bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Oral mucositis is associated with increased resource use among patients receiving treatment for cancers of the head and neck
Authors: Keefe D. M. , Garden A. , Barasch A. , Tischler R. , Brennan M. , Trotti A. , Vera-Llonch M. , Oster G. , Elting L. , Sonis S.
Published: March 2020

6070

Background: Oral mucositis (OM) is the oral manifestation of mucosal injury (MUI), and is a common, bothersome, and treatment-interrupting toxicity of chemoradiation therapy for squamous cell cancers (SCC) of the head and neck. Retrospective studies have reported that OM increases healthcare resource use. We present interim results of an international, multicenter, prospective study undertaken to characterize the clinical and economic burden of OM in patients with cancers of the oral cavity (OC), oropharynx (OP), larynx (L) and hypopharynx (HP). Methods: Patients (pts) with histologically proven SCC of the designated anatomical sites, whose planned treatment included full-cycle conventional or intensity modulated (IM) radiation therapy (RT) with or without chemotherapy, were enrolled at least one week prior to the start of treatment. Pts completed the Oral Mucositis Daily Questionnaire (OMDQ), a validated questionnaire developed to document patient-reported symptoms of OM and MUI including mouth and throat soreness (MTS), at baseline and daily throughout RT. MTS was assessed using a 5-point numeric rating scale, ranging from 0 (“no soreness”) to 4 (“extreme soreness”). Results: Of the first 61 pts to complete RT, 72% had cancers of the OC or OP, 49% received IMRT with concomitant chemotherapy, and 68% were male. 95% of pts reported OM symptoms (MTS>0); 80% had one or more scores =2. Pts with OC or OP cancers reported more symptoms than those with L or HP tumors (mean maximum score: 3.3 vs 2.8; p= 0.12). MTS scores were positively related to levels of resource use. Conclusions: Symptoms of radiation-induced OM are positively correlated with levels of resource utilization in patients with head and neck cancers.

No significant financial relationships to disclose.

[Table: see text]
Biweekly gemcitabine and oxaliplatin (GEMOX) in first-line metastatic or recurrent nasopharyngeal carcinoma (NPC)—An early report
Authors: Chan A. T. , Ma B. , Tung S. , Hui E. P. , Yuen K. K. , King A. , Leung S. F. , Chan I. , Chan M. , Zee B.
Published: March 2020

6071

Background: This multicenter phase II study evaluated the activity & safety of oxaliplatin (Ox), a 3rd generation platinum, in combination with gemcitabine (GEM) for the first time in the palliative setting for patients (pts) with undifferentiated/ poorly differentiated NPC. Methods: Pts with untreated metastatic (M1) or locoregionally recurrent (LR) NPC were treated with a biweekly ‘GEMOX’ regimen (D1: GEM, 1,000 mg/m2 at 10 mg/m2/min; D2: Ox, 100 mg/m2 over 2 hrs) for a max. of 12 cycles. Intrapatient dose escalation of GEM to 1,250 mg/m2 was allowed from cycle 2 onwards if no significant toxicity occurred in cycle 1. Response was assessed every 4 cycles (RECIST criteria). Results: 23 pts accrued before 31st July 06 were evaluated for toxicity & response; cut-off date for data analysis was 15th Oct 06. The median age was 53 yrs (range 38–72); 19 were men, all had ECOG status of 0–1. At enrolment, 7 pts (29%) had M1 disease only, 3 (12%) pts had LR only, & the rest both M1 & LR. All 7 pts with only LR received radical radiotherapy (RT) at initial diagnosis. A median of 11 cycles (range 3–13) were administered. Best overall response rate was 52%, with 12 partial responses & 11 stable diseases. The median duration of response was 7 months (range 0.8–15). Grade (gr) 3–4 hematological toxicities (CTCAE ver 3) included neutropenia in 7 pts (30%, only 1 pt had fever), thrombocytopenia in 5 pts (26%, 1 gr 4 case with mild gum bleeding). Gr 3–4 non-hematological toxicities included gr 3 diarrhoea in 2 pts, gr 4 Ox-related hypersensitivity reaction in 1 pt, gr 3 epistaxis in 2 pts. The commonest non-hematological toxicities were gr 1–2 Ox-related sensory neuropathy (22pts). There were no treatment-related deaths & only 1 pt withdrew from study due to drug-related toxicity. Conclusions: GEMOX is a promising regimen among pts with metastatic & recurrent NPC. Accrual is ongoing with a planned total sample of 40 pts.

No significant financial relationships to disclose.
Cisplatin plus gemcitabine (GC) as induction chemotherapy in locally advanced head and neck cancer (HANC)
Authors: Jamshed A. , Hussain R. , Ahmed S. , Rehman K. , Shehzad K. , Muhammad B. , Hameed S. , Shah M. A. , Azhar R. , Faruqui Z.
Published: March 2020

6073

Background: Cisplatin/infusional 5-fluorouracil chemotherapy is routinely administered as standard induction chemotherapy in advanced HANC. However, the optimum treatment remains to be defined. Gemcitabine is an active agent in HANC and few studies have evaluated induction GC in HANC. We have explored the activity and toxicity of GC as induction treatment in HANC and report the results. Methods: From August 2005 to September 2006, 55 patients with locally advanced HANC had induction chemotherapy with GC at Shaukat Khanum Memorial Cancer Hospital and Research Centre. We reviewed the medical records and prospectively collected data to determine activity and toxicity of induction GC. M:F ratio was 64%:36% with a median age of 50 years (range 19–80). All patients had histologically confirmed squamous cell carcinoma. The site of disease was nasopharynx, paranasal sinuses, oral cavity, oropharynx, larynx and hyopharynx in 4% (2), 11% (6), 51% (21), 2% (1), 11% (6) and 22% (11) respectively. According to AJCC staging 7% (4) had stage III and 93% (51) had stage IVa/IVb disease (T3N0 7%, T3N+ 2%, T4N0 38% and T4N+ 53%). Induction chemotherapy consisted of 2 cycles of cisplatin 75 mg/m2 day 1 and gemcitabine 1000 mg/m2 day 1 and 8 with treatment repeated three weekly. Fifty-three (94%) patients received 2 cycles as planned. Toxicity was scored after each cycle according to the NCI.CTC criteria. Response was assessed following completion of induction chemotherapy by clinical examination/MRI scan. Results: All patients were available for assessment of toxicity and response. A total of 111 cycles were delivered. The response rates are: complete 24% (13), partial 62% (34), no response 7% (4) and progression 7% (4). The overall response rate was 86% (complete 24%, partial 62%). No treatment related deaths occurred. Haematological G3/G4 toxicity included neutropenia (13%/7%) and thrombocytopenia (5%/0%). The non-haematological toxicity observed (nausea, vomiting and diarrhoea) was only G1/G2. Conclusions: GC is well tolerated with low toxicity and high anti tumour activity as neoadjuvant chemotherapy treatment in squamous cell head and neck cancer. Combination GC arm should be included in future trials.

No significant financial relationships to disclose.
Prognostic value of P53 and thymidylate synthase (TS) overexpression in patients with squamous cell carcinoma of the head and neck treated with neoadjuvant chemotherapy
Authors: Abderkader M. E. , Elsawy W. H. , Abdalla M. , Dorgham Y. T. , Elnemr M. M.
Published: March 2020

6081

Background: Neoadjuvant cisplatin-based chemotherapy has been widely used in the last decade for organ preservation or unresectable disease in advanced stage head and neck cancer. Thymidylate synthase (TS) and p53 are central molecules in the regulation of cell growth. Differences in the intracellular expression of these proteins by tumor cells may have predictive value for response to chemotherapy and early failure in patients with squamous cell cancer of the head and neck (SCCHN). We examined the expression of P53 and TS that have been associated with chemotherapy resistance. Methods: Immunohistochemistry was used to assess the tumor cell expression of TS and p53 in pre-therapy biopsies from 65 patients with SCCHN treated with induction chemotherapy. Results: The overall response rate for cisplatin-based neoadjuvant treatment was 80%. The expression of P53 and TS was associated with resistance to neoadjuvant treatment, but none reached statistical significance. Overall survival (OS) was strongly correlated with the absence of p53 expression. The OS at 3 years was 80% in the p53-negative group, whereas it was 29% in the p53-positive group for patients treated with neoadjuvant chemotherapy (P < 0.0001). Expression of TS was also significantly correlated with decreased OS after neoadjuvant treatment. In the TS-negative group, the 3-year OS rate was 69% compared with 38% in the TS-positive group (P = 0.0063). Conclusions: Our data showed that p53 and TS may be clinically important predictors of survival in patients receiving neoadjuvant chemotherapy for head and neck cancer.

No significant financial relationships to disclose.
Antitumor activity of imatinib in progressive, highly expressing KIT adenoid cystic carcinoma of the salivary glands: A phase II study
Authors: Guigay J. M. , Bidault F. , Temam S. , Janot F. , Raymond E. , Faivre S.
Published: March 2020

6086

Background: Adenoid cystic carcinoma (ACC) of the salivary glands is a rare orphan disease of the head and neck usually resistant to conventional chemotherapy, that was found to express KIT in 87% (39/45) of cases in our institutions. Methods: This study explored the antitumor effects of imatinib given at 800 mg daily in a phase II study for patients (pts) with recurrent or metastatic ACC failing locoregional treatments, presenting CT-scan documented progressive disease and highly (50–100% of tumor cells) expressing KIT. Primary endpoint of this study was time to tumor progression, secondary endpoints were tumor response and safety. Results. Since 2004, 17 pts (M/F: 5/12, median age 48, range 33–71) were included. Target lesions were pulmonary metastasis (13 pts), renal metastasis (1 pt), locoregional (2 pts) and pulmonary + locoregional (1 pt) recurrences. Previous treatment with chemotherapy was reported in 5 pts. Median duration of treatment was 6 months (range, 1–14 months). Toxicity was mild to moderate except for 2 pts who had grade 3–4 anemia/neutropenia and asthenia requiring dose reduction and early study withdrawal, respectively. Among 15 evaluable pts with tumor progression at study entry, 5 pts were stable after 6+, 8, 9, 12+ and 18+ months of follow-up and 2 pts displayed partial responses of 42% and 35% (RECIST). These objective responses were associated with early symptomatic improvement (dyspnea/pain) and occurred in platinum- resistant pulmonary metastasis and a radiation-pre-treated locoregional recurrence, lasting 14 months and 9+ months, respectively. Final accrual and TTP determinations are ongoing. Conclusion. Although sporadic, objective responses can be observed in patients with progressive ACC treated with imatinib as well as long-lasting tumor stabilisations.

No significant financial relationships to disclose.
Effect of adjuvant radiotherapy (RT) on overall survival (OS) for node positive head and neck squamous cell carcinoma (HNSCC)
Authors: Lavaf A. , Genden E. , Packer S. , Kao J.
Published: March 2020

6087

Background: Although adjuvant RT is often recommended for locally advanced HNSCC, its effect on OS or cancer-specific survival (CSS) has not been clearly demonstrated. Methods: Within the Surveillance, Epidemiology, and End Results (SEER) Database, we selected patients with locally invasive but node negative (SEER stage 2) or node positive HNSCC (SEER stage 3–4) treated either with surgery alone (S) or surgery and radiation (S+RT). This analysis included 13,145 patients from the SEER 17 database diagnosed between 1988 and 2001. Exclusion criteria included distant metastases, no RT records or death within 3 months of surgery. The median follow-up was 4.7 years. Results: Adjuvant RT was utilized in 55% of patients with stage 2 and 84% of stage 3–4 HNSCC. For Stage 2 HNSCC, adjuvant RT was associated with lower 5 year OS on univariate analysis (46.32% for S+RT vs. 49.76% for S, p=0.016) but not on multivariate analysis (HR 1.00, p=0.93). For Stage 3 HNSCC, RT improved 5 year OS associated with RT on univariate analysis (52% for S + RT vs. 41% for S, p<0.001) and multivariate analysis (HR 0.80, p=0.002). For Stage 4 HNSCC, RT significantly improved 5 year OS on univariate analysis (35% for S + RT vs. 25% for S, p<0.001) and multivariate analysis (HR 0.75, p<0.001). The addition of RT improved 5 year CSS for both stage 3 (59.7% vs. 51.4%) and stage 4 HNSCC (42.1% vs. 32.8%). Conclusions: In the largest reported analysis of adjuvant RT in locally advanced HNSCC, adjuvant RT results in an approximately 10% absolute increase in 5-year CSS and OS for node-positive HNSCC compared to S alone. The absolute benefit of RT is underestimated on univariate analysis because patients with poor prognostic factors are more frequently selected for adjuvant RT. Outcomes in this high-risk population remain suboptimal, emphasizing the need for continued investigation of innovative treatment approaches.

No significant financial relationships to disclose.
Sentinel lymph node biopsy is associated with a significantly improved survival compared to level Iand II axillary lymph node dissection in node-negative breast cancer patients
Authors: Langer I. , Guller U. , Schmitz S. Hsu , Ladewig A. , Viehl C. T. , Moch H. , Wight E. , Harder F. , Oertli D. , Zuber M.
Published: March 2020

609

Background: The sentinel lymph node (SLN) biopsy has emerged as the standard of care in evaluating the axillary lymph node status in early stage breast cancer patients. It is well known that step sectioning and immunohistochemistry of the SLN allow for a more accurate histopathologic examination. Conversely, it remains to be elucidated whether or not the more accurate SLN staging is associated with improved survival. Therefore, the objective of the present investigation was to evaluate if patients undergoing a SLN biopsy have an improved disease-free and overall survival compared to those undergoing ALND. Methods: From our prospective database 355 node negative patients with early stage breast cancer (pT1 und pT2 <=3cm, pN0/pNSN0) were assessed. Patients underwent either ALND (n=178) in the years 1990–1997 or a SLN biopsy (n=177) in 1998–2004. Long-term disease-free and overall survival were analysed for both groups. Log-rank tests were used for unadjusted analyses, a Cox proportional hazard regression model for risk-adjusted analyses. Results: The median follow- up was 48.2 months in the SLN group and 120.0 months in the ALND group. Patients in the SLN group had a significantly better disease-free (p=0.012) and overall survival (p=0.04) compared to the ALND group. In Cox proportional hazard regression analysis, the performed procedure (SLN compared to ALND) was an independent predictor for improved disease-free survival (hazard ratio 0.28, 95% confidence interval 0.11–0.75, p=0.011) and overall survival (hazard ratio 0.36, 95% confidence interval 0.14–0.89, p=0.027). Conclusion: The present analysis - the first one in the literature - provides compelling evidence that patients with a negative SLN have a significantly improved disease-free and overall survival compared to node negative patients undergoing ALND. This relevant finding is most likely due to an improved histopathologic staging accuracy. The significant survival benefit of node negative patients having SLN biopsy highlights yet another important advantage of the SLN concept in breast cancer.

No significant financial relationships to disclose.
Evolution of the randomized controlled trial (RCT) in oncology over three decades
Authors: Booth C. M. , Cescon D. W. , Wang L. , Tannock I. F. , Krzyzanowska M. K.
Published: March 2020

6515

Background: The RCT is the gold standard for establishing new therapies in oncology. Here we document changes with time in design, results, author conclusions and sponsorship. Methods: Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC) and non-small cell lung cancer (NSCLC) published 1975–2004 in 6 major journals were reviewed. Two authors independently abstracted data regarding trial design, effect size and author conclusions. Author conclusions were assigned a score from 1 to 7: 4/7 for a neutral statement, 7/7 and 1/7 for strong endorsement of experimental and control arm respectively. For each study the effect size for the primary endpoint was converted to a summary measure: hazard ratio [HR] for survival endpoints and relative risk [RR] for response rate. Descriptive statistics were used to analyze trends over time. Results: 326 eligible RCTs were included (48% breast, 24% CRC, 28% NSCLC). There was a significant increase in the number and size of RCTs (see Table ). Median rate of accrual increased from 7 patients/month in 1975–84 to 14 patients/month in 1995–2004 (p<0.001). There was an increase in multicenter (55 to 95%, p<0.001), international trials (26 to 52%, p<0.001) and for-profit sponsorship over time (6 to 57%, p<0.001). There was increasing use of survival (13 to 48%,) and decreasing use of response rate (32 to 14%) as primary endpoint (p<0.001). Authors have become more likely to strongly endorse the experimental arm despite no change in effect size over time (p=0.005). Studies sponsored by for-profit organizations were more likely to strongly endorse the experimental agent than studies not sponsored by for-profit groups (median author score 6/7 vs. 4/7, p<0.001). Conclusions: RCTs in oncology have become more common, larger, and are more likely to be sponsored by industry. Authors of modern RCTs are more likely to strongly endorse novel therapies despite no increase in the relative benefit of interventions. For-profit sponsorship is associated with stronger endorsement of the experimental arm.

No significant financial relationships to disclose.

[Table: see text]
Adverse event (AE) assessment lists for clinical trials (CTs) influence AE reporting rates: An evaluation of AE data collected on North Central Cancer Treatment Group CTs
Authors: Mahoney M. R. , Sargent D. J. , Campbell M. E. , Hobbs B. P. , Kugler J. W. , Alberts S. R. , Buckner J. C.
Published: March 2020

6517

Background: In NCCTG CTs a subset of AEs are assessed at each patient (pt) evaluation based on the known safety profile of agents(s). The NCCTG routinely pre-fills the “known” AE list onto CT Case Report Forms (CRFs). Newly identified AEs may expand the AE assessment list for ongoing CTs. Our survey of NCCTG AE data (JCO 2005), demonstrated that 85% of AEs reported were pre-filled on CRFs, of which, 83% did not actually occur (Grade 0). Extending this work, we evaluated the influence of pre-filling AEs on CRFs, relative to the final AE rates reported. Methods: Our non-random sample contains 507,899 AEs collected from 1/99–6/06 on 74 NCCTG CTs, 13 of which had AEs added to the CRF pre-fill list during the CT (2,604 pts, 3 Ph I/II, 8 Ph II, 2 Ph III, 9 investigational agents). Results: An average of 2.8 AEs (range 1–6) were added to CRFs for ongoing CTs, primarily for Oxaliplatin induced AEs. 58% (21/36) of AEs added during a CT were not reported prior to the addition, 22% (8) were not reported afterwards. 5 CTs had significantly higher AE rates (p<0.01) after expanding the AE list, most notably for required blood chemistries (SGOT/alk phos/creatinine/bilirubin 14.2 vs 0.72%). Overall, the same AEs were 4-fold (range 0–25) as likely to be reported when pre-filled on the CRF. Regardless of pre-filling, only 6% of the newly required AEs were Gr 3+. Conclusions: Our data suggest a significant difference between the AE rates reported if included in the CT CRF assessment list. This may significantly influence the reported results of a CT, explaining differential AE rates reported across CTs of the same agent(s). A prospective study is planned to formally evaluate this observation. Supported by NIH Grant CA25224.

No significant financial relationships to disclose.
Uncertainty around individualized predictions using nomograms: The concept of individualized prediction intervals
Authors: Iasonos A. , Schrag D. , Raj G. V. , Russo P. , Panageas K. S.
Published: March 2020

6526

Background: Nomograms have become popular in the clinical oncology community, because of their simplicity. Clinicians use nomograms to provide individualized prognostic estimates to patients based on their clinical and pathologic characteristics.We aim to evaluate the degree of uncertainty around individualized point estimates derived from a published nomogram. Methods: Predictions were evaluated from a published nomogram (Raj G.V et al, J Urol. 2007;177(1):53–8.), where the predicted outcome was clear cell (CC) histology in renal masses using pre-operative parameters.95% confidence intervals (CI) for each prediction were obtained from logistic regression using the SAS system.CIs depend on the covariate effect in the underlying model and the patient-specific values of the covariates, hence they differ from patient to patient.The width of the CI was used to assess the zone of uncertainty of the predictions for each individual patient in this cohort. Results: Predictions were obtained for each of the 299 patients in the cohort. The median width of the 95% CI around the point estimates was 18% (range 11–47%) indicating that 50% (147/299) of patients have ± 9% uncertainty and 95% (283/299) of patients have less than ±16% uncertainty around the estimate predicted by the nomogram. Only three patients (1%) have more than ±20% uncertainty around the nomogram derived estimate. For example, a 69-year-old male with a 3.9 cm renal mass, without vascular flow on Doppler ultrasound, has 18% probability of CC histology with 95% CI: 10–29%, whereas a 48-year-old female with 9.7cm renal mass without vascular flow has 18% probability of CC histology with 95% CI:7–41%. Conclusions: We demonstrate that patients with equal predicted probability from a nomogram may have different uncertainty around their prediction. When nomograms are used to convey prognostic information to patients, reporting strategies should incorporate the degree of uncertainty around the point estimates that are derived from the underlying regression models.Although, this strategy adds some degree of complexity to the graphical representation of results, it enhances the integrity of the exercise and conveys to patients the important message that uncertainty is inherent in prognostication.

No significant financial relationships to disclose.
Tailored chemotherapy (CT) information (info) faxed to general practitioners (GP) improves knowledge and confidence in managing side effects (SFX): Results from a randomized controlled trial (RCT)
Authors: Jefford M. H. , Baravelli C. , Dabscheck A. , Evans M. , Moloney M. , Schofield P.
Published: March 2020

6531

Background: The literature indicates discontinuity in patient (pt) care and poor communication between hospitals and community practice. GPs would like more info about CT, SFX and how to manage these. We aimed to develop standardized info for GPs about CT and to assess the impact of this in an RCT. Primary endpoints were: confidence managing pts having CT, knowledge of CT SFX, and satisfaction with both info and shared care of pts. Secondary endpoints included how useful and instructive GPs found the info. Methods: Peter Mac IRB approved the study. Initial focus group work with GPs informed the development of info about 23 CT regimens. GPs of pts due to commence a CT regimen for the first time were randomized to receive usual correspondence (UC) or UC plus info. Prior to randomization GPs were telephoned and verbal consent obtained. Telephone questionnaire (qstnre) assessed GPs confidence in managing pts and knowledge of CT SFX, as well as satisfaction with info and shared care of pts. GPs in the intervention group were then faxed the relevant info. One week later all GPs were phoned and completed a similar standardized qstnre. Measures used a 5 point scale/range. Results: 97 GPs managed 97 pts receiving 21 types of CT. GPs on average had 27.1 yrs clinical experience (SD=9.8) and were managing 5.5 pts receiving CT (SD=6.8). Of 97 GPs randomized, 81 (83.5%) completed the follow up qstnre. GPs confidence in managing CT SFX was fair at baseline (M=3.34, SD=0.69). GPs in the intervention group demonstrated a significantly greater increase in confidence (difference 0.36; p<0.01) and knowledge of CT SFX - eg febrile neutropenia (diff 0.55; p<0.01) - and close to significant effect for satisfaction with info / shared care (diff 0.35; p=0.051) compared with UC. GPs receiving info + UC also considered it significantly more useful (diff 1.48; p<0.001) and instructive (diff 1.88; p<0.001) than GPs who only received UC. Conclusions: Info about CT faxed to GPs is a simple, inexpensive intervention that increases GPs knowledge of CT SFX and confidence in managing pts. Further, GPs find this info more useful and instructive than UC alone. This intervention could have widespread application.

No significant financial relationships to disclose.
Descriptive study on the lost productivity in breast cancer patients
Authors: Bordeleau L. , Warr D. , Goodwin P. , Lathia N. , Jugovic O. , Mittmann N.
Published: March 2020

6542

Background: There is a paucity of data assessing the potential impact of breast cancer diagnosis on the productivity of affected women. The objective was to identify and quantify lost productivity, health utilities and quality of life experienced in women diagnosed with breast cancer. Methods: A consecutive cross-sectional cohort of women with breast cancer (at any stage) attending outpatient clinics at Mount Sinai Hospital/Princess Margaret Hospital were eligible and consented to participate in the study. Women completed questionnaires assessing demographic and disease related information, work productivity and activity impairment utility (EQ5D VAS) and quality of life (FACT-B). Results: Data from 103 patients age 56.5 ± 11.9 years (mean +SD) were collection. Distribution of stage at diagnosis was as follows: 0 (31%), I (26%), II (10%), III (5%), IV (17%), unknown (11%). Time since diagnosis was 30.0 ± 39.1 months. Most women had recently been on active treatment for their breast cancer: chemotherapy (47%), hormone manipulation (23%), herceptin (6%), radiation (27%) and unknown (15%). 9% of women had metastatic disease, 35% had an income between $0 and $30,000. 58% of women were working full time for pay before their diagnosis, whereas only 19% were working full time for pay at the time of the assessment. At the time of the assessment, 18% were on disability leave. 8.7% of the women retired between the times of their diagnosis to the current assessment. Of those still working, a mean of 8.7 ± 11.6 days were missed from work in the previous 30 days due to problems related to breast cancer. The average number of days that employed patients actually worked (N=27) was 16.0 ± 9.0 days (range 4–30 days). 8% of patients required paid health care assistance during the past 4 weeks. 44% of patients had a spouse as an unpaid caregiver, followed by child/parent (20%) and friend (13%). Mean overall health rated by the respondents using the EQ5D VAS was 73.2 ± 16.3. The FACT-B mean was 68.0 ± 12.5 (range 27 to 98). Conclusion: Breast cancer negatively impacts work productivity and overall activity. The significant use of both paid and unpaid assistance would amount to significant societal costs which are currently not included in most cost-effectiveness analyses.

No significant financial relationships to disclose.
Latina patient perspectives about informed decision making for surgical breast cancer treatment
Authors: Hawley S. , Janz N. , Hamilton A. , Katz S. J.
Published: March 2020

6544

Background: Although increasing informed decision making has been identified as a mechanism for reducing disparities in breast cancer treatment outcomes, little is known about these issues from the Latina perspective. Methods: 2,030 women with non- metastatic breast cancer diagnosed from 8/05–5/06 and reported to the Los Angeles County SEER registry were identified and mailed a survey shortly after receipt of surgical treatment. Latina and African American women were over-sampled. Survey data were merged to SEER clinical data. We report results on a 50% respondent sample (N=742) which will be updated based on a final respondent sample of 1,400 patients (projected response rate, 72%). Dependent variables were patient reports of how decisions were made (doctor-based, shared, patient-based); their preferred amount of decisional involvement; and two 5-item scales measuring satisfaction with decision-making and decisional regret. Results: 32% of women were white, 28% African American (AA), 20% Latina-English speaking (L-E), and 20% Latina-Spanish speaking (L- SP). About 28% of women in each ethnic group reported a surgeon-based, 33% a shared, and 38% a patient-based surgical treatment decision. L- SP women reported wanting more involvement in decision making more often than white, AA or L-E women (16% vs. 4%, 5%, 5%, respectively, p<0.001). All minority groups were less likely than white women to have high decisional satisfaction with L-SP women having the lowest satisfaction (w-74%, AA-63%, L-E-56%, L-SP-31%, p<0.001). L-SP women were more likely than white, AA or L-E women to have decisional regret (35% vs. 7%, 15%, 16%, respectively, p<0.001). Multivariate regression showed that Latina ethnicity and low literacy were independently associated with both low decisional satisfaction and high decisional regret (p<0.001). Conclusions: Latina women, especially Spanish speakers, report more dissatisfaction with the breast cancer surgical treatment decision-making process than other racial/ethnic groups. These results highlight the challenges to improving breast cancer treatment informed decision making for Latina women. Future interventions to improve satisfaction with the decision process should be tailored to ethnicity and acculturation.

No significant financial relationships to disclose.
Evaluation of quality measures for breast cancer care in a community setting
Authors: Dietrich L. L. , Ballandby R. , Lee J. , Sullivan D. , Mathiason M. A. , Landercasper J.
Published: March 2020

6545

Background: Compliance with National Initiative for Cancer Care Quality (NICCQ) quality indicators and National Comprehensive Cancer Network (NCCN) guidelines for breast cancer care are proposed measures of quality breast cancer care. Previously, we had determined NCCN guideline compliance rates for breast cancer care by physician review of electronic medical record (EMR). In the present study, we sought to compare NCCN guideline compliance and NICCQ adherence at our institution in regard to percent compliance, time taken to complete review, and comparison of physician reviewer (PR) versus non-physician reviewer (NPR). Methods: Review of the EMR was conducted for all 200 female patients who were newly diagnosed with breast cancer and treated at our multi-specialty institution in 2004. A PR and a NPR reviewed compliance with NICCQ quality indicators and NCCN guidelines for breast cancer care and time spent reviewing charts was recorded. Results: Adherence rate was less than 85% in only 7 of 36 NICCQ breast cancer quality measures for PR and only 6 of 36 for NPR. Patients overall received 91.5 % of NICCQ recommended care according to PR and 89.8% according to NPR. NICCQ measures were divided into categories to correspond with NCCN guideline categories and results are compared and summarized in the table below. Differences in observed compliance rates between PR and NPR were not significant for NCCN (except in pre-op workup where NPR was more accurate) or overall NICCQ audit, however differences were seen in individual NICCQ items with small numbers of patients. Average time for review of charts for NCCN guideline compliance vs. NICCQ adherence was not significantly different (6.8 vs. 6.3 minutes for PR and 8.3 vs. 8.9 minutes for the NPR). Conclusions: Our adherence rates for NICCQ and NCCN measures compare favorably with published values. Despite both being proposed quality measures, comparison of adherence rates for the two systems varied. PR is slightly faster than NPR but offset by PR's time value. A NPR performs as well, if not better, than a PR.

No significant financial relationships to disclose.

[Table: see text]