bluuebunny/crossref_metadata_2025_split huggingface dataset:
K-ras status and response in patients with advanced or metastatic cholangiocarcinoma treated with cetuximab plus gemcitabine-oxaliplatin (GEMOX): a single center phase II study
Authors: Gruenberger B. , Schueller J. , Tamandl D. , Kaczirek K. , Schernthaner G. , Gruenberger T. 
Published: August 2020

4586 Background: As known, the mutation status of the K-ras gene affects the response to cetuximab in colorectal cancer. Less is known about K-ras status and outcome in cholangiocarcinoma. Patients with advanced cholangiocarcinoma have a poor prognosis and until now, no standard palliative chemotherapy has been defined. The purpose of this prospective single-centre phase II study was to investigate the therapeutic efficacy and K-ras status dependence of cetuximab in combination with gemcitabine and oxaliplatin in the palliative first line treatment of these patients. Methods: Patients with locally advanced or metastatic cholangiocarcinoma or gallbladder cancer were treated with cetuximab 500 mg/m2 followed by 1000mg/m2 gemcitabine (day 1) and 100mg/m2 oxaliplatin (day 2) biweekly as first line therapy. Tumour samples were obtained from 25 of 30 patients (83%). We studied the k-ras mutation status and analyzed the association between k-ras mutation and tumor response, progression-free survival (PFS) and overall survival (OS). Results: From October 2006 until July 2008 thirty patients (15 male, 15 female) with a median age of 68 were enrolled. The overall response rate of evaluable patients (30) was 63,3%, including three patient with a complete response. 5 patients (16,7%) achieved stable disease and only 6 patients (20%) progressed under chemotherapy. K-ras mutation was detected in 3 patients (12%). All three patients did not progressed under chemotherapy. Neither PFS nor OS were affected by K-ras status. The median PFS of all 30 patients was 8.3 months (95% CI 5.85–10.81) and median OS was 12.7 months (95 CI 7.96–17.37). After a mean number of 7.5 cycles any WHO grade 3 drug-related adverse events occurred in 13 patients (43%), consisting of skin toxicity in 4 patients, thrombopenia in 3, neutropenia in 1, nausea in 1, diarrhoe in 1 and PNP in 4 patients; no grade 4 side effects were noticed Conclusions: Cetuximab in combination with GEMOX induces impressive response rates which were unrelated to k-ras status. PFS and OS were remarkably improved and therefore cetuximab in combination with GEMOX deserves further evaluation in prospective randomized trials. [Table: see text]
90-Yttrium-DOTA-octreotate for the treatment of advanced neuroendocrine tumors
Authors: Toumpanakis C. , Quigley A. , Srirajaskanthan R. , Marelli L. , Singhrao T. , Meyer T. , Buscombe J. , Caplin M. E. 
Published: August 2020

4594 Background: The expression of somatostatin receptors (SSTR) on Neuroendocrine Tumors (NETs) has led not only to tumour visualization utilizing SSTR scintigraphy, but also to the development of receptor-targeted radionuclide therapy. Isotopes such as 111-Indium, 90-Yttrium and 177-Lutetium are linked to somatostatin analogues and then internalized by tumour cells. The recent development of the peptide Octreotate has higher affinity for type 2 SSTR than Octreotide. Aim: to estimate efficacy and tolerability of 90-Yttrium-tyr3-DOTA-octreotate in patients with metastatic progressive NETs. Methods: 89 patients (median age: 51.5 years) with metastatic NETs were studied. All patients had shown signs of progression despite previous treatments. In all patients, the tumours had shown good uptake either in the OctreoScan or in the Ga-68 octreotate PET scan. 64 patients received 3 cycles and 25 patients received 2 cycles of 90-Yttrium-tyr3-DOTA-octreotate. The mean i.v. dose/cycle was 3100 MBq. 29/89 patients included a cycle of intra-arterial therapy with mean dose/cycle 2090 MBq for large volume liver disease. Symptomatic response to treatment was defined as the reduction of >50% to the symptom score and radiological response utilized RECIST criteria. Results: In all patients the post treatment scintigraphy demonstrated good uptake and localization by the tumors. In 59/89 (66%) symptomatic response was achieved. Utilizing RECIST criteria, 50/89 (56%) had disease stabilization (SD) of previously progressive disease and 7 (8%) had partial response (PR). 31/89 (35%) had continued tumor progression. The SD/PR (n=57) group had sustained response for median 17.2 months. Bone marrow toxicity (WHO grade II) was noted in 15/89 (16.8%), persistent in 4 patients with significant bone metastases. Four patients developed mild renal failure (WHO grade II), that was irreversible in one of them. Conclusions: 90Y-DOTA-octreotate is a well-tolerated and safe treatment for patients with progressive neuroendocrine tumors. Early results regarding efficacy are promising. No significant financial relationships to disclose.
Circulating endothelial cells (CEC) and angiogenic proteins monitoring in patients (pts) with advanced hepatocellular carcinoma (HCC) treated with bevacizumab
Authors: Boige V. , Baey C. , Dromain C. , Ducreux M. , Malka D. , Pignon J. , Farace F. 
Published: August 2020

4597 Objective: The objective of the study was to evaluate prognostic/predictive biomarkers in pts with advanced HCC treated in a phase II trial of bevacizumab monotherapy. Methods: Pts with unresectable HCC received bevacizumab at 5- 10 mg/kg biweekly. CEC and serum proteins (MMP2, MMP9, VEGF, sVEGFR2, IL6, IL8, and PIGF) levels were monitored at baseline (BL) and on days (D) 3, D15 and D60 after beginning of bevacizumab therapy, and correlated with tumor response and survival. CEC were measured in one ml erythocyte lysed whole blood by four-color flow cytometry (FCM) and identified by a CD45-CD31+CD146+ 7-amino- actinomycin (7AAD)- phenotype according to a method we established previously. Serum proteins were measured using standard ELISA. A mixed model was used to compare variations of the values over time according to response and logrank test for prognostic study. Results: Overall, 43 pts (33 men; median age, 65 years [range, 23–84]; Child-Pugh cirrhosis A5/A6/B7/B8:17/21/3/2; CLIP score 0/1/2/3/4/5: 2/8/14/13/2/1) received a median of 7 cycles of treatment with bevacizumab. Among the 38 pts evaluable for efficacy, 6 (16%) had confirmed partial response (PR), and 18 (47%) had stable disease (SD); 16 weeks disease control rate was 42%. BL CEC levels (n=36 pts; median, 14/mL; range, 0–71) were not correlated with tumor size, progression-free survival (PFS), and overall survival (OS), but were higher in pts with PR or SD compared with PD (p=0.02). A significant decrease in VEGF levels at D3 (n=37 pts, p<0.0001) and a trend toward higher VEGF levels in the PD group (p=0.07) were observed. BL IL8 levels superior to median value (n=43 pts, 80 pg/ml) were significantly correlated with shorter PFS and OS (p=0.03, p=0.04, respectively). No significant variation or relation to patient outcome was observed with the other proteins. Conclusions: These results suggest that BL CEC levels might be a useful biomarker to predict bevacizumab antitumor activity and that IL8 might have a strong prognostic value in patients with advanced HCC. Funding: Roche. [Table: see text]
A phase II trial of gemcitabine, docetaxel, and bevacizumab (GDB) in metastatic pancreas cancer
Authors: Picozzi V. J. , Canlas L. A. , Sicuro P. L. , Malpass T. W. 
Published: August 2020

4606 Background: Metastatic pancreas cancer (MPC) remains identified with poor outcome. Benchmark response statistics in MPC include response rate (RR) 20–30%, time to disease progression (TTP) 3.5–5.5 mo, median overall survival (OS) 6–9 mo and 1- year (yr) OS 20–30%. At our center, adding docetaxel (D) to G in MPC produced 6.0 mo TTP and 10.5 mo OS (Jacobs et.al. Canc Invest 2004). As bevacizumab (B) added to combination chemotherapy has produced major improvement in OS for other cancers (e.g. colon cancer), we chose to study the GDB regimen in MPC. Methods: Our study was phase II, single-phase. Eligiblity criteria included 1) diagnosis of MPC, 2) chemotherapy naivity, 3) ECOG performance status 0 /1, 4) organ function adequate for therapy. Therapy included G 1000 mg/m2 IV bolus, D 40 mg/m2 IV and B 10 mg/kg IV every 2 weeks (wks) for 1 yr unless disease progression or prohibitive treatment toxicity occurred. Patients were radiographically restaged every 8 wks. Primary endpoint was TTP. Secondary endpoints included therapy toxicity, radiographic RR (RECIST criteria), tumor marker RR (CA 19.9) and OS. Results: Of 27 enrolled patients (pts), 25 pts are currently evaluable for response, 24 pts for TTP. Median age is 58 yrs. Primary metastatic disease sites were liver (n=18), peritoneum ( n=6), lymph node ( n=2) and lung (n=1). 7/27 pts (26%) experienced grade 3 or higher treatment-related toxicity, including pulmonary (n=3), neutropenia (n=3), bleeding events (n=3), VTE (n=2), hypertension (n=1), hypokalemia (n=1) and skin rash (n=1). 1 pt died from respiratory failure, possibly therapy-related. To date, disease control at 8 wks is 100% (24/24 pts) radiographic RR is 48% (12/25 pts) and tumor marker RR is 95% (18/19 evaluable pts expressed CA19.9, median decline 80%, 5 pts normalized) . Of 24 pts evaluable for TTP, 9/18 (50%) initial pts achieved > 9 mo TTP (range 9.2–18.5 mo); the remaining 6 pts continue progression-free on therapy (range 2+-7+ mo). Median OS has not been reached and will be > 8.3 mo. Response data will be updated at the meeting. Conclusions: 1) The GDB regimen is overall well-tolerated; pulmonary toxicity was the major therapy-related toxicity concern. 2) GDB is significantly active in MPC as witnessed by response rates achieved. 3) Further study of the GDB regimen in MPC is warranted. [Table: see text]
Oral tyrosine kinase inhibitor masitinib in combination with gemcitabine in patients with advanced pancreatic cancer: A multicenter phase II study
Authors: Hammel P. , Mornex F. , Deplanque G. , Mitry E. , Levy P. , Seitz J. , Moussy A. , Hermine O. , Rougier P. , Raymond E. 
Published: August 2020

4617 Background: Masitinib, a tyrosine kinase inhibitor targeting c-Kit, PDGFR, FGFR3 and affecting the FAK pathway, can enhance the antiproliferative effects of gemcitabine (GEM) in human pancreatic cancer cells. This multicenter phase 2 study aimed to determine the efficacy and safety of masitinib in combination with GEM in the first-line treatment of patients with locally advanced (LAPC) or metastatic (MPC) pancreatic cancer. Methods: Patients received oral masitinib (9 mg/kg/d) and standard weekly infusion of GEM (1,000 mg/m2). Primary endpoint was time-to-progression (TTP). Our hypothesis for efficacy was a TTP over 2.1 months. Secondary endpoints included survival rates, tumor response (RECIST) and clinical benefit. Results: 22 patients, with LAPC (n=9) or MPC (n=13), KPS[80–100]/[70] (18/4) were enrolled and treated with masitinib plus GEM. Median TTP was 6.4 months, well beyond our threshold for efficacy (LAPC: 8.3 months, MPC: 2.7 months, KPS[80–100]: 6.4 months, KPS[70]: 0.8 months). At 12 months, 17% of LAPC and 14% of KPS[80–100] were progression-free; all MPC and KPS[70] patients had progressed. The disease control rate was 73% (LAPC: 89%, MPC: 62%, KPS[80–100]: 89%; KPS[70] patients progressed immediately). Median OS was 7.1 months (LAPC: 8.4 months, MPC: 6.8 months, KPS[80–100]: 8.0 months, KPS[70]: 4.4 months). At 18 months, the survival rate was 23%. However, when considering KPS[80–100] alone, it reached 28%. The 18-months survival rates were similar for LAPC (22%) and MPC (23%). 16% of the 19 patients evaluated experienced clinical benefit (LAPC: 38%, KPS[80–100]: 18%). One patient (5%) presented suspected grade 4 neutropenia. Main suspected grade 3 toxicity were anemia, lymphopenia (23%), leucopenia, neutropenia (18%), asthenia (14%), diarrhea, cytolytic hepatitis, and skin rash (9%). Altogether, the combination masitinib plus GEM did not seem to increase the toxicity commonly reported with GEM alone. Conclusions: The antitumor activity of the combination masitinib plus GEM is very promising and does not present limiting toxicities. Based on those encouraging data, a randomized phase III trial comparing masitinib plus GEM with GEM alone is now actively recruiting patients in the US and in Europe. [Table: see text]
Randomized phase III comparison of paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan, both followed by gefitinib, in patients (pts) with carcinoma of unknown primary site (CUP)
Authors: Hainsworth J. D. , Lane C. , Spigel D. R. , Shipley D. , Waterhouse D. , Bury M. , Greco F. A. 
Published: August 2020

4631 Background: Empiric chemotherapy for pts with CUP has resulted in modest survival improvements. Several regimens have been active in phase II trials, but no randomized comparison of newer regimens have been completed. In this multicenter randomized phase III trial, we compared the efficacy and toxicity of 2 active regimens. Methods: Previously untreated pts with CUP (adenocarcinoma, poorly differentiated adenocarcinoma, poorly differentiated carcinoma, poorly differentiated squamous carcinoma) were eligible. Pts with specific treatable syndromes were excluded. Additional eligibility: ECOG PS 0–2; controlled brain metastases; adequate organ function. Pts were randomized (1:1) to paclitaxel 200mg/m2 day 1/carboplatin AUC 6.0 day 1/etoposide 50mg/100mg alternating po days 1–10 (PCE) or gemcitabine 1000mg IV days 1, 8/irinotecan 100mg/m2 IV days 1, 8 (GI). Both regimens were repeated at 21-day intervals for 4–6 courses. Responding/stable pts then received gefitinib 250mg po qd until tumor progression. The primary endpoint was the 2-year survival rate. Initially, a total of 320 pts were planned, to allow detection of a 50% improvement in 2-year survival (from 20% to 30%). However, due to slow accrual, enrollment was stopped after 198 pts were randomized. Results: Between September 2003 and July 2008, 198 pts were randomized (PCE, 93 patients; GI 105 patients). Pt characteristics were similar in both groups. Median progression-free survival for PCE versus GI was 3.2 months versus 5.3 months, p=0.19. Median overall survivals were 7.4 months (PCE) versus 8.6 months (GI), p=0.34; 2-year survivals were 16% (PCE) and 19% (GI). Response rates were similar (PCE 19%, GI 20%). GI was less toxic, with lower rates of grade 3/4 neutropenia (11% vs. 35%; p< 0.01), febrile neutropenia (0% vs. 9%; p<0.01), thrombocytopenia (3% vs. 8%; p=.05), anemia (3% vs. 9%; p=0.05), and RBC transfusions (10% vs. 24%; p<0.01). Conclusions: The PCE and GI regimens had comparable efficacy in the treatment of CUP, while the GI regimen was better tolerated. The 2-year survival was similar (16%, 19%). Better treatments are needed for pts with CUP. [Table: see text]
Genotypic characterization of phenotypically defined triple-negative breast cancer
Authors: Sparano J. A. , Goldestin L. J. , Childs B. H. , Shak S. , Badve S. , Baehner F. L. , Davidson N. E. , Sledge G. W. , Gray R. 
Published: August 2020

500 Background: Triple negative breast cancer (TNBC) is associated with a higher risk of recurrence and earlier recurrences than other breast cancer phenotypes. We evaluated the genotypic features of TNBC compared with hormone receptor (HR)-positive disease, and also evaluated genotypic features associated with recurrence. Methods: RNA extracted from tumor samples obtained from 764 patients with stage I-III breast cancer was analyzed by RT-PCR for 371 genes. All patients received adjuvant chemotherapy (plus hormonal therapy in HR-positive disease) in trial E2197; HR and HER2 expression were evaluated by immunohistochemistry (IHC) in a central lab (J Clin Oncol 26:2473–2481). An unsupervised clustering analysis was performed in all samples (N=764). Cox proportional hazard models were used to identify differences in gene expression in TNBC versus HR-positive disease, and with recurrence in phenotypically defined (by IHC) TNBC (N=246) and HR-positive (N=465) disease. Results: Unsupervised analysis revealed two major clusters that differed with regard to HR expression by IHC. Supervised analysis comparing the TNBC vs. HR-positive phenotypes revealed 269 genes (73%) with significantly different expression (p<0.0001). The top 10% of genes exhibiting higher expression the TN group included genes associated with nucleosome assembly (CENPA), kinase activity (TTK), cell division (KIFC2), proliferation (BUB1), intracellular signaling (DEPDC1), DNA repair (CHK1), anti-apoptosis (GSTP1), and transcriptional regulation (MYBL2). There was increased expression of genes for which inhibitors are currently being evaluated, including AURKB and CHK1 in TNBC, and IGF1R and RhoC in HR-positive disease. Although GRB7 expression was significantly lower in the TN group, increased expression of GRB7 was the only gene in the TNBC group (but not the HR-positive group) associated with increased recurrence (p=0.04), and did not correlate with nodal status, tumor size, or grade. Conclusions: We genotypically characterized breast cancers that have also undergone rigorous phenotypic characterization.. There were significant differences in gene expression between the TN and HR-positive groups, including genes for which targeted agents are currently being evaluated in the clinic. [Table: see text]
Predicting the long-term risk of prostate cancer-specific mortality after radical prostatectomy
Authors: Stephenson A. J. , Klein E. A. , Kattan M. W. , Han M. , Partin A. W. , Walsh P. C. , Trock B. J. , Wood D. P. , Eggener S. E. , Eastham J. A. , Scardino P. T. 
Published: August 2020

5007 Background: Nomograms that predict prostate-specific antigen (PSA) defined biochemical recurrence (BCR) of prostate cancer after radical prostatectomy are the most widely used prediction tools in oncology for treatment decision making and counseling. While BCR universally antedates prostate cancer-specific mortality (PCSM), it is a limited surrogate endpoint due to its variable natural history. Nomograms that accurately predict the risk of PCSM are needed. Methods: Using Fine and Gray competing risk regression analysis, the clinical data and follow-up information of 11,521 patients treated with radical prostatectomy at four academic centers from 1987 to 2005 were modeled to predict PCSM. The model was externally validated on 12,893 patients treated at a separate institution during the same period. Results: The 15-year PCSM and all-cause mortality was 7% and 33%, respectively. The 15-year PCSM for patients with final pathological Gleason score 2–6, 3+4, 4+3, and 8–10 was 1%, 7%, 8%, and 49%, respectively. By pathologic stage, the risks were 2%, 7%, 29%, and 23% for organ-confined, extraprostatic extension, seminal vesicle invasion, and lymph node-positive prostate cancer. Of 3756 patients with organ-confined and Gleason 2–6 cancer, only 1 (0.03%) died from prostate cancer. Primary and secondary Gleason grade (p < 0.001 for both), seminal vesicle invasion (p < 0.001), and year of surgery (p = 0.002) were significant predictors of PCSM. A nomogram predicting 15-year PCSM based on pathologic parameters was accurate and discriminating with an externally-validated concordance index of 0.92. Conclusions: A nomogram has been constructed that predicts the long-term risk of PCSM after radical prostatectomy based on the pathologic grade and stage of the cancer. The presence of poorly differentiated cancer and seminal vesicle invasion are the prime determinants of PCSM. Our study suggests that biomarkers may have limited empiric prognostic utility as PCSM can be accurately predicted once the pathologic features of prostate cancer are known. No significant financial relationships to disclose.
Overall survival (OS) analysis of a phase II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer (mCRPC)
Authors: Kantoff P. W. , Schuetz T. , Blumenstein B. A. , Glode M. M. , Bilhartz D. , Gulley J. , Schlom J. , Laus R. , Godfrey W. 
Published: August 2020

5013 Background: Therapeutic poxviral vaccines for prostate cancer are safe with preliminary evidence of clinical benefit in phase I/II studies. PROSTVAC-VF (PV) comprises 2 recombinant viral vectors (Vaccinia and Fowlpox), each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). PV is administered subcutaneously in a heterologous prime-boost regimen with concurrent low-dose GM-CSF. Methods: 122 patients (pts) were treated in a multi-center, double-blind, RCT of a vaccination series. Pts were randomized 2:1 to PV + GM-CSF vs. placebo empty vector + control saline injections (C). Vaccinia-based vector was used for priming followed by 6 planned Fowlpox-based vector boosts. The trial completed enrollment in July 2005. Eligible pts had metastatic disease, a rising PSA despite castrate testosterone levels, and a Gleason score of ≤7. Pts with a history of prior chemotherapy use, visceral metastasis, or narcotic use were excluded. The 1º endpoint was progression free survival (PFS), with progression defined as 2 new lesions on bone scan or RECIST-defined progression. Vaccination was discontinued after progression. Results: 82 pts received PV and 40 received C. Pt characteristics were similar (means): age (72PV/76C), PSA (134PV/188C), Alk-Phos (142PV/159C), LDH (207PV/218C), Hgb (13PV/13C), and number bone metastatic sites (5.3PV/6.5C). Mean number of vaccinations was 5.4 PV and 5.3 C. PFS was similar in the 2 groups (p = 0.56). However, at 3 years post study, PV patients had a better overall survival than C patients (25 alive, 30%, PV, versus 7 alive, 17%, C) and a longer median survival (24.5 months PV, versus 16 months C); estimated hazard ratio 0.6 (95% CI 0.4–0.9); stratified log rank p = 0.016. Conclusions: In a RCT, PV immunotherapy was associated with an 8.5 month improvement in median OS in men with mCRPC. These data provide evidence of prolonged anti-tumor activity, but need to be confirmed in a larger phase III study. [Table: see text]