Completion Of Chemoradiotherapy Research Articles

Abstract A036: Quantitative molecular imaging of pancreatic tumor fibrosis for evaluation of response to neoadjuvant therapy: Pre-clinical and first-in-human application of collagen PET/MRI

Abstract Purpose: One of the major challenges in the management of pancreatic ductal adenocarcinoma (PDAC) is the lack of a reliable imaging tool to monitor tumor response to treatment. A high degree of fibrosis, mainly collagen type I, has been recognized as the hallmark of PDAC, which further increases in response to neoadjuvant chemoradiotherapy (CRT). This study introduces an image-guided paradigm for monitoring treatment response using the collagen type I specific PET imaging probe, 68Ga-CBP8 in mouse models and patients with PDAC. Methods: Subcutaneous mouse models of human PDAC were generated using FOLFIRNOX-sensitive (PANC1 and PDAC6) and FOLFIRINOX-resistant (SU8686) PDAC cells in nude mice (n=88). Mice were randomized into 2 groups of treatment with FOLFIRINOX or vehicle i.v. twice a week. Animals underwent PET/MRI with 68Ga-CBP8 (3.7-11.1 MBq) prior to, and at 7- and 15-days post-treatment (n=4-8/group). To assess the specificity of the probe, additional PANC1 tumor-bearing mice (n=4) were imaged with 68Ga-CBP8, and a collagen non-binding probe, 68Ga-CNBP (3.7-11 MBq). PET values were correlated with tumor growth over 21 days and quantification of fibrosis by Picrosirius red and IHC for collagen I, α-SMA, FAP-α, collagen rtPCR, and hydroxyproline assay. 8 patients (49-65 yrs.) with newly diagnosed PDAC underwent 68Ga-CBP8 PET (122-281 MBq) and standard MRI. Thus far, 3/8 subjects have undergone repeat PET/MRI after completion of neoadjuvant CRT. The pre-and post-CRT PET parameters for tumor and pancreas were compared and correlated with tumor size change, histology, and spatial analyses for PDAC and fibroblasts. Results: PET/MRI of PANC1 tumors showed significantly higher 68Ga-CBP8 uptake compared to control 68Ga-CNBP at each time point (p < 0.05), demonstrating the specificity of the probe in targeting collagen. PET values significantly increased over time in FOLFIRINOX-sensitive tumors (PANC1 %ID/cc: 0.8 ± 0.2 vs. 1.1 ± 0.3 vs. 1.9 ±0.2, p < 0.05 in day-0 vs. day-7 vs. day-15, respectively, p = 0.0005), whereas no significant change was seen in the probe uptake in the vehicle or resistant tumors (p > 0.05). There was a significant tumor growth reduction in responders compared to vehicle and resistant tumors. Histology showed a continuous increase of collagen in responding tumors (% collagen proportion area (CPA) in PANC1: 5.2 ± 3.8 vs. 16.2 ± 8.7 vs. 46.9 ± 6.0, p < 0.05, at Day-0 vs. Day-7 vs. Day-15, respectively, p < 0.0001), no change in resistant SU8686 (CPA: 33.0 ± 8.9 vs. 30.0 ± 9.7 vs. 28.1 ± 7.2, at Day-0 vs. Day-7 vs. Day-15, respectively, p = 0.66) and unchanged minimal collagen in pancreas. PET/MRI of patients showed a significantly higher SUVmean in the tumor compared to pancreas (2.4 ± 0.37 vs. 1.9 ± 0.31, p = 0.01), and a significantly higher uptake in the treated compared to untreated tumors (SUVmean: 2.8 ± 0.33 vs. 1.9 ± 0.56, p = 0.04). Response to treatment was confirmed on histology. Conclusion: Collagen PET could be used as a reliable non-invasive tool for monitoring response to neoadjuvant therapy in PDAC. Citation Format: Shadi A. Esfahani, Hua Ma, Shriya Krishna, Sergey Shuvaev, Arvin Hajmirzaian, Iris Zhou, Ciprian Catana, Mozhdeh Sojoodi, Eric Abston, David Ting, Pedram Heidari, Michael Lanuti, Kenneth Tanabe, Motaz Qadan, Carlos Fernandez de-Castillo, Aparna Parikh, Colin Weekes, Theodore Hong, Peter Caravan. Quantitative molecular imaging of pancreatic tumor fibrosis for evaluation of response to neoadjuvant therapy: Pre-clinical and first-in-human application of collagen PET/MRI [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A036.

Anus preservation in low rectal adenocarcinoma based on MMR/MSI status (APRAM): a study protocol for a randomised, controlled, open-label, multicentre phase III trial

BackgroundAnus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5 cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR/MSS/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR/MSI statuses, aiming to achieve a higher cCR rate with the W&W strategy and ultimately provide more patients with a chance of anus preservation.MethodsThis is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and/or N + tumours located within 5 cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR/MSI-H and pMMR/MSS. Patients in the dMMR/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET/CT as a supplementary method.DiscussionAPRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&W. Our study provides an accurate individual treatment mode based on the MMR/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits.Trial registrationClinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).

Brachytherapy in gynecological malignancies at a tertiary care hospital: An analysis.

Brachytherapy plays a crucial role in the standard of care for locally advanced gynecological malignancies. In this report, we present the experience from a tertiary teaching hospital, which is a referral center for image-guided brachytherapy (IGBT) in the management of locally advanced gynecological malignancies. This was a retrospective study of 130 patients referred to our hospital for IGBT after receiving initial external beam radiotherapy in their primary healthcare facilities, from January 2021 till January 2023. CT-based planning was done to delineate high-risk clinical target volume (HR-CTV). Dose of 6-7.5 Gy in 3-4 fractions was prescribed. Overall treatment time (OTT) was calculated, and patients were assessed for clinical response and toxicity after three months. All patients received IGBT using an intra-cavitary or interstitial technique. The D90 HR-CTV mean EQD2 dose was 28.34 ±2.78 Gy. The mean EQD2 dose to 2 cc of the bladder, rectum, and sigmoid was 18.31 ±5.19 Gy, 14.14 ±5.76 Gy, and 17.43 ±4.75 Gy, respectively. The median interval time between the last fraction of external beam radiation therapy (EBRT) and first evaluation in the hospital was 19 (range, 13-28) days (interquartile range [IQR]). The median time between the completion of chemoradiation and brachytherapy procedure was 25 (range, 19-33) days (IQR). The mean overall treatment time (OTT) was 63.5 ±14.7 days. This study highlights the established advantages of image-guided interstitial brachytherapy and associated challenges. To optimize the overall treatment duration, it is imperative to prioritize and update the referral processes for brachytherapy centers.

Clinical and pathological parameters predicting pathologic complete response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Objective The aim of this study is to identify possible clinical predictors of complete response after neoadjuvant treatment in locally advanced rectal cancer (LARC) patients. Background Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision and postoperative adjuvant chemotherapy for LARC is the standard of care with a local recurrence rate of only 5–10%. On the other hand, various people react differently to neoadjuvant CRT. Neoadjuvant CRT is well received by the majority of patients, with a pathologic complete response (pCR) occurring in 10–30% of cases. Predicting the response to neoadjuvant CRT is crucial from a clinical standpoint, since patients with pCR have a better prognosis and may require a different treatment plan than patients without pCR. As a result, predicting pCR following neoadjuvant CRT for rectal cancer continues to be extremely useful for treating physicians. To identify the clinical and pathological variables linked to a full response to preoperative CRT for rectal cancer, we assessed a group of patients with pCR in this study. Patients and methods The study included 153 patients with LARC that were enrolled in the study based on specific inclusion and exclusion criteria. Patients were treated by standard neoadjuvant therapy. Surgical resection was planned for 6–8 weeks after the completion of neoadjuvant CRT, irrespective of the response to CRT. Pathological examination was performed to assess pathological response in the resected specimen. pCR was defined as the absence of viable tumor cells in the surgical specimen, including lymph nodes. Results After neoadjuvant chemoradiation, the pCR rate for rectal cancer patients was 20.8%; patients were split into pCR and non-pCR groups. Age, sex, BMI, performance score, tumor stage, tumor differentiation, tumor location, and surgical method were all evenly distributed across the two groups. The results of the multivariate analysis showed that pretreatment lymph node status, tumor size, and a carcinoembryonic antigen level of less than or equal to 5 ng/ml were independent risk factors of an elevated likelihood of pCR, as was an interval of more than or equal to 8 weeks between the completion of chemoradiation and treatment. Conclusion The pCR in rectal cancer following neoadjuvant chemoradiation is predicted by pretreatment carcinoembryonic antigen level of less than or equal to 5 ng/ml, an interval of more than or equal to 8 weeks between the end of chemoradiation and surgical resection, tumor size greater than 5 cm, and pretreatment lymph node status. By utilizing these predictive variables, we are able to forecast patients’ outcomes and create flexible treatment plans. In certain, very specific situations, a wait-and-see policy might be appropriate.

Double fatal consequences of distance metastasis in nasopharyngeal carcinoma after a completed chemoradiation in pregnancy: A case report.

Distant metastasis in nasopharyngeal carcinoma (NPC) patients is one of the reasons for the decreased life expectancy with the most common metastasis spreads are to the bone, liver, and lung. Hepatoma is the most frequent liver malignancy and is one of the highest causes of cancer death worldwide and this can be as a result of NPC metastasis. The aim of this case report was to present a patient with hepatoma in pregnancy as a result of NPC metastasis. A 34-year-old pregnant female at 24-25 weeks of gestation presented with a chief complaint of heartburn and unbearable pain radiating to the back. Previous medical history reported that the patient had a liver enlargement. The patient was G4P2A1 with a single living intrauterine fetus and active fetal movements. The patient has a history of NPC and received a completed chemoradiation one month prior to hospital admission. Physical examination showed bilateral rales and palpable diffuse multiple nodule masses in the upper right abdominal quadrant. Laboratory examination revealed anemia, thrombocytopenia, negative hepatitis B surface antigen (HBsAg), and elevated liver markers. Abdominal ultrasonography results showed multiple diffuse nodules in the liver. The patient was diagnosed with a metastatic hepatoma based on the clinical and imaging findings. During hospitalization, the patient repeatedly experienced pleural effusion with suspicion metastases. A few days later, the fetal movements stopped and the ultrasonography indicated negative fetal heart rate. After experiencing respiratory distress for hours, the patient expired the day after. This case highlights that due to the potential adverse effects of chemotherapy and radiotherapy, the initiation of these therapies should be carefully decided to avoid adverse effects to mother and fetus.

Palliative radiotherapy for leptomeningeal metastases after photon-based intensity-modulated radiotherapy in a nasopharyngeal cancer patient.

Leptomeningeal metastasis is a rare in nasopharyngeal carcinoma, affecting less than 5% of patients with a poor prognosis. The aim of this case report was to present management of palliative radiotherapy in leptomeningeal metastasis of nasopharyngeal carcinoma patient. A 33-year-old female presented with nasopharyngeal carcinoma with stage III, T3N3M0, WHO type III. The patient has received chemoradiation with photon-based intensity-modulated radiotherapy (IMRT) technique at the dose of 70 Gy in 33 fractions and showed a satisfactory outcome in 12 months follow-up. Later, at 18 months after chemoradiation completion, the patient complained of worsening bilateral sciatic pain, particularly during coughing, with slight limitations in bilateral hip flexion observed during straight leg raises. The whole spine contrast-enhanced magnetic resonance imaging (MRI) examination showed nodular enhancement of leptomeningeal thickening at the T4 level of the spinal cord lower than S3. Palliative radiation therapy utilized a three-dimensional conformal radiation therapy (3D-CRT) technique producing 35 Gy in 14 fractions placed in a field spanning the T4-S3 vertebral bodies. Methotrexate was administered intravenously every two weeks for three cycles to ensure central nervous system penetration. After four months of follow-up, no evidence of disease was found at the primary site and metastatic areas on subsequent physical examination or imaging with MRI and there was satisfactory improvement in neurologic symptoms. In conclusion, leptomeningeal metastases with primary nasopharyngeal carcinoma are rare and typically cause neurological impairments in patients. Hematogenous or cerebrospinal fluid-mediated spread of the cancer is considered the most likely pathway for leptomeningeal dissemination. Strategic modalities, such as radiotherapy with chemotherapy, may improve outcomes in symptoms and quality of life.

QOL-15. THE PIVOTAL TRIDENT STUDY OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY WITH CHEMORADIATION, FOLLOWED BY MAINTENANCE TTFIELDS THERAPY/TEMOZOLOMIDE (TMZ), IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)

Abstract INTRODUCTION: TTFields are electric fields which act to disrupt processes necessary for cancer cell division and tumor progression. TTFields therapy is a noninvasive, locoregional treatment with US FDA approval for ndGBM and recurrent GBM, as well as pleural mesothelioma. TTFields therapy concomitant with maintenance TMZ is standard of care in ndGBM after chemoradiation based on the pivotal EF-14 study (NCT00916409) reporting significant improvements in progression-free survival (PFS) and overall survival (OS) vs TMZ alone. Preclinical and pilot clinical studies subsequently demonstrated that concomitant TTFields therapy also enhanced the therapeutic effect of radiotherapy (RT). TRIAL DESIGN: TRIDENT (EF-32, NCT04471844) is a pivotal multicenter study investigating TTFields therapy (200 kHz) concomitant with RT/TMZ in adult patients with histologically confirmed ndGBM. Eligibility criteria include life expectancy (≥ 3 months) and Karnofsky performance status (≥ 70). Patients (n≈950) stratified by MGMT promoter methylation status and extent of resection are randomly assigned 1:1 to receive TTFields therapy from the first day of chemoradiation (experimental arm), or approximately 4 weeks after completion of chemoradiation (control arm). All patients will receive TTFields therapy uninterrupted for 24 months, or until second disease progression (PFS2). The primary endpoint is median OS and other endpoints include survival rates at 1 and 2 years, PFS (overall, PFS2, and rates at 6 and 12 months), overall radiological response, safety, quality of life and dependence of OS on TTFields dose. The sample size is powered for a hazard ratio of < 0.8 (5% type I error). A stratified log-rank test will be used to test the hypothesis that OS is significantly improved with first line TTFields therapy/RT/TMZ vs RT/TMZ. This global study is open at sites in 11 countries.

Prospective Trial of Using Imaging to Predict Pathologic Response and Clinical Outcomes in Locally Advanced Esophageal Cancer

Trimodality therapy with chemoradiation (CRT) followed by esophagectomy is the standard of care for locally advanced esophageal cancer. An unresolved question is whether pathologic complete response (pCR) can be assessed non-invasively for patients post-CRT. In this study, we assessed whether diffusion-weighted imaging (DWI) with MRI or PET can be used as predictors of pCR and other clinical outcomes after CRT. Patients were enrolled on a single-arm institutional trial (PA13-0380) assessing the role of imaging in predicting outcomes in potentially resectable esophageal patients undergoing trimodality therapy. All patients received neoadjuvant CRT, and 29 patients had subsequent surgery. DWI MRI and PET scans were obtained at baseline, 2 weeks after the start of CRT (interim) and 4 to 6 weeks after completion of CRT (follow up). Apparent diffusion coefficients (ADCs) were calculated based on DWI images. Circulating tumor DNA was obtained for 27 patients post-radiation using CAPP-Seq. Mann-Whitney tests compared imaging changes associated with pCR. Discrimination of pCR by imaging changes was quantified by received operating characteristics. Youden's index was applied to select optimal thresholds. Kaplan-Meier analysis was performed to assess differences in overall survival (OS) and progression-free survival (PFS) by changes in DWI, PET, and ctDNA parameters. Our cohort of 60 patients had a median follow up of 42.7 months, age of 65.4 yrs, and ECOG of 1 at completion of CRT. 90% were male, 58% had a history of smoking, and 85% were white. 83% had adenocarcinoma with the rest squamous cell carcinoma. Stages of the patients ranged from IIA to IIIB. All had moderately (47%) or poorly (53%) differentiated disease. All received 41.4-50.4 Gy in 1.8 Gy fractions with the majority receiving 50.4 Gy (95%). 29 patients underwent surgery after CRT of which 8 (27.6%) had pCR. Mean ΔADC from baseline to mid-treatment was most associated with pCR (AUC = 0.98, p<0.001) for patients undergoing surgery. Max ΔADC from baseline to first follow-up was most associated with OS (p = 0.002) and PFS (p<0.001) for the whole cohort. 27 patients had ctDNA analyzed after RT with the presence of ctDNA significantly associated with worse OS (HR = 0.12, p = 0.05) and PFS (HR = 0.10, p = 0.002). Combining ctDNA and max ΔADC generated a model that was more predictive of OS and PFS than either alone. We found that neither the PET parameters of TLG or SUV max at baseline or changes in these parameters from baseline to mid-treatment or first follow-up were as predictive as DWI. We show that changes in DWI is associated with pCR, OS, and PFS in resectable esophageal cancer patients undergoing CRT. DWI was more predictive than PET and a model combining DWI and ctDNA was the most predictive of clinical outcomes. This study shows the significant promise of using DWI in potentially guiding treatment decisions in esophageal cancer patients and will require validation in a larger cohort.

"Evaluation of quality of life in patients with gastric adenocarcinoma receiving chemoradiotherapy: a cross-sectional study".

The aim of this study was to evaluate quality of life (QoL) in patients with gastric adenocarcinoma receiving adjuvant chemoradiotherapy (CRT). The European Organization for Cancer Research and Treatment Quality of Life Questionnaire-Core 30 (QLQ-C30) and site-specific module for gastric cancer (QLQ-STO22) were administered at four time points to 156 patients admitted to Cumhuriyet University Oncology Center between 2011 and 2018. The patient group comprised 76% men and 24% women with a median age of 61years (range, 18-88). During CRT, 12 patients (8%) discontinued treatment, 25 (16%) lost weight, and 42 (27%) had reduced performance. There was significant worsening in QLQ-C30 global health status and all functional and symptom scale scores at CRT completion. These changes were also clinically significant except for physical functioning scores and were supported by minimal clinically important difference measurements. In the QLQ-STO22, all symptoms except dry mouth and hair loss were negatively affected at CRT completion. In general, scores were improved at 1month after CRT and almost all scores reached baseline level by 6months. Certain scores were more adversely affected in women (global health status, physical functioning, role functioning, fatigue, pain, and insomnia), those who lost weight during CRT (emotional functioning), and those with CRT interruption (emotional functioning and anxiety). Although CRT reduces QoL in patients with gastric cancer, the effects tend to resolve within 6months after completing treatment. Female sex, weight loss, and CRT interruption negatively affected some QoL scores.

The Prevalence and Management of Synchronous Prostate and Rectal Cancer

Synchronous prostate and rectal cancer is rare and guidelines for co-management are not well established. This case series explores the prevalence of synchronous diagnosis and different treatment paradigms to propose a standardized approach to management. We retrospectively reviewed all radiation treatments between 1/2017 and 12/2022 for curative intent treatment to both prostate and rectal cancer. Synchronous was defined as rectal or prostate cancer diagnosed within a 6-month period of each other. We collected baseline characteristics and treatment paradigms including the sequencing of chemoradiation (CRT), chemotherapy (CT), prostate boost, and surgery. There were 10 out of 2204 total treated patients with prostate or rectal primary noted to have a synchronous diagnosis (0.45%). Table 1 shows characteristics and treatment approach for all patients with 50% receiving CRT and 50% CT alone first. At a median FU of 21.4 months, 2 patients did not complete therapy due to patient choice and both had progression of disease (POD). After completion of CRT, 6 patients underwent rectal surgery with 2 pathological complete response, and 2 patients proceeded with a Watch and Wait approach with clinical complete response on MRI. Prostate boost was delivered equally as often pre-surgery as post-surgery with both SBRT, EBRT and Seed Implant used. There was no grade 3+ RT related toxicity in the patients who completed all therapy. This series represents one of the largest synchronous prostate and rectal cancer cohorts treated with curative intent. Future collaborative work is needed to develop guidelines in the treatment of synchronous prostate and rectal cancers. Although a rare diagnosis, the heterogeneity of approaches has led us to propose a standardized approach to management of synchronous diagnosis with upfront chemotherapy followed by EBRT inclusive of prostate and rectum followed by boost via brachytherapy (SBRT in non-candidates).

Effect of External Beam Radiation Therapy (EBRT) and Brachytherapy (BT) on Circulating MDSC Populations in Patients Treated Definitively for Cervical Cancer

The immunosuppressive function of myeloid derived suppressor cells (MDSCs) has been implicated in the regulation of immune responses against cancer. MDSCs have been associated with progression and poor response to therapy in various types of cancer, including cervical cancer. Radiation treatment (RT) alters immune cell populations within the tumor and is thought to augment antitumor responses. However, whether RT also recruits immunosuppressive MDSC populations is not well understood. Here, we investigate how circulating MDSC populations change in response to RT and if changes in MDSC frequency or subsets is predictive of RT responses in cervical cancer patients. Newly diagnosed, treatment-naïve pts with locally advanced carcinoma of the cervix will be enrolled from July 2022 to July 2023. EBRT to the pelvis was delivered at a dose of 45 Gy in 25 fractions with a simultaneous integrated boost of 52-55 Gy to involved regional lymph nodes and parametria and concurrent weekly cisplatin. Gross tumor was boosted via interstitial or tandem ring BT (22.5-27.5 Gy) after completion of EBRT. Serial blood samples were collected prior to initiating therapy (T0), post-EBRT and pre-BT (T1), and one-month post-BT (T2). Treatment response was determined based on pre-treatment MRI compared to MRI post-EBRT. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood using density gradient centrifugation and stained for analysis via flow cytometry. MDSC populations were identified by Live/Dead-CD11b+CD33+HLA-DR- staining. MDSC subsets were further subdivided into granulocytic (G-, CD15+CD14-), monocytic (M-, CD15-CD14+), or early-MDSCs (e-, CD15-CD14-). Blood samples were collected at indicated time points for four patients (FIGO stage IIA-IIB). Three had partial responses to chemoradiotherapy (CRT), while one had a complete response. All three patients with partial response had an increase in total frequency of circulating MDSCs in response to EBRT/BT (mean %fx MDSC 16.6 at T0 to 35.9 at T2), and an increase in total MDSCs in two of these patients occurred with EBRT alone. Interestingly, the patient that had a complete response had fewer MDSCs at T2 relative to T0 (35.8% at T0 to 27% at T2). Proportion of MDSC subsets varied considerably among the patients, and all had altered distribution of subsets in response to RT. G-MDSCs expanded the most to RT while M-MDSCs and e-MDSCs were less affected (mean fold change from T0 to T2 G-MDSC 4.75, M-MDSC 1.27, e-MDSC 0.942). In this cohort of patients, an increase in MDSC frequency occurred after RT and altered subset distribution. Only the patient with a complete response had fewer total MDSCs following completion of CRT, suggesting further studies are needed to determine if circulating MDSCs could be a biomarker for treatment response to RT in cervical cancer.

Next-Generation Sequencing Analysis of Mutations in Circulating Tumor DNA from the Plasma of Patients with Head-Neck Cancer Undergoing Chemo-Radiotherapy Using a Pan-Cancer Cell-Free Assay.

Using next-generation sequencing (NGS), we investigated DNA mutations in the plasma tumor cell-free circulating DNA (ctDNA) of 38 patients with inoperable squamous cell head neck cancer (SCHNC) before and after the completion of chemoradiotherapy (CRT). Baseline mutations of the TP53 were recorded in 10/38 (26.3%) and persisted in 4/10 patients after CRT. ΤP53 mutations were further detected post CRT in 7/38 additional patients with undetectable mutations at baseline (overall rate 44.7%). Furthermore, 4/38 patients exhibited baseline mutations of the EGFR, AR, FGFR3, and FBXW3, and four new gene mutations were detected after CRT (MTOR, EGFR3, ALK, and SF3B1). Τ4 stage was related with a significantly higher rate of mutations (TP53 and overall). Mutations were observed in 8/30 (26.6%) responders (complete/partial response) vs. in 6/8 (75%) of the rest of the patients (p = 0.03). Significant poorer LRFS was noted for patients with mutations detected before and after CRT (p = 0.02). Patients who had detectable mutations either before or after CRT had significantly worse DMFS (p = 0.04 overall, and p = 0.02 for TP53 mutations). It was concluded that assessment of mutations before and after the end of CRT is essential to characterize patients with a high risk of locoregional recurrence or metastatic progression.

Prospective, Cell-Free Circulating Tumor DNA (ctDNA) Profiling in Locally Advanced Lung Cancer Treated with Chemoradiation

Liquid biopsy for cell-free circulating tumor DNA (ctDNA) allows for non-invasive, comprehensive genomic profiling. We explored the utility prospective liquid biopsy for (ctDNA) in among non-small cell lung cancer (NSCLC) patients treated with definitive chemoradiation. This prospective clinical cohort consists of unresectable, locally advanced NSCLC patients who had liquid biopsy testing prior to initiation of cancer therapy. Liquid biopsy testing was performed using a next-generation sequencing assay (MSK-ACCESS) which includes 129 genes and paired white blood cell sequencing. An FDA-recognized database (OncoKB) was utilized to classify alterations associated with radiation resistance (including KEAP1, NFE2L2, STK11, and PIK3CA) and radiation sensitivity (including ATM, ATR, BRCA1/2, ARID1A, MLH1 and other DNA Damage Repair Pathway alterations). We evaluated progression-free survival (PFS) from the completion of chemoradiation using the Log-rank test. Among 25 patients with prospective ctDNA testing prior to therapy initiation, 17 patients had stage III disease (68%), 8 patients had stage II disease (32%), 18 patients had adenocarcinoma (72%), 7 patients had squamous cell carcinoma (28%), and 23 (92%) were former or current smokers. The median radiation dose was 60 Gy in 30 fractions (range: 55 to 66 Gy in 20 to 33 fractions). 76% of patients (n = 18) had one or more alterations detected (median: 3 alterations, range: 1 - 8) including genomic markers of radiation response in 2 patients in BRCA1/2 (n = 2) and radiation resistance in 1 patient in KEAP1. The most common driver alteration detected was KRAS in 24% of the cohort (n = 6). Among patients with baseline detectable ctDNA, the median PFS was 21.3 months and was not reached among patients without baseline ctDNA detection (HR 4.54, p = 0.04). Using an institutional assay, the presence of baseline cell-free ctDNA appeared prognostic in patients with unresectable, locally advanced NSCLC treated with definitive chemoradiation. We also detected driver alterations and potential markers of radiation resistance and response using ctDNA testing. Prospective cell-free ctDNA profiling may offer pathways to therapy personalization among patients with locally advanced unresectable lung cancer.

A pharmacist-led opioid de-escalation program after completion of chemoradiotherapy in locally advanced head and neck cancer.

Persistent opioid use frequently leads to substantial negative impacts on quality of life, and as the outlook for numerous cancer types continues to improve, these complications become increasingly crucial. It is essential to acknowledge that extended or excessive opioid use may result in adverse effects in patients who completed radiation therapy (RT). In this time-series analysis, we compared the outcomes of patients who participated in the pharmacist-led opioid de-escalation (PLODE) program after completing concurrent radiotherapy (CRT) between June 2018 and February 2019 against patients who completed CRT between June 2017 and March 2018 and did not participate in the program. Among 61 patients, 16 (26%) used opioids after completing CRT and participated in the PLODE program. Before starting the program, 93 patients completed CRT between June 2017 and March 2018 and 32 (34%) used opioids at CRT completion. These patients were deemed the control group. In the PLODE group, outpatient pharmacist intervention was performed, with 29 total interventions related to opioid use, of which 16 (55%) recommended tapering or discontinuing opioids according to the definition of this program. Patients who participated in the PLODE program discontinued opioids significantly earlier than those in the control group (median time to opioid discontinuation 11 days vs. 24.5 days, p < 0.001). None of the patients in the PLODE group resumed opioid use following discontinuation or escalated opioid dosing due to worsening pain. This study showed the utility of pharmacist-initiated interventions for opioid use in patients with head and neck cancer who had completed CRT.

P07.09.B A RANDOMIZED PHASE 2B STUDY OF SURVIVIN VACCINE SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY-DIAGNOSED GLIOBLASTOMA (SURVIVE)

Abstract BACKGROUND Newly-diagnosed glioblastoma (nGBM) has a dismal prognosis with a median overall survival (OS) of nearly 16 months. nGBM cells have high expression of tumor-associated survivin protein. Survivin, localized to the cell surface through presentation by MHC class I molecules, is recognized by antibodies and cytotoxic T-lymphocytes (CTLs). A Phase 2a trial (NCT02455557) showed that a 15-amino acid-peptide-conjugate vaccine (SurVaxM) stimulates the production of survivin-directed antibodies and anti-tumor CTL in nGBM patients, resulting in a median OS of 25.9 months. This Phase 2b randomized controlled trial (RCT) aims to further investigate the efficacy of SurVaxM and adjuvant temozolomide for nGBM. METHODS This multicenter, placebo-controlled, investigator- and patient-blinded, in-progress RCT randomizes nGBM patients receiving standard of care to either SurVaxM (arm A) or saline placebo (arm B) in a 3:2 ratio at 15 sites. Included patients have age ≥18 years, normal organ function, Karnofsky Performance Status (KPS) ≥70, surgical resection, residual MRI contrast enhancement of ≤1 cm3 within 72 hours of resection, and adjuvant temozolomide (TMZ) therapy. Patients with recurrent, multicentric, brainstem- or cerebellar-origin GBM are excluded, as well as patients on tumor-treating fields or other immunotherapies. All patients undergo 3 phases: (1) vaccine priming (VP) phase, starting within 4 weeks after completion of chemoradiation, where 4 doses of SurVaxM or Placebo are administered every 2 weeks; (2) adjuvant TMZ phase, started after ≥1 VP dose; and (3) vaccine maintenance phase, started 8 weeks after VP, with SurVaxM or placebo given every 8 weeks. TMZ phase overlaps with VP and VM phases. The primary endpoint is median OS. Assuming a 1-year survival rate of 75% in the SurVaxM arm, comparable to the median OS in early phase trials, and 60% in the control arm, the study will enroll 265 patients, 159 in arm A and 106 in arm B. A log-rank test stratified by KPS (70-80 and 90-100), MGMT status (methylated and unmethylated), and IDH status (mutant and wild-type) will be used for analysis. Secondary endpoints per study arm are survival at 15, 18, and 24 months, median progression-free survival, toxicity, and progression-free survival at 3, 6, and 12 months. A single sequential OS-driven interim analysis is planned when 50% of OS events (deaths) occur. The study is expected to take 35 months, with ongoing accrual. RESULTS 69 patients have been enrolled as of April 11, 2023. CONCLUSION Findings from this trial will demonstrate the safety and efficacy of survivin vaccine in GBM (Clinical trial information: NCT05163080).

Immediate and long-term results of radiation therapy in combination with capecitabine and oxaliplatin in the treatment of patients with asquamous cell carcinoma of the anus

Introduction. The current standard of care is concurrent radiation therapy (RT) and chemotherapy with mitomycin or cisplatin in combination with fuoropyrimidine drugs. One possible option for effective chemotherapy regimens with a lower toxicity is the combination of oxaliplatin and capecitabine with RT. The purpose of the study: a retrospective evaluation of the results of combined treatment of 74 patients with squamous cell carcinoma of the anus (SCCA) with the use of oxaliplatin and capecitabine. Material and Methods. The study included 74 patients (men – 12.2 %, women – 87.8 %) with stage I–III SCCA. All patients underwent megavolt photon RT (2×25), a cumulative dose of 50 Gy and a boost of 10 Gy to the anal canal. From days 1 to 14 and from days 22 to 36 of RT, capecitabine was administered orally at a dose of 825 mg/m2 twice a day in combination with intravenous administration of oxaliplatin 50 mg/m2 on days 1, 8, 22, and 29 of RT. If a residual tumor 6 months after completion of chemoradiotherapy was found, patients underwent surgery. Results. All 74 patients underwent RT with a cumulative dose of 60 Gy. Chemotherapy, according to the protocol, was completed in 58 (78.4 %) patients. Grade 3-4 toxicity was noted in 11 (14.9 %) patients. In 64 patients (86.5 %), a complete clinical response was registered. At least one late radiation side effects according to the RTOG (LENT SOMA) scale was noted in 48 (98.0 %) patients, including grade 3-4 complications in 12 (24.5 %) patients. With a median follow-up of 40 months (3-82) cumulative three-year local recurrence rate, overall and relapse-free survival were 15.3 ± 4.5 %, 73.7 ± 5.7 % and 53.5 ± 6.4 %, respectively. Conclusion. Combined treatment of SCCA, based on the combination of RT with chemotherapy with oxaliplatin and capecitabine, is feasible and has acceptable acute toxicity. Additional clinical studies are needed using this chemotherapy regimen in combination with modern RT techniques.

Significance of neoadjuvant immunotherapy combined with chemotherapy in the treatment of larynx preservation in locally advanced hypopharyngeal squamous cell carcinoma

Objective:To evaluate the clinical significance of neoadjuvant immunotherapy combined with chemotherapy in the treatment of larynx preservation in locally advanced hypopharyngeal squamous cell carcinoma. Methods:Patients with locally advanced HPSCC（cT3-T4aN0-N3M0） were eligible. All received 2 cycles of pembrolizumab combined with docetaxel and platinum neoadjuvant induction therapy. After two cycles, the efficacy was evaluated, followed by radical chemoradiotherapy or surgery and adjuvant chemoradiotherapy according to the efficacy. The primary endpoints were objective response rate（ORR） ，larynx-preservation（LP） rate at 3 months post-treatment and the adverse reactions during neoadjuvant therapy. Results:From December 2021 to December 2022, 10 patients with locally advanced HPSCC（cT3-T4aN0-N3M0） were enrolled. After 2 cycles of the neoadjuvant therapy, 2 patients achieved complete response（CR）, 7 patients achieved partial response（PR）, 1 patient was stable disease（SD）, objective response rate（ORR） was 90%, and disease control rate（DCR） was 100%. 5 patients received radical chemoradiotherapy, 5 patients received surgery and adjuvant chemoradiotherapy, four of them received partial laryngectomy and partial hypopharyngeal resection surgery, and one of them received total laryngectomy and partial hypopharyngeal resection surgery. All patients were able to withstand adverse reactions of neoadjuvant therapy and successfully completed the whole treatment of HPSCC without grade 3-4 treatment-related adverse reactions. There was no recurrence or metastasis during 3-18 months of follow-up. 1 patient died of severe pneumonia 3 months after the completion of radical chemoradiotherapy. At 3 months after treatment, the larynx-preservation rate was 80%. Conclusion:Neoadjuvant immunotherapy combined with chemotherapy has good short-term efficacy and the adverse reactions were tolerable. It can improve the larynx-preservation rate of patients with locally advanced HPSCC, thus improving the prognosis and quality of life of patients.

Feasibility and Tolerability of Adjuvant Capecitabine-Based Chemoradiation in Patients With Breast Cancer and Residual Disease After Neoadjuvant Chemotherapy: A Prospective Clinical Trial

Addition of adjuvant capecitabine improves overall survival for patients with breast cancer lacking pathologic complete response to standard-of-care neoadjuvant chemotherapy. Combining radiosensitizing capecitabine concurrent with radiation may further improve disease control, although the feasibility and tolerability of chemoradiation in this setting is unknown. This study aimed to determine the feasibility of this combination. Secondary objectives included the effect of chemoradiation on physician-reported toxicity, patient-reported skin dermatitis, and patient-reported quality of life compared with patients with breast cancer treated with adjuvant radiation. Twenty patients with residual disease following standard neoadjuvant chemotherapy were enrolled in a prospective single-arm trial and treated with adjuvant capecitabine-based chemoradiation. Feasibility was defined as ≥75% of patients completing chemoradiation as planned. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 5.0 and the patient-reported radiation-induced skin reaction scale. Quality of life was measured using the RAND Short-Form 36-Item Health Survey. Eighteen patients (90%) completed chemoradiation without interruption or dose reduction. The incidence of grade ≥3 radiation dermatitis was 5% (1 of 20 patients). Patient-reported radiation dermatitis did not show a clinically meaningful difference following chemoradiation (mean increase, 55 points) compared with published reports of patients with breast cancer treated with adjuvant radiation alone (mean increase, 47 points). On the other hand, patient-reported quality of life demonstrated a clinically meaningful decline at the end of chemoradiation (mean, 46; SD, 7) compared with the reference population of patients treated with adjuvant radiation alone (mean, 50; SD, 6). Adjuvant chemoradiation with capecitabine is feasible and tolerable in patients with breast cancer. Although current studies using adjuvant capecitabine for residual disease following neoadjuvant chemotherapy have specified sequential treatment of capecitabine and radiation, these results support the conduct of randomized trials in this setting to investigate the efficacy of concurrent radiation with capecitabine and provide patient-reported toxicity estimates for trial design.

CEREBELLAR DIFFUSE MIDLINE GLIOMA, H3K27M ALTERED IN A FIFTY-FIVE-YEAR-OLD PATIENT

Abstract H3 K27M mutations were first identified in Pediatric Diffuse Intrinsic Pontine Glioma and are now recognized in gliomas occurring in other midline locations such as the thalamus, spinal cord and cerebellum. These gliomas were renamed to Diffuse Midline Glioma (DMG) H3 K27-altered in the 2021 WHO classification due to the discovery of alternate mechanisms of H3 K27 loss. These gliomas are more commonly found in children but also occur in adolescents and young adults. We present the case of a 55- year-old woman who presented with a 2.5-month history of nausea, vomiting and gait impairment. Imaging revealed a partially cystic, enhancing lesion in the midline of the cerebellum. She had a gross total resection with pathology revealing Diffuse Midline Glioma, H3K27 altered, subgroup DMG, H3 wildtype with EZHIP over-expression, WHO grade 4. The patient completed chemoradiation with temozolomide with plans to enroll in a clinical trial upon progression. However due to loss of ambulation and function she was admitted to hospice. The patient survived 24 months after her surgery, a period longer than the reported median overall survival in DMG with EZIP overexpression which is 16 months. This case illustrates the importance of considering DMG H3K27- altered glioma in adults older than 40 years who present with infiltrative IDH wildtype glioma in midline locations. Recognition of this diagnosis may allow enrollment in clinical trials and should prompt molecular testing for concurrent targetable alterations in the RAS-MAPK-pathway (e.g., mutations in BRAF V600E, FGFR1, NF1 and NTRK) and PI3K-mTOR pathway (e.g., PIK3CA mutation).

Factors associated with failure to start consolidation durvalumab after definitive chemoradiation for locally advanced NSCLC.

The introduction of consolidation immunotherapy after chemoradiotherapy has improved outcome for patients with locally advanced non-small cell lung cancer. However, not all patients receive this treatment. This study identifies factors associated with failure to start durvalumab as consolidation therapy with the aim of optimizing treatment, supportive care and prehabilitation to ensure that more patients complete the planned treatment. Patients from two clinical trials and a named patient use program, were included in this study. All patients received platinum-doublet chemotherapy concomitant with radiotherapy to a total dose of 60-66 gray. Patient characteristics, cancer treatment, toxicity, performance status and laboratory data before and after chemoradiotherapy were recorded and patients who never started durvalumab were compared with those who did. A total of 101 patients were included, of which 83 started treatments with durvalumab after chemoradiotherapy. The 18 patients who did not start durvalumab had significantly higher lactate dehydrogenase at baseline and a worse performance status, cumulative toxicity and higher c-reactive protein after completed chemoradiotherapy. Data also suggest that pre-treatment diabetes and reduced hemoglobin and/or diffusion capacity of the lungs for carbon monoxide contribute to the risk of treatment abruption. Treatment plan disruption rate was 18%. Systemic inflammation and performance status were associated with failure to receive durvalumab after chemoradiation. Further studies are needed to confirm findings and prospective trials should investigate whether prehabilitation and supportive treatment could help more patients finishing the planned treatment. clinicaltrials.gov, identifier NCT03798535; NCT04392505.