bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of preoperative panitumumab, 5-fluorouracil, and oxaliplatin with concurrent radiotherapy in locally advanced rectal cancer: Preliminary safety results (StarPan /STAR-02 Study)
Authors: Pinto C. , Di Fabio F. , Maiello E. , Di Tullio P. , Pini S. , Aschele C. , Garufi C. , Bochicchio A. , Pinotti G. , Latiano T. , Martoni A.
Published: August 2020

4110

Background: The aim of this phase II study is to assess the activity of preoperative external radiotherapy combined with panitumumab, oxaliplatin and 5-fluorouracil in locally advanced rectal cancer patients (pts). Methods: Pts entering the study had histologically-proven rectal adenocarcinoma, either uT3N+ or T4 N-/+ stage, with location <12 cm from the anal margin. Panitumumab was administered at a dose of 6 mg/kg IV, 2 weeks before the start of chemoradiotherapy, and then in combination with chemoradiotherapy, every 2 weeks for 3 times. 5-fluorouracil and oxaliplatin were administered according to an established schedule of STAR-01 Study (oxaliplatin 60 mg/m2 IV weekly for six times, and 5- fluorouracil 225 mg/m2/day continuous infusion IV d 1–38). Radiotherapy was delivered up to a dose of 50.4 Gy in daily fractions of 1.8 Gy. Rectal surgery was performed 7–8 weeks after the end of neoadjuvant treatment. Eight courses of adjuvant chemotherapy with FOLFOX4 plus panitumumab at a dose of 6 mg/kg, every 2 weeks, were given after surgery. The primary endpoint of the study was the complete pathological response rate. Results: From February 2007 to December 2008, 35 out of the 55 planned pts were enrolled. Twenty nine pts completed neoadjuvant treatment and 20 underwent surgery (15 pts ongoing). The characteristics of 29 pts were: males 19 (65.5%) and females 10 (34.5%); median age 58 years (range 39–78); median Karnofsky PS 100 (range 70–100); stage: uT3N+ 22 (75.9%), uT4N- 3 (10.3%), uT4N+ 4 (13.8%). The most frequent grade 1–4 side-effects were acneiform rash (96.2%), diarrhea (51.7%) and fatigue (14.3%). Grade 3 diarrhea was registered in 35.7% pts, and grade 3–4 cutaneous toxicity in 51.8%. No grade 3–4 hematological toxicity was found. The median cumulative dose of delivered radiotherapy was 50.4 Gy. The planned dose of panitumumab, 5-fluourouracil and oxaliplatin was administered in 83%, 72% and 67% of pts, respectively. Conclusions: Despite the moderate increase of diarrhea, these early results demonstrate that panitumumab can be safety added to 5-fluorouracil/oxaliplatin-based chemoradiotherapy, without compromising the concurrent radiotherapy dose.

No significant financial relationships to disclose.
A single-center study of the utility of squamous cell carcinoma antigen (SCCAg) levels in epidermoid carcinoma of the anal canal and margin (ECACM) treated with chemoradiation (CRT)
Authors: Swampillai A. , Williams M. , Osborne M. , Mawdsley S. , Hughes R. , Harrison M. , Glynne-Jones R.
Published: August 2020

4117

Background: SCCAg is a tumour marker expressed by ECACM, measured by microparticle enzyme immunoassay; normal range 0–150ng/dl. Methods: This retrospective study examined the role of SCCAg in staging and prediction of recurrence in 195 patients (pts); 76 m:119 f with ECACM treated 1997–2007. All 195 were treated with CRT- (50.4Gy in 28 fractions of 1.8 Gy with 5-fluorouracil (5-FU) + mitomycin (MMC). Radiotherapy comprised the schedule of the UK Anal cancer Trial (ACT II). Variations included 5FU and cisplat, and capecitabine. 30 had neo-adjuvant chemotherapy followed by CRT and 3 pts had planned surgery followed by CRT. Median follow up was 36 months (range 1 - 168). Median age was 61 years (range 30 -91). In 149 pts with SCCAg samples taken prior to CRT, 107 had one or more samples taken at follow up at 3 - 6 monthly intervals. Clinical stage at diagnosis- Tx (6) T1 (28), T2 (80), T3 (65), T4 (16), N0 (126), N+ (66) Nx (3). Results: Mean baseline SCCAg by cT and cN stage were: T1 93 (ng/dl), T2 300, T3 607, T4 882, N0 376, N+ 529 (correlation coeff: T: 0.47, N: 0.33, both p< 0.001). 135 patients had baseline SCCAg with a documented response on completion of CRT. The mean baseline SCCAg for pts achieving CR was 408 and non CR was 513 (p = 0.13). Sensitivity of baseline SCCAg to predict relapse was 0.56 (specificity 0.4). Sensitivity of two consecutive elevated SCC levels during the follow up period in patients who achieved a CR to predict for relapse was 0.56 and specificity 0.83. The positive likelihood ratio was 3.3 (1.8 - 6.1) and the negative was 0.53 (0.3 - 0.9). Conclusions: There is a correlation between T and N stage and baseline SCC. In follow-up, a sustained rise in SCCAg increases the odds of relapse three-fold. We recommend SCCAg measurement in the first year after CRT.

[Table: see text]
Impact of K-ras status on the effects of EGFR-targeted monoclonal antibody (MAb) therapy in advanced colorectal cancer (ACRC): A systematic review and meta-analysis of randomized controlled trials (RCTs)
Authors: Vale C. , Tierney J. F. , Meade A. , Fisher D. , Kaplan R. , Adams R. A. , Maughan T. S. , Parmar M. K.
Published: August 2020

4122

Background: A recent systematic review, based largely on non-randomised, retrospective studies, suggested that K-ras mutations may identify patients who do not benefit from cetuximab and panitumumab. In support of this hypothesis, four RCTs have shown a lack of benefit or detriment of EGFR-targeted therapy in patients with K-ras mutations. In this systematic review, we aim to provide a comprehensive and unbiased synthesis of the effects of these MAbs, by K-ras status, in both chemotherapy (CT) responsive and CT-refractory ACRC patients. Methods: A systematic review and meta-analysis of all relevant RCTs is ongoing. Progression-free survival (PFS) is the primary outcome, with survival and response as secondary outcomes. We have conducted systematic searches of a number of trial sources. Data on trial and patient characteristics, and outcome have been extracted from trial reports or presentations, for all patients and for K-ras wild-type and mutant cohorts. Where possible, trial results were pooled in a stratified-by- trial meta-analysis. For unpublished RCTs, or those published with insufficient information, we are seeking further data. Results: Searches identified 15 eligible RCTs in CT-responsive patients, 12 using cetuximab and 3 panitumumab. Three of these trials included bevacizumab in both arms. PFS has only been reported for 6 RCTs, so further data are needed to ensure an unbiased analysis. Only two RCTs were identified in CT-refractory patients. Together, these showed an improvement in PFS with anti-EGFR MAb (HR=0.61, 95% CI 0.49–0.76, p<0.0001). Furthermore, there was a significant difference in the size of the effect by K-ras status (interaction p<0.0001), with an improvement in PFS for patients with wild type K-ras, (HR=0.43, 95% CI 0.35–0.52, p<0.0001), but not those with mutant K-ras (HR=0.99 95% CI 0.80–1.23, p=0.93). Conclusions: These preliminary results suggest that the benefits of anti-EGFR MAb therapy, at least in CT-refractory patients, are confined to those with wild type K-ras. Results for CT-responsive patients, and updated analyses for CT-refractory patients, will be presented.

[Table: see text]
Oxaliplatin (OXP) plus protracted infusion 5-fluorouracil (PIFU) and external beam radiation (EBRT) prior to surgery (S) for potentially curable esophageal adenocarcinoma (EA): A Southwest Oncology Group (SWOG) phase II trial with molecular correlates (S0356)
Authors: Leichman L. , Goldman B. H. , Benedetti J. K. , Billingsley K. G. , Thomas C. R. , Iqbal S. , Lenz H. , Blanke C. , Gold P. J. , Corless C. L.
Published: August 2020

4513

Background: Although neoadjuvant combined modality therapy (NACMTX) has become a standard of care in the United States, median overall survival (OS) for patients (PTS) with EA has changed little over the past 25 years. Progression free survival (PFS) and OS after NACMTX depend on extent of primary tumor response. New regimens to increase pathologic complete response (pCR) are needed. Based on phase I data, SWOG designed a phase II trial (S0356) to test OXP with PI5FU and EBRT for PTS with EA. Objectives included pCR rate ≥ 25%, acceptable toxicity (TOX), PFS, OS and exploration of molecular parameters relevant to pCR. Methods: Eligibility: clinical stage II/III EA, ≥ 18 years, Zubrod PS ≤ 2, standard hematologic/non-hematologic values, and tumor < 2 cm into the gastric cardia. OXP 85 mg/m2 was given day (d) 1, 15 and 29; PI5FU 180 mg/m2/d was given d 8-d43. EBRT 180 cGy/d started d 8 x 25 fractions, 5 d/week to total dose 4500 cGy. S was planned 2–4 weeks after NACMTX, with a second cycle of OXP/ PI5FU after S. Central pathology review of surgical specimens was mandated. The trial used a 2-stage design; the trial was halted at 45 PTS to review pCR rate; it reopened to full accrual. Results: 98 PTS enrolled between 9/15/04 and 8/18/08. 6 PTS were ineligible; 2 PTS did not receive therapy (TX). 90 PTS, 84 men (93%), median age 61.7 years, were analyzed. 4 deaths (4.5%) were due to protocol TX; 2 due to NACMTX, 2 to S. 43% and 18% of PTS had grade 3/4 toxicity, respectively: 39% GI, 22% flu-like/fatigue, 17% pulmonary, 16% hematologic, 14% mucositis and 3% neurologic. 77 PTS (86%) underwent S. 30 PTS (33%) had pCR. 9 PTS (10%) had in-situ cancer or T1N0M0. <50% received postoperative CTX. Conclusions: OXP, PI5FU and EBRT for PTS with EA has produced the highest pCR rate reported to date for a cooperative group trial. Significant but manageable non-hematologic TOX was observed. S mortality is acceptable. Future trials built on this platform should plan to complete all TX before S. Tumor molecular profiles (analyses in progress) may predict benefit from this treatment. Data on PFS and OS will follow.

[Table: see text]
Disease-free survival as a surrogate endpoint for overall survival in an adjuvant trial of curatively resected stomach cancer using individual patient data meta-analysis
Authors: Burzykowski T. , Bang Y. ,   on behalf of the GASTRIC project
Published: August 2020

4517

Background: In investigations of the effectiveness of oncology drugs, overall survival (OS) is considered as the gold standard end point. However, the disadvantage of OS is that it requires an extended follow-up. A reasonable candidate for a surrogate for OS in the adjuvant setting is disease free survival (DFS). DFS is defined as recurrence of stomach cancer, all second cancers, or death from any cause. Recently, some evidence has been offered for the use of DFS as a surrogate for OS in, e.g., colorectal cancer. We evaluated 3 year DFS as a surrogate for 5 year OS in adjuvant trials of stomach cancer by using individual-patient data (IPD) meta- analysis validation criteria. Methods: The GASTRIC group initiated an IPD meta-analysis of all randomized clinical trials comparing chemotherapy versus surgery alone for patients with curatively resected stomach cancer. The validity of DFS at 3 years as a surrogate for OS at 5 years was investigated by using multiple analysis techniques, which included measures of correlation between the endpoints and between the treatment effects, and the percentage of agreement in the log-rank tests for the two endpoints at the trial level. Results: Among the 31 eligible trials, at most 25 collected the date of recurrence (5,014 pts). As of December 2008, IPD were available from 13 randomized controlled trials (3,161 patients). Seventy-seven percent of patients (1,280/1,652 pts) who recurred during the follow-up period, recurred within the first 3 years after study enrollment. At the trial level, 12 out of the 13 trials yielded the same conclusions for both endpoints at the 0.05 significance level. The R2 value between both endpoints was equal to 0.97 and Spearman's rank correlation was equal to 0.92. The R2 value between hazard ratios for OS and DFS was equal to 0.85 and Spearman's rank correlation was equal to 0.87. Conclusions: Our preliminary results, which are based on 63% of the targeted data, show that the 5-year OS and the 3-year DFS are highly correlated. Additionally, the hazard ratios for DFS and OS are also strongly associated. This suggests that 3-year DFS may be a good surrogate for a 5-year OS. The results based on the most recent update of the IPD will be presented during the conference.

No significant financial relationships to disclose.
Activity of gemcitabine in direct patient-derived xenografts and clinical outcome: Validation of an in vivo model for drug development
Authors: Hidalgo M. , Garrido-Laguna I. , Uson M. , De Oliveira E. , Schulick R. , Hruban R. H. , Maitra A. , Jimeno A. , Rubio-Viqueira B. , Rajeshkumar N. V.
Published: August 2020

4528

Background: Novel drugs are urgently needed for pancreatic ductal adenocarcinoma (PDA). Current preclinical models may not recapitulate the biology of human cancers. Direct xenografts have the potential to better represent the biology of human cancer. We have completed a clinical trial in which surgically resected PDAs were xenografted into nude mice thus generating an in vivo platform for drug development and biomarker identification. Methods: PDAs resected at Johns Hopkins Hospital are implanted into nude mice. From November 2005 to December 2008, 240 patients were consented, 236 operated, 102 were resectable PDAs thus fulfilling the inclusion criteria. 104 patients had other histologies and 34 were unresectable PDAs. Xenografted tumors were treated with gemcitabine and the activity in the xenograft correlated with patient clinical outcome. Results: Out of these 102 cases, 77 were xenografted, 53 were engrafted and reached the treatment phase. 35 out of the 53 originator patients were clinically treated with gemcitabine. The median overall survival of resected patients was 646 days (similar to 660 days from CONKO-001 trial). Patients whose carcinomas engrafted had a shorter median overall survival (319 vs. 728 days, p=0.002), probably reflecting a more aggressive tumor biology in the engrafted group. The response rate of gemcitabine in xenografts based on RECIST criteria was 8% (similar to response rate to gemcitabine in phase III trial by Moore et al.). In the adjuvant setting, the median disease free survival (DFS) was significantly longer in those patients predicted as sensitive by the xenograft model (568 vs. 286 days, p=0.037). In the metastatic setting, the median time to progression (TTP) was longer in those patients predicted as sensitive by the model (126 vs. 73 days) though this difference was not statistically significant. Overall the correlation between gemcitabine activity in this model and clinical outcome as measured by DFS was 0.71 in the subgroup of patients whose xenografts had a TGI lower than -10%. Conclusions: This preclinical model predicts gemcitabine outcome in the clinic in the adjuvant setting. Further studies to analyze the causes of shorter survival in patients whose PDA engrafted are warranted.

No significant financial relationships to disclose.
Integrated development of s-trans, trans-farnesylthiosalicyclic acid (FTS, salirasib) in advanced pancreatic cancer
Authors: Laheru D. , Rudek M. , Taylor G. , Goldsweig H. , Rajeshkumar N. V. , Linden S. , Angenendt M. , Le D. , Donehower R. , Jimeno A. , Hidalgo M.
Published: August 2020

4529

Background: The Ras signaling pathway stands as a strategic target in pancreatic cancer. S-trans,trans-farnesylthiosalicyclic acid (FTS) inhibits Ras dependent cell growth by dislodging all of the isoforms of Ras from membrane binding sites. Here we studied the activity of this agent in patients with advanced pancreatic cancer. Methods: Patients with treatment naïve advanced peri-ampullary cancer were treated with gemcitabine (Gem) administered at standard dose and schedule + FTS administered orally at doses of 200–800 mg bid 21 days of a 28 day cycle. Patients were treated until progression or protocol defined DLT. Plasma samples were collected when FTS was administered alone (C1D7 or C1D22) and in combination (C1D15 or C1D8) to characterize FTS pharmacokinetics. Plasma samples were collected when Gem was administered alone (C1D1) and in combination (C1D15 or C1D8) to characterize Gem pharmacokinetics. PBMCs and tissue biopsies pre treatment and during cycle 1 were collected to characterize the effect of Gem + FTS on levels of activated Ras protein. Treatment efficacy was assessed every other cycle. Results: Thirteen patients (8 male, 5 female, ages 40 to 80, ECOG 0–1) are enrolled to date. The most common adverse events were neutropenia, anemia, abdominal cramping, elevated liver function tests and diarrhea. At the time of this analysis, the progression free survival for these 13 patients is 4.7 months with median survival of >10.8 months and 1 year survival of 50%. Conclusions: 1. Salirasib in combination with gemcitabine appears to be safe with no PK interaction. 2. Salirasib in combination with gemcitabine at doses to 800 mg b.i.d. did not reach conventional MTD, although dose related diarrhea suggests better tolerance at doses up to 600 mg b.i.d. 3. Salirasib at doses of 400 to 800 mg b.i.d. in combination with gemcitabine demonstrated a PFS, MS and 1 year survival of 4.7 months, >10.8 months and 50% respectively. 4. Salirasib mechanism of Ras inhibition is confirmed by reduction of tumor Ras in pancreatic cancer patients. 5. Salirasib warrants evaluation in a controlled study with gemcitabine in pancreatic cancer; doses of 600 or 400 mg b.i.d. are recommended.

No significant financial relationships to disclose.
Effect of gender and age on overall survival in patients with esophageal cancer
Authors: Chhibar R. S. , Yang D. , Zhang W. , Lurje G. , Pohl A. , Ning Y. , El-Khoueiry A. , Iqbal S. , Lenz H. J.
Published: August 2020

4541

Background: The American Cancer Society estimated that during 2008 approximately 16,470 new esophageal cancer cases would be diagnosed in the United States. Previous studies indicate that the incidence of esophageal cancer is more in males than females; however the influence of sex in the progression of esophageal cancer is not clearly understood. In vitro and in vivo models showed that administration of estradiol significantly inhibited the growth of ER-positive and AR-positive KSE-1 tumors in both males and females in conjunction with an increase in the estradiol levels and a decrease in the DHT levels in the serum. Thus we tested the clinical significance of sex in the overall survival of esophageal cancer using SEER data. Methods: A total of 21,584 patients with localized and metastatic esophageal cancer from 1988–2004 were screened using the SEER registry. The patients were divided into age at diagnosis, sex and ethnicity. The analysis for overall survival was based on the Cox proportional hazards model adjusted for marital status, site of primary tumor, treatment, histology and tumor grade and stratified by year of diagnosis and SEER registry site. Pairwise interactions (age and sex, age and race, and sex and race) were also examined. Results: Females with localized esophageal cancer had significantly longer overall survival compared to males (p<0.001). In metastatic esophageal cancer, females seemed to have longer overall survival than males (p=0.054). Overall survival decreased with increasing age (p<0.001). African Americans with localized esophageal cancer have worse median overall survival compared to Caucasians (p<0.001). No significant difference was noted with respect to ethnicity in metastatic esophageal cancer (p=0.22). Also pairwise interactions did not have significant difference. Conclusions: This is the first and largest study showing gender as an independent prognostic factor in patients with localized and metastatic esophageal cancer. Females had a significant better overall survival than males in esophageal cancer suggesting that sex hormone pathways may have a potential impact on tumor progression. These data warrant further studies to explore the role of these pathways in the diagnosis and treatment of esophageal cancer.

No significant financial relationships to disclose.
Docetaxel, oxaliplatin, and capecitabine (TEX regimen) for patients with metastatic gastric cancer: Interim results from a phase II trial by the German AIO Group
Authors: Moehler M. H. , Thuss-Patience P. , Arnold D. , Grothe W. , Stein A. , Seufferlein T. , Mantovani Loeffler L. , Geissler M. , Hofheinz R. D. , Schmoll H.
Published: August 2020

4554

Background: Combination regimens of 3 drugs have shown promising activity as treatment for patients (pts) with metastatic gastric cancer (GC). Docetaxel combined with cisplatin and 5-FU (CF) improved overall survival and response rates when compared to standard CF. However, the identification of less toxic and more convenient variants of this regimen is still important. We have previously established a regimen with docetaxel (T) combined with oxaliplatin (E) and capecitabine (X) in a phase I trial [Grothe et al., Proc. ASCO 2006]. Results of a preplanned interim analysis of subsequent multicenter phase II trials of the TEX regimen are presented here. Methods: Pts with metastatic or locally advanced GC, adequate organ function, ECOG PS 0–2, and no prior chemotherapy for advanced disease (adjuvant allowed) were enrolled. TEX regimen was administered as defined: T 35 mg/m2 and E 70 mg/m2 on days (d) 1 and 8, with X 800 mg/m2 bid on d1–14 every 22 days Toxicity assessment was done 3-weekly while CT scans were repeated 9-weekly. Results: 35 of 48 pts were enrolled until 06/08: 28 male / 7 female, median age 59 (36–81) years, ECOG PS 0/1/2 69%/31%/0%, gastric / gastroesophageal cancer 60%/40%, distant metastases 96%, tumor in situ 37%. The most common toxicities reported were (CTC grade [gr] 3/4): diarrhea 20%/3%, vomiting 11%/3%, asthenia and neurotoxicity each 9%/0%. Mucositis and hand-foot-syndrome were observed in (grade 1+2 / grade 3) 29%/0% and 26%/3%, respectively. Hematoxicity was mild with grade 3 anemia in 10% and no other grade 3/4 toxicity except one episode of febrile neutropenia . Of 25 pts evaluable so far, first tumor response assessment revealed (RECIST criteria) partial response in 36% and stable disease in 40% of patients. Conclusions: TEX is a safe and tolerable regimen for patients with metastatic gastric cancer. Preliminary efficacy results indicate promising activity. Mature data including progression free survival will be presented at the meeting.

[Table: see text]
Pathological features of advanced gastric cancer (GC): Relationship to human epidermal growth factor receptor 2 (HER2) positivity in the global screening programme of the ToGA trial
Authors: Bang Y. , Chung H. , Xu J. , Lordick F. , Sawaki A. , Al-Sakaff N. , Lipatov O. , See C. , Rueschoff J. , Van Cutsem E.
Published: August 2020

4556

Background: HER2 positivity is thought to be a negative prognostic factor in GC, correlating with poor survival rates. Reported HER2-positivity rates in GC have varied widely (6–35%). The ToGA trial is evaluating the addition of trastuzumab (Herceptin) to chemotherapy in HER2-positive advanced GC. It is the first randomised Phase III trial to provide prospective information on HER2-positivity rates in GC. Enrollment is complete, with 3,883 patients screened in 24 countries. The pathological features of GC and the relationship with HER2 positivity will be examined. Methods: Advanced GC tumour samples were centrally screened by immunohistochemistry (IHC; HercepTest) and fluorescence in situ hybridisation (FISH; PharmDx) in parallel. A HER2-scoring system modified from the protocol in breast cancer (BC) was used: a score of IHC 3+ and/or FISH positive was defined as HER2 positive. Results: Final data showed an overall HER2-positivity rate of 22.1% evaluated from 3807 patients. The HER2-positivity rate was similar between Europe (23.6%) and Asia (23.5%). HER2-positivity rates were higher in gastro-oesophageal junction (GEJ) than stomach cancer (33.2% vs 20.9%; p<0.001) and in intestinal than diffuse/mixed cancer (32.2% vs 6.1%/20.4%; p<0.001). This is reflected in above-average HER2-positivity rates in countries with the highest GEJ:stomach cancer ratios (France 0.56 [HER2 positivity 26.9%]; Germany 0.53 [23.7%]; UK 0.33 [25.8%]) and intestinal:diffuse cancer ratios (UK 3.4 [HER2 positivity 25.8%]; Australia 2.6 [32.8%]; Japan 2.8 [27.8%]). The modified HER2-scoring system showed concordance between IHC and FISH results of 87.5%. In BC most IHC 0/1 samples are FISH negative but, in ToGA, the frequency of IHC 0/1 samples testing FISH positive was almost as high as IHC 2/FISH-positive samples (23% vs 26%). Conclusions: The overall HER2-positivity rate in advanced GC in ToGA is 22.1%. Variations in tumour location and type mostly explain the difference in HER2-positivity rates between countries. Efficacy data will enable further evaluation of the clinical significance of HER2 IHC and FISH scoring patterns.

[Table: see text]
Polymorphisms in epidermal growth factor (EGF) and proteinase activated receptor 1 (PAR-1) associated with tumor recurrence in localized adenocarcinoma (EA) of the esophagus treated with surgery alone
Authors: Lurje G. , Leers J. M. , Pohl A. , Oezcelik A. , Zhang W. , Yang D. , Hagen J. A. , DeMeester S. R. , DeMeester T. R. , Lenz H. J.
Published: August 2020

4564

Background: Tumor angiogenesis is a well-recognized aspect of human cancer biology and is mediated at least in part by EGF and PAR-1, which in turn may impact the process of tumor growth and progression. Systemic tumor recurrence after curative resection continues to be a significant problem in the management of patients with localized EA. Further, it is being increasingly recognized that esophageal squamous cell carcinoma and EA are separate and distinct disease groups and need to be considered individually. We therefore designed a large retrospective study of EA patients to identify novel molecular markers of prognosis to better define tumor stage and progression, and help to define novel targets, as well as surrogate-endpoints of disease progression and response to therapy. Methods: Between 1992 and 2005 normal esophageal tissue samples from 239 patients with localized EA treated with surgery alone were obtained at University of Southern California medical facilities. The median follow-up was 3.2 years. 114 out of 239 (48%) patients had tumor recurrence, with a probability of 5-year recurrence of 0.62 ± 0.04. DNA was isolated from formalin-fixed paraffin-embedded specimens and 10 angiogenesis related and functional gene polymorphisms were analyzed using a PCR-RFLP and 5´-end [γ-33P] ATP-labeled PCR method. Results: PAR-1 -506 ins/del (p-value=0.003; log-rank test) and EGF +61 A>G (p-value=0.034; log-rank test) are adverse prognostic markers in univariate analysis. After adjusting for covariates (gender, T1-, N-category, type of surgery) in the multivariable model, "high-expression" variants of PAR-1 (any insertion allele) (RR: 1.81; adjusted p-value = 0.011) and EGF (A/A) (RR: 1; adjusted p-value=0.035) remained significantly associated with time to recurrence, compared to other genotype combinations of PAR-1 (RR: 1) and EGF (RR: 0.65). Conclusions: This study supports the role of functional EGF and PAR-1 polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence. Prospective and biomarker-embedded clinical trials are needed to validate our findings.

[Table: see text]
Phase II study of cetuximab plus weekly cisplatin and 24-hour infusion of high-dose 5-fluorouracil and leucovorin for the first-line treatment of advanced gastric cancer
Authors: Yeh K. , Hsu C. , Hsu C. , Lin C. , Shen Y. , Wu S. , Chiou T. , Chao Y. , Cheng A.
Published: August 2020

4567

Background: Cisplatin-HDFL regimen, using weekly 24-hour infusions of cisplatin and high-dose 5-fluorouracil (5-FU) and leucovorin, is commonly used in Taiwan for patients with advanced gastric cancer (GC), showing an overall response rate of approximately 60% (95% CI: 45%-76%) [J Clin Oncol (Suppl) 2006; 24(18S): A14063 ]. We have demonstrated that cetuximab is cytotoxic to human GC cells, and has a chemosensitizing effect for cisplatin and 5-FU in GC cells [Proc AACR 2006; 47: A1233]. Methods: All patients had pathologically confirmed metastatic/ recurrent chemonaive GC, at least 1 measurable lesion, a fasting serum triglyceride level > 70 mg/dl, WHO PS 0/1/2, adequate hepatic, renal, and bone marrow functions. Cetuximab 400 mg/m2 was given as 2h infusion, initially (i.e., D1 of cycle 1); and followed by weekly 1h infusion of 250 mg/m2 (i.e., D8, D15, D22 of cycle 1, and D1, D8, D15, D22 of cycle 2). Cisplatin 35 mg/m2 was given as a 24h infusion, admixing with 5-FU 2,000 mg/m2 and leucovorin 300 mg/m2 (HDFL), D1, D8. A 24h infusion of HDFL was given on D15. Cycles were repeated every 28 days, and response evaluation was performed every 2 cycles & at the end of protocol treatment. The primary end-point was confirmed objective response rate (RR) by RECIST. Results: Between Dec. 2005 and Nov. 2008, 35 patients (M:19, F:16) with a median age of 56 (40–74) were enrolled and evaluable for response assessment. The overall RR was 68.6% (51–83%, 95% C.I.) with 1 CR and 23 PRs. Among a total of 269 cycles (median: 7, range: 2 to 22+ cycles) given, Gr3/4 neutropenia, infection, and hepatic toxicity developed in 6.0%, 4.8%, and 0.74% of 269 cycles, respectively. Two patients have developed acute hepatitis B flare-up among seven HBsAg (+) carriers, and were well controlled by lamivudine. Gr1, Gr2, and Gr3 acne- like rashes have developed in 57.1%, 31.4%, 5.7%; and Gr1, Gr2, Gr3 paronychia have developed in 40.0%, 8.6%, and 2.9% of 35 patients, respectively. Median PFS (range: 3 to 22+ months) and median OS (range: 3 to 35+ months) was11.0 and 14.5 months, respectively. Conclusions: Cetuximab plus infusional cisplatin-HDFL is a highly effective regimen with low toxicity and favourable survival in the first-line treatment of advanced GC.

No significant financial relationships to disclose.
Gastric cancer risk predisposition and prognostic significance of vascular endothelial growth factor (VEGF) gene polymorphisms in an Omani population
Authors: Al-Moundhri M. S. , Al-Nabhani M. , Burney I. , Rizvi A. , Al-Farsi A. , Al-Bahrani B.
Published: August 2020

4568

Background: VEGF plays a central role in the angiogenesis, tumor growth and metastasis. VEGF gene polymorphisms at various loci and gastric cancer (GC) risk predisposition and their prognostic significance were studied previously with controversial results Methods: We analyzed three VEGF polymorphisms (+405 G>C, -460T>C, and +936C>T) by extraction of genomic DNA from peripheral blood of 130 GC patients and 130 control subjects followed by VEGF genotyping using PCR-RFLP analysis and the determination of the polymorphisms GC risk predisposition and their prognostic significance Results: There was no significant association between the VEGF polymorphisms and gastric cancer risk. There was a significant correlation between +405 C/C genotype and poor tumor differentiation (p=0.007) and lymph node metastasis (p=0.03) and 460T/T genotype and poor differentiation (p=0.03) with statistical trend for lymph node involvement (p=0.05). VEGF gene polymorphisms had no significant effect on survival, but VEGF +405 G/G genotype had lower survival with hazard ratio 1.6 [95% CI, 0.9–2.9] compared to VEGF +405 CC/GC combined genotype (p=0.04). Multivariate analysis showed that disease stage at diagnosis, and +405 G/G genotype were independent variables of adverse prognostic significance. There were no associations between the common six haplotypes identified and GC risk predisposition and survival. Conclusions: The current study suggests that VEGF polymorphisms in GC patients may have predictive and prognostic significance.

No significant financial relationships to disclose.
A phase II study of ABT-869 in hepatocellular carcinoma (HCC): Interim analysis
Authors: Toh H. , Chen P. , Carr B. I. , Knox J. J. , Gill S. , Steinberg J. , Carlson D. M. , Qian J. , Qin Q. , Yong W.
Published: August 2020

4581

Background: ABT-869 is a novel orally active, potent and selective inhibitor of the vascular endothelial growth factor and platelet derived growth factor families of receptor tyrosine kinases. Results of an interim analysis of a phase 2 trial of ABT-869 in HCC are presented. Methods: An open-label, multicenter phase II trial (M06–879) of oral ABT-869 at 0.25 mg/kg daily in Child-Pugh A (C-PA) or QOD in Child-Pugh B (C-PB) patients (pts) until progressive disease (PD) or intolerable toxicity, is ongoing. Key eligibility criteria included unresectable or metastatic HCC; up to one prior line of systemic treatment; and at least one measurable lesion by computed tomography (CT) scan. The primary endpoint was the progression free (PF) rate at 16 weeks. Secondary endpoints included objective response rate (ORR), time to progression (TTP), progression free survival (PFS) and overall survival (OS). CT scans were assessed centrally and by the investigators; presented results are from central assessment. Results: 44 pts were enrolled from 09/07 to 08/08 at 6 centers internationally, with interim data available for 34 pts. There were 28 C-PA pts (median age, 63.5 y [range, 20- 81]) and 6 C-PB pts (median age, 64.5 y [range, 36–69]) and 73.5% received no prior systemic therapy. For the 19 evaluable C-PA pts included in the per-protocol interim analysis, 8 (42.1%) were progression free at 16 weeks [95% CI 20.3, 66.5]. The estimated ORR was 8.7% [95% CI, 1.1, 28] for the 23 C-PA pts and 0% for the 2 C-PB pts who had at least one post-baseline CT scan reviewed by central imaging. For all 34 pts, median TTP was 112 d [95% CI, 110, -], median PFS was 112 d [95% CI, 61, 168] and median OS was 295 d [95% CI, 182, 333]. The most common adverse events (AEs) for all pts were hypertension (41%), fatigue (47%), diarrhea (38%), rash (35%), proteinuria (24%), vomiting (24%), cough (24%) and oedema peripheral (24%). The most common grade 3/4 AEs for all pts were hypertension (20.6%) and fatigue (11.8%). Most AEs were mild/moderate and reversible with interruption/dose reductions/or discontinuation of ABT-869. Conclusions: ABT-869 appears to benefit HCC patients, with an estimated TTP of 112 days and an acceptable safety profile. Updated results from this ongoing study will be presented.

[Table: see text]
Continuous sunitinib treatment in patients with unresectable hepatocellular carcinoma (HCC): A multicenter phase II trial (SAKK 77/06 and SASL 23)
Authors: Koeberle D. , Montemurro M. , Samaras P. , Majno P. , Simcock M. , Kovacs K. , Inauen R. , Hess V. , Saletti P. , Bodoky G.
Published: August 2020

4591

Background: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenetic activity. Evidence for clinical activity in HCC was reported in 2 phase II trials [Zhu et al and Faivre et al, ASCO 2007] using either a 37.5 or a 50 mg daily dose in a 4 weeks on, 2 weeks off regimen. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients (pts) with HCC. Methods: Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease and Child-Pugh A or B liver dysfunction. Pts received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression free survival at 12 weeks (PFS12) defined as ‘success’ if the patient was alive and without tumor progression assessed by 12 weeks (± 7 days) after registration. A PFS12 of ≤ 20% was considered uninteresting and promising if ≥ 40%. Using the Simon-two minimax stage design with 90% power and 5% significance the sample size was 45 pts. Secondary endpoints included safety assessments, measurement of serum cobalamin levels and tumor density. Results: From September 2007 to August 2008 45 pts, mostly male (87%), were enrolled in 10 centers. Median age was 63 years, 89% had Child-Pugh A and 47% had distant metastases. Median largest lesion diameter was 84 mm (range: 18 - 280) and 18% had prior TACE. Reasons for stopping therapy were: PD 60%, symptomatic deterioration 16%, toxicity 11%, death 2% (due to tumor), and other reasons 4%; 7% remain on therapy. PFS12 was rated as success in 15 pts (33%) (95% CI: 20%, 49%) and failure in 27 (60%); 3 were not evaluable (due to refusal). Over the whole trial period 1 CR and 40% SD as best response were achieved. Median PFS, duration of disease stabilization, TTP and OS were 2.8, 3.2, 2.8 and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent and all deaths due to the tumor. Conclusions: Continuous SU treatment with 37.5 mg/d daily is feasible and demonstrates moderate activity in pts with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design the therapy is considered promising (> 13 PFS12 successes).

No significant financial relationships to disclose.
Detection of unknown primary neuroendocrine tumors (CUP-NET) using 68Ga DOTA-NOC receptor PET/CT
Authors: Hörsch D. , Prasad V. , Ambrosini V. , Hommann M. , Fanti S. , Baum R. P.
Published: August 2020

4599

Background: This bi-centric study aimed at determining the role of receptor PET/CT using 68Ga-DOTA-NOC in the detection of undiagnosed primary sites of neuroendocrine tumours (NETs). Methods: Overall 59 patients (M: F 33:26, age 65±9 yr) with documented NET and unknown primary, were enrolled. PET/CT was performed after injection of approximately 100 MBq (46–260 MBq) of 68Ga-DOTA-NOC. The maximum standardised uptake values (SUVmax) were calculated and compared with SUVmax in known pancreatic NET (pNET) and ileum / jejunum / duodenum (SI-NET). The results of PET/CT were also correlated with CT alone. Results: In 35/59 (59%) of patients, 68Ga-DOTA-NOC PET/CT localised the site of the primary: ileum/jejunum (14), pancreas (16), rectum (2), lungs (2) and paraganglioma (1). CT alone (on retrospective analyses) confirmed the findings in 12/59 (20%) patients. The mean SUVmax of identified previously unknown pNET and SI-Net were 18.6 ± 9.8 (range 7.8–34.8) and 9.1± 6.0 (range 4.2–27.8), respectively. SUVmax in patients with previously known pNET and SI-NET were 26.1± 14.5 (range 8.7–42.4) and 11.3±3.7 (range 5.6- 17.9). The SUVmax of the unknown pNET and SI-NET were significantly lower (p< 0.05) as compared to the ones with known primary tumour sites. 19% of the patients had high grade, and 81% low grade NET. In 4/59 patients the primary tumour was subsequently resected (2 pancretic, one ileal and one rectal tumour). Conclusions: Our data indicate that 68Ga- DOTA-NOC PET/CT is highly superior to 111In Octreoscan (17% detection rate for CUP according to literature) and can play a major role in the management of patients with CUP-NET.

No significant financial relationships to disclose.
A phase II trial of erlotinib in combination with gemcitabine and capecitabine in previously untreated metastatic/recurrent pancreatic cancer: Combined analysis with translational research
Authors: Oh D. , Lee K. , Lee K. , Sohn C. , Park Y. , Zang D. , Ryoo H. , Bang Y.
Published: August 2020

4607

Background: To confirm the efficacy and toxicity of erlotinib (E) in combination with gemcitabine (G) and capecitabine (C) when used as a first-line therapy in patients (pts) with metastatic/recurrent pancreatic cancer Methods: Pts with advanced pancreatic adenocarcinoma, with measurable lesion were eligible for the study. Other eligibility criteria included: no previous palliative chemotherapy, Karnofsky performance status (PS)≥50, adequate organ function. Locally advanced pancreatic cancer was excluded. E was given at a dose of 100mg daily from D1 to D28. G was given at a dose of 1000mg/m2 on D1,8,15 and C was given at a dose of 1660mg/m2/d from D1 to 21, repeated every 4 weeks. Response was assessed every 8 weeks. Tumor tissue and blood sample was analyzed for the translational research. Results: A total of 47 pts were enrolled between Feb 2007 and Feb 2008. (median age: 58 y, Karnofsky PS100/90/80/70/60 (6/26/9/5/1)). Forty three pts were evaluable for response. Partial responses were achieved in 14 patients, resulting in response rate of 32.6%. Twenty two pts (51.2%) had stable disease. Overall disease control rate was 83.7%. The PFS was 6.5 months (95% CI, 3.4–9.7) and the overall survival was 12.0 months (95% CI, 8.6–15.9). The Gr 3/4 hematologic toxicities were: neutropenia (6.8%), thrombocytopenia (3.2%), anemia (1.6%). The major Gr 3/4 nonhematologic toxicities were: nausea (1.6%), vomiting (1.6%), anorexia (5.3%), rash (0.5%). EGFR, pEGFR, TS, TP, DPD was overexpressed in 77.4%, 17.1%, 82.4%, 53.6% and 61.3% of tumor tissues respectively. EGFR amplification was not detected. Among these, the EGFR expression was significantly associated with shorter PFS and OS (p=0.029, p=0.005 respectively). K-RAS mutation was detected in 47.5%. PFS and OS were not different according to K-RAS mutation. RRM1 2455G>A, RRM1 2464G>A, CDA 79A>C, CDA 435C>T polymorphism did not influence on the PFS and OS. Conclusions: Erlotinib in combination with gemcitabine and capecitabine showed promising efficacy and good tolerability in metastatic pancreatic cancer. This efficacy was observed irrespective of K-RAS mutation, and the EGFR expression was poor prognostic factor for PFS and OS.

No significant financial relationships to disclose.
Final analysis of a multicenter, randomized phase II trial comparing three different chemoradiotherapy regimens in the treatment of patients with locally advanced, nonmetastatic pancreatic cancer
Authors: Wilkowski R. , Boeck S. , Ostermaier S. , Sauer R. , Herbst M. , Fietkau R. , Flentje M. , Bruns C. J. , Rau H. G. , Heinemann V.
Published: August 2020

4610

Background: To date, no standard treatment approach for patients (pts) with non-resectable, locally advanced pancreatic cancer (PC) is defined. Methods: Within a prospective phase II trial treatment-naive pts with locally advanced PC and adequate organ function were randomly assigned to three different CRT regimens; all pts received a conventionally fractionated radiotherapy of 50 Gy (with a daily dose of 2.0 Gy) and were randomized to either concurrent 5-FU as a 24h-infusion (350 mg/m2/d on each day of radiotherapy, RT-5FU arm), concurrent low-dose gemcitabine 300 mg/m2 and cisplatin 30 mg/m2 on days 1, 8, 22, and 29 (RT-GC arm), or the same concurrent treatment followed by a sequential chemotherapy with full- dose gemcitabine (1000 mg/m2) and cisplatin (50 mg/m2) every two weeks (RT-GC+GC arm). Treatment duration in the RT- GC+GC arm was upon disease progression or unacceptable toxicity. The primary study endpoint was the overall survival (OS) rate after 9 months (mo); secondary endpoints included response rate (WHO criteria), progression-free survival (PFS), resectability and toxicity. Results: Ninety-five patients (median age 64 years, 54% male, 50% KPS 90–100%) were recruited from 12 German centers. Seventy patients were evaluable for objective response: the intent-to-treat response rate (CR+PR) was 19% in the RT-5FU arm, 22% in the RT-GC arm and 13% in the RT-GC+GC arm, respectively. Overall, 18 pts (19%) underwent surgical resection after initial CRT (R0 in 8 pts). After a median follow-up of 8.6 mo, median PFS was estimated with 4 mo (RT-5FU), 5.6 mo (RT-GC) and 6 mo (RT- GC+GC), respectively (p=0.21). The corresponding median OS times were 9.6 mo, 9.3 mo and 7.3 mo (p=0.61). Hematological grade 3/4 toxicities were higher in the two gemcitabine/cisplatin-containing arms, but no grade 3/4 febrile neutopenia was observed. Regarding non-hematological toxicity, nausea/vomiting were more frequently in the RT-GC and RT-GC+GC arm, whereas diarrhea was more frequent in the RT-5FU arm. Conclusions: Based on these data, gemcitabine/cisplatin-based CRT does not achieve a higher clinical efficacy compared to RT-5FU, and is associated with increased hematological toxicity.

[Table: see text]
Soluble iC3b as an early marker for pancreatic adenocarcinoma compared to CA 19.9 and radiology
Authors: Marten A. , Büchler M. W. , Wente M. N. , Schmidt J.
Published: August 2020

4626

Background: Pancreatic adenocarcinoma as an aggressive tumor still lacks specific markers. Resection offers the only potential cure, and earlier diagnosis could benefit many patients. Here, we analyzed siC3b as a potential diagnostic marker.siC3b is generated in the fluid phase after binding of auto-antibodies to tumor cells and subsequent inactivation of the complement cascade by interaction with complement regulatory proteins. Methods: 232 plasma samples from subjects with adjuvant treatment after resection, from healthy volunteers and from vulnerable patients were collected prospectively and analyzed for siC3b. Every three months, patients underwent imaging and the results from siC3b ELISA were categorized according to radiological-defined recurrence within four months after blood withdrawal. Furthermore, regulatory factors of the complement system were analyzed on tumor cells and in urine. Results: The most important finding was that up to four months prior to radiological defined recurrence, siC3b plasma level is increased with a sensitivity and specificity resulting in an AUC of 0.85 which could be further increased by combining it with CA 19.9 (AUC = 0.92). Complement regulatory proteins are highly expressed on pancreatic carcinoma cells and detectable in patient's urine. Conclusions: In summary, screening for siC3b in subjects with an increased risk for PDAC (patients with chronic pancreatitis, hereditary pancreatitis, after curative resection and patients with a variety of familial cancer syndromes) allows for early detection with high sensitivity, as siC3b plasma levels are increased up to four months prior to radiological evidence. Sensitivity could be further increased by combining this approach with CA 19.9.

No significant financial relationships to disclose.
Gene expression signatures to predict the response of gastric cancer to cisplatin and fluorouracil
Authors: Kim H. K. , Choi I. J. , Kim C. G. , Oshima A. , Green J. E.
Published: August 2020

4628

Background: A prospective high-throughput gene expression study was conducted to identify transcriptional profiles predictive of a clinical response to cisplatin and fluorouracil (CF) combination chemotherapy and to identify dysregulated genes associated with acquired resistance to CF. Methods: Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer (MGC) patients (pts) prior to CF (n = 123) and following the development of resistance (n = 22) at the National Cancer Center of Korea from 2001 to 2006, and analyzed using CGH and expression microarrays. We developed 2 survival risk predictors. The first predictor was constructed using genes in DNA amplicons and identified in the expression signature that correlates with survival (intrinsic resistance signature). The second predictor was based on the acquired resistance signature, which was identified by comparing matched expression array data from initially responsive patients prior to treatment with profiles obtained at progressive disease. Results: Array CGH revealed the gene amplification of MYC, EGFR, and FGFR2 whose Affymetrix U133A signals significantly correlated with a poor prognosis (P values, 0.0154, 0.0096, and 0.0057) of training set pts (n = 96). Three-gene-predicted high-risk group of the validation cohort (n = 10) demonstrated a shorter median survival than low-risk (n = 17) group (7.4 vs 16.8 months; p = 0.047). The 3-gene signature, as a continuous variable, was the independent predictor for overall survival (OS) and time to progression (TTP) (adjusted P, 0.021, and 0.012). Importantly, the acquired resistance signature strongly overlapped the intrinsic resistance signature (LS P<10-5), and was highly enriched for MYC target genes (LS p = 2x10-5). A predictor based on MYC target genes within the acquired resistance signature was the independent predictor for OS and TTP of 101 separate pts (adjusted p, 0.015, and 0.011). Conclusions: Combined overexpression of MYC, EGFR, and FGFR2 predicts a poor response of MGC pts to CF. There is significant overlap between intrinsic and acquired resistance signatures of MGC, where the MYC gene network plays a central role. This is the first demonstration that the acquired resistance signature predicts the initial response to chemotherapy.

No significant financial relationships to disclose.