Concurrent Chemoradiotherapy In Treatment Research Articles

Enhancing outcome prediction of concurrent chemoradiation treatment in patients with locally advanced cervical cancer through plasma extracellular vesicle proteomics

Most patients with locally advanced cervical cancer (LACC) are primarily treated using concurrent chemoradiation (CCRT); however, LACC lacks reliable predictive biomarkers. Extracellular vesicles (EVs) could define the dynamic biological response to CCRT. However, the relationship between EVs and the therapeutic response to LACC is unestablished. Thus, we aimed to determine the relationship of plasma EVs pre- and post-CCRT in 62 patients with LACC. For proteomic analyses, EVs were isolated using ultracentrifugation (UC) with size exclusion chromatography or UC alone. We found that plasma particle concentration was significantly increased post-treatment in non-responders. After CCRT, there was a decrease in proteins related to serine protease and fibrinogen, which contribute to tumor microenvironment alteration. This reduction also extended to proteins involved in innate immune and viral immune responses, correlating with reduced tumor burden. Sparse partial least squares discriminant analysis revealed 8, 13, and 19 proteins at diagnosis, one month, and three months, respectively, influencing the CCRT response. Among these, FIBG, TFR1, HBA, and FINC are prognostic markers according to The Cancer Genome Atlas tissue gene expression database. Our discriminant model demonstrated excellent specificity and negative predictive value, underscoring the model's reliability in determining responsiveness to CCRT and highlighting the potential clinical applicability of EVs in improving outcomes in LACC.

Evaluation of Pneumonitis in a Phase II Study of Consolidation Immunotherapy with Nivolumab and Ipilimumab or Nivolumab Alone following Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-small Cell Lung Cancer (NSCLC)

Unresectable stage III Non-Small-Cell-Lung-Cancer (NSCLC) has had an evolving landscape of treatment options with the approvals of immuno-oncologic (IO) therapy. There have been relatively few studies that have evaluated the risk of pneumonitis in patients receiving IO after concurrent chemoradiation treatment (CCRT). This study is to evaluate the relationship of pneumonitis and radiation dose in patients receiving consolidative IO with Nivolumab or Nivolumab plus ipilimumab. Patients with stage III NSCLC who underwent CCRT were enrolled on BTCRC-LUN16-081, a randomized phase II trial assessing the efficacy of nivolumab or nivolumab plus ipilimumab as consolidation therapy. These patients were evaluated for radiation dose parameters and correlation with pneumonitis was examined. After CCRT, patients were enrolled to receive consolidative IO therapy on BTCRC-LUN16-081, and 104 patients had Dose Volume Histogram (DVH) information available for analysis. Of these patients, 58 (55.8%) had stage IIIA and 46 (44.2%) had stage IIIB disease according to 7th edition IASLC. During this period 29 patients (27.9%) had at least grade 2 pneumonitis. Utilizing logistic regression and evaluating different cut offs for lung V20, patients receiving a V20 of greater than 23% had a higher risk of grade 2 or greater pneumonitis (p-value 0.0246, 38% vs. 16%). There was no significant difference in rates of pneumonitis between the two different IO regimens. Traditional lung DVH cutoffs (V5>65%, V20>35%, mean >20 Gy) were not associated with pneumonitis in this study. The use of nivolumab or nivolumab plus ipilimumab after definitive CCRT is safe and effective. Lung V20 > 23% was associated with a higher risk of Grade 2 or higher pneumonitis. Radiation dose constraints for lungs in patients receiving consolidative IO after CCRT should continue to be evaluated and optimized when feasible.

Long-Term Outcomes and Toxicity in Esophageal Cancer Patients after Neoadjuvant or Definitive Concurrent Chemotherapy with Proton Beam Therapy

Proton-beam therapy (PT) is increasingly utilized over three dimensional-conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) photon irradiation for the treatment of various malignancies due to better toxicity reduction. We investigated the long-term outcomes and toxicity in esophageal cancer (EC) patients treated with PT as part of their neoadjuvant concurrent chemoradiation followed by surgery (nCRT) or definitive concurrent chemoradiation (dCRT) treatment regimen. All consecutively treated, American Joint Committee on Cancer 7th edition clinical stage I-IV EC patients from 2006 to 2022 were retrospectively analyzed. Standard RT dose for most patients was 50.4 Gy/28 fractions. nCRT patients had surgery within 4 months post-RT. Kaplan-Meier method was used to determine overall survival (OS), locoregional recurrence-free survival (LRRFS) and distant metastatic-free survival (DMFS). Acute and chronic RT-related toxicities were graded with Common Terminology Criteria for Adverse Events version 4.0. There were 510 EC PT patients: 204 (40%) had nCRT and 306 (60%) had dCRT. Most lesions were located in the lower esophagus, of adenocarcinoma histology and treated with passive scatter PT. Overall median follow-up was 72 months. Median, 3- and 5-year OS for all patients were 43 months, 54.1% and 44.9%, respectively. Median LRRFS and DMFS were not reached. Esophagitis was the most common grade ≥3 (G3+) toxicity (59 patients; 28.9%, including a G4 and a G5 toxicity), followed by nausea (29 patients; 14.2%) and esophageal stricture (26 patients, 12.7%). With nCRT, median, 3- and 5-year OS were 80 months, 64.7% and 56.1%, respectively, while the median LRRFS and DMFS were not reached again. Their most common G3+ toxicity was esophagitis in 14 patients (6.9%) followed by nausea (8 patients; 3.9%). An nCRT patient developed G4 RT pneumonitis. Pathological complete response (pCR) was observed in 58 patients (28.4%). Surgery-related pulmonary, cardiac and gastrointestinal complications were reported in 38 (18.6%), 40 (19.6%) and 43 (21.1%) patients, respectively. dCRT patients had a median follow-up of 65 months, and median, 3- and 5-year OS of 32 months, 46.7% and 37.0%, respectively. Although the median LRRFS was not reached, the median DMFS was 74 months. The most observed dCRT G3+ toxicity was esophagitis (45 patients, 22.1%: including both G4 and G5 patients) and then esophageal stricture (23 patients, 11.3%). A dCRT patient developed G4 fistula. To our knowledge, this is the largest single-institutional study on EC long-term outcomes and toxicity using PT. Our cohort reveals good outcomes and mostly mild CRT-related toxicities. Trimodality nCRT with protons demonstrates excellent outcomes relative to the CROSS trial (49.4 months) with identical pCR rate (29% in CROSS) and similar toxicity profile. nCRT with protons should be studied rigorously in the current randomized phase III trial NRG GI006.

Utility of Prophylactic Percutaneous Gastrostomy in Patients With Head and Neck Cancer Receiving Concurrent Chemoradiotherapy: A Multicenter Analysis.

Patients with head and neck cancer (HNC) have an elevated incidence of cachexia and malnutrition due to the tumor's location interfering with oral feeding. Concurrent chemoradiation (CCRT) can have an emetic effect and cause dysphagia and oral mucositis. Adequate nutrition improves immunity, raises the response to therapy, reduces adverse effects, and improves survival. Numerous studies have suggested the utility of nutritional support from percutaneous endoscopic gastrostomy (PEG) in HNC patients. Although PEG is usually considered a safe procedure, it has a mortality rate of 0-2.2% and a risk of other procedure-related complications of 17-40%. Our work intends to evaluate the utility of PEG in patients with locally advanced HNC who underwent CCRT. We performed a cohort study at three institutions. We included patients with HNC who underwent definitive CCRT treatment from January 2013 to December 2022.The study consisted of an observational, descriptive, retrospective analysis of prespecified clinical data. Descriptive statistics were used to compare the data between the PEG group and the non-PEG group. Analysis of covariance (ANCOVA) was used forcovariance analysis. Fisher's exact test was used to compare proportional data and Student's t-test was used to assess the differences in continuous data. Survival analysis was performed using the Kaplan-Meier estimator. P-values of<0.05 were considered to be indicative of statistical significance. The SPSS Statisticsversion 28.0 (Armonk, NY: IBM Corp.) was used to perform all statistical evaluations. We identified 90 eligible patients diagnosed with local advanced HNC who had received definitive CCRT with three weekly cycles of cisplatin as follows: 44 with a prophylactic PEG tube and 46 without a prophylactic PEG tube. Most patients were male (84.4%) and 50% of patients were diagnosed with stage IVa HNC at the time of diagnosis. There wasn't an effect of PEG placement on BMI at the end of CCRT after controlling for the effect ofbaseline BMI (F {1.84}=0.065 {p=0.799}).In the study population, BMI was significantly lower after CCRT (21.30 kg/m2 vs. 23.97 kg/m2), t (86)=12.389, p<0.001. In the subgroup with baseline BMI <18.5 kg/m2 (15 patients), 90% of patients with prophylactic PEG were able to complete the three planned cycles of chemotherapy vs. 66.7% in the non-PEG group. Ten patients in the PEG group (22.7%) referredfeeding tube dependency. Patients with dysphagia were 3.2 times more likely to have placed prophylactic PEG (p=0.007). The difference in overall survivaland progression-free survivalbetween the two groups was not statistically significant (p=0.57 and p=0.497, respectively). In this study using real-world data, we found a potentially protective effect of PEG in underweight patients with locally advanced HNC performing CCRT in order to complete three cycles of treatment.

Molecular markers impacting survival in patients receiving concurrent chemoradiation and Tumor-Treating Fields (TTF) in patients with newly diagnosed glioblastoma: secondary analysis of SPARE trial (P13-13.003)

<h3>Objective:</h3> The objective of this study was to evaluate the impact of molecular markers (PTEN, TP53, EGFR, and TERT) on overall survival (OS) and progression-free survival (PFS) of SPARE trial patients. <h3>Background:</h3> SPARE trial (Scalp-sparing radiation with concurrent temozolomide (TMZ) and tumor treating fields; NCT03477110) is a single-arm pilot study that demonstrated the safety and feasibility of concurrent TTF with chemoradiation for newly diagnosed glioblastomas (GBM). <h3>Design/Methods:</h3> This is a secondary analysis of the SPARE trial. Molecular markers of histologically-confirmed, IDH-wildtype GBM patients age ≥ 18 years old with a Karnofsky performance status (KPS) ≥ 60 who received concurrent chemoradiation and TTF followed by maintenance TMZ + TTF were evaluated. Molecular profile was evaluated with next-generation sequencing. Interaction of mutations in PTEN, TP53, EGFR, and TERT with TTF on OS and PFS was evaluated using a multivariable model. <h3>Results:</h3> A total of 30 patients were enrolled in the SPARE trial. 1 patient with IDH-mutant histology was excluded. The median age was 58 (range; 19–77). The median KPS was 90 (range; 70–100). 9 patients (31.0% ) had a methylated MGMT promotor. 14 patients (48.3%) were found to have PTEN mutation, 9 patients (31.0%) with EGFR alteration, 7 (24.1%) with TP53 mutation, and 23 patients (79.3%) with TERT mutated. MGMT methylation remained statistically significant for an increased OS (p=0.032; HR 7.18). TERT had a statistically significant OS benefit (p=0.012; HR 7.60). TERT also showed significant improvement in PFS. However, neither EGFR, TP53, nor PTEN showed any association of PFS or OS for patients who received concurrent TTF and chemoradiation treatment. <h3>Conclusions:</h3> In this secondary analysis, neither EGFR, TP53, nor PTEN mutation showed any association of PFS or OS. However, patients with TERT mutations showed improved OS. Due to the small sample size, further validation studies should be conducted. <b>Disclosure:</b> Ms. Kayne has nothing to disclose. Dr. Poiset has nothing to disclose. Dr. Ali has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Niazi has nothing to disclose. Dr. Cappelli has nothing to disclose. The institution of Dr. Alnahhas has received research support from Novocure. Dr. Shi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novocure. Dr. Shi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for zai lab. Dr. Shi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for varian. Dr. Shi has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for novocure.

Two-Stage Phase II Study of Envafolimab Combined with Endostar and Concurrent Chemoradiotherapy in Treatment of Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: Preliminary Results of Stage 1

<h3>Purpose/Objective(s)</h3> Concurrent chemoradiotherapy (CRT) is the standard of care for patients with unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC). In the era of immunotherapy, we performed a single-center, open-label phase II study of CRT combined with endostar (inhibitor of tumor angiogenesis) and envafolimab (PD-L1 checkpoint inhibitor) in patients with LA-ESCC. <h3>Materials/Methods</h3> Treatment-naïve patients with LA-ESCC were enrolled. Radiologists evaluated each patient to exclude the risk of esophageal fistula before enrollment. Involved field radiotherapy at doses of 50.4 Gy (1.8Gy QD), two cycles of paclitaxel liposome (150 mg /m²) and carboplatin (AUC=5) Q4W and 5 cycles of endostar (75mg × 48h, QW) were delivered. Envafolimab at 400 mg subcutaneous injection Q4W was started concurrently with CRT and continued for up to 12 cycles. In Stage 1, the primary endpoint was safety and tolerability. Secondary endpoint was objective response rate and the rate of endoscopic complete remission (EsCR) defined as absence of invasive cells in esophagoscopic biopsy. Responses were assessed by positron emission tomography-computed tomography (PET-CT) at baseline, 12 weeks after the CRT, and computed tomography (CT) at 4 weeks after the CRT, every 12 weeks thereafter. The esophagoscopic examination and biopsy were monitored at baseline, after 41.4 Gy radiation, and 1 month after the CRT To evaluate the efficacy. <h3>Results</h3> Between Sep. 8, 2021 and Nov. 15, 2022, 10 patients were enrolled in Stage-1. Treatment-related adverse events (TRAE) occurred in 9 (90%) patients, the most common of which was fatigue (30%), nausea (40%), thrombocytopenia (20%), leucopenia (60%), acute esophagitis (40%), thyroid dysfunction (10%), and Rash (20%). These occurred predominantly at grade 1 or 2 severity. The most frequent TRAE of grade 3 or worse was leucopenia (40%). No patient had pneumonitis, esophageal fistula. There were no deaths or treatment discontinuations due to serious adverse events. CT scan was completed in 10 patients, esophagoscopic examination biopsy in 9 of them, at 4 weeks after the CRT. All patients had a decrease in target lesion size on CT. The objective response rate was 100%. The pathology report of 8 patients revealed no cancerous cells was observed, resulting in an EsCR rate of 88.9%. <h3>Conclusion</h3> In the stage-1, Envafolimab combined with endostar and CRT was well tolerated with manageable toxicity for unresectable LA-ESCC patients. The preliminary results provide a basis for the ongoing stage 2 study. This trial is registered with ClinicalTrials.gov, number ChiCTR2100051606.

Molecular Markers Impacting Survival in Patients Receiving Concurrent Chemoradiation and Tumor-Treating Fields (TTF) in Patients with Newly Diagnosed Glioblastoma: Secondary Analysis of SPARE Trial

<h3>Purpose/Objective(s)</h3> SPARE trial (Scalp-sparing radiation with concurrent temozolomide and tumor treating fields; NCT03477110) is a single-arm pilot study that demonstrated the safety and feasibility of concurrent TTF with chemoradiation for newly diagnosed GBM. The current study is a secondary analysis evaluating the impact of molecular markers (PTEN, TP53, EGFR, and TERT) on overall survival (OS) and progression-free survival (PFS) of the patients in the trial. <h3>Materials/Methods</h3> This is a secondary analysis of SPARE trial. Molecular markers of histologically-confirmed, IDH-wildtype GBM patients age ≥ 18 years old with a KPS ≥ 60 who received concurrent chemoradiation and TTF followed by maintenance TMZ + TTF were evaluated. Molecular profile was evaluated with next-generation sequencing. Interaction of mutations in PTEN, TP53, EGFR, and TERT with TTF on OS and PFS was evaluated using a multivariable backward model. <h3>Results</h3> A total of 30 patients were enrolled in the SPARE trial, and 1 patient with IDH-mutant was excluded from the current analysis. All patients underwent concurrent TTF and chemoradiation. The median age is 58 (range; 19-77). The median KPS was 90 (range; 70-100). 9 patients (31.0%) have methylated MGMT promotor. 14 patients (48.3%) are found to have PTEN mutation, 9 patients (31.0%) with EGFR, 7 (24.1%) with TP53 mutation, and 23 patients (79.3%) with TERT mutated. MGMT methylation remained statistically significant for an increased OS (p=0.032; HR 7.18). TERT also had a statistically significant OS benefit (p=0.012; HR 7.60). MGMT and TERT also showed significant improvement in PFS. However, neither EGFR, TP53, nor PTEN showed any association of PFS or OS for patients who received concurrent TTF and chemoradiation treatment. <h3>Conclusion</h3> In this secondary analysis, patients with MGMT methylation showed better PFS and OS as expected. Neither EGRF, TP53, or PTEN mutation showed any association of PFS or OS. However, patients with TERT mutant showed improved OS with concurrent TTF with chemoradiation. A TERT mutation may be a new molecular biomarker in the described treatment approach. Due to the small sample size, further validation studies should be conducted.

Comparison of outcomes and side effects for neoadjuvant chemotherapy with weekly cisplatin and paclitaxel followed by chemoradiation vs. chemoradiation alone in stage IIB\u2013IVA cervical cancer: study protocol for a randomized controlled trial

BackgroundCurrently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). The effect of neoadjuvant chemotherapy in advanced cervical cancer is controversial. Studies have shown that the addition of a weekly regimen of neoadjuvant chemotherapy (NACT) followed by CCRT may be superior to a thrice-weekly regimen of NACT and CCRT. Among patients who had not received prior cisplatin, a cisplatin and paclitaxel (TP) regimen resulted in longer overall survival than other regimens. This study aims to investigate the feasibility, safety, and efficacy of NACT with weekly TP followed by CCRT.MethodsThis is a prospective, randomized, open-labeled, multicentered phase III study. Based on a 65% of 2-year disease-free survival (DFS) rate in the CCRT group and 80% of that in NACT followed by CCRT group, and on prerequisite conditions including an 8% loss to follow-up, a two-sided 5% of type I error probability, and an 80% of power, a total of 300 cases were required for enrollment. Patients with IIB–IVA cervical cancer will be randomly allocated in a 1:1 ratio to one of two intervention arms. In the study arm, patients will receive dose-dense cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly for 4 cycles followed by CCRT (45 Gy in 5 weeks concurrent with cisplatin 40 mg/m2 weekly) plus image-guided adaptive brachytherapy (IGBRT). In the control arm, patients will undergo CCRT treatment. The primary endpoint of the study is 2-year disease-free survival (DFS); the secondary endpoints are 5-year overall survival (OS) and disease-free survival (DFS), the response rate 3 months after treatment completion, grade III/IV adverse effects, and quality of life, and potential biomarkers for predicting treatment response will also be studied.DiscussionThe data gathered from the study will be used to determine whether NACT with weekly TP followed by CCRT may become an optimized treatment for locally advanced cervical cancer.Trial registrationChinese Clinical Trial Registry ChiCTR1900025327. Registered on 24 August 2019. medresman.org.cn ChiCTR1900025326

Stat1 confers sensitivity to radiation in cervical cancer cells by controlling Parp1 levels: a new perspective for Parp1 inhibition

Cervical cancer (CC) is the fourth most common cause of cancer-related death in women. According to international guidelines, a standard treatment for locally advanced cervical cancer (LACC) consists of exclusive concurrent chemoradiation treatment (CRT). However, chemoradioresistance and subsequent relapse and metastasis of cancer occur in many patients, and survival for these women has generally remained poor. Therefore, strategies to overcome resistance are urgently needed. We have recently reported a radiosensitizing effect of the signal transducer and activator of transcription 1 (STAT1) in CC, associated with the control of [Poly(ADP-ribose) polymerase −1] PARP1 levels, a key factor in cell response to DNA damage induced by radiation. Here, we sought to decipher the underlying mechanism of STAT1-mediated control of PARP1, elucidating its role as a radiosensitizer in CC. Functional and molecular biology studies demonstrated that STAT1 may act at both transcriptional and posttranscriptional levels to modulate PARP1 expression in CC cells. In light of these results, we tested the effect of Olaparib in sensitizing CC cells to radiation and investigated signaling pathways involved in the activity observed. Results showed that PARP1 inhibition, at clinically achievable doses, may indeed selectively improve the sensitivity of resistant CC cells to DNA-damaging treatment. The translational relevance of our findings was supported by preliminary results in a limited patient cohort, confirming that higher PARP1 levels are significantly associated with a radioresistant phenotype. Finally, bioinformatics analysis of GEPIA and TCGA databases, demonstrated that PARP1 mRNA is higher in CC than in normal tissues and that increased PARP1 mRNA expression levels are associated with poor prognosis of LACC patients. Overall, our data open new opportunities for the development of personalized treatments in women diagnosed with CC.

The preliminary efficacy and safety of KN046 plus concurrent chemoradiation therapy in recurrent and metastatic esophageal squamous cell carcinoma.

223 Background: Definitive or palliative chemoradiation therapy has been employed in the management of esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitor has improved outcomes in metastatic stage IV pts. Here we report the addition of KN046, a PD-L1/CTLA-4 bispecific antibody, to concurrent chemoradiation (CRT) therapy to determine the safety and efficacy of this approach (ChiCTR2000031544). Methods: Pts with recurrent or metastatic ESCC, not been treated by CRT or other systemic treatment within 6 months, were recruited and received palliative CRT consisting of cisplatin (75 mg/m2 IV Q3W for 4~6 cycles), paclitaxel (135~175 mg/m2 IV Q3W for 4-6 cycles) and radiation (SBRT or conventional and dose are determined at the investigator’s discretion according to institutional standard). KN046 at ascending doses of 1, 3 and 5 mg/kg Q3W was added within 7-14 days after the completion of radiation therapy (RT) and concurrently with chemotherapy, followed by KN046 Q2W maintenance. Dose limiting toxicities (DLTs) were assessed for the first treatment cycle of KN046. Anti-tumor activity was assessed according to RECIST 1.1 every 6 weeks within the first year, and every 12 weeks thereafter. Results: As of June 30, 2020, 18 subjects were enrolled and received KN046 treatment (1mg/kg, n = 3; 3mg/kg, n = 11; 5mg/kg, n = 4). The median KN046 exposure was 11.5 weeks. No DLT was reported. 3 (16.7%) subjects experienced Grade 3, KN046 related adverse events (1 Grade 3 pneumonitis and 2 Grade 3 colitis recovered after steroid and antibiotic Tx). For 18 evaluable subjects, the disease control rate and objective response rate were 94.4% and 44.4%, respectively. DOR and PFS were not matured yet as of cutoff date. At 3 mg/kg, objective response was observed in 5 out of 9 subjects (55.6%) with measurable disease and disease control rate was 100%; 7/9 (77.8%) subjects experienced further tumor reduction after initiation of KN046 treatment. It is worth to note that, 2 subjects at 3mg/kg achieved complete response after receiving KN046 treatment. Conclusions: The addition of KN046 to CRT was well tolerated and showed promising efficacy signal in recurrent or metastatic ESCC. This pilot study enables further investigation of a new treatment modality of KN046 with CRT in this detrimental disease with poor prognosis. Clinical trial information: 2000031544.

Expression of Immune Checkpoint Regulators, Cytotoxic T-Lymphocyte Antigen-4, and Programmed Death-Ligand 1 in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is the most common cancer arising from the nasopharynx with a poor prognosis. Targeting immune checkpoint is one of the new promising lines in cancer treatment. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-ligand 1 (PD-L1) are immune checkpoints that regulate T-cell immune function. This work aimed to assess the immunohistochemical expression of PD-L1 and CTLA-4 in NPC and their ability to predict survival and response therapy and to check their validity as immunotherapy targets. Twenty-six cases of NPC were studied by immunohistochemistry for PD-L1 and CTLA-4 and by nested polymerase chain reaction followed by DNA sequencing for the presence of EBNA-1 gene of Epstein-Barr virus (EBV). All investigated cases were diagnosed and treated in the Zagazig University Hospital in the period from August 2015 to July 2018. EBNA-1 gene was identified in 84.6% of the cases. Whereas the expression of PD-L1 was noted in 46.2% of all cases studied, 54.6% of EBV-associated NPCs were found to express PD-L1. There was a significant association between PD-L1 expression and the advanced stage of the tumor (P<0.001). CTLA-4 expression was observed in 88.4% of all NPC cases as cytoplasmic staining in both tumor cells and tumor-infiltrating lymphocytes. CTLA-4 expression in lymphocytes was associated with the presence of EBV. A significant association was detected between CTLA-4 and tumor-infiltrating lymphocyte expression on one side and the stage of the tumor on the other. High expression of CTLA-4 was significantly associated with disease progression and worse overall survival. PD-L1 and CTLA-4 are adverse prognostic markers in NPC. The authors propose that targeted therapy against PD-L1 and CTLA-4 will be a hopeful therapy for cases of NPC with resistance to concurrent chemoradiation treatment in Egypt, especially EBV-associated cases.

Impact of p53, HIF1a, Ki-67, CA-9, and GLUT1 Expression on Treatment Outcomes in Locally Advanced Cervical Cancer Patients Treated With Definitive Chemoradiation Therapy

The objective of this study was to assess the association between pretreatment p53, hypoxia inducible factor 1a (HIF1a), Ki-67, carbonic anhydrase-9 (CA-9), and glucose transporter 1 (GLUT1) expression in locally advanced cervical cancer patients treated definitively with concurrent chemoradiation therapy (CRT) and treatment outcomes including overall survival (OS), progression-free survival (PFS), local-regional control (LC), and distant metastases-free survival (DMFS). Twenty-eight patients treated definitively and consecutively for cervical cancer with CRT had p53, HIF1a, Ki-67, CA-9, and GLUT1 protein expression assessed and scored semiquantitatively by 3 pathologists, blinded to the treatment outcomes. Outcomes were stratified by p53 (H-score: <15 vs. ≥15), HIF1a (H-score: <95 vs. ≥95), Ki-67 (labeling index <41% vs. ≥41%), CA-9 (H-score: <15 vs. ≥15), and GLUT1 (H-score: <175 vs. ≥175) expression. OS, PFS, LC, and DMFS rates were calculated using the Kaplan-Meier method, and differences between groups were evaluated by the log-rank test. Notable clinical characteristics of the cohort included median age of 51 years (range: 32 to 74 y), FIGO stage IIB disease (57.2%), clinical node-negative disease (64.3%), squamous cell carcinoma (89.3%), and adenocarcinoma (10.7%). Treatment outcomes included 5-year OS (57.2%), PFS (48.1%), LC (72.1%), and DMFS (62.9%). For HIF1a H-score <95 and ≥95, the 5-year OS (52.0% and 68.4%, P=0.58), PFS (53.0% and 40.9%, P=0.75), LC (71.6% and 68.2%, P=0.92), and DMFS (59.7% and 52.0%, P=0.91) were not significantly different. For Ki-67 labeling index <41% and ≥41%, the 5-year OS (44.9% and 66.6%, P=0.35), PFS (38.9% and 55.4%, P=0.53), LC (57.7% and 85.7%, P=0.22), and DMFS (67.3% and 61.0%, P=0.94) were not significantly different. For CA-9 H-score <15 and ≥15, the 5-year OS (54.4% and 66.7%, P=0.39), PFS (57.3% and 40.0%, P=0.87), LC (70.0% and 70.0%, P=0.95), and DMFS (70.0% and 46.7%, P=0.94) were not significantly different. For GLUT1 H-score <175 and ≥175, the 5-year OS (43.6% and 43.6%, P=0.32), PFS (55.6% and 49.5%, P=0.72), LC (72.9% and 71.5%, P=0.97), and DMFS (62.5% and 59.6%, P=0.76) were not significantly different. For p53, H-score <15 and ≥15, the 5-year OS (62% and 53%), PFS (63% and 30.3%), LC (87.5% and 52%), and DMFS (79.6% and 41.6%). In this study population, HIF1a, Ki-67, CA-9, and GLUT1 expression did not predict treatment response or outcomes in locally advanced cervical cancer patients treated definitively with CRT. There was a nonstatistically significant trend towards worse outcomes with p53 expression.

OnCare Connect: A Text-Based Platform to Allow for Earlier Interventions to Decrease Toxicity Progression in Oncology Patients Receiving Chemoradiation

Patients undergoing combined chemotherapy and radiation therapy experience treatment-related toxicities and commonly have unplanned hospital visits as a result of these toxicities. Such unplanned hospital visits can lead to treatment delays and breaks, possibly compromising oncologic outcomes. A text-based platform, OnCare Connect, was used to target this clinical problem and propose a new approach to help manage cancer treatment-related toxicity. Fourteen Head & Neck and Lung cancer patients with locally advanced disease receiving concurrent chemoradiation treatment were enrolled onto OnCare Connect. Text messages were delivered using Way to Health, a HIPAA-compliant texting platform. Patients were enrolled onto OnCare Connect during their 6-7 weeks of treatment and had the option of continuing for 1 month after the end of treatment. Patients were texted at least 3 times each week for check-ins and were able to text in from 8am-8pm daily with questions. In this early phase, we explored the feasibility, safety, and acceptability of this novel technology, and used Fisher’s exact test to compare the CTCAEv4.0 toxicity outcomes of these 14 patients with matched control patients treated at our institution. From April-July 2019, 7 patients with lung cancer and 7 with head and neck cancer treated with concurrent chemoradiation were enrolled onto OnCare Connect. A total of 1,759 text messages were sent and received using Way to Health. OnCare Connect provided medical support 693 times across 867 text messages. The average time to respond to a patient-initiated text message was 3 minutes. A total of 413 treatment related symptoms were detected by OnCare Connect, of which 64 symptoms were detected prior to provider detection. These symptoms were detected an average of 4.5 days prior to first detection by a provider in clinic. Based on natural language processing, symptoms that were most frequently discussed with patients over text included fatigue, pain, nausea, diarrhea, and anorexia. Compared to 42 matched historical control patients, the 14 patients enrolled on OnCare Connect had fewer CTCAE grade 3+ toxicities (p<0.05). Patient enrolled on OnCare Connect had an average weight loss of 2.9lbs compared to 5.2 lbs. for historical control patients (p=0.12). The use of OnCare Connect resulted in fewer patient calls (p=0.08) and patient portal messages (0.04) during and after treatment completion. OnCare Connect connected, supported, and strengthened care at our institution. The patient-centered support texting platform that was created was able to detects symptoms earlier and creates pathways to support patients. OnCare Connect was additionally able to extend care capacity for care teams and provide quality and reliable care, resulting in fewer grade 3+ toxicities compared to matched control patients.

A 70-Gene Signature for Predicting Treatment Outcome in Advanced-Stage Cervical Cancer

Cervical cancer is the fourth most common cancer in women worldwide. The current approaches still have limitations in predicting the therapy outcome of each individual because of cancer heterogeneity. The goal of this study was to establish a gene expression signature that could help when choosing the right therapeutic method for the treatment of advanced-stage cervical cancer. The 666 patients were collected from four independent datasets. The 70-gene expression signature was established using univariate Cox proportional hazard regression analysis. The 70-gene signature was significantly different between low- and high-risk groups in the training dataset (p = 4.24e−6) and in the combined three validation datasets (p = 4.37e−3). Treatment of advanced-stage cancer patients in the high-risk group with molecular-targeted therapy combined with chemoradiotherapy yielded a better survival rate than with only chemoradiotherapy (p = 0.0746). However, treatment of the patients in the low-risk group with the combined therapy resulted in significantly lower survival (p = 0.00283). Functional classification of 70 genes revealed involvement of the angiogenesis pathway, specifically phosphatidylinositol 3-kinase signaling (p = 0.040), extracellular matrix organization (p = 0.0452), and cell adhesion (p = 0.011). The 70-gene signature could predict the prognosis and indicate an optimal therapeutic modality in molecular-targeted therapy or chemotherapy for advanced-stage cervical cancer.

Combining Systemic Therapy With Radiation: Head and Neck Cancer Treatments in an Era of Targeted Agents and Immunotherapy.

The addition of chemotherapy to radiation therapy (RT) has been established for decades to improve outcomes in patients with head and neck cancer (HNC). Concurrent chemoradiation increases both local control and overall survival but at the cost of significant toxicity, motivating extensive investigations to optimize the balance of clinical efficacy and adverse effects. This review discusses the rationale and seminal studies underlying the concurrent chemoradiation treatment paradigm in HNC, and describes attempts to better tailor systemic therapy beyond standard-of-care cisplatin, such as the use of alternate cytotoxic agents and nonstandard dosing regimens. Modern efforts to incorporate targeted therapies and immunotherapy are then summarized, particularly for patients unable to receive standard cytotoxic chemotherapy. Finally, mechanisms through which RT and systemic therapy cooperate to improve the therapeutic ratio are discussed, with a focus on the interaction between immunotherapy and RT, a rapidly emerging treatment paradigm. With increasing application of novel diagnostic and therapeutic approaches, determining the optimal concurrent systemic program to maximize RT efficacy will continue to evolve. Identification of patient- and tumor-specific factors will offer a unique opportunity to implement personalized oncologic care.

Abstract B05: Tumor evolution and oxidative stress in recurrent human papillomavirus-mediated oropharyngeal squamous cell carcinoma

Abstract Background: Human papillomavirus (HPV)-mediated head and neck squamous cell carcinomas (HPVmHNSCC) are more responsive to platinum-based concurrent chemoradiation treatment than non-HPVmHNSCC. Previously, our group demonstrated that recurrent HPVmHNSCC are genomically more characteristic of HPV-negative than non-recurrent HPVmHNSCC. Moreover, we observed a propensity for NFE2L2 hotspot mutations among HPVmHNSCC that recurred. Since NFE2L2 is a transcription factor regulating oxidative stress, we hypothesized that genes involved with the management of oxidative stress would be upregulated in recurrent HPVmHNSCC. Methods: We performed whole-exome sequencing (WES) and RNA-Seq on matched primary and metachronous HPVmHNSCC from the Universities of Pittsburgh (UPitt) and Washington (UW). Somatic nucleotide (SNVs) and copy number variants (CNVs) were quantified. Clonal evolution analyses were performed. Differential expression and gene set enrichment (GSEA) were quantified. Results: RNA-Seq was available for 10 tumor pairs and WES for 7/10. Consistent with prior WES data, KMT2D was the most frequently mutated gene. We found two unique NFE2L2 hotspot mutations in one paired set. The primary tumor had an NFE2L2H150Y mutation while the recurrent tumor had an NFE2L2E79K mutation. Metachronous tumors possessed significantly more deleterious somatic alterations in genes involved with regulation of oxidative stress and NFE2L2 networks compared to the primary tumors. Clonality analyses revealed a propensity for subclonal mutations in oxidative-stress related genes. RNA-Seq analysis revealed differential expression of genes involved in mitochondrial oxidative stress (MAP3K9) and oxidoreductase activity (CYP24A1, HEPHL1). Moreover, 6/8 enriched gene sets among the metachronous recurrent tumors by GSEA were involved with oxidative stress response, mitochondrial genes, and electron transport. Conclusions: Here, using WES and RNA-Seq of pairs of primary and metachronous HPVmHNSCC we identified increased expression of and somatic alterations in oxidative stress regulatory pathways in recurrent HPVmHNSCC that appear to occur later in tumor evolution. One possible explanation for this is that treatment selects for tumor clones that can withstand the oxidative environment induced by chemoradiation. Ultimately, understanding the role of oxidative stress response under therapy may be critical to mitigating recurrence and treating recurrences with a favorable genomic profile. Citation Format: Daniel Faden, Richard A. Harbison, Qing Zhang, Jeffrey Delrow, Umamaheswar Duvvuri. Tumor evolution and oxidative stress in recurrent human papillomavirus-mediated oropharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B05.

A Squamous Cell Gallbladder Carcinoma: A Case Report and Literature Review

: Squamous Cell (SQC) is rare type among gallbladder cancer (GBC) and it has very poor prognosis due to frequent local invasion and advanced stage at diagnosis. The clinical course and prognostic factors of them has not been known well until now. The aim of this report is to present an unresectable SQC-GBC case treated by concurrent chemo-radiation treatment (CCRT) and compare the results of treatment with previous reported case series. This is a case report of a 57 years old female patient, diagnosed as unresectable primary pure SQC of GBC with bile duct invasion and multiple liver and lymph node metastases. She underwent CCRT with best supportive care (BSC) including percutaneous and endoscopic drainage of malignant biliary obstruction, and partial response was achieved. However, patient was expired due to metastatic invasion of colon and uterus in 10 months after first diagnosis.

HSR20-086: Concurrent Chemoradiation Treatment Patterns for Stage III Non-Small Cell Lung Cancer in Veterans

HSR20-086: Concurrent Chemoradiation Treatment Patterns for Stage III Non-Small Cell Lung Cancer in Veterans

The Impact of High-Dose-Rate Brachytherapy: Measuring Clinical Outcomes in the Primary Treatment of Cervical Cancer

PurposeRadical concurrent chemoradiotherapy with combined external beam radiotherapy (EBRT) and brachytherapy is used to treat locally advanced cervical cancer. Our institution has transitioned to high-dose-rate (HDR) intracavitary brachytherapy (ICBT) from low-dose-rate (LDR) brachytherapy in 2008, and a review was conducted on the effect of this change on patient outcomes. Methods and MaterialsA single-arm retrospective chart review was performed on locally advanced (Fédération Internationale de Gynécologie et d’Obstétrique stage IB-IVA) patients with cervical cancer treated with combined external beam radiation therapy and HDR-ICBT with curative intent between 2008 and 2014. Clinical outcomes were evaluated, and multivariate analysis was performed to identify prognostic factors. ResultsOf the 76 patients selected, median age was 47.9 years and median follow-up was 5.2 years. Thirteen patients (17.1%) developed locoregional recurrence and 23 patients (30.3%) patients developed distant recurrence. Five-year progression-free survival and overall survival were 63.7% and 69.3%, respectively. A significant survival difference was found between stages (P < .001). Multivariate analysis found nodal involvement was strongly associated with poorer survival (P = .007). ConclusionsOur experience with the transition to HDR-ICBT as part of concurrent chemoradiotherapy in treatment of locally advanced cervical cancer resulted in acceptable long-term outcomes and toxicity to that of LDR brachytherapy. Potential further improvement of treatment outcomes for patients may be possible with image guided brachytherapy and the addition of effective systemic therapy.

A combined ANXA2-NDRG1-STAT1 gene signature predicts response to chemoradiotherapy in cervical cancer

BackgroundA better understanding of locally advanced cervical cancer (LACC) is mandatory for further improving the rates of disease control, since a significant proportion of patients still fail to respond or undergo relapse after concurrent chemoradiation treatment (CRT), and survival for these patients has generally remained poor.MethodsTo identify specific markers of CRT response, we compared pretreatment biopsies from LACC patients with pathological complete response (sensitive) with those from patients showing macroscopic residual tumor (resistant) after neoadjuvant CRT, using a proteomic approach integrated with gene expression profiling. The study of the underpinning mechanisms of chemoradiation response was carried out through in vitro models of cervical cancer.ResultsWe identified annexin A2 (ANXA2), N-myc downstream regulated gene 1 (NDRG1) and signal transducer and activator of transcription 1 (STAT1) as biomarkers of LACC patients’ responsiveness to CRT. The dataset collected through qPCR on these genes was used as training dataset to implement a Random Forest algorithm able to predict the response of new patients to this treatment. Mechanistic investigations demonstrated the key role of the identified genes in the balance between death and survival of tumor cells.ConclusionsOur results define a predictive gene signature that can help in cervical cancer patient stratification, thus providing a useful tool towards more personalized treatment modalities.