bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of anti-IGF1 therapy on muscle mass in metastatic pancreatic cancer.
Authors: Fogelman David R. , Khalil Mohamed Aly , Hassan Manal , Garg Naveen , Javle Milind M. , Katz Matthew H. G. , Holmes Holly Michelle , Abbruzzese James L.
Published: March 2020

4064

Background: IGF-1 plays a role in the growth of multiple tumor types, including pancreatic cancer. IGF-1 also serves as a growth factor for muscle. The impact of therapeutic targeting of IGF-1 on muscle mass is unknown. Methods: We evaluated muscle mass at L3 in patients enrolled in a randomized phase II study of MK-0646 (M), a monoclonal antibody directed against the IGF-1 protein, in patients with metastatic pancreatic cancer (MPC). We used the Slice-o-matic (ver 4.3) software to segregate CT images into muscle and fat components and measured muscle area (cm2) at baseline and after 2 and 4 months of treatment. Patients received either gemcitabine with erlotinib (G+E), G+E+M, or G+M. Differences between the groups were compared using t-tests. Results: 58 patients had both baseline and 2 month imaging available for analysis. Of these, 44 received M and 14 had G+E only. Baseline muscle mass between the two groups was similar: 146 cm2 and 142 cm2, respectively (P=0.47). After two months of treatment, both groups demonstrated decrease in muscle mass: 134 cm2 (8% loss) vs. 130 cm2 (6% loss) (P= 0.19). Of the 37 patients who had either PR or SD at 2 months, there was a non-significant increase in muscle mass loss among the patients receiving M (7.8% vs. 4.5%, p=.31). At 4 months, those remaining patients in the M group lost 6% (n=14) of muscle mass compared to 3% in the non-M group (n=5) (P=0.54). Each 1% loss of muscle mass increased the odds of dropout by 13% (p=.03, CI 1.0-27%) and predicted for poor survival (p=HR 1.08, p=.02). Conclusions: MPC patients can be expected to lose muscle mass even while having clinical benefit (PR or SD) from chemotherapy. Muscle loss correlated with a risk of study drop-out and death. There was a non-significant trend towards greater muscle mass loss in patients on anti-IGF-1R therapy. However, it is unclear if this loss translates into functional differences between patients. Clinical trial information: NCT00769483.
Prognostic implications of signet ring cell histology in esophageal adenocarcinoma: A SEER database analysis
Authors: Yendamuri Saikrishna S. , Huang Miriam , Malhotra Usha , Warren Graham Walter , Bogner Paul , Nwogu Chukwumere E. , Groman Adrienne , Demmy Todd L.
Published: March 2020

4067

Background: Signet ring cell esophageal adenocarcinoma histology has been difficult to study in a single institution series because of its relative rarity, yet has an anecdotal reputation for poor prognosis. We examined the Surveillance Epidemiology and End Results (SEER) database to assess the prognostic implications of this esophageal adenocarcinoma subtype. Methods: All patients with esophageal adenocarcinoma in the SEER database from 2004 – 2009 were included. Characteristics of patients with signet ring cell histology were compared to those without it. Univariate and multivariate analyses examining the relationship of signet ring cell histology with overall survival (censored at 72 months) were performed in all patients, as well as those undergoing surgical resection. Results: 597 of 11,838 (5%) study patients had signet ring cell histology. Patients with signet ring cell histology were similar in age, race, and gender distribution, but had a higher grade (p<0.001) and higher stage (p<0.001) at diagnosis. In both all-comers as well as those undergoing surgical resection, univariate analyses showed a worse survival in patients with signet ring cell esophageal cancer (HR = 1.24; 95% CI 1.13-1.37 and HR = 1.57; 95% CI 1.29-1.92 respectively). In multivariate analyses adjusting for age, gender, grade, stage, and race, patients with signet ring cell cancer had a worse prognosis than those with non-signet ring cell adenocarcinoma (HR = 1.20; 95% CI 1.09 -1.33). In surgically resected patients, this remained a trend, but did not reach statistical significance (HR = 1.16; 95% CI 0.94-1.42). Conclusions: This large study of esophageal adenocarcinoma confirms the clinical impression that signet ring cell variant of adenocarcinoma is associated with an advanced stage at presentation and a worse prognosis independent of stage of presentation.
Nomogram for predicting the benefit of neoadjuvant chemoradiotherapy for esophageal cancer: A SEER-Medicare analysis.
Authors: Eil Robert , Diggs Brian S. , Wang Samuel J. , Dolan James P. , Hunter John G. , Thomas Charles R.
Published: March 2020

4073

Background: The impact of neoadjuvant chemoradiotherapy for esophageal cancer remains difficult to establish for specific patient (pt) populations. The primary aim of this study was to create a web-based prediction tool that provides individualized survival projections based on clinically relevant tumor and treatment data. Methods: Pts diagnosed with esophageal cancer between 1997 and 2005 were selected from the Surveillance, Epidemiology, and End Results (SEER) Medicare database. The covariates chosen for retrospective analysis were: sex, T and N stage, histology, total lymph nodes examined, and receipt of neoadjuvant chemotherapy (CT), radiotherapy (RT), or chemoradiotherapy (CRT). After weighting correction by treatment groups, a log logistic regression model for overall survival (OS) was selected based on goodness of fit analysis. Based on bootstrap resampling with 100 repetitions the Concordance Index (CI) was 0.703. Results: 1,128 resected esophageal pts that either did or did not receive neoadjuvant treatment were appropriate for analysis. On log logistic multivariate analysis: age, sex, T stage, N stage, number of lymph nodes harvested, receipt of neoadjuvant CRT, and receipt of chemotherapy were significantly associated with OS. All T stages greater than 1 benefitted from neoadjuvant CRT (p=<0.001). No T stage benefitted from isolated neoadjuvant CT or RT. Patients with nodal metastases benefitted from neoadjuvant CRT (p=<0.001) and CT (p=0.002). Conclusions: SEER-Medicare pts with resected esophageal cancer can be used to produce a survival prediction tool that can: 1) serve as a counseling and decision aid to pts and caregivers regarding their postoperative prognosis and 2) assist in research protocol design. Patients T2 or greater or with lymph node metastases benefitted from neoadjuvant CRT based on our data. This nomogram may underestimate the benefit of neoadjuvant CRT due to its variable downstaging effect on final pathologic stage. This web based tool is available for use at http://skynet.ohsu.edu/nomograms .
Safety, tolerability, and efficacy of the first-in-class antibody IMAB362 targeting claudin 18.2 in patients with metastatic gastroesophageal adenocarcinomas.
Authors: Schuler Martin H. , Zvirbule Zanete , Lordick Florian , Krilova Anna , Helbig Ulrike , Schulze-Bergkamen Henning , Thuss-Patience Peter C. , von Wichert Goetz , Schulmann Karsten , Trarbach Tanja , Bauer Stefan , Mueller Christian , Al-Batran Salah-Eddin , Huber Christoph , Sahin Ugur , Tureci Oezlem
Published: March 2020

4080

Background: IMAB362 is a monoclonal antibody targeting isoform 2 of the tight junction component claudin 18 (CLDN18.2), a tumor-selective antigen frequently expressed in several types of epithelial adenocarcinomas. Preclinically, IMAB362 exerts its antitumor activity by ADCC, CDC, induction of apoptosis and inhibition of cell proliferation. Methods: Patients with treatment-refractory, metastatic gastroesophageal adenocarcinomas with CLDN18.2-positive tumors as determined by immunohistochemistry were enrolled in two clinical trials of IMAB362 monotherapy. A phase I inter-patient single dose escalation study (n=15, 5 dose groups from 33 mg/m² to 1000 mg/m² with 3 patients each, follow-up 4 weeks) was conducted followed by a phase II study (n=34, 300 mg/m2 [n=4] and 600 mg/m2[n=30]) administered every two weeks for 5 courses, imaging in week 11. Patients with disease control allowed to continue IMAB362 therapy until progression. Analysis of the phase II trial is ongoing. Results: In the phase I trial, all dose levels of IMAB362 were generally well tolerated. Nausea and vomiting were the most common adverse events (AEs). No dose limiting toxicity was observed at single doses up to 1,000 mg/m². Based on pharmacokinetic considerations and preclinical dose/response data, the recommended doses for the phase II multidose trial was 600 mg/m². In the phase II study, 34 patients were evaluable for safety. No grade 4 AEs occurred, grade 3 AEs were vomiting (n=8, 24%), nausea (n=4, 12%) and hypersensitivity (n=1, 3%). As of January 2013, 31 patients were evaluable for efficacy analysis. Four patients had achieved a confirmed partial response, and eight patients had disease stabilization (ORR=13%, DCR=39%). The longest observed response duration thus far was 40 weeks. Conclusions: IMAB362 antibody therapy of patients with advanced CLDN18.2-positive gastroesophageal adenocarcinomas is safe and well tolerated. Early evidence for antitumoral activity was observed in the phase II trial. Further clinical evaluation of IMAB362 in patients with CLDN18.2 tumors is warranted. Clinical trial information: NCT01197885.
NeoHx study: Perioperative treatment with trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in patients with HER2 resectable stomach or esophagogastric junction (EGJ) adenocarcinoma—R0 resection, pCR, and toxicity analysis.
Authors: Rivera Fernando , Jiménez Paula , Garcia Alfonso Pilar , Lopez Carlos , Gallego Javier , Limon M. Luisa , Alsina Maria , Lopez-Gomez Luis , Galán Maica , Falco Esther , Manzano Jose Luis , González Encarnación , Serrano Raquel , Fernandez Parra Eva , Jorge Monica
Published: March 2020

4098

Background: Perioperative chemotherapy has demonstrated better OS and DFS than surgery alone in resectable stomach or EGJ adenocarcinoma. Trastuzumab has improved OS when added to chemotherapy in pts with HER-2 + metastatic gastric cancer and is interesting to explore its role in the perioperative setting. Methods: A Spanish, multicenter, open-label phase II study evaluated the efficacy and toxicity profile of perioperative XELOX-T (capecitabine 1000 mg/m2/12h po days 1-14, oxaliplatin 130 mg/m2 day 1, trastuzumab 8 mg/kg→ mg/kg day 1, q3w ; 3 preoperative cycles and 3 postsurgery cycles followed by 12 cycles of trastuzumab monotherapy) in patients with T1-2N+M0 or T3-4NxM0 resectable stomach or EGJ adenocarcinoma, HER-2+ ( IHQ3+ or IHQ2+/FISH+). The primary endpoint was 18 months DFS, secondary endpoint included pCR, R0 resection rate, ORR and toxicity of preoperative treatment (NCI CTC v3.0 criteria). Results: From June 2010 to March 2012, 36 pts were included: median age 65 (39-85); ECOG 0/1/2: 16/19/1 pts; localization: stomach 21 pts, EGJ 15 pts; histologic type: intestinal: 23 pts, diffuse: 4 pts, mixed: 1pt, not specified 8 pts; TNM: T 4: 7 pts; N+: 31 pts. Preoperative XELOX-T: Response: PR: 14 pts (39%), SD: 18 pts, PD: 0 pts, NE: 4 pts. G-3-4 toxicity (≥ 5% of pts): diarrhea 22% and asthenia 5%. Surgery was performed in 31 pts: R0: 28 pts (78%, 95% CI: 61-90%), R1: 1 pt, R2: 2 pts (1 had peritoneal carcinomatosis); pCR was observed in 7 pts (19 %; 95% CI: 8-36%) and 22 pts (61%) were pN0. Two pts died due to surgical complications,. We do not have mature data about postoperative XELOX-T yet. Follow-up is still too short for DFS and OS. Conclusions: This preliminary analysis suggests that perioperative XELOX+T in HER-2 positive resectable stomach or esophagogastric junction adenocarcinoma is feasible and has interesting activity. Clinical trial information: NCT01130337.
Determination of the optimal cutoff percentage of residual tumors to define the pathologic response rate (pathRR) of gastric cancer (GC) treated with preoperative therapy (JCOG1004-A).
Authors: Nakamura Kenichi , Kuwata Takeshi , Shimoda Tadakazu , Mizusawa Junki , Katayama Hiroshi , Kushima Ryoji , Taniguchi Hirokazu , Katai Hitoshi , Yoshikawa Takaki , Yabusaki Hiroshi , Kawashima Yoshiyuki , Kawabata Ryohei , Fukushima Norimasa , Iwasaki Yoshiaki , Tsuburaya Akira , Kinoshita Taira , Sano Takeshi , Sasako Mitsuru , Fukuda Haruhiko
Published: March 2020

4104

Background: PathRR is a common endpoint used to assess the efficacy of preoperative therapy for GC. PathRR is estimated based on the percentage of the residual tumor area in the preexisting tumor bed. Various cut-off definitions that have used for past studies (e.g. 10%, 33%, 40%, 50%, 67%) often impair the comparability of pathRRs between studies. Methods: Individual patient data from four JCOG trials evaluating preoperative chemotherapy were used (JCOG0001, irinotecan+cisplatin, n=55; JCOG0002, S-1, n=55; JCOG0210, S-1+cisplatin, n=50; JCOG0405, S-1+cisplatin, n=53). Pathological specimens were evaluated from 173 out of 188 patients (92%) who underwent surgery. Residual and preexisting tumor areas were traced on a virtual microscopic slide by one pathologist and another confirmed these areas. The hazard ratio (HR) in overall survival was calculated for each cut-off percentage by stratified Cox regression analysis including the study as a stratification factor, and concordance probability estimates (CPE) were also calculated. Results: The numbers of patients with 0-10%/11-33%/34-50%/51-66%/67-100% residual tumors were 43/33/27/23/47, respectively. Overall, HR was the largest in the 10% cut-off and CPE was the largest in 33%. When patients with R1/R2 resections were excluded, both HR and CPE were the largest in the 10% cut-off. In subgroup analyses, almost all cut-offs predicted survival well regardless of the histologic type (intestinal/diffuse), and no cut-off predicted survival for type 4 (linitis plastica type) tumors. Conclusions: PathRR is not recommended for clinical trials including type 4 tumors. The 10% cut-off is recommended for non-type 4 tumors, though 33% is also applicable. [Table: see text]
The Chinese subgroup from a randomized phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone as second-line treatment of HER2-amplified advanced gastric cancer (AGC) in Asian countries.
Authors: Sun Guo-ping , Sun Yan , Xu Rui-hua , Xu Jian-Ming , Li Jin , Wang Jin-Wan , Qin Shukui , Feng Ji Feng , Ba Yi , Shen Lin , Bai Yu-Xian , Sun Yihong , Pan Hongming , Cheng Ying , Yu Shiying , Zhong Haijun , Bai Li , Luo Rongcheng , Kobayashi Mikiro , Ohtsu Atsushi
Published: March 2020

4109

Background: TyTAN is a randomized phase III study to evaluate lapatinib (L) plus paclitaxel (P) in pretreated HER2 amplified (HER2+) advanced gastric cancer (AGC). The disease characteristics and GC treatment pattern differed in Japan and in China, so a subgroup analysis was done for subjects recruited in mainland China. Methods: AGC subjects with prior 5-FU and/or cisplatin and HER2 amplification by fluorescence in situ hybridization (FISH) in tumor tissue were randomized 1:1 to L (1500mg QD) and P (80mg/m2, Day 1, 8, 15 q4w) or P alone (80mg/m2, Day 1, 8, 15 q4w). 1st endpoint was overall survival (OS). 2nd endpoints included progression free survival (PFS), overall response rate (ORR) and safety. A total of 95 subjects recruited from mainland China. Results: TyTAN was not significant in OS (HR0.84), but 2 months OS improvement was observed in L+P arm. The results from Chinese subgroup are shown in the Table. The most common adverse events in Chinese subjects were similar as in whole population (neutropenia, diarrhea, rash, leukopenia, anemia, fatigue). Compare to the overall results, less Chinese subjects reported nausea and vomiting. Conclusions: This analysis showed that there were clear regional differences as observed between subjects in China and Japan. The addition of L to P was associated with a clinically meaningful benefit in subjects recruited from mainland China. These data warrants further prospective evaluations on the impact of regional differences in the outcome of HER+ GC in East Asian patients. Clinical trial information: NCT00486954. [Table: see text]
Hepatic arterial infusion for unresectable intrahepatic cholangiocarcinoma: An update on survival from two prospective clinical trials.
Authors: Konstantinidis Ioannis , Do Richard Kinh Gian , Gultekin David H. , Gonen Mithat , Schwartz Lawrence H. , Fong Yuman , Allen Peter J. , D'Angelica Michael Ian , DeMatteo Ronald P. , Klimstra David S. , Kemeny Nancy E. , Jarnagin William R.
Published: March 2020

4116

Background: Patients with unresectable intrahepatic cholangiocarcinoma (IHC) experience poor survival. This study summarizes the long-term outcome of two previously reported clinical trials using hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (Dex) (with or without bevacizumab (Bev)) in advanced IHC. Methods: Prospectively collected clinicopathologic and survival data were retrospectively reviewed. Disease response was based on RECIST. All patients underwent pre-treatment dynamic contrast enhanced MRI (DCE-MRI), and tumor perfusion data were correlated with outcome. Results: Forty-four patients were analyzed (FUDR=26, FUDR/Bev=18). At a median follow-up of 30 months, 41 patients had died of disease and 3 were alive. Partial response was observed in 48% of patients, and another 50% had stable disease. Three patients underwent resection after HAI and 84% received additional HAI after removal from the study. Median survival was similar in both trials (FUDR=29 months vs. FUDR/Bev=28.5 months p=0.96). Ten patients (23%) survived ≥3 years including 5 (11%) ≥ 5 years. Tumor perfusion, as measured on pre-treatment DCE-MRI (area under the gadolinium concentration curve (AUC180)), was significantly higher in ≥3-year survivors, and was the only factor that distinguished this group from <3-year survivors (mean AUC180 48.9mM.s vs 32.3mM.s, respectively; p=0.003). Time to liver progression was longer in ≥3-year survivors (19.8 months vs 11.2 months, respectively; p=0.02). Conclusions: HAI chemotherapy can result in prolonged survival in unresectable IHC. Pre-treatment DCE-MRI may predict response and survival. [Table: see text]
Cisplatin and gemcitabine for advanced biliary tract cancer: A meta-analysis of two randomized trials.
Authors: Mizuno Nobumasa , Valle Juan W. , Furuse Junji , Jitlal Mark , Beare Sandy , Wasan Harpreet , Bridgewater John A. , Okusaka Takuji
Published: March 2020

4120

Background: Two recent randomised studies (ABC-02 [UK] and BT22 [Japan]) have demonstrated the superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone for patients with pathologically-proven advanced biliary tract cancer (BTC: cholangiocarcinoma, gallbladder and ampullary cancers). Methods: We performed a meta-analysis of individual patient-level data of these studies to establish the effect of CisGem vs. Gem on progression-free survival (PFS), overall survival (OS) and performed exploratory sub-group analyses. Results: A total of 493 patients, median age 64 years (range 23-84 years) with approximately equal sex distribution, were randomised (ABC-02 study n=410; BT22 study n=83) to receive either CisGem (n=245) or Gem (n=248). CisGem demonstrates a significant improvement in PFS (hazard ratio (HR)=0.64 (95%-CI: 0.53-0.76), p<0.001) and OS (HR=0.65 (95%-CI: 0.54-0.78), p<0.001) over Gem. This effect is most marked in patients with good performance status (PS 0-1): HR for PFS is 0.61 (95%-CI: 0.51-0.74), p<0.001 and HR for OS is 0.64 (95%-CI: 0.53-0.77), p<0.001. CisGem resulted in improved PFS and OS for intra- and extra-hepatic cholangiocarcinomas and gallbladder cancer. The treatment effect between UK and Japanese patients was consistent with respect to OS (HR=0.65, 95%-CI 0.53–0.79 and 0.65, 95%-CI 0.42–1.03, respectively); with similar median survival in the combination arms (median 11.7 and 11.1 months, respectively). Subgroups least likely to benefit included patients with ampullary tumours and poor performance score (PS2). Conclusions: CisGem is the standard of care for the first-line treatment of good-PS patients with advanced BTC regardless of ethnicity. Future studies should aim to enhance the effectiveness of this regimen in the first-line setting and establish the role of subsequent (second-line) therapy. Clinical trial information: ABC-02: NCT00262769, BT22; NCT00380588.
Phase II trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Heo Jeong , Breitbach Caroline , Cho Mong , Hwang Tae-Ho , Kim Chang Won , Jeon Ung Bae , Woo Hyun Young , Yoon Ki Tae , Lee Jun Woo , Burke James , Hickman Theresa , Longpre Lara , Patt Richard H. , Kirn David H.
Published: March 2020

4122^

Background: Pexa-Vec is a vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Pexa-Vec was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol 2008; Nature 2011). Preclinical and clinical data suggest that Pexa-Vec-induced acute vascular disruption sensitizes tumors to anti-angiogenic effects of sorafenib (Mol Ther 2011). Methods: Treatment-refractory HCC patients received Pexa-Vec for 3 weeks (Day 1 IV, Day 8 IT and Day 22 IT) followed by sorafenib at Day 25. The primary objective of the study was to determine the safety of Pexa-Vec followed by sorafenib. Secondary objectives include disease control rate based on mRECIST and Choi (hypodensity) response criteria after Pexa-Vec only (Day 25) and after sorafenib initiation (Week 6 and 12). Optional assessments included response by positron-emission tomography (PET). Data summarized prior to database lock. Results: Enrollment is completed: 25 patients of which 20 were refractory to sorafenib. The treatment regimen was well-tolerated. Transient flu-like symptoms, including fever (n=23; 92%), chills (n=19; 76%), headache and nausea (n=10; 40%), abdominal pain and lymphopenia (n=10; 40%) were the most common adverse events following Pexa-Vec. Sorafenib toxicities were consistent with the expected profile. After Pexa-Vec alone the Choi tumor response rate was 47%. Following subsequent sorafenib therapy, 75% had Choi responses, including 81% of sorafenib-failure patients. The mRECIST disease control rate was 62% with Pexa-Vec alone and 59% following initiation of sorafenib. Two of 4 patients evaluable for PET response exhibited decreased PET signal after Pexa-Vec. Conclusions: Pexa-Vec was well-tolerated and associated with Choi tumor responses and disease control in patients with advanced HCC. Subsequent sorafenib was well-tolerated and associated with Choi responses. Further trials of Pexa-Vec in HCC patients are warranted. Clinical trial information: NCT01171651.
Prospective phase II trial of sorafenib combined with doxorubicin eluting bead-transarterial chemoembolization for patients with unresectable hepatocellular carcinoma: Efficacy analysis.
Authors: Geschwind Jean-Francois , Feng Allen , Reyes Diane K. , Kamel Ihab R. , Gowdra Halappa Vivek , Corona-Villalobos Celia Pamela , Cosgrove David , Pawlik Timothy M.
Published: March 2020

4124

Background: This study reports the final analysis (n=50) of a prospective phase II study evaluating the efficacy of the combination of sorafenib and doxorubicin eluting bead transarterial chemoembolization (DEB-TACE) in patients with unresectable hepatocellular carcinoma (HCC). Methods: Protocol consisted of 6-week cycles with sorafenib at 800 mg/day beginning 1 week prior to DEB-TACE; up to 4 DEB-TACE treatments within 6 months. Tumor response was assessed by RECIST and EASL criteria using MRI at baseline and at 1 month follow-up. Time to untreatable progression (TTUP) was defined as the interval from initiation of sorafenib therapy until inability of patient to further receive intra-arterial therapy. Overall survival (OS) and TTUP were calculated with the Kaplan-Meier method; outcomes were stratified by BCLC A/B and C and compared with the log-rank test. Results: DEB-TACE + sorafenib successfully performed in 50 patients: mean 62yrs (range, 31-88 yrs), Child-Pugh A/B (92%/8%), BCLC A/B/C (10%/28%/62%), ECOG 0/1 (52%/48%), HCV/HBV (44%/8%), mean tumor burden 20%, mean tumor size 7.2cm (range, 1–17.6), and mean tumor enhancement 78%. Patients were enrolled for a median of 3 (range, 1-22) cycles including a median of 1 (range, 0-6) DEB-TACE procedure. Median dose regimen was 400mgQD and the median dose taken while on study was 318 mg/day (range, 100-800). 1 month follow-up showed a mean tumor enhancement reduction of 48.2% (n=46, p<0.001) and an average reduction in lesion diameter of 8.5%(n=48, p=0.02). The Disease Control Rate was 98% using the EASL amendment and RECIST. Median TTUP was 11.9 mths (95% CI, 1.8-22 mths) with a significant difference between BCLC A/B (median 22.9 mths) and BCLC C (median 6.2mths) patients (log-rank, p=0.01). Median OS was 24.5 mths (95% CI, 14.3-35 mths) with a significant difference between BCLC C (median 17.1 mths) and BCLC A/B (median 33.7 mths) patients (log-rank, p=0.001). Conclusions: The results of this phase II study suggest a potential benefit to the combination of sorafenib and DEB-TACE. Single arm and non-randomization are limitations of the study. Clinical trial information: NCT00844883.
Circulating oncometabolite 2-hydroxyglutarate (2HG) as a potential surrogate biomarker in patients with isocitrate dehydrogenase mutant (IDHm) intrahepatic cholangiocarcinoma (ICC).
Authors: Goyal Lipika , Borger Darrell R. , Yau Thomas , Poon Ronnie Tung Ping , Ancukiewicz Marek , Christiani David C. , Liebman Hannah M. , Yen Katharine , Straley Kimberly , Agresta Samuel V. , Faris Jason Edward , Kwak Eunice Lee , Clark Jeffrey W. , Ryan David P. , Tanabe Kenneth , Deshpande Vikram , Jain Rakesh K. , Iafrate Anthony John , Duda Dan G. , Zhu Andrew X.
Published: March 2020

4125

Background: Mutations in the genes encoding for IDH1 and IDH2 occur in ~20% of ICC patients (pts), and they lead to the production of the oncometabolite 2HG. We examined whether serum 2HG levels in IDHm ICC pts may 1) serve as a surrogate biomarker for IDH status, 2) correlate with tumor burden, and 3) correlate with circulating proangiogenic biomarkers. Methods: Blood samples from 33 ICC pts [11 IDHm, 22 IDH wild-type (IDHwt)] of different AJCC stages from MGH and 39 surgically resected ICC patients (7 IDHm, 32 IDHwt) from HKU were analyzed for serum 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry. Eight circulating proangiogenic biomarkers were measured in plasma using multiplex ELISA. Results: In the MGH cohort, median serum 2HG levels were significantly elevated in IDHm (478 ng/ml [interquartile range 174–643]) versus IDHwt ICC pts (118ng/ml [68–160])(p<0.001). Similarly, in the HKU cohort, the pre-resection median serum 2HG levels were significantly elevated in IDHm (343ng/ml [192–596]) versus IDHwt ICC pts (56ng/ml [42–81]) (p<0.0001). The area under ROC curve for prediction of an IDH mutation using 2HG was 93%; with a threshold of 2HG≥170ng/ml, the sensitivity was 83% and specificity was 90%. IDH2 mutations were more frequent in the HKU cohort (3/7, 43%) compared with the MGH cohort (0/11, 0%) (p<0.05), but 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. 2HG levels correlated directly with tumor burden (Spearman’s rho=0.89; p<0.05) in the HKU cohort. Median plasma levels of PlGF—a growth factor from the VEGF-family—were higher in IDHm (35pg/ml [33–40]) versus IDHwt ICC pts (median 26pg/ml [24–34]) from the HKU cohort (p<0.05). No other associations were seen between proangiogenic biomarkers and IDH status. Conclusions: IDHm ICC pts had significantly higher serum 2HG levels compared to IDHwt ICC pts. High serum 2HG correlated with increased tumor burden. Pre-resection circulating PlGF levels were higher in IDHm ICC versus IDHwt pts. These data support further exploration of circulating 2HG as potential surrogate and response biomarker in IDHm ICC.
Final analysis of GIDEON (Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma [HCC] and of Its Treatment with Sorafenib [Sor]) in >3000 Sor-treated patients (pts): Clinical findings in pts with liver dysfunction.
Authors: Marrero Jorge A. , Lencioni Riccardo , Ye Sheng-Long , Kudo Masatoshi , Bronowicki Jean-Pierre , Chen Xiao-Ping , Dagher Lucy , Furuse Junji , Geschwind Jean-Francois , Ladrón de Guevara Laura , Papandreou Christos , Sanyal Arun J. , Takayama Tadatoshi , Yoon Seung Kew , Nakajima Keiko , Venook Alan Paul
Published: March 2020

4126

Background: GIDEON is a prospective, non-interventional study. Completion of GIDEON creates a large, global database of >3000 Sor-treated unresectable HCC (uHCC) pts, allowing for evaluation of a broad pt population, including Child-Pugh (CP) B pts with more advanced liver dysfunction. Methods: Baseline characteristics were collected in pts for whom a decision to treat with Sor had been made in clinical practice. Adverse events (AEs), dosing, and outcomes data were collected during follow-up. Results: 3,202 pts were evaluable for safety. Overall, the incidence of AEs and drug-related (DR) AEs was similar across CP subgroups, although serious AEs (SAEs) were more common in CP-B than CP-A pts. The rate of DR AEs (event per patient-year) was also comparable between CP-A and CP-B pts. The average daily Sor dose was slightly higher in CP-B than CP-A pts; duration of treatment was longer in CP-A (Table). In the intent-to-treat population (n=3,213), median overall survival (OS) (months [95% CI]) was longer in CP-A (13.6 [12.8-14.7]) than CP-B pts (5.2 [4.6-6.3]); time to progression was similar: CP-A (4.7 [4.3-5.2]); CP-B (4.4 [3.5-5.5]). Median OS was shorter in pts with a higher CP-B score: 7 (6.2 [4.9-8.7]); 8 (4.8 [4.1-6.9]); 9 (3.7 [3.0-5.1]). Conclusions: Sor safety and dosing during treatment are generally consistent across pts irrespective of liver function. As anticipated, CP status is a strong prognostic factor for OS in uHCC pts. [Table: see text]
Diagnostic utility and prognostic performance of a 92-gene cancer classifier to molecularly profile periampullary adenocarcinomas (PAA).
Authors: Overman Michael J. , Wang Huamin , Schnabel Catherine A. , Anderson Jeffrey , Erlander Mark G. , Wolff Robert A. , Varadhachary Gauri R.
Published: March 2020

4133

Background: Due to the small anatomic size, multiplicity of epitheliums, and suboptimal diagnostics determining the site of origin of PAA is a challenge. We investigated the ability of a 92-gene RT-PCR assay (CancerTYPE ID) to categorize PAA and to prognostically stratify ampullary adenocarcinomas. Methods: 171 PAA patients who underwent pancreaticoduodenectomies were included; samples were histopathologically verified for tumor subtype determination: pancreatic (PAN), extrahepatic biliary (EB), ampullary (AMP), or duodenal (DOUD). Blinded FFPE tumor sections underwent molecular testing. Analytical sets were an initial 45 PAA set evaluating concordance to histopathological tumor types and prognostic performance, and a second set of 126 AMP and DOUD adenocarcinoma for validation of prognostic performance. Results: Of the initial 45 patient cohort, molecular classification of 43 (96%) evaluable samples (13 AMP, 10 PAN, 10 EB, 10 DOUD) showed 91% concordance: AMP [5 intestinal (int), 7 pancreaticobiliary (pb)], PAN [10 pb], DOUD [3 int, 7 gastroesophageal (ge)], EB [7 pb]. The 92-gene assay was prognostic with a median OS of 70 m for ge/int cases vs. 32 m for pb cases, P=0.05. Discordant classifications were ge for 1 AMP and 2 EB samples, and ovary for 1 EB case. Previous unsupervised RNA hierarchical clustering (Overman GI ASCO 2011 a161) of all 13 AMP cases had identified two prognostic groups (a good-prognosis int-like and a poor-prognosis pb-like), which were identical to the 92-gene classification for 12 of the 13 cases. Conclusions: In the initial cohort of 45 patients, the 92-gene assay demonstrated diagnostic utility for molecular site-of-origin classification of PAA; evaluation of the remaining 126 ampullary and duodenal cases will be presented. Results support exploration of this approach for the management of metastatic PAA (in which pathologic review of a primary resection specimen is not an option). Molecular classification of ampullary adenocarcinomas into intestinal and pancreaticobiliary subgroups is prognostically relevant; these and the gastric-like molecular profile of duodenal adenocarcinomas may have therapeutic implications.
Impact of multidisciplinary therapy on high-grade appendiceal adenocarcinoma (AA).
Authors: Beaty Karen A. , Royal Richard E. , Fournier Keith F. , Taggart Melissa W. , Overman Michael J. , Phillips Jonathan , Rafeeq Safia , Mansfield Paul F. , Wolff Robert A. , Eng Cathy
Published: March 2020

4134

Background: AA is a rare malignancy ranging from well-differentiated to poorly differentiated carcinoma, including those with signet ring cells. Optimal therapy for low grade peritoneal disease is cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC). However, some patients (pts) are suboptimal for CRS/HIPEC, and are considered for systemic chemotherapy (SC) alone, or SC + CRS. In light of our previously reported overall survival (OS) benefits for the role of SC in metastatic AA, here we explore the impact of surgical intervention on OS in these pts. Our aim was to clarify the OS benefit of multidisciplinary therapy (SC + CRS + HIPEC) in those pts with aggressive tumor biology. Methods: A retrospective chart review of AA pts registered in our tumor registry between Jan. 2005 to Dec. 2009 was undertaken to identify patients with AA who received SC. Electronic medical records (EMR) were reviewed for CRS, HIPEC, histology, SC, and OS. The K-M method and Log-Rank test were used for statistical analysis. Results: Of 143 AA pts, 52 (36%) pts were high grade with 33 (23%) having signet ring cells. After a median follow-up of 35M, high grade tumors were noted to have worse OS overall (24M vs 56M, p<.001). When comparing treatment received, and adjusting for tumor biology, those pts with high grade disease again fared worse, and experienced comparatively worse OS. However, those treated with SC + CRS + HIPEC experienced the longest median survival. Conclusions: Pts with peritoneal disease from high grade AA who completed SC with CRS + HIPEC experienced prolonged OS compared to those treated by SC +/- CRS. Our data suggest that SC + palliative CRS offers minimal benefit for high grade disease. Selection bias influences these results heavily; as those who do well proceed to complete all components of therapy. A treatment plan that includes SC + CRS + HIPEC can result in durable survival, and is a strategy that warrants further study emphasizing the importance of multidisciplinary management. [Table: see text]
Molecular characterization of nonpancreatic neuroendocrine neoplasms (NENS): First description of mutations in the tumor suppressor gene (TSG) SMARCB1 in NENS of colorectal origin using next-generation sequencing (NGS).
Authors: Capdevila Jaume , Landolfi Stefania , Jimenez Jose , Grande Enrique , Castellano Daniel E. , Barriuso Jorge , Teixido Cristina , Silberschmidt Daniel , Montero Maria Angeles , Palmer Hector G. , Felip Enriqueta , Tabernero Josep , Vivancos Ana
Published: March 2020

4135

Background: The knowledge of molecular aberrations that characterize the different types of NENS is still limited. Recent exome sequencing data has allowed the definition of the genetic basis of pancreatic NENS. We aimed to define the tumor genomic profiling in non-pancreatic NENS using NGS. Methods: FFPE samples from NENS of different non-pancreatic origins were analyzed. A single pathologist evaluated them for tumor content (cutoff >30% tumor cells) and lymphocyte infiltration. DNA was obtained and quality assessed by a qPCR-based method. We performed amplicon-seq using 476 primer pairs targeting hotspot mutation loci in oncogenes as well as TSG. An initial amplification step was performed, amplicon sizes ranging 80-120 bp. After that, 100 ng of dsDNA were used for standard indexed TruSeq Genomic sample preparation. Samples were pooled in two groups and sequenced in a MiSeq instrument (Illumina) in a 2X100 run. Reads were aligned (BWA), variants called (GATK) and annotated. Final individual manual check of mutations was performed. NENS types were classified following the 2010 WHO classification. Results: We analyzed 38 NENS samples of different origins and grades: 7 G3 colon, 8 G1/2 colon, 8 G1/2 ileum, 8 G1/2 gastric, and 7 G1/2 lung. We identified 24 mutations in several genes and different distribution regarding tumor origin was observed. G3 colon NENS presented mutations in KRAS (43%), APC (28%), and VHL (14%). Ileum NENS showed mutations in TP53 (50%), VHL (37%), FGFR3 (12%) and APC (12%). In G1/2 NENS of colon origin, mutations in SMARCB1 (37%), KRAS (12%) and NF2 (12%) were identified. Less frequent mutations were present in gastric and lung samples (KRAS, TP53 and FGFR3 in 12% each). Conclusions: A tumor origin specific mutation pattern has been observed for NENS. To our knowledge this is the first time to describe mutations in SMARCB1 TSG in this setting. Further investigation is warranted to define the role of SMARCB1 in the pathogenesis of NENS.
Paclitaxel, ifosfamide, and cisplatin (TIP) efficacy for first-line treatment of patients (pts) with intermediate- or poor-risk germ cell tumors (GCT).
Authors: Feldman Darren Richard , Hu James , Dorff Tanya B. , Patil Sujata , Van Alstine Lindsay Joy , Momen Lamia , Carousso Maryann , Hughes Amanda , Snively-Solomon Jolie , Ketchens Charlean , Sheinfeld Joel , Bains Manjit S. , Bajorin Dean F. , Bosl George J. , Motzer Robert John , Quinn David I.
Published: March 2020

4501

Background: Durable progression-free survival (PFS) rates for pts with intermediate- and poor-risk GCT approximate only 75% and 50%, respectively with standard BEP. This multicenter phase II study investigated first-line TIP in this population. Methods: Pts age ≥18 with untreated, IGCCCG intermediate- (LDH modified to ≥3x upper limit of normal) or poor-risk GCT were eligible. Pts received 4 cycles of TIP every 21 days, consisting of paclitaxel 120mg/m2 days 1-2; ifosfamide 1200mg/m2 days 1-5; and cisplatin 20mg/m2days 1-5, followed by G-CSF and levofloxacin for neutropenic fever prophylaxis. The primary endpoint was the complete response (CR) rate; secondary endpoints included PFS and toxicity. A Simon’s 2-stage design required a CR in ≥11/18 pts to proceed to stage 2, where with ≥27/41 CRs overall, the regimen would be considered active and worthy of further study. Results: Of 44 men (median age 27) enrolled; 38 had nonseminoma and 6 seminoma; 29 were poor-risk and 15 intermediate-risk. Primary site was testis in 30, mediastinum in 11, and retroperitoneum in 3. 42 pts had elevated markers and 14, 6, and 1 had liver, bone, and brain metastasis, respectively. The trial met its primary endpoint; of 41 evaluable pts, 28 achieved a CR (see Table) and 6 pts (5 with seminoma) achieved a partial response with negative markers (PR-). Two pts relapsed. With a median follow-up of 2.2 years, estimated 3-year PFS was 79% and 3-year overall survival (OS) 98% (see Table). There were no treatment-related deaths. Grade 3/4 toxicities were primarily hematologic and 6 (14%) pts developed neutropenic fever. Conclusions: TIP demonstrates promising efficacy and is well-tolerated in intermediate- and poor-risk GCT pts. A randomized trial of TIP vs. BEP has been initiated to compare efficacy. Clinical trial information: NCT00470366. [Table: see text]
Characterization of relapse in patients with clinical stage I (CSI) nonseminoma (NS-TC) managed with active surveillance (AS): A large multicenter study.
Authors: Kollmannsberger Christian K. , Tandstad Torgrim , Bedard Philippe L. , Jewett Michael A. S. , Cohn-Cedermark Gabriella , Chung Peter W. M. , Daugaard Gedske , Warde Padraig Richard , Moore Malcolm J. , Nichols Craig R.
Published: March 2020

4503

Background: Large single institution trials have demonstrated that AS for patients with CSI NS-TC is safe and effective. Information on timing and extent of relapse following AS has the potential to guide intensity and duration of imaging on AS. Methods: Retrospective clinical data on CSI patients were obtained from existing large databases, including institutions/regions which have a standardized policy of centralized management of testicular cancer including AS for patients with CSI NS-TC. In all, 1,034 patients with CSI NS-TC managed with AS were reviewed of whom 886 had no lymphovascular invasion (LVI-), 220 had lymphovascular invasion (LVI+) and 28 had unknown lymphovascular status (LVI unknown). Results: A total of 221 relapses occurred with 150/886 (17%) of LVI– pts , 60/120 (50%) LVI+ pts and 11/28 (39%) of LVI unknown pts (Table). Median follow-up was 63 months (1-163 months). At last follow up 1,013/1,034 (98%) were alive without disease, 16/1,034 (1.5%) were dead of other causes and 7/1,035 (0.05%) were alive with disease or dead of disease. Relapse was identified by marker elevation and/or abdominal imaging in almost all patients. Few patients relapsed with IGCCCC intermediate (18/221, 8%) or poor risk disease (3/221, 1.4%). Conclusions: AS for CSI NS-TC is safe and effective, using a policy of centralized management with loco-regional delivery of care. Our multinational outcomes compare well to single institutional reports. Relapse other than with IGCCC good risk disease was uncommon and death from disease was rare. Compared to patients with LVI-, relapses in LVI + CSI patients occur earlier and few relapses are detected past the first year of follow-up. This data may help in the design of follow up schedules tailored towards the relapse risk in CSI NS-TC AS. [Table: see text]
Association of IL8 polymorphisms with overall survival in patients with renal cell carcinoma in COMPARZ (pazopanib versus sunitinib phase III study).
Authors: Xu Chun-fang , Johnson Toby , Choueiri Toni K. , Deen Keith C. , Xue Zhengyu , Spraggs Colin F. , Bartlett-Pandite Arundathy N. , Carpenter Christopher , Motzer Robert John
Published: March 2020

4519

Background: Pazopanib and sunitinib are angiogenesis inhibitors approved for treatment of advanced renal cell carcinoma (RCC). COMPARZ, a phase III randomized clinical trial comparing pazopanib vs sunitinib for RCC, demonstrated similar efficacies for the two therapies but safety profiles differed. Our genetic analyses of previous pazopanib clinical trials found that IL8 polymorphisms may be associated with progression-free survival (PFS) and overall survival (OS). We attempted to validate these associations in the COMPARZ study. Methods: Of the 1110 participants in COMPARZ, 724 (65%) provided consent and DNA for pharmacogenetic analyses (pazopanib, N = 371; sunitinib, N = 353).Associations of IL8 polymorphisms (rs1126647 and rs4073) with PFS and OS were tested using the Cox proportional hazards model with baseline factors as covariates in a combined analysis of all patients and also separately in pazopanib-treated and sunitinib-treated patients. One-tailed P values were calculated for effects in the same direction as previously observed. Results: For PFS there was no significant association in the combined analysis or in pazopanib-treated patients, but there was a significant association in sunitinib-treated patients (P = 0.017). For OS there were significant associations in the combined analysis (P = 0.010) and in sunitinib-treated patients (P = 0.0043) but not in pazopanib-treated patients (P = 0.30). Hazard ratios (HRs) for genetic effects were not significantly different between sunitinib- and pazopanib-treated patients (two-tailed P = 0.23 for genotype-by-treatment interaction). Kaplan-Meier plots suggested a recessive genetic model in the combined data set, with median OS (95% CI) 23.7 months (15.4–29.1) for rs1126647 TT genotype compared to 35.5 months (30.8–∞) for AA or AT genotypes (HR = 1.66, P = 0.0007). Similar associations were seen for rs4073. Conclusions: Germline variants in IL8 are associated with survival outcome in patients with RCC who have received angiogenesis inhibitors. These findings may provide additional scientific insights in making treatment decisions and developing alternative therapies.
Nomogram to estimate the activity of second-line therapy for advanced urothelial carcinoma (UC).
Authors: Sonpavde Guru , Pond Gregory Russell , Agarwal Neeraj , Choueiri Toni K. , Qu Angela Q. , Fougeray Ronan , Salhi Yacine , Vaughn David J. , James Nicholas David , Niegisch Guenter , Albers Peter , Galsky Matt D. , Wong Yu-Ning , Stadler Walter Michael , O'Donnell Peter H. , Vogelzang Nicholas J. , Sridhar Srikala S. , Ko Yoo-Joung , Sternberg Cora N. , Bellmunt Joaquim
Published: March 2020

4524

Background: Prognostic factors may impact on endpoints used in phase II trials of second-line therapy for advanced UC. We aimed to study the impact of prognostic factors (liver metastasis [LM], anemia [Hb<10 g/dl], ECOG-performance status [PS] ≥1, time from prior chemotherapy [TFPC]) on PFS6 and RR. Methods: Twelve phase II trials evaluating second-line chemotherapy and/or biologics (n=748) in patients with progressive disease were pooled. PFS was defined as tumor progression or death from any cause. PFS6 was defined from the date of registration and calculated using the Kaplan-Meier method. RR was defined using RECIST 1.0. A nomogram predicting PFS6 was constructed using the RMS package in R (www.r-project.org). Results: Data regarding progression, Hb, LM, PS and TFPC were available from 570 patients. The mean age was 65.1 years, 45.3% had ECOG-PS ≥1, 30.2% had LM, 14.6% had anemia and TFPC was <6 months (mo) in 60.2%. The overall median PFS was 2.7 mo, PFS6 was 22.2% (95% CI: 18.8-25.9) and RR was 17.5% (95% CI: 14.5%-20.9%). For every unit increase in risk group, the hazard of progression increased by 41% and the odds of response decreased by 48% (Table). A nomogram was constructed to predict PFS6 on an individual patient level. Conclusions: PFS6 and RR vary as a function of prognostic factors in patients receiving second-line therapy for advanced UC. A nomogram incorporating prognostic factors might facilitate the evaluation of activity across phase II trials enrolling heterogeneous populations and can help to select and stratify patients for phase III evaluation of suitable agents. [Table: see text]