bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival and toxicity in patients with disseminated germ-cell cancer above 40 years of age.
Authors: Thomsen Frederik Birkebæk , Bandak Mikkel , Thomsen Maria Ferløv , Lauritsen Jakob , Christensen Ib Jarle , Gedske Daugaard Kirsten
Published: March 2020

4532

Background: The aim was to analyze treatment related toxicity and survival in patients aged 40 years or above (40+) treated with standard chemotherapy for germ-cell cancer (GCC). Methods: The study population comprised 135 40+ patients with disseminated GCC treated between 1984 – 2011 with either 3 or 4 cycles bleomycin, etoposide and cisplatin (BEP). A control-group of 135 patients aged 18-35 years was randomly selected matched on year of BEP treatment. All patients were followed until death or October 1st2011. Cumulated doses of BEP as well as bone-marrow toxicity, renal- and lung functions were recorded before, during and after termination of treatment. The expected mortality was calculated by extracting survival data for each patient matched on the date and age at the time of diagnosis. The cause of death was categorized as GCC, other malignancy or other. Results: The cumulated doses of BEP were comparable between the two groups and, generally, BEP was equally well tolerated. 40+ patients had increased cancer specific mortality, HR = 4.8 (P = 0.005). Especially patients with disease progression after first line chemotherapy had increased mortality (P = 0.015). The year of treatment (P = 0.32), histology (P = 0.30), CCI (P = 0.99), tobacco use (P = 0.16), alcohol consumption (P = 0.21), prophylactic G-CSF (P = 0.61), reduced doses of bleomycin (P = 0.11) and decreased renal function (P = 0.18) were not significantly associated with GCC mortality. However, patients with impaired lung function (<80% of expected) prior to treatment had an increased risk of GCC mortality (FVC (P = 0.03), DLCO (P = 0.01) and FEV1(P = 0.05)). Moreover, the 5-year overall survival in the 40+ group was 82.5% compared to the expected 5-year survival of the background population of 96.2% (P <0.001) and the estimated 5-year survival of 97.0% in the control-group (P <0.001). Conclusions: Reduced treatment intensity, or treatment related toxicity could not explain the increased mortality in 40+ GCC patients compared to a younger control-group. The 40+ group has a significantly lower response rate to BEP and a significantly higher mortality in case of disease progression. The worse prognosis could be related to tumor biology or increased co-morbidity.
Efficacy and safety of enzalutamide (ENZA) monotherapy in hormone-naive prostate cancer (HNPC).
Authors: Smith Matthew Raymond , Borre Michael , Rathenborg Per , Werbrouck Patrick , Van Poppel Hendrik , Heidenreich Axel , Iversen Peter , Baskin-Bey Edwina , Perabo Frank , Phung De , Tombal Bertrand
Published: March 2020

5001

Background: In locally-advanced prostate cancer, the antiandrogen bicalutamide (Bic) is used to maintain quality of life relative to castration therapy (LHRHa), but efficacy as a monotherapy is limited. ENZA is an oral androgen receptor (AR) inhibitor with higher AR–binding affinity vs Bic, and it prevents nuclear translocation, shows no DNA binding, and induces apoptosis. ENZA was approved in the US after prolonging overall survival in post-docetaxel metastatic castration resistant prostate cancer. This phase 2 study assessed ENZA monotherapy in patients (pts) with HNPC and noncastrate testosterone (T) ≥230 ng/dL. Methods: Pts with any stage HNPC (ECOG PS 0, life expectancy >1 y) requiring hormonal therapy received ENZA 160 mg/d for 25 wks. Primary endpoint was PSA response (≥80% decline at wk 25). Other endpoints were endocrine levels, pharmacokinetics, safety, and metabolic changes (body composition, bone biomarkers, lipids, and glycemic profiles). Results: 67 pts were enrolled. Median age was 73 y; 39% had metastases, 36% and 24% had prior prostatectomy and radiation, respectively. ENZA levels reached steady state after ~4 wks. Mean changes in metabolic outcomes at wk 25 included: –0.24% total body bone mineral density (BMD), –4.15% lean body mass, 6.85% fat body mass, 14.75% bone alkaline phosphatase, 4.55% total cholesterol, 6.48% triglycerides, –1.98% A1c, –0.10% fasting glucose, and 45.06% HOMA-IR. At wk 25, PSA response was 93% (62/67; 95% CI, 86%–99%); median PSA decrease was –99.6%. Mean T and estrogen increased 114% and 72%, respectively; other endocrine increases were observed, the highest was 185% for luteinizing hormone. Most common treatment-emergent AEs were grade 1 and included gynecomastia (36%), fatigue (34%), nipple pain (19%), and hot flush (18%). Five pts had serious AEs (none drug related). Conclusions: ENZA monotherapy achieved a high PSA response rate and marked PSA decline with efficacy similar to castration. In contrast to castration, BMD remained stable and metabolic variables (fat body mass, lipid and glycemic profiles) were not substantially impacted with ENZA monotherapy over the 6 month study period. Endocrine changes and AEs were consistent with potent AR inhibition. Clinical trial information: NCT01302041.
Follow-up results of NOAH, a randomized phase III trial evaluating neoadjuvant chemotherapy with trastuzumab (CT+H) followed by adjuvant H versus CT alone, in patients with HER2-positive locally advanced breast cancer.
Authors: Gianni Luca , Eiermann Wolfgang , Semiglazov Vladimir , Manikhas Alexey , Lluch Ana , Tjulandin Sergei , Zambetti Milvia , Vazquez Federico , Byakhov Mikhail J. , Lichinitser Mikhail , Climent Miguel Angel , Ciruelos Eva , Ojeda Belen , Mansutti Mauro , Bozhok Alla , Magazzu Domenico , Steinseifer Jutta , Valagussa Pinuccia , Baselga Jose
Published: March 2020

503

Background: The monoclonal antibody trastuzumab (H) has been shown to improve event-free survival (EFS) and pathologic complete response (pCR) in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without one year of trastuzumab in the primary analysis of the NOAH study (Gianni L, Lancet 2010). Updated EFS and overall survival (OS) results are now presented. Methods: In this international, multicenter, open-label, randomized phase III trial patients with locally advanced or inflammatory breast cancer were randomized 1:1 to receive CT+H followed by adjuvant H versus CT alone. A parallel cohort of 99 comparable patients with HER2-negative disease was included and treated with the same chemotherapy regimen. The neoadjuvant chemotherapy regimen included doxorubicin, paclitaxel, cyclophosphamide, methotrexate and 5-fluorouracil. The primary objective was to compare EFS defined as time from randomization to disease recurrence or progression [local, regional, distant or contralateral] or death due to any cause). Results: After a median follow up of 5.4 years, the EFS benefit with trastuzumab was confirmed. Cardiac tolerability was good despite concurrent administration of trastuzumab with doxorubicin. Two patients (2%) developed reversible symptomatic congestive heart failure and are presently alive. Conclusions: Present analysis confirms the significant EFS benefit observed in the primary analysis of the NOAH study, and shows a strong trend towards improved OS with the addition of trastuzumab to chemotherapy. pCR rate may be considered as a possible primary endpoint and early indicator of benefit in future neoadjuvant studies of HER2-targeted agents. Clinical trial information: 86043495. [Table: see text]
Post-treatment alterations in 18F-dihydrotestosterone (FDHT) and FDG PET/CT in metastatic castration-resistant prostate cancer (mCRPC) treated with cabozantinib.
Authors: Fox Josef J. , Haupt Eric C. , Humm John , Autio Karen A. , Rathkopf Dana E. , Vargas Hebert Alberto , Schöder Heiko , Hricak Hedvig , Larson Steven M. , Scher Howard I. , Morris Michael J.
Published: March 2020

5073

Background: Cabo is a multitargeted kinase inhibitor that has demonstrated complete and partial responses in mCRPC as assessed byTc-99 MDP bone scintigraphy. FDG and FDHT PET/CT demonstrate glucose metabolism and androgen receptor binding, respectively. We are exploring these tracers as response biomarkers in mCRPC treated with cabo. Methods: Patients (pts) treated with cabo were scanned with FDHT and FDG PET at baseline and after 6, 12, and 24 weeks (wks) of treatment. 5 index lesions were selected at baseline for each PET modality. The hottest slices from each were averaged (SUVmaxavg) and measured on post-treatment scans. The concordance of the post-treatment alterations of the two tracers (rise vs. decline) was examined, as were PSA alterations. Results: All 16 pts had FDG avid and 15 had FDHT avid disease. Baseline median FDHTmaxavg was 10.84 (3.52 – 18.52) and FDGmaxavg was 6.26 (2.74 – 14.7). Post-treatment alterations are described (Table). Conclusions: Most pts with mCRPC demonstrate diminution of FDHT uptake after 6 and 12 wks of treatment with cabo. These declines are matched by FDG 50-60% of the time, and correlate with PSA declines even less frequently. The etiology of the extent and degree of FDHT declines, and lack of concordance with post-treatment PSA changes, warrant further investigation, and correlation with other imaging modalities and clinical outcomes. Clinical trial information: NCT00588185. [Table: see text]
Aspirin use and mortality in men with localised prostate cancer: A cohort study.
Authors: Flahavan Evelyn M , Bennett Kathleen , Sharp Linda , Barron Thomas Ian
Published: March 2020

5084

Background: Cyclooxygenase-2 (COX-2) expression in prostate cancer has been associated with high grade tumours and poorer prognosis. Use of aspirin, a COX-2 inhibitor, has been associated with reduced prostate cancer mortality in some studies. These studies have not, however, provided information on the dose and timing of aspirin use. Methods: National Cancer Registry Ireland data was used to identify men with stage I-III prostate cancer (ICD10 C61) diagnosed 2001-2006. Aspirin use in the year preceding prostate cancer diagnosis was identified from linked prescription refill data (General Medical Services) and stratified by dose (low ≤75mg, high >75mg) and dosing intensity (proportion of days in that year with aspirin supply available). Cox proportional hazards models, adjusted for age, smoking status, year of incidence, comorbidity score, Gleason score, tumour size, pre-diagnostic statin use, and receipt of radiation (time varying) were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between aspirin use and all-cause and prostate cancer-specific mortality. Interactions with tumour characteristics were examined. Results: 2,936 men with stage I-III prostate cancer were identified (aspirin users, N=1,131; 38.5%). Median patient follow-up was 5.5 years. In multivariate analyses, aspirin use was not associated with a significant reduction in prostate cancer-specific (HR 0.90, 95% CI 0.68-1.20) or all-cause mortality (HR 0.98, 95% CI 0.84-1.15). In dose response analyses aspirin use was associated with a significantly lower risk of prostate cancer-specific mortality in men receiving >75mg of aspirin (HR 0.59, 95% CI 0.35-1.00, p=0.048) but not ≤75mg aspirin (HR 1.01, 95% CI 0.75-1.37, p=0.938). Stronger associations were also observed in men with higher aspirin dosing intensity or a Gleason score >7. Conclusions: Pre-diagnostic aspirin use, measured using objective prescription refill data, was associated with a significant reduction in prostate cancer-specific mortality in men with stage I-III prostate cancer receiving >75mg of aspirin. These results confirm previous findings, and provide important new information regarding the dose of aspirin associated with survival benefit.
Vasectomy and risk of lethal prostate cancer: A 24-year prospective study.
Authors: Mucci Lorelei A. , Siddiqui Mohummad Minhaj , Wilson Kathryn M , Epstein Mara Meyer , Rider Jennifer R , Martin Neil E , Kantoff Philip W. , Stampfer Meir J. , Giovannucci Edward L.
Published: March 2020

5086

Background: In the United States, 10 to 15 percent of adult men have undergone a vasectomy. There is conflicting evidence whether vasectomy is associated with increased prostate cancer risk. Methods: We undertook a prospective study among 49,432 men in the US Health Professionals Follow-up Study. The men were age 40 to 75 years at baseline in 1986 and were followed prospectively for cancer incidence and mortality through 2010; 6,398 incident cases of prostate cancer were diagnosed, including 734 with high grade (Gleason 8 – 10) and 813 with cancer causing death or bony metastasis (lethal). We used cox regression models to calculate hazard ratios (HR, 95% confidence intervals) of the association between vasectomy and incidence of high grade and lethal prostate cancer, adjusting for potential confounders. We examined associations in the total cohort, and in a subset of 12,371 men highly screened by PSA in order to disentangle potential diagnostic bias. Results: At baseline, 22 percent of men reported having had a vasectomy. Men who had undergone vasectomy were at increased risk of high-grade (HR 1.23, 95% CI: 1.04-1.47) and lethal (HR 1.20, 95% CI: 1.01-1.43) prostate cancer. In the highly screened cohort, the association was similar for high-grade cancer, and even stronger for lethal disease (HR 1.56, 1.03-2.36). The risk of lethal prostate cancer was higher among men who had a vasectomy before age 38 years compared to at older ages. The increased risks with vasectomy could not be explained by differences in hormone levels, prevalence of sexually transmitted infections, or cancer treatments. Conclusions: Data from this study support the hypothesis that vasectomy is associated with a small increased incidence of aggressive prostate cancer defined as high grade cancer and disease causing death or bony metastasis. Differences in diagnostic intensity or confounding bias do not explain this elevated risk.
Serum mass spectrometry analysis in primary ovarian cancer (OC) treated with surgery and adjuvant chemotherapy (CT).
Authors: Roder Heinrich , Kasimir-Bauer Sabine , Kimmig Rainer , Wimberger Pauline , Zeillinger Robert , Castillo-Tong Dan Cacsire , Sehouli Jalid , Vergote Ignace , Mahner Sven , Roder Joanna , Grigorieva Julia , Meyer Krista , Aktas Bahriye
Published: March 2020

5575

Background: To address the unmet need for non-invasive tests to predict outcomes in OC we investigated the effect of the serum test, VeriStrat (VS), in independent cohorts of OC patients (pts) who were treated with platinum based chemotherapy following surgery. VS assigns “Good” (VSG) and “Poor” (VSP) classifications and has been shown to be prognostic in various tumor types and predictive for certain treatments. Methods: Samples from primary OC pts from the University Hospital, Essen (ESSEN), N= 108, and from OVCAD consortium (Berlin, Leuven, Hamburg, Vienna), N = 138, were obtained within 1 week before surgery that was followed by platinum-based CT. VS testing was done blinded to clinical data. Overall survival (OS) was analyzed by Kaplan-Meier method and compared using log-rank p-values. Cox models were used in multivariate analysis. Associations with categorical variables were analyzed by Fisher’s exact test. Results: The cohorts had similar distribution of VSG/VSP classification: 73% VSG (ESSEN), 71% VSG (OVCAD). The distribution by histology (non-serous/serous), and nodal status were different (p = 0.003 and p = 0.049). The results for OS in all pts (ALL), in pts with tumor (and/or metastases) present post-surgery (TPPS-pos), and in pts with complete resection and no metastases (TPPS-neg) are presented in the Table. VS was not associated with circulating tumor cells (ESSEN, p=0.736). In a Cox model analysis for TPPS-pos groups VS was independently significant (p= 0.016, ESSEN) or trended to significance (p=0.063, OVCAD). Conclusions: VS demonstrated similar results in two independent cohorts; in ALL and TPPS-pos populations it significantly correlated with OS in ESSEN, showed same trends in OVCAD, and was not correlated with OS in TTPS-neg pts. While requiring further investigation, VS may provide useful prognostic information. [Table: see text]
Expression of glucose-regulated protein 78 (GRP78) and its regulator microrna-181 during the development and progression of ovarian cancer.
Authors: Barua Animesh , Yellapa Aparna , Grasso Salvatore A , Abramowicz Jacques S , Sharma Sameer , Guirguis Alfred S , Basu Sanjib , Bitterman Pincas
Published: March 2020

5579

Background: Ovarian cancer (OVCA) is a lethal malignancy of women with a distinct pattern of metastasis through peritoneal dissemination. Sustained exposure of the ovaries to oxidative stress due to inflammatory processes including ovulatory genotoxicity, makes the ovarian microenvironment conducive to malignant cell proliferation. GRP78 is a stress-inducible protein which resides in the endoplasmic reticulum of the cell. Thus GRP78 may be a marker of ovarian tumor associated stress and could represent a therapeutic target for OVCA. The goal of this study was to examine if GRP78 expression increases in association with OVCA development and determine the molecular mechanism of its increase in ovarian tumors. Methods: All tissues were collected from patients who underwent surgery and processed for immunohistochemistry (IHC), proteomic study (2D-WB) and miRNA expression. Expression of GRP78 was examined in paraffin sections of normal ovaries (n = 20), benign (serous cystadenoma, n = 15 and cystadenofibroma, n = 5) and ovaries with papillary serous carcinoma at early stage (n= 20 at stages I and II) and late stage (n = 20, stages III and IV) by IHC and confirmed by 2D-WB (representative samples). Changes in miRNA-181 (post-translation regulator of GRP78) expression were examined by qRT-PCR. Results: GRP78 expression by normal ovarian surface epithelium and epithelium of benign tumors was very weak. In contrast, the intensity of GRP78 expression was significantly (p<0.05) high in early stage OVCA and increased further in late stage OVCA. An immunoreactive band of 78kDa detected by 2D-WB confirmed IHC observations. In contrast, expression of miRNA-181 by malignant tumors significantly (p<0.05) decreased as the tumor progressed to late stages. Conclusions: The results of the present study suggest that GRP78 expression is associated with the development and progression of malignant ovarian tumors. Increase in GRP78 expression was associated with the down-regulation of miRNA-181. Expression of GRP78 by malignant ovarian epithelium represents a potential marker with usefulness for targeted drug delivery. Support: Elmer and Sylvia Sramek Foundation.
Changes in renal function following treatment for ovarian cancer.
Authors: Butler Matthew James , Stark Azadeh , Kirchner Lester , Gogoi Radhika , Leader Joseph B , Lewis Meredith W , Muggia Franco
Published: March 2020

5581

Background: Among women treated for Epithelial Ovarian Cancer (EOC), new or worsening renal dysfunction has been observed but not systematically studied. We conducted a retrospective cohort study to estimate the rate of decline in renal function following a diagnosis of EOC, compared with the rate of decline among the same patients prior to diagnosis. Methods: We study a historical cohort of women diagnosed with EOC between 1/1/2000 and 12/31/2011, who received health care services within a large community medical center. Data were retrieved from institutional electronic records. We develop a Generalized Estimating Equations (GEE) model to quantify changes in estimated glomerular filtration rate (eGFR) over time, with the date of EOC diagnosis as the reference point (time zero). All analyses were conducted using SAS version 9.2 (SAS Institute Inc., Carey, NC). Results: The cohort is comprised of of 323 women. At diagnosis, the mean age was 63.4 (± 13.5) years and the mean eGFR was 81.0 (± 22.7). There were 74 (22.9%) patients carrying a diagnosis of hypertension, 25 (7.7%) with diabetes, and 73 (22.6%) who were clinical obese. Prior to EOC diagnosis the decline in mean monthly eGFR was not significant (- 0.052, 95% CI -0.11-0.009, p = 0.092), after controlling for age, obesity, hypertension, and diabetes. This monthly decline increased by almost 4-fold (p = 0.0007) subsequent to EOC diagnosis. To discern the potential effect of chemotherapy on renal function, we conducted a secondary analysis on the 120 women for whom detailed chemotherapeutic data is available. For women who received standard first-line chemotherapy (paclitaxel and carboplatin) the rate of eGFR decline increased 10-fold (-0.025 vs. -0.25, p = .0066) relative to their baseline rate of decline. For those who received other regimens, the increase was 11.4 times (-0.025 vs. -0.286, p =.0011); this was not significantly higher than those receiving the standard regimen (p = 0.72). Conclusions: This ongoing study suggests that women treated for EOC suffer an accelerated rate of renal function decline, independent of major comorbid conditions, that is therefore attributable to the disease and/or its treatment.
Eribulin mesylate (Erib) plus capecitabine (X) for adjuvant treatment in post-menopausal estrogen receptor–positive (ER+) early-stage breast cancer: Phase II, multicenter, single-arm study.
Authors: Smith John W. , Rege Jessicca , Maniar Hina , Song James , Cox David , O'Shaughnessy Joyce
Published: March 2020

563

Background: Erib and X have both shown single agent activity in MBC; and X also has activity in ER+ adjuvant tx. This study was designed to evaluate the feasibility of the combination in the adjuvant setting. Methods: Female pts stage I-II, HER2 negative, ER+ BC received Erib at 1.4 mg/m2 iv D1 and D8 and X at 900 mg/m2 po bid on days 1-14 of 21 day cycle, for 4 cycles. The study was considered feasible if 80% of pts are able to achieve the target relative dose intensity (RDI) of at least 85% of the regimen and lower 95% confidence boundary (LCI) is above 70%. Results: Final results of 67pts enrolled are reported here. 88% pts completed 4 cycles of tx. Pt characteristics: Median age 62 yrs (range 28-80), ECOG 0(90%), stage 2(52%). 64/67 pts were evaluable for feasibility. The study met its primary endpoint demonstrating feasibility rate of 81%(95% LCI:71%) with average RDI of 91%. Results were mainly affected by X dose adjustments (Erib RDI-93%, X RDI-88%). X related dose reductions(24, (36%)), missed doses (57,(85%)) and discontinuations due to AE (11(16%)) were higher compared to that with Erib(14(21%), 5(8%) and 7(10%)), respectively. Most common AEs with dose reductions were gr 3/4 hand foot syndrome (HFS) (12%), neutropenia(8%), neuropathy(8%), and GI disorders(6%); and drug discontinuation were HFS(8%), neutropenia(3%), neuropathy(2%), and GI disorders(3%). Tx related AEs and SAE are reported in the Table. 14(21%) pts had an SAE with 12(18%) requiring hospitalization. Conclusions: Adjuvant tx with the Erib-X combination can be given safely with the majority of the patients able to achieve full dosing regimen. We plan to explore an alternative schedule of X(7wk on/off) with this regimen to see if it will further improve tolerability and the RDI. Clinical trial information: NCT01439282. [Table: see text]
Psychophysical functioning and quality of life in 94 patients affected by oropharyngeal cancer and treated with different therapeutic approaches.
Authors: Pedani Fulvia , Airoldi Mario , Garzaro Massimiliano , Torta Riccardo , Raimondo Luca , Riva Giuseppe , Varetto Antonella , Bellini Elisa , Salonia Laura , Pecorari Giancarlo
Published: March 2020

6039

Background: The treatment of oropharyngeal squamous cell carcinomas (OSCC) may heavily affect patient’s quality of life (QoL). Aim of our study was the evaluation of the impact of different treatments on physical and psychological functioning and on QoL of patients affected by stage III-IV disease. Methods: The enrolled sample was composed by 94 OSCC patients divided into 3 subgroups based on treatment modalities: surgery + adjuvant radiotherapy (S + RT: 30 patients), exclusive concomitant chemo-radiotherapy (CT + RT: 30 patients) and exclusive chemotherapy (CT) in 34 patients not suitable for surgery and/or radiotherapy. Psycho-oncological assessment included: Hospital Anxiety Depression Scale (HADS), Montgomery-Asberg Depression Scale (MADRS), Mini-Mental Adjustment to Cancer scale (MINI-MAC), EORTC QLQ C-30 questionnaire with the specific module Head and Neck 35 (H&N35). Results: The 60 patients primarily treated with S + RT or CT + RT presented superimposeable clinical and tumour characteristics while those treated with exclusive CT were affected by stage IV disease and in the 90% of cases underwent to previous treatment exclusive or combined treatment such as surgery, radiotherapy and chemotherapy. In the following table, data about physical and psychological functioning and on QoL of the 3 subgroups of patients are summarized. Conclusions: In stage III-IV OSCC treatments have a strong influence on QoL and coping styles. Patients treated with CT + RT were characterized by a lower percentage of self-reported anxiety and depression and higher EORTC Global QoL score. More than one third of patients treated with S + RT had overt symptoms of anxiety and depression. Stage IV patients treated with palliative CT had elevated level of anxiety, depression and low quality of life. Auto-evaluation is less effective in depression assessment. The role of concomitant psychological supportive care should be evaluated in these patients treated with different approaches. [Table: see text]
Hospital variation in bronchoscopy and esophagoscopy rates during head and neck cancer diagnostic evaluation.
Authors: Sun Gordon H. , Aliu Oluseyi , Moloci Nicholas M. , Mondschein Joshua Keith , Burke James F. , Hayward Rodney A.
Published: March 2020

6044

Background: Hospital variation in bronchoscopy and esophagoscopy rates while diagnosing head and neck cancer may reflect professional uncertainty about the effectiveness of these procedures and a lack of clinical guidelines on best practices. Furthermore, high-volume hospitals have demonstrated better outcomes for select oncologic procedures. We examined the association between hospital case volume and diagnostic bronchoscopy and esophagoscopy rates. Methods: This retrospective cohort study used the 2006-2010 Michigan State Ambulatory Surgery Databases, capturing all outpatient surgical cases in Michigan. Eligible cases included head and neck cancer patients who underwent laryngoscopy, bronchoscopy, and/or esophagoscopy. The primary outcome measure was the likelihood that a patient who underwent laryngoscopy during head and neck cancer diagnostic workup also underwent either bronchoscopy or esophagoscopy. We used hierarchical, mixed-effect logistic regression to measure the association between the primary outcome and hospital case volume (<100, 100-999, or ≥1,000 cases/hospital) while adjusting for patient-level variables such as age, sex, race, insurance status, and household income. Results: Of 17,828 head and neck cancer patients, 9,218 underwent diagnostic laryngoscopy. The 50 low-volume and 40 medium-volume hospitals performed significantly more concurrent bronchoscopies and esophagoscopies compared to the 2 high-volume hospitals (both p<0.001). After adjusting for patient characteristics, medium-volume and low-volume hospitals respectively had 9.3-fold and 7.8-fold higher odds of performing esophagoscopy relative to high-volume hospitals (p=0.003), although the association with bronchoscopy was no longer statistically significant. Conclusions: The proportion of head and neck cancer patients undergoing diagnostic laryngoscopy with concurrent esophagoscopy, but not bronchoscopy, varies significantly by hospital volume. A robust discussion of the comparative effectiveness of comprehensive and selective endoscopy will require further research into whether endoscopic volume correlates with tumor staging, survival, and other outcomes data.
Cetuximab with or without sorafenib in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN).
Authors: Gilbert Jill , Schell Michael J. , Zhao Xiuhua , Murphy Barbara A. , Tanvetyanon Tawee , Hayes David N. , Haigentz Missak , Saba Nabil F. , Nieva Jorge J. , Perez Jimena , Bishop Justin A. , Chung Christine H.
Published: March 2020

6047

Background: For patients with R/M SCCHN, cetuximab, a monoclonal antibody against EGFR, is approved as a single agent and has a survival benefit when combined with chemotherapy. We hypothesized that addition of sorafenib, a multi-kinase inhibitor of targets including VEGFR, to cetuximab may have greater clinical benefit than cetuximab alone. Methods: This trial was designed as a blinded, randomized phase II, placebo-controlled study of cetuximab at 400 mg/m2 IV on day 1 followed by 250 mg/m2 IV weekly plus placebo bid (Arm A) or cetuximab at the same dose and schedule plus sorafenib 400 mg po bid (Arm B), each in 21 day cycles. After 19 patients were enrolled, the trial was amended to remove the placebo (and blinding) due to issues with placebo tablet solubility. Target sample size was 84 patients with 83% power to detect a 2-month increase in PFS, the primary study endpoint. Interim analysis was planned at midpoint, requiring hazard ratio < 1 to proceed to the second stage of study. Serum cytokine and tumor HPV ISH and p16 analyses were performed. Results: Of 56 patients (ages 26-74, 80% male) enrolled, 53 patients received treatment and 41 were evaluable for response. Of the patients who received therapy, 26 received cetuximab only (Arm A). For Arm A, the mean number of cycles delivered was 4.3 (range 1-16) and the mean for Arm B was 3.3 (range 1-11). The most common grade 3/4 AEs were fatigue (2 A, 1 B), hypertension (3 B), infusion reaction (both arms), and diarrhea (2 B). Arm A had 2 PRs and Arm B had 4 PRs. Median OS was 7 mo and 5.9 mo respectively. Median PFS was 3.1 mo for both arms. 24 patients had pre-treatment cytokine measurements. Of the 12 measured cytokines, high TGFB1 level was significantly correlated with inferior PFS (4.6 mo vs 1.6 mo), regardless of arm (p=0.015). 38 patients had tumors available for p16 staining (31 neg and 7 pos). 3 of 7 p16 pos were also HPV ISH pos. The p16 neg patients had significantly improved PFS (3.5 mo vs 1.6 mo) regardless of arm (p=0.032) but no difference in OS (p=1.0). Conclusions: Both arms demonstrated clinical activity although no significant difference was observed. However, a subset of patients with p16 neg tumors or low serum TGFB1 may have a greater benefit with cetuximab-based therapy. Clinical trial information: NCI-2012-02847.
Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma.
Authors: Massarelli Erminia , Ginsberg Lawrence E. , Lin Heather , Tran Hai T. , Lee J. Jack , Williams Michelle D. , Blumenschein George R. , Lu Charles , Kies Merrill S. , Papadimitrakopoulou Vassiliki
Published: March 2020

6067

Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression but treatments targeting EGFR have met with limited clinical success. We hypothesized that everolimus (EV), an mTOR inhibitor, potentiates the activity of erlotinib (ER), an EGFR tyrosine kinase inhibitor, in platinum-resistant recurrent and/or metastatic HNSCC. Methods: This single-arm two-stage phase II clinical trial evaluated EV 5 mg and ER 150 mg orally daily in patients (pts) with platinum-resistant recurrent and/or metastatic HNSCC. Primary endpoints were response rate and 12-week progression-free survival (PFS). Plasma biomarkers by multianalyte profiling (Luminex Corp) and ELISA at baseline (20 pts), 4 weeks (18 pts) and 12 weeks (16 pts) as well as p16 expression in baseline tumor tissue (29 pts) were assessed in correlation with clinical results. Results: Of the 36 evaluable pts (median age 61 years, 29 males, 19 with oropharynx primaries, 15 with ≥2 lines of chemotherapy, 17 with prior cetuximab), 3 (8%) achieved partial response at 4 weeks, one of which was confirmed at 12 weeks, while 27 (75%) pts achieved disease stabilization at 4 weeks, 11 of which were confirmed at 12 weeks. The 12-week PFS was 49%, median PFS was 11.9 weeks and median overall survival (OS) was 10.25 months. Grade 3 toxicities included mucositis (17%), fatigue (14%), skin (8%), diarrhea (8%), and 5 pts withdrew from trial secondary to toxicity. High neutrophil gelatinase-associated lipocalin(NGAL) levels at baseline were associated with worse OS (HR 4.59; 95%CI 1.36, 15.46; p=0.014) and at 4 weeks with worse PFS (HR=12.29; 95% CI 1.26, 119.87; p=0.03) and OS (HR=6.21; 95% CI 0.95, 40.62; p=0.057). High carbonic anhydrase-9 (CA-9) levels at 4 weeks were associated with worse OS (HR=1.18; 95% CI 1.001, 1.41; p=0.049), while decreased CA-9 levels at 4 weeks were associated with better PFS (p=0.77). Conclusions: Efficacy for the combination ofEV and ER is reasonable however plasma markers of tumor invasion and hypoxia are associated with worse outcomes, and further biomarker analysis may define subsets of pts with significant therapeutic benefit. Clinical trial information: NCT00942734.
Choice of primary endpoints in first-line phase III trials of HER2-negative or HER2-unknown metastatic breast cancer (MBC).
Authors: Kümmel Sherko , Müller Volkmar , Lux Michael P , Weyer Geerd , Pintoffl Jan P , Jackisch Christian
Published: March 2020

607

Background: OS is considered the most clinically relevant endpoint in cancer therapy trials, but OS can be confounded by post-trial therapy, particularly in settings with long post-progression survival (PPS). Based on statistical modelling with 50,000 simulated trials, Broglio & Berry [JCNI 2009] suggested the association between improved progression-based endpoints (eg, PFS) and OS is weak in settings with PPS >12 months and can only be shown in very large trials. To test this hypothesis, we analysed efficacy outcomes and choice of primary endpoints in first-line MBC trials. Methods: Data wereanalysed from:randomised, controlled phase III trials comparing systemic chemotherapies and/or targeted agents; enrolling ≥150 pts; published in peer-reviewed journals from 2000–2011. Trials that enrolled only HER2-positive MBC pts or evaluated non-EU approved agents were excluded. Results: Of27 trials, 1 (3.7%) had OS as the primary endpoint, while 18 (66.7%) had progression-based parameters, commonly PFS (9 trials, 33.3%). A significant increase in progression-based parameters was seen in 14 trials (51.9%). All 5 trials (18.5%) showing a significant OS benefit had a PPS <12 months. Mean PPS was considerably longer in trials published in 2006–2011 vs 2000–2005 (14.1 ± 4.0 vs 9.7 ± 2.3 months, respectively), as was mean PFS (8.3 ± 2.2 vs 6.6 ± 1.6 months) and mean OS (25.4 ± 5.6 vs 18.6 ± 3.0 months). A weak correlation was seen between OS and PFS (Pearson’s coefficient r=0.32), but a higher correlation was seen in treatment arms with an OS benefit (r=0.59), as well as in treatment arms with a PPS <12 months (r=0.43) or older studies (r=0.51). Data were insufficient to allow a valid analysis of the effect of further-line therapies or cross-over on OS (16 trials reported further-line therapies; 9 cross-over therapy). Conclusions: In support of the hypothesis by Broglio & Berry, a significant OS advantage was shown exclusively in trials with a PPS <12 months. Due to the weak correlation between PFS and OS, it is difficult to determine the possible surrogacy of PFS for OS. Thus, as an OS benefit might be increasingly difficult to attain, progression-based parameters appear to be valid endpoints in MBC clinical trials.
Progression-free survival (PFS) as a measure of efficacy for anti-EGFR antibodies in recurrent/metastatic (R/M) squamous cell carcinoma of head and neck (SCCHN).
Authors: Misiukiewicz Krzysztof , Winder Lewis , Parides Michael , Bonomi Marcelo Raul , Posner Marshall R.
Published: March 2020

6078

Background: Anti-epidermal growth factor receptor (EGFR) antibodies show promise in treatment of SCCHN. Since the approval of cetuximab as a first-line treatment in R/M settings, other EGFR inhibitors have failed to achieve FDA approval due to failures to achieve survival benefits, despite significant improvements in PFS. Methods: We analyzed aggregate data from all published phase III clinical trials using EGFR monoclonal antibodies as first-line treatment in R/M SCCHN, to investigate PFS as a surrogate endpoint to overall survival (OS). Results: The limited data indicate a linear relationship between PFS and OS with a constant difference between them of 5 months. This estimate has a confidence interval of variability about an estimated mean, and a prediction interval of variability around an estimate for a single patient. The meta-analyzed (fixed effect) estimate of the relative risk of mortality is 0.63 and the standard error is 0.094 and is statistically significant. Conclusions: Approval of cetuximab in SCCHN was based on significant benefit to OS observed in the Extreme study, in which controls were notably prohibited from crossover at progression. Panitumumab showed comparable benefit in PFS, though expected OS endpoints were not achieved, possibly due to over-performance of standard arms benefiting from improved second line treatment (including Cetuximab) and crossover at progression. Though not included in our analysis, Zalutumumab also showed improvement in PFS as a second line therapy. We propose that PFS be considered as a surrogate endpoint for OS in SCCHN trials, in light of new second line therapies and improved survival outcomes seen over the past decade. [Table: see text]
Nimotuzumab with concurrent chemoradiotherapy in patients with locally advanced head and neck cancer (LASCCHN).
Authors: Somani Naresh , SM Karandikar , Bokil Kamlesh , Bhowmik Kumar Tapash , Agarwal Shyam
Published: March 2020

6084

Background: Nimotuzumab is a humanized monoclonal antibody targeting EGFR receptors. Unlike other anti-EGFR monoclonal antibodies, it has demonstrated to be safe and effective when combined with chemotherapy or/and radiotherapy. We evaluated safety and efficacy of concurrently administrating nimotuzumab with chemo-radiotherapy in patients with locally advanced inoperable squamous cell carcinomas of head and neck region in a usual health care setting. Methods: Open-label single-arm study. Patients of age 18 years and above with histologically confirmed squamous cell cancer of head and neck region in an inoperable stage (stage III & IV) having an ECOG ≤ 2 were included in the study. Informed consent was obtained from all the patients. The patient were administered injection cisplatin (30 mg/m2 IV) and nimotuzumab (200 mg IV) weekly for six weeks along with radiotherapy of 6600cGy over 33 fractions. Patients were evaluated based on RECIST criteria 24 weeks after the last cycle of chemotherapy. Results: Fifty seven patients were enrolled in the study. Mean age of the patients was 51yr (29 yr-79 yr). Most common site of cancer was oral cavity 32 (56.14%). Fourty six (80.70%) patients completed 6 cycles of therapy. ORR was 80.7%, 34 with CR (59.6%), 12 with PR (21%), 8 with SD (14%), 3 with PD (5.2%). Most common adverse event seen was mucositis (33%) but there was no grade III or IV adverse event. Conclusions: Addition of anti-EGFR monoclonal antibody (nimotuzumab) is safe and efficacious based on the loco-regional response and confirms the available phase II data. The long-term survival benefits based on this encouraging response rate needs to be further evaluated especially in patients with inoperable LASCCN.
The potential of miR-630, an IGF1R regulator, as a predictive biomarker for HER2-targeted drugs.
Authors: Corcoran Claire , Rani Sweta , Breslin Susan , Ghobrial Irene M. , Crown John , O'Driscoll Lorraine
Published: March 2020

620

Background: Innate or acquired resistance to current HER-targeting drugs indicates that their use for HER2-overexpressing breast cancer (BC) treatment may be compromised. miRNAs may have potential as diagnostic, prognostic and predictive biomarkers for treatment response, as well as therapeutic targets and replacement therapies. We aimed to investigate miR-630 as a predictive biomarker for response to a range of HER-drugs and as a potential target for increasing sensitivity to the same. Methods: Following global miRNA profiling using taqman low density arrays, the reduced expression of miR-630 in cells and corresponding conditioned medium (CM) of HER2-positive BC cell lines with acquired/innate lapatinib (L) resistance (SKBR3-LR, HCC1954-LR, MDA-MB-453) was confirmed by qPCR. miR-630 mimics and inhibitors were used to assess cell response to current (L, trastuzumab (T)) and emerging (neratinib (N), afatinib (A)) HER-targeting drugs. Targetscan prediction software and immunoblotting were used to determine miR-630 regulated proteins. Results: miR-630 levels were significantly decreased in cells and CM with acquired lapatinib resistance compared to their age-matched controls. Decreased miR-630 was also observed for innately resistant MDA-MB-453 compared to innately sensitive SKBR3.Administration of miR-630 mimic significantly sensitised resistant cells to all 4 drugs tested. Specifically, miR-630 mimic increased the anti-proliferative effects of L by 31% (SKBR3-LR), 9% (HCC1954-LR) and 9% (MDA-MB-453). Similarly, miR-630 mimic improved the efficacy of T (11-35%), N (4-17%) and A (9-25%); (range for different cell lines). Inhibition of miR-630 in sensitive parent cells induced an insensitive/resistant phenotype, significantly reducing the efficacy of all 4 drugs tested. Interestingly, miR-630 also significantly regulates cell motility, invasion and anoikis resistance implicating this miRNA in overall cell aggressiveness. Conclusions: This data suggests a potential role for miR-630 as a predictive biomarker for HER-targeting drugs as well as an additional therapeutic target for HER2-overexpressing BC. Acknowledgements: MTCI SFI SRC (08/SRC/B1410), MKF and HEA’s PRTLI Cycle 5 to TBSI.
Comparison of discontinuation, health care resource utilization (HRU), and costs between metastatic breast cancer (mBC) patients (pts) who received trastuzumab (T) in an office clinic versus outpatient hospital setting.
Authors: Brammer Melissa , Lalla Deepa , Gauthier Geneviève , Guérin Annie , Giguere-Duval Philippe , Wu Eric Q. , Santos Eduardo
Published: March 2020

642

Background: T treatment for mBC may be administered in an office clinic or outpatient hospital setting. This study assesses the impact of the site of care on T discontinuation risk, HRU, and costs. Methods: Adult women with mBC who received ≥2 T infusions in an outpatient hospital or office clinic setting were selected from the US-based Humana database (2007-2012). Pts were required to be continuous eligible in their healthcare plan for ≥6 months prior and ≥2 months following the first T infusion (index date). Pts were classified, based on their index site of care, into one of the following cohorts: 1) office clinic, or 2) outpatient hospital. Outcomes were measured from the index date up to the end of continuous eligibility/data availability, a change in the site of care, or 12 months after the index date, whichever occurred first. Treatment discontinuation (gap ≥45 consecutive days) was compared between cohorts using multivariate Cox-proportional hazards model. Monthly healthcare costs (2012 USD) and HRU were compared between cohorts using multivariate generalized linear/two-part models, and multivariate negative binomial regression models, respectively. Results: A total of 280 pts met the inclusion criteria; 64% and 36% in the office clinic and outpatient hospital cohort, respectively. Baseline characteristics were similar between cohorts. However, differences were found in terms of insurance plan type, year of index date and comorbid conditions (chronic pulmonary disease and peripheral vascular disorder). After adjusting for confounding factors, the outpatient hospital cohort had a 1.5 time higher risk of treatment discontinuation (p=.043) and incurred an incremental monthly cost of $1,954 (p=<.001), mainly driven by higher office clinic and outpatient hospital costs ($1,483 p=.016). No differences were observed in HRU. Conclusions: Pts in the office clinics cohort were less likely to discontinue T and were associated with lower monthly total healthcare costs. Future research should examine the impact early discontinuation may have on clinical outcomes.
Burnout and career satisfaction among U.S. oncologists: Results of the 2012 ASCO survey.
Authors: Shanafelt Tait D. , Gradishar William , Kosty Michael P. , Satele Daniel , Chew Helen K. , Horn Leora , Chu Quyen , Sloan Jeff , Clark William B. , Hanley Amy E. , Pippen John E. , Raymond Marilyn J.
Published: March 2020

6533

Background: Although it can be rewarding, caring for patients with cancer is also demanding and stressful. Oncologists work long hours, supervise administration of highly toxic therapy, and continually observe death and suffering. While isolated studies have explored burnout in national samples of U.S. oncologists (last in 2003), little is known about the personal and professional characteristics related to burnout and career satisfaction. Methods: Between October 2012 - January 2013, ASCO conducted a national surveyof ~3000 U.S. oncologists evaluating burnout and career satisfaction. The survey sample was constructed from the member registry to include an equal number of men/women and an equal proportion of individuals from all career stages (<10 yrs, 10-19 yrs, >20 yrs). Validated tools were used to assess burnout and well-being. Results: As of January 2012, 1041 (35%) oncologists had returned surveys (median age 52 years; 50% women). Among responders, 355 (34%) were in academic practice (AP) and 447 (43%) in private practice (PP) with the remainder in other settings (e.g. military, veterans, industry). Oncologists worked an average of 51 hours/week and saw a mean of 51 outpatients/week. Although average hours worked for oncologists in PP and academic practice were similar (AP=54.6/wk; PP=54.2/wk), profound differences in other practice characteristics were observed with respect to sub-specialization (AP=81%; PP=17%), time devoted to clinical care, patients seen per week (AP=37; PP=74), time devoted to education, and method of compensation. Relative to 2011, 23% of oncologists reported a >10% decline in take home pay in 2012 (>10% decline AP=8%; PP=34%). Overall, 454 (45%) of oncologists had at least one symptom of burnout (e.g. emotional exhaustion, depersonalization) on the Maslach Burnout Inventory (AP=47%; PP=51%; p=0.19). While a majority were satisfied with their career (83%) and specialty (80%) choice, both measures of career satisfaction were lower for PP relative to AP (all p<0.005). Conclusions: Burnout is common among oncologists. Detailed multivariate analyses to identify personal and professional characteristics associated with burnout and career satisfaction are underway and will be presented.