bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between genetic markers and quality of life (QOL) in stage III colon cancer (CC) patients (pts) prior to adjuvant treatment (N0147).
Authors: Sloan Jeff A. , Shi Qian , Lee Adam , Diasio Robert B. , Pavey Emily S , Sargent Daniel J. , Goldberg Richard M. , Sinicrope Frank A. , Mahoney Michelle R. , Alberts Steven R.
Published: March 2020

3617

Background: In metastatic colorectal cancer (CRC), previous studies suggested potential relationships between certain drug metabolizing (DM) genes (DPYD, ERCC2, GSTP1 and TYMS) and QOL prior to receipt of chemotherapy (Sloan, Plenary Session ASCO 2004). The current study is the first to examine relationships between similar DM genes and QOL in stage III CC pts. Methods: 1,583 CC pts on a randomized adjuvant stage III, phase III trial received FOLFOX, FOLFIRI, or either +/- Cetuximab. Genomic DNA and baseline QOL data via linear analogue self assessment (LASA) scales with 4 QOL variables were obtained. 53 DM SNPs were selected for known functional effect within potential regulatory sites. Two-sample t-tests assessed differences in QOL between pts with variants and wild-type status. Differences of at least 10 points on a 0-100 point QOL score were considered clinically significant. Results: 14 relationships between DM genes and QOL were detected at the nominal p < 0.05 level; six of these were related to DPYD, ERCC2, GSTP1 and TYMS. Relationships were also observed at the 0.05 level with polymorphisms of genes DPYS, ERCC1, MGMT, MTHFR, OPRT and UGT1A1 based on unadjusted and adjusted association tests. GSTP1 I105V and OPRT 5’UTR 28 A>G markers differed on fatigue scores (p=0.04, 0.005, respectively). Variants on MTHFR R594Q were associated with higher mental acuity scores (p=0.02). These relationships remained after adjusting for age, gender, race, T stage, PS, disease site, lymph nodes involved, and grade. The robustness of the observed associations varied with the multiple comparison adjustment method. Conclusions: Similar to the earlier study of stage IV CRC, we observed a possible relationship in pts with Stage III CC with regard to DM genes and QOL, although these relationships were more modest than observed in Stage IV pts. These DM genes may be in linkage disequilibrium with other genetic variants that more directly affect behavior and QOL. Further genome wide association studies are needed to clarify these relationships.
Effect of the 12-gene colon cancer assay results on treatment recommendations in patients with stage II colon cancer.
Authors: Cartwright Thomas H. , Chao Calvin , Lopatin Margarita , Bentley Tanya G. , Broder Michael S. , Chang Eunice
Published: March 2020

3626

Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has been clinically validated as an independent predictor of individual recurrence risk in stage II colon cancer patients following surgery. As a result, physicians have been ordering the Oncotype DX assay for stage II colon cancer patients since January 2010, yet no data exist on the assay’s impact on adjuvant treatment planning in clinical practice. We performed a survey to characterize the impact of the assay on adjuvant treatment recommendations in stage II colon cancer. Methods: U.S. medical oncologists (n=346) who ordered Oncotype DX for ≥3 patients with stage II colon cancer were contacted and asked to complete a web-based survey regarding the single most recent stage II colon cancer patient for whom the assay was ordered. The survey was developed through cognitive interviews with four medical oncologists, and the protocol was institutional review board approved. Results: We analyzed survey results from 116 eligible physicians. Physicians were more often in community (86%) than academic or other practices, and had a median of 14.5 years (range, 2-40) of practice experience. The median patient age was 62 years (range, 32–85). Most patients (81%) had T3 disease. Patients had ≤8, 9-11 and ≥12 nodes examined 3%, 13% and 84% of the time and 38% had comorbidities. Of the 76 patients tested for MMR/MSI, 13 (17%) were MMR-D or MSI-H and 46 (61%) were MMR-P or MSI-L; 17 (22%) unknown. Median RS was 20 (range, 1-77). Before obtaining the RS, chemotherapy was planned in 52 (45%) patients, observation in 40 (34%), and there was no recommendation in 24 (21%). For the 92 patients with pre-assay recommendations, recommended treatment changed after obtaining the RS for 27 patients (29%). Treatment intensity decreased for 18 (67%) and increased for 9 (33%) of 27 changed recommendations. A significant trend of decreasing treatment intensity with lower RS values was observed (p=.0035). Conclusions: These findings indicate that for stage II colon cancer patients, treatment recommendations were changed by RS results in 29% of patients. Use of the Oncotype DX assay may lead to reductions in treatment intensity, contributing to the assay’s cost effectiveness.
Use of gene set analysis (GSA) for molecular classification of responders and nonresponders to FOLFOX therapy in colorectal cancer (CRC).
Authors: Yip Stephen , Cheang Maggie Chon U. , Kennecke Hagen F.
Published: March 2020

3628

Background: Folinic acid (FOL) fluorouracil (F) and oxaliplatin (OX) chemotherapy is a commonly used therapy for CRC. Lacking in current literature are clinically relevant classifiers for potential responders. GSA technique is statistical method that detects significance of sets of genes, instead of examining a gene-by-gene basis. The objective of this study was to identify differential functionally annotated gene expression profiles associated with response to FOLFOX therapy in CRC tumors using gene-by-gene and GSA approaches. Methods: Genome wide expression profile data were collected on pre-treatment tumor tissues from patients with unresectable CRC receiving FOLFOX therapy (n = 83, Affymetrix HG U133A, GSE28702, Tsuji et al. BJC 2012). Gene expression was compared between responders (n = 42) and Non-responders (n = 41). GSA was conducted on 3272 curated gene sets from the Molecular Signatures Database (Subramanian, Tamayo et al. 2005, PNAS 102, 15545-15550) annotated by biological pathway, biochemical function and clinical behavior. Significant analysis of Microarray (SAM) and GSA (Tibshirani et al.) was done to identify gene sets associated with FOLFOX response. Results: Differential expressions of 23 genes were significantly associated with response, based on a single gene approach (p-value < 0.05). 13 of these were located on Chromosome 17 (p < 0.001). Among these, the top 5 ranked genes included NPEPPS, MBTD1, CEP44, LTA4H and CPNE4 which are involved in metal ion binding and aminopeptidase activity. GSA revealed only 44 out of 3272 gene sets were significantly associated with response, with a false discovery rate less than 25%. Increased expression of B-lymphocyte differentiation and Ras-signalling-related gene sets was associated with responders while mTOR signaling and hematopoietic stem cell-related genes set were associated with non-responders. Conclusions: Our data showed that differential biological pathways could be identified to predict response to FOLFOX therapy for CRC patients. Analysis may be useful to help define clinically relevant biologic subtypes among patients with metastatic colorectal cancer.
Evaluation of the prognostic utility of miRNA and multiple genetic markers in stage IIA colon cancer.
Authors: Mambo Elizabeth , Sanford Tiffany , Buddavarapu Kalyan , Adai Alex , Lebourgeois Paul A. , Rasmussan Karen , Garmire Lana
Published: March 2020

3630

Background: The variable prognoses of stage II colon cancer subjects have provoked a therapeutic dilemma of who should receive adjuvant therapy. Presently, prognosis is evaluated on often subjective histopathological features. Reliable, objective markers that can accurately predict recurrence risk are needed. Using retrospectively collected tumor samples with known clinical outcome, we evaluated the prognostic utility of miRNA together with clinicopathological features and molecular markers with suggestive prognostic value. Methods: We evaluated the expression of miRNA in 118 stage IIA FFPE tumors (73 non-recurrent, NR; 45 recurrent, R) using the Affymetrix Gene Chip V1.0 microarray, and performed RT-qPCR to verify select miRNAs. We also sequenced KRAS codons 12/13, and BRAF codon 600, and assessed MSI status using a fluorescent PCR-based assay. MMR protein expression was determined by IHC. An empirical approach was applied to screen miRNA using combinatorial criteria of microarray 2-way ANOVA analysis, Kaplan-Meier curve logrank, and single and multivariate Cox-regression. miRNA was the most significant predictor among all histopathological and molecular features (FDR<0.05). A miRNA classifier was built with nested two-layer cross-validation. Results: The top miRNA model was selected based on AUC estimates and Cox-regression p-value. This model included 30 miRNAs; 25 of these were common with the empirical approach, confirming the robustness of candidate selection. The miRNA classifier distinguished R from NR cases with an AUC of ~0.74. Among all histopathological and molecular features evaluated, grade was significantly associated with disease-free survival (logrank p<0.05). Both single variate and multivariate Cox analysis revealed that grade and PMS2 status were strongly associated with recurrence (p<0.05). Lastly, lack of expression of PMS2 and MLH1, BRAF V600E and MSI was highly correlated (Φ coefficient > 0.6), and associated with non-recurrent disease. Conclusions: These data provide strong support for miRNAs as independent prognostic biomarkers for stage IIA colon cancer.Validation work is ongoing to demonstrate the potential utility of these miRNAs in patient stratification.
Adverse prognostic impact of heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma (EAC).
Authors: Yoon Harry H. , Shi Qian , Sukov William R. , Sattler Christopher A. , Wiktor Anne E. , Wu Tsung-Teh , Diasio Robert B. , Jenkins Robert B. , Sinicrope Frank A.
Published: March 2020

4009

Background: HER2 expression in upper digestive cancer is reported to be heterogeneous, which substantially affects interpretation of HER2 positivity in the clinic. Yet the frequency and prognostic impact of HER2 genetic heterogeneity and polysomy 17 (poly17) are unknown in EAC. Methods: HER2 amplification (fluorescence in situ hybridization) and protein expression were examined in untreated surgical EAC specimens (N = 661) at Mayo Clinic. HER2 genetic heterogeneity was defined per ASCO/CAP as amplification (HER2/CEP17 ratio ≥ 2) in 5-50% of cancer cells; poly17 refers to ≥ 3 copies of chromosome 17. Most tumors were T3-4 (68%) or lymph node (LN)-positive (73%). Cox models were used to assess disease-specific (DSS) and overall survival (OS). Results: HER2 amplification was detected in 117 of 661 EACs (18%), of which 20 (17%) showed HER2 heterogeneity. HER2 heterogeneous tumors had a significantly higher frequency of poly17 and high tumor grade. HER2 heterogeneity by amplification vs expression were correlated. Since heterogeneity was limited to HER2-amplified tumors, survival analysis was stratified by amplification status. In multivariable analysis, only HER2 heterogeneity and metastatic LN number were prognostic (Table). Conclusions: Among HER2 amplified EACs, 17% show HER2 heterogeneity, which is associated with increased poly17 and independently predicts 2-fold higher risk of cancer-specific death. Among HER2-nonamplified cases, poly17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and evaluation of benefit from HER2 targeted therapy. [Table: see text]
Impact of insulin-like growth factor 1 receptor (IGF1R) and amphiregulin (AREG) expressions on survival in patients with stage II/III gastric cancer enrolled in the ACTS-GC study.
Authors: Ichikawa Wataru , Terashima Masanori , Ochiai Atsushi , Kitada Koji , Kurahashi Issei , Sakuramoto Shinichi , Katai Hitoshi , Sano Takeshi , Imamura Hiroshi , Sasako Mitsuru
Published: March 2020

4012

Background: Exploratory biomarker analysis was conducted to identify factors related to outcomes of patients enrolled in the ACTS-GC study, a randomized controlled trial comparing adjuvant S-1 administration with surgery alone in 1,059 patients with stage II/III gastric cancer. Methods: Formalin-fixed paraffin-embedded surgical specimens were retrospectively examined in 829 patients (78.3%), and 63 genes involved in pyrimidine metabolic pathway, growth factor signaling pathway, apoptosis, DNA repair, etc., were analyzed by quantitative real-time RT-PCR after TaqMan assay-based pre-amplification. Gene expression levels were normalized to the geometric mean expressions of GAPDH, ACTB, and RPLP0, used as reference genes. The expression of each gene was categorized into low and high values at those median. The impacts of gene expression on survival were analyzed using the 5-year survival data of the ACTS-GC. The Benjamini and Hochberg procedure was used to control the false discovery rate (FDR). Results: Among 63 screened genes, IGF1R and AREG most strongly correlated with overall survival (OS), with FDR of 0.0048 and 0.018, respectively. OS was significantly worse in IGF1R high patients than in IGF1R low patients, but better in AREG high patients than in AREG low patients. The hazard ratio (HR) for death in the analysis of OS (S-1 vs. surgery alone) was lower in the high IGF1R group (HR, 0.55; 95%CI, 0.40-0.76) than in the low IGF1R group (HR, 0.72; 95%CI, 0.49-1.06). Likewise, the HR for death in the analysis of OS (S-1 vs. surgery alone) was much smaller in the low AREG group (HR, 0.57; 95%CI, 0.41-0.79) than in the high AREG group (HR, 0.74; 95%CI, 0.51-1.08). Interactions were not statistically significant. Conclusions: IGFR1 gene expression was associated with poor outcomes after curative resection of stage II/III gastric cancer, whereas AREG gene expression was associated with good outcomes. No interaction for survival was evident between S-1 and these gene expressions.
Updated results of the GEST study: Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer in Japan and Taiwan.
Authors: Fukutomi Akira , Okusaka Takuji , Sugimori Kazuya , Ueno Hideki , Ioka Tatsuya , Ohkawa Shinichi , Boku Narikazu , Yamao Kenji , Mizumoto Kazuhiro , Furuse Junji , Funakoshi Akihiro , Hatori Takashi , Yamaguchi Taketo , Egawa Shinichi , Sato Atsushi , Ohashi Yasuo , Cheng Ann-Lii , Tanaka Masao
Published: March 2020

4035

Background: The GEST study (Ioka et al. ASCO 2011, Abstract 4007) demonstrated the non-inferiority of S-1 to GEM with respect to the primary endpoint of overall survival (OS) in patients with pancreatic cancer (PC). We now report the updated results of this study. Methods: The GEST study was a randomized, 3-arm, phase III study. Chemotherapy-naive patients with unresectable advanced PC, an ECOG Performance status (PS) of 0-1, and adequate organ functions were randomly assigned to receive GEM (1000 mg/m2, iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w), or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint was OS, used to assess the non-inferiority of S-1 and the superiority of GS to GEM. Patient information was updated in July 2011. Results: At the time of this follow-up analysis, median follow-up was 29.8 months with 795 OS events, compared with 18.4 months with 710 OS events out of 832 patients at the previous analysis. Median OS was 8.8 months (95% CI: 8.0–9.7) in the GEM group and 9.7 months (95% CI: 7.6-10.8) in the S-1 group (HR=0.96, 97.5% CI: 0.79-1.17, p<0.001 for non-inferiority), which is consistent with prior results (HR=0.96, 97.5% CI: 0.78-1.18, p<0.001). In the GS group, median OS was 9.9 months (95% CI: 9.0-11.2). The HR was 0.91 (97.5%CI: 0.75-1.11, p=0.28 for superiority versus the GEM group). On subgroup analysis, GS was associated with a non-statistically significant trend toward better OS compared with GEM among patients with locally advanced disease and those with a PS of 1. Median OS was 12.7 months (95% CI: 9.7–14.9) in the GEM group and 15.9 months (95% CI: 13.0-19.7) in the GS group (HR=0.72, 95% CI: 0.51-1.03) among patients with locally advanced disease, and 6.2 months (95% CI: 4.9–8.3) in the GEM group and 9.6 months (95% CI: 8.0-10.9) in the GS group (HR=0.62, 95% CI: 0.46-0.83) among patients with a PS of 1. Conclusions: The non-inferiority of S-1 to Gem in terms of the primary endpoint of OS was reconfirmed. Monotherapy with S-1 can be used as one of the standard treatments for advanced PC. As for GS therapy, there is room for further investigation.
A phase II multi-institutional study to evaluate gemcitabine and fractionated stereotactic body radiotherapy for unresectable, locally advanced pancreatic adenocarcinoma.
Authors: Herman Joseph M. , Chang Daniel Tandel , Goodman Karyn A. , Wild Aaron Tyler , Laheru Dan , Zheng Lei , Diaz Luis A. , Le Dung Thi , Raman Siva P , Leal Jeffrey P , Chaudhry Muhammad Ali , Sugar Elizabeth , Columbo Laurie Ann , Tom Ashlyn , Limaye Maneesha R , Edil Barish H , Oteiza Katharine , Hacker-Prietz Amy , Wolfgang Christopher Lee , Koong Albert
Published: March 2020

4045

Background: Phase I/II studies with single-fraction (25 Gy) stereotactic body radiotherapy (SBRT) for pancreatic ductal adenocarcinoma (PDA) have shown local progression free survival (LPFS) rates of >90%, but are limited by late GI toxicity and minimal tumor response. We performed a phase II multi-center trial of gemcitabine (GEM) and fractionated SBRT to determine if a high rate of LPFS with reduced toxicity could be achieved. Methods: After multidisciplinary review, 32 pts with locally advanced PDA received GEM in sequence with SBRT (6.6 Gy in 5 consecutive daily fractions, 33 Gy total). LPFS, metastasis free survival (MFS), and overall survival (OS) were measured from date of tissue diagnosis. Objective tumor response (OTR) was assessed by RECIST/PERCIST. EORTC QLQ-C30/PAN26 questionnaires were used to measure QOL. Results: Median f-up was 12 mos (range, 2-23). Mean age was 69.9 yrs (SD, 9.8) and 62% were male. Pts received a mean of 2.2 (SD, 1.0) GEM doses prior to SBRT and 8.3 (SD, 5.6) doses total. All pts completed SBRT. Median OS was 15.9 months (95% CI, 12.7-18.8). Stratification by CA19-9 > or < 90 at diagnosis yielded a hazard ratio of 6.2 for > 90 (p=0.021). Median LPFS has not been reached and median MFS was 10.2 mos (95% CI, 2.9-17.5). LPFS rate at 1 year was 87%. OTR on CT was seen in 41%, while 41% had stable disease and 18% progressed. Tumor metabolic activity decreased in 17/18 patients with pre/post-SBRT PET available. Mean peak SUV was 4.0 pre-SBRT versus 2.4 post-SBRT (p=0.002). Median CA19-9 was reduced from 124.7 prior to SBRT to 43.9 afterwards. Acute toxicity included: grade 2 anorexia (37%), fatigue (28%), nausea (22%), abd pain (19%), weight loss (9%), diarrhea (3%); gr 3 nausea (9%); and gr 4 nausea (6%). Late gr ≥3 GI toxicity was seen in 9%. Mean QOL score 4 wks post-SBRT was similar to baseline (p=0.38). At 6 mos there was a trend towards improved QOL (p=0.07). Conclusions: Fractionated SBRT with GEM achieves high rates of LPFS and tumor response. Minimal grade ≥3 acute and late toxicity was observed. SBRT is more likely to benefit patients with Ca-19-9 <90. A combination of SBRT with more aggressive chemotherapy may further improve outcomes.
Addition of algenpantucel-L immunotherapy to standard of care (SOC) adjuvant therapy for pancreatic cancer.
Authors: Hardacre Jeffrey M , Mulcahy Mary Frances , Small William , Talamonti Mark S. , Obel Jennifer Carrie , Rocha Lima Caio Max S. , Safran Howard , Lenz Heinz-Josef , Chiorean E. Gabriela , Vahanian Nicholas N. , Link Charles J.
Published: March 2020

4049

Background: Resected pancreatic cancer carries a one year survival rate of ~65%. Algenpantucel (HyperAcute-Pancreas, HAPa) exploits the hyperacute rejection mechanism of xenotransplantation by administering genetically modified, irradiated, allogeneic tumor cells expressing aGal moieties on their surface. We propose that addition of algenpantucel-L to SOC adjuvant therapy may improve survival for patients with resected pancreatic cancer. Methods: Open-label, dose-finding, Phase 2 study (16 sites) evaluating HAPa (100/300 M cells / dose) + SOC (RTOG-9704: Gemcitabine + 5-FU-XRT) for resected pancreatic cancer patients. Primary endpoint: 1-year disease-free survival (DFS). Secondary Endpoints: overall survival (OS), toxicity and immunologic analysis. Results: : 70 patients, median age 62 years, 47% female, 81% lymph node positive, median tumor size 3.2 cm, and 17% post-operative CA 19-9 ≥ 180 received SOC + HAPa. 1-year DFS of 63% and OS of 86% compares favorably to historical controls (~45%% and 65%, respectively) for this high risk population. Subgroup analysis of patients receiving 300M cells /dose shows a higher 12-month DFS compared to 100M cells/dose, 81% vs. 52% (p = 0.02). Likewise, patients receiving 300M cells/dose tended to better 1-year survival compared to a 100M cells/dose, 96% vs. 80% (p = 0.053). Forty-four (63%) developed strong (G1-G3) skin reactions at the injection sites including many long term survival patients with periodic skin flares at injection sites far beyond their last vaccination. In 13/45 (29%) tested patients, an increase of >30% in anti-mesothelin Ab titer was seen after immunization. Thirty-nine (56%) presented with eosinophilia (range: 5- 45%), including one patient with persistent eosinophilia and stable lung metastasis for over 2 years. Conclusions: Addition of HAPa to standard adjuvant therapy for resected pancreatic cancer shows promising immunological activation and may improve survival. A multi-institutional, phase 3 study is currently underway.
Tumor IGF-1 expression as a predictive biomarker for IGF1R-directed therapy in advanced pancreatic cancer (APC).
Authors: Javle Milind M. , Shroff Rachna T. , Varadhachary Gauri R. , Wolff Robert A. , Fogelman David R. , Bhosale Priya , Wang Xuemei , Kar Siddhartha P. , Overman Michael J. , Sathyanarayanan Sriram , Ayers Mark , Mauro David J. , Abbruzzese James L.
Published: March 2020

4054

Background: IGF-1 up-regulates PC proliferation and invasiveness through activation of PI3K/Akt signaling pathway and down-regulates PTEN. We investigated IGF-1 expression in tissue and blood as potential predictive markers in phase II study of IGF1R-directed monoclonal antibody, MK-0646 in APC. Prior phase I established the MTD of MK0646 at 5 mg/kg with gemcitabine (G) and erlotinib (E) and 10 mg/kg with G alone. Methods: Patients (pts) with stage IV, previously untreated APC, ECOG PS 0-1, adequate hematologic and organ function were enrolled. Arm A: G 1,000 mg/m2 over 100 min, weekly x 3, MK-0646 weekly x 4; Arm B: G 1000 mg/m2 and MK-0646 + E 100 mg daily. Arm C (control) was G 1,000 mg/m2 + E 100 mg. Cycles were repeated every 4 weeks. Pts were equally randomized in the 3 arms. Primary study objective was progression-free survival (PFS). Pre-treatment peripheral blood samples were measured for IGF-1 level by ELISA; archival core biopsies were analyzed for IGF-1 mRNA expression. RNA extraction from FFPE samples used Roche Transcriptor First Strand cDNA Synthesis Kit. TaqMan PreAmp technique was used to amplify target cDNA prior to TaqMan RT-PCR analysis. Cox proportional hazards model for PFS analyzed the interaction between tissue IGF-1 expression and treatment. Results: 50 pts were enrolled (A=15, B=16,C=16 pts, 3 ineligible). Median PFS of arms A, B and C were 5.5 months (95% CI: 3.9 – NA), 3.0 months (95% CI:1.8 – 5.6) and 2.0 months (95% CI: 1.8 – NA), respectively (log-rank test; p = 0.17). Median OS of A was 11.3 months (95% CI: 8.9 – NA), B 8.9 months (95% CI: 5.3 – NA) and C 5.7 months (95% CI: 2.0 – NA) (log-rank test; p = 0.44). 35 archival core biopsies were analyzed, 21 had adequate tissue for analysis. Using a Multivariable Cox proportional hazards model for PFS, where IGF-1 was dichotomized at the median, there was a 76% reduction in the risk of disease progression or death in arm A as compared with the control (arm C) at high IGF-1 level (p = 0.16). When IGF-1 was fitted as a continuous variable, this reduction was 96% (p = 0.08). There was no correlation between tissue and serum IGF-1. Conclusions: Tissue expression of IGF-1 level may represent a promising predictive biomarker for IGF1R-directed therapy in APC.
Phase II study of oxaliplatin and sorafenib in advanced gastric cancer after failure of cisplatin-fluoropyrimidine-based (PF) treatment.
Authors: Gallego Rosa , Martin-Richard Marta , Pericay Carles , Garcia-Foncillas Jesus , Queralt Bernardo , Casado Esther , Feliu Jaime , Vega Iranzazu , Juez Ignacio , Visa Laura , Saigí Eugeni , Garcia-Albeniz Xabier , Barnadas Agust , Maurel Joan ,   GEMCAD
Published: March 2020

4079

Background: PF-based chemotherapy is the standard first line treatment in advanced GC. Although some drugs as taxanes or oxaliplatin (Ox) have shown efficacy in combination with P or F, no established second line exists. RAF/MEK/ERK pathway activation as well as VEGF expression have been related with more advanced GC. Sorafenib (S) is a potent Raf and VEGFR inhibitor and Ox has demonstrated non-cross resistance with P. Methods: A multicenter phase II to evaluate the efficacy of OX- S combination in gastric or GEJ adenocarcinoma (pts) with progressive disease after CF based first line chemotherapy, was planned. Other inclusion criteria: ECOG 0-2, measurable disease and adequate organ function. Treatment doses were Ox 130mg/m2/3 weeks and S 800 mg/bid/d until progression or toxicity. CT scan evaluation every 3 cycles. The study followed a A-Hern single-stage design (HR = 1.67, median expected PFS of 4.3m if treatment ineffective, sample size: 43). The study was closed with the inclusion of 40 pts, maintaining a power > 87%. Ten pts would have to be alive and free of progression at 12m to consider the study positive. Results: Forty pts were included and evaluable for PFS. Thirty-six pts were evaluable for response. Median age was 63 ( range 39 - 76) years, ECOG 0/1/2 in 36/59/5 % of pts. PFS to 1st line was > 6m in 59% of pts. One CR and, 47.2% of SD were observed. Gr ¾ toxicity (%) was: neutropenia (9.8), thrombocitopenia (7.3), neurotoxicity (4.9) and diarrhea (4.9). Median PFS was 3 (95 %CI: 2.3-4.1 )m and median OS was 6.5 ( 95% CI: 5.2-9.6)m. PFS at 12 m was 0%. Median OS in pts with PFS to 1º line > 6m/ <6m was 9.7m and 5.6m respectively (p0.04). Conclusions: The combination of Oxaliplatin-Sorafenib in advanced GC patients previously treated with CF shows a safe profile but these results do not support the implementation of a phase III trial. Our results show that PFS under a CP-based first line therapy determine subgroups of GC patients with different clinical behaviors.
Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, and oxaliplatin with or without docetaxel, in elderly patients with locally advanced esophagogastric cancer.
Authors: Lorenzen Sylvie , Pauligk Claudia , Homann Nils , Schmalenberg Harald , Tauchert Felix , Jäger Elke , Al-Batran Salah-Eddin
Published: March 2020

4080

Background: The aim of this study was to determine feasibility and efficacy of perioperative chemotherapy in elderly, potentially operable esophagogastric cancer patients. Methods: Patients aged 65 or older with locally advanced esophagogastric adenocarcinoma were randomized to perioperative chemotherapy consisting of four preoperative and four postoperative cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) with or without docetaxel 50mg/m² (FLOT), every 2 weeks. Results: 44 patients with a median age of 70 years were randomized to either FLO (22) or FLOT (22) chemotherapy. In the FLO and FLOT group, 20 and 18 patients completed four cycles of preoperative chemotherapy and 17(77.3%) and 15(68.2%) patients proceeded to surgery, with 88.2% and 93.3% R0 resections, respectively. FLOT was associated with significantly more treatment-related NCI-CTC grade 3/4 adverse events, including neutropenia (p<.0001), leukopenia (p<.0001), stomatitis (p=0.02) and nausea (p=0.02) and a higher rate of patients experiencing a ≥10-points deterioration of EORTC QoL global health status scores (FLOT, 54%; FLO 23.1%) at 8 weeks. No perioperative mortality was observed, however postoperative morbidity was nearly doubled with the FLOT regimen (60% versus 35.3% for FLO), mostly due to wound infections in the FLOT group (20%). 11 (64.7%) and 9 (60.0%) of patients in the FLO/FLOT group were able to undergo postoperative chemotherapy. Compared with the FLO group, the FLOT group had a better response rate (61.9% vs. 18.2%) and a trend towards an improved median disease free survival (21.1 vs. 12.0 months; p=0.09). Conclusions: Age alone is not a contra-indication for the selection of patients for three-drug regimens in the multimodal treatment approach. FLOT seems to be more effective than FLO, but is associated with an increased toxicity and higher postoperative morbidity. Therefore, careful patient selection is warranted.
Lenalidomide for second-line treatment of advanced hepatocellular cancer (HCC): A Brown University Oncology Group phase II study.
Authors: Safran Howard , Charpentier Kevin , Kaubisch Andreas , Dubel Gregory , Perez Kimberly , Faricy-Anderson Katherine E. , Miner Thomas J. , Victor Joel , Taber Angela Marie , Bakalarski Pamela , Wingate Patti , Mantripragada Kalyan C , Luppe Denise , Rosati Kayla , Espat Joseph , Isdale Debora , Eng Yoko , Martel Diane , Berz David , Wands Jack
Published: March 2020

4098

Background: Lenalidomide inhibits fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF) and multiple tumor growth pathways. There is no standard of care for patients who progress after sorafenib. Therefore, we performed a phase II study to determine the activity of lenalidomide in second-line HCC therapy. Methods: Patients with advanced HCC who progressed on or were intolerant to sorafenib were eligible. Prior chemoembolization, RFA, or surgery were allowed. Eligibility criteria also included bilirubin <4 mg/dL, AST and ALT <5 times upper limit of normal, ECOG performance status 0-2, platelet count >60,000/mm3, absolute neutrophil count >1000/mm3, and creatinine <2mg/dL. Patients were treated with lenalidomide 25mg orally days 1-21 of a 28 day cycle until disease progression or unacceptable toxicities. The planned original sample size was 25 patients but when early activity was demonstrated the study was expanded to 40 patients. Results: The study has completed accrual of 40 patients. The median age was 60.5 years (17-88 years). Nineteen patients were Child-Pugh A, 16 patients were B, and 5 patients were C. Twenty four patients had extrahepatic disease. Preliminary data is available on the first 37 patients. One patient had grade 4 neutropenia. Grade 3 toxicities included ANC (n=2), fatigue (n=4), rash (n=2), arthritis (n=1), diarrhea (n=1), dehydration (n=2). One patient developed variceal bleeding which precipitated encephalopathy and death. Of the 32 patients with elevated baseline AFP, nine (28%) had a >50% reduction including one patient with a reduction in AFP from 56,900ng/ml to 5 ng/ml. Six of the first 37 patients (16%) had a radiographic partial response. Two patients achieved a complete response and have not progressed at 36 and 32 months. Conclusions: Lenalidomide can be administered to patients with advanced HCC and significant hepatic dysfunction. Promising, and in a small percentage of patients, dramatic and durable activity has been demonstrated. Investigations are underway to explore the mechanism of action of lenalidomide in HCC.
A phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Knox Jennifer J. , Qin Rui , Strosberg Jonathan R. , Kaubisch Andreas , El-Khoueiry Anthony B. , Bekaii-Saab Tanios B , Erlichman Charles
Published: March 2020

4099

Background: There is strong rationale to combine an m-TOR inhibitor (TEM) with a VEGF inhibitor (BEV) as a potentially active and well tolerated treatment for HCC. Both agents have shown modest single agent activity in HCC and so evaluated here in a phase II trial. Methods: A modified 2-stage Simon design planned 25 or 50 patients (pts) to test the null hypothesis that true tumor response rate is at most 10% andtrue 6-mo progression-free survival rate (PFS) (by RECIST) is at most 65%, or no better than single agent BEV (6 mo PR >2 pts or PFS 6 mo >18 out of 25.) Toxicity, TTP, PFS and survival were 2nd endpoints. Eligible pts had confirmed HCC with disease unresectable or amenable to other localised therapies, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR class of agents. TEM was administered at starting dose 25 mg IV d1,8,15,22 with BEV at 10mg/kg IV d 1, 15, all q 28 days (1 cycle). Imaging was q 8 wks. Results: From 09/09 to 09/11, 27 eligible pts were enrolled with 25 evaluable for toxicity and efficacy. Med age 59 yrs, 85% male, PS 0/1: 35/65, 58% metastatic, >85% BCLC stage C. With med 6 cycles (range 1-14) delivered, most pts (88%) experienced a grade 3+ adverse event (a/e.) Common grade 3 a/es related to treatment included thrombocytopenia (40%), neutropenia (20%), leucopenia (12%), fatigue (8%), anemia, mucositis, dyspnea, diarrhea, bleeds, fistula, infections (4% each). There was one possible treatment related death. Per protocol dose reductions/discontinuation for TEM-related a/es were most common. There were 2 confirmed PRs and 16 pts progression-free by 6 mos. A third pt developed a late PR at cycle 13. Median TTP on study was 6 mos, median PFS was 7.4 mos and median survival was 8.3 mos, with 13 pts still alive. Accrual closed at end of stage 1 as neither the number of responses nor the PFS at 6 mos passed the futility stopping rule set for this combination. Conclusions: This multicenter study is the first HCC trial evaluating the BEV/TEM doublet. Despite manageable toxicity, the ORR and 6 mo PFS did not surpass assumptions based on single agent BEV in HCC. Further study of BEV/TEM combination in this advanced HCC population is not recommended.
A phase II trial of MEK inhibitor BAY 86-9766 in combination with sorafenib as first-line systemic treatment for patients with unresectable hepatocellular carcinoma (HCC).
Authors: Lim Ho Yeong , Yen Chia-Jui , Tak Won-Young , Heo Jeong , Choi Hye Jin , Lin Cheng-Yao , Yoon Jung-Hwan , Hsu Chiun , Rau Kun-Ming , Poon Ronnie Tung Ping , Yeo Winnie , Park Joong-Won , Tay Miah Hiang , Hsieh Wen Son , Kappeler Christian , Rajagopalan Prabhu , Krissel Heiko
Published: March 2020

4103

Background: Sorafenib (S) is the only approved systemic treatment for unresectable HCC. Nevertheless, there remains an unmet medical need for more effective treatment options for this disease. BAY 86-9766 (B) is an oral, allosteric inhibitor of MEK, a key component of the MAP kinase pathway. This study evaluated the efficacy and safety of a combination therapy with B plus S in patients (pts) with HCC. Methods: This is a single arm, open-label, phase 2 study. Eligible were pts with unresectable HCC, Child-Pugh Class A, performance status (PS) 0-1, and no prior systemic anticancer therapy for HCC. Pts started Cycle 1 (21 days) with B 50 mg bid orally plus S 600 mg daily (200 mg AM, 400 mg PM) orally. If there was no hand-foot skin reaction, fatigue, or gastrointestinal toxicity ≥ grade 2, S was escalated to 400 mg bid from Cycle 2 on. Treatment continued until progression or withdrawal criteria were met. Tumor assessment was performed every 6 weeks during treatment. Safety was evaluated every week for the first 6 weeks and every 3 weeks thereafter. Results: Seventy pts from Asia started study treatment. Pts were predominantly male (86%); median age was 56 years; 54% had PS of 0 and 46% PS of 1. The vast majority had liver cirrhosis (83%) and infection with HBV (76%) or HCV (17%). Sixty-five were evaluable for efficacy per protocol. Three pts (5%) had confirmed partial response and 25 pts (38%) had prolonged stable disease (≥10 weeks), with a disease control rate of 43%. Median time-to-progression was 4.1 months. Survival data are not mature, yet. The most frequent drug-related adverse events (AEs) were rash (60%), diarrhea (59%), AST elevation (43%), vomiting (30%), nausea (29%), ALT elevation (26%), and anorexia (26%). There were 4 Grade 5 related AEs (hepatic failure, sepsis/hepatic encephalopathy, tumor lysis syndrome, and unknown cause, respectively). Dose modifications due to AEs were necessary in almost all pts. The median daily dose was 64.2 mg for B and 443.3 mg for S, respectively. Conclusions: B in combination with S showed antitumor activity in pts with HCC. However, frequent dose modifications due to AEs might have limited the treatment effect of this combination.
Adjuvant chemotherapy following curative intent hepatectomy for intrahepatic cholangiocarcinoma: Results from a multi-institutional analysis of 575 patients.
Authors: Ribero Dario , Pinna Antonio Daniele , Nuzzo Gennaro , Guglielmi Alfredo , Aldrighetti Luca , Giulini Stefano Maria , Gerunda Giorgio Enrico , Ponti Antonio , Tomatis Mariano , Leone Francesco , Aglietta Massimo , Berloco Pasquale , Calise Fulvio , Opocher Enrico , Gruttadauria Salvatore , Torzilli Guido , Capussotti Lorenzo
Published: March 2020

4110

Background: Surgical resection alone is the standard of care for patients with resectable intrahepatic cholangiocarcinoma (IHC). This study evaluates the benefit of adjuvant chemotherapy (AdjCTx) following curative intent hepatectomy for IHC. Methods: Clinicopathologic and long-term outcome data of 575 consecutive patients treated with curative intent hepatectomy for IHC (1995-2011) were extracted from a multi-institutional registry. After excluding operative mortality and M1 (n=46), Cox regression analysis was used to identify independent determinants of early recurrence (i.e., within 3 years). Propensity scores, which are used in observational studies to reduce selection bias by equating groups on the basis of relevant covariates, were calculated and utilized to match patients who had or had not AdjCTx (one-to-one match). Cases whose propensity score deviated more than 0.10 were considered unmatched and excluded from the analysis. Primary end-point was recurrence-free survival (RFS) at 3-years. Results: At a median FU of 42 months, 247 patients had recurred. Predictors of recurrence were LN metastases (HR 1.83 [1.36-2.44]), radical resection (HR 0.64 [0.45-0.9]), an elevated preoperative CA19.9 (HR 1.54 [1.15-2.07]), vascular invasion (HR 1.97 [1.49-2.61]), multiple tumors (HR 2.21 [1.71-2.86]), and size (analysed as continuous variable) (HR 1.01 [1.01-1.01]). After matching, no difference was observed between patients who had or had not AdjCTx (n=155 per group; 3-yrs RFS 28.3% vs. 38.0%, respectively; p=NS). When the analysis was restricted to patients who had gemcitabine, GEMOX or FOLFOX for 3 or more cycles (n=64 per group) again no difference emerged between patients who had or had not AdjCTx (3-yrs RFS 27.7% vs. 40.0% respectively, p=NS ). Conclusions: Our data suggest that AdjCTx following resection of IHC does not increase 3-years RFS.
A phase II trial of gemcitabine, irinotecan, and panitumumab in advanced cholangiocarcinoma, with correlative analysis of EGFR, KRAS, and BRAF: An interim report.
Authors: Sohal Davendra , Teitelbaum Ursina R. , Uehara Takeshi , Mykulowycz Kristine , Watt Christopher D. , Damjanov Nevena , Giantonio Bruce J. , Carberry Mary , Wissel Paul Stephen , Jacobs-Small Mona , O'Dwyer Peter J. , Sepulveda Antonia , Sun Weijing
Published: March 2020

4111

Background: Cholangiocarcinoma is an aggressive neoplasm. Current chemotherapy approaches achieve modest results. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan, in patients with advanced cholangiocarcinoma. Molecular analysis of EGFR pathway genes was planned as well. Methods: Patients with advanced (unresectable or metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate liver, kidney and bone marrow function were treated with panitumumab (9 mg/kg) on day 1, and gemcitabine (1000 mg/m2) and irinotecan (100 mg/m2) on days 1 and 8 of a 21-day cycle. Tissue specimens were collected at diagnosis for correlative molecular analyses. Primary objective is to evaluate the 5-month progression-free survival (PFS) rate. Secondary objectives include overall response rate (ORR), overall survival (OS) and toxicity of the combination. Mutational analysis of EGFR (del 19; 858), KRAS (codons 12, 13) and BRAF (V600E) was done on samples with adequate material for testing. Results: There have been 26 (of planned 42) patients recruited to the study. A median of 6 (0-30) cycles were administered. There were no treatment related deaths. The most common gr 3 or higher toxicities were neutropenia (10 pts, 38%), thrombocytopenia (10 pts, 38%), skin rash (10 pts, 38%) and diarrhea (3 pts, 12%). During the study, there were 3 CR, 6 PR, 10 SD (disease control rate of 90%), and 2 PD (by RECIST) in 21 evaluable pts. Two pts went on to have surgical resection. Median OS is 12.7 months. Of 13 testable samples, no EGFR or BRAF mutations were identified; however, there were 7 KRAS mutations. Retrospective analysis showed no difference in OS by KRAS mutation status. Conclusions: Interim evaluation of this ongoing study showed encouraging tolerability and efficacy of this regimen. Several patients have KRAS mutations; there appears to be no association with response, however. The pre-specified efficacy criteria to continue enrollment were met.
SWOG 0941: A phase II study of sorafenib and erlotinib in patients (pts) with advanced gallbladder cancer or cholangiocarcinoma.
Authors: El-Khoueiry Anthony B. , Rankin Cathryn J , Iqbal Syma , Micetich Kenneth C. , Kayaleh Omar , Lenz Heinz-Josef , Blanke C. D.
Published: March 2020

4113

Background: The treatment of pts with advanced biliary cancers represents a therapeutic challenge. The vascular endothelial growth factor and epidermal growth factor receptor pathways play an important role in biliary carcinogenesis, as evidenced by their up-regulation and prognostic impact. Methods: The primary objective was progression free survival (PFS) (improvement in PFS from 4 to 8 months); secondary endpoints included overall survival (OS), objective response rate, and toxicity. A two-stage design was used; if 13 or more eligible pts of the 25 initially accrued were alive without progression at 4 months, an additional 25 were to be accrued. Eligibility criteria included no prior treatment for advanced or metastatic disease, histologic diagnosis of gallbladder cancer or cholangiocarcinoma, presence of measurable disease, Zubrod performance status 0-1, AST/ALT ≤ 5 IULN, total bilirubin ≤1.5 IULN, adequate hematologic function. Pts were treated with sorafenib 400 mg PO BID and erlotinib 100 mg PO q daily continuously. Restaging scans were performed every 8 weeks. Results: 32 eligible pts were accrued. 30 pts were evaluable for response. 2 patients (7 %) had an unconfirmed partial response (95% CI:1%-23%), and 8 pts (27%) had stable disease. Median PFS was 2 months (95% CI: 2-3 months). 22/32 patients progressed or died within 4 months of registration. Median OS was 6 months (95% CI: 3 -7 months). The study failed to meet its primary endpoint to proceed to the second stage of accrual. There were 3 deaths on study, 1 of which was possibly related to treatment. 19 patients (59%) had grade 3 or 4 toxicities: AST/ALT (22%), bilirubin (16%), alkaline phosphatase (16%), hypertension (16%), diarrhea (9%), hepatic infection (6%). Conclusions: This multicenter study was the first to evaluate the combination of sorafenib and erlotinib in pts with advanced biliary cancers. Despite manageable toxicity, the study failed to meet its primary endpoint. Correlative studies on collected tissue and blood are ongoing; improved pt selection based on tumor biology and molecular markers is necessary for future evaluation of targeted therapies in this disease.
Multiparametric quantitative functional MRI for assessing early changes in volumetric functional tumor burden in hepatocellular carcinoma treated by intra-arterial therapies.
Authors: Gowdra Halappa Vivek , Bonekamp Susanne , Corona Villalobos Celia Pamela , Cosgrove David , Diaz Luis A. , Pawlik Timothy M , Geschwind Jean-Francois , Kamel Ihab R.
Published: March 2020

4114

Background: Hepatocellular carcinoma (HCC) is the most common primary malignant disease of the liver. Intra-arterial therapy (IAT) has been shown to improve survival and is commonly used in unresectable HCC. Assessing response to IAT as early as possible using objective criteria is paramount for clinical care. The purpose of this study was to evaluate volumetric diffusion weighted (DWI) and contrast Enhanced MR imaging (CE-MRI) changes for assessing early treatment response to IAT in hepatocellular carcinoma. Methods: This study included 177 lesions of HCC in 107 patients (85 Male, mean age 64 years) with BCLC A (19) B (44) C (36) D (8) treated by IAT. All patients had pre-IAT and 3-4 weeks follow up MRI with DWI and CE-MR. Tumors were segmented using semi automated software to provide volumetric functional analysis of DWI and CE- MRI as well as percent tumor burden. Statistical analyses include paired t-test, Kaplan-Meier curves, log rank test and multivariate analysis with cox model. Results: There was significant increase in volumetric ADC and significant decrease in volumetric arterial (AE) and venous (VE) enhancement after IAT. Patients with tumor burden of < 10% had improved survival compared to patients with high tumor burden of >10% (log rank p <.008 ) This survival benefit was larger among patients with tumor burden of < 10% who demonstrated an increase in volumetric ADC (>20%. Overall survival (OS) 33.5 mo) and decrease in volumetric VE (>50% OS 35.2 mo) compared to patients with high tumor burden >10% who no favorable response in ADC ( OS 14.1 mo) or VE (OS 16.5 mo) (Log rank p < .001) . In multivariate analysis factors associated with favorable prognosis were: increased ADC, (Hazard Ratio (HR) = 0.44, 95% CI =0.24 - 0.80) decreased VE, (HR = 0.43, 95% CI = 0.22 - 0.84) and BCLC A and B (HR = 0.31, 95% CI =0.18 - 0.54). Conclusions: Volumetric functional analysis of DWI and CE-MR are reliable imaging biomarkers of treatment response and tumor necrosis were able to differentiate responders and non responders. Early assessment of treatment response by volumetric functional MRI predicts prognosis in patients undergoing IAT in HCC.