bluuebunny/crossref_metadata_2025 huggingface dataset:
Tolerability of fluoropyrimidines appears to differ by region
Authors: Haller D. G. , Cassidy J. , Clarke S. , Cunningham D. , Van Cutsem E. , Hoff P. , Rothenberg M. , Saltz L. , Schmoll H. J. , Twelves C.
Published: March 2020

3514

Background: Limited information is available regarding regional differences in tolerability for fluoropyrimidines. This is an initial assessment of the Roche phase III databases on patients treated for metastatic colorectal cancer (MCRC) and adjuvant colon cancer. Methods: Retrospective multivariate analyses (logistic regression) were performed using pooled data from two identical studies (n=1189) in MCRC comparing capecitabine (X) monotherapy with i.v. 5-FU/LV (Mayo regimen) [Hoff et al. and Van Cutsem et al. JCO 2001], and from an adjuvant study (n=1861) comparing XELOX (X+oxaliplatin) with either the Mayo or Roswell Park 5-FU/LV regimens [Schmoll et al. ASCO 2005]. Treatment-related safety parameters evaluated were: all grade 3/4 AEs, grade 3/4 GI events (diarrhea, nausea, vomiting, stomatitis), and grade 3/4 neutropenia events (febrile neutropenia, neutropenia reported as AE or lab value). Dependent variables for 1st-line MCRC data were: US vs. non-US; and for adjuvant colon cancer: US vs. non-US, US vs. Asia, and RoW (rest of the world) vs. Asia. Factors in the adjusted relative risk model were: age, gender, PS, BSA, BMI, baseline creatinine clearance and treatment (X vs. 5-FU/LV; XELOX vs. Mayo vs. RP). Results: Region was significantly associated with grade 3/4 AEs and grade 3/4 GI events in both settings ( table ). There were no relevant interactions between region and type of fluoropyrimidine treatment. Reporting of grade 3/4 neurosensory toxicity was similar in the US and outside US. Conclusions: Differences in the rates of grade 3/4 toxicity were significantly associated with the region of the world in which the patients were treated. Patients treated in the US experienced the highest rates of grade 3/4 toxicity (see table ). This difference was observed for both X and for 5-FU. The reasons for these differences remain to be elucidated. Acknowledgements: C. Allegra, J. Bertino, J-Y Douillard, B. Gustavsson, G. Milano, M. O’Connell, Y. Rustum, J. Tabernero, J. Fagerberg, F. Gilberg, and F. Sirzen.

[Table: see text]

[Table: see text]
Adjuvant therapy (AT) with raltitrexed (RAL) in colorectal cancer (CRC) patients (pts) intolerant of 5-fluorouracil (5FU)
Authors: Wilson K. S. , Barnett J. B. , Gill S. , Khoo K. E. , Fitzgerald C. A.
Published: March 2020

3571

Background: Severe 5FU toxicity in AT of CRC may require discontinuation or change of therapy. RAL, a TS inhibitor, has different toxicity but similar efficacy in metastatic CRC. Excess mortality from RAL in the PETACC trial has limited its role in CRC AT. RAL AT (3 mg/m2 IV q3w) was offered at BCCA to pts with demonstrated intolerance to bolus (Mayo) 5FU. We sought to explore retrospectively the safety & efficacy of RAL AT in these pts. Methods: A search of BCCA Pharmacy & Clinical Records from Oct. 1999 to June 2004 identified CRC pts who received 5FU AT and RAL AT. Data was collected on pt and disease characteristics, therapy & follow-up (FU) status. Kaplan-Meier survival proportions were compared with historical experience. Results: Of 1,456 CRC pts who received 5FU AT, 44 pts (3%) received RAL following 5FU intolerance (42 pts GI/hem toxicity, 2 pts due to angina). Median age was 62.3 y (range 39.8 - 83.2); 31 female; 31 colon primary. Stage III: 39 pts (88.6%); N2: 14 (31.8%). Median # 5FU cycles given prior to RAL was 2 (1 - 4). 21 pts (48%) had only 1 cycle of 5FU before RAL. Grade ≥3 toxicities from 5FU occurred in 39 pts; 17 pts were hospitalised for 2 - 29d (median 8). Twelve of 44 pts also received RT. Median # RAL cycles: 5 (1–8); 77% received >3 cycles; 84% completed all planned RAL. Gr 1, 2, 3 RAL toxicity rates: 55%, 27%, 7% respectively. 1 pt was hospitalised (4 days, FN); no deaths. Median FU of living pts is 4.2 yr (range 1.4 - 6.5). Median survival for all pts is not yet reached. 3 Year Relapse free (RFS) and Overall Survival (OS) proportions were 72% (95% CI 58.5% - 85.5%) and 83.2% (95% CI 71.8% - 94.6%) resp. Stage III 3 Year RFS was 70.8% (95% CI 56.1% - 85.5%) and 3 Year OS was 83.6% (95% CI 71.4% - 95.8%). For N1 & N2 pts, 3 Year RFS was 83.8% (95% CI 69.3% - 98.3%) and 49% (95% CI 22.3% - 75.7%), and OS 91.4% (95% CI 80% - 100%) & 70.7% (95% CI 46.4% - 95%) resp. Conclusions: Severe 5FU intolerance was seen in 3% of pts. RAL AT can be given safely if further 5FU is contraindicated. Outcomes appear similar to historical experience with 5FU AT.

[Table: see text]

No significant financial relationships to disclose.
Phase II clinical study of combination therapy with irinotecan and S-1(IRIS) for inoperable recurrent advanced colorectal cancer: Hokkaido Gastrointestinal Cancer Study Group study HGCSG-0302)
Authors: Komatsu Y. , Yuki S. , Akita H. , Kudo M. , Tateyama M. , Saga T. , Megro T. , Suzuki G. , Sakata Y. , Asaka M.
Published: March 2020

3589

Background: We planned to conduct a phase II clinical study of combination therapy with irinotecan and S-1, a new oral anticancer drug of the fluorinated pyrimidine type. We reported the interium reports of this study in colorectal cancer patients at GI cancer Symposium 2006. Methods: The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20–75 years. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. Results: Forty patients were enrolled in the present study. There were 23 men and 17 women. The median age was 62 years (range: 34 to 74 years). Two patient showed grade 4 neutropenia, but the next course could be given safely after dose reduction. Three patients had grade 3 diarrhea, but therapy could be continued with addition of an antidiarrheal drug. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Interim analysis suggested excellent results, with a response rate of 50%. To date, 231 cycles (median 8, range 1–19) have been administered. Median relative dose intensity was 97% for S-1 and 87% for irinotecan. 36 pts are evaluable for efficacy: RR was 47.2% (95% CI, 30.9–63.5%) and Disease Control Rate (PR + SD) was seen in 94.4% of pts. PFS of this regimen is 320 days. MST is not reached. Conclusions: IRIS therapy achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer. It seems that IRIS is a good treatment equal to FOLFIRI. In addition, this regimen could qualify as a candidate for future combination therapy with a molecular-targeting drug. The latest data will be reported at the meeting.

No significant financial relationships to disclose.
Molecular staging with CM10 ProteinChip and SELDI-MS-TOF for colorectal cancer patients before surgery
Authors: Chen Y. , Xu W. , Zheng S. , Zhang S.
Published: March 2020

3612

Background: The objectives of this are to detect the serum proteomic patterns by using SELDI-TOF-MS technology and CM10 ProteinChip in colorectal cancer (CRC) patients, and to evaluate the significance of the proteomic patterns in the tumor staging of colorectal cancer. Methods: SELDI-TOF-MS and CM10 ProteinChip were used to detect the serum proteomic patterns of 76 colorectal cancer patients which including 10 Stage I, 19 Stage II, 16 Stage III and 31 Stage IV patients. Models for various stages were developed and validated by using Support Vector Machine, Discriminant Analysis and time-series analysis methods. Results: The first model, formed by 6 protein peaks (M/Z: 2759.58, 2964.66, 2048.01, 4795.90, 4139.77 and 37761.60 Da), could be used to distinguish local CRC patients (StageIand Stage II) from regional CRC patients (Stage III) with an accuracy of 86.67% (39/45). The second model, formed by 3 protein peaks (M/Z: 6885.30, 2058.32 and 8567.75 Da), could be used to distinguish locoregional CRC patients (Stage I,Stage II and Stage III) from systematic CRC patients (Stage IV) with an accuracy of 75.00% (57/76). The third model could distinguish Stage I from Stage II with an accuracy of 86.21% (25/29). The fourth model could distinguish Stage I from Stage III with an accuracy of 84.62% (22/26). The fifth model could distinguish Stage II from Stage III with an accuracy of 85.71% (30/35). The sixth model could distinguish Stage II from Stage IV with an accuracy of 80.00% (40/50). The seventh model could distinguish Stage III from Stage IV with an accuracy of 78.72% (37/47). All four stages could be distinguished by using a two-dimensional scattered spots figure. Conclusion: We conclude that this method is promising in the staging of colorectal cancer patients before surgery.

No significant financial relationships to disclose.
PGC-1 expression level in human colorectal cancer: A predictor of lymph node metastasis
Authors: Kwon H. , Shin S. , Roh M. S. , Choi H. J. , Kwak J. , Yang Y. S. , Park J.
Published: March 2020

3616

Background: Previous study showed that the expression of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivator-1 (PGC-1) was correlated with clinical outcome in breast cancer. However, no published data are available about the biological and clinical significance of PGC-1 in colorectal cancer. Thus, our aim was to explore the expression of PPARγ and PGC-1 in colorectal cancer as well as their association with other clinicopathological features, and to evaluate the role of PPARγ and PGC-1 as a prognostic indicator of colorectal cancer. Methods: We have investigated the presence of PPARγ and PGC-1 in human colorectal cancer tissues and adjacent normal tissues from 108 primary colorectal cancer patients by immunohistochemistry. The correlation between their expression and clinicopathologic features was investigated. Three-year overall survival of patients with different expression of PPARγ and PGC-1 were analyzed by the Kaplan-Meier method. Results: No significant correlation was found between PPARγ expression and age at surgery, gender, histopathologic differentiation, depth of infiltration, relapse, and Dukes’ stage. No significant correlation was found between PGC-1 expression and age at surgery, the histopathologic differentiation, the depth of infiltration, and relapse. However, PGC-1 expression was closely related to Duke’s stage and nodal metastasis (p=0.024 and p=0.020, respectively). Survival analysis showed that the PGC-1-positive group has a reduced overall survival (p=0.0367). Conclusions: Based on our results, PGC-1 may be valuable marker of nodal metastasis and represent a biomarker of poor prognosis in colorectal cancer.

No significant financial relationships to disclose.
P53 as a predictor of tumor burden in lymph nodes (LN) in colon cancer (Cca) patients (pts) undergoing sentinel lymph node (SLN) mapping (M)
Authors: Sehgal R. , Saha S. , Wiese D. , Parker R. , Huang W. , Arora M. , Doan K. , Ganatra R. , Yestrepsky B. , Yee C. , Patel M.
Published: March 2020

3617

Background: p53 and LN status(S) are important prognostic markers in Cca. Our study was done to evaluate whether p53 S could predict tumor burden in LNs in Cca undergoing SLNM. Methods: Pts with Cca underwent SLNM to determine the LN S. A portion of tumor was used for detection of p53 S by IHC.p53 Histo Score (HS) was defined as (Intensity of stain in cells from 0–4 +1) × (% cells staining). HS of 180 was taken as cut off for significance based on previous studies on solid tumors. Metastatic foci in SLNs and nonSLNs were measured in greatest diameter by ocular micrometer. For overall tumor burden in SLNs and nonSLNs,all metastatic foci were added for each pt. Results: SLNM was successful in 100% of the 117 consecutive pts with Cca. Pts with distant metastasis (mets) (18) and skip mets (9) were excluded. Of the remaining 90 pts,39% were SLN positive (+ve) and 61% were SLN negative (-ve). HS of ≤ 180 was found in 66% and HS >180 was found in 34% of the pts. In 55 SLN -ve pts 76% had HS ≤ 180 while 24% had HS >180. In 35 SLN +ve pts, 49% had HS of ≤ 180 and 51% had HS >180. ( Table ) Of SLN +ve pts, size of metastatic tumor in LNs was available in 86% of pts. Average (av.) non SLN met size was 0.95 cms in pts with HS ≤ 180 and 3.4 cms in pts with HS > 180. Av. SLN met size was 0.63 cms in pts with HS ≤ 180 and 0.9 cms in pts with HS>180 ( Table ). No statistical significance was found among T stage of pts with HS >180 vs ≤ 180. Conclusion: Pts with p53 HS >180 showed significantly greater tumor burden in both SLNs and non SLNs as compared to pts with HS ≤ 180. Also probability of having SLN -ve disease is higher in pts with HS ≤ 180 as compared to pts with HS >180 in Cca. Thus,even in SLN -ve pts, high HS may indicate a worse prognosis. Hence,a high p53 HS might predict pts with Cca having higher tumor burden in LNs and thus identify an aggressive subgroup of pts.

[Table: see text]

No significant financial relationships to disclose.
Population based study of prognostic factors in stage II colon cancer
Authors: Morris M. J. , Iacopetta B. , Platell C.
Published: March 2020

3619

Background: Guidelines for the use of adjuvant chemotherapy in stage II colorectal cancer state this treatment may be considered to patients whose tumours show features of poor prognosis. The aim of the current study was to evaluate the prognostic significance of commonly reported clinical and pathological features of this disease. Methods: A population-based observational study encompassing all stage II colon cancer patients diagnosed in the state of Western Australia from 1993–2003 inclusive. A total of 1306 cases treated by surgery alone were identified and had a median follow-up of 59 months (range 0–145). Results: Multivariate analysis revealed the only independent prognostic factors for disease-specific survival were T4 stage (HR=1.75, 95%CI [1.32–2.32], P<0.0001) and vascular invasion (HR=1.63, 95%CI [1.15–2.30], P<0.0001). In the younger patient group (≤75 yrs) who are more likely to be considered for chemotherapy, the same two features showed independent prognostic significance but with higher HR values (1.96 and 2.73 respectively). T4 and/or the presence of vascular invasion identified a “poor” prognosis group comprising 26% of younger cases and having a 5-year survival rate of 71%. The remaining “good” prognosis group showed 84% survival at 5 years follow-up. Conclusion: This study highlights the importance of accurate pathological assessment of T stage and vascular invasion for the prognostic stratification of stage II colon cancer and their subsequent consideration for adjuvant chemotherapy.

No significant financial relationships to disclose.
QoL and resource use analysis of tegafur-uracil/LV or 5-FU/LV in first-line metastatic colorectal cancer (mCRC): Final results of a multicenter phase II study
Authors: Sizer B. , Makris A. , Barone C. , Mainwaring P. , Eggleton P.
Published: March 2020

3631

Background: Tegafur-uracil (UFT) is an effective oral fluoropyrimidine for patients with mCRC. Aims of this prospective phase II study were to evaluate quality of life (QoL), patient preference and healthcare resource use in patients receiving oral UFT/LV or i.v. 5-FU/LV as first-line therapy for mCRC. Safety and efficacy were also assessed. Methods: 243 patients in 3 countries (Austria, Italy and UK) were randomized in a 2:1 ratio to receive either UFT 300mg/m2/d + LV 90mg/d for 28d q5w, or i.v. 5-FU 425mg/m2/d + LV 20mg/m2/d for 5d q4w. Patients were assessed at baseline and every cycle for symptoms, adverse events (AEs), and overall response rate (ORR). QoL was evaluated using EORTC QLQ-C30, and patients completed a preference questionnaire at baseline, end of cycle 1, and end of study. Data on hospital attendances (in- and out-patient), physician visits, concomitant medication use and other healthcare resources were collected for every cycle and during study follow up. Results: 162 patients received UFT/LV (median 3 cycles) and 81 i.v. bolus 5-FU/LV (median 4 cycles). Patient demographics were similar in both groups: median age was 70y (range 39–83) for UFT/LV and 69y (41–80) for 5-FU/LV; 92% of patients were ECOG PS ≤1. QoL was maintained in the UFT/LV group with little variation across time whereas QoL deteriorated with 5-FU/LV. Most patients in the UFT/LV (85–95%) and 5-FU/LV (49–66%) groups stated a preference for oral treatment with the most common reason being ‘taken at home’ (83%). Fewer UFT/LV patients had one or more hospitalizations for AEs (21% vs. 36%). Clinical benefit (ORR+SD) was 32% with UFT/LV (41% evaluable for response) and 32% with 5-FU/LV (45% evaluable). Median time to disease progression was 173d (95% CI 140–199) for UFT/LV and 168d (95% CI 133–205) for 5-FU/LV. Median overall survival was 385d (95% CI 296–472) for UFT/LV and 330d (95% CI 252–484) for 5-FU/LV. Conclusions: UFT with LV has comparable efficacy to i.v. 5-FU/LV in first-line mCRC, with the advantages of favorable QoL, patient preference for oral treatment, and fewer hospitalizations for managing AEs.

[Table: see text]
Tissue factor, angiogenesis and thrombosis in pancreatic cancer
Authors: Khorana A. A. , Francis C. W. , Ryan C. K. , Taubman M. B. , Hu Y. C. , Ahrendt S. A.
Published: March 2020

4001

Background: Coagulation proteins are commonly activated in pancreatic cancer and are closely linked to regulation of angiogenesis. We investigated tumor cell expression of tissue factor (TF), the prime initiator of coagulation, and its association with parameters of angiogenesis, venous thromboembolism (VTE) and survival. Methods: Tissue cores from a bi-institutional retrospective series of patients consecutively resected between January 1994 and February 2002 and followed for a median period of 16 months were used to build a pancreatic cancer tissue microarray. TF expression was graded semiquantitatively using immunohistochemistry (IHC)(grade 0:negative, grade 1: 1- 33% positive, grade 2: 34- 66% positive and grade 3: > 66% cells positive) in pancreatic intraductal dysplasia (n=5) and resected pancreatic cancer (n=122). Study endpoints included correlation of TF with VEGF expression by IHC, microvessel density (MVD), clinical VTE and survival in resected patients. Patients with history of VTE, on anticoagulation or with inadequate follow-up were excluded from analysis of VTE outcomes (n=33). Results: TF expression was observed in all specimens with intraductal dysplasia and 108 resected pancreatic cancers (89%) but not in uninvolved pancreas. Sixty-six patients (54%) with resected pancreatic cancer were found to have high TF expression (defined as ≥ grade 2, the median score), and 56 patients (46%) had low or no TF expression. Tumors with high TF expression were more likely to also express VEGF (80% versus 27% with low TF expression, p<0.0001). Tumors with high TF expression had a higher median MVD (8 versus 5/tissue core with low TF expression, p=0.01). Resected patients with high TF expression had a VTE rate of 20% compared to 5.5% in patients with low TF expression (p=0.04). Median survival in tumors with high TF was 17.9 months versus 12.6 months in those with low TF (p=0.16). Conclusions: TF expression appears to occur early in pancreatic cancer pathogenesis. This is the first report describing an association of TF expression with VEGF expression, increased MVD and clinical VTE in resected pancreatic cancer, confirming the linkage of thrombosis and angiogenesis. Targeting TF in pancreatic cancer could affect both neoplastic and thrombotic outcomes.

No significant financial relationships to disclose.
Phase II study of lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase 1 and 2 (Her2/Neu) in patients (pts) with advanced biliary tree cancer (BTC) or hepatocellular cancer (HCC). A California Consortium (CCC-P) Trial
Authors: Ramanathan R. K. , Belani C. P. , Singh D. A. , Tanaka M. , Lenz H. J. , Yen Y. , Kindler H. L. , Iqbal S. , Longmate J. , Gandara D. R.
Published: March 2020

4010

Background: Advanced BTC (gallbladder, bile duct) and HCC respond poorly to systemic chemotherapy. Lapatinib is an oral inhibitor of EGFR and Her/2-neu with evidence of activity in a number of tumor types. Both BTC and HCC overexpress EGFR 1 and 2. In addition, Her2/neu somatic mutations have been reported in HCC, and may predict response to EGFR targeted agents (Bekaii-Saab et al, A 4037, ASCO 2005). This trial conducted by the CCC-P and Univ. Chicago, is designed to determine the efficacy of lapatinib in BTC and HCC pts. Methods: A two-stage design is utilized and pts are stratified by tumor type (BTC or HCC); the study has a 90% power to detect a true response rate ≥20%. Two initial groups of 17 patients for BTC and HCC were accrued; one response from each was required to proceed with accrual to a total of 37 patients in each group. Adequate hematologic, renal, and hepatic function is required. Eligible pts are in Child A group and have ECOG PS of 0–2. One prior treatment regimen is allowed. Lapatinib dose is 1,500 mg/d orally without interruption. One cycle is 28 days and radiological assessment is done every 8 weeks. Results: 49 pts have been accrued (BTC 19 and HCC 30). Pt Characteristics: Male 59%, ECOG PS 0 (18 pts), ECOG PS 1 (22 pts). Median age 66 yrs (range19–82). Median cycles 2 (range 1–12). Grade 3/4 toxicity was noted in 19 pts and included fatigue in 4 pts, elevation of liver enzymes in 4 pts and diarrhea in 2 pts. Nausea, vomiting, rash, anemia and thrombocytopenia were noted in 1 pt each. There was no evidence of cardiac dysfunction. In 17 evaulable pts with BTC, no responses were observed, 5 had stable disease (SD). Among the first 17 pts with HCC, 2 confirmed partial responses have been recorded. In addition 8 pts have SD. The progression free survival is 1.8 mo for both BTC and HCC. Tumor and blood specimens are being analyzed for expression of EGFR, HER-2/neu, status of downstream signal pathway molecules, and correlation to response. Conclusions: Lapatinib is well-tolerated. No activity in BTC was noted and that cohort is closed. Lapatinib activity in HCC is encouraging, and study is close to completion. Source of support: NCI-NO1-CM-57018–16.

[Table: see text]
Surgery plus ELFE (epirubicin, leucovorin, 5-fluorouracil and etoposide) vs surgery alone in radically resected gastric cancer (GC): Final results of a randomised phase III trial by the Gruppo Oncologico dell’ Italia Meridionale (GOIM)
Authors: De Vita F. , Giuliani F. , Gebbia V. , Galizia G. , Orditura M. , Maiello E. , Romito S. , Cartenì G. , Manzione L. , Catalano G. , Colucci G.
Published: March 2020

4014

Background: In a previous phase II study the ELFE regimen resulted to be active and well tolerated for the treatment of advanced GC (Am J Clin Oncol 22:262;1999). Based on this background the G.O.I.M. conducted a randomised phase III study (trial 9602) to evaluate efficacy and toxicity of ELFE regimen as adjuvant therapy for radically resected GC patients (pts). Methods: All enrolled pts underwent total or subtotal gastrectomy with at least a D1 lymphoadenectomy. After stratification for nodal involvement (N+ vs N-) pts were randomised to follow-up alone (116 pts) or 6 cycles of ELFE regimen ( EPI 60mg/m2 d1, LV100 mg/m2 d 1–5, 5FU 375 mg/m2 d 1–5, VP-16 100 mg/m2 d1–3, every 3 weeks). Results: From June 1997 to June 2001, 228 pts with stage IB-IIIB GC were enrolled. Pts characteristics were: median age 63 yrs (29–70); total gastrectomy 148 pts; N+ 163 pts; PS 0–1 according ECOG scale 210. A total number of 638 cycles were delivered with a median number of 5/pt. During chemotherapy, the most frequent G3–4 side-effects graded according to NCI-CTC included alopecia (32%), neutropenia (26%), diarrhea (26%), nausea/emesis (17%), thrombocytopenia (12%) and stomatitis (11%). With a median follow-up of 60 months, the 5-years overall survival was 48% in the treatment arm and 43.5% in the control arm ( p=0.610); the 5-years disease-free survival was 44% in the treatment arm and 39% in the control arm ( p=0.305). Between patients with positive nodes the 5-years overall survival was 41% in the treatment arm and 34% in the control arm( p=0.068), while the 5-years disease-free survival was 39% in the treatment arm and 31% in the control arm (p=0.052). Multivariate analysis showed TNM stage as the only covariate that was independently associated with overall and disease-free survival. Conclusions: In radically resected GC adjuvantELFE chemotherapy produces an absolute difference in overall survival and disease-free survival at 5 years respectively of 4.5% and 5%, but this advantage was not statistically significant.

No significant financial relationships to disclose.
Phase II trial of preoperative cisplatin-irinotecan followed by concurrent cisplatin-irinotecan and radiotherapy: PET scan after induction therapy may identify early treatment failure
Authors: Ilson D. H. , Bains M. , Rizk N. , Shah M. , Rusch V. , Capanu M. , Flores R. , Kelsen D. , Park B. , Kepler S. , Minsky B.
Published: March 2020

4023

Background: Response on PET scan during preoperative chemotherapy (chemo) for esophageal cancer (EC) has prognostic significance [JCO 19:3058;2001]. Induction chemo with weekly irinotecan(I)/cisplatin(C) relieves dysphagia, and weekly I/C administered with radiotherapy (RT) is well tolerated [ProcASCO 23:Abs 4017;2005]. We completed a Phase II trial of induction I/C followed by I/C/RT followed by surgery. Repeat PET scan was performed after induction chemo and prior to RT. Methods: Patients (pts) with resectable EC/GE junction carcinoma were staged with EUS, PET, and CT scan. Induction chemo consisted of I-65 mg/m2 and C-30 mg/m2 weeks 1,2,4,5, and weeks 7,8,10,11 with RT (180 cGy daily fractions to 5040 cGy). PET scan was repeated at week 6. Esophagectomy was planned 4–8 weeks after RT. Results: 60 pts were enrolled: 6 inevaluable, 54 evaluable, 3 await surgery; 49 male (91%), 5 female (9%), 41 adenocarcinoma (76%), 13 squamous (24%), median age 59, median PS 0, EUS T3N1 35 (65%), N1 40 (74%). Of 41 pts with dysphagia, 31 (76%) had resolution/improvement with induction chemo and 3/54 (6%) required a feeding tube. Of 51 pts, 3 clinical complete responders (CR) deferred surgery (1 refusal, 2 medically inoperable). Of 48 pts, 4 progressed during induction (8%), 9 progressed during RT (19%), and 35 underwent R0 resection (73%). 9/48 (19%) achieved pathologic CR. The median overall survival was 35.4 mos (median follow up 15 mos). In exploratory analysis in 54 pts, response after induction on the week 6 PET scan measured as a decline in SUV, correlated with time to tumor progression (TTP). The mean change in SUV was 43%. A set point of 22% or greater decline in SUV (PET responder) yielded the greatest distinction in TTP (PET responders TTP 18.5 mos, vs nonresponders 5.5 mos, p = 0.03). 4 pts with progression during induction crossed over to RT with paclitaxel: 3 (2 squamous, 1 adenocarcinoma) achieved durable disease control (one pathologic CR, one pathologic PR, one clinical CR). Conclusions: Response on PET scan during induction chemo for EC may identify early treatment failures, and may direct pts to successful salvage with alternative chemo during RT. Supported by a grant from Pfizer.

[Table: see text]
Randomized phase II trial comparing gemcitabine/cisplatin-based chemoradiotherapy (CRT) to 5-FU-based CRT in patients with locally advanced pancreatic cancer
Authors: Wilkowski R. , Rau H. , Bruns C. , Wagner A. , Sauer R. , Hohenberger W. , Koelbl O. , Heinemann V.
Published: March 2020

4038

Background: CRT is a relevant treatment option for patients with unresectable pancreatic cancer. Up to now, 5-FU has been the drug of choice for concurrent CRT. Based on evidence that also gemcitabine may improve the antitumor activity of radiation, a randomized phase II trial was undertaken. Methods: Patients with locally advanced, non-metastatic and histologically proven pancreatic cancer were included into a three-arm trial. In arm treatment arm A, radiation (CTV I up to 50.0 Gy, conventional fractionation) was applied concurrently with protracted venous infusion of 5-FU (350 mg/m2/irradiation day). In treatment arm B, patients received radiotherapy together with gemcitabine (300 mg/m2/d 30 minute infusion) and cisplatin (30 mg/m2/d 60 minute infusion) applied on days 1, 8, 22, and 29. In treatment arm C, patients received an identical regimen of CRT as described for arm B which was followed by 4 cycles of chemotherapy with gemcitabine (1000mg/m2, 30 min iv) plus cisplatin (50mg/m2) applied at 2-week intervals. Patients were stratified for Karnofsky performance status (KPS ≥80% vs. <80%). The primary end-point of the trial was the 9-months survival rate. Results: Ninety-six patients with a median age of 63.5 years (range 40–75 years) were included into the trial from 01/02 until 06/05 (arm A: 32 patients, arm B: 33 patients, arm C: 31 patients). Two patients did not complete CRT. At the time of evaluation, 66 patients (70.2%) had died. 9-months survival rate was 60%, 58%, and 46% in treatment arms A, B, and C, respectively. Median overall survival in arm A was 9.6 mo (95% CI, 8.7–10.5 mo), in arm B 9.6 mo (95%CI, 7.4–11.8 mo), and in arm C 6.1 mo (95% CI, 1.6–10 mo). Secondary end-points such as treatment-related toxicity, response rate, secondary resectability, and time to progression are under evaluation. Conclusions: CRT with gemcitabine plus cisplatin is not superior to 5-FU-based CRT with regard to the primary end-point of 9-months survival rate. Updated results will be presented at the meeting.

No significant financial relationships to disclose.
Concomitant administration of weekly oxaliplatin, 5FU continuous infusion and radiotherapy in locally advanced pancreatic cancer (LAPC): A GERCOR phase II study
Authors: Moureau-Zabotto L. , Phélip J. , Afchain P. , Mineur L. , André T. , Vendrely V. , Lledo G. , Dupuis O. , Touboul E. , Balosso J.
Published: March 2020

4039

Background: According to previous GERCOR studies in LAPC, concomitant chemoradiation therapy (CCRT) is indicated for non-progressive patients (pts) after systemic chemotherapy (CT). In order to improve the results of a classical 5FU-based CCRT, this study was designed to assess the efficacy and toxicity of weekly oxaliplatin (Ox), 5FU continuous infusion (c.i.) and radiation therapy (RT) in LAPC pts. Methods: Eligibility criteria included non resectable pathologically-proven LAPC, age > 18 yrs, PS < 2, and no prior CT or RT. All patients were first treated with 4 cycles of GEMOX (gemcitabine 1000 mg/m2, 100 min IV, d1; Ox 100 mg/m2, 2h IV, d2, every 2 wk). One month after cycle 4, non-progressive pts with PS < 2 received 45 Gy (25 fractions, 5 d/wk) + 10 Gy (concomitant boost in macroscopic tumor during wks 4 & 5, six hours apart large volume irradiation), combined with 250 mg/m2/d 5FU c.i. and weekly Ox. Initial 50 mg/m2 Ox dose was increased to 60 mg/m2 in absence of unacceptable toxicity after the 3 first included pts. Results: 60 pts were included (29 F/ 31 M, age 65.8 ± 9.6 yrs, range 37 - 80). 50 pts (83%) received CCRT, while 10 did not for the following reasons: metastatic progression (7 pts), OMS>2 (1), and CT toxicity (2). 44 pts (73 %) received the full planned CCRT dose-intensity. NCI-CTC grade 3–4 toxicities during CCRT and the following month (% of pts) were : neutropenia (14%), thrombocytopenia (10%), nausea-vomiting (20%), diarrhea (12%) and neuropathy (2%). 2 toxic deaths occurred during CCRT. With a median follow up of 15 mo, median progression-free survival (PFS) and overall survival (OS) of the whole population were 7.6 mo and 13.8 mo, respectively. For pts who received CCRT, median PFS and OS were 9.4 and 13.9 mo, respectively (2.6 and 9.9 mo, respectively, for pts who did not received CCRT). Conclusion: Chemotherapy before CCRT can identify pts who might potentially benefit of CCRT. Concomitant administration of weekly Ox, continuous IV FU and RT in LAPC is feasible with an acceptable toxicity. The results in terms of PFS and OS compare favourably with a classical 5FU-based CCRT.

[Table: see text]
Changing patterns of prognosticators during long-term follow-up of gastric cancer after D2–3 resection and adjuvant chemotherapy: 15-year follow-up at one Korean institution
Authors: Jeung H. C. , Moon Y. W. , Rha S. Y. , Noh S. H. , Kim G. E. , Kim B. S. , Chung H. C.
Published: March 2020

4050

Background: Clinical outcome of long-term follow-up after 5 years of gastrectomy, such as recurrence or survival rate, recurrence patterns, and prognosticators, have not been studied well. We evaluated long-term natural history of gastric cancer with a median follow up duration of 15 years after D2–3 resection and adjuvant chemotherapy at a single institution. Especially in survived patients after 5 years of surgery, we analyzed risk factors for recurrence or survival. Methods: A total of 525 patients with stage IB to IVM0 (AJCC 2002) were accrued between 1984 and 1996. As a standard surgery, radical gastrectomy with D2–3 lymphadenectomy was performed. All the patients had adjuvant 5-FU plus adriamycin chemotherapy and 160 of them had also immunotherapy with poly A:U. Results: The median follow-up duration was 191 months. 15 patients (2.9%) were lost to follow-up with median follow-up of 45 months. 15-year disease-free and overall survival rates were 49.5% and 42.9%, respectively. In survivors after 5 years, recurrence rate was 16.0% (11.3% between 5 and 10 years; 4.7% after 10 years). The dominant recurrence patterns were distant metastasis (29.0%) between 5 and 10 years and secondary cancer (53.9%) after 10 years of surgery. Stage (IB vs II vs IIIA vs IIIB vs IVM0) was a clear-cut prognosticator during 5 years of gastrectomy, but its significance was lost between 5 to 10 years. At this time, only stage IVM0 was a significant poor prognosticator for gastric cancer-specific recurrence (HR = 6.61; P = 0.000) and cancer-specific death (HR = 7.04, P = 0.000). However, stage did not represent any significance after 10 years of surgery. Conclusions: In gastric carcinoma with D2–3 resection and adjuvant treatment, late recurrences after 5 years of surgery were not rare. Prognosticators were different in survivors after 5-years, 5–10 years and more than 10 years of surgery.

No significant financial relationships to disclose.
Thymidylate synthase polymorphisms and its mRNA expression levels as independent chemo-predictive markers in esophageal adenocarcinoma patients receiving 5-fluorouracil chemotherapy
Authors: Kuramochi H. , Tanaka K. , Lehman B. J. , Dunst C. M. , Oh D. S. , Demeester S. R. , Hagen J. A. , Danenberg K. D. , Demeester T. R. , Danenberg P. V.
Published: March 2020

4063

Background: Thymidylate synthase (TS) has either a two or three 28bp tandemly repeated sequence in the 5’ untranslated (UTR) region. The triple repeat allele (3R) is classified into 2 subgroups (3RG, 3RC) according to a G/C polymorphism in the 3R sequences. Another polymorphism is a 6bp deletion in the 3’-UTR region. The genotype with either 3RG allele or 6bp insertion allele has been reported to be associated with high TS expression and chemoresistance to 5-FU. Methods: 83 patients with esophageal adenocarcinoma were assessed. Thirty-four had received 5-FU containing chemotherapy (16 adjuvant therapy, 12 upon recurrence, 3 both adjuvant and recurrence, 3 neoadjuvant) and 49 were treated with surgery alone. Surgically resected tumor tissues were analyzed for TS genotype and TS mRNA expression using a quantitative real-time RT-PCR method after microdissection. Results: No survival difference was seen between the patients with 3RG allele (3RG group) and non-3RG group among surgery-alone patients. However, among patients with a history of 5-FU-based chemotherapy, the non-3RG group showed significantly better overall survival compared to the 3RG group (p = 0.02). Moreover, whereas chemotherapy produced a significant increase in survival for the non-3RG group patients, those in the 3RG group obtained no survival benefit from chemotherapy. Patients with low TS mRNA levels had significantly better survival than the patients with high TS mRNA levels (p = 0.03) among chemotherapy-treated patients, despite the fact that there was no difference of median TS mRNA levels between 3RG and non-3RG group. Those who had both the non-3RG genotype and low TS mRNA levels obtained a significantly better survival benefit from chemotherapy than others (p = 0.02). The 3’-UTR polymorphism did not appeared to be associated with overall survival. Conclusions: The status of the TS 5’-UTR polymorphism and TS mRNA expression are independent predictive markers for survival benefit from 5-FU-based therapy in patients with esophageal adenocarcinoma.

[Table: see text]
Randomised phase II study evaluating weekly docetaxel in combination with cisplatin and 5FU or capecitabine in metastatic oesophago-gastric cancer
Authors: Tebbutt N. , Gebski V. , Strickland A. , Gibbs D. , Walpole E. , Ganju V. , Goldstein D. , Munro S. , Harrod M. , Van Hazel G.
Published: March 2020

4067

Background: Docetaxel (T), cisplatin (C) and 5FU (F) are active agents in oesophago-gastric cancer. A recent phase III study using TCF achieved a survival advantage but was associated with high rates of haematological toxicity (30% incidence of febrile neutropenia/neutropenic infection) as well as non-haematological side effects (Moiseyenko et al, 2005 Pr ASCO abstr 4002). Weekly docetaxel is associated with a lower incidence of haematological toxicity. This randomised phase II study aimed to test weekly docetaxel based combination chemotherapy regimens with the aim of maintaining the activity of docetaxel based combination regimens but reducing toxicity. Methods: Eligibility included; histologically confirmed, metastatic oesophageal or gastric (OG) carcinoma, measurable disease, PS0–2, adequate organ function, no prior treatment, informed consent. Pts were randomised to receive weekly (w) T 30 mg/m2 d1, 8 C 60 mg/m2 d1 F 200 mg/m2/d continuously q 3w or wT 30 mg/m2 d1, d8 and capecitabine (×)1600 mg/m2/d d1–14 q3w. The primary endpoint is confirmed response rate (RR), with each arm analysed independently. Simon’s 2 stage design was used, with 5/21 responses required in the first stage to allow continuation to 48 pts per arm. Results: 79 pts enrolled to date. Protocol specified interim analysis of efficacy after 21 pts per arm and of toxicity after 25 pts per arm ( Table ). In the first 21 pts per arm; 12 responses (11 confirmed) in wTCF arm, 6 responses (5 confirmed) in wTX arm. Trial continues accrual to target of 48 pts per arm. Complete accrual expected by April 2006. Updated data will be presented at the meeting. Conclusions: wTCF and wTX have encouraging activity and and a more favourable toxicity profile than TCF administered 3-weekly.

[Table: see text]

[Table: see text]
A phase II study of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin (FOLFOXIRI) as a first-line chemotherapy in metastatic gastric cancer
Authors: Lee J. , Kang W. , Lee S. , Kwon J. , Kim H. , Lee H. , Lim H. , Park J. , Park Y. , Park K.
Published: March 2020

4076

Background: Previous phase II study showed a high efficacy and safety of FOLFOXIRI (irinotecan, oxaliplatin, 5-fluorouracil, leucovorin) combination chemotherapy in metastatic colorectal cancer. This non-randomized open label phase II study evaluated the efficacy and safety of FOLFOXIRI in metastatic or recurrent gastric cancer patients. Methods: Patients with: histologically proven, bidimensionally measurable, metastatic gastric adenocarcinoma, age 18 - 70 years, with a performance status 0 - 2, no prior chemotherapy or at least 12 months after adjuvant therapy, life expectancy > 3 months, signed written informed consent were eligible. Treatment consisted of irinotecan 150 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 100 mg/m2 day and 5-fluorouracil 2000 mg/m2 as a 48-h continuous infusion starting on day 1, repeated every 2 weeks until unacceptable toxicity, patients’ refusal, or up to 12 cycles. The planned sample size was 48 and the primary endpoint was response rate. Results: From August 2004 to August 2005, 48 patients were prospectively enrolled. The median age was 54 years (24 - 69) and male:female ratio was 1.3:1. In total, 379 cycles were administered with a median of 9 cycles per patient (range, 1–12) and 45/48 patients were evaluable for treatment response. Three patients were not assessable for response due patients’ refusal for further chemotherapy following the first cycle. By per-protocol analysis, the objective response rate was 73.3 % (95% CI, 60.8–85.8) with 2 CRs and 31 PRs. Four patients (9%) had stable disease and 8 patients (18%) had progressive disease. The estimated median survival of all patients was 14.0 months (95% CI, 11.8 - 16.2 ) and the estimated median time-to-progression was 8.9 months (95% CI, 6.7–11.0). In total of 379 cycles administered, most common grade 3/4 toxicities were neutropenia (11% of all cycles) and emesis (12%). Grade 2 peripheral neuropathy occurred in 5 patients. One (2%) patient had severe tumor bleeding and 5 (10%) patients experienced grade 3 diarrhea. Conclusions: FOLFOXIRI combination chemotherapy showed a very promising preliminary anti-tumor activity and was generally well tolerated as a first-line treatment for patients with metastatic gastric cancer.

No significant financial relationships to disclose.
Small bowel adenocarcinoma: A review of 491 cases
Authors: Halfdanarson T. R. , Quevedo F. , McWilliams R. R.
Published: March 2020

4127

Background: Small bowel adenocarcinoma (SBA) is a rare tumor accounting for less than 2% of all GI tumors. The prognosis of advanced disease is poor. Benefits of adjuvant therapy following complete resection are uncertain. Methods: We retrospectively reviewed the records of 491 pts with primary SBA diagnosed at the Mayo Clinic from 1970–2005. Patients with ampullary and periampullary tumors were excluded. Results: 303 pts (62%) were male and the median age was 62 years. 280 (57%) of the tumors were located in the duodenum, 143 (29%) in the jejunum, 48 (10%) in the ileum and in 20 (9%) the location was not specified. Abdominal pain was the most common principal symptom occurring in 203 pts (43%), followed by anemia/GI bleeding in 104 pts (22%) and nausea/vomiting in 76 pts (16%). The most common histologic grading was 3, occurring in 224 pts (45%). 79 pts (16%) grade 4, 170 pts (35%) grade 2, with 7 (1.4%) grade 1. The TNM staging was as follows: 0: 3 (0.6%), I: 36 (7.3%), II: 133 (27.1%), III: 137 (27.9) and IV: 163 (33.2). In 18 pts (3.7%), data were insufficient for staging. The median survival for the entire cohort was 20.7 months, with 5 and 10 year survival 26% and 19% respectively. Increasing age (p < 0.0001), male sex (p = 0.026), advanced stage (p < 0.0001), grade 4 tumors (p = 0.005) and residual disease after surgery (p < 0.0001) were independently associated with shortened survival in a multivariate analysis. Neither adjuvant chemoradiation (n = 40) nor 5-FU based chemotherapy (n = 33) improved overall survival after complete resection, even after adjusting for age, sex, location, lymph node status and grade (RR 1.17, p = 0.45). This remained true for the subset of patients with resected duodenal tumors as well (RR 1.06, p = 0.83). The use of chemotherapy was associated with prolonged survival in patients with metastatic disease. The median survival and 1-year survival was 15.3 mos vs. 3.1 mos and 59% vs. 5.9% respectively (p < 0.0001), in this highly selected group. Conclusion: SBA is a rare tumor with a relatively poor prognosis. Complete resection of all disease offers the only chance of cure. The benefits of adjuvant therapy remain unknown, but chemotherapy in the metastatic setting may provide survival benefit.

No significant financial relationships to disclose.
A combination of capecitabine and thalidomide in patients with hepatocellular carcinoma
Authors: Jeong W. , Chun H. G. , Cer D. , Sekhri V. , Kim-Schluger L. , Wolf D.
Published: March 2020

4142

Background: Based on the single-agent efficacies observed in phase II trials (Cancer 2004;101:578–586 and Cancer 2005;103:749–755), a pilot trial with a combination of oral capecitabine and thalidomide has been conducted in patients with unresectable, recurrent or metastatic hepatocellular carcinoma (HCC) to evaluate its efficacy and toxicity. Methods: The regimen consisted of capecitabine at a dose of 750 mg/m2 po bid for 14 days every 3 weeks and thalidomide at 400 mg po bed time. Eligibility criteria included histological diagnosis of HCC, measurable disease, no prior systemic therapy, age ≥18 years, ECOG performance score (PS) of ≤2, adequate hematological, hepatic and gastrointestinal functions, no metabolic encephalopathy, and informed consent. Results: A total of 29 patients have been accrued. Two patients had never received the protocol therapy due to rapid deterioration of clinical condition after registration. Twenty-seven have been treated according to the protocol. Patient characteristics included median (range) age -60 (48–77) years; male -24; median ECOG PS -1; cirrhosis -22; hepatitis C antibody -19; hepatitis B surface antigen -4; hemochromatosis -1; extrahepatic metastasis -5. Eight patients were not evaluable for response since they received less than 2 cycles of protocol therapy. Five patients had grade 3 but asymptomatic, transient hyperbilirubinemia. Three patients had grade 1 hand-foot syndrome. Three patients had excessive somnolence which required a reduction of thalidomide dose to 200 mg. Among 19 patients evaluable for response (received ≥ 3 cycles of capecitabine), 1 patient had complete response for 5 months (Time to progression [TTP] -7 months), 4 had partial responses (TTP -2.5, 5.0, 6.0, & 7.0 months) and 4 had stable diseases for ≥ 3 months. Conclusions: This result suggests clinical efficacy of the combination of oral capecitabine and thalidomide, at given doses and schedules, with acceptable safety profile in patients with HCC (Supported by a grant from Celgene Corporation).

No significant financial relationships to disclose.
Gene expression profiling identifies two distinct papillary renal cell carcinoma (RCC) subgroups of contrasting prognosis
Authors: Teh B. T. , Yang X. J. , Tan M. , Kim H. L. , Stadler W. , Vogelzang N. G. , Amato R. , Figlin R. , Belldegrun A. , Rogers C. G.
Published: March 2020

4503

Background: Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphological classification of PRCC into Type 1 and Type 2 tumors has been recently proposed, but its biological relevance remains uncertain. Methods: We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analysis. Comparative genomic microarray analysis (CGMA) was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples, with 15 independent tumors. Results: We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histological subtypes: Type 1, low-grade Type 2 and mixed Type 1/low-grade Type 2 tumors. The second class, with poor survival, corresponded to high-grade Type 2 tumors (n = 11). Dysregulation of G1/S and G2/M checkpoint genes were found in Class 1 and Class 2 tumors respectively, alongside characteristic chromosomal aberrations. We identified a 7-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in Class 1 tumors, and of topoisomerase IIα in Class 2 tumors. Conclusions: We report two molecular subclasses of PRCC, which are biologically and clinically distinct, which may be readily distinguished in a clinical setting. This may also have therapeutic implications.

No significant financial relationships to disclose.