bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of total hysterectomy with survival among newly diagnosed uterine cancer patients with distant organ metastasis.
Authors: Wang Yuefeng , Tillmanns Todd D. , Farmer Michael , Rinker Lillian , Somer Bradley G. , Ballo Matthew T.
Published: May 2019

5583

Background: There is growing evidence that definitive local therapies (surgery or radiotherapy) may increase patient’s survival for some types of metastatic cancers. However, the role of total abdominal hysterectomy (TAH) for newly diagnosed uterine cancer with distant organ metastasis has not been established. The objective of this study is to determine the potential overall survival (OS) benefit associated with TAH for distant metastatic uterine cancer. Methods: The National Cancer Database was analyzed to evaluate OS for newly diagnosed uterine cancer patients with metastasis to brain, lung, liver, bone or distant lymph node, treated with chemotherapy with or without TAH. Those without treatment, treated with definitive pelvic radiotherapy, or without baseline variables were excluded. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. In order to control the selection biases, we performed Landmark analysis, and survival analysis by the sequence of chemotherapy and TAH. Separate survival analysis was performed for patients who received chemotherapy plus definitive pelvic radiotherapy (RT) or chemotherapy plus TAH and definitive pelvic RT. Results: From 2010 to 2014, 1,809 uterine cancer patients with distant organ metastasis received chemotherapy alone and 1,388 patients received chemotherapy plus TAH. At a median follow-up of 13.4 months, addition of TAH to chemotherapy was associated with improved survival on univariate (HR 0.57; P < 0.001) and multivariate analysis (HR 0.59; P < 0.001) compared to chemotherapy alone. Propensity score-matched analysis demonstrated superior median survival (19.8 vs 11.0 months) and 2-year OS (44% vs 28%) with TAH (multivariate HR 0.59; P < 0.001). Landmark analyses limited to long-term survivors of ≥0.5, ≥1, and ≥2 years showed improved OS with TAH in all subsets (all P < 0.05). The benefit of TAH was present among not only those involving one metastatic site (HR 0.59; P < 0.001), but also those involving multiple metastatic sites (HR 0.60; P < 0.001). Separate survival analyses showed chemotherapy plus definitive pelvic RT or chemotherapy plus TAH and RT were both superior to chemotherapy alone. Conclusions: In this large contemporary analysis, uterine cancer patients with distant organ metastasis receiving TAH and chemotherapy had substantial longer survival than patients treated with chemotherapy alone. Prospective trials evaluating TAH for metastatic uterine cancer are warranted.
Trends of endometrial cancer incidence from 2000 to 2015 in the United States.
Authors: Mukthinuthalapati V V Pavan Kedar , Farooq Muhammad Zain , Gupta Shweta
Published: May 2019

5591

Background: Recent studies have shown that obesity related cancers are increasing in incidence in the US as the rates of obesity rise and some cancers, like colorectal cancer, are occurring in younger age groups. We studied trends in incidence of endometrial cancer (EC), one of the obesity related cancers, in a population wide analysis. Methods: We analyzed data from all cases of EC between 2000 and 2015 from 18 US cancer registries using the National Cancer Institute’s Surveillance, Epidemiology and End Results Program. SEER*Stat was used to query the database for annual percent changes (APC), incidence ratios and percent change in incidence across different age groups, years of diagnosis, histologic subtypes, grade and race. We also studied the reported rates and trends of obesity in the US. Results: APC of age-adjusted EC incidence between 2000 and 2015 was +0.9% (95% confidence interval (CI) 1.1-0.6, p value<0.05). Incidence of EC rose from 17.8 per 100,000 to 19.7 per 100,000 during the same duration. APC for EC incidence for age groups 20-39 and >40 were +3.2% (p-value <0.05) and +0.8% (p value <0.05), respectively. For the age-group 20-39, endometrioid EC was the only histologic subtype that rose in incidence, with an APC of +5.5% and absolute percentage change of 156%. The APC of EC in 20-39 age group was more for whites (3.5%, p-value<0.05) and Asians (2.2%, p-value<0.05) than blacks (1.8, p-value <0.05). CDC reported an increase in obesity rates in adults from 30.5% in 2000 to 37.7% in 2014. Table shows trends of EC incidence in age groups 20-39 and >40 years across various histologic subtypes. (Abbreviations: S significant, NS not significant, NC non-calculable). Conclusions: Endometrial cancer, especially of endometrioid histology, is increasing in incidence and is occurring more often in the younger population. The concomitant rise in obesity rates during the same period point towards a possible causality of the increased in incidence of EC. Population based strategies are needed to decrease the trends in obesity so as to decrease the risk of endometrial cancer in younger women. [Table: see text]
Genomic-based predictive biomarkers to anti-HER2 therapies: A combined analysis of CALGB 40601 (Alliance) and PAMELA clinical trials.
Authors: Fernandez-Martinez Aranzazu , Tanioka Maki , Fan Cheng , Parker Joel S. , Hoadley Katherine A. , Krop Ian E. , Cortes Javier , Llombart Cussac Antonio , Nuciforo Paolo , Galván Patricia , Pascual Tomas , Partridge Ann H. , Prat Aleix , Carey Lisa A. , Perou Charles M.
Published: May 2019

571

Background: In HER2-positive breast cancer, new biomarkers of response are needed in order to direct multi-agent anti-HER2 combinations towards patients in whom they are truly needed. CALGB 40601 and PAMELA trials tested neoadjuvant dual HER2 blockade and included gene expression analysis aimed to evaluate different genomic biomarkers of trastuzumab and/or lapatinib benefit. Methods: Gene expression by mRNA sequencing (RNAseq) was performed on 265 and 142 pre-treatment tumors of the CALGB 40601 and the PAMELA clinical trials respectively. Intrinsic subtypes were determined by nCounter PAM50-predictor on the PAMELA samples. A new HER2-positive specific gene-centering method was trained on the PAMELA RNAseq data, and showed a higher concordance with PAM50 predictions obtained from nCounter platform. This method was then applied to CALGB 40601 samples. Results: In the combined cohort, the subtype distribution was 10% Luminal A, 8% Luminal B, 62% HER2-enriched (HER2-E), 10% Basal and 10% Normal-like. The pCR rate was significantly higher in HER2-E vs. not HER2-E subtypes (48.6% vs. 20.7%; P < 0.001). HER2-E subtype correlation, ERBB2 amplicon and B-cell genomic signatures were associated with pCR, while luminal signatures were associated with non-responders. In multivariate analysis HER2-E subtype, ERBB2 mRNA and IgG signature expression were independent predictors of response to paclitaxel + trastuzumab +/-lapatinib (OR = 1.98, OR = 1.51, OR = 1.48, respectively, P <0.05). The event free survival analysis at 5 years in the CALGB 40601 cohort showed a benefit of dual vs single anti-HER2-blockade (HR 0.35, P <0.05). Within the HER2-E, ERBB2-high and IgG–high subpopulations, there were also a benefit of dual vs. single anti-HER2 treatment (HR = 0.32, HR = 0.15, HR =0.15, respectively, P <0.05). Conclusions: Intrinsic subtype, ERBB2 mRNA levels, and IgG genomic signature are independent predictive biomarkers of response in the combined cohort. The clinical implementation of these biomarkers could help to design future escalation/de-escalation clinical trials in the HER2-positive neoadjuvant setting. Support: U10CA180821, U10CA180882, U24CA196171, P50-CA58223, GSK, SPORE, BCRF and SEOM. https://acknowledgments.alliancefound.org .
Germline mutation status and therapy response in high-risk early breast cancer: Results of the GeparOcto study (NCT02125344).
Authors: Pohl-Rescigno Esther , Hauke Jan , Rhiem Kerstin , Möbus Volker , Furlanetto Jenny , Denkert Carsten , Fasching Peter A. , Hanusch Claus , Tesch Hans , Weber-Lassalle Nana , Müller Volkmar , Untch Michael , Luebbe Kristina , Lederer Bianca , Jackisch Christian , Nekljudova Valentina , Schmutzler Rita K. , Loibl Sibylle , Schneeweiss Andreas , Hahnen Eric
Published: May 2019

573

Background: GeparOcto compared the efficacy of two neoadjuvant treatment (NAT) regimens in high-risk early breast cancer (BC): Sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly paclitaxel plus non-pegylated liposomal doxorubicin (PM), plus carboplatin (PMCb) in triple-negative BC (TNBC). There was no difference in pathologic complete response (pCR) rates (Schneeweiss et al. Eur J Cancer 2019). Here, we stratified pCR rates according to germline mutation status. Methods: Germline (g) mutation analysis of BRCA1/2 and 16 further BC predisposition genes in 914 patients (pts) enrolled (393 pts with TNBC, iddEPC n = 194, PMCb n = 199; 156 pts with HER2-/HR+ BC, iddEPC n = 75, PM n = 81; and 365 pts with HER2+ BC, iddEPC n = 182, PM n = 183). Results: The gBRCA1/2 mutation prevalence was 17.6% in TNBC, 14.1% in HER2-/HR+ BC and 1.4% in HER2+ BC. Overall, pts with gBRCA1/2 mutations achieved higher pCR rates than gBRCA1/2 wildtype pts (60.4% vs 46.7%, OR 1.74, P = 0.012), with more pronounced effects in the PM(Cb) arm (68.1% vs 45.7%, OR 2.53, P = 0.005). Among gBRCA1/2 wildtype pts, 76 carried mutations in non- BRCA1/2 predisposition genes. pCR rates were similar to those observed in pts without any mutation. Conclusions: Pts with gBRCA1/2 mutations benefitted most from NAT with highest pCR rates achieved in the gBRCA1/2 TNBC / PMCb group. The role of Cb for NAT of gBRCA1/2 TNBC should be further explored. Clinical trial information: NCT02125344. [Table: see text]
Open label, phase II trial of neoadjuvant TAK-228 plus tamoxifen in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer-ANETT.
Authors: Koca Emre , Niravath Polly Ann , Ensor Joe , Patel Tejal Amar , Li Xiaoxian , Hemati Pej , Wong Helen , Qian Wei , Boone Toniva , Zhao Jing , Ramshesh Priya V. , Cohen Adam Louis , Murthy Asha , Nair Sindhu , Darcourt Jorge German , Belcheva Anna , Kaklamani Virginia G. , Chang Jenny Chee Ning
Published: May 2019

584

Background: Neoadjuvant endocrine therapy is standard care for women with hormone receptor-positive breast cancer. However, both primary and acquired endocrine resistance is not uncommon, thereby limiting efficacy. [1] The PI3K-Akt-mTOR pathway is a major mediator of endocrine resistance. [2,3] Therefore, we determined the efficacy and safety of the mTORC1/2 inhibitor TAK-228 in combination with tamoxifen in neoadjuvant setting. Methods: In this single-arm, open-label phase II trial, newly diagnosed patients with stage I−III ER-positive, HER2-negative breast cancer received TAK-228 (30 mg weekly) and tamoxifen (20 mg daily) for 16 weeks until 2-4 weeks prior to surgery. The primary endpoint was the change in Ki67 after 6 weeks. Secondary endpoints included pathological complete response rate (pCR), preoperative endocrine prognostic index (PEPI) score, and safety. Results: Of the 28 patients enrolled in the study, 3 were excluded due to non-compliance. Mean patient age was 51.7 years. Most patients had stage I or II disease (12 [43%] each); 4 (14%) had stage III disease. Mean Ki67 was significantly lowered from baseline to Week 6 (17.2% vs. 15.2%, p = 0.0023). Interestingly, mean Ki67 increased to 20.1% from baseline to the time of surgery. This may have been due to a rebound effect, as TAK-228 was discontinued 2-4 weeks prior to surgery. Tumor size also significantly decreased from baseline to surgery, with a median decrease of 0.75 centimeters (p < 0.0001). PEPI score was intermediate risk (score 1−3) in 6 patients and high risk group (score ≥4) in 15 patients. No patients achieved a PEPI score of 0 and no pCR was achieved. Overall, the combination was well tolerated, the most common side effects were nausea (72%), vomiting (72%), fatigue (72%), mucositis (45%), and headache (45%). The any Grade 3 AE rate was 7.7%. Conclusions: The TAK-228 and tamoxifen combination was found to be an effective neoadjuvant strategy with a favorable safety profile in newly diagnosed patients with hormone receptor-positive breast cancer. Further molecular analysis (PI3K-Akt-mTOR pathway) are pending and will be presented. Clinical trial information: NCT02988986.
Correlation of the tumor mutational burden with the composition of the immune cell subpopulations in peripheral blood of triple-negative breast cancer patients undergoing neoadjuvant therapy with durvalumab: Results from the prospectively randomized GeparNuevo trial.
Authors: Seliger Barbara , Karn Thomas , Denkert Carsten , Schneeweiss Andreas , Hanusch Claus , Blohmer Jens Uwe , Jackisch Christian , van Mackelenbergh Marion , Marme Frederik , Mueller Volkmar , Huober Jens Bodo , Untch Michael , Loibl Sibylle , Mueller Anja , Biehl Katharina , Weber Karsten Ernst , Massa Chiara
Published: May 2019

588

Background: The GeparNuevo trial is a randomized, double-blind, multi-center phase II trial of neoadjuvant therapy in patients with early-stage triple negative breast cancer (TNBC) investigating the role of durvalumab, an anti-PD-L1 antibody, which blocks PD-L1 binding to PD1 and CD80, in addition to standard chemotherapy with nab-Paclitaxel (nab-Pac) followed by Epirubicin plus Cyclophosphamid (EC; Loibl S et al. ASCO 2018). Since the tumor mutational burden (TMB) has been suggested to be associated with a better outcome of patients undergoing immunotherapy and an increased T cell response, we determined whether there exists a link between TMB and immune cell composition, frequency and function in patients of the GeparNuevo trial. Methods: In order to determine possible predictive and / or prognostic biomarkers, tumor biopsies taken at recruitment from 149 patients out of the 174 enrolled patients underwent deep sequencing in order to determine the TMB. In addition, for 120 patients blood samples were taken at recruitment and during different time points of treatment (after durvalumab pre-treatment, after Nab-Pac and at surgery after EC) and evaluated using multicolor flow cytometry by monitoring the absolute cell counts of T cells, B cells and NK cells as well as the frequency, composition and functionality of different immune cell populations. Results: The TMB of the GeparNuevo cohort was in line with published data with a mean of 1.8 mutations/MB (range 0.02 – 7.65), respectively. Preliminary evaluation demonstrated a significant correlation of TMB with blood parameters, in particular with subsets of CD8+ T cells. Interestingly, the data suggest a negative correlation of TMB with the frequency of effector cells while a positive correlation exists with the effector memory cells at recruitment. In depth analyses of a correlation with treatment arm and clinical responses are currently performed. Conclusions: Using this approach we hope to identify biomarkers, which will allow a better selection of TNBC patients undergoing specific immunotherapies. Clinical trial information: NCT02685059.
Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Authors: Rischin Danny , Harrington Kevin J. , Greil Richard , Soulieres Denis , Tahara Makoto , de Castro Gilberto , Psyrri Amanda , Baste Neus , Neupane Prakash C. , Bratland Ase , Fuereder Thorsten , Hughes Brett Gordon Maxwell , Mesia Ricard , Ngamphaiboon Nuttapong , Rordorf Tamara , Wan Ishak Wan Zamaniah , Zhang Yayan , Jin Fan , Gumuscu Burak , Burtness Barbara
Published: May 2019

6000

Background:
KEYNOTE-048 is a phase 3 study of P or P + chemo (C) vs EXTREME (E) as 1L therapy for R/M HNSCC (NCT02358031). At the second interim analysis (IA2), P significantly improved OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 populations and had noninferior OS in the total population with favorable safety; P+C significantly improved OS in the total population with comparable safety. We present the protocol-specified final results.
Methods:
882 pts with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W for 24 mo (n = 301), P for 24 mo + 6 cycles of C (cisplatin 100 mg/m
2
or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m
2
/d for 4 d Q3W) (n = 281), or E (cetuximab 400 mg/m
2
loading/250 mg/m
2
QW + 6 cycles of chemo) (n = 300). OS superiority was tested sequentially for P+C vs E in the CPS ≥20 population, then the CPS ≥1 population, and for P vs E in the total population (superiority thresholds: one-sided
P
= .0023, .0026, and .0059, respectively). Data cutoff was 25 Feb 2019 (~25 mo after last pt randomized).
Results:
P+C significantly improved OS vs E in the CPS ≥20 (HR 0.60, 95% CI 0.45-0.82,
P
= .0004; median 14.7 vs 11.0 mo) and CPS ≥1 (HR 0.65, 95% CI 0.53-0.80,
P
< .0001; median 13.6 vs 10.4 mo) populations. HR (95% CI) for PFS was 0.76 (0.58-1.01) for CPS ≥20 and 0.84 (0.69-1.02) for CPS ≥1. ORR (P+C vs E) was 42.9% vs 38.2% for CPS ≥20 and 36.4% vs 35.7% for CPS ≥1; median DOR was 7.1 vs 4.2 mo and 6.7 vs 4.3 mo, respectively. P did not significantly improve OS vs E in the total population (HR 0.83, 95% CI 0.70-0.99,
P
= .0199; median 11.5 vs 10.7 mo). HR (95% CI) for PFS was 1.29 (1.09-1.53). ORR (P vs E) was 16.9% vs 36.0%; median DOR was 22.6 vs 4.5 mo. All-cause gr 3-5 AE rates were 54.7% for P, 85.1% for P+C, and 83.3% for E.
Conclusion:
Overall, KEYNOTE-048 showed that compared with E, P+C had superior OS in the PD-L1 CPS ≥20, CPS ≥1, and total populations with comparable safety and P had superior OS in the CPS ≥20 and ≥1 populations, noninferior OS in the total population, and favorable safety. These results support pembrolizumab and pembrolizumab + platinum + 5-FU as new 1L standards of care for R/M HNSCC.
Clinical trial information: NCT02358031.
Ado-trastuzumab emtansine in patients with HER2 amplified salivary gland cancers (SGCs): Results from a phase II basket trial.
Authors: Li Bob T. , Shen Ronglai , Offin Michael , Buonocore Darren J. , Myers Mackenzie L. , Venkatesh Aishwarya , Razavi Pedram , Ginsberg Michelle S. , Ulaner Gary A. , Solit David B. , Hyman David Michael , Rudin Charles M. , Gedvilaite Erika , Tsui Dana , Arcila Maria E. , Kris Mark G. , Weitsman Gregory , Ng Tony , Scaltriti Maurizio , Ho Alan Loh
Published: May 2019

6001

Background: SGCs are rare tumors with no approved therapy for metastatic disease. HER2 amplification occurs in 8% among all SGC histologies, and 25-33% of the aggressive salivary duct carcinoma (SDC) histologic subtype. We hypothesized that ado-trastuzumab emtansine, a HER2 targeted antibody drug conjugate, may be clinically active in these patients. Methods: A cohort of patients with HER2 amplified SGCs were enrolled into a multi-histology basket trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) by RECIST v1.1 or PERCIST. A Simon two-stage optimal design was applied with type I error rate under 2.7%, power of 89%, H0 10%, H1 40%; H0 will be rejected if 6 or more responses are observed in 24 patients. Other endpoints include duration of response (DOR), progression-free survival (PFS), and toxicity. HER2 amplification was identified by next generation sequencing (NGS), and tumors were subsequently tested by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Fluorescence lifetime imaging microscopy - Förster resonance energy transfer (FLIM-FRET) assessed the propensity for HER2-HER3 heterodimerization, which leads to receptor internalization. Results: 10 patients with HER2 amplified SGCs were treated. The median age was 65 (range 36-90 years), 90% were male. The median lines of prior systemic therapy was 2 (range 0-3). ORR was 90% (9/10, 95% CI 56-100%) including 5 complete responses after prior trastuzumab, pertuzumab and anti-androgen therapy. After a median follow up period of 12 months (range 4-20 months), median DOR (range 2-19+) and median PFS (95% CI 4–22+ months) were not reached. Toxicities included grade 1 or 2 infusion reaction, thrombocytopenia and transaminitis; there were no treatment related deaths. HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with HER2/CEP17≥2 by FISH (8/8 tested) or IHC3+ (10/10 tested). FLIM-FRET tested positive in 3/3. Conclusions: Ado-trastuzumab emtansine is highly efficacious in patients with HER2 amplified SGCs as identified by NGS. This study has met its primary endpoint, and cohort expansion is warranted to confirm these results. Clinical trial information: NCT02675829.
Gemcitabine and cisplatin (GP) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC): A phase 3, multicenter, randomized controlled trial.
Authors: Ma Jun , Zhang Yuan , Sun Ying , Xie Fangyun , Hu Weihan , Hu Guoqing , Zhang Ning , Yang Kun-Yu , Zhu Xiaodong , Jin Feng , Cheng Zhi-Bin , Shi Mei , Han Fei , Tian Ye , Sun Yan , Mo Hao-Yuan , Li Jin-Gao
Published: May 2019

6003

Background: GP regimen has been established as the standard first-line treatment option for patients with recurrent/metastatic NPC. However, its efficacy in locoregionally advanced disease remains unclear. Methods: Patients with previously untreated, non-metastatic stage III-IVB (except T3-4N0M0, AJCC 7th) NPC, aged 18–64 years without severe comorbidities were eligible. They were randomly assigned (1:1) to receive GP IC (gemcitabine 1 g/m2on days 1 & 8, cisplatin 80 mg/m2 on day 1, q3w for 3 cycles) plus CCRT (cisplatin 100 mg/m2, q3w for 3 cycles, concurrently with intensity-modulated radiotherapy) or CCRT alone. The primary endpoint was failure-free survival (FFS). The calculated sample size was 238 per group, with an 80% power (two-sided α 0.05) to detect a treatment failure hazard ratio (HR) of 0.52. Results: From Dec 2013 to Sep 2016, 480 patients from 12 centers were randomly assigned to IC+CCRT (n = 242) or CCRT alone (n = 238) group. Baseline characteristics were well balanced. After a median follow-up of 39 months, 3-year FFS was 85.8% in the IC+CCRT group and 77.2% in the CCRT alone group (intention-to-treat population; HR 0.53, 95% confidence interval 0.34–0.81; P = 0.003). In GP+CCRT group, 239 patients started GP IC and 231 (96.7%) completed all three cycles. The most common ≥grade 3 adverse events (AE) in IC+CCRT and CCRT group were mucositis (28.9% vs. 32.1%), neutropenia (28.0% vs. 10.5%) and leukopenia (26.4% vs. 20.3%). Conclusions: Adding GP IC to CCRT significantly improved FFS in locoregionally advanced NPC and is well tolerated with favorable toxicity profile. Clinical trial information: NCT01872962. [Table: see text]
Neck dissections based on sentinel lymph node navigation versus elective neck dissections in early oral cancers: A randomized, multicenter, non-inferiority trial.
Authors: Hasegawa Yasuhisa , Tsukahara Kiyoaki , Yoshimoto Seiichi , Miura Kouki , Yokoyama Junkichi , Hirano Shigeru , Uemura Hirokazu , Sugasawa Masashi , Yoshizaki Tomokazu , Homma Akihiro , Chikamatsu Kazuaki , Suzuki Mikio , Shiotani Akihiro , Matsuzuka Takashi , Kohno Naoyuki , Miyazaki Masakazu , Oze Isao , Matsuo Keitaro , Kosuda Shigeru , Yatabe Yasushi
Published: May 2019

6007

Background: The objective of the study is to evaluate the non-Inferiority of survival, the superiority of postoperative disability, and the complication of the neck in neck dissections based on sentinel lymph node navigation in early oral cancer patients, compared with standard selective neck dissections. Methods: This study was a randomized, multicenter, non-inferiority trial at 16 institutions in Japan. Eligibility criteria included histologically confirmed squamous cell carcinoma in the oral cavity; clinical categories T1 and T2, N0M0 by UICC TNM classification 7th edition, clinical depth of invasion (DOI) of T1 was over 4mm (defined as late T1); previously untreated; age at least 18 years; and written informed consent. We randomly assigned patients (1:1) to receive either sentinel lymph node biopsy (SNB) or standard selective neck dissections (ND) with stratification of T category (lateT1 vs T2) and subsite (tongue vs others). The primary endpoint was 3-year overall survival with a non-inferiority margin of 12%. Sentinel nodes (SNs) were detected using radioisotope method and examined with multislice frozen section analysis intraoperatively, following HE and cytokeratin stain for a final postoperative diagnosis. Patients with positive SNs had neck dissections in a one-stage or back up procedure. Results: Between November 2011 and January 2016, 271 patients were enrolled and randomized to SNB group (134 patients) and ND group (137 patients) with a median follow-up of 37 months (IQR 36-39). Pathological positive nodal status was 34% (46/132) in SNB group and 26% (34/133) in ND group (Chi-Square p = 0.10). 3-year overall survival in SNB group was 89% (95%CI 82-93%), which was non-inferior to that in ND group (86%, 95%CI 79-91%). 3-year relapse-free survival was 80% (95%CI 72-86%) in SNB group and 81% (95%CI 73-87%) in ND group. Arm abduction of postoperative 1 and 3 months in ND group was disturbed significantly compared with SNB group. Conclusions: SNB navigated ND could replace elective ND without survival disadvantage and reduce postoperative disability of the neck in patients with early oral cancer. Clinical trial information: 000006510.
Discordant treatment response in primary tumors and lymph node metastases after four weeks of preoperative PD-1 blockade in head and neck squamous cell carcinoma (HNSCC).
Authors: Luginbuhl Adam , Johnson Jennifer Maria , Tuluc Madalina , Mardekian Stacey , Harshyne Larry , Leiby Benjamin , Zinner Ralph , Curry Joseph M. , Cognetti David M. , Rodeck Ulrich , Argiris Athanassios
Published: May 2019

6016

Background: Discordant radiographic responses are described in other tumor types in response to immunotherapy with response at some anatomic sites and progression in others. Here we determined the frequency of discordant treatment effects (TE) in HNSCC patients treated with immunotherapy in the context of a neoadjuvant trial. Methods: 23 Patients with resectable primary HNSCC were 1:1 randomized to receive nivolumab (240 mg IV Q 2 weeks x 2) or nivolumab and tadalafil 10 mg daily. Surgery was performed 4 weeks after the first nivolumab infusion. Resection specimens were graded histopathologically by two pathologists. Areas exhibiting TE (defined by fibrosis with chronic inflammation, foamy macrophage reaction and multinucleated giant cells) were expressed relative to the total tumor area. This was assessed in the primary tumor and all lymph nodes (LN). Each primary lesion and individual LN was defined as a) no response 0%TE, b) minimal response 1-19%TE, c) response 20-99% or d) complete response 100%. Concordance was defined if primary lesion and LNs were in the same ordinal data set. Results: 11/23 (48%) of subjects experienced concordant ΤΕ in the primary tumor and LNs. Within this cohort, 3 patients had a complete pathologic response both at the primary site and LNs. In contrast, 12/23 patients (52%) revealed discordant ΤΕ between the primary tumor sites (average of 17% TE) and involved LNs (average of 62% TE), (p= 0.018; signed rank test). Interestingly, in the discordant group, TE effects in LNs were invariably greater than in primary lesions. In 5 of 11 patients with multiple involved LN, the TE varied between nodes. This included patients with adjacent LNs demonstrating 0% and 100% TE in the same level. Systemic and local immune parameters as they relate to concordant and discordant TEs in individual patients will be presented including a type 1 immune bias. Conclusions: Early histologic evaluation of TE in patients with HNSCC receiving immunotherapy demonstrate a wide variety of response between the primary tumor and LNs. Further investigations will lend insight into complex interactions of cancer cells with the microenvironment. Clinical trial information: NCT03238365.
Mature results of the LCCC1413 phase II trial of de-intensified chemoradiotherapy for HPV-associated oropharyngeal squamous cell carcinoma.
Authors: Chera Bhishamjit S. , Amdur Robert , Shen Colette J. , Gupta Gaorav P. , Tan Xianming , Knowles Mary , Hayes David N. , Weiss Jared , Grilley-Olson Juneko E. , Patel Shetal Arvind , Zanation Adam M. , Hackman Trevor , Zevallos Jose , Blumberg Jeffrey , Patel Samip , Kasibhatla Mohit , Sheets Nathan Christopher , Weissler Mark Christian , Yarbrough Wendell Gray , Mendenhall William M.
Published: May 2019

6022

Background: To report the mature results from a prospective phase II clinical trial of highly de-intensified chemoradiotherapy (CRT) for patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: 1) T0-T3, N0-N2, M0, 2) p16 positive, and 3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin 30 mg/m2(second choice was cetuximab). Patients with T0-T2 N0-1 disease did not receive chemotherapy. All patients had a 10 to 12-week post-treatment PET/CT to determine need for planned neck dissection. The primary study endpoint was 2 year progression free survival (PFS). Secondary endpoint measures include 2 year local control (LC), regional control (RC), distant metastasis free survival (DMFS), cause specific survival (CSS) and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 & H&N35). Results: 114 patients were enrolled (median f/u of 28.8 months, range 2.6 to 51.4) with 84 having a minimum follow-up of 2 years. Smoking status was as follows: 47% never, 33% ≤ 10 pack years, and 19% > 10 pack years. Post-treatment PET/CT complete response rate was 93% at the primary site and 80% in the neck. Eleven patients had planned neck dissection with 4 having pathological residual disease. Two year LC, RC, DMFS, PFS, CSS, and OS were the following: 96%, 99%, 91%, 88%, 97%, and 95%. Neither smoking status nor receipt of cetuximab correlated with recurrence. Four patients with recurrent disease had PIK3CA mutations. Thirty four percent of patients required a feeding tube (none permanent) for a median of 10.5 weeks. Mean pre- and 2-year post-treatment EORTC QOL scores were: Global 79/83 (lower worse), Swallowing 8/9 (higher worse), Dry Mouth 14/45 (higher worse), and Sticky Saliva 9/28 (higher worse). Mean pre- and 2 year post-treatment PRO-CTCAE (0 to 4 scale, higher worse) scores were: Swallowing 0.5/0.7 and Dry mouth 0.4/1.4. There were no ≥ Grade 3 late adverse events. Conclusions: Clinical outcomes with a highly de-intensified CRT regimen of 60 Gy IMRT with concurrent low-dose cisplatin are excellent in patients with HPV-associated OPSCC. Clinical trial information: NCT02281955.
NRG-HN003: Phase I and expansion cohort study of adjuvant cisplatin, intensity-modulated radiation therapy (IMRT), and MK-3475 (Pembrolizumab) in high-risk head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Harris Jonathan , Uppaluri Ravindra , Yao Min , Ferris Robert L. , Chen Josephine , Jordan Richard C. , Joshi Nikhil Purushottam , Jujjuvaparu Srinivas , Blakaj Dukagjin , Razaq Mohammad , Sheqwara Jawad , Mell Loren K. , Sen Neilayan , Clump David Anthony , Garg Madhur , Yilmaz Emrullah , Le Quynh-Thu
Published: May 2019

6023

Background: Pembrolizumab, an anti-PD1 monoclonal antibody, improves survival in advanced HNSCC. Patients with pathologic high risk, HPV-negative HNSCC have a high recurrence rate despite adjuvant cisplatin-IMRT (CRT), the current standard. Immunosuppression is induced by HNSCC and CRT, and may be reversible by targeting PD1. Methods: We conducted a phase I trial with expansion cohort to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to adjuvant CRT (NCT02775812). Eligibility: oral cavity, pharynx, or larynx primary; HPV-negative; pathologic high risk (positive margin or extranodal extension [ENE]); Zubrod 0-1. During phase I, patients enrolled in descending cohorts of 12 (Table). RP2S was declared if ≤ 3 dose-limiting toxicities (DLT) occurred. DLT was defined as ≥ Grade 3 non-hematologic adverse event (AE) related to pembrolizumab, immune-related (ir)AE requiring > 2 weeks of systemic steroids, or unacceptable delay in IMRT. The expansion cohort enrolled 20. Results: From Nov 2016-Oct 2018, 34 eligible patients enrolled at 22 NRG institutions. During the first cohort, 1 DLT was observed (Grade 3 fever). RP2S was declared as Schedule 3 and the expansion cohort triggered. Among all 34 patients, median age was 60 years (26-83); 68% were male; 74% had Zubrod 1; 85% had oral cavity; 88% had ENE; 21% had positive margin. During expansion, 3 additional patients with DLT were observed: wound infection; diverticulitis; nausea. No DLT unacceptably delayed IMRT. Twenty-eight of 34 (82%) received ≥ 5 doses of pembrolizumab; 17 (50%) got all 8 doses. Thirty-one of 32 (97%) DLT-evaluable patients received all adjuvant RT; 1 withdrew consent after starting protocol. Conclusions: The RP2S is pembrolizumab 200 mg IV q 3 weeks for 8 doses, starting the week before adjuvant CRT. This regimen was safe and feasible in a cooperative group setting. irAE were rare in this population. Clinical trial information: NCT02775812. [Table: see text]
Safety and antitumor activity of accelerator-based boron neutron capture therapy in patients with inoperable recurrent and locally advanced head and neck cancer: A phase II study.
Authors: Hirose Katsumi , Konno Akiyoshi , Yoshimoto Seiichi , Ono Koji , Otsuki Naoki , Hatazawa Jun , Hiratsuka Junichi , Takai Yoshihiro
Published: May 2019

6028

Background: To assess safety and efficacy of accelerator-based boron neutron capture therapy (AB-BNCT) using cyclotron-based neutron generator, BNCT30, and 10B-boronophenylalanine (borofalan(10B)) agent, SPM-011, in patients with recurrent squamous cell carcinoma (R-HNSCC) or recurrent/locally advanced non-squamous cell carcinoma (R/LA-HNNSCC) of the head and neck. Methods: The multi-institutional open-label, a world-first phase II trial of AB-BNCT in patients with inoperable R-HNSCC which present resistance to platinum-based chemotherapy, or with inoperable R/LA-HNNSCC, was conducted to assess safety and antitumor activity of AB-BNCT with BNCT30 and SPM-011. SPM-011 was administered at 200 mg/kg/h intravenously for 2 hours, followed by neutron irradiation with continuous infusion of SPM-011 at 100 mg/kg/h. The irradiated dose for tumor was determined passively as a mucosal maximum dose was given 12 Gy-Eq in calculation with a blood boron concentration measured just before the start of neutron irradiation. Primary endpoint was objective response rate (ORR) by central review. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) ver 1.1 every 4 weeks for the first 3 months and every 12 weeks thereafter. Results: Eight R-HNSCC and thirteen R/LA-HNNSCC patients were enrolled and received AB-BNCT. All R-HNSCC patients had prior radiotherapy with a median dose of 65.5 Gy (range 59.4–76.0). The median irradiation time was 43 min (range 26–65). The median tumor minimum dose was 31.0 Gy-Eq (range 16.1–42.6). For adverse event, nausea (81%), dysgeusia (71%), parotitis (67%) were observed more frequently. The ORR for all patients were 71.4%, and CR/PR were 50.0%/25.0% in R-HNSCC and 7.7%/61.5% in R/LA-HNNSCC. At a median follow up of 18.8 months (range 9.2–29.0), 1-year PFS and OS by investigator assessment were 70.6% and 100%, respectively. The data for antitumor activity is still immature and will be further updated. Conclusions: AB-BNCT for R-HNSCC and R/LA-HNNSCC demonstrated an acceptable safety profile and a promising antitumor activity.
Hyperprogressive disease (HPD) in head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint inhibitors (ICI).
Authors: Alfieri Salvatore , Ferrara Roberto , Calareso Giuseppina , Cavalieri Stefano , Platini Francesca , Mancinelli Moela , Resteghini Carlo , Orlandi Ester , Iacovelli Nicola Alessandro , Ferella Letizia , Piazza Cesare , Apollonio Giulia , Galbiati Donata , Bossi Paolo , Bergamini Cristiana , Locati Laura Deborah , Licitra Lisa F.
Published: May 2019

6029

Background: HPD was described in 9% of cancer patients (pts) treated in phase I trials, in 13.8% of advanced non-small cell lung cancer and 29% of 34 HNSCC pts upon ICI. A better definition of the hallmarks and survival outcomes of HPD pts in a larger cohort of HNSCC is still lacking. Methods: We retrospectively analyzed all advanced HNSCC pts treated with ICI at our Institution between October 2014 and December 2018. Three scans, performed before ICI, at baseline and at first evaluation during ICI, were assessed according to RECIST 1.1. Tumor Growth Kinetics (TGK) pre- (TGKpre) and post-baseline (TGKpost) were measured as previously reported (Saâda-Bouzid E, Ann Oncol 2017). Pts were defined HPD if they had progression at first radiological evaluation and TGKpost/TGKpre ≥2. Correlation between HPD and clinical characteristics was performed by Fisher or t-student test. Median overall survival (mOS) and progression free survival (mPFS) were estimated using the Kaplan-Meier method and compared between HPD and non-HPD using the log-rank test. Results: Ninety pts were eligible: 18% were female, 4% had ECOG PS ≥ 2, 73% smoking history, 37% oropharyngeal cancer (61% HPV+), 65% locoregional disease (89% previously irradiated), 54% received combined immunotherapy, 75% in ≥ 2nd line. Two out of 90 pts had TGKpre = 0 and were not evaluable for TGK ratio. HPD was observed in 7.9% (7/88) of pts. HPD pts were significantly younger compared to non-HPD pts (median age 53 ± 3.7 vs 63.3 ± 0.9 years, p = 0.002) and had a significantly higher median neutrophil-lymphocyte ratio (NLR) (11.5 ± 3.5 vs 6.4 ± 0.4, p = 0.004). Overall, mOS and mPFS were 7.5 (95% CI: 4.2-10.8) and 2.2 months (95% CI: 0.9-3.4), respectively. At a median follow-up of 20.9 months (95% CI: 19-22.8), HPD pts had a significantly worse mPFS compared to non-HPD pts [1.8 (95% CI: 1.5-2.2) vs 3.5 (95% CI: 2.2-4.8) months; p = 0.001]. HPD correlated with a not significant trend in lower mOS compared to non-HPD group [3.7 (95% CI: 2.4-5.1) vs 8.3 (95% CI: 4.1-12.5) months; p = 0.348]. Three (43%) out of 7 HPD pts early switched to chemotherapy after PD to ICI having a mOS of 8.1 months (range 3.7-25.3). Excluding these 3 pts, HPD correlated with a significantly worse mOS compared to non-HPD [2.6 (95% CI: 1.9-3.3) vs 8.3 (95% CI: 4.1-12.5) months; p = 0.006]. Conclusions: HPD was identified in 7.9% of HNSCC and correlated with younger age and higher NLR. HPD pts who did not receive a subsequent treatment had poorer mPFS and mOS. The assessment of HPD in a control cohort of advanced HNSCC upon standard chemotherapy is ongoing.
Metformin treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients induces an anti-tumorigenic immune response.
Authors: Karivedu Vidhya , Yaniv Benyamin , Asman Melissa , Palackdharry Sarah , Gulati Shuchi , Jandarov Roman , Hashemi Sadraei Nooshin , Takiar Vinita , Wise-Draper Trisha Michel
Published: May 2019

6037

Background: Metformin is a biguanide, widely used oral hypoglycemic agent. Metformin has also shown to inhibit tumor growth and progression in a wide variety of cancers including Head and Neck Squamous Cell Carcinoma (HNSCC). Metformin activates AMP protein kinase (AMPK) related pathways leading to inactivation of mammalian target of rapamycin (mTOR) and suppression of its downstream effectors. In addition, metformin is postulated to alter immune regulation in the tumor microenvironment leading to increased tumor cell killing. Here, we report our findings on the impact of metformin on T cells, NK cells and cytokines from patient peripheral blood mononuclear cells (PBMCs) from a phase I open-label single site dose escalation study combining metformin and chemoradiation (CRT) in HNSCC (NCT02325401). Methods: In this study, we evaluated the immune cell phenotypes and cytokine profiles of peripheral blood in patients before and after metformin treatment on trial by using flow cytometry and cytokine magnetic bead assays (Luminex). Cytokine profiles were further studied in co-culture experiments combining PBMCs, HNSCC cell lines, and metformin. Results: Patients who received metformin developed expanded NK cell populations, increased NKG2D expression, and a shift in their CD8+ T-cell memory phenotypes. Patient serum ELISA examination revealed increased anti-tumorigenic cytokine profiles. Metformin treatment of HNSCC cell lines in vitro as well as HNSCC PBMCs ex vivo resulted in downregulation of STAT3 compared to healthy controls. Downregulation of STAT3 may be a potential mechanism in which metformin stimulates NK cells. Conclusions: Here we show evidence that metformin treatment has a direct effect on the innate immune system in patients with HNSCC, inducing an anti-tumorigenic immune response suggesting that metformin continues to be a good candidate to yield improved clinical outcomes in patients with advanced stage HNSCC. Clinical trial information: NCT02325401.
Role of the oral and gut microbiota as a biomarker in locoregionally advanced oropharyngeal squamous cell carcinoma (ROMA LA-OPSCC).
Authors: Oliva Bernal Marc , Schneeberger Pierre H.H. , Taylor Rachel , Rey Victor , Hansen Aaron Richard , Taylor Kirsty , Bayley Andrew , Hope Andrew , Hosni Ali , Bratman Scott Victor , Ringash Jolie , Gilbert Ralph William , Weinreb Ilan , Perez-Ordonez Bayardo , Waldron John , Xu Wei , Guttman David , Siu Lillian L. , Coburn Bryan , Spreafico Anna
Published: May 2019

6045

Background: The ROMA LA-OPSCC ( NCT03759730) study prospectively evaluated the oral and gut microbiota in a single-centre cohort of LA-OPSCC patients (pts) receiving chemoradiotherapy (CRT). Methods: LA-OPSCC pts treated with definitive CRT (IMRT plus single-agent cisplatin) were eligible. Oral swabs over the tumor site and stool samples were collected at baseline and end of CRT (EOT). Taxonomic profiles were generated by 16S rRNA sequencing. ANOSIM/Kruskal-Wallis tests were used to identify differences between baseline and EOT samples. Results: A total of 96 samples were collected from 24 evaluable pts (100% compliance). Baseline characteristics: median age = 61 (range, 50-71); smoking status current/former/never = 5/11/8; HPV+/- = 23/1; stage I/II/III/IVA = 7/7/9/1; use of antibiotics = 12 pts. In oral swabs, decreased Shannon diversity ( p< 0.01) and changes in abundance (adjusted p value: q< 0.05) of multiple taxa including Prevotella, Veillonella, and Streptococcuswere observed at EOT vs baseline. Stool diversity did not differ between baseline and EOT ( p= 0.42), but abundance of Ruminoccocus and Roseburia decreased ( q< 0.05). CRT-associated changes remained significant when controlled for stage, smoking, antibiotics, cisplatin dose and mucositis grade ( p< 0.01). In HPV+ pts, stage I-II baseline oral swabs had higher relative abundance of Clostridium IV ( p= 0.02) and Escherichia ( p= 0.04) than stage III, which had higher Fusobacterium ( p =0.03) and Gemella ( p< 0.01). Relative abundance of Actinobacteria (p < 0.01), Proteobacteria (p < 0.01) and Firmicutes (p = 0.03) was higher in stool from stage III pts . Akkermansia muciniphila was present in 57% of the stage I-II stool samples, and 11% in stage III ( p= 0.04). Conclusions: CRT in LA-OPSCC is associated with increases in potentially pathogenic genera in the oropharynx. HPV+ stage III disease was associated with higher Fusobacterium in the oropharynx, which has been implicated in tumor metastases, and with decreased prevalence of the immunotherapy-response-associated species Akkermansia in stool. These preliminary observations suggest an opportunity for the evaluation of IO based therapies or manipulation of the gut microbiota in this patient population. Clinical trial information: NCT03759730.
Impact of tobacco smoking on radiotherapy outcomes in 1875 HPV-positive oropharynx cancer patients.
Authors: Lassen Pernille , Huang Shao Hui , Su Jie , O'Sullivan Brian , Waldron John , Andersen Maria , Primdahl Hanne , Johansen Jorgen , Kristensen Claus , Andersen Elo , Alsner Jan , Lilja-Fisher Jacob , Bratman Scott Victor , Spreafico Anna , de Almeida John R. , Xu Wei , Overgaard Jens
Published: May 2019

6047

Background: This study investigates the impact of smoking on radiotherapy (RT) outcome and survival in a population based cohort of HPV+ oropharynx cancer (OPC). Methods: We identified all OPC with positive p16 staining from 2007 –2015 who received curative IMRT according to approved guidelines in two oncology groups. Associations between smoking and locoregional control (LRC) and distant control (DC) were estimated by competing risk regression. Disease free survival (DFS) and overall survival (OS) were estimated by proportional-hazards regression model. Multivariable analyses (MVA) adjusted for age, gender, performance status (PS), T- and N-category, and treatment regimen. Results: A total of 1875 patients were included. Median age was 59.2 [31.3-86.8]; 79% (1481) were males; 96% (1651) had PS <2; 71% (1337) received concurrent chemo-radiotherapy (CRT) +/- hypoxic modification (Nimorazole); and 538 (29%) received RT alone +/- Nimorazole. 23% (425) were current smokers (at time of diagnosis) and 46% (853) were ex-smokers. Median smoking pack-years (PY) was 20.1 in the total cohort, and higher in current smokers vs ex-smokers (38 vs 20 PY, p<0.001). 63% of current smokers had >30 PYs. Median follow-up was 4.8 years. Actuarial 5-year univariate analysis showed that current smokers had a reduced probability of LRC (85% vs 92%, p=0.002), DC (88% vs 92%, p=0.046), DFS (69% vs 84%, p<0.001), and OS (73% vs 88%, p=<0.001) compared to never-smokers (n=567). Outcomes for ex-smokers and never-smokers were similar. In MVA current smoking retained strong independent significance for LRC (HR 1.73 [1.18-2.53]), DFS (1.79 [1.35-2.36]) and OS (2.06 [1.49-2.84]). However, DC was not significantly influenced by current smoking status (1.27 [0.83-1.95]). Similar observations were found for >30PY. Conclusions: Heavy lifetime and current smoking negatively impacts LRC and survival in HPV+ OPC. While smoking mediated hypoxia could interfere with RT efficacy, a putative impact on tumor biology remains uncertain in the absence of a detriment to distant metastasis risk. The findings support encouraging smoking cessation to improve therapeutic efficacy of RT and to avoid excess smoking related mortality.