bluuebunny/crossref_metadata_2025_split huggingface dataset:
S0216: A Southwest Oncology Group (SWOG) phase II trial of docetaxel (T), cisplatin (P), and fluorouracil (F) induction followed by accelerated fractionation/concomitant boost (AF/CB) radiotherapy (RT) and concurrent cisplatin for advanced head and neck squamous cell cancer (HNSCC)
Authors: Adelstein D. J. , Moon J. , Hanna E. , Shankar Giri P. G. , Mills G. M. , Wolf G. T. , Urba S. G. 
Published: March 2020

6014 Background: Randomized trials have suggested benefit from three-drug taxane-containing induction chemotherapy, and from AF/CB RT in patients (pts) with locoregionally advanced HNSCC. In an effort to optimize non-operative therapy, this SWOG phase II trial combined these two interventions with standard concurrent single-agent cisplatin. Methods: Eligibility required a diagnosis of untreated stage III or IV (M0) HNSCC deemed appropriate for RT with curative intent, a performance status of 0–1, and adequate hematologic, renal, and hepatic function. Two courses of induction TPF (T 75 mg/m2 day (d)1, P 100 mg/m2 d1, and F 1,000 mg/m2/d as a 24 hour continuous IV infusion d1–4) were given, 21 days apart. Stable or responding pts received definitive AF/CB RT; 54 Gy in 30 fractions (fx) to the total volume, with a concomitant boost of 18 Gy in 12 fx given on the last 12 treatment days. Concurrent cisplatin (100 mg/m2) was given on d1 and d22 of the RT. An accrual of 60 pts was planned using a one-stage study design. The primary endpoint was overall survival (OS). Secondary endpoints were toxicity and response. Results: Between 3/1/03 and 8/15/04, 76 pts were enrolled; 74 were eligible and evaluable. The median age was 54 years; 82% were male, and 77% white. 52 pts (70%) had stage IV disease. 40 pts (54%) experienced at least one grade (G)4 toxicity during induction, including neutropenia in 32, with fever in 13. 62 pts completed induction and began concurrent chemoradiotherapy (CCRT); 50 completed all planned treatment. 57 pts have been evaluated for toxicity from CCRT. At least one G4 toxicity was noted in 20 pts, including neutropenia in 6, with fever in 3. There were 2 treatment-related deaths during induction, and 2 during CCRT. With a median follow-up of 27 months, the 2-year projected OS is 72% (95% CI 62%-83%), with a projected progression-free survival (PFS) of 66% (95% CI 55%-77%). Conclusions: TPF induction followed by AF/CB RT and concurrent cisplatin is toxic but feasible within a cooperative group. In this cohort of pts with advanced HNSCC, OS and PFS are encouraging, and justify further study of this approach. No significant financial relationships to disclose.
A phase II study of gefitinib in patients with advanced thyroid cancer
Authors: Pennell N. A. , Daniels G. H. , Haddad R. I. , Ross D. S. , Wirth L. J. , Fidias P. H. , Temel J. S. , Gurubhagavatula S. , Clark J. R. , Lynch T. J. 
Published: March 2020

6020 Background: There are few effective treatments for locally advanced or metastatic thyroid cancers that are refractory to radioactive iodine (RaI). The epidermal growth factor receptor (EGFR) is highly expressed on normal and malignant thyroid tissue, and has been associated with a worse prognosis in well-differentiated thyroid cancer. The EGFR tyrosine kinase inhibitor gefitinib is effective in inhibiting the growth of thyroid cancer cells in vitro. This study sought to determine the efficacy and tolerability of gefitinib in patients with advanced thyroid cancer. Methods: In this open-label phase II trial, patients with RaI-refractory, locally advanced or metastatic thyroid cancer received 250mg of daily gefitinib. Anaplastic and medullary thyroid carcinoma were considered RaI refractory based on histology. The primary endpoint was overall response rate. Secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), and tumor marker responses. Tumor markers consisted of serum thyroglobulin (Tg) in the differentiated cancers and serum calcitonin and carcinoembryonic antigen in medullary thyroid cancer. Results: A total of 27 patients were enrolled. 59% were male and the median age was 65. Histologic subtypes included papillary (41%), follicular (22%), anaplastic (19%), medullary (15%), and Hürthle cell carcinoma (4%). There were no objective tumor responses among the 25 patients evaluated, at which point the trial was halted. However, 32% of patients had objective reductions in tumor volume that did not meet criteria for PR. 48%, 24%, and 12% of patients had stable disease (SD) after 3, 6, and 12 months of treatment. Median PFS and OS were 3.7 [95% CI; 1.8, 5.7] and 17.5 months [9.2, not yet reached]. Five patients with SD had a decrease in Tg to <90% of baseline level that was maintained for at least 3 months. Gefitinib was well tolerated, with 11% of patients experiencing grade 3 toxicity. Conclusions: Gefitinib therapy did not result in any objective tumor responses. However, reductions in tumor volume, falling Tg levels, and prolonged SD in a subset of patients may indicate biologic activity. The OS of 17.5 months was superior to historical rates in this population. However, the significance of this is difficult to interpret in the absence of a randomized comparison group. No significant financial relationships to disclose.
EGFR expression by immunohistochemistry (IHC) and response to chemotherapy and cetuximab in squamous cell carcinoma of the head and neck (SCCHN)
Authors: Kies M. S. , Ghebremichael M. S. , Katz T. L. , Herbst R. S. , Youssoufian H. , Burtness B. 
Published: March 2020

6024 Background: There is modest activity for cetuximab in recurrent SCCHN. Molecular markers for patient selection are desirable. Burtness et al (JCO 23:8646, 2005) reported that high EGFR expression predicted for tumor resistance to chemotherapy (CT) with or without cetuximab. We have studied an independent cohort of patients from the IMC-9816 study (Herbst et al, JCO 23:5578, 2005) using the same EGFR immunoreactivity staining technique. Methods: Slides were prepared from formalin fixed paraffin embedded tissue with the DAKO kit, with staining intensity graded on an ordinal scale 0–3 and staining density assessed according to the percentage of cells stained. High expression was defined as staining intensity 3 + on = 80% of cells. Tumor samples were available in 77 pts from the initial cohort of 132 patients with recurrent SCCHN who received cisplatin-based CT. Of the latter, 76 patients were assessed to have stable (SD 51) or progressive disease (PD 25) and then treated with cetuximab and cisplatin. An amendment permitted further enrollment of patients with PD after off study cisplatin therapy (N 54). Of a total of 130 pts who received cetuximab and cisplatin, tumor samples were available from 86. Results: There was no association of response with EGFR expression. Responses to CT are tabulated. Of the 86 SD and PD pts receiving CT and cetuximab, responses were observed in 3 of 44 and 7 of 42 pts with low and high EGFR expression, respectively (p=0.191). In a survival analysis of patients treated with cetuximab, the hazard ratio for subjects with high EGFR was 0.835, p=0.40. Conclusions: Conventional IHC, even when supplemented by staining intensity and staining density, does not predict for responsiveness of SCCHN to CT, with or without cetuximab. Future studies may require more quantitative methods, possibly subcellular localization, and measurement of other EGFR pathway targets, ligand content and probably “down-stream” effectors. No significant financial relationships to disclose. [Table: see text]
Promoter hypermethylation of GPX3 as a predictor for chemoresistance and survival in head and neck cancer patients
Authors: Guo Z. , Chen Z. , Yang Z. , Schumaker L. , Cullen K. J. 
Published: March 2020

6027 Background: Resistance of cancer cells to cisplatin and its analogues is the major limitation in clinical application of cisplatin-based chemotherapy. The mechanisms by which cancer cells develop resistance to the drugs are still unclear, and there is no way currently to predict the drug resistance of individual tumors. By genome-wide scanning of hypermethylated genes on head and neck cancer cells, we identified glutathione peroxidase 3 (GPX3) as one of the strong candidates whose promoter hypermethylation may be associated with head and neck chemoresistance. In this study, we investigated the potential predictive value of GPX3 methylation for head and neck cancer chemoresistance and patient prognosis. Methods: Promoter methylation and expression of GPX3 gene in head and neck cancer cell lines were examined by plasmid cloning, bisulfite DNA sequencing, reverse transcription-PCR and Western blot. GPX3 methylation in primary cancer tissues was assessed by real-time methylation-specific PCR (MSP). Forty-six head and neck cancer cases, for which chemotherapy response and survival were known, were selected for analysis. Correlation of GPX3 methylation and chemoresistance was tested using two-sided Fisher’s Exact Test and its prediction for patient survival was assessed using Kaplan-Meier survival analysis. Results: Loss of GPX3 expression was observed in 4 of 8 head and neck cancer cell lines and was consistent with cisplatin resistance. Demethylating treatment of the cell lines negative for GPX3 expression significantly restored its expression. Bisulfite DNA sequencing showed that the 5’ flanking promoter region of GPX3 was heavily hypermethylated in all cell lines with expression-silencing of the gene. In the 46 head and neck cancer cases analyzed by MSP, 15 of 23 non-responding cases (65%) showed GPX3 methylation, while 4 of 23 complete and partial response cases (17%) contained low levels of GPX3 methylation (Relative Risk 3.343, two sided Fisher’s exact test, P=0.002). Kaplan-Meier survival analysis showed a relative risk of death of 1.942 in patients with GPX3 methylation. Conclusions: Our findings suggest that GPX3 methylation is a strong candidate predictor for chemoresistance and prognosis of head and neck cancer patients. No significant financial relationships to disclose.
Value of intensity modulated radiotherapy for local control and salivary flow compared with conventional radiotherapy for stage II nasopharyngeal carcinoma
Authors: Kwong D. L. , McMillan A. , Pow E. , Sham J. 
Published: March 2020

6036 Background: Xerostomia is ubiquitous after conventional radiotherapy (CRT) for nasopharyngeal carcinoma (NPC). Intensity modulated radiotherapy (IMRT) has been advocated to spare the parotids for early disease. However, in T2 disease where there is a need to cover parapharyngeal involvement, it is uncertain if IMRT can still preserve salivary function without compromising local control. Methods: Patients with T2N0/1M0 NPC to be treated with RT alone were eligible. Patients were randomized to receive CRT or IMRT. The end points were salivary flow and local control. The aim was to recruit 25 patients for salivary flow study in each arm. All patients underwent stimulated parotid (SPS) and whole salivary (SWS) flow assessment before RT and at 2, 6 and 12 months after RT. Results: From 2000 to 2005, 42 and 40 patients were randomized to IMRT and CRT respectively. 19 (47.5%) and 27 (64.3%) of patients treated with CRT and IMRT had N1 disease respectively (p=0.18). The median dose for CRT patients was 68 Gy and 75% patients received additional parapharyngeal boost dose of 10 Gy. The median dose to NP for patient treated with IMRT was 70 Gy with no additional boost. Disease control and survival rates were shown in the Table. 25 patients in each arm underwent prospective salivary flow assessment. There was gradual recovery of SWS and SPS among patients treated with IMRT while patient on CRT showed no improvement over time. The mean SWS and SPS flow at 12 months were 26% and 114% of baseline among patients treated with IMRT, compared with 5% and 0% among patients treated with CRT. There was significant difference in SWS and SPS between patients treated with IMRT and CRT at 2, 6 and 12 months post-RT. The average mean dose to parotid gland was 41Gy. Conclusions: IMRT can reserve salivary flow despite a relatively high mean dose to the parotid glands. The significant improvement in local control with IMRT was unexpected but can be due to better coverage of disease with 3-dimensional planning. No significant financial relationships to disclose.
Phase II trial of irinotecan (Ir) plus cisplatin (CDDP) in patients with recurrent or metastatic squamous carcinoma of the head and neck (SCCHN)
Authors: Gilbert J. , Cmelak A. , Burkey B. , Sinard R. , Yarborough W. , Netterville J. , Paty V. , Chung C. , Hudson T. , Murphy B. 
Published: March 2020

6041 Background: Prognosis for recurrent or metastatic SCCHN patients remains poor with median survivals of 6–9 months. Therapies targeting this group are needed. We conducted a single arm Phase II trial of Ir plus CDDP in patients with recurrent or metastatic SCCHN. The goal of this trial was to evaluate the efficacy and toxicity of this combination in advanced SCCHN. Methods: Eligible patients had incurable SCCHN, an ECOG PS of 0–2 and were chemonaive (no prior chemotherapy or chemotherapy for primary disease at least 6 months prior to study entry). A two-stage accrual design (Simon) was used. Irinotecan 65 mg/m2 and CDDP 30 mg/m2 were administered weekly for 4 weeks, followed by a 2 week rest for a 6 week cycle. Due to GI toxicity and neutropenia, the Ir was decreased to 50 mg/m2 with CDDP 30 mg/m2. Response assessment was made after every cycle using WHO criteria. The primary endpoint was response rate. Results: Forty patients were enrolled (male: 33, female:7). Median age was 58 (33–79). Forty and 32 patients were evaluable for toxicity and response, respectively. Reasons for unevaluable: 7 without at least 1 full cycle of therapy; 1 patient with incomplete records. Overall response rate was 34% (11/32 PR) with 18% SD (6/32). Median progression free survival was 2.6 months. The median overall survival was 8.2 months. Toxicity was substantial at Ir 65 mg/m2 with a rate of Grade (G) 3 or 4 toxicity of 82% compared to 56% at Ir 50 mg/m2. For both dose levels, G 3 or 4 nausea and vomiting (23%), diarrhea (15%) and neutropenia (35%) were the most common toxicities. Conclusions: The combination of irinotecan and cisplatin is active in a poor prognosis group of patients. Toxicity of irinotecan at 65 mg/m2 with CDDP 30 mg/m2 is substantial. Irinotecan 50 mg/m2 and CDDP 30 mg/m2 is tolerable and provides a 34% response rate. No significant financial relationships to disclose.
A phase II trial of sorafenib in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC): A Southwest Oncology Group (SWOG) trial
Authors: Williamson S. K. , Moon J. , Huang C. H. , Guaglianone P. , Wolf G. T. , Urba S. G. 
Published: March 2020

6044 Background: Sorafenib is a potent Raf-1, B-Raf kinase inhibitor and inhibits tyrosine kinases associated with VEGFR-2, 3 and PDGFR-B. We conducted a phase II trial to evaluate the efficacy of BAY 43–9006 in patients with metastatic or recurrent HNSCC. Methods: Chemotherapy naïve patients with histologically proven HNSCC either metastatic, persisted or recurred following definitive treatment, and not amenable to salvage surgical resection were eligible. Patients may have received only one induction or adjuvant chemotherapy regimen provided that at least 6 months elapsed since the last course was administered. Patients must have adequate organ function and a Performance Status of = 1. Sorafenib was administered orally at 400 mg BID on a continuous basis, in 28-day cycles. Responses were evaluated every 8 weeks according to RECIST criteria. The accrual goal was 40 patients. Results: Final accrual was 44 patients. Three patients are ineligible: two with no measurable disease and one with inadequate baseline disease assessment. One eligible patient did not receive any treatment due to noncompliance and is not analyzable. Of the 38 eligible patients assessed for adverse events, there was one Grade 4 toxic event, an asymptomatic pulmonary embolus. Grade 3 toxicities include 3 patients with hand/foot syndrome, 4 with stomatitis, 2 with anorexia and one episode each of esophagitis, dysphagia, xerostomia, hypertension, fatigue, anemia, nausea, hyponatremia and decubitus ulcer. The most common grade 2 toxic events were fatigue, anorexia, stomatitis, and hypertension. Thirty-four eligible patients have been evaluated for response with one confirmed and one unconfirmed partial response. The estimated confirmed response probability is 3% (95% CI: 0 –13%). Two patients remain on treatment. Median follow-up is 9 mos. Median progression-free survival is 4 mos (95% CI: 3 - 4 mos) and median overall survival is 8 mos (95% CI: 7 - 11 mos). In previous SWOG phase II single agent trials in this patient population the median progression-free survival is 2 mos and overall survival is 6 mos. Conclusion: Sorafenib is well tolerated. Although response was poor, PFS and OS compare favorably with previous SWOG phase II single agent trials. No significant financial relationships to disclose.
Role of EGFR but not HER2 or HER3 gene copy number in predicting sensitivity of head and neck squamous cell carcinoma (SCCHN) cell lines to EGFR tyrosine kinase inhibitors
Authors: Varella-Garcia M. , Acheson K. , Marshall G. B. , McCormack R. M. , Ryan A. , Hirsch F. R. , Bunn P. A. , Hickinson D. M. , Speake G. 
Published: March 2020

6063 Background: EGFR gene copy number has previously been reported to predict for improved overall survival in NSCLC patients treated with gefitinib (IRESSA) or erlotinib compared with placebo [JCO 2006;24:5034–42 & N Engl J Med 2005;353:133–44]. The utility of EGFR gene copy number as a predictive biomarker in other tumour types such as squamous cell carcinoma of the head and neck (SCCHN) is currently under clinical investigation. The present study examined a panel of 20 SCCHN cell lines to identify potential biomarkers predicting in vitro sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Methods: A panel of 20 SCCHN cell lines was screened for sensitivity to gefitinib, vandetanib or erlotinib using a viable cell number endpoint, with G150 values determined for each cell line (inhibitor concentration required to give 50% growth inhibition). Cell lines were blinded and assessed for EGFR, HER2 and HER3 protein expression by ELISA, mutation status by dye-terminator sequencing, and gene copy number by fluorescence in situ hybridisation (FISH). Results: A broad range in sensitivity was observed for all compounds across the panel of 20 SCCHN cell lines (G150 ranging from 0.001uM to =10uM). 12 cell lines were positive for EGFR genomic gain. Sensitivity (GI50 <1uM) to all EGFR TKIs was seen in 11 lines and resistance (GI50 >8uM) in 5 lines. Of the sensitive cell lines, 9 were positive for EGFR genomic gain compared with only 1 of the resistant lines. Furthermore, EGFR protein expression also had a direct association with EGFR TKI sensitivity. In contrast, only 4 cell lines were positive for HER2 or HER3 genomic gain and there was no correlation with sensitivity. The most sensitive cell line was positive for EGFR genomic gain and was the only line to have an EGFR TK mutation (S768I in exon 20). Conclusions: EGFR gene copy number and protein expression appeared to have predictive value in identifying SCCHN cell lines sensitive to EGFR TKIs. No significant financial relationships to disclose.
RET oncogene mutations in a large Korean kindred with familial medullary thyroid carcinoma
Authors: Lee Y. , Park H. , Jung J. , Lim Y. , Uchino S. 
Published: March 2020

6066 Background: Familial medullary thyroid carcinoma (FMTC) is related to germ-line mutations in the RET proto-oncogene. The mutations concern mainly cystein residues in exons 10 and 11, whereas noncystein mutations in exons 13–16 are rare. These mutations have been recorded in the different populations, but to date there is no corresponding study in Korean families. In this study, we identify the RET mutations in the Korean family with FMTC and propose therapeutic approach in managing the disorder. Methods: The large family consists of 4 generations with a total of 32 individuals. There was a history of MTC in five members of the family. The index case was a 67-yr- old woman who underwent total thyroidectomy and both modified radical neck dissection in our hospital at the age of 48. We analysed exons 10, 11, 13, 14, 15 and 16 in index patients using DNA sequencing. Twenty-nine subjects from the family were clinically assessed and subsequently molecularly analysed for the presence of RET gene mutations. Results: We have found a missense TGC?AGC mutation at codon 618 in Exon 10. This transversion leads to the substitution of cystein with serin. The mutation was detected in all five MTC patients as well as in 6 asymptomatic relatives. The mutation shows a wide clinical heterogenecity, as there are carrier patients with age of diagnosis ranging from 9 to 64 years. Conclusions: It is likely that the mutation causes FMTC, because no other mutation was found in RET. This study showed 100% accordance between presence of the disease and gene carrier status is reported. Total preventive thyroidectomy has been recommended in all carriers of RET genetic defects. No significant financial relationships to disclose.
Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck (SCCHN)
Authors: Savvides P. , Greskovich J. , Bokar J. , Stepnick D. W. , Fu P. , Johnson F. , Patel C. , Wasman J. , Remick S. , Lavertu P. 
Published: March 2020

6068 Background: VEGF expression has been shown to be up regulated in SCCHN, representing a promising therapeutic target. Bevacizumab is an anti-VEGF monoclonal antibody that may potentiate the efficacy of concurrent radiation and docetaxel. This trial represents the first attempt, to the best of our knowledge, to establish the efficacy and toxicities of the addition of bevacizumab to concurrent radiation with docetaxel in patients with locally advanced SCCHN. Methods: Patients with previously untreated stage III-IVb SCCHN receive standard once-daily radiation (70.2Gy, 1.8Gy/day), weekly docetaxel (20 mg/m2/week for the duration of radiation) and biweekly bevacizumab (5 mg/kg/two weeks) during and for up to one year following radiation. A total of 30 patients will be enrolled in this study. Results: Twelve of 30 planned patients (11 males), mean age 58 years (range 49–66), all with stage IV disease have been enrolled. Primary site: pharynx (n=8) and larynx (n=4). 10 patients have completed concurrent chemoradiation. After a median followup of 9 months (range: 0 –13), 9 patients remain in complete response, 1 patient developed metastatic disease. 6/10 patients underwent planned neck dissection and they all had a pathologic complete response. 6/9 patients, in complete response, are currently receiving adjuvant bevacizumab. The remaining 3 patients are currently off adjuvant bevacizumab treatment for area of radiation necrosis of larynx (n=1), pharyngoesophageal stenosis (n=1), status post cholecystectomy with pathology revealing acute hemorrhagic cholecystitis with transmural gangrenous necrosis (n=1). Conclusions: For patients with locally advanced SCCHN, preliminary data suggest that the addition of bevacizumab to concurrent radiation with docetaxel is feasible, safe and active. Supported in part by Genentech, NIH grants P30 CA43703 and M01 RR-000080 Clinicaltrials.gov identifier: NCT00281840 [Table: see text]