPV-associated oropharyngeal squamous cell carcinoma: A single-arm, phase II trial (IChoice-01).

e18069 Background: De-intensification in chemoradiation provides a strategy to optimize the trade-off between treatment efficacy and toxicities in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). However, the failure of RTOG 1016 and De-ESCALaTE indicated the pitfall of de-escalation in an unselective population and the importance of patient selection for future study design. Induction chemotherapy (IC), as a potential biomarker, has been adopted in several trials to screen candidates for de-intensified treatment based on its tumor response. In present trial, we investigated the feasibility of selectively de-intensified chemoradiotherapy by reducing radiation dose and omitting concurrent chemotherapy guided by response to IC. Methods: From Jan 2019 to July 2021, 48 patients with p16 positive OPSCC, T1-2/N1-3M0 (excluding T1N1M0 patients with single and≤3cm lymph node) or T3-4N0-3M0 according to the UICC/AJCC 8th staging system were enrolled. All of them received two cycles of IC with cisplatin and docetaxel. Those with major response to IC (defined as cCR or ≥50% cPR of both primary site and lymph nodes) received de-intensified treatment with intensity modulated radiation therapy (IMRT) alone with 60Gy to high-risk and 54Gy to low-risk regions (Di cohort). Those with less than major response were given standard chemoradiotherapy with 70Gy to both primary tumor and positive lymph nodes, 63Gy to high-risk and 56Gy to low-risk regions, concurrently with two cycles of cisplatin (St cohort). The primary endpoint was 2-year progression-free survival (PFS). Results: 26/48 (54.2%) patients entered Di cohort while other 22/48 (45.8%) patients entered St cohort. With a median follow-up time of 20.5 months (2.8-36.7months), 3 deaths (1 in Di cohort and 2 in St cohort), 5 loco-regional recurrence (1 in Di cohort and 4 in St cohort) and 6 distant metastases (1 in Di cohort and 5 in St cohort) were documented. The 2-year PFS rates for Di and St cohort were 100% and 60.0% (P = 0.002) with overall survival (OS) rates of 100% and 83.1% (P = 0.062), loco-regional recurrence-free survival (LRFS) rates of 100% and 77.0% (P = 0.035), metastasis-free survival (MFS) rates of 100% and 66.8% (P = 0.011), respectively. Conclusions: For major responders to IC, reduced-dose radiation with omitted concurrent chemotherapy yielded good survival results. In comparison, patients resistant to IC showed poor prognosis even under standard-dose chemoradiotherapy, calling for treatment intensification or development of novel therapeutic agents. Selective de-intensification of chemoradiation guided by response to IC is promising in HPV-associated OPSCC and warrants further evaluation in future studies. Clinical trial information: NCT04012502.

Low doses of visible electromagnetic radiation activating endogenous nonspecific antitumor resistance in patients with cervical cancer.

e17506 Background: Ionizing radiation inhibits the immunological reactivity of the body and the system of nonspecific antitumor resistance in patients with cervical cancer (CC). The purpose of this study was to activate the system of nonspecific antitumor resistance using visible electromagnetic radiation in CC patients receiving chemoradiotherapy. Methods: The study included 30 patients, mean age 61 years, with stage IIIb CC (T3bNxM0). The main group (n = 15) received standard chemoradiotherapy (CRT): irradiation of the primary focus 80 Gy, lymphatic paths 55 Gy, with radiomodification with cisplatin 40mg/m2; the patients were additionally exposed to visible electromagnetic radiation: the red spectrum λ = 640 nm on the cubital vein projection (exposure time 5 minutes, dose 6.86 J/cm2), twice a week (the total of 14 sessions). The method is based on the ability of monochrome red light to induce photobioadaptive processes in the body, leading to the formation of non-specific antistress reactions, activation of reparative and regenerative tissue reactions with an increase in the synthetic, phagocytic activity of neutrophils and the growth of the immunity lymphoid indicators. The control group included 12 patients receiving only standard CRT. Parameters of nonspecific antitumor adaptation reactions were evaluated. Results: Lower abdominal pain and discomfort were managed in 20% of patients of the main group on day 8, in 30% on day 10, and in 50% on day 14. In the control group, the symptoms were managed in 40% of patients only on day 22. More rapid regression of the cervical tumor was registered in patients of the main group, as well as decreased infiltration of the parametrium and vaginal fornices, disappearance of bloody discharge, management of intoxication syndrome. Gastrointestinal toxicity (nausea, diarrhea, flatulence) was noted in 10% of patients in the main group and in 100% controls. 7 patients in the control group developed leukopenia; in the main group, it was not observed. MRI-confirmed complete tumor regression amounted to 88% in the main group and 65% in the control group. CRT was completed within 7 weeks in the main group and 8.5 weeks in the control group. Conclusions: Low doses of electromagnetic radiation of the red spectrum activate endogenous nonspecific antitumor resistance of the body by forming nonspecific antistress reactions of activation and increasing the immunity lymphoid indicators, which improves the efficacy of CRT.

Final data from the phase 2a single-arm trial of SurVaxM for newly diagnosed glioblastoma.

2037 Background: Newly diagnosed glioblastoma (nGBM) routinely treated with surgery, radiation, and temozolomide (TMZ), still result in early progression and near-universal lethality within 5 years. Tumor associated “survivin” is expressed in &gt;95% of nGBM and targetable by SurVaxM immunotherapy. Results from the recently completed multi-center phase 2a trial of SurVaxM in nGBM are presented. Methods: nGBM patients (pts) were enrolled at 5 trial sites. Eligibility criteria included: age ≥ 18, Karnofsky performance status ≥70, IHC confirmation of survivin expression, expression of HLA-A*02, A*03, A*11 or A*24 MHC-I alleles and residual contrast enhancement of ≤1 cm3 by MRI within 72h post-resection. Pts received standard TMZ chemoradiation followed by initiation of 4 priming doses of SurVaxM (500 mcg in emulsion with Montanide ISA 51, every 2 weeks) with 100 mcg sargramostim. Maintenance doses of SurVaxM-Montanide plus sargramostim were thereafter administered every 12 weeks. Adjuvant TMZ was administered for at least 6 cycles, after at least the first dose of SurVaxM and beginning no sooner than 28 days after completion of chemoradiation. Pts were monitored by MRI every 8 weeks, and progression was assessed using modified RANO criteria. The primary endpoint was 70% progression free survival (PFS) at 6 mos. Primary analyses of median PFS (mPFS) and median overall survival (OS) were measured from first immunization. Safety, tolerability, and immune responsiveness were also determined. Results: 63 pts with nGBM were enrolled, comprised of 38 males and 25 females with a median age of 60 years. The cohort was consistent with the 4 commonly observed primary molecular GBM subtypes (classical, mesenchymal, neural and proneural). SurVaxM was well tolerated, with no serious adverse events. A strong positive correlation, accounting for censoring, was observed between PFS and OS of all pts (r = 0.79; 95% CI (0.66,0.87)). SurVaxM was immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers in both methylated and unmethylated MGMT pts and both groups showed clinical benefit. Conclusions: SurVaxM appeared to be safe and well-tolerated in pts with nGBM. SurVaxM was effective at stimulating survivin-specific immune responses and the primary endpoint was met. SurVaxM represents a promising therapy for nGBM, including for those pts with unmethylated MGMT genes. For pts treated with SurVaxM, PFS may be an acceptable surrogate for OS. Clinical trial information: NCT02455557. [Table: see text]

NANORAY-312: A phase III pivotal study of NBTXR3 activated by investigator’s choice of radiotherapy alone or radiotherapy in combination with cetuximab for platinum-based chemotherapy-ineligible elderly patients with locally advanced head and neck squamous cell carcinoma.

TPS6110 Background: Elderly patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are largely underrepresented in clinical trials (CT). Broad access to CTs in this population is challenging due to an increased prevalence of comorbidities and ageing-related conditions. However, as population-age increases, more and more elderly patients are diagnosed with LA-HNSCC although many are not eligible to receive standard cisplatin-based concurrent chemoradiation (CRT). CRT-related toxicities, treatment burden and compliance are a concern. NBTXR3, a first-in-class radioenhancer, composed of functionalized hafnium oxide nanoparticles, is administered by one-time intratumoral injection and activated by radiotherapy (RT). NBTXR3 is designed to locally amplify the tumor-killing effect of radiotherapy without additional toxicity to surrounding healthy tissue. NBTXR3 has been shown to prime the adaptive immune response in cancer models. NBTXR3 obtained EU marketing approval in preoperative treatment of locally advanced soft tissue sarcomas. In a Phase I trial of NBTXR3 + RT alone in elderly LA-HNSCC patients, the combination was shown to be safe and an Objective Response Rate (ORR) of 85.4% and CRR of 51.2% was reported at ASTRO 2021. A pivotal randomized phase III study was initiated and is now recruiting. Methods: NANORAY-312 [NCT04892173] is a global, open-label, randomized (1:1), 2-arm, Investigator's choice Phase III (Pivotal Stage) study to investigate the efficacy and safety of NBTXR3/RT±cetuximab versus RT±cetuximab in treatment-naïve, platinum-ineligible, elderly patients with LA-HNSCC. 500 patients will be enrolled. Eligible patients are ≥65 years with at least one measurable (RECIST 1.1) biopsy-confirmed T3-4 (AJCC v8) SCC of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx which is amenable for intratumoral injection. For patients with oropharyngeal cancer, human papilloma virus (HPV) status must be known. In addition to the primary tumor, a single accessible LN in the neck is eligible for intranodal injection. The primary objective is PFS. The key secondary endpoint is OS. Other secondary endpoints include ORR, safety and tolerability and quality of life. Enrollment began in January 2022 and is ongoing. Clinical trial information: NCT04892173.

Durvalumab (D) and PET-directed chemoradiation (CRT) after induction FOLFOX for esophageal adenocarcinoma: Final results.

4029 Background: Induction FOLFOX followed by PET-directed CRT prior to surgery demonstrated positive results in the CALGB 80803 study. We investigated the safety and efficacy of adding D, an anti-PD-L1 antibody, to PET-directed CRT. Methods: Patients (pts) with locally advanced esophageal/GEJ adenocarcinoma were enrolled. Pts received 2 cycles of mFOLFOX6 prior to repeat PET/CT. PET responders (≥35% reduction in SUV (PETr)) received 5-FU/capecitabine and oxaliplatin with RT to 50.4Gy, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received D 1,500 mg q4W ×2 starting 2 weeks prior to CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts with R0 resections received adjuvant D 1,500mg q4W ×6. The primary endpoint was the pathologic complete response (pCR) rate. Results: 36 pts were enrolled. Clinical ≥T3 disease was seen in 32 pts (88.9%, cT4 = 3) and ≥N1 in 23 (63.9%) pts. PD-L1 CPS was ≥1 in 25 (71.4%) of 35 tested with 14 (40%) ≥5. Microsatellite instability (MSI) was identified in 3 (8.3%) pts. 25 (70%) pts were PETr. Preop treatment was well tolerated with no new safety signals. Three pts had disease progression prior to surgery. pCR was identified in 8 (22.2%) pts and 22 (64.7%) had major pathologic response (MPR; ypTanyN0 + ≥90% response). Those with MSI tumors had ≥90% treatment response (1 pCR, 1: ypT1aN0 99% response, 1: ypT2N0, 90% response). 17 (73.9%) of 23 cN+ pts had ypN0 disease. MPR was associated with PD-L1 ≥1 (p = 0.03) and with a higher tumor mutational burden (TMB; p = 0.016) on MSK-IMPACT testing. Adjuvant D was commenced in 27 pts, with a median number of 6 cycles. Early discontinuation was due to risks of visits due to COVID19 (4, 15%), progressive disease (3, 11%), late surgical complications (2, 7%) and immune toxicity (1, 4%). With a median follow-up of 30 months, OS rates were 92% [95%CI: 83%-100%] and 85 % [95%CI: 74%-98%] at 12 and 24 months post induction. 12 and 24-month PFS rates were 81% [95%CI: 69%-95%] and 71% [95%CI: 58%-88%] respectively. In the 33 operated pts, 12 and 24-month disease free survival was 82% [95%CI: 70%-96%] and 78% [95%CI: 65%-94%], respectively. In addition to SUV on PET, total lesion glycolysis (TLG) was correlated with pathologic response. In cases with borderline change in SUV, TLG could predict response to treatment. One PETnr with 30.8% reduction in SUV had 88.1% reduction in TLG and pCR. Conversely, a PETr (-36.3%) who had an increase in TLG (39.3%) had only 40% treatment response on pathology. Conclusions: The addition of D to induction FOLFOX and PET-directed CRT prior to surgery is safe and appears effective with a high rate of pathologic response, as well as encouraging survival data. PD-L1 CPS≥1 and higher TMB may be associated with MPR. TLG is a novel PET variable that should be studied prospectively. Additional correlatives and comparison to a cohort treated with standard PET-directed CRT will be presented. Clinical trial information: NCT02962063.

Safety results of NRG-LU004: Phase I trial of accelerated or conventionally fractionated radiotherapy combined with durvalumab in PD-L1–high locally advanced non-small cell lung cancer.

8513 Background: In advanced non-small cell lung cancer (NSCLC), high Programmed-Death-1 Ligand (PD-L1) (&gt;50%) expression demonstrate superior response and survival with immune checkpoint inhibitors compared to chemotherapy. We hypothesize that it is safe and feasible to substitute durvalumab instead of chemotherapy concurrently with radiotherapy (RT) in patients with Locally Advanced-NSCLC (LA-NSCLC) and high PD-L1. Methods: NRG-LU004 (NCT03801902) is a Phase I study for patients with stage II-III unresectable or inoperable, LA-NSCLC with PD-L1&gt; 50% (Dako 22C3 or Ventana SP263) expression. There were safety and expansion phases with a primary endpoint of safety. Patients started with 1500 mg durvalumab Q4 weeks and thoracic RT within 2 weeks from 1st infusion. Durvalumab continued once a month up to 1 year. In the safety cohort, 6 patients in cohort 1 were treated with accelerated fractionated RT (ACRT) to 60 Gy in 15 fractions, followed by a required safety hold for 90 days. During cohort 1 safety hold, cohort 2 patients were treated with conventional RT 60 Gy in 30 fractions (CONV) followed by a 60-day safety hold. A cohort advanced to the expansion phase to enroll 6 more patients if safety criteria (0-1 patients with a dose limiting toxicity [DLT]) were met. If both cohorts were deemed safe, patients would be randomized 1:1 to ACRT or CONV with safety defined as &lt; 4 of 12 evaluable patients per arm experiencing a DLT. Feasibility was defined as at least 80% of patients in each arm receiving at least 80% of the planned dose of durvalumab during the first 8 weeks. Results: 24 evaluable patients enrolled between January 2019 and June 2021. No DLTs were reported in cohort 1, and 1 (unrelated bronchopulmonary hemorrhage leading to discontinuation of durvalumab) in cohort 2. Both safety cohorts advanced to the expansion phase. All but one patient (CONV) received RT per protocol/with an acceptable variation. At the time of analysis, 24% had received all 13 cycles of durvalumab. For the ACRT cohort, there were 4 grade 3, 1 grade 4 (lymphopenia), and 1 grade 5 AE (lung infection, assessed as unrelated to therapy). For CONV, there were 8 grade 3, 0 grade 4, and 1 grade 5 AE (respiratory failure, unrelated to therapy). For feasibility, 10 of 12 (85%) patients in the ACRT cohort received the second dose of durvalumab (2 not received due to shingles and unrelated death), while 9 of 12 (75%) of the CONV cohort received the second dose (reasons for not receiving: viral hepatitis, bronchopulmonary hemorrhage, and respiratory failure, all assessed as unrelated to therapy). Conclusions: Chemotherapy-free thoracic RT approaches (ACRT or CONV RT) are safe, when given with concurrent durvalumab in patients with PD-L1 high LA-NSCLC. A trial to compare immunoradiotherapy and consolidation durvalumab to standard chemoradiation and consolidation durvalumab is planned. Clinical trial information: NCT03801902.

Mass Transport Model of Radiation Response: Calibration and Application to Chemoradiation for Pancreatic Cancer

The benefit of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) remains unclear. We hypothesized that a new mechanistic mathematical model of chemotherapy and radiation response could predict clinical outcomes a priori, using a previously described baseline measurement of perfusion from computed tomography scans, normalized area under the enhancement curve (nAUC). We simplified an existing mass transport model that predicted cancer cell death by replacing previously unknown variables with averaged direct measurements from randomly selected pathologic sections of untreated PDAC. This allowed using nAUC as the sole model input to approximate tumor perfusion. We then compared the predicted cancer cell death to the actual cell death measured from corresponding resected tumors treated with neoadjuvant chemoradiation in a calibration cohort (n = 80) and prospective cohort (n = 25). After calibration, we applied the model to 2 separate cohorts for pathologic and clinical associations: targeted therapy cohort (n = 101), cetuximab/bevacizumab + radiosensitizing chemotherapy, and standard chemoradiation cohort (n = 81), radiosensitizing chemotherapy to 50.4 Gy in 28 fractions. We established the relationship between pretreatment computed v nAUC to pathologically verified blood volume fraction of the tumor (r = 0.65; P = .009) and fractional tumor cell death (r = 0.97-0.99; P < .0001) in the calibration and prospective cohorts. On multivariate analyses, accounting for traditional covariates, nAUC independently associated with overall survival in all cohorts (mean hazard ratios, 0.14-0.31). Receiver operator characteristic analyses revealed discrimination of good and bad prognostic groups in the cohorts with area under the curve values of 0.64 to 0.71. This work presents a new mathematical modeling approach to predict clinical response from chemotherapy and radiation for PDAC. Our findings indicate that oxygen/drug diffusion strongly influences clinical responses and that nAUC is a potential tool to select patients with PDAC for radiation therapy.

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.

CONCURRENT CHEMORADIATION WITH WEEKLY CISPLATIN AND PACLITAXEL IN LOCALLY ADVANCED CARCINOMA CERVIX

Introduction:Carcinoma cervix is the most common gynaecological malignancy in women. Concurrent chemoradiotherapy is an effective treatment for locoregionally advanced squamous cell carcinoma of the cervix, with established benefits in both organ preservation and survival. Aims:1. To assess the immediate locoregional response rates of locally advanced squamous cell carcinoma of the cervix treated with concurrent chemoradiotherapy using weekly low dose cisplatin and low dose paclitaxel followed by HDR intracavitary brachytherapy. 2. To assess the acute toxicity. Materials and methods:This is a single arm prospective study in which 30 patients with cervical carcinoma of stages IB2-IIIB, presenting to our hospital, were given concurrent chemoradiation: EBRT 50Gy/25# with weekly Cisplatin 30mg/m2 and Paclitaxel 30mg/m2 followed by intracavitary brachytherapy 8Gy/2# and response was assessed, both clinical and radiological, at the end of 6 weeks after completion of therapy, using RECIST criteria. Toxicity was assessed using RTOG morbidity scoring. Results:Clinically, there was complete locoregional response in 27 patients (90%), partial response in 3 patients (10%). Acute toxicities were observed but they were manageable. Diarrhea presented as grade I, II and III in 5 (16.7%), 3 (10%) and 2 (6.7%) patients respectively. Grade Ihaematological toxicity was seen in 7 patients (23.3%) and grade II in 3 patients (10%) during the 5th week of chemo-radiation. Grade I and II skin reactions were seen in 7 patients (23.3%) with grade III reactions in one patient. Grade I bladder toxicity is seen is 2 patients (6.7%). Conclusion:This study shows including a taxane as a radiosensitiser, in the standard concurrent chemoradiation with weekly cisplatin schedule, yields better loco-regional response with acceptable toxicity, especially in locally advanced stages and those with pelvic nodal involvement.