bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of gefitinib and docetaxel for patients (pts) with advanced pancreatic adenocarcinoma (APC) progressing after first-line therapy. Final results
Authors: Brell J. M. , Matin K. , Evans T. , Volkin R. L. , Keifer G. J. , Schlesselman J. J. , Dranko S. , Rath L. , Schmotzer A. , Ramanathan R. K.
Published: March 2020

4586

Background: Gemcitabine is the standard-of-care for APC; the epidermal growth factor receptor (EGFR) inhibitor erlotinib is sometimes added to initial therapy. Pre-clinical data supports the addition of the EGFR inhibitor gefitinib to docetaxel, an agent with activity in APC. Because there is no standard treatment after gemcitabine failure, this combination was examined in a phase II study. Methods: Pts were required to have APC and have failed one prior treatment regimen; EGFR over-expression was not required. The initial docetaxel dose was 75 mg/m2 on day one every 21 days . Due to febrile neutropenia in 8 of 18 pts, the dose was reduced to 60 mg/m2. Gefitinib 250 mg/day orally was given continuously. Accrual of 41 pts was planned in a one-stage design to identify a targeted 50% improvement in median survival from 3.5 to 5.3 months (mo) by one-sided log-rank test (80% power, a = 0.05). Results: Forty five pts met eligibility and signed consent; 41 pts received treatment and were evaluable. Pt characteristics: 68% male, median age 63 yrs. (range 47 - 82). ECOG performance status (PS) 0 - 1 in all pts, except for 3 with PS of 2. Common treatment-related Grade 3 - 4 toxicities were: febrile neutropenia / infection in 11 pts (27%), with most events occurring at docetaxel dose of 75 mg/ m2 (8 of 18 pts); fatigue (7%), nausea (7%), diarrhea (5%) and vomiting (2%). Only 3 pts discontinued treatment due to toxicities and more than 2 cycles were administered to 40% of patients. The median survival was 4.7 mo (95% CI 2.9 - 5.7 mo). Time to progression was 1.8 months. There was one partial response (PR) and stable disease (SD) in 14 pts. Conclusion: The combination of gefitinib (250 mg/d) and docetaxel (60 mg/ m2) had evidence of some efficacy with one PR and SD in 14 pts. The median survival was 4.7 mo, somewhat lower than our intended target (5.3 mo). The tolerability and feasibility of second-line therapy for APC was demonstrated, and results of this study can be used as a benchmark to evaluate novel therapies in subsequent studies. (Supported by Astra Zeneca Pharmaceuticals)

No significant financial relationships to disclose.
Smad4 is predictive for response in neoadjuvant treated esophageal squamous cell carcinoma
Authors: Brücher B. L. , Pühringer-Oppermann F. , Sarbia M.
Published: March 2020

4591

Background: The evaluation of the prevalence of TGF-β1-pathway gene expressions (TGF-β1, Smad7 and Smad4) and its predictive value for histopathological response in patients with esophageal squamous cell carcinoma and neoadjuvant radiochemotherapy. Methods: RNA was prepared from pretherapeutic taken formalin-fixed and paraffin-embedded biopsies of 98 patients with histological proven locally advanced ESCC (cT3, cN0/+, cM0), who underwent preoperative combined simultaneous RTx/CTx with consecutive esophagectomy. All tumor biopsies underwent tumor-cell-microdissection, RNA-extraction and real-time TaqMan reverse transcriptase- polymerase chain reaction. RT-PCR-measurements were made by doublet measuring. Quantitative mRNA expression of TGFβ1 and its downstream effectors Smad4 and Smad7 was correlated with histopathological response by the percentage of residual tumor cells. Analysis was performed by dichotomized calculation and for determination of a cut-off by ROC-analysis. Results: Dichotomized analysis revealed the following median values: Smad4=0.098± 0.7 (CI: 0.024–0.396), Smad7=1.9250±1.7 (CI: 0.4–16.1) and TGFβ1=6.427±4.86 (CI: 0- 25.7). Cross-tabs-analysis for histopathological response disclosed the following correlations: TGFβ1 (p=0.671), Smad7 (p=0.672) and Smad4 (p=0.038). ROC-analysis revealed a Smad4-cut-off of 0.0635 by an area-under-curve of 6280 (p=0.038). Consecutive re-cross-tabs-analysis of histopathological response revealed a sensitivity of 80% (p=0.013). The pretherapeutic predictive value of Smad4 was 73%. Medians in survival was not reached during follow-up, whether TGFβ1 (p=0.519), Smad7 (p=0.5728) nor Smad4 (p=0.552). Histopathological responders showed a significant better survival compared to nonresponders (p<0.0001). Conclusions: High levels of Smad4 gene expression are significantly correlated with histopathological response. ROC-Analysis identified a cut-off of Smad4 with a sensitivity of 80% and a predictive value of 73%.

No significant financial relationships to disclose.
Characteristics, treatment and outcome of patients with hepatocellular carcinoma (HCC) in the United States: An analysis of 328 patients from 1998–2005
Authors: Stadler Z. K. , Stuart K. E.
Published: March 2020

4615

Background: International studies have described the clinical characteristics and outcomes of patients with HCC. However, patient demographics, tumor characteristics, extent of liver disease, risk factors, treatment and outcome are less well established in the United States (US) where HCC remains rare. Methods: We identified 328 patients presenting to Beth Israel Deaconess Medical Center with a new diagnosis of HCC from 1998–2005. Characteristics including risk factors, underlying liver disease, tumor morphology and treatment were entered into a retrospective database. Child-Pugh grade and Cancer of the Liver Italian Program (CLIP) score were determined. Survival analysis was performed and data compared to our previously published HCC cohort from 1985–1995. Results: Patient characteristics were: Median age: 62; Male: 81%; Alcohol use (EtOH): 44%; Hepatitis C (HCV): 38%; Hepatitis B (HBV): 21%; No Risk Factor: 15%. EtOH was more common in HCV (57%) than in HBV (18%) patients. Treatment modality was: liver transplantation (LT) 14.4%, surgical resection 7.8%, chemoembolization or radiofrequency ablation (CE/RFA) 36%, chemotherapy 22%, no treatment 16%. Median overall survival was 13.5 months. Significantly better median survival was associated with Child-Pugh grade A (20.3 mos.), uninodular tumor in <50% of liver (34.3 mos.), absence of portal vein thrombosis (19.2 mos.), CLIP score of 0 (42.5 mos.), background of HBV (32.9 mos.) and No EtOH (16.2 mos.). Treatment correlated with survival: LT, resection, or CE/RFA showed significantly better survival than chemotherapy or no treatment. In comparison to the 1985–95 cohort, median survival improved from 10 to 13.5 months. The 1998–05 cohort had more HBV/HCV (57% versus 20%), more favorable tumor characteristics, less severe liver disease, and more LT (14.4% versus 2.8%). Conclusions: In this single US institution, survival of HCC patients improved by 35% over two decades. Our results are consistent with nationwide trends of increased prevalence of viral infection, screening to find earlier disease, and more widespread use of aggressive treatments. Changing patterns of approaching the cirrhotic patient with HCC may be leading to slightly better results.

No significant financial relationships to disclose.
Phase II study of gemcitabine, oxaliplatin in combination with bevacizumab (GEMOX-B) in patients with unresectable or metastatic biliary tract and gallbladder cancers
Authors: Clark J. W. , Meyerhardt J. A. , Sahani D. V. , Namasivayam S. , Abrams T. A. , Stuart K. , Bhargava P. , Blaszkowsky L. S. , Jain S. R. , Zhu A. X.
Published: March 2020

4625

Background: Patients (Pts) with unresectable or metastatic biliary tract cancer (BTC) and gallbladder cancer (GBC) have a poor prognosis. Vascular endothelial growth factor (VEGF) expression has been detected in BTC and GBC. Increased angiogenesis has been correlated with advanced stage of disease and poor prognosis. Given reported activity of gemcitabine (GEM) and oxaliplatin (OX) in BTC/GBC and potential benefits of targeting the VEGF pathway with bevacizumab (B), we performed a study to examine the efficacy and tolerability of GEM, OX and B (GEMOX-B) in unresectable or metastatic BTC/GBC. Methods: Eligibility criteria included unresectable or metastatic measurable BTC/GBC, 0–1 prior chemotherapy regimens, performance status = 2, and adequate organ function. No clinically significant cardiovascular disease or history of active bleeding. Pts were treated with all 3 drugs intravenously on days 1 and 15 every 28 days (one cycle): B was given first at 10 mg/kg, followed by GEM at 1000 mg/m2 as dose rate infusion at 10 mg/m2/minute, and OX at 85 mg/m2. Whole body FDG-PET scan was obtained at baseline and after cycle 2. The primary endpoint of the study was progression-free survival (PFS). Results: 19 pts (10 BTC and 9 GBC) have been enrolled since May 17, 2006: median age = 69 (25–82), M/F = 13/6, ECOG 0/1/2 = 7/10/2. Treatment has been well tolerated with no grade 4–5 toxicities seen. Treatment related grade 3 toxicities included (number of pts): hypertension (2), neutropenia (1), transient SGPT elevation (1), proteinuria (1), neuropathy (1), and fatigue (1). Of 11 pts followed for at least 4 months, 3 had confirmed partial responses (PR), 5 had stable disease (SD) of at least 4 cycles, and 3 had progressive disease (PD) per RECIST criteria. Five pts had more than 50% decrease in CA19–9 levels. Of 16 PET studies analyzed, changes in SUV values from baseline to after 2 cycles of treatment were: 11 PRs, 4 SDs, 1 PD per EORTC criteria. Conclusions: GEMOX-B can be safely administered with tolerable safety profiles in patients with advanced BTC/GBC. Early evidence of antitumor activity was seen. A decreased SUV in FDG-PET following GEMOX-B treatment was observed in the majority of patients.

No significant financial relationships to disclose.
Small cell carcinoma of the esophagus: Review of the Memorial Sloan-Kettering Cancer Center (MSKCC) experience
Authors: Ku G. Y. , Kelsen D. , Minsky B. , Rusch V. , Bains M. , Ilson D. H.
Published: March 2020

4631

Background: Esophageal small cell carcinoma (ESC) is rare and accounts for <1% of all esophageal cancers. It is treated like pulmonary SC but the optimal approach of surgery, chemotherapy or radiotherapy is unknown. Prior series (Chest 107:179, Cancer 88:262) indicate a poor median overall survival (OS) of 7–12 months (mos), rare long-term (LT) survival and the need for surgery as part of curative therapy. Methods: We reviewed records of patients (pts) with ESC treated from 1980 to 2005. All pathology was reviewed at MSKCC. Results: 24 pts were identified, with records available for 21. 86% male, 14% female, median age 60, 67% smokers. 81% had pure SC histology, with 85% of tumors in the lower esophagus or gastroesophageal junction. 13/21 (62%) had limited disease (LD) by VALSG criteria. For extensive disease (ED), liver (63%) was most common metastatic site (mets). Treatment for LD was: chemotherapy (chemo) only (3 pts, 23%), surgery only (1 pt, 8%), surgery and adjuvant chemo (3 pts) and chemoradiation (CRT) without surgery (6 pts, 46%). The most common chemo given was cisplatin/carboplatin and etoposide (81%). Pts with ED received chemo alone. Overall median survival was 19.8 mos (range, 1.5 mos to 11.2+ years (yrs)); for LD Pts, 22.3 mos (range, 6 mos to 11.2+ yrs); for ED Pts, 10.9 mos (range, 1.5 mos to 2.2 yrs). At median follow-up of 32 mos, 5 pts are alive (4 without disease (NED) and 1 with disease); 2 pts are alive >5 yrs. 4 originally had LD and 3 of 4 received CRT only without surgery. None received whole brain radiation (WBXRT). 1 LD pt treated with surgery and adjuvant chemo recurred after 4 yrs, was salvaged with CRT and is NED 11.2 yrs after diagnosis. Of 18 pts with progression, 10 (56%) had new mets. Most common site was liver (4 pts) and only 1 pt had brain mets. Of 6 pts with LD who received CRT only, 3 recurred (1 local and 2 distant). Of 4 pts with LD who underwent surgery, all recurred (1 local, 3 distant). Conclusions: Pts with ESC with LD who received CRT without surgery can have LT survival. The role of surgery remains unclear. LT survival for 1 pt who underwent salvage CRT for recurrence after surgery argues for aggressive therapy for recurrence. Unlike pulmonary SC, brain mets are uncommon and WBXRT may not be needed for LT survival.

No significant financial relationships to disclose.
A multi-center phase II study of S-1 plus paclitaxel as first-line therapy in patients with advanced or relapsed gastric cancer
Authors: Lee J. J. , Kim S. Y. , Chung H. C. , Lee K. H. , Song H. S. , Woo I. S. , Hong Y. S. , Kang W. K. , Choi J. H. , Choi I. S.
Published: March 2020

4634

Background: S-1 is an oral prodrug of 5-fluorouracil (5-FU) including two modulators to enhance the antitumor effect and to decrease gastrointestinal toxicity. Paclitaxel has the synergistic antitumor effect with 5-FU. This study were planned to evaluate the efficacy and safety of S-1 and paclitaxel combination therapy in advanced gastric cancer. Methods: Eligible patients had untreated advanced or relapsed gastric cancer with measurable lesion(s), histologic proof, ECOG PS 0–2, adequate organ function, and signed informed consent. Treatment consisted of S-1 35mg/m2 p.o. b.i.d. on days 1–14 plus paclitaxel 70mg/m2 i.v. on days 1& 8 of a 21-day cycle. Measurable and/or unmeasurable lesion was assessed after every 2 courses with RECIST criteria. Results: A total of 56 patients (M/F=37/19) were enrolled. The median age was 59 years with advanced (n=43) and relapsed (n=13) gastric cancer. The common metastatic lesions were abdominal lymph nodes (71%), liver (39%), and peritoneum (21%). Out of 53 evaluable patients, there was 1 (2%) CR, 25 (47%) PRs, 21 (40%) SDs, and 6 (11%) PDs. Objective tumor response was 49%. Median duration of response was 5.4+months after the confirmation of response. Median follow-up was 9.6 month. Median PFS was 7.7 months and median survival was 14.6 months. Median number of cycle was 6 (range, 1–14). The relative dose intensity of S-1 and paclitaxel was 93%, both. The most common causes of delayed cycle and dose reduction were neutropenia and diarrhea, respectively. All 56 patients were assessed for safety. This treatment was well tolerated with grade 3/4 neutropenia in 14%/5%, grade 3 febrile neutropenia in 5%, grade 2/3 N/V in 21%/0%, anorexia in 18%/2%, diarrhea in 9%/4%, stomatitis in 7%/4%, and neuropathy 7%/0% of patients. Conclusions: S-1 and paclitaxel combination chemotherapy showed significant antitumor effect with manageable and tolerable toxicities in patients with advanced gastric cancer. (This study was partially supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (0412-CR01–0704–0001))

No significant financial relationships to disclose.
Different chromosomal alterations correlate with gene expression in African American (AA) versus Caucasian American (CA) prostate cancer (PC) patients
Authors: Jean-Gilles J. , Satagopan J. , Zhou Q. , Dash A. , Yu J. , Lee P. , Scher H. I. , Gerald W. , Osman I.
Published: March 2020

5000

Background: We used a genome wide approach to identify chromosomal and gene expression alterations that might explain the aggressive clinical behavior of PC in AA compared with CA patients. Methods: We frequency matched 20 AA with 20 CA patients for potential confounding factors (PSA, age, Gleason grade, pathologic stage). We utilized array-CGH (Spectral Genomics), to identify noteworthy genomic regions with significantly different chromosomal alterations between the 2 groups. RNA samples were available for 19 AA and 14 CA patients. Gene expressions were examined using Affymetrix HG-U133 Plus 2.0 arrays. Correlations were examined between the noteworthy altered chromosomal regions and gene expression. Results: Regions of chromosomal gain or loss in each sample were determined using the circular binary segmentation approach coupled with an outlier detection method to identify singleton markers exhibiting alterations. We identified 28 chromosomal regions that were significantly different between the 2 cohorts (Fisher’s exact test). 11 regions (3q28- 29, 3q25–26, 4p12–14, 4p13, 9q21, 10q11, 11q14, 12p13, 14q12, 16p11, 20p11–20q11) were more commonly altered in AA patients compared to CA patients (P<0.005). The altered chromosomal regions were associated with corresponding gene expression changes. Gene ontology and pathway analyses showed a relatively short list of affected pathways: insulin, STAT, TGF-beta signalings, proteosome degradation, integrin- mediated cell adhesion, adipose and calcium metabolisms. Hierarchical clustering of the 33 patients (19 AA and 14 CA) based on the shortlist of gene expressions showed two clusters, one consisting of CA and the other with AA patients, with only 3 AA patients showing similar gene expression to CA group and vice versa. Conclusions: Data demonstrate the presence of biologic differences between the AA and CA cohort of patients studied and suggest that the disproportionately unfavorable outcome of PC in AA patients cannot solely be explained by advanced tumor at presentation. Validation in an independent larger sample size is a prerequisite before further conclusions can be made.

No significant financial relationships to disclose.
A randomized, placebo-controlled trial of celecoxib in men prior to receiving prostatectomy for clinically localized adenocarcinoma of the prostate: Evaluation of drug-specific biomarker modulation
Authors: Carducci M. A. , Walczak J. R. , Heath E. , Nelson W. G. , DeMarzo A. M. , Zahurak M. , Dannenberg A. J. , Parnes H. , DeWeese T. L. , Partin A. W.
Published: March 2020

5001

Background: Cyclooxygenase-2 (COX-2) has been postulated as a pharmacological target for preventing a variety of epithelial malignancies including prostate cancer (PCa). We conducted a randomized, double-blind study evaluating celecoxib (C) on biomarkers in normal and PCa tissue at prostatectomy (RRP). Methods: Patients with Gleason sum ≥ 7, pre-study PSA ≥ 15 ng/ml, clinical stage T2b, T2c, or any combination of PSA, Stage, or two or more cores positive for PCa received either C at 400 mg po bid or placebo for 4–6 wks pre-RRP. The primary endpoint was to compare and correlate tissue PG levels with histologic and secondary endpoints performed on prostate tissue and serum from the two comparable groups. Outcomes included PG levels, quantitative RT-PCR for mRNA levels of COX-1 and COX-2, oxidized DNA bases; measurement of apoptosis, proliferation, angiogenic-potential assays and histologic comparison of treated/untreated tissue specimens; PSA levels; and tissue levels of C. Estimates of change in endpoints required 30 patients per arm. Results: Seventy three subjects consented with 64 randomized and included in the intent to treat analysis; 2 had missing data for primary endpoints. Age, baseline PSA, race and Gleason score were comparable across treatment groups. The regimen was well tolerated with no serious adverse events. There was no treatment effect observed in the PG, COX mRNA levels or oxidized DNA base levels in the RRP specimens. Tumor tissue contained significantly less COX-2 mRNA levels than benign tissue (p=<0.0001). Of the markers of apoptosis and proliferation assessed, Ki-67 was higher in tumor samples, and p21 was less in C treated samples. Celecoxib was present in tumor tissue demonstrating that it reached the target, but there were no observed effects in the study endpoints. There was no toxicity greater grade 1 except hepatic toxicity in a placebo group subject. Conclusions: Our results show a lack of effect of C on PCa despite demonstrating that C was present in tissue samples. At this time, we cannot recommend further studies of C as a PCa preventative agent when dosed at 400 mg PO BID. The study was supported by a grant from the NCI, DCP (#NO1-CN-95000–46) and Pfizer, Inc.

No significant financial relationships to disclose.
Sunitinib in metastatic renal cell carcinoma (mRCC): Preliminary assessment of toxicity in an expanded access trial with subpopulation analysis
Authors: Gore M. E. , Porta C. , Oudard S. , Bjarnason G. , Castellano D. , Szczylik C. , Mainwaring P. N. , Schöffski P. , Rini B. I. , Bukowski R. M.
Published: March 2020

5010

Background: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs and PDGFRs, approved multinationally for advanced RCC. The primary aim of this international, open-label trial was to provide sunitinib to mRCC pts who failed =1 prior systemic therapy and were ineligible for other sunitinib trials or had no access to sunitinib before regulatory approval in their country. Methods: Eligibility criteria were minimized to broaden the enrolment population. Pts who were 18 yrs of age or older with histologically-confirmed mRCC received oral sunitinib 50 mg/day in 6-wk cycles (4 wks on Tx, 2 wks off). Physical exam, safety and concomitant meds were assessed every 4 wks. Results: As of Sept 1, 2006, 4,000 pts were enrolled from 181 sites in 36 countries; 2,158 pts (median age, 59 [19- 85]; male/female, 74%/26%) were included in this analysis. Baseline demographics included 106 pts (5%) with non-clear cell histology; 173 pts (8%) with brain mets; 158 pts (7%) with prior antiangiogenic Tx; and 288 pts (13%) with ECOG PS =2. Median Tx duration was 128 days (range 1- 2444) with interruptions in 17% of pts and dose reductions in 30%; 672 pts (31%) discontinued, of which 80 pts (12%) discontinued due to AEs. The median Tx duration was similar to the overall population regardless of age or site of metastatic disease at baseline (brain, bone, lung, liver, lymph nodes or other), but was longer in pts with ECOG PS 0/1 (154 days, range 1–2,444) than with ECOG PS =2 (83 days, range 1–449). The most common treatment-related AEs were diarrhea (39% any grade, 3% grade 3/4), fatigue (35%, 7%) and nausea (33%, 2%), the incidences of which were similar in pts regardless of age or site of baseline metastatic disease; overall, they occurred more frequently in pts with ECOG PS 0/1 vs. ECOG PS =2 (42% vs. 21%, 38% vs. 23%; and 34% vs. 25%, respectively), but differences in grade 3/4 severity were not observed. Median overall survival has not been reached; 19% of pts have died, the lowest incidence among pts with ECOG PS 0/1 (15%) and highest in pts with ECOG PS =2 (43%) and brain mets (34%). Conclusions: Preliminary observations suggest that sunitinib is associated with acceptable tolerability in an expanded access trial regardless of age or site of baseline metastatic disease.

[Table: see text]
Randomised prospective study of intermittent versus continuous androgen suppression in advanced prostate cancer
Authors: Miller K. , Steiner U. , Lingnau A. , Keilholz U. , Witzsch U. , Haider A. , Wachter U. , Rüssel C. , Altwein J.
Published: March 2020

5015

Background: Based on results of animal experiments intermittent androgen blockade was suggested to delay progression of advanced prostate cancer to the hormone refractory stage. We conducted a prospective randomized study to compare intermittent with continuous androgen suppression. Methods: This was a multi-centre, randomised, two-arm study comparing treatment with goserelin + bicalutamide (intermittent, group A) vs. goserelin + bicalutamide (continuous, group B). The primary endpoint was time to clinical and/or biochemical progression of the disease despite androgen suppression. Secondary enpoints were survival time, patient’s quality of life (QoL) and toxicity. Patients eligibility criteria were: histologically confirmed adenocarcinoma of the prostate in clinical stage T1–4N1–3M0 or T1–4N0–3M1 (D1 oder D2). After an induction phase of 24 weeks with MAB, 335 patients whose PSA decreased under 4 ng/ml or = 90% from baseline were randomized. Results: About two-thirds of the patients of both the intermittent and the continuous therapy arm (65% versus 66%, ITT population) experienced a clinical and/or biochemical disease progression due to any reason during this study. The median time to disease progression was longer for patients randomised to the intermittent therapy arm (16.6 months) compared with patients randomised to the continuous therapy arm (11.5 months). This difference however was not statistically significant (log rank test, p=0.1758). The median time to death from any cause was 51.4 month in the intermittent arm compared and 53.8 months in the continuous therapy arm (p = 0.658). There were no differences in the incidence of patients with AEs or SAEs or in any other safety parameter between patients treated intermittently and patients treated continuously. Patients’ self-assessment of their overall health and of their sexual activity appeared to be favourable in the intermittent compared with the continuous therapy arm. 88% of all patients treated intermittently experienced more than 50% of the number of treatment days as treatment-free days. Conclusions: Intermittent therapy in D1 and D2 prostate cancer patients appears to be safe and feasible. Off treatment periods are > 40 % and attribute to patients quality of life.

No significant financial relationships to disclose.
A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC)
Authors: Amato R. J. , Harris P. , Dalton M. , Khan M. , Alter R. , Zhai Q. , Brady J. R. , Jac J. , Hauke R. , Srinivas S.
Published: March 2020

5026

Background: Sorafenib has demonstrated activity with limited toxicity at a dose of 400 mg bid in MRCC pts. This presents an opportunity to explore a more intensive drug administration. This study allowed individual pt titration designed to evaluate the ability for pts to dose escalate. Response rate (RR), time to progression (TTP) and overall survival (OS) will be assessed. Methods: Eligibility included; pathologic diagnosis of a component of clear cell, progressive measurable MRCC, no more than 1 prior therapy, karnofsky performance status (KPS) = 70%, adequate organ/marrow function and no active CNS involvement. Initial dose 400 mg bid, daily. Dose escalation defined in the table below: Re-evaluation is performed every 8 weeks. RECIST criteria is utilized. Results: 46 patients have been enrolled. 44 are evaluable. 37 male/7 female, median age 50 years (43–79). 19 pts received prior therapy. 39 pts had a KPS of 100%, 5/90%. Sites of disease included; lung, nodal, liver, bone, adrenal, pancreas and kidney. 26 pts 1 metastatic site, 12 /2, 6/3 or more. 22 pts continue to receive sorafenib therapy; 2/800 mg, 7/1,200 mg, and 13/1,600 mg. 8 pts complete response (CR), 14 pts/partial response (PR) and 14 pts stable for 3+ months. Median duration of therapy is 6+ (range 0.2+ - 12+) months. 2 pts have not been reevaluated. Treatment related adverse events to-date; hand/foot syndrome, skin rash, diarrhea, alopecia, fatigue, hypertension, hypophosphatemia, and elevated amylase/lipase. Conclusion: 91% of pts were escalated to 1,200 mg or 1,600 mg per day. Dose escalated sorafenib has promising anti-tumor activity in pts with MRCC as demonstrated by a 52% CR/PR rate. Anti-tumor activity is further suggested by prolonged TTP = 3 months for 33% of pts. Independent radiology review is in progress. Intra-patient dose escalation data in association with anti-tumor activity and toxicity will be presented.

[Table: see text]

[Table: see text]
Correlation of survival with tumor histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma (adv RCC) receiving temsirolimus (TEMSR) or interferon-alpha (IFN)
Authors: Dutcher J. P. , Szczylik C. , Tannir N. , Benedetto P. , Ruff P. , Hsu A. , Berkenblit A. , Thiele A. , Strahs A. , Feingold J.
Published: March 2020

5033

Background: Temsirolimus is a novel mTOR inhibitor and has demonstrated significantly longer overall survival (OS, P=0.0069) and progression-free survival (PFS, P=0.0001) vs IFN for patients (pts) with previously untreated adv RCC with poor-risk features (Hudes et al. ASCO 2006). Planned and post-hoc analyses were performed to assess the influence of tumor histology (clear- cell vs other), age (<65 y vs =65 y), and prognostic-risk groups (intermediate vs poor; Motzer et al. JCO 20:289) on survival in pts treated with TEMSR or IFN. Methods: Pts received IFN 3 million units [MU] subcutaneously 3x weekly, escalating to 18 MU; TEMSR 25-mg intravenous infusion weekly; or TEMSR 15-mg infusion plus IFN 6 MU. Kaplan-Meier analysis and a Cox proportional hazards model were used to analyze OS and PFS for pt subsets. Histologies were reported by investigators. Results: The proportion of pts with different histologies was balanced across the 2 arms (81% clear-cell; 13% indeterminate, 6% non-clear-cell). Of those with additional subtype data, 75% were papillary. For pts with clear-cell tumors, median OS and PFS were longer for TEMSR vs IFN with hazard ratios (HR) of 0.82 and 0.76, respectively ( Table ). For pts with other tumor histologies, median OS and PFS also were longer for TEMSR vs IFN with HR of 0.49 and 0.38, respectively. Among pts <65 y, median OS and PFS were longer for TEMSR than for IFN (OS: TEMSR [n=145] 12.0 mo; IFN [n=142] 6.9 mo; HR=0.62 [95% CI, 0.47, 0.82]; PFS: TEMSR 5.6 mo; IFN 3.1 mo; HR=0.61 [0.47, 0.79]). There was no difference in OS or PFS for pts =65 y treated with TEMSR or IFN but TEMSR had a better side effect profile than IFN. OS and PFS for pts with intermediate- or poor-risk features will be reported. Conclusions: TEMSR benefits pts with clear-cell RCC and other histologies as well as younger and older pts.

[Table: see text]

No significant financial relationships to disclose.
The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Safety and efficacy in patients (pts) with non-clear cell (NCC) renal cell carcinoma (RCC)
Authors: Stadler W. M. , Figlin R. A. , Ernstoff M. S. , Curti B. , Pendergrass K. , Srinivas S. , Canfield V. , Weissman C. , Poulin- Costello M. , Bukowski R. M.
Published: March 2020

5036

Background: A phase III trial showed that sorafenib (SOR) doubled progression-free survival (PFS) in previously treated pts with clear cell RCC. Activity of SOR in pts with NCC RCC has not been previously reported. Methods: Pts eligible for this open-label, nonrandomized trial in North America were not eligible for other SOR clinical trials, had recovered from prior treatment-related toxicity, and had advanced RCC; ECOG PS of 0–2; age =15 yrs; no treatment with other investigational drugs within 4 wks; life expectancy >2 mos; no active coronary artery disease, ischemia or hypertension; and no severe renal impairment requiring dialysis. In the US, ARCCS enrollment ended with SOR approval in 12/05, and pts were transitioned to commercial drug with NCC pts being eligible for an additional 6-mo follow-up in an extension protocol (EP), which was designed to better assess PFS in NCC. Tumor assessments and radiological evaluations were conducted every 4 wks in the main protocol and every 8 wks in the EP. Results: Of 2,488 pts valid for safety in ARCCS, 212 (8.5%) had NCC RCC classified as papillary, chromophobe, collecting duct, or oncocytoma, of whom 24 enrolled in the EP. Baseline characteristics and efficacy are shown in the table . Grade 3 and 4 adverse events (AEs) with > 2% incidence across all histologies included fatigue 7.1%, hand-foot skin reaction 6.6%, rash/ desquamation 6.2%, hypertension 4.7%, abdominal pain 3.8% dyspnea 3.8%, pleural effusion 3.3%, nausea 3.8%, vomiting 2.4%, and ascites 2.4%. Grade 3 and 4 serious AEs were reported in 20% of patients. Of those enrolled in the EP with NCC, median PFS was 34.5 wks (65.2% censored). Conclusions: SOR was well tolerated among pts with NCC RCC. Within the limitations of no central pathologic review, SOR toxicity in NCC RCC was similar to that in the broader ARCCS population and SOR may have antitumor activity in papillary and chromophobe subtypes.

[Table: see text]

[Table: see text]
Differences in treatment in stage III breast cancer in African American women
Authors: Rizzo M. , Reisman N. , Gabram S. G. , Bumpers H. L. , Okoli J. , Brawley O. W. , Lund M.
Published: March 2020

504

Background: Stage III breast carcinomas account for about 6–7% of all invasive breast cancers diagnosed annually in the US. Locally advanced breast cancer (Stage IIIA) and inflammatory breast cancer (Stage IIIB T4d) are now recognized as two distinct clinical pathologic entities, characterized by different prognostic factors profiles. The aim of this study was to compare differences in treatment in women with Stage III breast cancer in an inner city Cancer Center serving a large African American population. Methods: Retrospective review was performed on all Stage III primary breast cancers diagnosed and or treated from 2000 to 2005. Results: Of the 684 primary invasive breast cancers, 96 (14%) were Stage III (45 were Stage IIIA, 33 were Stage IIIB and 12 were inflammatory breast cancer) and 83 of the 96 (86%) were among African American women. The 6 Stage IIIC cases were excluded from analyses. To all patients was offered a combination of chemotherapy, surgery and radiation therapy. All patients with primary or residual tumors ≥ 5 cm or ≥ 3 positive axillary nodes were considered for chest wall and axillary radiation therapy; 48 of 74 received radiotherapy. Stage IIIA patients were less likely to receive neoadjuvant chemotherapy and were more likely to have ≥ 3 positive axillary nodes. Nineteen patients refused chemotherapy. The table summarizes our findings. Conclusions: In this predominantly African American female population, Stage III breast cancers were about twice as prevalent as observed nationally and a high number of these Stage III patients refused adjuvant and neoadjuvant chemotherapy. The benefit of chemotherapy and radiotherapy in improving prognosis for Stage III breast cancers is well established. Thus, reasons for refusal of chemotherapy and lack of radiotherapy need further investigation.

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No significant financial relationships to disclose.
Use of carbonic anhydrase IX (CAIX) expression and Von Hippel Lindau (VHL) gene mutation status to predict survival in renal cell carcinoma
Authors: Pantuck A. J. , Trinh Q. , Karakiewicz P. I. , Fergelot P. , Rioux-Leclercq N. , Figlin R. , Said J. , Belldegrun A. , Patard J.
Published: March 2020

5042

Background: VHL gene mutations induce the expression of CAIX, and previous studies have shown that low CAIX results in worse prognosis for RCC. We attempt to further describe the relationship between CAIX expression, VHL gene mutations and tumor characteristics. Methods: Radical nephrectomy was performed in 100 patients at 2 centers. Genomic DNA was extracted from frozen tumor samples using the QIAmp DNA mini kit. Four amplimers covering the whole coding sequence of the VHL gene were synthesized by PCR and sequenced by Big Dye. Mutation bearing sequences were confirmed by a second round of sequencing. The monoclonal antibody M75 was used to score the expression of the CAIX protein. Life table, Kaplan-Meier and Cox regression analyses addressed RCC-specific mortality (RCC-SM). Results: VHL mutations were identified in 58 patients (58%) and CAIX tumor expression ranged from 0% to 100%. Low CAIX expression (<85%) was associated with absence of VHL mutation (p=0.02), larger tumors (p=0.002), higher T stage (p=0.007), nodal metastases (p=0.001) and higher Fuhrman grade (p=0.006). Absence of VHL mutation was associated with worse ECOG (p=0.005), higher T stage (p=0.01) and presence of nodal (p=0.03) and distant metastases (p=0.02). Categorically-coded, CAIX was a statistically significant predictor of RCC-SM (p=0.002), while VHL mutation approached statistical significance (p=0.08) and a trend was observed for worse survival when VHL was not mutated. Patients with both high CAIX and VHL mutation had better survival (95.9% 1 year and 6 year median survival) than their counterparts with low CAIX expression and absence of VHL mutation (62.9% 1 year and 1.5 year median survival) (p<0.001). In Cox regression analyses, neither CAIX (p=0.06) nor VHL (p=0.4) achieved independent predictor status, when adjusted for age, gender, TNM stage, tumor size, Fuhrman and ECOG. Conclusions: Low CAIX expression is associated with the absence of VHL mutation and aggressive tumor characteristics, and is a statistically significant predictor of poor prognosis in patients with clear cell RCC.

No significant financial relationships to disclose.
Thyroid function test (TFT) abnormalities in patients (pts) with metastatic renal cell carcinoma (RCC) treated with sorafenib
Authors: Tamaskar I. R. , Unnithan J. , Garcia J. A. , Dreicer R. , Wood L. , Iochimescu A. , Bukowski R. , Rini B.
Published: March 2020

5048

Background: Sorafenib is an orally bioavailable VEGF receptor inhibitor with anti-tumor activity in metastatic RCC. Sunitinib, another VEGF receptor inhibitor, induces biochemical hypothyroidism in 85% of metastatic RCC pts, the majority of whom have signs or symptoms of hypothyroidism (Rini BI et al. JNCI 2007 99(1):81–83). Thus, the incidence of TFT abnormalities in pts with metastatic RCC receiving sorafenib was investigated. Methods: The medical records of pts with metastatic RCC receiving sorafenib in one of five clinical trials at the Cleveland Clinic Taussig Cancer Center were reviewed. TFTs (TSH, T4, FTI and T3), patient demographics and clinical outcomes were recorded. Results: Between February 2004 and November 2006, 71 pts (49 males, 22 females) were treated with sorafenib. Baseline pt characteristics included a median age of 62 years (range, 35–87), 87% of pts had clear cell histology and 97% had prior nephrectomy. Forty-two pts had TFTs measured while receiving sorafenib and 19/42 pts (45%; 95% CI: 30–61%) had abnormal TFTs. The TFT abnormalities were consistent with hypothyroidism (13 pts), euthyroid sick syndrome (2 pts) or hyperthyroidism (4 pts). The median values in pts with abnormal TFTs were: TSH-7 μU/ml, T3–79 ng/dl, T4–12.7 μg/dl, FTI- 5.4; these values are just outside the normal laboratory ranges. The majority of pts did not have clinical signs or symptoms that could be attributed solely to thyroid dysfunction; only one pt (2%) received thyroid hormone replacement. The estimated progression free survival for pts with normal TFTs is 7.5 months vs. 6.1 months for pts with abnormal TFTs (p=0.79). Conclusion: Mild biochemical TFTs abnormalities are common in pts with metastatic RCC treated with sorafenib. However, severe TFT abnormalities and/or clinical signs/symptoms of thyroid dysfunction are not seen, and thyroid replacement therapy is not often indicated. In contrast to sunitinib, where the high incidence and clinical relevance of thyroid dysfunction requires routine monitoring, pts with metastatic RCC receiving sorafenib should have TFTs monitored only if clinically indicated.

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A multivariate prognostic nomogram incorporating PSA kinetics in hormone-refractory metastatic prostate cancer (HRPC)
Authors: Eisenberger M. , Garrett-Mayer E. S. , Ou Yang Y. , de Wit R. , Tannock I. , Armstrong A. J.
Published: March 2020

5058

Background: To develop a prognostic model and nomogram using baseline clinical variables to predict death among men with metastatic hormone-refractory prostate cancer (HRPC). Methods: TAX 327 was a clinical trial that randomized 1,006 men with metastatic HRPC to receive 3-weekly or weekly docetaxel or mitoxantrone, each with prednisone. Of these, 635 men had baseline data that included PSA kinetics, with 518 mortality events recorded as of November 2006. We developed a multivariate Cox model and nomogram to predict survival at two, three, and five years. Results: Ten independent prognostic factors were identified in multivariate analysis and include: 1) presence of liver metastases (HR 1.64, p=0.02), 2) number of metastatic sites (HR 1.58 if =2 sites, p=0.001), 3) clinically significant pain at baseline (HR 1.46, p<0.0001), 4) Karnofsky Performance Status (HR 1.42 if =70, p=0.01), 5) type of progression at baseline (HR 1.40 for measurable disease progression and 1.28 for bone scan progression, p=0.002 and 0.014 respectively), 6) pretreatment PSA doubling time (PSADT, HR 1.20 if <55 days, p=0.048), 7) baseline PSA (HR 1.17 per log rise, p<0.0001), 8) tumor grade (HR 1.18 for high grade, p=0.076), 9) alkaline phosphatase (HR 1.26 per log rise, p<0.0001), and 10) hemoglobin (HR 1.10 per unit decline, p=0.006). A PSADT <55 days (median value for this dataset) was associated with other adverse prognostic factors, but was independently associated with shortened overall survival. Men with a PSA less than the median of 114 ng/ml and longer PSADT (=55 days) had a median survival of 24.7 months, while those with higher PSA and shorter PSADT had a median survival of 13.8 months. A nomogram was developed based on this Cox multivariate model and validated internally using bootstrap methods, with a concordance index of 0.69. Conclusions: This multivariate model identified several prognostic factors in men with metastatic HRPC including PSADT, and led to the successful development of a clinically applicable nomogram. External prospective validation may support the wider use of this prognostic baseline model for men with HRPC treated with chemotherapy.

No significant financial relationships to disclose.
Androgen deprivation therapy (ADT) for node postive prostate cancer
Authors: Wong Y. , Freedland S. , Hudes G. , Mitra N. , Montagnet C. , Armstrong K.
Published: March 2020

5061

Background: The role of ADT for men with node positive prostate cancer following radical prostatectomy (RP) is unclear. One randomized trial has shown a survival advantage for men treated with immediate adjuvant (adj) ADT compared treatment at onset of clinical metastases. However, benefit of immediate therapy is less clear in the PSA era when ADT can initiated at the time of biochemical relapse. Methods: We used linked Surveillance, Epidemiology and End Results-Medicare Data to identify a cohort of men who underwent RP between 1991–1999 and were found to have positive regional lymph nodes. We searched Medicare claims to identify men with claims for ADT (hormonal therapy or orchiectomy) within 3 years of diagnosis. We excluded men who received ADT prior to RP. We classified men as receiving adj ADT if they received treatment within 120 days of RP and compared them to men who had not received adj ADT. We used propensity scores to balance potential confounders of receiving adj ADT (age, tumor characteristics, extent of nodal disease, demographics). We used Cox proportional hazard methods to estimate the impact of adj ADT on overall survival (OS) adjusting for propensity score. We conducted a sensitivity analysis using 90, 150, 180 and 365 days as the time limit for adj ADT. Results: 719 men were identified, of whom 190 received adjuvant ADT within 120 days of RP. There was no statistically significant difference in overall survival between the men who did or did not receive adj ADT (HR 0.96 95% CI 0.70–1.32) The results were similar for men who received ADT within 90 and 150 days. However, when the definition of adj ADT was moved to 180 days (HR 1.08 (0.80–1.47)) and 365 days (HR 1.24 (0.92–1.65)) the men receiving adj ADT had a slightly higher risk of death, suggesting some in the adj ADT groups using these later definitions may have received therapy as salvage therapy for progressive disease. Conclusions: This observational study suggests that in the PSA era when men can be started on ADT at the time of biochemical recurrence, overall survival may not be significantly compromised by deferring immediate ADT in men with positive lymph nodes following RP. Further clinical research is needed to better understand which patients are likely to benefit from immediate ADT, and which men can be spared the long term toxicities.

[Table: see text]
Gefitinib (G) plus prednisone (P) versus placebo (pl) plus prednisone in the treatment of hormone-refractory prostate cancer (HRPC): A randomized phase II trial
Authors: Boccardo F. , Rubagotti A. , Tacchini L. , Lapini A. , Cruciani G. , De Rubertis G. , Battaglia M. , Conti G.
Published: March 2020

5070

Background: In spite of EGF-R overexpression in 40%-80% of pts with HRPC, the results achieved so far with G, a selective EGF-R tyrosine kinase inhibitor have been dismal. This trial was designed to investigate the activity of G when combined with P, a common therapeutic option for HRPC pts. Methods: HRPC pts unresponsive to antiandrogen withdrawal were given P (10 mg/d) plus G (250 mg/d) or pl. On progression, pts initially assigned to pl were offered the possibility to receive G. This was a one-stage trial, and 37 pts per arm were required. Best PSA response (any decrease = 50% in baseline PSA confirmed 4 wks apart) was the primary end-point. Time to disease progression, OS and toxicity were secondary end-points. Results: 82 pts were enrolled (GP: 38; plP: 44). Groups were well balanced in respect to median age (75 vs 74 yrs); WHO PS (0 in both); baseline PSA (52 vs 44 ng/ml); bone disease (87% vs 84%) Gleason score 7 (58% vs 52%); prior treatment. At a median follow-up time of 29 mos (26–32), overall 77 pts progression and 51 died. PSA resp was recorded in 16% and 11% of pts in GP and plP groups. Median time to progression was 4.0 (3.5–4.5) and 4.5 (3.5–5.0) mos, respectively. In both groups, median PSA level increased during the first 8 wks of treatment (GP:13%; plP: 32%) while it decreased thereafter. Median time to death was 26.5 (16–37) and 20.5 (14–27) mos in the GP and plP groups, respectively (HR: 0.69, 0.39–1.23; p=.2). However, OS of pts given either early or delayed treatment with G was significantly longer (26.5 vs 17.5 mos; HR: 0.49, 0.28–0.87, p=.01). This advantage was maintained also after multivariate analysis by Gleason score, baseline PSA, Hb and PAL, WHO PS and pain score. AEs (any grade) occurred in 19 pts in each arm. However diarrhea and skin rash were more common in the GP group (12% vs 0% and 14% vs 2%, respectively). Conclusions: G when combined to P showed a moderate toxicity, achieved PSA control and prolonged pts survival. The efficacy of GP in HRPC warrants to be further investigated.

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No significant financial relationships to disclose.
Radium-223 in the treatment of metastatic hormone refractory prostate cancer (HRPC): Results from a randomized, placebo-controlled, phase II study
Authors: Nilsson S. , Franzén L. , Tyrrell C. , Blom R. , Tennvall J. , Lennernäs B. , Johannessen D. C. , Sokal M. , Parker C. , Bruland Ø. S.
Published: March 2020

5071

Background: The alpha emitter radium-223 is a bone-seeking radionuclide studied as a novel treatment for patients with HRPC and bone metastases. Ra-223 showed minimal toxicity in a phase 1 study (Nilsson S, et al., Clin Cancer Res 2005;11 (12): 4451–59). Here we present outcome data from a randomised phase II study. Methods: Patients with HRPC and bone pain requiring external beam radiotherapy were randomized to treatment with 4 injections of either Ra-223 (50 kBq/kg b.w.) or saline (placebo) every 4 weeks. The primary endpoints were change in bone-alkaline phosphatase (ALP) levels from baseline to 4 weeks after last injection (previously reported (Bruland ØS, et al. Clin Cancer Res 2006;12:6250s-57s), and time to occurrence of Skeletal Related Events (SREs). Secondary endpoints included toxicity, PSA progression and overall survival. Results: 33 patients were randomised to Ra-223 and 31 to placebo. The two groups were well balanced with respect to standard prognostic factors. Mild, transient haematological toxicity was seen after Ra-223. Long term toxicity was not observed. SAEs were observed in 8 patients in the Ra-223 group versus 14 in the placebo group. Based on intention to treat analysis, the median time to PSA progression was 26 versus 8 weeks (p=0.047) for Ra-223 versus placebo, respectively. The median time to first SRE was 28 versus 26 weeks (p= 0.164). The median overall survival was 65.3 weeks versus 46.4 weeks (p = 0.066). The hazard ratio for overall survival, adjusted for baseline PSA, albumin, LDH and performance status was 2.11 (95 % CI: 1.08 - 4.13, p=0.029). At 18 months, 15 (45%) versus 8 (26%) patients patients were still alive. Conclusions: Alpharadin was extremely well tolerated, with minimal myelotoxicity, and with encouraging evidence of efficacy. Larger clinical trials are warranted to study the impact of Alpharadin on the prevention of SREs and on overall survival in HRPC. The bone targeting properties of Alpharadin, may also be applicable to the treatment of skeletal metastasis from other primary cancers.

[Table: see text]