bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of axitinib (AG-013736 [AG]) in patients (pts) with advanced thyroid cancers
Authors: Cohen E. E. , Vokes E. E. , Rosen L. S. , Kies M. S. , Forastiere A. A. , Worden F. P. , Kane M. A. , Liau K. F. , Shalinsky D. R. , Cohen R. B. 
Published: March 2020

6008 Background: Elevated VEGF-A and VEGF-C have been reported in thyroid tumor tissue compared with normal thyroid. AG is a potent, small molecule inhibitor of VEGF receptors 1, 2 and 3. The efficacy and safety of AG therapy in pts with advanced thyroid cancers was examined in this single-arm, multi-center study. Methods: 60 pts with metastatic or unresectable locally-advanced thyroid cancer refractory to, or not suitable candidates for, 131iodine (131I) treatment, with measurable disease received AG at a starting dose of 5 mg orally BID. The primary endpoint was response rate (RR) by RECIST criteria. A Simon 2-stage minimax design was used (a=0.1; β=0.1; null RR=5%; alternative RR=20%). Samples were collected pretreatment and q8wks to explore relationships between clinical response and plasma soluble proteins. Results: Median age was 59 yrs (26–84), 35 (58%) were male. Histological subtypes included papillary: 29 pts (48%); follicular: 15 pts (25%)-11 (18%) with Hurthle cell variant; medullary: 12 pts (20%); anaplastic: 2 pts (3%), and other/unknown: 2 pts (3%). 53 pts (88%) had prior surgery, 42 (70%) had prior 131I treatment, 27 (45%) had prior external beam radiation, and 9 (15%) had prior chemotherapy. Partial response (PR) by investigator report was achieved in 13 pts (22% CI: 12.1, 34.2), with 31- 68% maximum tumor regression and duration of response (DOR) of 1–16 months. 30 pts (50%) have stable disease with a duration range of 4–13 months and 13–67% maximum tumor regression in 28 pts. Response assessments are ongoing. The treatment duration range is 6–670 days with 38 pts currently on study. Median PFS has not been reached with a median follow up of 273 days. The most common treatment-related adverse events were fatigue (37%), proteinuria (27%), stomatitis/mucositis (25%), diarrhea (22%), hypertension (20%) and nausea (18%). AG therapy consistently decreased soluble VEGFR2 and VEGFR3, and increased VEGF in the blood, demonstrating pharmacodynamic activity against targeted VEGF receptors. Conclusions: AG has substantial anti-tumor activity in advanced thyroid cancer with demonstrated pharmacodynamic activity. A global pivotal trial testing AG in doxorubicin refractory thyroid cancer is ongoing. [Table: see text]
Intratumoral epidermal growth factor receptor (EGFR) antisense (AS) DNA in recurrent squamous cell carcinoma of the head and neck (SCCHN): A phase I trial
Authors: Lai S. Y. , Lui V. W. , Koppikar P. J. , Thomas S. M. , Gooding W. E. , Seethala R. R. , Branstetter B. F. , Argiris A. , Grandis J. R. 
Published: March 2020

6009 Background: SCCHN is characterized by upregulation of the EGFR where EGFR expression levels in the tumor correlate with decreased survival. We developed a novel anti-EGFR therapy with a therapeutic gene consisting of an EGFR AS sequence under the control of the U6 promoter in a pNGVL backbone. We conducted a phase I clinical trial to evaluate the safety and biological effects of EGFR AS in patients with advanced SCCHN. Methods: Patients (pts) with recurrent SCCHN refractory to standard therapies with at least one evaluable and accessible lesion were enrolled in a phase I trial. EGFR AS dose was escalated in successive cohorts of pts (classic “3+3” design) in 6 dose levels: 60 μg, 120 μg, 240 μg, 480 μg, 960 μg and 1920 μg at a concentration of 1 μg/μL. Pts received weekly intratumoral injections of EGFR AS × 4 weeks. Tumors were biopsied before and after the completion of therapy. In addition to treatment response as assessed by tumor volume measurements (PET/CT), levels of target proteins and phosphoproteins were assessed in the tumors. Results: 17 pts were enrolled (median age: 57 years; 15 M / 2 F). No grade 3/4 or dose-limiting toxicities were noted. 4 grade 1 toxicities were reported: injection site pain/swelling (2), localized edema (1) and lethargy (1). EGFR AS was present in the tumor after injection as demonstrated by PCR. 5 pts (29%; 95% CI 10–56%) achieved an objective response (RECIST), including 2 CRs (pCRs confirmed by biopsy) and 3 PRs; 2 pts had stable disease as best response. Median duration of response was 4.5 months (3.0–23.1). Median survival for the entire cohort was 5.4 months with a median survival in responders of 7.9 months. 1 pt who achieved CR is alive without progression at 23.1+ months. Immunohistochemical studies demonstrated decreased EGFR in 2 pts with CR. Assessment of downstream signaling molecules is in progress. Conclusions: Intratumoral EGFR AS was safe and resulted in impressive antitumor activity in pts with recurrent, incurable SCCHN. We plan to study further the use of EGFR AS as an integral component in the curative therapy of SCCHN. No significant financial relationships to disclose.
Initial results from a phase II trial of motesanib diphosphate (AMG 706) in patients with differentiated thyroid cancer (DTC)
Authors: Sherman S. I. , Schlumberger M. J. , Droz J. , Hoffmann M. , Wirth L. , Bastholt L. , Martins R. G. , Licitra L. , Shi Y. , Stepan D. E. 
Published: March 2020

6017 Background: This phase 2 study evaluated the safety and efficacy of AMG 706, an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF, and Kit receptors and RET, in pts with advanced DTC or medullary thyroid cancer (MTC). Presented here are results from the DTC stratum. Methods: This was a multicenter, phase 2, open-label, single-arm study of pts with advanced thyroid cancer stratified by DTC or MTC (planned n=80 each). The primary endpoint was objective tumor response per modified RECIST by independent central review. Secondary DTC endpoints were duration of response and progression-free survival (PFS). Pts = 18 yrs with progressive, 131I-resistant disease, ECOG 0–2, and no prior treatment with VEGFr MKIs received AMG 706 125mg QD until disease progression or unacceptable toxicity. Assessments included tumor response (q8w), pharmacokinetics (PK), and safety. Results: 93 pts with DTC were enrolled and received at least 1 dose of AMG 706. DTC subtypes were: papillary, 58%; Hürthle cell, 18%; follicular, 16%; other, 8%. Median (range) age was 62 (36–81) yrs. 20% of pts had prior chemotherapy; 96% had prior 131I therapy. With median follow-up of 32 wks, objective tumor response (CR or PR) rate (95% CI) was 12% (6.1, 20.2); SD, n=64 (69%; durable SD =24 wks, 24%); PD, n=7 (8%). Median (95% CI) time to response was 103 (53, 161) days; median PFS was 276 (221, not estimable) days. 85% of pts were alive >8 months after starting therapy. All pts (100%) had some treatment- emergent adverse events (AE): grade 3, 55%; grade 4, 10%; grade 5, 5% (all grade 5 were deemed unrelated to AMG 706). Common AEs included diarrhea (70%; 11% grade 3), fatigue (58%; 5% grade 3), hypertension (49%; 22% grade 3), headache (43%; 4% grade 3), nausea (40%; 2% grade 3), and hypothyroidism and/or increased TSH (17%; no grade 3); none of these were grade 4 or 5. 6% of pts had cholecystitis. PK results showed that AMG 706 PK at 125mg QD was comparable to data obtained in other monotherapy studies at the same dose level. Conclusions: In this study of pts with advanced 131I-resistant DTC, AMG 706 showed encouraging antitumor activity and had tolerable and manageable toxicities. Further investigation is warranted. No significant financial relationships to disclose.
Sorafenib targets BRAF and VEGFR in metastatic thyroid carcinoma
Authors: Gupta V. , Puttaswamy K. , Lassoued W. , Redlinger M. , Ransone K. , Gold K. , Lee W. , LiVolsi V. , Fraker D. , Mandel S. , Brose M. S. 
Published: March 2020

6019 Background. There is no effective therapy for patients with metastatic thyroid cancer not cured by surgery or treatment with I131. Sorafenib is a promising multi-tyrosine kinase inhibitor for patients with metastatic PTC (mPTC). Although the primary targets of sorafenib are thought to include BRAF and VEGFR, this has been the subject of debate. Whether sorafenib primarily acts on the tumor cells (TC) or endothelial cells (EC) and how BRAF mutation status (45% of PTC harbor V600E) relates to response is also unknown. Methods. Responses of patients with metastatic, iodine-refractory PTC, enrolled into our phase II study of sorafenib were monitored by PET at 4 wks and CTs every 2 mos. Sorafenib activity was studied using immunohistochemistry (IHC) for pERK, pAKT, and pVEGFR-2, while Ki-67 showed proliferating cells in tumor tissue pre- and on treatment. BRAF mutation status was determined by DNA sequencing. Results. Of 15 patients, five patients achieved a PR, three are stable (SD), two progressed, and three patients with SD withdrew due to toxicity. Target lesions decreased on average 31%. Eight of 10 PET scans showed decreased activity at 4 weeks. IHC on tissue from 2 patients (at 1 and 2 wks, both BRAFwt) showed 50% decrease in pERK (downstream of VEGFR2 and BRAF) and 30% decrease in pAKT (downstream of VEGFR2). p-ERK and p-AKT were altered in both the TC and EC. Ki-67 decreased from 10% to <1%. No change in VEGFR-2 was seen; but, pVEGFR-2 completely disappeared in one sample while the other showed a small decrease. Quantitative analysis using a multispectral imaging system confirmed the changes observed by IHC. In tissue from a patient at 17 months on sorafenib, the decrease in pERK and pAKT appeared to be the same or reversed, suggesting compensatory changes in these pathways in resistant but stable disease. Conclusions. Our study shows the early clinical and biologic activity of sorafenib in patients with mPTC and the targets of early suppression. Importantly, it also reveals compensatory changes in target molecules in cells resistant to therapy. These cells are the likely source of tumor resistance that has been seen to develop to other similar targeted agents. Sorafenib is the first viable treatment option for patients with mPTC, and these results provide key insights into the mechanisms of action and resistance of this drug. No significant financial relationships to disclose.
Corroboration of polymorphisms in the aromatase (CYP19A1) gene with response to neoadjuvant therapy with letrozole in postmenopausal women with stages II-II ER/PgR-positive breast cancer
Authors: Lopez-Guerrero J. A. , Garcia-Casado Z. , Guerrero-Zotano A. L. , Calatrava A. , Ruiz-Sauri A. , Fernandez-Serra A. , Ruiz A. , Llombart-Bosch A. , Guillem-Porta V. , Llombart-Cussac A. 
Published: March 2020

602 Background: Aromatase (CYP19A1) is the main enzyme implicated in estrogen biosynthesis. Polymorphisms in CYP19A1 can affect both aromatase expression and activity leading to changes in the estrogen levels. These changes have been previously associated with pathogenesis of estrogen-dependent diseases, including breast cancer. The purpose of this study is to evaluate whether the genotype of CYP19A1 can have an effect on the response to endocrine therapy with the aromatase inhibitor letrozole (L). Methods: We retrospectively analyzed a series of 58 postmenopausal women with stage II-III ER/PgR[+] breast cancer treated with L as neoadjuvant therapy. Response was evaluated by radiology (mammogram or ultrasound) at four months L (OMS) and data was available in 56 cases. A total of ten single nucleotide polymorphisms (SNPs) spanning the gene, a TCT insertion/deletion and a (TTTA)n repeat were evaluated. The (TTTA)n repeat was analyzed by using GeneScan to detect polymorphism length, TCT Ins/Del by direct sequencing and SNPs by allelic discrimination using TaqMan SNP Genotyping Assays (Applied Biosystems). Logistic regression analysis was used to estimate the most accurate predictive model for response to therapy. Results: Median age of our series was 77 years (range: 68 to 90). Twenty women (36%) responded to 4 months L, while 38 (67%) did not (2 PD and 36 EE). Allelic frequencies were determined for each polymorphism and the global genotype data was evaluated in a logistic regression analysis. In a first step, the analysis with the genetic information for the 12 polymorphisms resulted in a model that predicted radiological response to L with an accuracy of 80% (85% specifity, 69% sensibility). However, a reduction to 4 informative polymorphisms generated a simpler predictive model with an accuracy of 76% (76.5% specifity, 75% sensibility). Conclusions: Polymorphism analysis of CYP19A1 could predict for response to neoadjuvant therapy with L. A validation of this predictive model in an independent series is ongoing. No significant financial relationships to disclose.
Concomitant chemoradiation versus radiotherapy in advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly cisplatin: Final result of a phase III trial
Authors: Sharma A. , Mohanti B. K. , Thakar A. , Bahadur S. , Bhasker S. , Bahl A. 
Published: March 2020

6030 Background: Studies have confirmed the role of concomitant chemoradiation (CTRT) in the treatment of advanced SCCHN, however, there is no large study reported from India. Consensus about type and schedule of the chemotherapy is unclear e.g. single agent Vs combination; daily/weekly/three weekly. This study was undertaken to know effectiveness of weekly Cisplatin (DDP). Methods: prospective randomized phase III study. 153 untreated stage II-IV oropharyngeal and nasopharyngeal cancer patients were randomly assigned to one of the two treatment arm; Arm (A) Radical radiotherapy 70 Gy/ 35# over 7 weeks; Arm (B) CTRT; Cisplatin 40mg/m2 weekly for 6 doses beginning day 1 of radiation treatment plus radiotherapy as in arm (A). The objective endpoints were- to know (i) the responses, (ii) toxicity profile and (iii) overall survival in the two treatment groups. Protocol was approved by local ethics committee. Study period was from June 2003 to July 2005. Results: Number of patients were 76 (A) and 77 (B) in two arms respectively. CR was 70.7 Vs 78.9% in arm A and B. Toxicity- grade III and IV toxicities were 16% and 40% respectively in 2 arms (p=<0.05). There were more frequent interruptions (9.3% Vs 28.9%) and hospitalization (20% Vs 40.8%) (p=<0.05) in CTRT arm. Survival- with median follow up of 17 months overall survival was significantly higher in CTRT arm (p=0.024); 27 months (95%CI 15.2–36.8) for RT Vs not reached (NR) for CTRT group. Three year OS was 42% Vs 62% respectively. Conclusion: This trial confirms that CTRT using single agent weekly DDP is safe and superior to RT in advanced SCCHN but treatment interruptions and toxicities are of concern for developing country’s cancer care infrastructures. No significant financial relationships to disclose. [Table: see text]
Long-term outcomes with concurrent carboplatin, paclitaxel, and radiation therapy in locally advanced, inoperable head and neck cancer
Authors: Ferris R. L. , Agarwala S. S. , Cano E. , Heron D. E. , Johnson J. , Myers E. , Sandulache V. , Wang Y. , Bahri S. , Argiris A. 
Published: March 2020

6032 Background: Our goal was to evaluate long-term outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) treated with carboplatin, paclitaxel, and radiotherapy. Methods: We conducted a phase II trial in inoperable patients with locally advanced SCCHN. Carboplatin 100 mg/m2 and paclitaxel 40 mg/m2 were administered intravenously once a week during external beam radiotherapy (once daily, 180 cGy/fraction) for 6–7 weeks. Interstitial brachytherapy was used as a boost in selected patients with primary malignancies of the oral cavity and the oropharynx. Results: 55 patients were enrolled. 52 patients (95%) had stage IV and 51 (93%) had technically unresectable disease; 62% had an oropharyngeal primary site. 21 patients underwent brachytherapy boost. Grade 3 or 4 mucositis occurred in 30% of patients. One death occurred during treatment; it was related to complications of gastrostomy tube (G-tube) placement. Forty of 50 evaluable patients (80%) had an objective response, with a complete response rate of 52%. With a median follow-up of 69 months years for surviving patients, the 5-year progression-free survival (PFS) was 36% and the 5-year overall survival (OS) was 35%. Two of the 18 long-term survivors of >50 months were G-tube feeding dependent. Patients undergoing brachytherapy boost (n=21) had similar outcomes compared with the rest of the patients. In multivariate analysis, baseline hemoglobin levels and N stage were predictive of survival. Conclusion: Treatment with concurrent carboplatin, paclitaxel and radiation is safe and offers curative potential for poor prognosis patients with locally advanced SCCHN. No significant financial relationships to disclose.
Randomized phase II study of concomitant chemoradiotherapy with 5-fluorouracil-hydroxyurea (FHX) compared to FHX and bevazicumab (BFHX) in intermediate stage head and neck cancer (HNC)
Authors: Choong N. W. , Haraf D. J. , Cohen E. E. , Stenson K. M. , Blair E. A. , Dekker A. , Williams R. , Karrison T. G. , Vokes E. E. 
Published: March 2020

6034 Background: Preclinical data supports inhibition of vascular endothelial growth factor (VEGF) to improve tumor radiosensitivity. Phase I data demonstates that BFHX was tolerable in HNC (Seiwert, pASCO2006). Here we present preliminary toxicity data from a randomized phase II trial in pts with PS 0–2, stage II-IV (T2–4 N0–1 M0) HNC. Methods: Pts were randomized (2:1) to receive either BFHX or FHX. Planned sample size is 72pts. Chemotherapy consists of 5- FU (600 mg/m2/day continuous infusion for 120 hrs), hydroxyurea (500 mg PO q12 hours for 11 doses) with or without bevacizumab (10 mg/kg IV on day 1), concurrently with twice daily RT on a week on-week off schedule. Results: 21pts (BFHX 14pt and FHX 7pt) have completed therapy and are evaluable for toxicity. Pt characteristics in the BFHX and FHX arms are: median age 61 vs. 55 yrs, males 78% vs. 85%, stage II-III 57% vs. 86% and IV 43% vs. 14%. All pts have PS 0–1. 20 pts are evaluable for toxicity. Two episodes of gr3 leukopenia and one episode of gr 3 neutropenia were observed in the BFHX arm; whereas no gr3 hematologic toxicities were seen in the FHX arm. Mucositis (Gr3 - BFHX 85% vs. FHX 86%) and dermatitis (Gr3 - 0% vs. 14%) were observed in every pt. Other common non- hematologic toxicities were pain (100% vs. 86%), fatigue (77% vs. 86%) and anorexia (62% vs. 51%). No hemorrhagic events were observed. In the BFHX arm, one episode of deep venous thrombosis and one non-neutropenic death from sepsis were observed. Pathologic complete response rates were 92% and 100% in the BFHX and FHX arms, respectively. Conclusions: Preliminary results support the tolerability of BFHX. Toxicity appears to be similar to FHX with an apparent increase in leukopenia consistent with prior reports. Bleeding complications were not increased with BFHX. No significant financial relationships to disclose.
Factors influencing performance of MRI in newly diagnosed breast cancer patients
Authors: Lehman C. , Gatsonis C. , Kuhl C. , Hendrick E. , Pisano E. , Hanna L. , Peacock S. , Smazal S. , Maki D. , Schnall M. 
Published: March 2020

604 Background: There is wide variation in the use of breast MRI to screen the contralateral breast in patients recently diagnosed with unilateral breast cancer. Some centers routinely scan all patients with a recent diagnosis of breast cancer while others restrict breast MRI to patients with dense breast tissue, patients who are pre-menopausal, or patients with infiltrating lobular carcinoma. This international study evaluated performance measures of MRI by mammographic density, menopausal status and type of index cancer. Methods: 969 women from 21 sites with a recent diagnosis of unilateral breast cancer and a negative mammogram and CBE of the contralateral breast underwent breast MRI. Presence of breast cancer in the contralateral breast was determined by cancer positive breast biopsy within 12 months after study entry. Performance measures of breast MRI (cancer yield, sensitivity, specificity, negative predictive value, positive predictive value, biopsy rate) were compared between participant subsets defined by mammographic density (fatty vs dense), menopausal status (pre/peri menopausal vs post menopausal) and type of index cancer (invasive vs in situ and lobular vs non-lobular). Results: Performance measures of breast MRI were not influenced by breast density or index cancer histology. Cancer yield of MRI in dense breast women was 3% in both fatty and dense breasted women. Although cancer yield and sensitivity of MRI did not vary based on menopausal status, specificity was significantly higher among post-menopausal women in comparison to pre- or peri-menopausal women (p-value=0.002) as was positive biopsy rate (p-value 0.009). Conclusions: Performance of MRI in screening the contralateral breast in the newly diagnosed breast cancer patient is not influenced by breast density or index cancer histology. Specificity and positive biopsy rate are higher in post-menopausal women, which may be related to hormonal influences on breast tissue enhancement. [Table: see text]
First safety and response results of a randomized phase III study with liposomal platin in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: Jehn C. F. , Siebmann S. , Pecher G. , Wernicke K. , Possinger K. , Lüftner D. 
Published: March 2020

6040 Background: Cisplatin is one of the most active chemotherapeutic agents used in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). However, its clinical efficacy is limited by its renal- and hematotoxicity profile. In a randomized, multicenter phase III trial, we replaced conventional cisplatin by a liposomal formulation of cisplatin (lipoplatin), and compared the safety and efficacy profiles of patients (pts) in the two treatment arms. Methods: Arm A: 100 mg/m2/d lipoplatin (d 1,8,15) plus 1,000 mg/m2/d 5-FU (d 1–5) q3w for 6 cycles; arm B: 100 mg/m2/d cisplatin (d 1) plus 1,000 mg/m2/d 5-FU (day 1–5) q3w for 6 cycles. Inclusion criteria: histologically confirmed SCCHN, age 18–75, renal function (creatinine clearance >50 ml/min) and primary metastatic disease or progressive SCCHN. Results: 62 pts were randomized, from which 43 pts (39 m; 4 w) were evaluable for outcome and toxicity. In the cisplatin arm hematotoxicity was more frequent (grades I/II: 28 pts, grades III/IV: 2 pts) than in the lipoplatin arm (grades I/II: 15 pts, grades III/IV: 3 pts). The rate of anemia was similar between the treatment arms. 13 pts in the lipoplatin arm experienced renal toxicity with (grade I: 3pts) and (grade II: 10 pts), as measured by a reduction of the creatinine clearance (grade I: 99–75 ml/min; grade II: 74–50 ml/min; grade III: <50 ml/min). Renal toxicity occurred in 8 patients in the cisplatin arm with 1 pt (grade I) and 3 pts (grade II), however 5 pts developed grade III. No renal toxicity grade III was developed in the lipoplatin arm until now. Outcome was as follows: lipoplatin arm: PR: 3 pts; SD: 13 pts; PD: 9 pts; cisplatin arm: PR: 8 pts; SD: 9 pts; PD: 1 pts. Thus, the non-PD pts (PR or SD) was 16/25 (64 %) in the lipoplatin arm vs 17/18 (94%) cases in the cisplatin arm. Conclusions: Liposomal platin seems to reduce both the renal and hematological toxicity as compared to conventional cisplatin to a clinically relevant extent. This reduction of side effects will influence the chance to preserve the dose density of chemotherapy, and thereby, the efficacy of treatment. No significant financial relationships to disclose.