bluuebunny/crossref_metadata_2025 huggingface dataset:
PET scanning and patient reported dysphagia before and after chemotherapy (CT) for prediction of pathological response after CT and chemoradiotherapy (CRT) in patients with locally advanced esophageal cancer (EC): A multicenter phase ll trial of the Swiss
Authors: Ribi K. , Nitzsche E. , Schuller J. , Klaeser B. , Hany T. , Roth A. , Hess V. , Zuend M. , Lombriser N. , Ruhstaller T.
Published: March 2020

4587

Background: Only responding patients (pts) ultimately benefit from preoperative therapy for locally advanced EC. To predict response quality after CRT and detect non-responders earlier, we evaluated changes from baseline in FDG uptake by PET scans and patient reported dysphagia after two cycles of CT. Methods: Pts with resectable, locally advanced squamous cell carcinoma or adenocarcinoma of the esophagus were treated with 2 cycles of CT with docetaxel/cisplatin (DC) q3w followed by CRT (DC weekly x5 with concomitant 45 Gy RT) and surgery. PET imaging using [F]-deoxyglucose (FDG) uptake and subjective dysphagia assessment using a quality of life module specific to EC (EORTC QLQ-OES24) were performed at baseline and after the 2nd cycle of CT. 40% decrease of FDG uptake was prospectively hypothesized to be an early predictor for a pathological complete remission (tumor regression grade 1, TRG) and subtotal regression (TRG 2) after the CRT. The predictive value of improvement in dysphagia was tested by analysis of covariance with baseline dysphagia as covariate. Results: Out of included 66 pts, 56 completed preoperative therapy and surgery. Dysphagia scores (range 0–100) were available in 51 pts, mean changes were 14 (n=13), 12 (n=16) and 12 (n=22) for pts with TRG 1, 2 or >2, respectively, lacking any significance. 44 pts had two PET scans (5: centers not participating, 3: no FDG-uptake at baseline, 4: second scan too late or not done). Mean FDG-decrease was 49% (n=7), 44% (n=17), 15% (n=20) for pts with TRG 1, 2 or >2, respectively. Less than 40% reduction in FDG uptake predicted non-response (TRG>2) with sensitivity 70%, specificity 50%, negative predictive value 70% and positive predictive value 50%. FDG- uptake reduction indicated reduced risk of TRG>2 in a logistic regression model (p<0.01, 95%-CI 2–273). Conclusions: Decreased FDG uptake in sequential PET scans strongly correlates with tumor response, but is not accurate enough to early identify non- responders. Early improvement of dysphagia after 2 cycles CT did not predict TRG after CRT.

No significant financial relationships to disclose.
Prognosis of hepatocellular carcinoma (HCC): Comparison of four staging systems in two French clinical trials
Authors: Collette S. , Bonnetain F. , Paoletti X. , Doffoel M. , Bouche O. , Raoul J. L. , Rougier P. , Masskouri F. , Bedenne L. , Barbare J. C.
Published: March 2020

4589

Background: The aims of our study were to compare performances of 4 staging systems and to explore how to improve prognostic classification among French patients with HCC whose main aetiology is alcoholic cirrhosis. Methods: We have pooled 2 RCTs in palliative condition from Federation Francophone de Cancerologie Digestive (FFCD): - FFCD 9403 comparing tamoxifen vs symptomatic treatment and - FFCD 9402 comparing chemoembolization + tamoxifen vs tamoxifen alone. They had respectively included 416 and 122 patients. Performance of Okuda, Cancer of the Liver Italian Program (CLIP), Barcelona Clinic Liver Cancer group (BCLC) and GRoupe d’Etude et de Traitement du Carcinome Hépatocellulaire scores have been compared using: Akaike information criteria (AIC), discriminatory ability (Harrell’s c and the Royston’s D statistics), monocity of gradients and predictive accuracy (Schemper statistics Vs). To explore how to improve classifications univariate and multivariate Cox model were performed. Variables with univariate p< 0.10 have been retained for multivariate analyses. A forward selection procedure has then been implemented. Bootstraps validation was performed to test the robustness of our results. Analyses were done for each trial and for the pooled database with trial stratification. Results: Median OS was 5,3 months (IC 95%: [4,6; 6,2]), 402 patients had (75%) an alcoholic cirrhosis aetiology . As shown in Table 1 , CLIP staging had the best properties, followed by Okuda and BCLC. Performances of all staging systems were rather disappointing. WHO staging for CLIP or alphafetoprotein for BCLC allowed a significant improvement of prognostic information. Conclusions: Our results suggest that CLIP staging seems to be most adapted to french patients, it could be better by associating WHO PS. An external validation of our result will be performed on another trial in palliative condition.

[Table: see text]

No significant financial relationships to disclose.
A phase II study of weekly paclitaxel and doxifluridine (an intermediate metabolite of capecitabine) combination chemotherapy for advanced/recurrent gastric cancer
Authors: Takeyoshi I. , Makita F. , Tanahashi Y. , Iwazaki S. , Nakamura S. , Ishikawa H. , Ogawa T. , Ohya T. , Kawate S. , Horiguchi J. , Morishita Y.
Published: March 2020

4593

Background: Paclitaxel and doxifluridine (5’-DFUR; an intermediate metabolite of capecitabine), which have distinct mechanisms of action and toxicity profiles, each have considerable single-agent activity in gastric cancer. A synergistic interaction between these two drugs was suggested from the taxane-induced upregulation of thymidine phosphorylase, which converts 5’-DFUR to 5-FU. Therefore, this study evaluated the antitumor activity and toxicities of paclitaxel and 5’-DFUR in combination in patients with advanced/recurrent gastric cancer (AGC) Methods: Patients with histologically confirmed AGC, which was unresectable or metastatic, PS 0–2, and over 20 years old were eligible for this study. The treatment included paclitaxel 80 mg/m2 i.v. on days 1, 8, and 15 every 4 weeks and doxifluridine 533 mg/m2 p.o. on days 1–5/week until there was disease progression or the appearance of unacceptable toxicity. Results: Between April 2003 and May 2006,104 patients were enrolled in this study. Their median age was 67.0 years (range: 36–82) and 87 patients were male. Forty-three patients had advanced gastric cancer and 61 had recurrent gastric cancer. After a median of 3 (range: 1- 21) cycles of chemotherapy, 104 patients were evaluated for toxicity and 93 patients were evaluated for response. In the intention-to-treat analysis, the overall response rate was 32.3% (95% C.I., 22.8–41.8%), including 2 CR, 28 PRs, 37 SDs, 16 PDs, and 10 NEs. The first-line therapy involved 48 patients (primary advanced or surgery alone) in whom the response rate was 41.7% (95% C.I., 27.7–55.6%). The second-line therapy involved 40 patients (72.5% TS-1 failure) in whom the response rate was 22.5% (95% C.I., 9.6–35.4%). The median overall survival was 287 days. The actual dose intensity was 81.7% (85/104) of the planned dose during the first two cycles for both drugs. Commonly observed grade 3/4 adverse events were leukopenia (13.5%), anorexia (3.8%), fatigue (3.8%), and diarrhea (2.9%).There was no neutropenic fever or treatment-related death. Conclusions: These data suggest that Paclitaxel and 5’-DFUR combination chemotherapy is a well tolerated convenient out-patient combination with very promising efficacy for AGC.

No significant financial relationships to disclose.
Low expression of bax predicts poor prognosis in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy
Authors: Kang S. , Han J. , Lee K. , Choi J. , Park J. , Lee H. , Kim H. , Kim J. , Kang S. , Oh Y. , Sheen S.
Published: March 2020

4597

Background: The present study evaluated the prognostic significance of apoptosis-related proteins, p53, bcl-2, bax, and galectin-3 in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy (CRT). Methods: Sixty-three patients with locally advanced esophageal cancer (stage II-IV) were treated with definitive CRT using 5-fluorouracil and cisplatin combined with radiotherapy. Pretreatment tumor biopsy specimens were analyzed for p53, bcl-2, bax, and galectin-3 expression by immunohistochemistry. Results: High expression of bax, p53, bcl-2, and galectin-3 was observed in 67%, 47%, 24%, and 29% of patients, respectively. The median overall survival (OS) of total patients was 14 months with 16% of 3-year OS. High expression of p53, bcl- 2, and galectin-3 did not demonstrate correlation with clinicopathologic characteristics, including patient outcome. Low expression of bax was significantly correlated with clinical complete response (p=0.023). Low expression of bax was also associated with poor OS (median, 8 months vs. 16 months; P=0.0008) in univariate analysis. In multivariate analysis, low expression of bax was the most significant independent predictor of poor OS (p=0.01) followed by clinical complete response and low radiation dose. Conclusions: Low expression of bax was significantly associated with the poor survival of patients with locally advanced esophageal cancer treated with CRT using 5-fluorouracil and cisplatin. Immunohistochemical staining for bax with a pretreatment biopsy specimen might be useful to select the optimal treatment options for these patients.

No significant financial relationships to disclose.
Pharmacogenetic profiling and clinical outcome of patients (pts) with advanced gastric cancer (AGC) treated with S-1 monotherapy
Authors: Ichikawa W. , Takahashi T. , Sasaki Y.
Published: March 2020

4600

Background: Intra-tumor gene expressions of thymidylate synthase (TS) and orotate phosphoribosyltranseferase (OPRT) have been indicated to be positive predictive markers for the clinical outcome of pts treated by S-1 monotherapy for AGC (Int J Cancer 119:1245,2006). The aim of this study is to investigate whether polymorphisms with putative influence on S-1 activity are associated with clinical outcomes of pts with AGC. Patients and Methods: The study population consisted of consecutive 55 pts with AGC from 01/1999 to 03/2002 in our institute. All patients homogenously received the S-1 monotherapy (80mg/sqm/day, 4 wks with 2-wks drug holiday) as a first line treatment. The overall response rate was 40% and the median overall survival (OS) was 8.0 months (range, 2.1 to 23.0 months). Genomic DNA obtained before starting chemotherapy was used for genotyping 8 polymorphisms in 5 genes (DPD, TS, OPRT, MTHFR, CYP2A6). Results: No alleles of DPYD*2 were found in this Japanese cohort. There were no association among the clinical outcome, such as tumor response and OS, and genotypes including tandem repeat (VNTR) in TS 5’UTR, G/C polymorphism with in the 3R VNTR, OPRT G638C, MTHFR C677T, CYP2A6*4, and CYP2A6*9. Even if TS 5’UTR and G/C polymorphism were combined, TS 5’UTR 3G genotype (2R/3G, 3C/3G, 3G/3G) was not associated with the clinical outcome. Only 6-bp insertion/deletion (ins/del) in the TS 3’UTR was closely related to both tumor response and OS. The response rates were 23% and 55% in pts with del/del genotype and pts with ins/ins or ins/del, respectively, with a statistical significance (P=0.015). The median OS was 9.5 months in pts with the ins allele versus 6.2 months in pts with del homozygote (P=0.0345). Conclusion: This exploratory study shows that polymorphism in TS 3’UTR may influence clinical outcomes of AGC pts treated by S-1.

No significant financial relationships to disclose.
A phase II trial of perioperative chemotherapy with folinic acid, 5-fluorouracil, and oxaliplatin in potentially resectable gastric cancer with regional lymph node metastasis
Authors: Im S. , Kim S. , Kim J. , Lee H. , Kim M. , Kim S. , Kang W. , Yang H. , Song I. , Bang Y.
Published: March 2020

4602

Background: Peri-operative chemotherapy in operable advanced gastric cancer (AGC) is still in a controversial area. Results from MAGIC trial suggest that a peri-operative regimen of ECF (epirubicin, cisplatin, 5-FU) decreased tumor size and significantly improved PFS and OS in patients with operable AGC (NEJM 355: 11, 2006). The aim of this study was to evaluate the efficacy and toxicity of folinic acid (FA), infusional 5-fluorouracil (5-FU), and oxaliplatin (modified FOLFOX6), administered every 2 wks in potentially operable AGC with regional lymph node (LN) metastasis. Methods: Previously untreated gastric adenocarcinoma patients with measurable LN on CT scan (clinical stage: cT2 or cT3, N+) were eligible. Staging also included a PET-CT and endoscopic ultrasonography (EUS). Patients received 4 cycles of neoadjuvant therapy with FA 100 mg/m2 (2-hr i.v.), 5-FU 2.4 g/m2 (46-hr continuous infusion), and oxaliplatin 100 mg/m2 (2-hr i.v.), followed by curative radical surgery including D2 dissection and 4 cycles of adjuvant modified FOLFOX6. Clinical responses were assessed by RECIST using CT scan before surgery and early metabolic responses were assessed by PET-CT after 2 cycles of chemotherapy. Results: Thirty-one patients were enrolled from Oct. 2004 to Nov. 2006 and currently, 29 of them are evaluable for response. Median age was 56 yrs (range, 35–69). Most patients had EUS T3N1or2 designation. Of 29 evaluable patients, PR were observed in 19 (66%), SD in 9 (31%), and PD in 1 (3%) patient. Early metabolic responses (SUV decrement = 35% by PET-CT) were significantly correlated with conventional radiographic response (p=0.037). The R0 resection rate was 90% and pathologic CR was 7%. Median follow-up duration was 11.8 mo. and median PFS has not been reached yet. Total 219 cycles were administered. G3/4 neutropenia occurred in 6 cycles (3.0%). Nausea G3/4 occurred in 1 cycle (0.5%) and diarrhea in 1 cycle (0.5%). There were no cases of peripheral neuropathy G3/4 or febrile neutropenia G3/4. Conclusions: Peri-operative chemotherapy with modified FOLFOX6 is very effective and feasible in patients with potentially resectable AGC with regional LN metastasis. Early response can be predicted by PET-CT.

No significant financial relationships to disclose.
A systematic review and meta-analysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for advanced gastric cancer
Authors: Yan T. D. , Black D. , Sugarbaker P. H. , Yonemura Y. , Zhu J. , Morris D. L.
Published: March 2020

4614

Objectives: Despite the use of adjuvant systemic chemotherapy or radiotherapy, the long-term survival in patients with stage III and IV gastric cancer remains limited. The purpose of this systematic review and meta-analysis was to determine the effectiveness and safety of adjuvant intraperitoneal chemotherapy for patients with advanced gastric cancer. Methods: Studies eligible for this systematic review included those in which patients with gastric cancer were randomly assigned to receive surgery combined with intraperitoneal chemotherapy versus surgery without intraperitoneal chemotherapy. All forms of intraperitoneal chemotherapy in addition to surgery were included. There were no language restrictions. Quality of the trials was assessed by a predetermined checklist. The primary end-point of the meta-analysis was overall survival, defined as the time from random assignment to the last follow-up or death. Secondary end-points were the differences in the incidence of recurrence, morbidity and mortality. Results: Thirteen reports of randomised controlled trials (RCTs) were included for appraisal and data extraction. Ten reports were judged fair-quality and subjected to the meta-analysis. A significant improvement in survival was associated with hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) alone (HR = 0.60; 95% CI = 0.43 to 0.83; p = 0.002) or combined with early postoperative intraperitoneal chemotherapy (EPIC) (HR = 0.45; 95% CI = 0.29 to 0.68; p = 0.0002). Survival improvement was marginally significant (HR = 0.67; 95% CI = 0.44 to 1.01; p = 0.06) with normothermic intraoperative intraperitoneal chemotherapy, but not significant with EPIC alone or delayed postoperative intraperitoneal chemotherapy. Intraperitoneal chemotherapy was also found to be associated with higher risks for intra-abdominal abscess (RR = 2.37; 95% CI = 1.32 to 4.26; p = 0.003) and neutropenia (RR = 4.33; 95% CI = 1.49 to 12.61; p = 0.007). Conclusion: The present meta-analysis indicates that HIIC with or without EPIC after resection of advanced gastric primary cancer is associated with an improved overall survival. However, increased risks of intra-abdominal abscess and neutropenia are demonstrated.

No significant financial relationships to disclose.
Phase 2 study of talabostat/gemcitabine in Stage IV pancreatic cancer
Authors: Nugent F. W. , Cunningham C. , Barve M. A. , Fisher W. , Patel H. , Meiri E. , Oza Y. V. , Yang Z. , Jurkowski E. C. , Uprichard M. J.
Published: March 2020

4616

Background: Talabostat is an oral small molecule inhibitor of fibroblast activation protein (FAP), a stromal enzyme with collagenase and dipeptidyl peptidase activity. Talabostat also upregulates cytokine and chemokine production, resulting in immune stimulation. Talabostat is active in pancreatic tumor xenograft models and enhances the activity of gemcitabine in mice. Therefore, a clinical trial in patients with metastatic pancreatic cancer was initiated. Methods: Open-label, single-arm, Phase 2 study in 60 evaluable patients with Stage IV pancreatic cancer. Study treatment is administered in 4 x 4-week cycles; gemcitabine 1g/m2 weekly for 4 weeks in Cycle 1, then once weekly for 3 of 4 weeks. Talabostat 200mcg tablets are given BID for 6 days following each gemcitabine infusion; dose-escalation to 300mcg BID is allowed post-Cycle 1. Either agent alone or in combination can be continued beyond 4 cycles depending on tolerability. Eligible patients have measureable Stage IV pancreatic adenocarcinoma (per RECIST) are chemotherapy-naive, have a KPS ≥50, no CNS metastases, transaminases < 3 X ULN, and total bilirubin < 1.5 X ULN. Primary endpoint is 6-month survival with secondary endpoints of overall survival, PFS, pain, and quality-of-life. Tumor response or PD is assessed per RECIST. Results: As of the cut-off date, 46 patients (30 men, 16 women, median age 66 [range 43–88 years]) have received study treatment. Most patients (76%) were Stage IV at original diagnosis, and 72% have a KPS of 80 or higher. Ten of 21 evaluable patients treated as of June 30, 2006 meet 6-month survival. Median overall survival is currently estimated at 4.8 months (95% CI: 2.9, NE) in all 46 patients, and median PFS at 3.5 months (95% CI: 2.0, 4.9). Tumor responses have been reported in 3 patients: one CR and 2 PRs. Pain and QOL have not yet been analyzed. AEs are consistent with those of gemcitabine, with the exception of edema in 28.3% of patients. Grade 3 anemia, neutropenia, hyponatremia hyperbilirubinemia, and increased alk phos are reported in 2 patients each. No Grade 4 AEs have been reported in more than one patient. Conclusions: Talabostat/gemcitabine shows activity in metastatic pancreatic cancer and can be safety administered. Enrollment completed in early January 2007, and final results will be presented at the annual meeting.

No significant financial relationships to disclose.
Simplified LV5FU2-irinotecan (FOLFIRI) in the first-line therapy of well-differentiated endocrine carcinomas of the duodeno- pancreatic area: Preliminary results of the FFCD 0302 phase II trial with GTE participation
Authors: Cadiot G. , Bonnetain F. , Landi B. , Bouché O. , Mitry E. , Bedenne L. , Ruszniewski P. , Ricard F. , Vitry F. , Jouve J. L.
Published: March 2020

4620

Introduction: Few chemotherapies have been tested in the first-line treatment of endocrine carcinomas. The aim of the study was to evaluate the efficacy of FOLFIRI in the first-line therapy of evolutive, metastatic or locally invasive, well-differentiated endocrine carcinomas of the duodeno-pancreatic area. Methods: To show a 6-month tumoral non-progression (RECIST) rate ≥ 60% (a = 5%), 20 pts had to be included in a phase II, prospective, multicentric trial. Inclusion criteria were : well-differentiated endocrine carcinoma of the duodeno-pancreatic area, functioning or non functioning, with hepatic or extra-hepatic metastases or locally invasive tumor > 50 mm, not resectable; tumoral growth within 6 months; no previous antitumoral therapy except interferon ( = 3 months) or somatostatin analogs; PS 0–2. Treatment administration every 14 days : D1 : irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5 FU 400 mg/m2 bolus; D1-D2 : 5 FU 2,400 mg/m2 in 46 hrs. Evaluation (clinical, radiological, biological) every 3 months. In case of progression during a chemotherapy free-interval following an objective tumoral response, treatment was reintroduced. All analyses were performed in intent to treat. Data cut off was done at July 1st 2006. Results: Between May 2004 and July 2005, 20 pts (13 M, 7 F) were included with median age 57 yrs (37–82). 19 pts had liver metastases and 1 pt had metastatic lymph nodes. 5 tumors were functioning; 2 pts had MEN 1. Median proliferation index was 7% (0–58). All pts were treated and evaluation at 6 months for the primary endpoint was available in 19 pts. The 6-month non-progression rate was 75% (CI 95% = 51–91%,), including 14 stabilization (70%) and 1 partial response (5%). 4 pts had 1 chemotherapy free-interval and 2 pts had 2 with reintroduction of the same chemotherapy regimen. Median number of cycles was 11.5 (1–28). 80% had at least 1 grade 3–4 toxicity and 25% had grade 3–4 hematological toxicity. 10% had grade 3 diarrhoea.. Conclusion: FOLFIRI has an antitumoral effect in the first-line therapy of evolutive well-differentiated pancreatic endocrine carcinomas. Frequency of grade 3–4 toxicities can be explained by length of therapy.

No significant financial relationships to disclose.
Identification of prognostic biomarkers for gastric cancer by gene expression analysis
Authors: Yamada Y. , Arao T. , Nishio K. , Koizumi F. , Saito D. , Gotoda T. , Shimoda T. , Taniguchi H. , Shirao K. , Saijo N. , Sasako M.
Published: March 2020

4623

Background: Endoscopic biopsy before chemotherapy provides an excellent opportunity for studying biomarkers related to therapy-induced tumor responses or overall survival. This study was designed to identify prognostic biomarkers in patients with unresected gastric cancer. Methods: Samples were taken from histologically proved primary gastric cancers in 40 patients before chemotherapy. Microarray analysis was performed using Affymetrix HG-U133Plus2.0 GeneChips after RNA quality checks of the samples. Correlations between gene expression data and survival time were statistically evaluated with a univariate Cox proportional-hazards model. Identified genes were validated by real time RT-PCR analysis in same 40 test-set samples. Then, PCR-validated genes were evaluated for independent samples (validation set) to predict survival. Results: We obtained 185 candidate genes that were significantly associated with survival (p<0.005) on univariate testing in the 40 test-set sample. Real time RT-PCR analysis identified 5 genes that were reproducibly related to survival on the log-rank test (p<0.01). PCR analysis with each of these 5 genes discriminated short-term survivors with a sensitivity of 71% and a specificity of 46–77% in the test set. For the independent 19-sample validation set, single-gene PCR analysis had a sensitivity of 50–81% and a specificity of 38–62%. A multi-gene prediction panel will be evaluated. Conclusions: Gene expression profiling by microarray and real time RT-PCR is useful for predicting overall survival in gastric cancer.

No significant financial relationships to disclose.
A novel multimodality treatment for resectable pancreatic cancer (PC)
Authors: Takamori H. , Kanemitsu K. , Chikamoto A. , Ishiko T. , Beppu T. , Hirota M. , Baba H.
Published: March 2020

4630

Background: Patients with PC often suffer from tumor recurrence despite curative resection, thus indicating that systemic therapy added to local control might be required to further improve the survival. The aim of this phase II trial was to assess the feasibility and tolerance as well as overall survival of a novel multimodality therapy composed of pancreatic resection and intraoperative radiation therapy (IORT) combined with neoadjuvant (NAC) and adjuvant (AC) combination chemotherapy for patients with PC. Methods: Eligibility criteria included: no distant metastases / no tumor extension to the CA or the SMA by imaging, tumor size ≥ 1 cm, ECOG PS ≤ 2, age < 80, and normal organ function. For NAC, 5-FU was administered at a dose of 125 mg/m2 on days 1–5 every week as a continuous pancreatic and hepatic arterial infusion, and gemcitabine was infused intravenously at a dose of 800 mg/m2 for 30 min once weekly for 2 weeks. Pancreatic resection combined with IORT (30 Gy, 12 Mev of electron beam) was performed after a one-week rest following the completion of NAC. AC was performed in the same regimen as NAC after the recovery from surgery. We performed intension to treat analyses. Results: Between 2001 and 2006, 32 pts were enrolled: 32 received NAC, 28 received AC, and 28 received IORT. Of 32 pts given NAC, 13 had grade 3–4 hematological toxicity. All pts underwent surgery, including R0 resection in 26 pts, without delay by NAC- related toxicity. Of 28 pts given AC, 18 had grade 3–4 hematological, and 6 had non-hematological toxicity, although no chemotherapy-related death was observed. The median follow-up period was 20 months (rang 3.9 to 67.4). Overall survivals at 1, 3, and 5 years were 77.0 %, 60.2 %, and 48.1 %, respectively. Median survival was 38.5 months. Conclusions: This new multimodality treatment is feasible and tolerable, and may contribute to the survival benefit of patients with PC.

No significant financial relationships to disclose.
Cyberknife stereotactic radiosurgery in patients with primary hepatocellular carcinoma
Authors: Kang K. , Choi B. , Jang H. , Bae S. , Ryu M. , Kang Y. , Jang J. , Choi G. , Choi I.
Published: March 2020

4645

Background: Conventional radiotherapy has historically played a limited role in the primary treatment of hepatocellular carcinoma (HCC). This study evaluated the effect of Cyberknife stereotactic radiosurgery (SRS) with for both for small primary non-resectable HCC, and for advanced HCC with portal vein tumor thrombosis (PVTT). Methods: From March 2004 to March 2005, thirty one patients with HCC were treated Cyberknife SRS was used for 32 lesions in patients with SRS for primary HCC. There was performed in 22 patients (23 lesions) with targeting to the primary HCC was treated (Group A), and in 9 patients with targeting to the PVTT was treated (Group B). The total SRS doses treated were 30–39 Gy (median, 36 Gy) to the 70–85%, 3 fractions and the target volume was of 3.6–57.3 cc (median, 25.2 cc). Results: The median follow up was 10.5 months. A complete response (CR) was achieved in 10 lesions, a partial response (PR) in 13 lesions, stable disease was noted in 6 lesions, and disease progression in 3 lesions. The response rate (CR+PR) was 71.9% (group A: 82.6%, group B: 44.4%). The level of serum alpha-fetoprotein after the treatment was decreased significantly in 17 patients (54.8%) (group A: 54.5%, group B: 55.5%). Complications were observed in 15 patients, among them, greater than grade 3 complication was observed in two patients of group A (gastric ulcer bleeding (1), liver necrosis (1)). Conclusions: These results suggest that Cyberknife SRS could be considered as an effective and safe treatment for primary HCC. For PVTT, Cyberknife SRS as the only curative tool, and produced acceptable local control in this study.

No significant financial relationships to disclose.
Comprehensive analysis of ERCC, XPD, and XRCC polymorphisms: Association with clinical outcomes in patients with advanced gastric cancer
Authors: Keam B. , Kim H. , Im S. , Ham H. , Han S. , Cho E. , Lee J. , Oh D. , Kim T. , Bang Y.
Published: March 2020

4649

Background: Platinum-DNA adducts are repaired by nucleotide excision repair (NER) pathway, in which genes of the excision repair cross-complementation 1 (ERCC1), xeroderma pigmentosum group D (XPD) and X-ray repair cross-complementing group (XRCC) have an important role. The purpose of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of these genes and the clinical outcomes to combination chemotherapy of 5-FU and oxaliplatin in advanced gastric cancer (AGC). Methods: We searched SNPs of NER pathway genes from database of the International Hapmap Project. Tagging SNPs and halpotype blocks were founded by linakage disequilibrium and haplotype analysis. Whole blood samples were obtained from the patients before chemotherapy. DNA was extracted from the peripheral blood mononuclear cells and the genotyping was performed by SNaPshot methods. Seventy three metastatic or relapsed AGC patients received modified FOLFOX-6 as a first-line palliative chemotherapy and were analyzed. Results: By searching the database of the International Hapmap Project, we found 17 SNPs in ERCC, 69 SNPs in XPD, 78 SNPs in XRCC. We found that some SNPs played a role as a tagging SNP and belonged to haplotype block (5 tapping SNPs and one haplotype block in ERCC, 8 tapping SNPs and two haplotype blocks in XPD, 9 tapping SNPs and two haplotype block in XRCC). Tagging SNPs were analyzed and matched with clinical significance. Among the 22 tagging SNPs of NER pathway genes, only XPD-C156A SNP (rs238406) showed clinical correlation. AA genotype of XPD C156A showed higher response rate (CC: CA: AA= 29.2%: 43.3%: 63.2%, p=0.083) and toxicities (neutropenia of grade 3 or 4) (CC: CA: AA= 4.3%: 3.2%: 21.1%, p=0.060) than CC or CA genotypes. Conclusions: Our results suggest that some SNPs of ERCC, XPD and XRCC showed linkage disequilibrium and belonged to haplotype blocks. And XPD-C156A SNP showed clinical correlation in AGC patients treated with modified FOLFOX-6 regimen. These findings require independent prospective confirmation.

[Table: see text]
Multicenter phase II study of combined neoadjuvant docetaxel and androgen ablation (ADT) prior to radical prostatectomy (RP) for patients (pts) with high risk localized prostate cancer (LCaP): Pathologic outcomes and 3-year follow-up analyses
Authors: Winquist E. , Chi K. N. , Chin J. , Goldenberg L. , Klotz L. , Berry S. , Saad F. , Perrotte P. , Ruether D. , Trachtenberg J. , Gleave M. E.
Published: March 2020

5002

Background: Pts with high risk LCaP (cT3, Gleason score > 7 &/or PSA > 20) have an increased risk of relapse with a biochemical failure rate of >50% at 3 years after RP. Docetaxel is active in hormone refractory prostate cancer & potentially beneficial if combined with ADT for treatment naïve disease. The objectives of this trial were to assess the pathologic outcomes & feasibility of docetaxel + ADT in men with LCaP prior to RP. Methods: A phase II multi-center study of newly diagnosed previously untreated pts with clinically LCaP with high-risk features. All pts received ADT (buserelin acetate 6.3 mg q8 weeks x 3 and anti-androgen for 4 weeks) plus docetaxel (35 mg/m2 weekly for 6 out of 8 weeks for 3 cycles) prior to RP. Results: 72 men with a median age of 59 years (range 46–78) were enrolled at 6 sites. Baseline characteristics included: clinical stage T1C, T2 & T3 in 14%, 47% & 39%; and Gleason score <7, 7 & >7 in 10%, 30% & 60% of pts; respectively. Median baseline PSA was 10.8 μg/L (range 1.6–65.6) with PSA < 10 in 47%, 10–20 in 24% & >20 in 29% of pts. Eight pts did not complete protocol therapy because of toxicity (n=4), withdrawal of consent (n=1), or other reasons (n=3). 1 pt had myocardial infarction day 1 post-operatively & 1 pt had DVT 1.5 months after RP. No other major post-operative complications were reported. Of the 64 pts completing protocol therapy, 2 had a complete pathologic response and pathologic stage was T2 in 34 (53%) and T3 in 28 (44%) pts. Four pts had N1 disease & positive surgical margins were identified in 17 (27%). On multivariate Cox regression analysis only baseline Gleason score (=7 vs. >7) was associated with PSA recurrence-free survival (hazard ratio 4.58, 95% CI 1.32–15.93). At a median follow-up of 42.7 months (range 25.6–65.6), 19 (30%) pts have relapsed. Three pts have died at 32.0, 40.0 & 40.3 months, with all deaths attributed to prostate cancer. Conclusions: Combined ADT and docetaxel prior to RP was feasible and resulted in encouraging pathologic outcomes and PSA- recurrence free survival. These data further support the rationale for randomized trials determining the efficacy of chemo-hormonal therapy in pts with clinically LCaP.

[Table: see text]
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival of the TAX 327 study
Authors: Berthold D. R. , Pond G. , DeWit R. , Eisenberger M. , Tannock I. F.
Published: March 2020

5005

Background: The TAX-327 study compared 3 weekly docetaxel (D3), weekly docetaxel (D1) or mitoxantrone (M), each with prednisone (P) for 1006 patients (pts) with metastatic hormone resistant prostate cancer (mHRPC). The original analysis, undertaken in August 2003 when 557 deaths had occurred, showed significantly better survival and response rates for pain, PSA and quality of life for D3 when compared with M (Tannock et al, NEJM 2004;351:1502–12). Here we present the updated survival analysis. Methods: Investigators were asked to provide date of death or last follow up for all patients alive in August 2003. Results: By December 2007 data on 276 additional deaths were obtained (total 833 deaths, see Table ). The survival benefit of D3 as compared with M has persisted with extended follow up while D1 continues to show no significant survival advantage. More patients (17.9% and 16.7%) survived =3 years in the D3 and D1 arms compared to M (13.7%). Similar trends in survival between treatment arms were seen for pts above and below 65 years of age, for those with and without pain at baseline, and for those with baseline PSA above and below median value of 115ng/ml. Conclusions: The present analysis confirms previous findings that survival is significantly longer with D3 than with M. Survival update is ongoing.

[Table: see text]

No significant financial relationships to disclose.
PSA density as a predictor of aggressive prostate cancer on repeat prostate biopsy
Authors: Rogosin S. , Collins L. , Mongoue-Tchokote S. , Blank B. H. , Beer T. M. , Mori M. , Garzotto M.
Published: March 2020

5007

Background: Prostate biopsy procedures carry a high false-negative rate. However, since Gleason score is strongly associated with cancer-specific mortality; efforts to identify men who harbor high-grade prostate cancer will likely assist in patient selection for repeat biopsies. We sought to identify risk factors for the detection of aggressive prostate cancer (Gleason ≥ 7) on repeat biopsy. Methods: Clinical and pathologic variables collected from subjects undergoing a repeat biopsy included all prostate specific antigen (PSA) values, PSA density (PSAD), PSA doubling time (PSADT). PSADT was examined using PSAs up to the first biopsy, and also in an exploratory analysis using both pre- and post-biopsy PSAs. Predictors of aggressive prostate cancer were identified using recursive partitioning and a stepwise Cox regression model. Results: 511 patients with initial negative biopsies underwent 1,319 biopsy procedures. Median follow-up was 3.7 years. Aggressive cancer was diagnosed in 52 of 511 (10.18%) patients. Recursive partitioning analysis selected PSAD as the sole factor for distinguishing high- and low-risk groups. Based on K-M analysis, a PSAD <= 0.304 ng/ml/cc carried 2 and 5 year aggressive cancer detection rates of 4% (± 1.9%) and 9% (± 3.5%) respectively, whereas a PSAD > 0.304 ng/ml/cc carried cancer detection rates of 23% (± 11.9%) and 36% (±15.3%) at 2 and 5 years (p-value <.0001). Independent prognostic factors included (HR, 95% CI): PSA >= 9.7 (2.565, 1.404 - 4.688), PSAD 0.13 - < 0.19 ng/ml/cc (0.423, 0.179 - 0.999) and volume >= 43.3 cc (0.454, 0.247 - 0.833). PSADT became significant when all PSA data were analyzed: PSADT < 2 years (4.203, 1.894 - 9.325) and PSADT >= 5 years (0.17, 0.89- 0.326). Conclusions: In decision tree analysis, a high PSAD is predictive of aggressive prostate cancer on a repeat biopsy. In addition, high PSA, lower PSAD and prostate volume are predictive of aggressive prostate cancer. However in follow-up using all PSA values, a PSADT < 2 yrs. becomes the most significant predictor of aggressive cancer. Such data may help identify the most appropriate patients for a repeat biopsy and could reduce the rate of unnecessary biopsies and the inherent over-treatment of prostate cancer.

No significant financial relationships to disclose.
Use of Von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF) -targeted therapy in metastatic renal cell carcinoma (RCC)
Authors: Choueiri T. K. , Vaziri S. A. , Rini B. I. , Elson P. , Bhalla I. , Jaeger E. , Weinberg V. , Waldman F. M. , Zhou M. , Bukowski R. M. , Ganapathi R.
Published: March 2020

5012

Background: The clinical response to VEGF-targeted therapy in metastatic RCC is robust, yet variability in outcome exists. VHL is often mutated in RCC, but the relation to therapeutic outcome is unclear. Identification of tumor molecular characteristics associated with outcome would aid in patient selection and interpretation of clinical trials. Materials and Methods: Patients with metastatic, clear-cell RCC with available baseline frozen or paraffin-embedded tumor samples who received VEGF-targeted monotherapy with sunitinb, sorafenib, axitinib or bevacizumab at Cleveland Clinic or University of California San Francisco, were included. Patient characteristics, VHL gene status (mutated or not mutated) and objective response rate (ORR) were documented. ORR was investigator-assessed per RECIST criteria. Fisher’s exact test and logistic regression models were used to assess ORR in univariate and multivariate analyses, respectively. Results: One-hundred twenty-three patients were evaluable. The ORR was 36.5% for the entire cohort. VHL mutation was found in 48% of patients and was seen across all three exons. Patients with VHL mutation had an ORR of 46% versus 28% for pts without a mutated VHL gene (p=0.06). In multivariate analysis, presence of a VHL mutation remained an independent prognostic factor associated with improved ORR (p=.02) when multiple clinical prognostic factors (ECOG PS, hemoglobin, corrected calcium, LDH, prior radiation, prior therapy and number of metastatic sites) were also considered. Conclusion: This is the first large study testing the impact of VHL mutation on response to VEGF-targeted agents in metastatic RCC. Although objective responses were more likely among patients with mutated VHL gene, lack of VHL mutation did not preclude a response. Additional tissue analysis and identification of biomarkers relevant to response to VEGF-targeted agents in metastatic RCC are warranted.

[Table: see text]
Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: Survival and biomarker analysis
Authors: Bukowski R. M. , Eisen T. , Szczylik C. , Stadler W. M. , Simantov R. , Shan M. , Elting J. , Pena C. , Escudier B.
Published: March 2020

5023

Background: Based on the significant PFS benefit of sorafenib (SOR) vs placebo (P) in a Phase III advanced RCC trial, P patients were unblinded and crossed over to SOR in May 2005. Final OS and biomarker data are reported. Methods: Final OS analysis was planned at ∼540 events (a=0.037 after adjusting for previous analyses). To minimize effect of crossover on OS, a secondary analysis was planned censoring P data on June 30, 2005 (a=0.037). Plasma VEGF and sVEGFR2 were measured by ELISA at baseline (BL), cycle (C) 1 day (D) 21, and C3D1. pERK was assayed by IHC. Results: 903 patients were randomized (SOR, 451; P, 452). The only OS analysis before crossover (May 2005) showed an estimated 39% OS improvement for SOR vs P (HR=0.72; p=0.018) (ECCO 2005); 216 P patients had crossed to SOR. OS analysis 6 months after crossover (Nov 2005) showed a 30% improvement in OS for SOR vs P (HR=0.77, p=0.015) (ASCO 2006). These OS differences did not reach prespecified O’Brien-Fleming statistical boundaries. Final OS (Sep 2006) at 561 deaths showed an improvement of 13.5% for SOR vs P and was not significant (median 17.8 vs 15.2 months; HR=0.88; p=0.146; a=0.037). Secondary analysis censoring P data (June 2005) showed a significant OS benefit for SOR vs P (HR=0.78, 95% CI: 0.62, 0.97; p=0.0287; a=0.037), suggesting crossover had confounded OS. Changes in VEGF (n=712) and sVEGFR2 (n=717) were observed after SOR treatment (AACR 2006); VEGF increased 32% (n=279) at C1D21 and 47% (n=203) at C3D1, and sVEGFR2 decreased 18% (n=282) and 24% (n=206). Using a COX proportional hazards model, BL VEGF was an independent prognostic factor (p=0.014); patients with high BL VEGF (>131 pg/ml) had poorer prognosis and a trend towards greater PFS benefit with SOR (SOR vs P, HR=0.48 vs 0.64 for high vs low VEGF, p=0.096). BL sVEGFR2, changes in VEGF or sVEGFR2 at C1D21, and pERK levels in limited diagnostic tumor biopsies were not predictive of SOR response. Conclusion: SOR demonstrated a PFS benefit in advanced RCC, although ITT final OS analysis showed a confounding effect of crossover. Significant OS benefit of SOR was seen in a planned secondary analysis adjusting for crossover. VEGF levels have prognostic importance, and SOR-associated changes in VEGF and sVEGFR2 are consistent with inhibition of VEGF signaling.

No significant financial relationships to disclose.
Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: Phase I safety and activity results
Authors: Merchan J. R. , Liu G. , Fitch T. , Picus J. , Qin R. , Pitot H. C. , Maples W. , Erlichman C.
Published: March 2020

5034

Background: The mammalian target of rapamicin (mTOR) and vascular endothelial growth factor (VEGF) pathways are critically involved in the pathogenesis and progression of clear cell renal cell carcinoma. Methods: The goal of the phase I portion of the trial was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combination of the mTOR inhibitor CCI-779 (C) and the anti-VEGF monoclonal antibody Bevacizumab (B). Patients with measurable stage IV clear cell RCC, performance status 0–2 and good organ function were eligible. Up to two prior treatment regimens were allowed. Treatment consisted of 25 mg IV weekly C and escalating IV doses of B (level 1= 5 mg/kg; level 2= 10 mg/kg) every other week. A cycle was defined as 4 weeks. Results: A total of 10 male and 2 female patients, median age 66 yrs (50–77) were enrolled to the phase I portion of the trial. PS: 0/1= 6/6; prior nephrectomy = 10; prior systemic therapy = 7 (prior cytokine therapy = 6); Number of metastatic sites: 1/2/≥3 = 2/2/8; one patient (out of 6) in dose level 1 experienced DLT which consisted of grade 3 hypertriglyceridemia. 1/6 patient in dose level 2 experienced DLT with grade 3 mucositis. Other grade 3 toxicities that were not DLTs included hypertension, proteinuria, hemorrhage, nausea/vomiting, dehydration, anorexia, pneumonitis, anemia, and hypophosphatemia. The best responses in the 12 evaluable patients included 7 PRs and 3 SDs. One patient had PD due to symptomatic deterioration and in one patient response information is not available at the time of this submission. Conclusions: Combination therapy with CCI-779 and Bevacizumab is safe and shows promising clinical antitumor activity. The recommended phase II dose is CCI-779 25 mg/week with bevacizumab 10 mg/kg every other week. The phase II study in stage IV renal cell cancer patients refractory to FDA approved receptor tyrosine kinase inhibitors is under way. The goals of the phase II portion are to determine the proportion of patients who have not had disease progression at 6 months, safety, response rates and correlative biomarker studies including determination of the tumor’s VHL-HIF-VEGF status, PTEN/AKT expression, plasma angiogenic activity and angiogenic cytokines. Supported by NCI N01-CM-62205

No significant financial relationships to disclose.
Predicative value of [18F]-FDG PET scan for pathological complete response to neoadjuvant chemotherapy in breast cancer
Authors: Favier L. , Berriolo-Riedinger A. , Coudert B. , Touzery C. , Riedinger J. , Toubeau M. , Arnould L. , Brunotte F. , Fumoleau P.
Published: March 2020

505

Background: To evaluate, in breast cancer patients treated by neoadjuvant chemotherapy, the early predictive value of the FDG uptake decrease for the assessment of the pathological complete response (pCR). Methods: Forty seven women with non metastatic with conventional imaging, non inflammatory, large or locally advanced breast cancer were included. Pathological tumour regression determined on surgical resection specimens served as the gold standard for the assessment of the neoadjuvant chemotherapy response. According to the Sataloff classification, patients were classified in two groups: patients with a pathological complete response (pCR) and patients with a pathological non complete response (non pCR). FDG uptake of breast lesions was evaluated before and after the first course of neoadjuvant chemotherapy, using Standard Uptake Value maximum (SUV) corrected by body surface area and glycaemia. Relations between baseline [18F]-FDG uptake and clinical, histopathological and biological parameters were assessed by Mann-Whitney test. Predictive value of the FDG decrease for the assessment of the pCR was studied with logistic regression analysis. Results: An elevated baseline SUV was found independently associated with a high mitotic activity (p<0.002), tumour grading (p<0.004), high score of nuclear pleomorphism (p= 0.03) and positive hormonal receptor status (p<0.005). After completion of chemotherapy, 11 (23%) of the 47 breast tumours examined at surgery showed a pCR while 36 (77%) showed a non pCR. The relative decrease (ΔSUV) after the first course of neoadjuvant chemotherapy was significantly greater in the pCR group than in the non pCR group (p< 10-4). A SUV decrease of 85.4% ± 21.9% in pCR patients versus 22.6% ± 36.6% in non pCR patients was found. ΔSUV<-60% predicted pCR with an accuracy of 87%. With multivariate logistic regression analyses, ΔSUV<-60% was the only predictive factor of the pCR Conclusions: In breast cancer patients treated by neoadjuvant chemotherapy, the FDG uptake decrease, after only one course of treatment, is an early and powerful predictor of the pCR.

No significant financial relationships to disclose.