bluuebunny/crossref_metadata_2025 huggingface dataset:
Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) mRNA expression in patients with metastatic gastric cancer receiving first-line chemotherapy
Authors: Pauligk C. , Wirtz R. , Steinmetz K. , Hartmann J. T. , Homann N. , Hofheinz R. D. , Petry C. , Altmannsberger H. M. , Jäger E. , Al-Batran S.
Published: August 2020

4547

Background: In preclinical tumor models, VEGF and MMP-9 induced each other, resulting in the enhancement of tumor angiogenesis and the formation of metastases. This study evaluated MMP-9 and VEGF in patients (pts) with metastatic gastric cancer. Methods: Patient tumor samples from a phase III trial of the AIO were prospectively collected. VEGF and MMP-9 mRNA were isolated from paraffin embedded tissues using a new patented method based on nanotechnology. The expression was then assessed by qRT-PCR and by immunohistochemistry (IHC). Results: A total of 137 (training cohort 96; validation cohort 41) out of 220 pts enrolled were analyzed. In the training cohort, increased MMP-9 levels were strongly associated with increased VEGF expression, resistance to chemotherapy and shorter progression-free and overall survival. At the cut-off with the highest predictive value, the rate of disease progression as best response associated with elevated MMP9 expression was 50% (vs. 22.4%; Fisher's test p=.027) and median overall survival (OS) was 3.1 months (vs. 8.7 months, log rank p=.0000165). This prognostic value for survival was maintained when data were analyzed in the multivariate setting (relative hazard ratio for death 3.67, p=.00045) or were categorized according to the quartile (p=.004) or median (p=.024) distributions for MMP-9. VEGF showed a prognostic effect in pts with low MMP-9 expression, only. In the validation cohort, the prognostic value of increased MMP-9 expression could be confirmed at the best cut off derived from the training cohort, with the hazard ratio for death being 3.45 (p=.02). Interestingly, in the IHC, stromal but not tumoral MMP-9 protein expression predicted survival (log rank p=.033). Conclusions: Tumoral MMP-9 mRNA expression levels are the first validated molecular prognostic factor in metastatic gastric cancer. These results have implications for novel anti-protease/ anti-VEGF treatment strategies.

[Table: see text]
A randomized phase II trial of weekly docetaxel plus either cisplatin or oxaliplatin in patients with previously untreated advanced gastric cancer: Preliminary results
Authors: Sym S. , Park S. , Park J. , Kwon K. , Jung I. , Cho E. , Lee W. , Chung M. , Shin D. , Lee J.
Published: August 2020

4566

Background: Docetaxel, in combination with cisplatin or oxaliplatin, has demonstrated efficacy against AGC. This randomized phase II trial evaluated two weekly docetaxel-based regimens to see which would be most promising according to objective response rate (ORR) as first-line therapy in AGC. Methods: Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric adenocarcinoma and a performance status ≤2 were randomly assigned to receive docetaxel (35 mg/m2) weekly on days 1 and 8 of a 21-day cycle plus either cisplatin (60 mg/m2 on day 1) (arm A) or oxaliplatin (120 mg/m2 on day 1) (arm B). Toxicity was assessed on days 1, 8, and 21 of each cycle, and response was evaluated every 2 cycles. Results: Between March 2007 and December 2008, 61 eligible patients entered. In Arm A, 29 patients were evaluable for objective response and 31 for safety. In Arm B, 28 patients were evaluable for objective response and 30 for safety. Median age was 52 years and disease status was comparable for both arms. Ten of 29 (34.5%) patients had a confirmed objective response in the arm A (95% confidence interval [CI] 17.1–51.8%) and 11 of 28 (39.2%) patients had a confirmed objective response in the arm B (95% CI 21.1- 57.2%). No significant difference was noted between the arms both for ORR (p=0.202) or for disease control (58.6% and 82.1%, respectively, p=0.082). Median progression free survival time was 4.4 month in the arm A and 4.3 months in the arm B (Hazard ratio = 0.936; 95% CI, 0.503–1.744; p = 0.836). There was no relevant difference in the occurrence of overall grade ¾ toxicity between the two arms (51.6% vs. 46.6%, respectively; p=0.800). Neutropenia was the most common grade 3/4 toxicity (32.3% vs. 36.6%, respectively). There was one treatment related death in Arm B. Conclusions: The preliminary results showed that both treatment arms have similar clinical efficacy as front-line treatment in AGC. Each regimen has a manageable tolerability profile. The accrual is ongoing.

No significant financial relationships to disclose.
Registry of gastric cancer treatment evaluation (REGATE): Baseline characteristics of 10,299 patients from 22 countries
Authors: Ter-Ovanesov M. D. , Bang Y. , Yalcin S. , Roth A. , Zalcberg J. R. , Soloviev V. , Mallath M. K. , Ecstein- Fraisse E. B. , Wu C.
Published: August 2020

4575

Background: Gastric cancer (GC) is the second most common cause of cancer death in the world. Recent advances in diagnosis and treatment provide new options in the management of this poor-prognosis disease. REGATE is an international disease registry designed to assess real-world practice patterns for patients (pts) with GC. Methods: Pts with newly diagnosed GC were enrolled. The target sample size was calculated according to the GC prevalence in participating countries. Data were collected at 2 visits occurring within a 10-month timeframe: baseline (pts and tumor characteristics, treatment plan) and after completion of initial treatment (actual therapy received). Characteristics of the patients at the time of enrollment are described. Results: From August 2004 to July 2008, 10,299 pts were enrolled by 223 investigators in 22 countries (Asia-Pacific 43%, Europe 31%, Latin-America 20%, and North Africa 6%). Characteristics are as follows. Median age 60 years (range: 18–104) with 23% of pts <50 years. Male 65%, female 35%; 91% of pts were symptomatic; 8% had family history of GC; and 32% had H. pylori infection. GC was diagnosed by endoscopy in 95% of pts. Primary tumor location: antrum 39%, body 39%, proximal 17%. Histopathological type was assessed using WHO, Lauren, and/or Ming classifications in 75%, 60% and 31% of pts, respectively. The most common histopathological sub-types were diffuse (51%) and intestinal (44%) according to Lauren; signet ring cell (41%) and tubular (22%) according to WHO. Most patients (55%) had a poorly/undifferentiated tumor. AJCC stage at diagnosis: I-21%, II-20%, III-21%, IV-38%. Initial choice of planned therapy was mainly based on stage (69% of pts) and determined by either a multidisciplinary team (41%) or a surgeon alone (37%). Conclusions: REGATE is the largest prospective international disease registry that provides new insight into the characteristics of patients with newly diagnosed GC. Results including worldwide treatment patterns over time are expected after all patients have completed their initial treatment.

[Table: see text]
Adequate lymph node assessment for extrahepatic bile duct cancer: Do the data support the current AJCC recommendations?
Authors: Ito K. , Ito H. , Gonen M. , Allen P. J. , D’Angelica M. I. , Fong Y. , DeMatteo R. P. , Blumgart L. H. , Jarnagin W. R.
Published: August 2020

4576

Background: AJCC staging manual 6th edition states that histologic examination of at least 3 lymph nodes (LN) is required for adequate N stage determination for extrahepatic bile duct cancer (EHBDCA). We hypothesize that this recommendation is insufficient and will lead to underestimation of N stage of EHBDCA. Methods: 257 patients (144 hilar [HCCA] and 113 distal [DCA] cholangiocarcinoma) who underwent curative intent resection for EHBDCA at our institution (1993 -2007) were analyzed. Final disease staging, including lymph node status and total number of nodes examined, was obtained from the pathology report. Differences in disease specific survival (DSS), according to nodal status, were compared using log rank test. R1 resections (n=51) were excluded from this analysis. Results: There were 89 patients (34.6%) with LN metastasis. On multivariate analysis, LN metastasis was an independent prognostic factor of poor survival (median DSS N0 vs N1: 53.3 months vs 19.3 months, p<0.0001, HR= 2.2 [95%CI: 1.5 - 3.2]). Median total LN count (TLNC) was 6 (range: 0 - 42). There was a significant difference in TLNC between HCCA and DCA (median = 3 [range: 0 - 16] vs 12 [range: 1 - 42], p<0.001, respectively). Among patients who underwent R0 resection for EHBDCA, “N0” based on TLNC < 11 was associated with worse DSS than “N0” based on TLNC > 11. When analyzed separately, “N0” based on TLNC < 7 for HCCA and < 11 for DCA revealed poorer DSS than “N0” based on greater TLNC ( Table ). Conclusions: The recommendation for LN assessment of EHBDCA by AJCC 6th Edition (“at least 3”) could lead the underestimation of N stage. HCCA and DCA should have separate recommendations for adequate LN assessment.

[Table: see text]

No significant financial relationships to disclose.
A randomized phase II trial of intra-arterial chemotherapy using a novel lipophilic platinum derivative (SM-11355) in comparison with zinostatin stimalamer in patients with hepatocellular carcinoma
Authors: Okusaka T. , Kasugai H. , Ishii H. ,   SM-11355 Japan Study Group
Published: August 2020

4583

Background: SM-11355 (Miriplatin Hydrate) is a platinum complex developed to treat HCC via administration into the hepatic artery as a sustained-release formulation suspended in lipiodol. We conducted a phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355 using zinostatin stimalamer as a control. Methods: Patients with unresectable HCC were randomized 2:1 to receive an injection of SM-11355 or zinostatin stimalamer suspended in lipiodol into the hepatic artery at doses of up to 6 mL (SM-11355: 120 mg; zinostatin stimalamer: 6 mg) according to the tumor size. A second injection was given 4–12 weeks after the first injection. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I. The primary endpoint was achievement of TE V, which was defined as disappearance or 100% necrosis of all treated tumors. Lipiodol accumulation in tumors was regarded as indicating necrosis. Results: The study included 126 patients, of whom 122 were evaluable for efficacy and toxicity (SM-11355, n=83; zinostatin stimalamer, n=39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and zinostatin stimalamer groups, respectively. The most frequent drug-related adverse events (AEs) of ≥ grade 3 (shown as SM-11355 vs. zinostatin stimalamer) were elevated AST (26.5 vs. 33.3%), elevated ALT (22.9 vs. 20.5%), thrombocytopenia (12.0 vs. 7.7%), and hyperbilirubinemia (9.6 vs. 5.1%). Serious AEs occurred in 9 (10.8%) and 3 (7.7%) patients in the SM-11355 and zinostatin stimalamer groups, respectively. The AEs with the largest difference in frequency between the two groups (SM-11355 vs. zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year survival rates were 75.9 and 70.3% in the SM-11355 and zinostatin stimalamer groups, respectively, and the 3-year survival rates were 58.4 vs. 48.7%, respectively. Conclusions: Our results suggest that SM-11355 in lipiodol has similar efficacy to that of zinostatin stimalamer, and that repeated dosing is possible without hepatic vascular injury in cases of relapse.

No significant financial relationships to disclose.
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]
Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-α2a (IFN) in metastatic renal cell carcinoma (mRCC)
Authors: Escudier B. J. , Bellmunt J. , Negrier S. , Melichar B. , Bracarda S. , Ravaud A. , Golding S. , Jethwa S. ,   on behalf of the AVOREN Investigators
Published: August 2020

5020

Background: In the AVOREN trial, BEV (Avastin) + IFN significantly improved PFS and ORR compared with placebo + IFN in pts with mRCC [Escudier, Lancet. 2007]. The study was unblinded after interim analysis due to significant superiority of BEV + IFN and the DSMB recommended crossover of pts from placebo to BEV (n = 13). We report here the results of the final analysis. Methods: Eligible pts had predominantly clear-cell mRCC, prior nephrectomy, no prior systemic therapy for metastatic disease, KPS ≥70%, no CNS metastases and adequate organ function. Pts were randomised to IFN (9MIU tiw) + BEV (10 mg/kg q2w) or placebo until disease progression. Primary endpoint was OS, with pre-planned stratified and unstratified analyses according to regional regulatory requirements. Results: 649 pts were randomised to BEV + IFN (n = 327) or placebo + IFN (n = 322). An independent radiological review confirmed previous investigator assessments, showing PFS of 10.4 vs 5.5 months (HR 0.57) and a response rate of 31% vs 12% in the two arms, verifying the robustness of the investigator analysis. At the time of final OS analysis (444 events), median follow-up was 22.9 months in the BEV arm and 20.6 months in the placebo arm. Final median OS stratified for region and Motzer score was 23.3 months in the BEV + IFN arm and 21.3 months in the IFN + placebo arm (HR 0.86 [95% CI: 0.72–1.04], p = 0.1291). No new or unexpected AEs were observed. More pts in the IFN + placebo arm than the BEV + IFN arm received post-protocol therapy, including TKIs, mTOR inhibitors, cytokines and chemotherapy: 180 (55%) in the BEV + IFN arm and 202 (63%) in the IFN + placebo arm. Exploratory analysis showed that median OS in pts receiving second-line TKI therapy (BEV + IFN, n = 96; IFN + placebo, n = 81) was 38.6 months vs 33.2 months (HR = 0.77 [95% CI: 0.51–1.15], p = 0.1948). Further subgroup analyses will be presented. Conclusions: BEV + IFN is a first-line standard of care for pts with mRCC, improving PFS and ORR, with a trend toward improved OS, compared with IFN. The observed OS results may have been influenced by subsequent anti-neoplastic therapy, which was not prespecified in the protocol and represents an uncontrolled element of the OS analysis.

[Table: see text]
Discovery of the methylation of the metastasis suppressor gene KiSS-1 in bladder cancer
Authors: Sanchez-Carbayo M. , Orenes E. , Gil M. , Piulats J. M. , Alvarez M. , Bellmunt J. , Palou J. , Cordon-Cardo C. , Ecke T. , Lopez-Beltran A.
Published: August 2020

5023

Background: In an attempt to uncover the mechanisms by which the metastasis suppressor gene, KiSS1, is lost in bladder progression, we tested the hypothesis of epigenetic silencing. An enriched 5’-CpG islands was identified around the transcription start site of KiSS1, supporting its susceptibility to be epigenetically modified by hypermethylation. To the best of our knowledge, KiSS1 had not been reported to be epigenetically altered in bladder cancer or any other tumor type. In this report, the impact and clinical relevance of KiSS1 methylation along bladder cancer progression was evaluated using in vitro strategies as well as on tissue specimens. Methods: The methylation status of KiSS1 was analyzed by two polymerase chain reaction (PCR) analysis strategies of bisulfite-modified genomic DNA. First, by genomic sequencing of both strands of KiSS1 promoter and second, by methylated specific PCR (MS-PCR). The epigenetic silencing of KiSS1 by hypermethylation was tested in bladder cancer cells (n = 12) before and after azacytidine treatment. The methylation status of KiSS1 promoter was then evaluated by MS-PCR in a large series of 524 bladder tumors. KiSS1 transcript expression were analyzed by RTPCR on bladder tumors (n = 177) for which KiSS1 methylation was assessed by MS-PCR. Results: KiSS1 hypermethylation was frequent in the bladder cancer cells analyzed and associated with low gene expression by RT-PCR. KiSS-1 expression was increased in vitro by the demethylating agent azacytidine in methylated cells. KiSS1 was found to be frequently methylated in a large series of 524 bladder tumors (68.1%). KiSS1 methylation was significantly associated with tumor stage (p < 0.001) and tumor grade (p < 0.001). Interestingly, a significant association was found between transcript levels by quantitative RT-PCR in bladder tumors and increasing tumor stage (p < 0.001). Moreover, the presence of KiSS1 methylation was associated with low transcript expression (p < 0.001). Conclusions: KiSS1 was identified to be epigenetically modified in bladder cancer. The association of KiSS1 methylation with cancer progression suggests the utility of incorporating KiSS1 methylation assessment in the clinical management of patients affected by uroepithelial neoplasias.

No significant financial relationships to disclose.
A risk-adapted study of cisplatin and etoposide, with or without ifosfamide, in patients with metastatic seminoma: Results of the GETUG S99 multicenter prospective study
Authors: Fizazi K. , Aubelle M. , Delva R. , Chevreau C. , Caty A. , Kerbrat P. , Rolland F. , Priou F. , Laplanche A.
Published: August 2020

5031

Background: Cisplatin plus etoposide-based chemotherapy is the recommended treatment and results in a high cure rate in patients (pts) with metastatic seminoma (Eur Urol 2008, 53: 478–96). Whether pts with good-prognosis and intermediate-prognosis metastatic seminoma should be treated differently or not has not been defined. Methods: From December 1999 to September 2008, pts with pure seminoma, a normal serum alpha-feto protein value, and evidence of metastases were included in this prospective study. Pts with a good prognosis according to the IGGCCG classification were treated with 4 cycles of EP (cisplatin 20 mg/m2/day and etoposide 100 mg/m2/day x 5 days, every 3 weeks). Pts with an intermediate prognosis according to the IGCCCG or MRC classifications (extra-pulmonary visceral metastases or supra-diaphragmatic metastases plus serum LDH> 2 x N) (J Clin Oncol. 1997;15:594–603; Eur J Cancer. 1999;33:1347–1350) were treated with 4 cycles of VIP + G-CSF (cisplatin 20 mg/m2/day, ifosfamide 1.2 g/m2/day, and etoposide 75 mg/m2/day x 5 days, every 3 weeks + G-CSF). Toxicity was assessed using the NCI-CTC scale. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: 133 pts were included in this study. Median age was 36 years (20–66). The median follow-up is 3.6 years (0.4–9.1). 110 (83%) pts had good-prognosis metastatic seminoma and received EP. Grade 3–4 toxicity included mainly neutropenia (41%) and neutropenic fever (13%). The 3-year PFS rate in good-prognosis pts is 94% (87–97), and the OS rate is 99% (94–100). 23 (17%) pts had intermediate-prognosis disease and received VIP + G-CSF. Toxicity included grade 3–4 neutropenia (32%), neutropenic fever (18%), grade 3–4 thrombocytopenia (18%), and grade 3–4 anemia (19%). Platelet and erythrocyte transfusions were required in 32% and 36% of pts, respectively . The 3-year PFS rate is 86% (67–95), and the OS rate is 91% (72–97) in intermediate-prognosis pts. Overall, 92 pts (69%) had post-chemotherapy residual masses and 75 pts (56%) were managed with 18Flurorodeoxyglucose positron emission tomography. Conclusions: This risk-adapted chemotherapy yielded an excellent outcome with an OS rate of 97% in metastatic seminoma.

No significant financial relationships to disclose.
Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC)
Authors: Bhargava P. , Esteves B. , Nosov D. A. , Lipatov O. N. , Lyulko A. A. , Anischenko A. A. , Chacko R. T. , Lee P. , Al-Adhami M. , Ryan J.
Published: August 2020

5032

Background: AV-951 is a potent inhibitor of VEGFR-1, 2 & 3 kinases (IC50 0.21, 0.16 and 0.24 nM respectively), and inhibits cKit and PDGFR at 10-times higher concentrations (IC50 1.63 and 1.72 nM respectively). In a phase II RDT of AV-951 (1.5 mg/day; 3 wks on, 1 wk off) in RCC, preliminary ORR at wk 16 was 28% (ASCO GU. 2008; abstract #283). Methods: Pts with locally advanced or metastatic RCC (any histology) and no prior VEGF-targeted therapy received AV-951 for 16 wks, after which further treatment was assigned based on response. Pts with ≥ 25% tumor shrinkage continued treatment with AV-951, while pts with < 25% change from baseline were randomly assigned to receive AV-951 or placebo for 12 wks (double-blinded). The primary end points were (1) objective response rate (ORR) at 16 wks, (2) percentage of randomly assigned pts remaining progression free at 12 wks following randomization, (3) safety profile. Results: 272 pts were enrolled: 70% male, 93% white, median age 56 yrs. 53% pts were treatement naïve, 72% had undergone nephrectomy and 83% had RCC with clear cell component. With a median duration of treatment of 5 mo (range 0–12 mo), the investigator assessed ORR (CR+PR) is 27.2% (30% in clear cell RCC), SD 60.5% and Disease Control Rate (CR/PR + SD) 88%. 118 (43%) pts were randomized to AV-951 or placebo. The most common treatment-related AEs (all grades) were hypertension (HTN, 42%) and dysphonia (16%). Guidelines for management of HTN were provided to investigators, and 52% pts received anti-hypertensives. Minimal (all grades) diarrhea (9%), fatigue (8%), stomatitis (3%) and hand-foot syndrome (2%) were observed. Laboratory abnormalities (all grades) were notable for minimal neutropenia (8%) and elevations of AST (21%) and ALT (21%). AEs led to dose reduction in 4% and treatment discontinuation in 5.5% of pts. Conclusions: Interim results of this phase II study demonstrate that AV-951 is active in RCC. The AE profile of AV-951 is consistent with that of a selective VEGFR inhibitor, with minimal off-target toxicities. Updated results of ORR (including independent radiology assessment), safety, percentage of randomly assigned pts remaining progression free at 12 wks, and overall PFS will be presented.

[Table: see text]
Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma (RCC): Safety and activity in RTKI refractory RCC patients
Authors: Merchan J. R. , Pitot H. C. , Qin R. , Liu G. , Fitch T. R. , Picus J. , Maples W. J. , Erlichman C.
Published: August 2020

5039

Background: Combined mTOR and VEGF blockade is a potentially promising and rational strategy for the treatment of advanced RCC. We previously reported the phase I safety and efficacy results of CCI 779 (C) +bevacizumab (B) n RTKI naïve stage IV RCC patients (pts) (J Clin Oncol. 2007;25[18S Suppl]:5034). We now report the interim results of the phase 2 study of C+B in RTKI refractory RCC patients. Methods: Design: Open label, phase I/II study of C+B in advanced RCC pts. Patients with measurable stage IV RCC with a component of clear/conventional cell type, performance status 0–2 and good organ function were eligible. Up to two prior treatment regimens were allowed (at least one prior RTKI). Phase II dose was C = 25 mg IV weekly and B = 10 mg/kg every 2 weeks repeated in 4 week cycles. The primary objective of the phase II portion was to assess the proportion of patients who were progression-free 6 months after study entry. Secondary objectives were assessment of response rates and toxicity. Accrual goal = 40 pts. Results: Thirty-five pts have been enrolled into the phase 2 portion to date with 4 pts ineligible. Twenty-five pts are evaluable for response assessment and 29 pts are evaluable for toxicity. Baseline characteristics (N: 35): M/F: 28/7; Number of met. sites: 1/2/3+: 15/9/11; prior nephrectomy: 31; Number of prior therapies: 1 = 29; 2 = 2. Most common (>5%) Gr 3–4 AEs (N = 29) included fatigue (6), hypercholesterolemia (2), hypertriglyceridemia (2), anorexia (2), rash (2), and anemia (2). Responses were: PR/SD/PD = 4 (16%)/18 (72%)/3 (12%). Median number of cycles administered was 4. Six month progression free rates will mature by may 2009. Conclusions: C+B combination at the recommended phase 2 doses is feasible and well tolerated. Clinical benefit rates (PR/SD) in RTKI refractory RCC patients (88%) are encouraging. Data on 6 month progression-free rates are expected to mature in 4/09. Updated data on safety, response rates, and 6-month progression free rates will be presented on all evaluable patients. Correlative studies on available plasma, serum and tumor samples for angiogenic and molecular biomarkers are underway. Supported by N01-CM62205, R21 CA 119545–02, and Commonwealth Foundation.

[Table: see text]