bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety assessment of niraparib individualized starting dose in patients with platinum-sensitive recurrent ovarian cancer: A randomized, double-blind, placebo-controlled, phase III NORA trial.
Authors: Wang Jing , Wu Xiaohua , Zhu Jianqing , Yin Rutie , Yang Jiaxin , Huang Qidan , Wu Lingying , Liu Ziling , Gao Yunong , Wang Danbo , Lou Ge , Yang Hongying , Zhou Qi , Kong Beihua , Huang Yi , Chen Lipai , Li Guiling , An Ruifang , Tan Tao , Dong Juan
Published: June 2021

5535

Background: To present the safety profile of niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (PSROC) included in the NORA trial. Methods: The double-blind, randomized, placebo-controlled, multicenter, phase III NORA trial (NCT03705156) included adult (≥18 years) Chinese women with PSROC who received ≥2 prior lines of platinum-based chemotherapy. Post ≤8 weeks of the last chemotherapy, patients were randomized (2:1) to receive oral niraparib (300 mg/day or 200 mg/day for patients with bodyweight <77 kg or platelet count <150 × 103/µL) or matched placebo. The primary endpoint was progression free survival, reported previously. Safety was assessed in terms of treatment emergent adverse events (TEAEs) related to hematologic toxicity (anemia/platelet count decreased and neutrophil count decreased) and non-hematologic toxicity (nausea/vomiting/constipation/insomnia/palpitations/hypertension). Adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The data cutoff was February 1, 2020. Results: Of 265 patients included, the first 16 patients were given oral niraparib or matched placebo at a fixed starting dose of 300mg while 249 patients received individualized starting dose of niraparib (n = 166) or matched placebo (n = 83) based on baseline bodyweight and platelet count. The incidence of any TEAEs and grade ≥3 TEAEs was 100% and 50.8%, respectively in niraparib group, while 95.5% and 19.3%, respectively in placebo. Incidence of all grades of hematologic toxicity, gastrointestinal adverse events (nausea, constipation and vomiting), insomnia, palpitation and hypertension were highest in the first month after treatment with a gradual decrease in the further months. The median time to onset of grade ≥3 anemia, decreased neutrophil count and decreased platelet count were 87, 28, and 22 days, respectively, in the niraparib group. In niraparib group, any TEAEs that lead to dose reduction was observed in 59.9% of patients. Only 2 (1.1%) patients discontinued the treatment due to platelet count decreased and no patients discontinued niraparib treatment due to anemia or neutrophil count decreased. Overall, only 4% of patients in the niraparib group and 5.7% in the placebo group discontinued the treatment due to TEAEs. Conclusions: The lower incidence of TEAEs and the discontinuation rates indicate improved safety profile of niraparib with individualized starting dose in PSROC. Clinical trial information: NCT03705156.
Trends in the incidence of endometrial cancer among young women in the United States, 2001 to 2017.
Authors: Guo Fangjian , Levine Lyuba , Berenson Abbey
Published: June 2021

5578

Background: Endometrial cancer at this time is predominantly being looked at as a disease of postmenopausal population. Increased obesity has been identified as an important risk factor for endometrial cancer. An overall increase incidence of endometrial hyperplasia and endometrial carcinoma in obese premenopausal women has been reported. A close examination of the relationship between trends in endometrial cancer incidence and obesity prevalence in young women will provide important information for prevention and early screening of the disease and its precursors. This study was to assess current trends in endometrial cancer incidence in women ages 20-29 and 30-39 years in relationship to obesity in the US. Methods: We used data on US adult women 20-39 years old from the National Program for Cancer Registries and Surveillance, Epidemiology, and End Results Incidence–U.S. Cancer Statistics 2001–2017 database. This database covered essentially all young female population between 2001 and 2017 in the US (Puerto Rico not included). Incidence was age adjusted to the 2020 U.S. standard population. We also examined the trends in obesity prevalence among females 18-34 years old using data from the National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999-2014. Results: There were 24,446 cases of endometrial cancer among young adult women aged 20-39 years during 2001-2017. Endometrial cancer incidence increased from 0.6 per 100,000 in 2001 to 1.2 per 100,000 in 2017 (APC 3.6, 95% CI 2.9-4.4) among young women 20-29 years old, and increased from 4.6 per 100,000 in 2001 to 7.5 per 100,000 in 2017 (APC 3.0, 95% CI 2.7-3.3) among women 30-39 years old. Obesity prevalence also increased significantly from 1988-2014 among females 18-34 years old. Incidence of endometrial cancer and obesity prevalence were both higher in Hispanics than in other racial/ethnic groups. Conclusions: The significant increasing incidence in endometrial cancer among young adult women is in accordance with the concurrent increasing prevalence in obesity in young girls and women in the US. This indicates that endometrial cancer screening might need to be considered at much earlier age among patients with abnormal bleeding and certain ethnic populations.
Computational features of TIL architecture are differentially prognostic of uterine cancer between African and Caucasian American women.
Authors: Azarianpour Esfahani Sepideh , Fu Pingfu , Mahdi Haider , Madabhushi Anant
Published: June 2021

5585

Background: Although the vast majority of endometrial cancer (EC) is early-stage and thus, curable by surgery, chemotherapy, and radiotherapy (with at least 85% 5-year OS), a fraction of them are aggressive neoplasms such as high-grade or deeply invasive lesions and thus exhibit poor prognosis. African American (AA) women are disproportionately affected by high-grade EC and have 80% higher mortality rate compared with Caucasian American (CA) women. In this work, we evaluated the prognostic ability of computational measurements of architecture of tumor-infiltrating lymphocytes (ArcTIL) from H&E slide images for EC. We also investigated the presence of morphologic differences in terms of ArcTIL features between AA and CA women and whether ArcTIL based population-specific models were more prognostic of OS in AA women compared to a population-agnostic model. Methods: The study included digitized H&E tissue slides from 445 post-surgery EC patients from TCGA, with further chemotherapy, or radiotherapy, including only the AA and CA patients, patients without reported race or from other populations were excluded. The dataset was divided into discovery (D1, n = 300), and a validation set (D2, n = 145), while ensuring population balance between two splits (D1(AA) = 65, D1(CA) = 235, D2(AA) = 37, D2(CA) = 108). A machine learning approach was employed to identify tumor regions, and tumor-associated stroma on the diagnostic slides and then used to automatically identify TILs within these compartments. Graph network theory based computational algorithms were used to capture 85 quantitative descriptors of the architectural patterns of intratumoral and stromal TILs. A multivariable Cox regression model (MCRM) was used to create population specific-prognostic models (MAA, MCA) and a population-agnostic model (MAA+CA)) to predict OS. All 3 models were evaluated on D2(AA), D2(CA), and D2. Results: MAA identified 4 prognostic features relating to interaction of TIL clusters with cancer nuclei in stromal compartment and was prognostic of OS on D2(AA) (see Table) but not prognostic in D2(CA) nor D2(AA+CA). MCA and MAA+CA identified respectively 7 and 6 prognostic features relating to interaction of TIL clusters with cancer nuclei (both in the epithelial and stromal regions) and were prognostic of OS on D2(CA) and D2, but not prognostic in D2(AA). Conclusions: Our findings suggest an important role of stromal TIL architecture in prognosticating OS in AA women with EC, while epithelial TIL features were more prognostic in CA women. These findings need to be validated in larger, multi-site validation sets.[Table: see text]
Association of the presence of estrogen and progesterone receptors in uterine carcinosarcoma with improved survival and increased immunogenicity.
Authors: Jones Nathaniel L. , Wu Sharon , Xiu Joanne , Rocconi Rodney Paul , Erickson Britt Kristina , Thaker Premal H. , Brown Jubilee , Herzog Thomas J. , Holloway Robert W. , Korn Wolfgang Michael , Powell Matthew A. , Wilhite Annelise M.
Published: June 2021

5588

Background: Recent data has shed light on molecular profiles of uterine carcinosarcoma (UCS), but few have correlated molecular profiles with prognosis. In a preliminary data analysis, we found that hormone receptors (HR)—estrogen receptor (ER) and progesterone receptor (PR)—expression was associated with improved OS. Here, we investigate the molecular profile differences between ER+/- and PR +/- tumors. Methods: Tumor samples were analyzed using Next-Generation sequencing of DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) at the Caris Life Sciences Laboratory (Phoenix, AZ).ER and PR tested by IHC on whole tumor (cut-off: +1, 10%). PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC an NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined cohorts. Statistical significance was determined by chi-square and Wilcoxon rank sum test and p-values adjusted for multiple comparisons (q) to be <0.05. Results: 1,144 UCS tumors were included. (ER+, n=261; PR+, n=197; HR+ (ER+ and PR+), n=168). Median OS for patients with hormone receptor (HR)+ tumors was significantly longer than for patients with HR- tumors (months: 34.8 vs 17.4; HR(95% CI): 0.67 (0.53-0.84), p<0.01). This remained significant for ER (29.4 vs 17.3) and PR (25.3 vs 18.7) individually. ER+ tumors had fewer alterations in the TP53 pathway (71.4% vs 82.1%) in the WNT (19.5% vs 5.8%) pathway than ER- tumors (q<0.05). PR+ tumors had similar findings in the TP53 and WNT pathways, and also more alterations in the DNA damage sensor pathway. Both ER+ and PR+ UCS tumors had significantly increased MSI-H (ER: 10.9% vs 5.5%, PR: 12.9% vs 5.5%) and TMB-H (ER: 16.8% vs 6.0%; PR: 19.5% vs 6.1%) (all q<0.05) compared to ER- and PR- tumors. They also had increased T-reg cells in their immune micro-environment and increased expression of the immune checkpoint gene IDO1 (q<0.05; Table). Conclusions: HR+ tumors have distinct molecular profiles from HR- tumors. ER+ and PR+ UCS tumors appear more immunogenic with more frequent MSI-H status, TMB-H, increased infiltrating regulatory T-cells and IDO1 expression, suggesting possible benefit with immune-oncology (IO) therapy. This may contribute to the observed improved OS, but more data are needed to determine if HR status is a marker of response to IO therapy.[Table: see text]
Adding carbon nanoparticles to dual-tracers for the sentinel node evaluation after neoadjuvant chemotherapy in patients with pretreatment node-positive breast cancers: The TT-SLNB trial.
Authors: Chen Jie , Yang Jiqiao , He Tao , Wu Yunhao , Jiang Xian , Fu Zhoukai , Lv Qing , Lu Shan , Wang Xiaodong , Li Hongjiang , Wang Jing
Published: June 2021

566

Background: This study measures the feasibility and accuracy of sentinel lymph node biopsy (SLNB) with triple-tracers (TT-SLNB) which combines carbon nanoparticles (CNS) with dual tracers of radioisotope and blue dye, hoping to achieve an optimized method of SLNB after neoadjuvant chemotherapy (NAC) in ycN0 breast cancer patients with pretreatment positive axillary lymph nodes. Methods: Clinically node-negative invasive breast cancer patients with pre-NAC positive axillary lymph nodes who received surgeries from November 2020 to January 2021 were included. CNS was injected at the peritumoral site the day before surgery. Standard dual-tracer (SD)-SLNs were defined as blue-colored and/or hot nodes, and TT-SLNs were defined as lymph nodes detected by any of hot, blue-stained, black-stained, and/or palpated SLNs. All patients received subsequent axillary lymph node dissection. Detection rate (DR), false-negative rate (FNR), negative predictive value (NPV) and accuracy of SLNB were calculated. Results: Seventy-six of 121 (62.8%) breast cancer patients converted to cN0 after NAC and received TT-SLNB. After NAC, 28.95% (22/76) achieved overall (breast and axilla) pCR. The DR was 94.74% (72/76), 88.16% (67/76) and 96.05% (73/76) for SLNB with single-tracer of CNS (CNS-SLNB), SD-SLNB, and TT-SLNB, respectively. The FNR was 22.86% (8/35) for CNS-SLNB and 10% (3/30) for SD-SLNB. The FNR of TT-SLNB was 5.71% (2/35), which was significantly lower than those of CNS-SLNB and SD-SLNB. The NPV and accuracy was 95.0% and 97.3% for TT-SLNB, respectively. Moreover, a significant relation was seen between the pretreatment clinical T classification and the DR of TT-SLNB (Fisher’s exact test, p= 0.010). Conclusions: TT-SLNB revealed ideal performance in post-NAC ycN0 patients with pretreatment node-positive breast cancers. The application of TT-SLNB reached a better balance between more accurate axillary evaluation and less intervention. Clinical trial information: ChiCTR2000039814. [Table: see text]
A phase II trial cohort of nivolumab plus ipilimumab in patients (Pts) with recurrent/metastatic salivary gland cancers (R/M SGCs).
Authors: Burman Bharat , Sherman Eric Jeffrey , Dunn Lara , Fetten James Vincent , Michel Loren S. , Morris Luc G.T. , Ostrovnaya Irina , Haque Sofia , Pfister David G. , Ho Alan Loh
Published: June 2021

6002

Background: R/M SGCs are a diverse group of malignant neoplasms arising from the major or minor salivary glands and have no standard treatment. The impact of combining PD-1/CTLA-4 checkpoint blockade in R/M SGCs is unknown. Methods: In a Simon's two-stage minimax phase II trial, pts with progressive R/M SGCs (any histology except adenoid cystic carcinoma (ACC)) were enrolled and treated with nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (1 cycle = 6 weeks). Imaging, using RECIST v1.1 response assessment, was scheduled to be performed approximately every 12 weeks. The primary endpoint was best overall response (BOR = complete response [CR]+partial response [PR]) per RECIST v1.1. To detect a difference between an unacceptable BOR of 5% and a desirable BOR of 20% (one-sided type I error of 10%, power of 90%), at least 1 in the first 18 pts required an observed response. At least 4 responses of 32 total pts were needed to meet the primary endpoint. Treatment beyond progression of disease (PD) was allowed at the discretion of the investigator. A second cohort of pts with ACC was analyzed and reported separately. Results: From 7/25/2017-7/16/2020, 32 pts were enrolled and evaluable for the primary endpoint. There was 3 confirmed PRs in the first 18 pts, therefore enrollment of the second stage continued. BOR rate was 16% (5/32). Seven pts never reached a first disease assessment and were classified as non-responders: 5 due to clinical PD, 1 due to toxicity, and 1 pt withdrew. Four pts discontinued the trial for toxicities: pancytopenia (1), blurry vision (1), cardiomyopathy/hyperglycemia (1), and neutropenic sepsis (1), and mucositis (1). The 5 confirmed responders had regressions ranging from -66% to -100% in target lesions, with a duration of therapy ranging from 15.7 to 29.5 months (treatment ongoing for one as of 2/6/20). Conclusions: This cohort met its primary endpoint, and the responses observed were dramatic and durable. Paired biopsy and peripheral blood samples will be analyzed to elucidate insights into mechanisms of response and resistance to dual checkpoint blockade. Clinical trial information: NCT03172624.
Adjuvant capecitabine in locoregionally advanced nasopharyngeal carcinoma: A multicenter randomized controlled phase III trial.
Authors: Miao Jingjing , Wang Lin , Tan Sze Huey , Li Jin-Gao , Yi Junlin , Zhang Ye , Gong Xiaochang , Yanqun Xiang , Chen Qiu-Yan , Chen Mingyuan , Lv Xing , Xia Weixiong , Tang Lin-Quan , Deng Xiao-Wu , Guo Xiang , Mai Hai-Qiang , Han Fei , Chua Melvin Lee Kiang , Zhao Chong
Published: June 2021

6005

Background: We conducted a multicenter, randomized controlled phase III clinical trial (NCT02143388) to investigate the efficacy and toxicity of adjuvant capecitabine (AC) in addition to concurrent cisplatin and radiotherapy (CCRT) compared to CCRT alone in high-risk locoregionally advanced nasopharyngeal carcinoma (LANPC) patients. Methods: Eligibility criteria included AJCC/UICC 7th ed TNM stage III-IVb and one of the following features: T3-4N2 or T1-4N3 or pre-treatment plasma EBV DNA concentration of >20,000 copy/ml or gross primary tumor volume (GTVnx) of >30 cm3 or a maximum standard uptake value (SUVmax) of >10.0 by 18FDG PET-CT within the primary tumor or multiple neck node metastases, with any larger than 4 cm. All patients were randomly assigned in a 1:1 ratio to receive CCRT (3-weekly cisplatin at 100 mg/m2 for 2-3 cycles) followed by AC (1000 mg/m2 bi-daily for 14 days every 21-day cycle for 8 cycles), or CCRT alone. The prescribed radiation doses were 68-72 Gy/30-32 fractions to the PTVnx, 60-68 Gy/30-32 fractions to PTVnd, 60-64Gy/30-32 fractions to PTVhigh-risk, 54-58Gy/30-32 fractions to PTVlow-risk. Primary end point was failure-free survival (FFS). Results: Between Mar 2014 to Jul 2018, 180 patients were recruited (90 patients in CCRT+AC arm and 90 in CCRT alone arm). All patients completed RT and ≥2 cycles of concurrent cisplatin in both treatment arms (cumulative dose intensities for cisplatin were 200 mg/m2 in both arms). 85 (94.4%) patients went on to receive AC, with 71 (78.9%) patients completing 8 cycles; 19 (22.4%) patients had dose reduction of AC. With a median follow-up of 44.8 mo, the 3-y FFS was significantly superior in the CCRT+AC arm than the CCRT arm for the intention-to-treat cohort (87.7% vs 73.3%; HR: 0.52 [95% CI: 0.29-0.77], P = 0.037). 3-year overall, distant metastasis-free and locoregional relapse-free survival were 92.6% vs 88.9% (HR [95% CI]: 0.66 [0.28-1.59]), 88.8% vs. 81.1% (HR: 0.67 [0.33-1.33]) and 91.5% vs 80.0% (HR: 0.50 [0.25-1.00]), respectively. Incidences of G3-4 acute toxicities were 57.8% (52 of 90) in CCRT+AC arm and 51.1% (46 of 90) in CCRT alone arm, with a higher incidence of hand foot syndrome (3.5% vs 0%), xerostomia (11.1% vs 3.3%), mucositis (23.3% vs 16.7%), and anemia (5.6% vs 2.2%) in the CCRT+AC arm. G3-4 late toxicities occurred in 13.3% (12 of 90) and 9.0% (8 of 89), respectively. Conclusions: The addition of capecitabine to CCRT conferred a superior disease control than CCRT alone in high-risk LANPC. Survivals in ITT and PP set. Clinical trial information: NCT02143388. [Table: see text]
Enhanced pathologic tumor response with two cycles of neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC).
Authors: Uppaluri Ravindra , Chernock Rebecca , Mansour Mena , Jackson Ryan , Rich Jason , Pipkorn Patrik , Paniello Randal C , Puram Sidharth , Zevallos Jose P. , Annino Donald J. , Goguen Laura A. , Morris Luc , Haddad Robert I. , Hanna Glenn J. , Oppelt Peter John , Dunn Lara , Ley Jessica C. , Kallogjeri Dorina , Egloff Ann Marie , Adkins Douglas
Published: June 2021

6008

Background: We reported that one cycle of neoadjuvant pembrolizumab induced pathologic tumor response in >10% (pTR-any) and in >50% (pTR-2) of the resection bed in 44% and 22% of patients (pts) with surgically resectable HPV-negative, Stage III/IV HNSCC ( Clin Cancer Res 2020). We hypothesized that two cycles of neoadjuvant pembrolizumab would induce pTR-2 in 50% of pts. Increasing the pathologic response rate may favorably impact clinical outcomes. Methods: Multi-institutional phase 2 trial where pts with locally advanced, HPV-negative HNSCC received two cycles of pembrolizumab (200 mg), given 42 and 21 days prior to surgery. Resected tumor was analyzed by two independent pathologists for pTR (tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris) in the resection bed (primary tumor and/or lymph nodes). Additional definitions: pTR-1 (>10-49%) and major pathologic response ( > 90%). The primary endpoint was pTR-2. A sample size of 26 pts was needed to detect a significantly higher pTR-2 rate of 50%, with 80% power using a one-sided alpha level of 0.05. Pts were followed for serious adverse events (AEs) for 30 days after surgery and for AEs of clinical interest for 90 days following the last dose of pembrolizumab. Pts underwent baseline blood collection and tumor biopsies to match with blood and surgical specimens obtained post-pembrolizumab. Planned correlatives included PD-L1 expression, immune function, and molecular signatures of activation in the pre- and post-treatment blood and tumor tissue. Results: Characteristics of 29 enrolled and treated pts were median age 62 (30-82) yrs, smoking history 62% (18 pts); clinical stage T2 (n = 6), T3 (n = 5), T4 (n = 18) and N0/1 (n = 17), N2 (n = 12). All treated patients received two cycles of neoadjuvant pembrolizumab, which was tolerated well with only one (3%) grade 3 AE (rash) and no grade 4 AEs. The primary endpoint was evaluable in 25 pts, and not evaluable in 4 pts (one pt withdrew before surgery and in three pts, pTR review was pending). pTR-2 occurred in 44% (11 of 25 pts), and 4 (16%) of these pts had a major pathologic response including 1 (4%) pathologic CR at the primary site. Conclusions: Two (vs one) cycles of neoadjuvant pembrolizumab resulted in a two-fold increase in the frequency of pTR-2 (44% vs 22%). These data imply that the frequency of pTR to neoadjuvant pembrolizumab can be improved by increasing the number of cycles and the treatment interval. Clinical trial information: NCT02296684.
A randomized phase II trial of diffusion-weighted MR imaging-guided radiotherapy plus chemotherapy versus standard chemoradiotherapy in locoregional advanced nasopharyngeal carcinoma.
Authors: Liu Feng , Fu Shengnan , Chen Yanzhu , Yan Ouying , He Lili , Jiang Cuihong , Wu Xiangwei , Han Yaqian , Wang Hui
Published: June 2021

6018

Background: We hypothesized that diffusion-weighted MR imaging (DWI) guided dose-painting radiotherapy (DP-RT) was associated with improved tumor control and survival compared with standard CT-based radiotherapy in locoregionally advanced nasopharyngeal carcinoma (NPC). The purpose of this randomized phase II trial was to compare the efficacy and toxicity of DWI guided DP-RT plus chemotherapy versus standard CT-based radiotherapy plus chemotherapy in locoregionally advanced NPC. Methods: Two hundred and fifty-six patients with stage III-IVa (8th AJCC) NPC were randomly assigned to receive DWI-guided dose-painting radiotherapy plus chemotherapy (DP-RT group, n = 128) or standard CT-based radiotherapy plus chemotherapy (CT-based RT group, n = 128). Patients in both groups received 3 cycles of induction chemotherapy followed by cisplatin-based concurrent chemoradiotherapy. In DP-RT group, subvolume GTVnx-DWI (gross tumor volume of nasopharynx in DWI) was defined as the areas within the GTVnx (gross tumor volume of nasopharynx) with an apparent diffusion coefficient (ADC) below the mean ADC (ADC < mean). The dose to GTVnx-DWI was escalated to DT 75.2 Gy/32 Fx in patients with T1-2 disease, and DT 77.55 Gy/33 Fx in those with T3-4 disease, in 2.35 Gy per fraction. In CT-based RT group (n = 128), PGTVnx was irradiated at DT 70.4-72.6 Gy/32-33 Fx in 2.2 Gy per fraction. This trial is registered with chictr.org.cn, number ChiCTR1800015779. Results: Compared with standard CT-based radiotherapy, DWI-guided DP-RT significantly improved 2-year local recurrence-free survival (LRFS, 100% vs. 95.4%; P = 0.024), distant metastasis-free survival (DMFS, 97.9% vs. 90.6%; P = 0.006), disease free survival (DFS, 93.2% vs. 86.8%; P = 0.021), and overall survival (OS, 100% vs. 95.2%; P = 0.038). No statistically significant differences in acute and late toxic effects were observed. Multivariate analysis showed that dose painting (DWI-guided DP-RT vs CT-based RT without DP) was a significant independent prognostic factor for DMFS and DFS (P = 0.021 and P = 0.020, respectively). Conclusions: Diffusion-weighted MR imaging guided dose-painting radiotherapy plus chemotherapy is associated with a considerable survival benefit, without increasing toxicity, as compared with standard CT-based radiotherapy plus chemotherapy, among patients with locoregionally advanced nasopharyngeal carcinoma. Clinical trial information: ChiCTR1800015779.
A phase 2 study of liposomal irinotecan with 5-fluorouracil and leucovorin in squamous cell carcinoma of head and neck or esophagus after prior platinum-based chemotherapy or chemoradiotherapy.
Authors: Bai Li-Yuan , Yang Muh-Hwa , Chiang Nai-Jung , Wu Shang-Yin , Lin Chen-Yuan , Lien Ming-Yu , Chen Jia-Hong , Chang Mu-Hsin , Hsieh Ching-Yun , Hong Ruey-Long , Kao Hsiang-fong , Ye Ren-Hua , Chen Shang-Hung , Hsiao Chin-Fu , Chen Li-Tzong , Liu Tsang-Wu
Published: June 2021

6025

Background: Liposomal irinotecan (nal-IRI) + 5-FU/LV has been approved and used in treating patients with metastatic pancreatic cancer after gemcitabine-based therapy through the NAPOLI-1 study result. This phase 2 trial evaluated the activity of NAPOLI-1 regimen in patients with squamous cell carcinoma (SCC) of head and neck (H&N) or esophagus that progressed on or recur after platinum-based chemotherapy or concurrent chemoradiotherapy. Methods: Patients with histologically confirmed SCC of H&N or esophagus whose disease progressed while on or progressed/recurred within 6 months after platinum-based chemotherapy or chemoradiotherapy, and unsuitable for further surgical or radiation intervention were eligible. Prior anti-EGFR or anti-PD1/anti-PDL1 treatment was allowed. The regimen consisted of nal-IRI 70 mg/m2 (irinotecan free base) followed by LV 400 mg/m2 and 5-FU 2400 mg/m2, every 2 weeks. A Simon’s 2-stage design was used with planned 30 evaluable patients in the first stage and 52 evaluable patients in total. The primary endpoint is objective tumor response. Results: From December 2018 to April 2020, 59 subjects were enrolled, including 16 with esophagus cancer and 43 with H&N cancer. Thirty-seven (63%) patients had metastatic disease at enrollment. The mean of treatment cycles were 5 (range, 1-21). Among the total 59 enrolled subjects, 53 subjects (14 esophagus cancer, 39 H&N cancer) were evaluable for objective tumor response. The disease control rate in esophagus cancer was 50% (7 SD, intent-to-treat (ITT) population 43.8%). For H&N patients, 1 CR, 4 PR, and 23 SD resulted in the response rate 12.8% (11.6% in ITT population) and disease control rate 72% (65% in ITT population). The median progression free survival (N = 59) was 2.5 months (esophagus/H&N: 1.5/2.7 months) and the median overall survival was 5.9 months (esophagus/H&N: 4.2/7.3 months). Seventy-eight percent of patients had ≥grade 3 treatment-related adverse events. The most frequent ≥grade 3 toxicities were decreased lymphocyte count (50.8%), decreased neutrophil count (42.4%), and decreased white blood count (33.9%). Only 3 patients (5%) had grade 3 diarrhea during the treatment period. Conclusions: This study showed the modest efficacy and manageable toxicity profile of nal-IRI+5-FU/LV in platinum-refractory locally advanced or metastatic H&N or esophagus cancer patients. Clinical benefits including complete tumor response were noted in H&N patients. The role of this regimen in selective patients and the efficacy of combination with immunotherapeutic agents warrant further explorations. Clinical trial information: NCT03712397.
Preliminary results of the efficacy and safety of all-trans retinoic acid combined with low-dose apatinib in the treatment of patients with recurrent/metastatic adenoid cystic carcinoma of the head and neck.
Authors: Ye Lulu , Zhang Lin , Li Rongrong , Zhu Guopei
Published: June 2021

6026

Background: There is no standard treatment for recurrent/metastatic adenoid cystic carcinoma of the head and neck (R/M ACCHN). Moreover, MYB and/or NOTCH1 mutation can lead to worse prognosis. Currently, anti-angiogenic targeted therapy is a relatively effective treatment option, but the accompanied toxicities may hinder the continuous medication. All-trans retinoic acid (ATRA) induces differentiation and promotes apoptosis, enhancing the cytotoxicity of anti-tumor agents; on the other hand, inhibits c-MYB and/or NOTCH1 expression. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor 2. We reported the preliminary results of the efficacy and safety of ATRA combined with low-dose apatinib in patients with R/M ACC. Methods: In this exploratory study, patients with pathologically or histologically confirmed advanced, R/M ACC with measurable disease were screened. Patients who previously received anti-angiogenic therapy then withdrew due to toxicities could be recruited. ATRA was administered orally at a dose of 20 mg twice a day, and apatinib was administered orally at a dose of 250 mg once a day. The primary endpoint was objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors v1.1. Results: Between March 2019 and April 2020, a total of 16 patients were enrolled. The median age was 53 years (range: 35-69), and 7 (44%) patients were male. Four (25%) patients received ATRA plus apatinib as the third-line therapy, while 12 (75%) received as the second-line therapy. Of 16 patients, 3 (19%) achieved partial response and 13 (81%) achieved stable disease (SD), with ORR of 19% and disease control rate of 100%, respectively. Among patients with SD, 12 (75%) showed tumor shrinkage (3%-28%) and 1 (6%) showed minor tumor enlargement (2%). The median follow-up time was 14.5 months (range: 8.1-22.1). Throughout the period, 5 (42%) patients developed disease progression. The 6-month and 12-month progression-free survival rates were 100% and 80%, respectively. Grade 3 adverse events included hand-foot syndrome (1 [6%]) and proteinuria (1 [6%]). No grade ≥4 adverse events occurred. Conclusions: ATRA combined with low-dose anti-angiogenic drug apatinib could be a potential treatment option for patients with R/M ACC, including those with pretreated advanced ACC after progression on or intolerance to other therapies. These encouraging results were worth further investigations, and a randomized phase 2 trial in ongoing (the Aplus study, NCT04433169).
Interim analysis of IMMUNEBOOST-HPV: A multicenter, randomized, open label, phase II study evaluating the feasibility, and tolerance of neoadjuvant nivolumab in high-risk HPV driven oropharynx cancer.
Authors: Mirghani Haitham , Even Caroline , Larive Alicia , Fayette Jerome , Benezery Karen , Clatot Florian , Geoffrois Lionnel , Tao Yungan , Nguyen France , Fabiano Emmanuelle , Kreps Sarah , Neidhardt Eve Marie , Garic Florence , Auperin Anne , Blanchard Pierre
Published: June 2021

6037

Background: Among HPV-positive Oropharyngeal Cancer (OPC) patients (pts), some has a less favorable prognosis (T4, N2/N3, smokers >10 pack-year [p/y]). We assume that neoadjuvant immunotherapy might improve their oncological outcomes, so we tested nivolumab (N) prior to ChemoRadiaTion (CRT). Methods: The study population is restricted to HPV positive OPC pts (both p16+ & HPV-DNA+) with advanced disease (T4, N2/N3) or a smoking history >10 p/y. Pts were randomly allocated 1:2 to receive either cisplatin-based CRT (n=20) or 2 cycles of N 240 mg followed by CRT (n=41). The Primary Endpoint (PE) is the rate of pts who can receive Full Treatment in Due Time (FTDT), according to these criteria: a) 2 N infusions on day 1 and on day 14-16 b) CRT started between days 28-37 after the 1st N infusion c) No RT break ≥1 week d) RT dose received >95% of theoretical dose e) Cisplatin dose received ≥200 mg/m² To achieve FTDT, all criteria are required in the Experimental Arm (EA) while only criteria c), d), and e) are required in the Control Arm (CA). In the EA, the trial was designed in 2 steps, with FTDT rate of 88% considered as inacceptable versus an alternative of 98%, a type I error of 0.10, and a type 2 error of 0.08. As per protocol, patient accrual was temporarily suspended after inclusion of 19 pts in the EA (1st step) and results were reviewed by an Independent Data Monitoring Committee (IDMC). To resume pts’ inclusion, FTDT had to be achieved in 18 pts in the EA. Results: From 07/2019 to 09/2020, 30 pts were enrolled including 11 in the CA (demographics are summarized in table). 2 pts in the EA did not reach the PE. For the 1st patient, the cisplatin dose was <200 mg/m2 due to grade 1 hearing loss and grade 2 tinnitus (1st cycle: 100 mg/m2, 2nd cycle: 80 mg/m2, no 3rd cycle). For the 2nd patient, CRT began at D38 due to logistical issues (maintenance of RT devices). As this delay was unrelated to N or to patient's condition, the IDMC considered that the inclusions could resume for the 2nd step. 7 N-related Adverse Events (AE) were reported in 4 pts including 3 serious AE (ankylosing spondylitis flare-up, colitis, diabetic ketoacidosis). Conclusions: Neoadjuvant N before CRT seems feasible for the treatment of OPC pts. The trial has reopened to inclusion as recommended by the IDMC. Clinical trial information: NCT03838263. [Table: see text]
Molecular profiling and targeted agents in recurrent, metastatic salivary gland tumor (R/M SGT) patients (pts) treated at two academic centers.
Authors: Hernando-Calvo Alberto , Rezqallah Alejandra , Malone Eoghan Ruadh , Saavedra Santa Gadea Omar , Spreafico Anna , Vieito Maria , Weinreb Ilan , Aguilar Susana , Eliason Anneli , Assaf Juan David , Rodriguez Angela , Bescos Coro , Lajkosz Katherine , Lorente Juan , Jennings Sarah , Felip Enriqueta , Garralda Elena , Siu Lillian L. , Hansen Aaron Richard , Brana Irene
Published: June 2021

6081

Background: Treatment selection based on actionable alterations (AAs) is an appealing strategy for pts with R/M SGT. The GEMS-001 study (NCT02069730) at Princess Margaret Cancer Centre (PM) and the Vall D´Hebron Institute of Oncology (VHIO) pre-screening program facilitate the identification of AAs for R/M SGT pts and treatment selection. Methods: We analyzed R/M SGT treated at PM and VHIO from 2015 to 2020. Clinicopathological features, molecular alterations and treatment modalities were correlated with outcomes. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Clinical benefit rate (CBR) was defined by pts with partial response or stable disease ≥4 months. Clinical actionability of multigene panel testing (NGS) and immunohistochemistry (IHC) were assessed as per institutional molecular tumor boards or investigators. Pts were opportunistically matched to available therapies from each center. Results: In total 206 pts were enrolled. On IHC, HER2 overexpression was present in 9%, Androgen Receptor (AR) 33%, Estrogen/Progesterone Receptor (ER/PR) 11% and ALK overexpression 0%. On NGS, PIK3CA mutation (mut) was in 9%, NTRK fusion 6%, NOTCH1-3 mut 5%, HRAS mut 6%, ERBB2/3 alterations (alt) 4% and FGFR1-4 alt 3%. Up to 92 pts (45%) displayed at least 1 AA and 36 pts (18%) had ≥2 AAs. A total of 60 pts (29%) were matched to AAs. Of those matched, median age was 60 years (range 33-84), M:F 21:39, 95% ECOG≤1 with a median number of prior treatment lines 0 (range 0-3), and their AAs included 26 AR, 9 HER2 or ERBB2 overexpression, 9 PIK3CA mut, 3 NTRK fusion, 3 FGFR1-3 alt and 10 other AAs (2 ER/PR overexpression, 2 EGFR mut, 1 c-kit mut, 1 BAP1 mut, 1 Non-V600 BRAF mut, 1 CDKN2A mut, 1 CHEK2 mut and 1 PTCH1 mut). Overall, ORR was 27% for the matched population. See table for outcomes. Conclusions: In our cohort, almost one third of the population received therapies matched to AAs. Our results suggest that targeted therapies have promising activity in pts with R/M SGT supporting comprehensive molecular and IHC profiling in treatment determination.[Table: see text]
Should we routinely screen for frailty prior to gynecologic oncology surgery? Frailty as a potential predictor of adverse postoperative outcomes in elderly patients.
Authors: Mah Sarah , Anpalagan Tharani , Marcucci Maura , Reade Clare , Jimenez Waldo , Eiriksson Lua Ruhiyyih , Carlson Vanessa , Walker Millie , Nguyen Julie My Van
Published: June 2021

6517

Background: Frailty is increasingly recognized as an adverse prognostic factor of postoperative morbidity and survival in several surgical disciplines. There is no consensus on routine frailty screening in Gynecologic Oncology. Our goal was to evaluate the predictive role of the National Surgical Quality Improvement Program(NSQIP) comorbidity-based modified Frailty Index-5(mFI-5) in Gynecologic Oncology patients over the age of 70. Methods: Elective laparotomies between 01/2016-09/2020 at the Juravinski Hospital in Hamilton, ON were reviewed using prospectively-collected NSQIP data and chart review. Complication severity was assessed by Clavidien-Dindo classification. The primary outcome was rate of 30-day grade III-V complications. Secondary outcomes were: grade II-V complications, myocardial injury, length of stay(LOS), non-home discharge, and non-initiation/non-completion of adjuvant chemotherapy. Logistic regression analysis was performed. Survival analysis and receiver-operator characteristic curves are underway. Results: In this cohort of 259 patients, frail patients(mFI-5≥2) were at significantly greater risk of grade III-V complications (OR23.77, 95%CI 9.69-66.26, p < 0.0001), grade II-V complications (OR3.8, 95%CI 1.96-7.85, p = 0.0002), myocardial injury (OR3.44, 95%CI 1.66-7.05, p = 0.0009), LOS≥5days (OR2.96, 95%CI 1.61-5.52, p = 0.0006), non-home discharge (OR7.37, 95%CI 2.81-20.46, p < 0.0001), and non-initiation/non-completion of chemotherapy (OR7.34, 95%CI 2.43-23.06, p = 0.0006), than non-frail patients on univariate analysis(UVA). On multivariable analysis, frailty remained independently associated with grade II-V complications and grade III-V complications (OR4.64, 95%CI 2.31-9.94, p < 0.0001, controlling for stage, operative duration and intraoperative complication, and OR24.49, 95%CI 9.72-70.67, p < 0.0001, adjusting for BMI, stage and operative duration, respectively). On UVA, age, surgical complexity score, and smoking were not predictive of complications. Frailty also independently predicted non-home discharge (OR7.37, 95%CI 2.81-20.46, p < 0.0001) when adjusting for age. Conclusions: Frailty as assessed with mFI-5, independent of age, strongly predicted morbidity and non-home discharge after Gynecologic Oncology surgery. Strategies for perioperative optimization could help address these disparities. mFI-5 is a concise tool that can be used for routine frailty screening and risk stratification.
Association of parental cancer and school absenteeism, medical financial hardship, healthcare use, and psychological distress among minor children.
Authors: Zheng Zhiyuan , Zhao Jingxuan , Han Xuesong , Nogueira Leticia , Yabroff Robin Robin
Published: June 2021

6544

Background: A cancer diagnosis can affect the entire family, including minor children. However, little is known about the association of parental cancer on minor children’s school absenteeism, family’s financial ability to afford healthcare for children, as well as healthcare use, psychological distress, and behavioral problems. Methods: The 2015 to 2018 National Health Interview Survey was used to identify minor children (ages 5-17 years) whose parent(s) reported a cancer history (n = 695, representing 1.2 million children) and children whose parent did not report a cancer history (n = 19,122, representing 35.7 million children). Separate multivariable logistic regressions were used to compare school absenteeism, financial hardship, healthcare use, and psychological distress among children with and without parental cancer history. All analyses adjusted for children’s age group (5-11 years, 12-14 years, and 15-17 years), sex, family income as a percentage of the federal poverty line, marital status of their parents, survey year, and region. Results: Children of cancer survivors were more likely to receive annual well-child checkups, experience school absenteeism, take prescription medications for more than 3 months, visit hospital emergency rooms, suffer psychological distress, and have behavioral problems than children of parents without a cancer history (Table). Conclusions: Parental cancer history is associated with disruption in their minor children’s life. The associated psychological distress and physical and emotional health among these children may develop into more severe health issues in adulthood. Special attention to minor children of parents with a cancer history may be required to help prevent development of longer-term physical and mental health problems.[Table: see text]
Prevalence of discordant QTc values among cancer patients by the Bazett, Fridericia, and Framingham formulae: Evidence for a standardized approach.
Authors: Parish P. Christopher , Muluneh Benyam , Hicks Charles , Jensen Brian , Zeidner Joshua F. , Richardson Daniel R.
Published: June 2021

6575

Background: Many chemotherapies have the potential to prolong the QT interval, requiring monitoring of the corrected QT (QTc) to prevent life-threatening arrhythmias. Most clinical guidelines recommend adjusting/holding chemotherapy with Grade 3 or higher toxicity by CTCAE (QTc≥500). Several formulae are used for QTc monitoring including Bazett, Fridericia, and Framingham. The most commonly used formula, Bazett, is well-documented to result in inappropriately high QTc values although the potential impact of this overcorrection on cancer treatment is unknown. We aimed to describe the prevalence of QTc prolongation among cancer patients and the effects on CTCAE adverse event grading by various QTc formulae to determine the potential impact on clinical management. Methods: We performed a single-center retrospective analysis of QT values from electrocardiograms (ECGs) collected January 2010-April 2020 and evaluated associations between QTc values, medications, and patient characteristics. QTc prolonging agents were determined by FDA package insert and cross-referenced with CredibleMeds.org. Results: 20,017 ECGs were evaluated. 18.6% (3,730) met ACC/ACCF/HRS criteria for prolonged QTc by ≥1 QT correction formula (either Bazett, Fridericia, or Framingham). 7.5% (1,494) were prolonged with all three formulae, and 8.6% (1,635) were prolonged only with Bazett. The CTCAE classification using the Bazett formula differed from both Fridericia and Framingham in 37.9% (7,583) of the ECGs. In contrast, Fridericia and Framingham formulae resulted in the same CTCAE classification in 94.5% (18,912). Of 1,789 ECGs classified as Grade 3 toxicity by Bazett, 72.0% (1,288, 6.4% of all ECGs) were classified as Grade 2 or less by both Fridericia and Framingham. 12.0% (2,340) of all ECGs were taken from patients (n = 421) on 24 different QT-prolonging chemotherapies. In 38.8% (909) of the ECGs, the CTCAE classification using the Bazett formula differed from both Fridericia and Framingham while use of Fridericia and Framingham formulae resulted in the same classification in 93.0% (2,176) of the ECGs. Of 293 ECGs classified as Grade 3 toxicity by Bazett, 65.2% (191) were classified as Grade 2 or less by both Fridericia and Framingham. Conclusions: To our knowledge, this is the largest analysis of discrepancies between different QTc formulae in patients receiving chemotherapy. These findings demonstrate an unacceptably high rate of discordance between formulae. Discordant data can lead to inconsistent clinical management and adverse event grading underscoring the urgent need to standardize QTc monitoring and reporting. These findings support the discontinuation of the routine use of the Bazett correction formula among cancer patients as CTCAE Grade 3 reporting from the Bazett formula is unreliable in over 65% of cases.
Adult Philadelphia-like B-cell acute lymphoblastic leukemia: Characteristics, outcomes, and role of allogeneic hematopoietic cell transplantation in comparison to Philadelphia-positive and Philadelphia-negative acute lymphoblastic leukemia.
Authors: Abdel Rahman Zaid , Heckman Michael , Anagnostou Theodora , White Launia , Kloft-Nelson Sara M. , Knudson Ryan A. , Alkhateeb Hassan , Sproat Lisa Ostrosky , Khera Nandita , Murthy Hemant S. , Ayala Ernesto , Hogan William J. , Roy Vivek , Peterson Jess , Kharfan-Dabaja Mohamed , Ketterling Rhett P. , Litzow Mark Robert , Patnaik Mrinal , Foran James M. , Greipp Patricia T.
Published: June 2021

7022

Background: Philadelphia-like Acute Lymphoblastic Leukemia (Ph-like ALL) is a high-risk subset of adult ALL. Until recently, there has not been a systematic platform to recognize this entity in clinical practice. Furthermore, data regarding the role of allogeneic hematopoietic cell transplantation (allo-HCT) is lacking. We conducted this study to identify patients with Ph-like ALL and describe their outcomes in comparison to Ph+ and Ph- ALL with emphasis on the role of allo-HCT. Methods: To identify cases of Ph-like ALL, available diagnostic cytogenetic pellets for patients in the Mayo Clinic ALL cohort (N=365) were tested using a targeted fluorescence in situ hybridization (FISH) panel developed by the Mayo Clinic Genomics Laboratory and includes probes to detect Ph-like-specific rearrangements (i.e., ABL1, ABL2, PDGFRB, JAK2 and CRLF2). Results: Thirty-three (9%) patients with Ph-like ALL were identified, the remaining patients were classified as Ph+ (N=132, 36%) or Ph- ALL (N=200, 55%). Patients with Ph-like ALL were younger (Median: 39 vs. 50 vs. 49 years, P=.01), had higher WBC (Median: 27.9 vs. 21.5 vs. 4.5 x109/L, P<.001), were less likely to achieve CR (91% vs. 99% vs. 96%, P=.02), more likely to be MRD+ (64% vs. 34% vs. 36%, P=.03), had a higher relapse rate (5-year: 39% vs. 24% vs. 38%, P=.01) and lower OS (5-year: 41% vs. 64% vs. 49%, P=.02), see Table. Patients who achieved MRD negativity had better OS (MRD+ vs MRD-, P=.01). Importantly, no statistically significant difference in OS, relapse or non-relapse mortality were noted between the 3 groups in patients who underwent allo-HCT in CR1. Conclusions: Ph-like ALL is a high risk subgroup with increased prevalence in younger adults. Allo-HCT appears to offset the poor prognosis associated with this entity. A targeted FISH panel offers timely recognition of this entity in a clinical setting.[Table: see text]