bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant dose-dense sequential biweekly epirubicin and cyclophosphamide followed by docetaxel and trastuzumab for HER2+ operable breast cancer
Authors: Blakely L. , Somer B. , Keaton M. , Hermann R. , Schnell F. , Cobb P. , Johns A. , Walker M. , Schwartzberg L. 
Published: August 2020

595 Background: Neoadjuvant (Neo) chemotherapy (CT) with trastuzumab (H) improves pathologic complete response (pCR) rate for HER2+ breast cancer. Dose-dense regimens improve outcome in the adjuvant setting but have not been fully evaluated as preoperative therapy. We designed this regimen to utilize full doses of active agents including docetaxel (T) and H in a novel biweekly schedule to explore efficacy and safety. Methods: Patients (pts) with biopsy proven, clinical stage IIA-IIIC, noninflammatory breast cancer were eligible. HER2+ by FISH was determined locally. CT consisted of epirubicin (E) 100 mg/m2 and cyclophosphamide (C) 600 mg/m2 Q 14 days x 4 followed by T 75 mg/m2 and H 6 mg/kg loading dose, then 4 mg/kg Q 14 days x 4, all with pegfilgrastim support. Surgery was scheduled 20–24 weeks from start after a fifth cycle of H 4mg/kg. EF was measured prior to CT, after EC, after TH and at 6, 12 and 24 months after surgery. Additional adjuvant H to complete 1 year of therapy by conventional schedule was recommended after surgery. The primary endpoint was pCR for invasive cancer in breast and lymph nodes. Results: 30 pts were enrolled at 5 centers: median age was 50.1 (range, 31–72); ethnicity African-American 14, Caucasian 14, other 2; clinical stage IIA, 14, IIB, 4, IIIA, 7, IIIB/C, 5; ER+ 18, PR+ 14; grade 3, 21 and grade 2, 8. Twenty eight pts were evaluable for pathologic response- 2 withdrew before completing treatment, 1 for toxicity. Dose delivery on schedule was >95% for all drugs. Clinical response prior to surgery was cCR 20; cPR 5; and stable 2 pts. Pathologic response: pCR 16 (57%) including 4 with residual DCIS only; 9 pPR, and 2 stable. Mean EF was 63.1 (range, 51–81) before treatment, 62.4 (49–75) after EC and 58.3 (35–74) after TH. Two pts had EF <50% during Neo, one with clinical CHF and 1 additional pt developed CHF during adjuvant single agent H. Both pts had symptomatic improvement with cessation of H. Adverse events were generally mild with 14 grade 3 AEs including 3 episodes of dyspnea and no grade 3 skin toxicity or any grade 4 toxicity noted. Conclusions: Sequential Neo dose-dense Q 14 day EC followed by Q 14 day TH yields a high pCR rate in HER2+ breast cancer with acceptable toxicity profile and no new safety signals noted. No significant financial relationships to disclose.
Prognostic significance of HPV and p16 status in patients with oropharyngeal cancer treated on a large international phase III trial
Authors: Rischin D. , Young R. , Fisher R. , Fox S. , Le Q. , Peters L. , Choi J. , O'Sullivan B. , Giralt J. , McArthur G. ,   Tran-Tasman Radiation Oncology Group
Published: August 2020

6004 Background: Previous studies have reported that in patients with oropharyngeal cancer (OPC) the presence of human papilloma virus (HPV) is associated with an improved prognosis. We sought to determine the prognostic importance of HPV and p16 in patients with OPC treated with concurrent chemoradiation on a large international phase III trial. Methods: Patients with previously untreated Stage III or IV head and neck squamous cell cancer were randomized to receive definitive radiotherapy concurrently with either cisplatin or cisplatin plus tirapazamine. In this substudy, analyses were restricted to patients with OPC who received > 60 Gy and did not have major radiation deviations predicted to impact on tumor control. HPV 16/18 were detected by in situ hybridization and scored as detected or undetected. p16 was detected by immunohistochemistry. Nuclear and cytoplasmic staining intensity of tumor cells was scored as grade 0–3, with grade 2 and 3 called positive. Log rank and Cox regression used for survival analyses. p values were 2-sided . Results: 384 out of 861 patients had OPC and met the eligibility criteria. Slides were available for HPV assay in 195 and for p16 in 186, and for both in 173. 54/195 (28%) were HPV positive, 107/186 (58%) were p16 positive. HPV pos tumors were associated with better 2-year overall survival (OS) (94 v 77%, p = 0.007) and better failure-free survival (FFS) (86 v 75%, p = 0.035) compared to HPV neg tumors. Similarly p16 pos tumors were associated with better 2-year OS (92 v 75%, p = 0.004) and FFS (87 v 72%, p = 0.003) compared to p16 neg . After adjustment for stage, Hb and ECOG PS, HPV pos had better OS than HPV neg (HR 0.29, p = 0.018), and p16 pos had better OS than p16 neg (HR 0.39, p = 0.013). When the HPV and p16 results were combined the relative HRs for OS were: HPVpos/p16pos 0.35 (45 patients, 26% of cases), HPVpos/p16neg 0 (3pts, 2%), HPVneg/p16pos 0.73 (58pts, 33%), HPVneg/p16neg 1.79 (67 pts, 39%). Conclusions: Our results confirm the prognostic significance of tumor HPV status in oropharyngeal cancer treated with chemoradiation, but also show that p16 identifies a larger group with an improved prognosis. The HPV neg/p16 pos population has a better prognosis compared to patients with HPV neg/p16 neg tumors. No significant financial relationships to disclose.
Phase II study of dasatinib in the treatment of head and neck squamous cell carcinoma (HNSCC)
Authors: Brooks H. D. , Glisson B. , Lu C. , Sabichi A. , Johnson F. , Ginsberg L. , Bekele B. , Papadimitrakopoulou V. 
Published: August 2020

6022 Background: Dasatinib is a potent inhibitor of src-family kinases, ephA2, PDGFR, Abl, and c-kit. A single-center, open-label, phase II trial was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of dasatinib in recurrent or metastatic HNSCC. Methods: Pts with measurable disease by RECIST, who received 0 or 1 prior regimen for recurrent or metastatic HNSCC with an ECOG performance status 0–1 and tumor tissue appropriate for IHC and FISH were eligible. Dasatinib 100 mg bid was given for 28-day cycles. Primary endpoints were 12-wk progression-free survival (PFS) and objective response rate (ORR). Pts who took at least 1 dose of dasatinib and who died or left study before 12 wks were counted as progressive disease (PD). A 2 stage design, closure after accrual of 15 pts was required if PFS was 45% or less and ORR was 0. Otherwise, planned accrual was 35. Response was assessed at 4 and 12 wks. PK was studied in pts receiving dasatinib per PEG. Biomarkers relevant to Src pathway were planned in tissue and blood. Results: Fifteen pts were accrued. To date, 13 pts are evaluable for response, and 15 pts for toxicity. No grade 3/4 hematologic toxicities were noted. Grade 2–4 nonhematologic toxicities(n): pleural effusion(2), nausea/vomiting(2), dehydration(1), diarrhea(1), dyspnea(1). Toxicity led to hospitalization of 4 pts and drug discontinuation in 5 pts. ORR was 0. One pt was stable at 12 wks (PFS: 7.6%). This pt stopped drug at 15 wks due to toxicity, but also had PD. One pt died on study and cause was deemed unlikely related. Conclusions: Dosed at 100mg bid, dasatinib led to a characteristic toxicity profile in this pt population. Rates of hospitalization and discontinuation for toxicity were fairly high. Final efficacy parameters are pending evaluation of 2 pts. Evaluation of PK and tissue/blood biomarkers is ongoing. No significant financial relationships to disclose.
Predictors of tumor progression during neoadjuvant chemotherapy in breast cancer
Authors: Caudle A. S. , Gonzalez-Angulo A. M. , Kelly H. K. , Liu P. , Pusztai L. , Symmans W. F. , Kuerer H. M. , Mittendorf E. A. , Hortobagyi G. N. , Meric-Bernstam F. 
Published: August 2020

603 Background: While most patients with breast cancer receiving neoadjuvant chemotherapy (NCT) have some tumor response, a small proportion progress during therapy. Although several groups have looked at markers for response, none have specifically evaluated markers for progression. The goal of this study was to identify predictors of tumor progression during NCT with the ultimate aim of identifying the subset of patients who may benefit from a first-line surgical approach. Methods: Patients with stage I-III breast cancer treated at a single comprehensive cancer center with NCT between 1994 and 2007 were included. Data was obtained from a review of medical records of patients in a prospectively acquired database. Chemotherapy consisted of anthracycline and/or taxane-based regimens. Statistical analysis was performed using univariate and multivariate analysis with logistic regression analyzing patients with some response or stable disease versus patients with progression. Results: 1928 patients received NCT: 1762 (91%) had some response (minor, partial, or complete), 107 (6%) had stable disease (SD), and 59 (3%) progressed (PD) on at least one NCT regimen. Clinical factors that correlate with PD in univariate analysis include presenting T (T3 vs T1, p = 0.002) and AJCC stage (stage IIIb/IIIc vs I/II/III, p = 0.02). Predictive histopathological features were high tumor grade (p = 0.005), high Ki-67 (p = 0.002), and negative ER and PR status (p < 0.0001 and p = 0.0006). Patients with PD were more likely to be treated with a taxane (79% vs 88%, p = 0.04). In the post-NCT surgical specimens, patients with PD were more likely to have higher T stage (p < 0.0001), lymph node metastasis (p = 0.01), and lymphovascular invasion (p = 0.02). On multivariate analysis, pre-NCT T status and ER status were the most important predictors of progression. Conclusions: Pre-treatment characteristics predictive of disease progression on NCT include advanced tumors, high tumor grade, high Ki-67, and negative ER or PR status. Since high grade and negative ER/PR status have also been associated with a complete pathologic response to NCT, there is a clear need for more specific molecular predictors of response and progression in order to select appropriate treatment in these patients. No significant financial relationships to disclose.
Multiagent concurrent chemoradiotherapy (MACCRT) and gefitinib in locoregionally advanced head and neck squamous cell cancer (HNSCC)
Authors: Rodriguez C. P. , Adelstein D. J. , Saxton J. P. , Rybicki L. A. , Lorenz R. R. , Wood B. G. , Scharpf J. , Lee W. T. , Ives D. I. 
Published: August 2020

6037 Background: In patients (pts) with stage III-IV HNSCC, MACCRT has led to excellent locoregional control. Distant metastases (DM) are now the most common cause of treatment failure. This phase II study tested whether the oral EGFR inhibitor gefitinib (G) added to our Cleveland Clinic MACCRT regimen would decrease DM and improve survival. Methods: Between 4/03 and 9/07, 60 previously untreated pts with stage III-IV (M0) HNSCC, and a performance status of <1 were enrolled on this study. Pts received hyperfractionated radiation (72–74.4 Gy at 120cGy bid) and concurrent chemotherapy with cisplatin (20 mg/m2/day) and fluorouracil (1,000 mg/m2/day), both given as 96-hour continuous IV infusions during weeks 1 and 4. G 250 mg daily was begun on day 1 of the radiation and continued for 2 years. The results were retrospectively compared to our previous study of 44 pts treated with the same MACCRT regimen without G between 1/96 and 9/00. Results: The study population included a preponderance of Caucasian (97%) males (88%) with stage IV (80%) oropharynx tumors (68%), and with a median age of 58 (range 24–75) years. Patient and tumor characteristics were similar to the non-G treated historical cohort. When comparing the G vs. non-G treated pts, acute toxicities including transient renal dysfunction (28% v. 5% p = 0.002) and all-cause re-hospitalization (83% v. 64%, p = 0.022) were worse. Myelosuppression was similar. G-specific toxicity included > grade 1 rash in 60% and diarrhea in 35%. There were 5 deaths during treatment in the G group v. one in the non-G group (p = 0.19). Only a projected 44% of pts will complete the 2-year course of G. With a median follow-up in this trial of 37 (range 13–64) months, 3-year Kaplan-Meier outcome estimates do not differ between the study and the historical cohorts. Local control without surgery is 80% v. 88% (p = 0.21), DM control is 86% v. 76% (p = 0.19), freedom from recurrence is 72% v. 71% (p = 0.79), and overall survival is 67% v. 68% (p = 0.63) respectively. Conclusions: The addition of G to our MACCRT regimen was difficult for pts to complete. It did not improve any measured outcome and was associated with increased toxicity when compared to historical controls. [Table: see text]
Gefitinib for advanced cutaneous squamous cell carcinoma of head and neck: Phase II trial
Authors: Weber R. S. , Lustig R. A. , El-Naggar A. K. , Rosenthal D. I. , Kim E. S. , Wistuba I. I. , Tang X. M. , Wan F. F. , Taylor S. A. , Glisson B. S. 
Published: August 2020

6054 Background: Advanced head and neck cutaneous squamous cell carcinoma (HN cSCC) carries a 30–40% risk of death by 2 years with standard therapies. Small molecular inhibitors of the epidermal growth factor receptor (EGFR) may have an impact. We evaluated gefitinib as an induction therapy in a high-risk patient (pt) group prior to definitive therapy to determine efficacy, toxicity and feasibility. Correlative studies of EGFR expression, gene mutation, and ploidy may serve as predictors of response. Methods: Eligible pts must have HN cSCC >2cm, regional nodal metastases, peri-neural invasion, or deep invasion and must be candidates for definitive locoregional therapy with surgery and/or radiation. Two 30-day induction cycles of gefitinib (250mg po qd). Pts are assessed clinically after 15 days. If a response is noted, gefitinib is continued. For pts with stable disease, the dose is escalated to 500mg qd. Pts with progressive disease go off study. Total and phosphorylated (p) EGFR protein expression was analyzed by immunohistochemistry and gene copy number by fluorescent in-situ hybridization (FISH). Results: To date, 23 pts are enrolled and 22 are evaluable for responses and toxicities. Complete responses (CR) were noted in 3 pts, partial response (PR) 7, stable disease (SD) 5, and progressive disease (PD) 7 (68.1% response per RECIST criteria). Minimal side effects are associated with gefitinib (cutaneous and GI related). EGFR and p-EGFR protein overexpression were observed in 5 of 11 (45.5%) pts tested thus far. Eight of the pts were FISH negative with respect to EGFR gene expression: 7 had low trisomy and 1 had low polysomy. Two were FISH positive and expressed high polysomy. No gene amplification was detected. No statistically significant correlations between EGFR gene or protein expression and responses to administration of gefitinib were found at this point in the analysis. Protein and gene expression analyses are ongoing. Conclusions: The preliminary results from our study are encouraging and suggest that anti-EGFR therapy may have a role in the adjuvant treatment of HN cSCC. Correlative studies may help identify pts most likely to respond to anti-EGFR therapy. No significant financial relationships to disclose.
Phase II trial evaluating imatinib (I) in patients (pts) with anaplastic thyroid carcinoma (ATC)
Authors: Ha H. T. , Lee J. S. , Urba S. , Koenig R. J. , Sisson J. , Giordano T. , Worden F. P. 
Published: August 2020

6057 Background: There is no standard treatment for ATC. Response to doxorubicin ranges between 5–22%; median survival ranges between 3–6 months. Affymetrix gene chip showed PDGFR overexpression in ATC. In p53 mutated/deficient ATC cell lines, c-Abl is overexpressed, and selective inhibition of c-Abl resulted in cytostatic effect. (I) inhibits tyrosine kinase activity of Bcr-Abl and PDGF. We hypothesize that ATC that overexpress PDGFR or Abl will respond to (I). Methods: Pts ≥ 18 years old with histologically confirmed ATC, overexpressing PDGFR or c-Abl by immunohistochemistry who had measurable disease were eligible. Pts must have Zubrod performance status ≤ 1, and adequate hepatic and renal function. Prior chemotherapy, chemoradiation, radiation therapy, or surgery must have been completed at least 28 days prior to registration. (I) was administered at 400mg orally twice daily without drug holiday. Response to treatment was assessed after every 8 weeks. Pts with complete response (CR)/partial responses (PR)/stable disease (SD) were treated until disease progression. The study was terminated early due to poor accrual. Results: From February 2004 to May 2007, eleven pts from our institution were enrolled and were started on (I) (6 men; 5 women) with a median age of 63 years (ranges 53–80). At baseline, 4/11 pts (36%) had locoregional disease, 5/11 pts (45%) had distant metastases, and 2/11 pts (18%) had both. Nine pts had prior chemoradiation, and 7 pts had thyroidectomy. Out of 11 pts, 8 were evaluable for response; 3 were excluded for lack of follow up radiological evaluation. The overall responses at 8 weeks were CR 0/8; PR 2/8 (25%); SD 4/8 (50%); and PD 2/8 (25%). The median time to follow up was 26 months (ranges 23–30 months). The estimate of 6-month progression free survival was 27% (95% CI, 7–54%). The estimate of 6-month overall survival was 46% (95% CI, 17–71%). The most common G3 toxicity was lymphopenia in 45%; other G3 toxicities included edema (27%), anemia (18%), and hyponatremia (18%). There was no G4 or higher or treatment related death. Conclusions: (I) appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing pts with a rare malignancy at a single institution, investigation of (I) in ATC may be warranted in a multi-institution setting. No significant financial relationships to disclose.
Phase II trial of sorafenib (bay 43–9006) in patients with advanced anaplastic carcinoma of the thyroid (ATC)
Authors: Nagaiah G. , Fu P. , Wasman J. K. , Cooney M. M. , Mooney C. , Afshin D. , Lavertu P. , Bokar J. , Savvides P. , Remick S. C. 
Published: August 2020

6058 Background: Sorafenib (bay 43–9006) is an oral, small molecule tyrosine kinase inhibitor of the raf-1 protein kinase receptor, VEGFR2 and PDGFR-β with antiangiogenic properties. We are conducting an open label, phase II study of sorafenib in patients with biopsy-proven ATC to evaluate if its objective response rate is >20% and to further characterize its safety profile. Methods: Patients with progressive ATC, after cytotoxic chemotherapy with or without radiation were given sorafenib, on a fixed dosing schedule of 400 mg PO bid on 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or patient refusal. Response was evaluated every 8 weeks with body scans using RECIST criteria. We employed a 2-stage study design: if none of the first 18 patients respond the study is terminated, otherwise accrual is continued to a total of 36 patients at which point if ≤3 of the patients respond, the treatment option is rejected. Results: To date 16 patients (10 male) have enrolled in the study. Median age is 55 years; with (range 28–79). Median time on study is 2 months. Median number of cycles given is 2 (range 1–27). Two of 15 evaluable patients (13%) have partial response (PR) and 4 patients (27%) have stable disease (SD). Median duration of PR/SD is 5.1 months (range 1–24.7months). Median time to progression is 1.5 months. Median duration of survival is 3.5 months (range 1–26 months). All patients at time of reporting are deceased. Most common toxicities are lymphopenia (81%) and fatigue (62%). Grade 3 toxicities include lymphopenia (25%), rash with desquamation, weight loss, and chest pain (all 12%). Grade 4 toxicities include dyspnea (6%) and lymphopenia (6%). There has been no significant cardiovascular toxicity. One patient died on study with rapidly progressive disease. Conclusions: Sorafenib demonstrates objective tumor response in the first 15 evaluable and pretreated patients with advanced ATC. This trial is ongoing and supported in part by NIH grant nos. CA62502. [Table: see text]
Coronary heart disease (CHD) and stroke risk associated with breast cancer (CA) irradiation (RT) based on patient baseline cardiac risk profile
Authors: Chen R. C. , Hankinson S. E. , Harris J. R. , Chen W. Y. 
Published: August 2020

606 Background: Although population-based studies showed increased fatal and non-fatal CHD risk associated with left-sided breast RT, presumably from “bystander” cardiac dose, how RT interacts with underlying cardiac risk factors to influence these outcomes is unclear. We used data from the Nurses’ Health Study (NHS) to examine the effect of RT on fatal and non-fatal CHD, stratified by baseline CHD risk factors. Methods: 121,700 female registered nurses enrolled in 1976. Ongoing biennial medical information collected includes CHD risk factors, cardiac events, CA diagnosis, treatment, and cause of death. Medical record review confirms CA diagnoses and cardiac events. Numerous publications establishing the causes of CHD and cardiac mortality have resulted. 3863 women have developed stage 0-III breast CA and received RT. Proportional hazards models were used to assess the association between left-sided RT and CHD development, after adjusting for age and CHD risk factors. Results: During 38,538 person-years follow-up after breast CA diagnosis, 126 CHD events developed. In age- adjusted univariate models, left-sided RT (vs. right-sided), diabetes, parental CHD before age 60, and smoking were significantly associated with fatal and non-fatal CHD; aspirin and postmenopausal hormone use were protective. Crude incidence of CHD after left-sided RT was 396 per 100,000 person-years, compared to 259 after right-sided RT. A multivariable model that accounted for the above plus other risk factors (hypertension, hyperlipidemia, physical activity, alcohol use) and stage showed that left-sided RT was independently associated with CHD development (rate ratio, RR 1.5, 95% CI 1.1–2.2). Stratified analyses by the presence of hypertension, hyperlipidemia, and smoking showed similar RR from left-sided RT in all subgroups. In contrast, left-sided RT did not affect risk of stroke in multivariable analysis (RR 0.7, 95% CI 0.4–1.2). Conclusions: Left-sided RT is an independent CHD risk factor, and indicates a similar RR to patients in all subgroups of baseline CHD risk, though absolute risk increase was larger in women who had additional risk factors. Breast CA survivors after left-sided RT may need long-term cardiac follow-up and management. No significant financial relationships to disclose.