bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative recombinant adenoviral human p53 gene combined with intensity-modulated radiation therapy in treatment of stage IV papillary thyroid carcinoma: A randomized clinical study.
Authors: Zhu Jingqiang
Published: March 2020

5550

Background: Most of stage IV papillary thyroid carcinoma (PTC) is initially unresectable due to invading surrounding structures, and is also commonly resistant to standard radio- or chemo-therapy. P53 gene therapy could increase tumor radiosensitivity and inhibit tumor angiogenesis. This study is to evaluate the benefits of pre-operative recombinant adenoviral human p53 gene (rAd-p53) combined with intensity-modulated radiation therapy (IMRT) in treatment of stage IV PTC. Methods: Forty-six patients with historically-diagnosed stage IV PTC, satisfying the inclusion criteria, were randomly assigned into two groups: experimental group (EG) control group (CG). EG received intratumoral injection of 2-4×1012 rAd-p53 viral particles (VP) per 3 days for 10 times and IMRT once per day for 28 days at a total dose of 65 Gy. CG received the same IMRT therapy. Once month after the combined treatment, patients were assessed for resectability. A radical surgery was performed on the patients with a resectable tumor. All the patients received standard I131 therapy 1-1.5 months after surgery or after the last IMRT. Results: EG including 25 cases, 19 females and 6 males, had a radical surgery rate of 76% (19/25), one-year survival rate of 96%, and no local recurrence and distant metastases for patients having a surgery. The tumors in six patients of EG were still unresectable. But all these six patients had a local partial response. The tissue sample analyses showed increased fibrous tissues, apoptotic cells, and increased Bax and p21 protein and mRNA levels. CG including 21 cases, 15 females and 6 males, had a radical surgery rate of 47.6% (10/21), one-year survival rate of 81.0%, and distant metastatic rate of 20% (2/10) for patients having a surgery. The local partial response rate of unresectable patients in CG was 72.7% (8/11). There were no changes in Bax and p21 protein and mRNA levels. The main side effects of rAd-p53 were self-limited fever, occurring in 24 of EG patients. Conclusions: Pre-perative rAd-p53 combinedwith IMRT in treatment of the stage IV PTC increases radical surgical rate and response rate, and improves long-term efficacy.
Recombinant adenoviral human p53 gene combined with radio- and chemotherapy in treatment of advanced nasopharyngeal carcinoma: A randomized clinical study.
Authors: Lan Guiping , SI Yongfeng , Qin Yangda , Deng Zhuoxia , HE Chengcheng , Huang Bo , LU Jinlong
Published: March 2020

5558

Background: Studies showed p53 gene therapy could enhance the anti-tumor effect of both chemo- and radiotherapy. The anti-tumor function of p53 gene is associated with up-regulated expression of p21 and Bax. Here, we investigate the beneficial role of recombinant adenoviral human p53 gene (rAd-p53) combined with chemoradiotherapy in treatment of advanced nasopharyngeal carcinoma (NPC), and p21 and Bax protein expression in pre- and post-treatment tumor tissues. Methods: Sixty-three patients with historically-diagnosed advanced NPC, with ECOG performance status less than 2, life expectancy greater than 3 months and adequate organ function tests, were randomly assigned into two groups: 32 in experimental group (EG) and 31 in control group (CG). EG received intratumoral injection of 1×1012 rAd-p53 viral particles (VP) per 3 days for 6-8 times, carboplatin 300 mg/m2 on day1 and continuous infusion of a total dose of 2000 mg/m2 of 5-Fu on day1-5 for 3 cycles, and radiotherapy at a dose of 2Gy/fraction for a total dose of 70-76 Gy/35-38f. CG received the same chemo- and radiotherapy. Pre- and post-treatment tissue samples were analyzed for Bax and p21 protein levels. Results: The median follow-up time was 28 months. EG achieved a complete response rate (CR) of 62.5% and overall response rate (RR) of 90.6%, both rates being statistically significantly higher than that of CG (CR=35.5%, RR=74.2%). One-year of overall survival (OS) was 100.0% for EG and 90.3% for CG, and one year of progress free survival (PFS) was 96.7% and 77.4% for EG and CG, respectively. Two-year OS was 95.7% and 86.4% for EG and CG, respectively, and two-year of PFS was 79.6% and 73.5% for EG and CG, respectively. After treatment, both Bax and p21 protein levels in EG increased significantly. In CG, both proteins levels also increased after treatment but not significantly. The main side effects of rAd-p53 were self-limited fever, occurring in all of EG patients. Conclusions: RAd-p53 as a component of the comprehensive therapy for advanced NPC contributes significant beneficial effects. Increased levels of Bax and p21proteins after treatment represent two mechanisms of p53 anti-tumor activities.
EGFR-KRAS genotyping and EGFR-CDX2 expression in sinonasal intestinal type adenocarcinomas: Toward a new targeted therapy?
Authors: Choussy Olivier , Abramovici Olivia , Paviot Alexandre , Lamy Aude , Dehesdin Daniele , Sabourin Jean-Christophe
Published: March 2020

5565

Background: Sinonasal carcinomas are very rare tumors which are sometimes not eligible for curative surgery. Alternative therapies (i.e. conventional chemotherapies/radiotherapy) are used but with poor results. Therefore, the need for a more efficient treatment is mandatory. Aims of our study: Comparing EGFR and KRAS genetic profiles, EGFR and CDX2 phenotypes of sinonasal intestinal type adenocarcinomas (ITAC) with colorectal adenocarcinomas (CRC). Methods: 41 patients were treated in our institution between 1983 and 2007. All pathological specimens were reclassified according to the 2005 WHO classification. An immunohistochemical (IHC) study was carried out for EGFR and CDX2 expression. We were able to analyze 38 of the 41 specimens for KRAS and EGFR mutations. SNaPshot multiplex system was used to determine the presence of the most common mutations which are located in exon 18, 20 and 21 for EGFR and in exon 2 (codon 12 and13) for KRAS. Fragment analysis method was used for EGFR exon 19 deletions. Results: Thirty five of the 38 patients were classified as ITAC (33 men and 2 women). The mean age was 64.5 years. Exposure to wood work was found in 29 cases (85%). CDX2 expression was present in 31 (89%) cases of ITAC and absent in all non intestinal adenocarcinomas (3 cases). EGFR was expressed in 29 ITACs (83%) with various degrees of IHC expression: 19 (56 %) 1+, 7 (21%) 2+, and 3 with 3+ immunopositivity. No EGFR mutation was found in the whole population; 5 ITAC patients (14%) disclosed KRAS mutations. Conclusions: Histological, phenotype and genetic profiles of ITAC are very similar to those of colorectal adenocarcinoma. These results suggest that ITACs with wt KRAS could respond to anti MoAb anti-EGFR therapy in the same way as metastatic CRC. We propose that all sinonasal tumors should undergo: firstly, CDX2 IHC in order to confirm the ITAC histological subtype and then KRAS genotyping to select the wt population which could benefit from such anti EGFR targeted therapy.
ECOG 1308: A phase II trial of induction chemotherapy followed by cetuximab with low dose versus standard dose IMRT in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx (OP).
Authors: Marur Shanthi , Lee Ju-Whei , Cmelak Anthony , Zhao Weiqiang , Westra William H. , Chung Christine H. , Gillison Maura L. , Gilbert Jill , Bauman Julie E. , Wagner Lynne I. , Ferris Robert L. , Trevarthen David R. , Colevas A. Dimitrios , Jahagirdar Balkrishna N. , Burtness Barbara ,   Eastern Cooperative Oncology Group
Published: March 2020

5566

Background: Human papillomavirus (HPV) infection is now recognized as a risk factor of oropharyngeal squamous cell carcinoma (OPSCC) and approximately 60% of OPSCC are HPV positive (+). ECOG 2399 using induction chemotherapy (IC) followed by chemoradiation demonstrated significantly improved 2-yr progression-free survival (PFS; 85% vs. 50%, p=0.05) and overall survival (OS; 94% vs. 58%p=0.004). These results have generated interest in development of less toxic regimens for HPV(+) patients with lower dose radiation. Methods: Design: This is a phase II clinical trial .The primary objective is the estimation of the 2-year PFS in the reduced dose RT arm. Secondary objectives include toxicity, OS, objective response, quality of life (QOL) and correlative studies of biomarkers. Eligibility Criteria: Patients with Stage III or IV resectable HPV(+) OPSCC. HPV(+) disease is defined as p16 IHC strongly (+) on at least 70% of cells, and/or HPV-16 ISH (+).Treatment : Patients received IC with a combination of paclitaxel 90mg/m2 on days 1,8, and 15, cisplatin 75mg/m2 on day 1, and cetuximab loading dose of 400 mg/m2 on day 1, cycle 1 followed by cetuximab 250 mg/m2 weekly, thereafter. Each cycle was 21 days for a total of 3 cycles. After completion of IC, patients were assessed clinically with a complete head and neck exam and imaging studies. Those with clinical CR at primary site received radiation to 54Gy plus cetuximab. Patients with clinical PR or SD at primary site received standard dose RT with cetuximab. Correlative Studies: The expression of biomarkers on tumor and blood samples and QOL parameters will be correlated with the clinical outcomes. Results: Current enrollment: Target accrual was 83 patients. The study accrued 90 patients from March 17, 2010 to accrual on October 19, 2011. Baseline characteristics reveal; median age 57 years, 94% male, 95% white, 47% never smokers, 10% <10 pack year (pyr) smoking, 38% >10 pyr smoking, 84% not current smokers, 39% node (N) stage N2b and 29% N2c, 22% tumor (T) stage T1, 52% T2, 16% T3, and 10% T4. Conclusions: Enrollment has just completed with no data analysis available.
Paranasal sinus squamous cell carcinomas (PNSSCC) incidence and survival trends.
Authors: Ansa Benjamin , Goodman Michael , Ward Kevin , Kono Scott A. , Owonikoko Taofeek Kunle , Grist William , Wadsworth Trad , El-Deiry Mark , Chen Amy Y. , Ramalingam Suresh S , Beitler Jonathan Jay , Khuri Fadlo Raja , Shin Dong M , Saba Nabil F.
Published: March 2020

5570

Background: PNSSCC are rare, accounting for 3 percent of all head and neck malignancies. They generally present with local invasion and have a high rate of local recurrence. There has been little information on the trends in incidence and survival of PNSSCC and no randomized trials to guide therapy. We analyzed the incidence rates and survival outcomes for patients diagnosed with PNSSCC in the SEER database. Methods: Data were obtained from the U.S. National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Newly diagnosed PNSSCC reported to SEER from 1973 through 2008 were categorized according to the patient’s sex, age, year of diagnosis, and stage. The incidence and survival were then examined and compared across different demographic and disease-related categories. Results: A total of2,323 patients were identified. The mean age was 62 years, range: 14-85 yrs; males- accounted for 62.7%. Whites accounted for 75.8%, blacks for 12.2 % and 12.0% were of asian or pacific islanders and other groups. Maxillary sinus primary accounted for 76.3%, ethmoid (10.2%), sphenoid (4.3%). The disease was localized in 9.5%, had regional spread in 72.0% and distant disease in 12.2%, at diagnosis. A statistically significant decrease (Annual Percent Change of -1.6%, 95%CI= [-2.0, -1.1]) in the overall incidence was observed by Joinpoint analysis (p<0.01). The decrease in incidence was significant in patients with maxillary sinus (p<0.01) and was more pronounced in the white population compared to other groups. Both the observed and relative 5-year survival significantly increased over time and this was more notable in the white population compared to other groups. The observed 5-year survival rate increased from 24.9% (95% CI = [20.3-29.6]) during the 1975-1983 time-period to 40.8% (95% CI = [33.4-48.0]) during the most recent period of 2002-2008. Conclusions: There has been a decline in the overall incidence of PNSSCC more notably in the white population and for patients with maxillary sinus tumors. The 5-year observed and relative survival has significantly increased. Our findings should incite more efforts to understand the factors behind the change in incidence and survival.
Predictors for response to cetuximab in a prospective clinical trial (E2303) of patients with head and neck squamous cell carcinoma (HNSCC).
Authors: Psyrri Amanda , Lee Ju-Whei , Pectasides Eirini , Vassilakopoulou Maria , Burtness Barbara , Rimm David , Wanebo Harold J. , Forastiere Arlene A.
Published: March 2020

5576

Background: Theidentification of resistance mechanisms to Epidermal Growth Factor Receptor (EGFR) inhibitors remains critical lack in the management of HNSCC. We sought to determine predictors for response to cetuximab in a phase II clinical trial. Methods: 63 patients (pts) with operable stage III/IV HNSCC participated in E2303, an Eastern Cooperative Oncology Group (ECOG) phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel and carboplatin x 6 followed by chemoradiotherapy with the same regimen. A tissue microarray was constructed and EGFR, ERK1/2, Met, pAkt and STAT protein expression levels were assessed using AQUA. The objectives of analysis were to determine association of biomarkers with E2303 efficacy outcomes (best objective response (OR), overall survival (OS), progression-free survival (PFS), and event-free survival (EFS)). The logistic regression model was used to examine relationship between marker measurements (on a continuous scale) and OR. The univariate and multivariate Cox proportional hazards models were used to evaluate the relationship between markers and event-time distributions. Fisher’s exact test was used to evaluate differences in response rate between groups (high vs. low AQUA scores). Event-time distributions were estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Cytoplasmic ERK1/2 levels weresignificantly associated with PFS and OS (p=0.03 and 0.01, respectively). Nuclear ERK1/2 levels were significantly associated with OS (p=0.02) and tended towards significance for PFS (p=0.09). The multivariate Cox regression analysis shows that cytoplasmic and nuclear ERK1/2 are significantly associated with OS and PFS after controlling for primary site and disease stage, respectively There was no significant association between cytoplasmic or nuclear ERK1/2 status and OR (p-values 0.98 and 0.41, respectively).No association was found between expression of any of other biomarkers and outcome measures. Our data analysis was based on 35 pts with marker data available. Conclusions: Ras/MAPK/ERKpathway may be associated with resistance to cetuximab in HNSCC.
A combined evaluation strategy of FDG PET/CT and contrast-enhanced diagnostic CT (ceCT) for lymph nodes in the neck.
Authors: Gandikota Neetha , Ng Su Ann , Cotter Ryan , Akin Yildiz , Som Peter M. , Genden Eric , Heiba Sherif , Kostakoglu Lale
Published: March 2020

5578

Background: Accurate assessment of cervical lymph nodes (LNs) for determination of metastatic involvement is of prime importance for management. Our objective was to determine the incremental value of combining metabolic and morphologic information in the differentiation between benign and malignant LNs. Methods: A total of101 pts with head and neck squamous cell (n=91) or thyroid cancer (n=6) or lymphoma (n=4) were included in the study. PET/CT and neck ceCT were acquired simultaneously or sequentially at staging (n=48) or restaging (n=53). In 131 LNs, variables evaluated includes SUVmax, size, shape (elliptical vs non-elliptical), presence of extracapsular extension (Ecext-irregular margins), necrosis, and fatty hilum. Histopathology (n=96) and 12 mo follow-up (n=35) were used for confirmation of the findings. ROC analyses determined the SUVmax cut-off. Results: Of131 LNs, malignancy wasconfirmed in 49 (37%).Results are shown in table. In the detection of malignancy, SUVmax of 4.5 yielded the best balance between the sensitivity and specificity, performing better than all CT variables alone. Combination analysis improved results only when SUVmax (4.5) was added to Ecext. However, best combination results were obtained at a SUV cut-off of 3.7. Higher SUV cut-off did not significantly improve overall performance of SUVmax alone (Table). Conclusions: In the differentiation of malignant from benign LNs, SUVmax (4.5) yields better results than CT variables alone. However combining a lower SUVmax (3.7) with Ecext produced the best results. Increasing SUVmax cut-off only produced a gain in specificity at a significant cost of sensitivity. [Table: see text]
A phase I/II study of concurrent nab-paclitaxel, carboplatin, and IMRT for locally advanced squamous cancer of the head and neck (LASCCHN).
Authors: Tishler Roy B. , Lorch Jochen H. , Sher David J , Clark John Ross , Chan Annie W , Suda Margaret , Balboni Tracy A. , Busse Paul M. , Haddad Robert I. , Wirth Lori J.
Published: March 2020

5579

Background: We studied escalating doses of weekly nab-paclitaxel (Abraxane, AB) combined with weekly carboplatin (CP) and daily IMRT in patients with LASCCHN to determine the safety and optimal dosing of AB. The favorable biodistribution of AB, an albumin bound formulation of paclitaxel, may allow for intensified locoregional treatment without increasing normal tissue toxicity. Methods: An AB dose escalation was performed, initially using concurrent weekly CP (AUC = 1.5), Erbitux (ER) and daily IMRT to 70 Gy. After ER was dropped, dose escalation of AB from 20 mg/m2 to 50 mg/m2 was performed in 10 mg/m2 increments using a 3 + 3 study design. Results: A total of 28 patients have enrolled and all have completed treatment. Patients ranged in age from 42 to 72 years old (median = 59), with follow up from 3 to 48 months (median = 25). Most patient had oropharyngeal primaries (n=22) and stage III (n=8) or IV (n=20) disease; 18 were HPV+, 6 HPV- and 4 unknown. Initially 6 patients received weekly AB (20 mg/m2), ER and CP, but ER was dropped due to greater than anticipated mucositis and dysphagia. Subsequently, 3 patients each received CP with AB at 20, 30 and 40 mg/m2 weekly and a total of 13 received CP with AB at 50 mg/m2. The median radiation dose is 70 Gy and the median number of weekly chemotherapy cycles is 7. The primary toxicities were Grade 3 dysphagia, mucositis and dermatitis in 24 of 28 patients. Only 3 (of 28) PEG tubes remain at 4, 6 and 14 months. No DLTs were observed at any dose level. There have been 5 recurrences, with 4 being local-regional. Two patients have died of disease and 26 are alive. Conclusions: Concurrent AB, CP, and IMRT is a safe chemoradiotherapy combination in LASCCHN with early data demonstrating feasibility and efficacy.
HPV and survival in patients with oropharyngeal squamous cell cancer of the head and neck (OPC) treated with induction chemotherapy followed by chemoradiotherapy (ST) versus chemoradiotherapy alone (CRT): The Dana-Farber experience.
Authors: Lorch Jochen H. , Hanna Glenn , Dai Wei , Thotakura Vijaya , Nair Vidya , Jaffa Zachary , Posner Marshall R. , Limaye Sewanti Atul , Rabinowits Guilherme , Tishler Roy B. , Sher David J , Haddad Robert I.
Published: March 2020

5582

Background: HPV status is a major prognostic marker for survival in patients with OPC. We examined overall survival (OS) and progression free survival (PFS) in patients with OPC and known HPV status treated at Dana-Farber Cancer Institute with ST and CRT between 2002 and 2011. Methods: 280 patients with OPC and known HPV status were identified retrospectively and clinical information was recorded. Results: 174 patients were treated with CRT (124 HPV positive, 50 HPV negative) and 106 patients were treated with ST (77 HPV positive, 29 HPV negative). For all 280 patients, OS and PFS were significantly better for patients who were HPV positive compared to those who were HPV negative. 3 year OS was 89.1% for HPV positive (95% CI, 83.8-94.7) and 70.5% for HPV negative patients (95%CI, 59.9-83%, HR 0.37, p=0.0007). Among HPV positive patients treated with CRT, 13/124 had died at 3 years (OS 88.5%, 95%CI 81.7-95.9) while 13 deaths were recorded among 50 HPV negative patients (OS 72.2%, 95% CI 59.1-88.2, HR 0.38, p=0.011). PFS at 3 years was also significantly better for HPV positive versus HPV negative patients(81.7% vs 58.8%, HR 0.42, p=0.006). In the group treated with ST, outcomes were similar despite a higher rate of stage IV versus stage III disease compared to the group treated with CRT (100% stage IV in ST versus 77% stage IV and 23% stage III disease in CRT group). Three year OS was 89.7% for HPV positive and 68.2% in the HPV negative group (8/77 HPV pos vs 10/29 HPV neg, HR 0.33, p=0.015). PFS was borderline better for HPV positive patients (81% vs 61.7%, HR 0.48, p= 0.058). Conclusions: We present the DFCI experience treating OPC with ST and CRT for patients with known HPV status over one decade.OS and PFS were superior for HPV positive versus HPV negative patients. Outcomes were virtually identical for patients treated with CRT versus ST despite a higher rate of stage IV disease in the ST group. Outcomes for the HPV negative patients in particular were superior compared to the published literature.
Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation (XRT) in recurrent squamous cell carcinoma of the head and neck (SCCHN): Long-term follow-up of Radiation Therapy Oncology Group (RTOG) protocol 9911.
Authors: Langer Corey J. , Harris Jonathan , Horwitz Eric M. , Kies Merrill S. , Curran Walter J. , Wong Stuart J. , Zhang Qiang , Ang K. Kian ,   Radiation Therapy Oncology Group
Published: March 2020

5583

Background: Loco-regionally recurrent SCCHN or new second primary tumor (SPT) in a previous radiation field, if not curable by surgery, is virtually always fatal. Chemotherapy alone yields a median survival time (MST) of no more than 10 to 11 months, 1- and 2- year overall survival (OS) rates of 35% and 10-15% at best. Concurrent re-irradiation and chemotherapy is an alternative strategy. Methods: Eligibility for RTOG protocol 9911 stipulated measurable, recurrent SCCHN or SPT in a previous radiation field, PS 0-1, and adequate end-organ indices. Patients (pts) received twice-daily XRT (1.5 Gy per fraction BID x 5 d every 2 weeks x4), plus cisplatin 15 mg/m2 IV QD x 5 and paclitaxel 20 mg/m2 IV QD x 5 every 2 weeks x 4. G-CSF was administered days 6 - 13 of each 2-week cycle. Primary endpoints were OS and progression-free survival PFS at 1 and 2 yrs. Secondary endpoints included acute/late toxicities and patterns of failure. Results: 105 patients were enrolled from March 2000 through June 2003. 100 patients were analyzable (76% male, med age 60 yrs). Oropharynx (41%) and oral cavity (27%) were the predominant primary sites. 23% had SPT. Median prior XRT dose was 65.7 Gy. 73% of pts completed all chemotherapy. Grade > 4 acute toxicity occurred in 28%, grade > 4 acute hematologic toxicity in 21%. 9 treatment-related deaths (9%) occurred: five in the acute setting, four late (including three carotid hemorrhages at 116, 427 and 2772 days). 1-, 2-, and 5-year OS rates were 50%, 27%, and 15% respectively. PFS at 1, 2, and 5 yrs were 35%, 18%, and 7%. 64.9% died from the incident cancer, 3.2% from SPT, and 21.2% from other, non-cancer causes. Estimated 10 yr survival is 5% with 6 pts still alive, including 2 free from relapse. Conclusions: Despite a high incidence of grade 5 toxicity, 1-, 2-, and 5- yr OS rates for split-course bid XRT and concurrent cisplatin/paclitaxel exceed results usually seen with chemotherapy alone. At 5-10 yrs, we have observed longterm survivors free of recurrence.
Second primary tumors in head and neck squamous cell carcinoma patients: A cross-sectional study.
Authors: Landeiro Luciana Garcia , Trufelli Damila , Matos Leandro Luongo , Cubero Daniel de Iracema Gomes , Kanda Jossi Ledo , Del Giglio Auro , Castro Gilberto
Published: March 2020

5588

Background: Head and neck squamous cell carcinoma (HNSCC) patients (pts) are at elevated risk of developing a second primary tumor (SPT). Here we aimed to study the frequency of SPTs and those characteristics related to an increased probability of SPT occurrence. Methods: It is a cross-sectional study in pts diagnosed with SCC primary located in oral cavity, oropharynx, hypopharynx or larynx, treated in two Brazilian institutions, with an index tumor diagnosed from Jan/2000 to Jan/2009. All pts were followed according the current recommendations, including clinical visits, imaging and endoscopic procedures. A SPT was defined following the Warren and Gates criteria (Am J Cancer 51:1358,1932), and they were classified as synchronous or metachronous if detected less or more than six months after the diagnosis of the index tumor, respectively. Results: 38 out of 318 HNSCC pts (12%) were diagnosed with 41 SPTs in their follow-up, being 12 synchronous (29%) and 29 metachronous (71%), all classified as SCC. Regarding the index tumor, it was primary located in oral cavity (114 pts, 36%), oropharynx (87 pts, 27%), larynx (83 pts, 26%) and hypopharynx (34 pts, 11%), and staged as I-II (30%) or III-IV (67%). The SPTs were located more frequently in oral cavity (27%), lungs (27%), oropharynx (15%) and esophagus (12%) and staged as I-II (44%) or III-IV (42%). Among the 29 metachronous SPTs, 12 (41%) were diagnosed in the first two years of follow-up, 11 (38%) between two and five years, and 6 (21%) after five years. Considering all the studied HNSCC pts and index tumor characteristics, including primary site, persistence of tabacco and alcohol habits, and treatment, none was identified as related to an increased probability of developing a SPT. In the median follow-up of 40 mo., the median overall survival was not reached in all 318 HNSCC pts. No difference in overall survival was observed between those pts diagnosed or not with a SPT (HR 0.35, p=0.555). Conclusions: We found a 12% incidence of SPTs in these HNSCC pts. At diagnosis, SPTs were located more frequently in oral cavity and lungs, in advanced stages, and may occur even after five years after the index tumor. More efficient primary and secondary preventive strategies of SPTs must be developed.
Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial.
Authors: Piccart-Gebhart Martine J. , Noguchi Shinzaburo , Pritchard Kathleen I. , Burris Howard A. , Rugo Hope S. , Gnant Michael , Hortobagyi Gabriel N. , Melichar Bohuslav , Petrakova Katarina , Arena Francis P. , Xu Cindy , Cahana Ayelet , Taran Tanya , Sahmoud Tarek , Lebwohl David Edward , Campone Mario , Baselga José
Published: March 2020

559

Background: Current treatment options for postmenopausal patients with estrogen-receptor–positive (ER+) breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. The BOLERO-2 trial supports the activity of everolimus (EVE; an oral mammalian target of rapamycin [mTOR] inhibitor) added to the steroidal aromatase inhibitor exemestane (EXE) to prolong progression-free survival (PFS) in this patient population. Long-term PFS and survival data are awaited. Methods: BOLERO-2 is a phase III double-blind, randomized, international trial comparing EVE (10 mg once daily) plus EXE (25 mg once daily) versus placebo (PBO) plus EXE in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs (letrozole or anastrozole). Patients were randomized (2:1) to EVE + EXE or PBO + EXE. The primary endpoint was PFS by local investigator assessment. Main secondary endpoints included centrally assessed PFS, overall survival (OS), safety, bone turnover, and overall response rate (ORR). Results: Baseline disease characteristics including tumor burden and prior cancer therapy were well balanced between treatment arms (N = 724). Median PFS was doubled and response rates were consistently improved with EVE + EXE (n = 485) vs PBO + EXE (n = 239) in interim analyses. Median PFS by local assessment was ~3 mo with PBO + EXE vs 6.9 mo (hazard ratio [HR] = 0.43; P < .0001) and 7.4 mo (HR = 0.44; P < .0001) with EVE + EXE at 7.5 mo and 12.5 mo follow-up, respectively. Fewer deaths were reported with EVE + EXE (17.2%) vs PBO + EXE (22.7%) at 12.5 mo follow-up. Safety profiles were consistent with previous reports for mTOR inhibitors. PFS data including 528 events (protocol-specified final analysis), and updated OS and safety data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in patients with NSAI-refractory advanced ER+ BC. There were fewer deaths among patients receiving EVE, and further follow-up will evaluate the effect of EVE on OS.
A phase II trial of the multitargeted kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer (MTC).
Authors: Schlumberger Martin , Jarzab Barbara , Cabanillas Maria E. , Robinson Bruce , Pacini Furio , Ball Douglas Wilmot , McCaffrey Judith C , Newbold Kate , Allison Roger , Martins Renato , Licitra Lisa F. , Shah Manisha H. , Bodenner Donald , Elisei Rossella , Burmeister Lynn A. , Funahashi Yasuhiro , Sellecchia Rita , Andresen Corina , O'Brien James P. , Sherman Steven I.
Published: March 2020

5591

Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of lenvatinib partial responses (PR) were observed in thyroid as well as melanoma, endometrial, and renal cancers. Methods: Patients (pts) with unresectable MTC and disease progression demonstrated by RECIST during the prior 12 months were enrolled. Pts may have received prior VEGFR targeted therapy. Pts were treated with a starting dose of lenvatinib 24 mg once daily in 28 day cycles until disease progression or development of unmanageable toxicities. Primary end point was Response Rate (RR) by RECIST. Tumor genetic analysis and circulating cytokine and angiogenic factors (CAF) analysis were performed. Results: 59 pts were enrolled (med age: 52; Male: 63%;) and are evaluable for response. 54% of pts required dose reduction for management of toxicity, and 22% were withdrawn from therapy due to toxicity. The most common treatment-related adverse events were proteinuria 58% (Gr3: 2%), diarrhea 56% (Gr3: 5%), hypertension 48% (Gr3: 7%), fatigue 44% (Gr3: 5%), decreased appetite 41% (Gr3: 5%), nausea 34% (Gr3: 0), and weight decreased 32% (Gr3: 3%). No Gr4 events were reported for these event categories. Confirmed PRs were observed in 21pts (RR: 36%, 95% CI: 24-49) based on independent imaging review (IIR) and 29 pts (RR: 49%, 95% CI: 36-62) based on investigator assessment. For pts who received prior VEGFR-directed treatment (n=26) RR=35% (IIR); with no prior VEGFR-directed treatment (n=33) RR=36 % (IIR). Median PFS by IRR is 9.0 mo (95% CI: 7.0-) (based on minimum 8 mo. f/u, 46% events observed). There was no clear difference in treatment response between RET-mutant (RET-mu) and RET-wild type (RET-wt) patients. Low baseline levels of ANG2, sTie-2, HGF and IL-8 were associated with greater tumor shrinkage and prolonged PFS whereas high baseline levels of VEGF and sVEGFR3 were associated with greater tumor shrinkage. Conclusions: Lenvatinib administered orally at a dose of 24 mg once daily to patients with MTC is associated with manageable toxicity and a RR of 36%, identifying lenvatinib as a promising new potential therapeutic agent for treating patients affected with this disease.
Final results of a phase II study of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCCHN).
Authors: Blumenschein George R. , Glisson Bonnie S. , Lu Charles , Sabichi Anita Lyn , Ginsberg Lawrence E. , Bartos Claudia I. , Feng Lei , Tran Hai T. , El-Naggar Adel K. , Lippman Scott Michael , Kies Merrill S.
Published: March 2020

5592

Background: Cytotoxic chemotherapy (CT) is the current standard treatment for metastatic/recurrent SCCHN. The prognosis for these patients (PTS) is poor with a median progression free survival (PFS) of 4 months with CT. Survival in PTS with SCCHN may correlate inversely with the number of angiogenic growth factors secreted. Sorafenib is a potent inhibitor of c-Raf, b-Raf, VEGFR-1/2/3 and PDGFR-β. To investigate the hypothesis that a multi-targeted TKI added to chemotherapy would improve outcomes in patients with metastatic/recurrent SCCHN, we performed a phase II trial of   paclitaxel and carboplatin and sorafenib (PCS). Methods: PTS were required to have ECOG PS 0-1, measurable disease, controlled blood pressure, and may have received one regimen of induction, concomitant or adjuvant CT, but not CT for recurrent/metastatic disease. Sites of primary disease excluded nasopharynx and paranasal sinus. Treatment consisted P 200mg/m2 and C AUC 6 intravenously on day 1 followed by S 400 mg orally bid (days 2-19) in every 3-week cycles.  Primary endpoint was PFS, targeting median PFS of 6 months (M). Secondary endpoints include overall survival (OS), response rate (RR), exploratory biomarkers, and toxicity. Results: Forty-eight PTS with SCCHN were enrolled with 44 PTS evaluable for PFS and response using RECIST. Median age: 56 years (22-79 years), 89% male, median ECOG PS 1.  Median follow-up was 24.1 M.  RR was 55% (n=24), disease control rate was 84% (n=37), median PFS was 8.51 M (95% CI: 5.98 ~ 13 months), and median OS was 22.6 M (95% CI: 13.1 - NA months). Grade ³3 treatment related toxicities included hand-foot syndrome (n=10), neutropenia (n=5), pain (n=6), elevated lipase (n=4), elevated amylase (n=3), anemia (n=3), fatigue (n=2), hypertension (n=2), neuropathy (n=2), febrile neutropenia (n=2), and thrombocytopenia (n=2).  Conclusions: The combination of PCS was well tolerated and had encouraging activity in recurrent/metastatic SCCHN. Blood-based and tissue biomarkers are being analyzed.  Final outcomes, toxicity, and correlative biomarker data will be reported.
Contralateral parotid volume as an objective marker for adaptive radiotherapy in head and neck cancer.
Authors: Gagnon Patrick James , Simeonova Anna , Fuss Martin , Weintraub Sheri , Thomas Charles R. , Holland John M
Published: March 2020

5596^

Background: Deformable image registration simplifies the process of adaptive radiotherapy and allows for sophisticated dosimetric analyses of anatomic changes. Lacking is an objective measurement that could reliably predict for undesirable dosimetric changes during a course of radiotherapy. We analyzed daily changes in contralateral parotid volume and correlated these changes to mean dose delivered to the parotid gland over a course of radiotherapy in four patients. Methods: Daily cone-beam CT (CBCT) scans of four patients were imported into the MIM Maestro software. The simulation CT scan was registered to 35 daily CBCT’s per patient using a sequence of rigid and deformable registrations. Parotid contours were resampled and a deformed reconstruction of the planning CT was exported to the Eclipse treatment planning software. The CT reconstructions were extended superiorly and inferiorly and the original fluence map was re-computed on the reconstructions with the isocenter at daily treatment position. Mean dose percent change and mean volume percent change were calculated for all CBCT’s and averaged across all patients. Average mean dose percent change was plotted against average mean volume change and evaluated with simple regression analysis. Results: A mean of 31 CBCT’s per patient were evaluated. Contralateral parotid volume percent changes for all patients were -31%, -40%, -40%, and -22% with a mean percent change of -33%. Mean dose percent changes were 25%, 35%, 19%, and 25% with a mean percent change of 26% and a mean absolute dose increase to the parotids of 6.8 Gy. Simple regression analysis identified a coefficient of determination (R2) of 0.23 where the independent variable is volume percent change and the dependent variable is mean dose percent change. Conclusions: Daily or weekly volume assessment of critical volumes is feasible utilizing deformable image registration and CBCT. Our data suggests there may be a correlation between parotid volume changes and increases in mean parotid dose though no causality is inferred. This relationship could be useful as a simple objective volumetric threshold measurement to prompt adaptive re-planning and warrants further investigation.
Effect of MDV3100, an androgen receptor signaling inhibitor, on tumor growth of estrogen and androgen receptor-positive (ER+/AR+) breast cancer xenografts.
Authors: Elias Anthony D. , Cochrane Dawn R. , Jacobsen Britta M. , Cittelly Diana M. , Howe Erin N. , Jean Annie , Spoelstra Nicole S. , Protter Andrew A , Richer Jennifer K.
Published: March 2020

564

Background: The androgen receptor (AR) is detected by immunohistochemistry in approximately 75% of all invasive breast cancer; with ~88% of ER+ tumors expressing AR. Potent inhibition of AR activity could be a therapeutic strategy in ER+/AR+ breast cancer. MDV3100 is an androgen receptor signaling inhibitor (ARSI), which inhibits AR activity via three mechanisms: inhibition of androgen binding to AR, inhibition of AR nuclear translocation, and inhibition of nuclear AR-DNA binding. MDV3100 has demonstrated an overall survival benefit in men with post-docetaxel prostate cancer. Methods: Two ER+/AR+ breast cancer cell lines, MCF7 and BCK4 (recently derived from a pleurocentesis), were used to assess the proliferative effect of dihydrotestosterone (DHT) and estradiol (E2). The efficacy of MDV3100 at blocking DHT-mediated proliferation was compared to bicalutamide in ER+/AR+ breast cancer cells. MCF7 xenograft studies were performed to determine if MDV3100 can affect DHT or E2 mediated proliferation in vivo. Results: Both bicalutamide and MDV3100 inhibited DHT-mediated proliferation of ER+/AR+ cell lines. Although MDV3100 binds AR very effectively and does not bind ER, it also uniquely inhibited E2-mediated proliferation, while bicalutamide slightly enhanced E2 mediated proliferation. Results presented here demonstrate that MDV3100 inhibited E2-stimulated tumor growth of MCF7 mammary xenografts as effectively as tamoxifen. Conclusions: MDV3100 blocked both DHT- and E2-mediated growth of breast cancer cells, whereas bicalutamide enhanced E2-mediated proliferation. MDV3100 may have unique therapeutic utility in patients with AR+ breast cancer, regardless of ER status. Funding: DOD Breast Cancer Program Idea Award BC074403, Avon Foundation for Women, and University of Colorado Cancer Center pilot project funds to JKR.
ERβ mRNA expression in ERα-negative and triple-negative breast cancers.
Authors: Choi Young , Kim Hadong , Kim Tae-Hoon
Published: March 2020

574

Background: ERα is the main prognostic and therapeutic marker in breast cancer (BC). About 30% of BC cases are negative for ER (ERα-) and do not benefit from antiestrogen therapy (TAM). We aim to study ER-beta (ERβ) expression in ERα- and triple negative (TN) cancers to explore alternate pathway of treatment in this cohort. Methods: We studied 67 ERα- BC cases including 44 TN together with 74 ERα +BC cases obtained from patients aged 29 to 97 years old between 2003 and 2010. The histology included 110 intraductal, 12 medullary and 19 other types. 78 cases were grade 3, 52 were grade 2, and 11 were grade 1. RNA was extracted from FFPE and mRNA levels of ERβ isoform and ERα were determined by real-time quantitative reverse transcription PCR. IHC stains were done on TMA the sections for ERα, PR, Her-2, Ki-67, CK5/6 and Cyclin D1. Results: ERβ isoforms were highly expressed in ERα-, TN, basal-like and HER2 type BC cases. ERβ2 was the major ERβ variant expressed. Ki-67 proliferating cells (>20% nuclear staining) were mostly in ERα- rather than ERα+ cases (69.0% vs. 31.0%) as were cyclin D1- cells (82.2% vs. 17.8%). On the other hand, in ERα+ BC, ERα mRNA expression was consistently high and upregulated, and ERβ, low and down regulated, and the ratio of ERα+ to ERβ+ ranged from 3 to 100. ERβ1, 2 and 5 were co-expressed with ERα in 56%, 63%, and 30% of cases, respectively. Overall, ERβ mRNA levels did not show any significant correlation with age, tumor size, lymph node status and histological grades. Conclusions: ERβ-dependent proliferating tumor cells may render them more sensitive to TAM, and increase the effectiveness of TAM and its metabolites in ERα- and TN cases. Increased overall survival after adjuvant TAM ERα-BC may be directly related to ERβ over-expression. ERβ isoform is potential selective therapeutic target in a sub-cohort of ERα- BC. Additionally, when ERβ and ERα are co-expressed, ERβ appears to play a distinct role from its action in ERα- BC. [Table: see text]
Assessment of method of breast cancer detection and Oncotype DX recurrence score.
Authors: Kelly Ciara Marie , Parker Imelda , McCaffrey John , Crown John , O'Connor Miriam , McGee Sharon F. , Pusztai Lajos , Kelly Catherine M.
Published: March 2020

581

Background: Data indicate that screen-detected (SD) cancers show more favourable pathological characteristics and have a better prognosis compared to symptomatic or interval cancers (SY). These findings can be partly explained by length time and lead time biases. OncotypeDX recurrence score (RS) provides prognostic information independent of traditional clinicopathological variables and provides a robust measure of tumour proliferation. The objective of this study was to determine whether the RS would vary depending on the method of detection (MOD) in patients with lymph node-negative, ER-positive, HER-2 negative breast cancer (BC). Methods: We included patients with ER-positive, lymph node-negative and HER2-negative BC who underwent OncotypeDX testing as part of routine care or a clinical trial. We retrospectively reviewed patient charts and extracted information on MOD (SD versus SY), clinicopathological variables and RS. Chi-squared test was used to test for differences between categorical variables and MOD. Analysis of variance (ANOVA) was used to investigate the relationship between RS and MOD and clinicopathological variables. Results: We identified 596 patients from 4 academic hospitals (Mater University Hospital n= 98 (16%), St Vincent’s Hospital n= 161 (27%), Waterford Regional Hospital n= 27 (4%) and University of Texas, MD Anderson Cancer Center n= 310 (52%)). There were 359 (60 %) SD- detected and 237 (40%) SY-detected breast cancers. Clinicopathological variables were similar for age at diagnosis (56 versus 52 years), tumour size (16mm versus 18mm), grade (63% versus 61% grade 2; 15% versus 15% grade I; 21% versus 24% grade 3) and LVI (18% versus 18%) for SY compared to SD, respectively. The number of patients in each group with low (51% versus 50%), intermediate (41% each) or high (8% versus 9%) RS was similar in the SD compared to SY groups, respectively. There was a statistically significant association between RS and tumour grade (P=<0.001) and lymphovascular invasion (P=<0.001). We did not observe a statistically significant association between RS and MOD (P=0.086). Conclusions: In patients with clinically intermediate breast cancer sent for OncotypeDX testing we found no association between RS and MOD.
The role of Ki-67 in molecular breast cancer classification.
Authors: Stathopoulos George , Malamos Nikolaos , Markopoulos Christos , Polychronis Athanasios , Rigatos Sotirios , Yannopoulou A , Kaparelou Maria , Armakolas Athanasios
Published: March 2020

583

Background: The Ki-67 antigen was identified the involvement in early steps of polymerase I-dependent ribosomal RNA synthesis. Although it seems that the protein has an important function in cell division, its exact role is still obscure and there is little published work on its overall function. The aim of the present study is to evaluate the contribution of Ki-67 level in respect of tumor recurrence in molecular classified groups of breast cancer patients. Methods: Breast cancer tumor samples were examined for histological confirmation and for estrogen and progesterone receptors, c-erb-B2 expression, proliferation with Grade and Ki-67. Ki-67 was divided in percentage levels, up to 20 and higher than 20%. Immunohistochemistry and Fluorescence in situ hybridization is described for the results of ER, PR, c-erb-B2, Ki-67 biomarkers. Formaldehyde – fixed breast samples were paraffin wax embedded and processed for paraffin sections. The primary antibodies used were: The monoclinal antibody ID5 (M7047, Dakocytomation, Carpinteria, CA) for the detection of ER, the monoclonal anti-PR antibody 636 was used. For the detection of Ki-67 we used monoclonal mouse anti-human Ki-67 MIB-1. The patients molecular classification was Luminal A, Luminal B, Her-2 subtype and basal cell (triple negative). Results: 847 breast cancer patients were recruited. 291 were group as Luminal A, 228 as Luminal B, 221 Her-2 subtype and 107 triple negative. Follow-up was from 3 years to 15 years since diagnosis. It was found that in Luminal A patients, none had Ki-67 higher than 20% and the recurrence was in 10.65%. In Luminal B, the Ki-67 was higher than 20% in 61% of the patients and recurrence 23.68%. In Her-2 subtype >20% Ki-67 was 78.94%, recurrence 17.19%. In triple negative > 20% Ki-67 was in 68.75% and recurrence in 29.90% of the patients. Conclusions: The data presented here indicate that Ki-67 level may be considered as one of valuable biomarkers in breast cancer patients process and recurrence.
Relapse rate after adjuvant trastuzumab in the northeast of Italy: Preliminary data from a multicenter observational study in a clinical setting.
Authors: Mustacchi Giorgio , Molino Annamaria , Fiorio Elena , Brunello Antonella , Zagonel Vittorina , Ferro Antonella , Caldara Alessia , Iop Aldo , Bonura Salvatore , Stefani Micaela , Bernardi Daniele
Published: March 2020

586

Background: Relapse Rate (RR) after adjuvant trastuzumab (AT) reported in clinical trials is between 15 and 21%. Information on RR and clinical behaviour of HER2-POS metastatic disease after AT outside clinical trials is limited. At ASCO Meeting 2010 RR was reported 8% (Abs 1080) to 10% (Abs 684), with a Survival Post Progression (SPP) of 8.8 and 5.7 months, respectively. It is useful to increase informations about metastatic HER2-POS disease after AT, outside clinical trials. Methods: HER2-POS consecutive cases treated with AT in 6 Hospitals of North East Italy were anonymously collected and merged. The following data were analyzed: Stage, ER/PgR Status, Chemotherapy regimens (CHT) , follow up, RR, Disease Free Survival (DFS), Overall Survival (OS) and SPP. Results: The number of patients was 413, median age 55 (24-84). Anatomic Stage was I in 39.7%, II in 40,3%, III in 24.4%. ER/PgR neg cases were 164 (41.6%). Given CHT were Anthra-based 33.4% and Anthra-Taxane 54.5%. At a mean follow up of 35 months (7-115) RR was 10.8% (45 cases), with a mean DFS of 23.8 months (3.2-74). Among relapsed patients, 37/45 (82.2%) had ER/PgR neg tumors. One patient died NED for CHF and 22 for metastatic disease, with a mean OS of 37.1 months (10.2-87.9). Mean SPP was 17.8 months. According to DFS <12 mos , >12<24 and >24, mean OS was 31.3, 31.7 and 56.12(p=0.03) months; SPP was 24.2, 14.4 and 17.8 months, respectively. Conclusions: In our experience RR after AT is lower than in published Phase III clinical trials. ER/PgR neg status seems a negative prognostic factor (82.2% in the relapsed population vs 41.6% overall). OS is similar for patients relapsed within 24 months but SPP is 10 months longer in very early relapses. Relapse after 2 years is correlated with a long OS (nearly 5 years), with SPP shorter vs early relapse (17.8 vs 24.2 months). Our preliminary results suggest different disease behaviors in relapsed HER2-POS Breast Cancer after AT, with different DFS and SPP, suggesting a different effect of further therapies. Considering the small RR, the study target accrual is proceeding to collect up to more than 1000 AT treated patients, including post-progression treatments, not available at the moment.