bluuebunny/crossref_metadata_2025 huggingface dataset:
ODALIE Study, a retrospective analysis of a real-life cohort of patients with de novo advanced high grade epithelial ovarian cancer treated with a first-line platinum- and taxane-based chemotherapy combined with bevacizumab.
Authors: Bétrian Sarah Lagarde , Penault Llorca Frederique , Pautier Patricia , Joly Florence , Ray-Coquard Isabelle Laure , Costaz Hélène , Sauterey Baptiste , Floquet Anne , De La Motte Rouge Thibault , Gourgou Sophie , Marchal Frédéric , Guillemet Cecile , Petit Thierry , Rouzier Roman , Simon Gaetane , Gladieff Laurence
Published: June 2022

e17577

Background: PARP inhibitors (PARPi) demonstrated improvement in progression-free survival (PFS) following a first line platinum-based chemotherapy including bevacizumab for HRD-positive advanced ovarian carcinoma (OC) patients (pts) (PAOLA-1 study). We aimed to describe real-world (rw) clinical outcomes in patients with de novo high grade epithelial advanced ovarian cancer (HGEOC) treated with a first-line platinum- and taxane-based chemotherapy combined with bevacizumab. Methods: Using the Epidemiological Strategy and Medical Economics (ESME) Ovarian Cancer (OC) Data Platform [NCT03275298], a French EHR-derived database centralizing deidentified data of consecutive patients diagnosed and/or treated in 18 French comprehensive cancer centers since 2011, we identified all patients with de novo FIGO stage III/IV HGEOC diagnosed between 01 October 2012 and 31 January 2017, with a documented response to a first-line platinum-based chemotherapy and a maintenance treatment with bevacizumab ( PAOLA-like control group population). Data cut-off was 06 August 2020. Endpoints (overall survival, PFS and time to subsequent treatment) were estimated using the Kaplan-Meier method. Subgroups were analysed according to the BRCA-derived status. Results: Of 10,263 OC cases in the ESME-OC cohort, 382 patients, with a median follow-up of 47.8 months (CI 95% 44.4-49.1), were analysed. Median age was 61 years (q1-q3: 56-68). 290 pts (75.9%) had a FIGO stage III, 361 pts (94.5%) had at least one surgery, 141 (39.1%) and 210 (58.5%) of them had a primary cytoreductive surgery and an interval surgery respectively. BRCA deleterious mutations were present in 72 pts (22.3%). Median progression free survival was 23.2 months (CI 95% 20.9-24.8) in overall population and 25.3 months (CI 95% 19.7-23.8) in BRCA mutated pts, comparable to the control arm of PAOLA-1 when considering the difference in the PFS definition (from first CT versus from randomization in PAOLA study). Estimated 24-months overall survival rate was 45.7% (95% CI: 40.7- 50.7) and 53.9% (95% CI: 42.4 - 65.5) in BRCA mutated pts. Conclusions: Analyses of our large real-world French ESME-OC cohort are powerful tools to confirm clinical outcomes in HGEOC pts. Our data confirmed the reproducibility of the results observed in randomized clinical trials for de novo HGEOC pts with a documented response to a first line with bevacizumab maintenance therapy.
Analytical evaluation of a commercial in-house homologous recombination deficiency (HRD) assay for patients with epithelial ovarian cancers and its concordance with a reference standard.
Authors: Ranghiero Alberto , Rappa Alessandra , Vacirca Davide , Colombo Nicoletta , Guerini Rocco Elena , Barberis Massimo
Published: June 2022

e17592

Background: Homologous recombination deficiency (HRD) is a common feature of epithelial ovarian cancers (EOCs) as approximately half of EOCs have molecular aberrations in homologous recombination repair (HRR) genes, including BRCA1/2 gene mutations. Poly ADP-ribose Polymerase inhibitors (PARPi) have reformed the management of BRCA1/2 mutant ovarian cancer patients and demonstrated activity also in tumor with HRD status. The evaluation of HRD together with BRCA1/2 gene alterations is nowadays critical to guide the therapy decision for all patients with EOC. Different methods to assessed HRD have been reported and different assays are being implemented in clinical practice. Here, we sought to evaluate the analytical validity of a commercial in house HRD assay as compared to a reference standard method. Methods: 59 consecutive case of EOCs were included in this study. DNA extracted from representative formalin-fixed paraffin-embedded (FFPE) tissue block of each case were subjected to next-generation sequencing (NGS) analysis of BRCA1/2 genes alterations and HRD status using the AmoyDx HRD Focus Panel (Amoy Diagnostics Ltd, Xiamen, Fujian, China). HRD status was assesses through AmoyDx Genomic Scar Score (GSS) considering the length, type and location of the genome-wide chromosomal copy number variation through SNP probes spread throughout the genome. Cases with a GSS > 50 were considered as HRD positive. For each case the same FFPE tissue block was sent to Myriad Genetic Laboratories for myChoice CDx testing as reference standard. Assay concordance was measured as positive (PPA), negative (NPA) and overall (OPA) percentage of agreement according to the different scores proposed by the manufacturers. Results: HRD status data were available for 52 (88.1%) and 56 (94.9%) samples considering in-house and reference standard assay, respectively, and 49 cases was available for concordance analyses. AmoyDx HRD Focus Panel identified 23/49 samples (46.9%) as HRD positive and 26 (53.1%) as HRD negative. The concordance of HRD status between AmoyDx HRD Focus Panel and myChoice CDx was 100% and 81,2% for positive (PPA) and negative (NPA) cases respectively, with an overall analytical concordance (OPA) of 87.8%. No discordance was seen in BRCA1/2 status between in-house and reference standard assay (OPA: 100%). Conclusions: The HRD status assessed by AmoyDx HRD Focus Panel is highly concordant with that obtained using the current standard reference method. Commercial in-house test may offer a cost-effective, reliable and robust alternative to the centralized assay for the evaluation of HRD status in patient with EOC.
The tumor immune microenvironment correlates with neoadjuvant chemotherapy response in high-grade serous ovarian cancer.
Authors: Zhu Lei , Cao Guangming , Hua Dingchao , Cui Lina , Zhao Xiaochen , Wang Shuzhen
Published: June 2022

e17605

Background: Platinum-based neoadjuvant chemotherapy (NACT) plus interval debulking surgery (IDS) and adjuvant chemotherapy has been an established alternative for advanced epithelial ovarian cancer (EOC). The chemotherapy response score (CRS) has been applied to assess the efficacy of NACT in high-grade serous ovarian cancer (HGSOC). The purpose of this study was to assess the effect of NACT on tumor immune microenvironment (TIME) of HGSOC, and the correlation between the TIME and CRS. Methods: All patients underwent NACT with IDS. Formalin-fixed paraffin-embedded tissue samples were collected from pretreatment biopsy specimens and the corresponding post-NACT surgical specimens. The densities and percentage of various cell populations within the TIME were analyzed by multiplex immunohistochemistry (3DMedcines Inc.), including specific tumor infiltrating lymphocytes (TILs) (CD8+T cell, FOXP3+CD4+Treg cell and CD20+B cell), tumor associated macrophages (TAMs), NK cells (CD56 dim and CD56 bright). Patients were divided into three groups according to CRS based on pathological reaction of surgical specimens: CRS1 shows no or minimal response, CRS2 shows moderate response and CRS3 usually shows complete or near-complete response. Statistical analyses were performed using GraphPad Prism 7.0. P < 0.05 was considered statistically significant. Results: A total of 25 HGSOC patients were enrolled in this study, 32% (8/25) of patients with CRS 1, 64% (16/25) with CRS 2, and 4% (1/25) with CRS 3. After NACT, patients with CRS 2 or 3 had a significant increase of the densities of CD20+B cells in stroma (pre-NACT 15.71/mm3 vs. post-NACT 87.82/mm3, p = 0.048). We also observed borderline significant increases of percentage of CD20+B cells, the densities and percentage of CD8+T cells in stroma after NACT (pre-NACT vs. post-NACT, 0.32% vs.1.54%, 56.35/mm3 vs. 311.35/mm3, 0.95% vs. 5.48%, respectively). Meanwhile, no significant change in CD4+T, TAMs and NK cells. In patients with CRS 1, we observed a significant increase of the densities and percentage of CD4+FOXP3+Treg in stroma (pre-NACT vs. post-NACT, 1.38/mm3 vs. 19.75/mm3, p = 0.01; 0.04% vs. 0.41%, p = 0.017, respectively), while CD8+T, CD20+B, TAMs and NK cells did not change significantly. Additionally, we found a significant difference in CD56 bright NK infiltration when comparing CRS 2 or 3 group with CRS1 group in post-NACT (0.5/mm3 vs.12/mm3, p = 0.049; 0.005% vs. 0.23%, p = 0.048). Conclusions: These data suggest immune infiltrate in TIME may serve as a biomarker to predict response to NACT in HGSOC. The infiltration of CD8+ T and CD20+ B cell was more pronounced in CRS2 or 3, while the enhanced infiltration of FOXP3+CD4+Treg cells is associated with immunosuppressive TIME and poor response (CRS1). The mechanism of lymphocyte regulation is not completely understood, thereby deserving further investigation.
Real-world outcomes and prognostic factors in uterine leiomyosarcom: A single center experience from India.
Authors: Palo Upasana , Roy Arunava , Ghosh Anik , Mondal Debapriya , Chakraborti Basumita , Bhaumik Jaydip
Published: June 2022

e17620

Background: Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignancy with dismal prognosis, often diagnosed incidentally after surgery for presumed benign disorders. There is a dearth of prospective data particularly in Indian women owing to its rarity. Published studies differ about prognostic factors, and the role of adjuvant treatment in uLMS. Methods: Prospectively maintained uterine cancer electronic database was used to include uLMS patients with adequate clinical information who underwent treatment between January 1, 2012 and December 31, 2021. Progression-free survival (PFS) and overall survival (OS) were calculated for the entire population, while recurrence-free survival (RFS) was calculated for the patients who had curative intent treatment. Various potential prognostic factors were tested using univariate and multivariate analysis. Results: Among 44 identified patients of uLMS, 32 women with sufficient information were included in the study. Majority of the patients had early stage disease at diagnosis including 19 (59.4%) patients with FIGO stage I tumors. Twenty three (71.9%) patients were diagnosed incidentally after surgery. Curative intent treatment was offered to 26 patients (81.3%) while 6 (18.7%) patients had palliative treatment. Median tumor size was 9 cm (interquartile range [IQR] 7-15), and the median mitotic count was 16 per 10 high power fields (hpf) (IQR, 12-25). Eleven patients (34.3%) received adjuvant chemotherapy while 15 patients (46.9%) remained on surveillance. After a median follow-up of 63.8 months, 22 patients (68.8%) had disease recurrence and 23 (71.9%) patients had died. Lung was the most common site (64.3%) of recurrence, followed by bone (18.8%), and abdominal cavity (12.5%). The median PFS and OS for the whole population were 20.7 months (95% confidence interval [CI] 13.7 - 27.7) and 28 months (95% CI 19.7 - 36.3) respectively. The 5-year PFS estimate was 20% while the 5-year survival probability was 25%. Stage specific 5-year OS probabilities for stage I, II, III, and IV were 45%, 40%, 20%, and 8% respectively. Patients who received adjuvant chemotherapy had longer RFS than those who were observed after primary surgery (median 59·9 months [95% CI 19.5–100.3] vs 20.5 months [95% CI 15.8-25.3]; hazard ratio [HR] 0·13 [95% CI 0.02-0.85; p = 0·03). Lower stage (FIGO stage I-II) (HR 0.15 [95% CI 0.03-0.67]; p = 0.013), and lower mitotic count (< 15/10 hpf) (HR 0.13 [95% CI 0.03-0.61]; p = 0.01) were independent prognostic factors associated with better survival. Conclusions: This 10-year experience of uLMS from an Indian tertiary care cancer center shows poor survival across stages with a high rate of recurrence. Only stage and mitotic count were found to be independent prognostic factors. The finding of RFS benefit with adjuvant chemotherapy warrants larger prospective studies to evaluate the role of adjuvant therapy in uLMS.
Squamous metaplasia in endometrial cancer changing local hormonal tumor profile.
Authors: Kornienko Svetlana V. , Frantsiyants Elena M. , Bandovkina Valeria A. , Moiseenko Tatiana I. , Adamyan Meri L. , Chernikova Natalia V. , Poryvaev Yuriy A. , Tumanyan Sergey V. , Maksimova Natalia A. , Boyko Konstantin P. , Gurnak Viktor V. , Arzamastseva M. A. , Egorova Anna S. , Verenikina Ekaterina V. , Ardzha Anna Yu , Kit Oleg I.
Published: June 2022

e17621

Background: An imbalance of sex hormones in endometrial cancer (EC) towards hyperestrogenism together with progesterone deficiency is considered to stimulate proliferation and suppress endometrial apoptosis. EC with squamous metaplasia is characterized by a more severe clinical course and the lack of an adequate response to standard treatment. The purpose of this study was to analyze the local hormonal profiles of tumors with squamous metaplasia in patients with obesity. Methods: The main group included 20 EC patients with squamous metaplasia, and control group included 35 patients with endometrioid adenocarcinoma: T1-3N0-1M0, mean age 64±3.2 years. Intact endometrial tissues were obtained during surgical treatment of patients with uterine fibroids (n = 20). All patients gave their written informed consent for the study. Levels of estradiol (E2), estrone (E1), testosterone (T), progesterone (P4), estrogen receptors ERα and ERβ, progesterone receptor RP4 and androgen receptors RA were measured by ELISA in samples of tumor and peritumoral (PT) tissues. Statistical processing of results was performed using the Statistica 10. Results: Tumor tissues of patients with EC, regardless of the histological structure, showed higher levels of estrogens and androgens and their receptors, compared with the intact endometrium, without significant changes in levels of progesterone and its receptor. In the main group, compared with the control group, E1 levels in tumors were lower by 1.6 times, E2 by 1.3 times (p < 0.05), but T higher by 2.4 times, ERα by 1.7 times, ERβ by 1.5 times (p < 0.05). PT, compared with the intact endometrium, had lower levels of E1 and E2 by 2 times and 1.5 times, P4 by 5.1 times, and T was lower only in PT with squamous metaplasia by 2.8 times. Levels of all steroid hormone receptors in PT were higher, regardless of the histological type of tumors. In PT of the main group, levels of E1 were 1.3 times lower (p < 0.05) than in controls, P4 – by 2.2 times, T – by 2.8 times, RP4 – by 1.7 times and ERβ by 1.8 times (p < 0.05), but ERα was 3.2 times higher. Conclusions: Tumors with squamous metaplasia, compared with endometrioid adenocarcinoma, are characterized by an imbalance of steroid hormones towards the predominance of androgens, and ERα plays a dominant role among estrogen receptors. The tumor probably synthesizes sex steroids independently and also pumps them over from the surrounding area. At the same time, malignant endometrial tumors, regardless of their histological structure, are more saturated with estrogens, androgens and their receptors, compared with the intact endometrium.
Adjuvant chemotherapy followed by adjuvant radiotherapy for treatment of high risk endometrial cancers: A retrospective review.
Authors: Kulkarni Anjali , Le Tien , Babadagli Ege , Samant Rajiv
Published: June 2022

e17626

Background: Endometrial cancer is the most common gynecologic malignancy in North America (1-3). Patients who are considered to be high risk for recurrence are commonly treated with a combination of adjuvant chemotherapy and radiation. However, the optimal sequence of these therapies has not been defined. The purpose of this study is to review our progression-free survival (PFS) outcomes and recurrence rates and compare to established outcomes in the literature. Methods: A retrospective chart review was performed on all patients diagnosed with endometrial cancer who received adjuvant chemotherapy and radiation between Jan. 1, 2005 to Dec. 31, 2017 at The Ottawa Hospital. Main inclusion criteria for the study were stage III endometrial cancers of any histology, stage I-II endometrial cancers with serous or clear cell histology and stage IV endometrioid adenocarcinomas of the endometrium. The primary outcome of interest is the overall progression-free survival (PFS), defined as the time from surgery to disease recurrence or death by any cause. Results: A total of 140 patients were included in the study. Of these, 52 (37.1%) had endometrioid histology, 75 (53.6%) had serous, and 11 (7.9%) had clear cell histology. Of the total sample, 41 (29.3%) were stage 1 at diagnosis, 24 (17.1%) were stage 2, 68 (48.6%) were stage 3 and 7 (5.0%) were stage 4. The median start time to chemotherapy was 49 days after initial surgery. 130 (92.9%) completed a total of 6 cycles of chemotherapy (majority treated with carboplatin and paclitaxel). 92% of the patients completed radiation following chemotherapy; majority received external beam radiation +/- a brachytherapy boost. Radiation was started withing 4-6 weeks of completing chemotherapy. 42 (30.0%) patients were diagnosed with a recurrence during the time of follow-up and 7 were diagnosed with progressive disease on treatment. Of the recurrences, 2 (4.8%) were local, 5 (11.9%) were locoregional, 8 (19.0%) were isolated para-aortic, and 27 (64.3%) were distant. The median follow-up time for our sample was 63.9 months. The median PFS and overall survival for our sample was not reached. The estimated mean 5 year PFS was 0.69 and OS was 0.66. Conclusions: Although radiation prevents locoregional recurrences, chemotherapy improves survival outcomes in locally advanced and aggressive histology endometrial cancer. Previous reported outcomes have been based on giving adjuvant radiation first, followed by chemotherapy (4,5). Our results demonstrate that giving adjuvant chemotherapy first and then delivering radiation after may be the optimal approach since it leads to survival outcomes that compare favourably with the published literature and very few locoregional relapses.
Real world evidence for use of NACT in locally advanced external auditory canal cancer.
Authors: Rai Rahul Kumar , Patil Vijay Maruti , Noronha Vanita , Menon Nandini Sharrel , Saha Saswata , Alone Mitali , Pai P. S. , Laskar Sarbani , Prabhash Kumar
Published: June 2022

e18000

Background: The management of very locally advanced external auditory canal cancers (LAEACC) is complicated, has a dismal prognosis and there is limited literature available for guidance. At our institute, we have offered neoadjuvant chemotherapy (NACT) to such patients. The objective of the current analysis was to study the outcomes and adverse events with this approach. Methods: We identified 16 patients with LAEACC over a period of 10 years (2010-2020) from the neoadjuvant chemotherapy (NACT) database of the Head and Neck department at our hospital. All patients were seen in a multidisciplinary clinic before and after NACT. Further local therapy was planned as per the response and ECOG PS of the patient. SPSS version 20 was used for analysis. Descriptive statistics were performed and Kaplan-Meier analysis was done to evaluate overall survival and progression-free survival. Results: Out of 16 patients enrolled in the study, 14 patients eventually received NACT. The median age was 59.5 years (27 - 83), the male to female ratio was 7:1 and the ECOG PS was 0-1 in 14 (87.5%) and PS 2 in rest. The regimen offered was a 2 drug regimen of taxane and platinum in 11 patients and a 3 drug regimen of TPF in (7.14%) patients. The median cycle received was 2. Post NACT 6 (42.85%) patients underwent surgery, 5 (35.71%) received radical CTRT and 3 (21.42%) patients received palliative treatment. The median progression-free survival was 1.67 years [95% CI (0.364 - 6.175)] while the median overall survival was 2.0 years [95% CI (0.455 - 6.175)]. Conclusions: Locally advanced EACC where upfront surgery is not feasible, NACT can be considered an option as patients receiving NACT have a 44.44% response rate and surgical resection rate of 42.8%.
Clinical utility of circulating tumor DNA in patients with head and neck cancers.
Authors: Onyshchenko Mykola , Rock Adam , Sila Chad , LaBarbera Katie , Rathore Richa , Ji Ping , McPhaul Laron
Published: June 2022

e18003

Background: Globally, head and neck cancers (HNCs) account for over 900,000 cases annually with a meager overall survival rate of 50%. While early-stage HNCs may be amenable to surgery, advanced disease is treated with systemic therapy or chemoradiation. For localized disease, chemo-radiation is often curative, but is associated with severe toxicity. Assessment of systemic treatment in the era of immunotherapy is often challenging due to the pseudoprogression phenomenon. In general, surveillance is limited to clinical follow-up and radiological imaging due to the lack of a sensitive and specific biomarker to assess treatment response and disease progression. Circulating tumor DNA (ctDNA) has shown promise as a reliable marker of disease activity in several solid tumors. In this study we evaluated the clinical utility of ctDNA for monitoring of therapeutic response and disease progression in patients with HNCs. Methods: ctDNA analysis was performed utilizing a personalized, tumor-informed ctDNA assay (Signatera™ bespoke mPCR NGS assay) in patients with advanced stage (III, IV) HNC who underwent chemoradiation or systemic therapy. ctDNA levels were measured at diagnosis, throughout treatment and during remission. The primary endpoint was correlation of ctDNA kinetics with radiological response. The secondary endpoint was the rate of ctDNA positivity during remission. Additional data collected included patient demographics and tumor clinicopathologic characteristics. Analysis was conducted using descriptive statistics. Results: ctDNA kinetics from 15 patients with squamous HNCs were analyzed. Due to insufficient time points, 5 five patients were excluded from this analysis. At diagnosis, 9/10 (90%) patients were ctDNA-positive, with baseline ctDNA levels ranging from 0.2 to 8500 mean tumor molecules (MTM)/mL of plasma. Patients received either chemoradiation (7/10) or (chemo)immunotherapy (3/10). Among patients who received chemoradiation, 4 out of 7 cleared ctDNA in less than 40 days, while 2 out of 7 had persistent ctDNA after 40 days. Those who showed ctDNA clearance had a continued response at 3-6 month follow-up both by ctDNA and by standard of care imaging. The 2 patients that did not clear ctDNA by day 40 ultimately relapsed on imaging and had rising ctDNA levels within 3 months of completion of chemoradiation. The patient who was ctDNA negative at baseline remained negative throughout the treatment and follow up. Of the patients who received chemo(immunotherapy), 2/3 cleared ctDNA after 2 cycles of therapy and continued to be in remission. The remaining patient who did not show ctDNA clearance became refractory to treatment. Conclusions: Our study demonstrates the feasibility of personalized and tumor-informed ctDNA in patients with advanced HNCs. Monitoring of ctDNA kinetics during therapy may enable prediction of therapeutic response and early disease progression to guide clinical decision-making.
Real-world time on treatment analysis of pembrolizumab treated recurrent/metastatic head & neck squamous cell carcinoma (R/M HNSCC) patients stratified by ECOG PS in the United States.
Authors: Black Christopher Matthew , Wang Liya , Ramakrishnan Karthik , Turzhitsky Vladimir
Published: June 2022

e18007

Background: There is limited evidence on the real-world use of pembrolizumab therapy post-approval in 1L R/M HNSCC. The study estimated real-world time on treatment (rwToT) of pembrolizumab monotherapy and pembrolizumab + platinum + 5FU for 1L R/M HNSCC patients, stratified by ECOG PS. Methods: This retrospective study of the nationwide de-identified electronic health record (EHR)-derived Flatiron Health Advanced H&N database selected patients initiating pembrolizumab monotherapy or pembrolizumab + platinum + 5FU between 07/01/19 - 12/31/20 with follow-up until 07/31/21. Patients with prior platinum-based therapy ≤6 months, prior primary cancers, or treatment with a clinical study drug were excluded. rwToT was defined as length of time between first and last documented administration date pembrolizumab. Patients with a record of next line of therapy, death, or treatment gap ≥120 days from the last administration date were considered discontinued. Patients without a discontinuation event were censored at the end of follow up. Kaplan-Meier analysis was conducted to assess median rwToT and landmark on-treatment rates. All results were stratified by ECOG PS 0-1 (similar to KEYNOTE-048, the registrational clinical trial) and ECOG PS 2-3. Results: A total of 402 patients initiated 1L treatment with pembrolizumab therapy. Of those patients, 297 (73.9%) had a recorded ECOG PS score, majority with an ECOG PS score of 0/1 (Overall: 77.8%, pembrolizumab monotherapy: 70.5%, pembrolizumab + platinum + 5-FU: 84.1%). The median rwToT was higher among the ECOG 0/1 patients compared to ECOG 2/3 patients for both regimens (pembrolizumab monotherapy: 4.4 vs 2.2 months, pembrolizumab + platinum + 5-FU: 5.0 vs 3.5 months). Conclusions: In the real-world, treatment duration with pembrolizumab monotherapy or pembrolizumab+platinum+5-FU in 1L R/M HNSCC was similar to KEYNOTE-048, when restricted to a trial-matched population of ECOG PS 0-1 patients. Treatment duration tended to be shorter in the real-world ECOG PS 2/3 population, who are commonly excluded from clinical trials.[Table: see text]
PEP503 (NBTXR3), a radioenhancer, in combination with concurrent chemoradiation (CCRT) in locally advanced or recurrent head and neck squamous cell carcinoma (HNSCC): Dose-finding of a phase 1b/2 trial.
Authors: Wang Cheng-Hsu , Chao K.S.Clifford , Chen Ping-Tsung , Yeh Kun-Yun , Chen Yen-Chao , Chen Yao-Liang , Yang Shih-Wei , Wu Tsung-Han , Chang Pei-Hung , Young Chi-Kuang , Tsan Din-Li , Tsai Ming-Hsui , Hsieh Ching-Yun , Chen Wen-Cheng , Tsai Yuan-Hsiung , Hsu Cheng-Ming , Chang John W. C. , Yu Wei-Che , Shen Bor-Nian
Published: June 2022

e18041

Background: PEP503 (aka NBTXR3), a novel radioenhancer composed of functionalized hafnium oxide nanoparticles, is designed for intratumoral injection to increase radiation energy deposition within solid tumors and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. PEP503 nanoparticles plus RT has been tested in elderly HNSCC patients and has demonstrated a good safety profile. The phase 1b part of the study aimed to test the feasibility and the recommended phase 2 dose (RP2D) of PEP503 intratumoral injection when added with low-dose (LD) weekly cisplatin-containing chemoradiation (CCRT) in HNSCC. Methods: Patients who had T3-4 locally advanced HNSCC suitable for CCRT were eligible. An intratumoral single injection of PEP503 was performed 24 to 72 hours before the start of CCRT: consisting of IMRT (70̃72 Gy, 2-2.12 Gy/fraction) and weekly cisplatin (low dose, 40 mg/m2) concurrently during IMRT. Traditional 3+3 design was planned for dose escalation and 5 levels of PEP503 were planned, including 5%, 10%, 15%, 22%, and 33% of the baseline GTV by MRI. PEP503 Intra-tumor dispersion was anayzed by CT-scan. Results: Twelve (12) patients (male/female: 11/1; oral cavity/oropharynx: 11/1) were enrolled, with 3, 6, and 3 patients at 5%, 10%, and 15% PEP503 dose levels, respectively, in combination with LD cisplatin CCRT. DLTs were observed in one patient at 10% dose level which were G3 ALT and G3 AST increased. Common G3 AEs observed across dose levels were stomatitis (50.0%), WBC decreased (33.3%), decreased appetite (16.7%), neutrophil count decreased (16.7%), and leukopenia (16.7%), and only one G4 AE (hyponatraemia) was observed. CT images demonstrated PEP503 within the tumor contour after injection throughout the CCRT period. Hafnium, for all patients, was either not detected or below the Lower Limit of Quantification (LLOQ) in the circulation 60 minutes after PEP503 intratumoral injection, and not found in urine. DCR was achieved in 100% of patients with responding patients for an ORR of 58.3%. No subjects received salvage surgery after study treatment. Study was terminated early before MTD and RP2D could be determined. Conclusions: Adding PEP503, a radioenhancer, via a single intratumoral injection to weekly cisplatin-containing CCRT was feasible and safe for patients with locally advanced or recurrent LA-HNSCC. RP2D was not reached due to study early termination. Clinical trial information: NCT02901483.
High-risk non-16 human papillomavirus genotypes in head and neck squamous cell carcinoma.
Authors: Wotman Michael , Ferrandino Rocco , Gold Brandon , Albstein Nicole , Alpert Naomi , Junn Jacqueline , Westra William , Posner Marshall R.
Published: June 2022

e18052

Background: Oropharyngeal cancer patients with Human Papillomavirus (HPV)-associated disease have more favorable outcomes. HPV16 is the primary genotype in this population. Our knowledge of the impact of high-risk non-16 HPV (HRN16) subtypes on survival is limited. The objective of this study is to investigate the incidence, demographics, and survival outcomes of HRN16 genotypes in patients with HPV-positive head and neck squamous cell carcinoma (HNSCC). Methods: This is a retrospective chart review of patients diagnosed with HPV+ HNSCC from 2012-2021 at the Mount Sinai Health System. Genotyping was performed with polymerase chain reaction (PCR). Demographic, clinical and tumor data was extracted from electronic medical records.The primary outcomes are overall survival (OS) and event-free survival (EFS) for patients with non-metastatic disease at presentation, treated with curative-intent, with > 6 months follow-up.Survival analysis was performed by Kaplan-Meier method. Results: 733 patients had HPV+ HNSCC, and 109 (14.9%) are HRN16 subtypes. Mean age at diagnosis is 62.4 years. Most individuals are non-Hispanic white males, non-active smokers, social drinkers, and have good performance status (Table). A majority has non-metastatic oropharyngeal cancer treated with standard of care (SOC) definitive therapy. The predominate genotypes are HPV35 (39.4%, n = 41), HPV33 (27.9%, n = 29), and HPV18 (14.4%, n = 15). Survival analysis demonstrated no significant differences in OS (log-rank p = 0.90) and EFS (log-rank p = 0.19) among the different HRN16 subtypes. There was a trend for better EFS for HPV35. Conclusions: HRN16 genotype may not meaningfully impact patient outcomes in HNSCC. Larger multivariate analyses may identify specific site and genotype differences in survival comparedwith HPV16-assoicated disease and indicate if patients with selected HRN16 subtypes are candidates for treatment de-escalation.[Table: see text]
Can immediate reconstruction with submandibular gland transposition broaden indications for transoral surgery for tonsillar cancer?
Authors: Robert Wang , Bigcas Jo-Lawrence , Okuyemi Oluwafunmilola , Yang Albert , Young Allen
Published: June 2022

e18054

Background: Stratification based on pathologic parameters allows for reduced adjuvant radiotherapy in intermediate risk and observation alone for low risk oropharyngeal p16+ cancer (E3311 ECOG-ACRIN trial). Selection for transoral surgery (TOS), usually robotically assisted, for tonsillar cancers depends on the size and invasiveness of the primary tumor, involvement of adjacent parts such as the soft palate, proximity to external carotid artery branches, medial ipsilateral carotid artery that might be exposed with radical resection, and the likelihood of substantial communication between the oropharynx and internal neck structures. Postoperative recovery can be associated with substantial pain and dysphagia and a length of stay of > 5 days. There is a paucity of simple options for sealing the neck from the pharynx to prevent neck infection, exposure of larger vessels and salivary fistula, so large and deep tonsillar cancers are usually given chemoradiation. Larger surgical defects healing secondarily tend to require longer recoveries due to dysphagia and odynophagia. Methods: A prospective study of vascularized ipsilateral submandibular gland transposition flaps to primarily repair the surgical defect after TOS to resect previously untreated tonsillar cancers was performed from 2019 to 2022. A total of 19 patients underwent resection and repair. These included those with cancers extending to the soft palate (4) and medial position of internal carotid artery adjacent to the tumor (1). All had obvious communication between the neck and the pharynx after TOS, and had branches of the facial and external carotid arteries to the deep resection site ligated with neck dissection, prior to TOS. The submandibular gland flaps were sewn in place using robot assistance and hand. One patient had an extended flap with accompanying submental skin to repair the soft palate. Results: Partial dehiscence superiorly at the palate was the most common complication at 11%. None developed salivary fistulas or deep neck infections. Iatrogenic facial artery pedicle injury that was repaired occurred in one case. Oral intake was started at 1-3 days and length of stay averaged 5 days. There were no bleeding episodes at the TOS sites of cancer resection. All resections had clear margins. All submandibular gland flaps survived, with one patient having attached adipose tissue debrided in the office, healing uneventfully thereafter. Conclusions: The ability to primarily repair after resection of more extensive tonsillar cancers, that leave large communications between the pharynx and the neck, with a readily accessible and easy to harvest submandibular gland flap may change those previously selected for chemoradiation to be able to have TOS instead as initial treatment. This would allow for more pathological risk assessment of tonsil cancers and decreased adjuvant treatment when appropriate.
Osteoradionecrosis in head and neck cancer patients: Risk factors and comparison of grading systems.
Authors: Lee Junhyung , El-Maghrabi Amr , Keshavarzi Sareh , Xu Wei , Huang Shao Hui , Waldron John , Kim John , Ringash Jolie , Hahn Ezra , Cho John , Bratman Scott Victor , Eng Lawson , de Almeida John R , Goldstein David Paul , Irish Jonathan Crawford , Chepeha Douglas Brian , Hope Andrew J. , Glogauer Michael , Watson Erin , Hosni Ali
Published: June 2022

e18057

Background: We aimed to identify the incidence and risk factors for osteoradionecrosis (ORN) in head and neck cancer (HNC) patients. We also compared frequency of severity scores across different ORN grading systems. Methods: Retrospective review was conducted for HNC patients who were managed at our institution (2011-2018) with curative-intent definitive, pre- or post-operative intensity-modulated radiation therapy (IMRT) with 45Gy, and underwent pre-IMRT dental evaluation. Jaw ORN was defined based on: 1) clinical signs (exposed bone, bone spicules, sequestra, infection and fistula), 2) radiological finding (abnormal bone pattern, radiographic sequestra and pathological fracture), and 3) treatment required and response to therapy, either conservative (chlorhexidine rinse, antibiotics, PENTOCLO, and hyperbaric oxygen) or surgical (sequestrectomy, debridement, and jaw resection). ORN events were retrospectively graded using 6 different grading systems. Pre-IMRT periodontal condition (PC) was classified by universal multi-dimensional staging system based on number of teeth and bone loss (stages 0 to IV). Multivariable analysis (MVA) using logistic regression was applied to identify risk factors of ORN. Results: A total of 2735 HNC patients were included; median age 61 years, 30% (n = 807) current/ex-smokers, 72% (n = 1914) had moderate to severe PC (stage II-IV), 53% (n = 1459) oral cavity/oropharynx (OC/OP) primary tumor. The median IMRT dose was 70Gy/35 fractions, 43% (n = 1170) received concurrent chemotherapy, and 37% (n = 1006) underwent surgery. A total of 227 patients (8.3%) developed ORN. There was discrepancy in different grading system for capturing and reporting the degree of severity (i.e. grade) of ORN (table). On MVA, risk factors for ORN were: current/ex-smoker (OR 1.5, 95% CI: 1.12-2, p< 0.01), stage II-IV PC (OR 1.7, 95% CI: 1.17-2.36, p< 0.01), primary OC/OP tumor (OR 4.4, 95% CI: 3.08-6.29, p< 0.001], and IMRT dose prescription ≥60Gy (OR 3.5, 95%CI: 1.11-11.33, p< 0.01). Conclusions: ORN is relatively uncommon in HNC patients, however it can be under-reported by different grading systems. Risk factors for ORN were: smoking history, pre-IMRT poor PC condition, OC/OP primary tumor, and higher dose (≥60Gy) IMRT.[Table: see text]
Changing patterns of second primary malignancies and cause-specific mortality among patients with major salivary glands cancers in the United States: A population-based study.
Authors: Chamarti Karthik , Bakhati Bibek , Rudraraju Vasudha , Mannem Maneesh , Rajput Maryam , Garza John , Bajaj Kelash
Published: June 2022

e18081

Background: Salivary gland neoplasms are rare entities that comprise approximately 5% of all head and neck malignancies. The incidence of major salivary gland (MSG) cancers has increased about 54% from 1970 to 2000 in the United States (US). We undertook this study to investigate the risk of second primary malignancies (SPMs) and cause-specific mortality (CSM) in patients with MSG cancers using a national registry from the US. Methods: We estimated the incidence of SPMs among two-month survivors of MSG cancers using the Surveillance, Epidemiology, and End Results (SEER)-18 registries between 2008 to 2018. The risk of SPMs were calculated using standardized incidence ratios (SIRs) and the CSM by standardized mortality ratios (SMRs) and absolute excess risk (AER)/10,000 population. Results: We included 845 patients with MSG cancers in this study. The median age of diagnosis was 67 yrs (range 0 - 85 yrs). The median follow-up duration was 24 months (range 0 - 130 months). The median latency period for SPM development was 30 months (range 4 - 117 months). A total of 38 (4.5%) patients developed 41 SPMs at last follow-up. The SPM risk for cohort was significantly elevated (SIR = 1.81, 95% confidence interval [CI] = 1.30 - 2.46) compared with general population. The SPM risk was statistically higher among males (SIR = 2.42, 95% CI = 1.66 - 3.42) but not significant in females (SIR = 0.95, 95% CI = 0.44 - 1.81). Specific sites with highest SPMs risk included tonsil (SIR = 52.45, 95% CI = 1.33 - 292.22) followed by oral cavity (SIR = 15.55, 95% CI = 7.11 - 29.52). The risk for tonsil cancers were high from 5 to 10 years of initial diagnosis. While risk for oral cavity cancers, remained high throughout follow-up period. At the last follow-up, 214 (25%) patients had died. There was statistically significant risk of mortality due to MSG cancers (SMR = 5,453.61, 95% CI = 4,385.34 - 6,703.41, AER = 517.87) and oral cavity cancers (SMR = 663.40, 95% CI = 537.97 - 809.29, AER = 557.41) (Table). Conclusions: Our study concludes that men with MSG cancers are at an increased risk for SPMs compared to women. The risk of specific SPMs (tonsil and oral cavity cancers) was high even after a long period from the initial diagnosis of MSG cancers. This highlights the need for long-term surveillance in these patients for SPMs development.[Table: see text]
Trends in early phase clinical trials: A tale of exponential economic growth and access.
Authors: Reddy Neha K. , Coleman Niamh , Subbiah Vivek
Published: June 2022

e18504

Background: There has been exponential economic growth in the BRIC (Brazil, Russia, India and China) nations in recent years, and outsourcing of clinical trials to these countries has occurred in tandem. Our study aimed to assess the current status of early phase oncology clinical trial recruitment in the BRIC countries, to assess the impact of these emerging economies and global markets in health care. Methods: We reviewed the open-access clinical trial registry, clinicaltrials.gov, for registered interventional recruiting early phase trials (Phase I/II) in the BRIC countries in adults and analyzed each country separately and collectively. We extracted descriptive data and established a database and proceeded to perform literature review and examine trends in early phase clinical trials. Results: We identified 888 recruiting early phase clinical trials in BRIC countries; China had 95% (842/888) of the trials, Brazil 1.5% (13/888), Russia 3.4% (30/888) and India 0.34% (3/888). For tumor specific studies, gastrointestinal (17%, 148/888), lung 11% (94/888) and breast (17%, 53/888) cancers were the most studied. Most trials were industry-sponsored (76%, 675/888); and most conducted in a single country (95%, 846). Industry-sponsored studies comprised 96% in China (635/842), 87% in Russia (26/30), 92% in Brazil (12/13), 67% (2/3) in India. Overall, immunotherapy agents in single and combination treatment strategies were the most common agent under investigation, with novel therapies such as CAR T-cell therapy (eg. CAR-T/TCR NK-CAR CAR-T/TCR-T Cell) being increasingly used in China (168 single agent trials, 30 trials in combination: 24% of trials in China). In contrast, CAR T-cell therapy trials were not yet in BRIC nations outside of China. Combination studies were frequent (33%, 293/888), and included a variety of combination strategies utilizing targeted therapies, immunotherapies, chemotherapies, antibody drug conjugates and novel biologics. Conclusions: Despite the economic explosion and shift of non-oncology clinical trials to BRIC nations, US and Europe continue to dominate in the design and conduct of early phase clinical trials in hematology and oncology. However, there has been exponential growth in early phase trial testing in China, which now accounts for 18.5% of the world’s population and has the majority (95%) of trials in BRIC nations. Contrastingly, India, which accounts for 17.7% of world’s population, has < 1% of BRIC nation trials. In keeping with trends in the US and Europe, there is a dominance of industry-sponsored studies in BRIC countries. Globally, early phase trials are increasing in their complexity with ongoing interest in immune modulation as a treatment strategy.
Disparities in endometrial cancer clinical trial participation.
Authors: Ko Emily Meichun , Alvarez Rafael , Heintz Jonathan , Simpkins Fiona , Smith Anna Jo Bodurtha
Published: June 2022

e18514

Background: Clinical trial participation may be a way to mitigate disparities in endometrial cancer. Our objective was to examine the association of clinical trial participation with patient, health system, and cancer factors in endometrial cancer. Methods: We conducted a retrospective cohort study of patients with endometrial cancer diagnosed from 2013-2021 using the nationwide de-identified electronic health record-derived Flatiron Health database. We used multi-level Poisson regression modeling to analyze the association of clinical trial participation (receipt of clinical trial drug) with patient, sociodemographic, health system, and cancer factors. Results: Of 4,662 patients with endometrial cancer, 3.9% (95% CI 3.3-4.5) were ever enrolled in a clinical drug trial. While Black patients accounted for 12% of endometrial cancers and 59% of high-risk histologies (MMT, serous, clear cell), only 3% were enrolled in clinical trials. Black patients were 57% less likely to enroll in a clinical trial (95%CI 0.26-0.72), and this disparity persisted in academic and community settings. Having a more aggressive cancer histology and living in the Southeast were associated with higher rates of clinical trial enrollment. Conclusions: Despite higher rates of aggressive cancer histologies, Black patients were disproportionately under-enrolled in endometrial cancer drug trials. Efforts to increase clinical trial diversity are needed.[Table: see text]
Using EHR data to compare survival disparities in major cancer types.
Authors: Cui Wanting , Finkelstein Joseph
Published: June 2022

e18517

Background: The aim of our study is to provide a comparative overview of survival disparities in 5 major cancer types: breast cancer, colorectal cancer, lung cancer, multiple myeloma and prostate cancer, within one health system in New York City. Using this approach, we aim at initial assessment of potential drivers of disparities in cancer survival, especially for those who deceased in a short amount of time after diagnosis. Methods: A limited dataset was generated from electronic medical records from Mount Sinai Health System for the five cancer types from January 2003 to November 2020. We extracted 2 subsets from the original dataset: patients who survived less than 1 year between diagnoses and death, and patients who have survived for over 5 years after diagnoses. We performed logistic regression to investigate the effect of demographical factors on patients’ duration of survival after cancer diagnosis. Results: There are 1280 patients who survived less than 1 year and 20,816 patients who survived over 5 years. Although there are less overall colorectal cancer and lung cancer diagnoses, there are significantly more patients who deceased within a short of period of time from these 2 cancers, comparing to the other 3 cancer types. Race was an important factor. There was significantly more proportions of black patients deceased in a short period of time than in a long time after diagnosis. Percentage of individuals with short survival in Blacks and Whites was respectively 41.4% and 22.2% for lung cancer, 9.8% and 7.1% for colorectal cancer, 2.9% and 0.7% for breast cancer, 6.8% and 4.0% for multiple myeloma, and 1.4% and 0.8% for prostate cancer. This disparity was observed in all five cancer types. When comparing within race, there were significantly higher proportions of black patients survived a short time than those survived a long time for all 5 cancer types. When comparing with other races, black patients who were diagnosed with lung cancer or breast cancer were more likely to be deceased in a short time after diagnosis compare to white patients. And Hispanic patients with lung cancer were also at risk of shorter survival length compared to white patients. Thus, promoting routine cancer screening is important in black and Hispanic communities. Conclusions: Logistic regression identified factors increasing likelihood of shorter survival that included older age, and being male, Black or Hispanic. We concluded that further analysis of broader spectrum of risk factors is warranted.