bluuebunny/crossref_metadata_2025 huggingface dataset:
LiverMetSurvey: Analysis of clinicopathologic factors associated with the efficacy of preoperative chemotherapy in 2,122 patients with colorectal liver metastases
Authors: Adam R. , Aloia T. , Figueras J. , Capussotti L. , Poston G. , Mentha G. , Selzner M.
Published: March 2020

3521

Background: LiverMetSurvey is an international, internet-based registry designed to assess the efficacy of multimodality treatment options for colorectal liver metastases (CLM) by analyzing outcomes following hepatic resection (HR) in a large number of patients. Methods: Data were analyzed for the 2,122 patients entered into LiverMetSurvey by six hepatobiliary centers from inception to August 2004 (HR: 1974 to 2004; 1,306 men: 816 women; mean age: 61 years). The distributions of potential prognostic factors including age, sex, primary tumor site, timing of metastasis diagnosis, tumor number, diameter of the largest metastasis, bilaterality, and treatment with chemotherapy were compared to survivals using univariate and multivariate statistics. Results: Metastases originated in the colon in 69% of patients and were synchronous (diagnosed within 3 mo of primary tumor treatment) in 49% of patients. 34% of patients had ≥ 3 metastases and tumors were distributed bilaterally in 43% of cases. The mean size of the largest metastasis was 41.8 mm. 55% of patients were treated with preoperative systemic chemotherapy. Following resection, 60-day mortality was 1.2% and median, 5-year, and 10-year overall survivals (OS) were 46 mo, 42%, and 26%, respectively. Variables independently associated with poor prognosis included number of metastases > 3 (p<0.0001), bilateral metastases (p=0.0002), and size of the largest metastasis > 5 cm (p=0.03). Preoperative chemotherapy (PC) did not appear to benefit patients with solitary CLM (5-yr OS: PC 45% vs. no PC 58%), but was associated with improved survival in patients with > 5 metastases (5-yr OS: PC 22% vs. no PC 12%). Conclusions: Assessment of outcomes for the first 2,122 registrants to LiverMetSurvey not only confirms the prognostic importance of intrahepatic tumor burden, but also indicates that the ability of preoperative systemic chemotherapy to improve survivals is limited to patients with multiple (> 5) metastases. In addition, this analysis demonstrates the potential for LiverMetSurvey, which is now prospectively enrolling patients from over 40 centers, to determine the therapeutic value of current and future treatment strategies.

No significant financial relationships to disclose.
Circulating endothelial cells (CEC) and circulating tumor cells (CTC) in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Cohen S. J. , Terstappen L. W. , Punt C. J. , Mitchell E. P. , Fynan T. M. , Li T. , Matera J. , Doyle G. V. , Meropol N. J.
Published: March 2020

3531

Background: Lack of validated surrogate endpoints is an impediment to developing new cancer therapy. We hypothesized that CTC and CEC could predict outcome in pts undergoing treatment for mCRC. Methods: Eligible pts for this multicenter study had mCRC, and were initiating 1st, 2nd, or 3rd-line systemic therapy. Blood was obtained at baseline and 3–4 weeks after treatment initiation for enumeration of CTC/CEC. CTC/7.5ml and CEC/4ml of blood were measured with the CellSearch System. CTC were immunomagnetically enriched targeting CD326 (EpCAM), stained with DAPI, cytokeratin 8,18,19, and CD45. CEC expressing CD146 were immunomagnetically enriched and stained with DAPI, CD105, and counterstained with CD45. Cell morphology was confirmed in all cases. Results: In 139 controlsCTC were virtually absent (0 CTC in 135 and 1 CTC in 4). For 131 pts with mCRC, >1CTC was detected before therapy in 40/131(31%) (range 0–73) and 3–4 weeks after starting therapy in 12/131 (9%) (range 0–100) (p<0.0001, McNemar’s test). Pts with >1 CTC at baseline and 3–4 weeks did not differ by line of therapy (1st line: 28/93 [30.1%] at baseline, 7/93 [7.5%] at 3–4 weeks; second/third-line: 6/24 [25%] at baseline, 3/24 [12.5%] at 3–4 weeks, p=0.57, Breslow-Day test). For 15/131 (11.5%) a 2-fold increase and for 53/131 (40.5%) a 2-fold decrease in CTC was found after treatment. Using 249 controls, a normal reference range of 4–80 CEC/4 ml of blood was established. In 16/131 (12.2%) pts >80 CEC were detected before (range 1–1342) and in 18/131(13.7%) after start of therapy (range 2–519) (p=0.71, McNemar’s test). Pts with >80 CEC at baseline and 3–4 weeks did not differ by line of therapy (1st line: 9/93 [9.7%] at baseline, 13/93 [14%] at 3–4 weeks; 2nd/3rd line: 5/24 [20.8%] at baseline, 2/24 [8.3%] at 3–4 weeks, p=0.16, Breslow-Day test). In 37/131 (28.2%) a 2-fold increase and in 35/131 (26.7%) a 2-fold decrease in CEC was found after initiation of therapy. Conclusions: Isolating and enumerating CTC/CEC in pts receiving therapy for mCRC is feasible. CTC generally decrease with therapy, while change in CEC has greater variability. Enrollment in this 400 patient multicenter study is nearing completion, and definitive analysis of relationship of CTC/CEC change to clinical outcome is planned.

[Table: see text]
Polymorphism in sodium-channel alpha 1-subunit (SCN1A) predicts response, TTP, survival, and toxicity in patients with metastatic colorectal cancer treated with 5-FU/oxaliplatin
Authors: Nagashima F. , Zhang W. , Yang D. , Gordon M. , Schultheis A. , Fazzone W. , Azuma M. , El-Khoueiry A. , Iqbal S. , Lenz H. J.
Published: March 2020

3533

Background: Genetic polymorphisms in DNA repair and drug metabolism pathways have been shown to be associated with efficacy and toxicity in patients with metastatic colon cancer treated with 5-FU/oxaliplatin. Recent studies demonstrated in in vitro models that the neurotoxicity associated with oxaliplatin may be linked to an effect on neuronal voltage-gated sodium channels (VGSC). In vitro and in vivo models showed that increased VGSC alpha gene expression was associated with metastatic potential, proliferation and progression of breast and prostate cancer indicating a role in predicting toxicity and efficacy to chemotherapy. We tested the hypothesis whether VGSC gene polymorphisms may predict clinical outcome in a phase II study of combination oxaliplatin with 5-FU in patients with colorectal cancer refractory to 5-FU and/or irinotecan based chemotherapy. Methods: 173 patients were enrolled in this phase II study. 152 patients (male/female; 78/74, median age; 60), median follow up of 18.6 months, response rate of 19%, median time to tumor progression 4.2 months and median survival of 10.3 months. Grade 3/4 toxicity was seen in 60% with GI toxicity of 42% and Neurotoxicity of 11%. The dose of oxaliplatin was 130mg/m2 every 3 weeks and 5-FU was 200mg/m2/day CI for 10 weeks followed by 2 weeks rest. We tested the 12 VGSC genes polymorphisms (SCN1A, 1B, 1A1, 1A2, 1A3, 1A4, 1A5, 1A A3169G SNP, 1A C1702T Nonsense Mutation, 1A T1067A SNP, 1A C3637T SNP, SCN8A Ref SNP 303802). Genomic DNA was extracted from peripheral blood samples and polymorphisms were analyzed by PCR-based RFLP technique. Results: Patients with SCN1A T1067A SNP T/T genotype showed a significant better response rate (p=0.02, 21.9% [23/105] vs. 11.3% [5/44]), TTP (p=0.02, 4.6 months vs. 3.4 months), overall survival (p<.001, 12.3 months. vs. 8.0 months.), and frequency of grade 3/4 toxicity (p=.002) compare to patients with T/A genotype. No A/A genotype was observed. Conclusions: SCN1A gene polymorphism may be potential molecular marker for survival and toxicity in patients with colorectal cancer treated with 5-FU/oxaliplatin. In vitro studies are ongoing to identify the mechanism of resistance by SCN1A.

[Table: see text]
Risk factors for gastrointestinal perforations in patients with metastatic colorectal cancer receiving bevacizumab plus chemotherapy
Authors: Sugrue M. , Kozloff M. , Hainsworth J. , Badarinath S. , Cohn A. , Flynn P. , Steis R. , Dong W. , Sarkar S. , Grothey A.
Published: March 2020

3535

Background: Bevacizumab (BV) prolongs overall survival and progression-free survival when added to standard chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of pts with mCRC receiving BV plus first-line chemotherapy (CT). Incidence rate, temporal pattern, and potential risk factors associated with gastrointestinal perforation (GIP) were explored. Methods: Baseline patient characteristics (BC), including prospectively identified potential risk factors for GIP, were collected at study entry. Safety data were collected every 3 months (mo). Logistic regression models, adjusted and unadjusted for treatment assignment, were used to identify BC potentially associated with GIP. Results: 1968 pts were enrolled between Feb 2004 and Jun 2005. Median study follow-up was 10 mo as of Nov 4, 2005. GIPs were observed in 34 pts (1.7%). For pts with GIP, median time to first event was 2.1 mo; the majority of events were non-fatal and occurred within the first 3 mo after starting BV. BC including GI medical history (chronic aspirin or NSAID use, peptic ulcer disease, diverticulosis) were similar in pts with or without GIP and with earlier or later GIP onset (≤ or >3 mo from start of BV). Although adjusted models did not show any significant BC, GIP rates were numerically higher in pts with primary tumor intact (2.6%) vs. resected (1.6%). Furthermore, univariate analyses revealed a significant difference between intact (2.3%) and resected (0.8%) primary tumor for earlier GIP (≤3 mo from start of BV). The majority of pts with GIP had at least one of the following: acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, tumor at GIP site, abdominal carcinomatosis, prior abdominal or pelvic radiation therapy. Conclusions: Preliminary analyses indicate the incidence of GIP in this large, community-based observational registry is similar to that previously reported in phase III mCRC trials with BV. No associations between specific BCs and an increased risk of GIP were identified. Patients with primary tumor intact were more likely to incur a GIP within the first 3 mo of starting BV and CT.

[Table: see text]
Impact of bevacizumab dose reduction on clinical outcomes for patients treated on the Eastern Cooperative Oncology Group’s Study E3200
Authors: Giantonio B. J. , Catalano P. J. , O’Dwyer P. J. , Meropol N. J. , Benson A. B.
Published: March 2020

3538

Background: E3200 demonstrated improved survival (OS) for previously treated metastatic colorectal cancer patients who received second-line therapy with bevacizumab (10 mg/kg) in combination with FOLFOX4. Dose reductions of bevacizumab to 5 mg/kg were allowed for: hypertension, bleeding and thrombosis of ≤ grade 2; proteinuria of > 2 grams/24 that resolved to <0.5 grams/24hrs; liver function abnormalities ≥ grade 3 that resolved to ≤ grade 1. Methods: Data on dose modifications of bevacizumab were obtained from a post-study survey of participating institutions for all participants. Median OS and progression-free survival (PFS) were determined based upon a dose reduction any time during treatment. Hazard ratios (HR) for OS and PFS were stratified by number of cycles (1–5, 6–10, 11+) to adjust for the time-varying nature of dose reductions. Results: Surveys were received on 84% of E3200 patients treated with bevacizumab. Dose reductions of bevacizumab were performed in 134 of 240 (55.8%) patients treated with FOLFOX + bevacizumab (Arm A) and 77 of 205 (37.6%) patients treated with bevacizumab alone (Arm C). The average number of cycles of bevacizumab administered at a dose reduction for Arm A is 42% and for Arm C is 52%. Conclusions: OS and PFS on E3200 were not compromised for patients who underwent dose reductions of bevacizumab.

[Table: see text]

[Table: see text]
A phase II study of oxaliplatin (OX), capecitabine (CAP), and bevacizumab (BV) in the treatment of metastatic colorectal cancer
Authors: Bendell J. C. , Fernando N. , Morse M. , Blobe G. , Yu D. , Sutton L. , Schaffer S. , Honeycutt W. , Franklin A. , Hurwitz H.
Published: March 2020

3541

Background: BV, a monoclonal antibody against vascular endothelial growth factor, provides a survival advantage when added to first line therapy for metastatic colorectal cancer. CAP allows for fluoropyrimide treatment without the inconvenience of an infusion pump. We aimed to investigate the combination of OX, CAP, and BV (XeloxA) as a more convenient and active regimen. Methods: Pts with untreated metastatic colorectal cancer received OX 85 mg/m2 d1, CAP 1000 mg/m2 BID d1–5 and 8–12, and BV 10 mg/kg d1. Cycles were repeated every two weeks. The starting dose of CAP was changed to 850 mg/m2 BID due to toxicity in the first 28 patients. Data were analyzed under an intention to treat method. Results: 50 pts received therapy (28M, 22F), median age 55 (range 24–81). Data were available on 49 pts. The most common toxicity was diarrhea, with 12/49 (24%) having grade 3 diarrhea, and 22% with grade 2. After the dose reduction of CAP, 3/21 (14%) pts had grade 3 diarrhea and 2/21 (10%) with grade 2 as compared to 32% grade 3 and 32% grade 2 at the higher dose. At the higher dose of CAP 4% of pts had grade 3 hand-foot syndrome (HFS) and 39% had grade 2. At the lower dose, 10% had grade 3 and 5% had grade 2. Other grade 3 toxicities were minimal, including neurotoxicity (8%), vomiting (6%), and neutropenia (4%). There were 23 responses, 1 CR and 22 PR (RR=47%; 95% CI: 33%-62%). 21 pts had stable disease (43%). Median progression free survival (PFS) was 10.7 months (95% CI: 8.6–13.6). Conclusions: XeloxA is a well tolerated, active regimen in the first line treatment of metastatic colorectal cancer. RR and PFS data approximate that of infusional 5-FU regimens in combination with BV without the necessity of an infusion pump.

[Table: see text]
Evidence for improved pathologic complete response (PCR) rate after preoperative chemoradiotherapy with 5-FU/oxaliplatin (5FU/OX) for rectal cancer
Authors: Dolinsky C. M. , Mahmoud N. N. , Mick R. , Sun W. , Whittington R. W. , Solin L. J. , Haller D. G. , Giantonio B. J. , O’Dwyer P. J. , Fry R. D. , Metz J. M.
Published: March 2020

3567

Background: The use of preoperative chemoradiotherapy (chemo/RT) with 5-FU for locally advanced rectal cancer has increased dramatically. The addition of oxaliplatin (OX) to preoperative 5-FU may be a more active regimen than 5-FU alone. This retrospective study was undertaken to describe clinical outcomes in patients (pts) with rectal cancer treated with 5FU/OX or 5-FU alone. Methods: Between 11/90 and 4/05, 114 pts with rectal adenocarcinoma underwent preoperative chemo/RT at the University of Pennsylvania. Chemotherapy consisted of 5FU/OX in 36 (32%) pts and 78 (68%) pts received 5-FU. All pts received preoperative RT (median dose 5040 cGy). The two groups were balanced in terms of demographic and tumor related factors including tumor size, stage and distance from the anal verge. Median follow-up from preoperative chemo/RT was 24 months (range 2–125 months). A total of 105 (92%) pts had surgical resections; 61 (58%) with LAR, 44 (42%) with APR. PCR was defined as either no evidence of viable malignant cells in specimen or scattered, isolated malignant cells without gross residual disease. Non-surgical pts were counted as treatment failures. Results: The PCR rate was 36.1% (95% CI 20.4–51.8%) in 5FU/OX pts and 12.8% (95% CI 5.4–20.2%) in 5-FU pts. The probability of observing 13 PCRs in 36 5FU/OX pts if the actual PCR rate was 15% is equal to 0.001. Rates of any grade III/IV toxicity were similar between each regimen (20% 5FU/OX vs. 17% 5FU). Long term outcomes (2yr rate±SE) of local control, freedom from distant failure and progression-free survival in 23 pts who achieved a PCR were: 100%, 94%±6% and 94%±6%, respectively. In 85 pts with gross residual disease, these rates were: 87%±5, 77%±5% and 71%±6%, respectively. Conclusion: In this retrospective study, patients receiving 5FU/OX with radiation had a higher rate of PCR than those receiving 5FU alone. Overall, a PCR may lead to improved long-term outcomes. A prospective randomized trial to test superiority of the 5FU/OX regimen is warranted.

[Table: see text]
Chemotherapy-free intervals (CFI) in patients with metastatic colorectal cancer (MRC)
Authors: Plantade A. , Afchain P. , Tournigand C. , Maindrault-Goebel F. , Chibaudel B. , Bourges O. , Perez-Staub N. , Larsen A. , Louvet C. , De Gramont A.
Published: March 2020

3581

Background: Median survival in patients (pts) with MRC can reach 20 months with chemotherapy and should further improve with combined targeted therapies. CFI should be considered in order to improve quality of life of long survivors. Methods: 197 pts responders or stable with chemotherapy in a single institution benefited from CFI of at least 3 months, for any reason, in a 12 year period (1992–2005). Therapy was rechallenged in case of disease progression. Duration of CFI and overall survival (OS) were analyzed according to therapy and prognostic factors. Results: In 146 pts who had a CFI after a first-line, chemotherapy was 5FU-based in 32 pts, oxaliplatin-based in 103 pts (FOLFOX alone in 64 pts, FOLFOX followed by 5FU in 39 pts), irinotecan-based in 11 pts. In 51 pts who had a CFI after a second-line, chemotherapy was 5FU-based in 6 pts, oxaliplatin-based in 30 pts, irinotecan-based in 15 pts. There was no correlation between therapy duration before CFI and CFI duration, p=.66. Median CFI duration was 29 weeks (wks) in first line and 21 wks in second line, p=.0005. Median therapy duration and CFI were 42 and 26 wks after 5FU-based chemotherapy, 12 and 27 wks after FOLFOX and 36 and 37 wks after FOLFOX followed by 5FU, p=.001 and p=.12, respectively. In first-line, CFI lasted a median of 39 wks in 15 pts in complete response, 29 wks in 61 partial responders and 27 wks in 70 stable pts, p=.33. Among patients who had a CFI after a first-line therapy, those with good prognostic factors (PS 0, normal LDH and alkaline phosphatases <3UNV) experienced a longer CFI and a longer OS than others, median 27 vs 25 wks (p=.025) and 139 vs 108 wks (p=.007), respectively. Conclusions: CFI should be considered especially in good prognosis patients and in first-line therapy. The Optimox 2 study which compares 5FU maintenance therapy and CFI after FOLFOX should further evaluate CFI.

[Table: see text]
Phase II pharmacodynamic study of the fibroblast activation protein inhibitor Val-boro-Pro in patients with metastatic colorectal cancer
Authors: Cheng J. D. , Cohen S. J. , Stzempkowski-Brun B. , Magalong K. , Christiansen V. J. , McKee P. A. , Alpaugh R. K. , Lee H. , Weiner L. M. , Meropol N. J.
Published: March 2020

3594

Background: Fibroblast activation protein (FAP) is selectively expressed by carcinoma stromal fibroblasts, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. FAP potentiates tumor growth in a murine model of human epithelial cancers. Val-boro-Pro, a boronic acid inhibitor of FAP protease activity, attenuates tumor growth in a mouse colorectal cancer model characterized by FAP expression by tumor-associated fibroblasts. We therefore initiated this first clinical trial of Val-boro-Pro in patients with colorectal cancer. Methods: Patients (pts) with previously treated, measurable metastatic colorectal cancer (CRC) were initially treated with 400 μg of Val-boro-Pro orally twice daily continuously. Due to unacceptable toxicities in the first 3 patients (including 1 grade 5 renal failure), the starting dose was reduced to 200 μg orally twice daily, with intrapatient dose escalation to 300 μg bid permitted after 4 weeks. The primary endpoint is response rate, with secondary endpoints including time to progression, and in vivo laboratory correlates of FAP inhibitory activity. Results: 20 patients (12 women, 8 men) with ECOG performance status 0–1 have been treated at 200 μg orally twice daily. The median age is 58 (range 41–80). At 200 μg bid, grade 1–2 adverse events include fatigue (12 pts), anorexia (7 pts), edema (7 pts), and fever (5 pts). The most common laboratory abnormalities are grade 1–2 anemia (7 pts), elevated alkaline phosphatase (4 pts), and hypoalbuminemia (3 pts). Grade 3–4 events are elevated alkaline phosphatase (1 pt, grade 3) and headache/syncope (1 pt, grade 3). Analyses of the first 9 patient plasma samples demonstrate a 92% (S.D. 2%) inhibition of dipeptidyl peptidase activity, and 22% increase in the FAP substrate α2-antiplasmin. Conclusions: Val-boro-Pro 200 μg orally bid is biologically active and well-tolerated, with toxicities likely related to cytokine upregulation. A planned interim analysis for clinical response will be conducted after treatment of 23 evaluable patients. The selectivity of FAP expression for tumor fibroblasts provides a unique opportunity to investigate and manipulate stromal contributions to tumor growth and invasion.

No significant financial relationships to disclose.
Phenotypic expression of Bax is a predictive marker of 5-fluorouracil treatment in colorectal cancer
Authors: Manne U. , Suarez-Cuervo C. , Jhala N. C. , Posey J. , Herring C. B. , Meleth S. , Grizzle W. E.
Published: March 2020

3605

Background: The anti-tumor activity of 5-fluorouracil (5-FU) has been related to its ability to induce apoptosis. Therefore, we assessed the predictive value of phenotypic expression of key apoptotic molecules in colorectal adenocarcinomas (CRC) of patients treated with 5-FU-based adjuvant therapies. Methods: Archival tissues of CRCs from 56 patients who received a complete regimen of 5-FU-based chemotherapy after surgery, and 56 age, gender, ethnicity, tumor stage, tumor location, and tumor differentiation matched patients who had undergone only surgery (without any pre- or post-surgery chemo- or radiation therapy), were evaluated for immunophenotypic expression of Bax, Bcl-2 and nuclear accumulation of p53 (p53nac). Immunophenotypic expression of these markers was categorized into low and high expressors and cut-point values were determined based on their expression in benign epithelium. These tumors Ability of these markers in predicting the efficacy of 5-FU-based treatment was assessed by estimating overall survival utilizing the Kaplan-Meier and Cox proportional hazards methods. Results: There was no significant difference in overall survival rates between the two patient categories (logrank P=0.487). However, a better survival was observed for patients who received chemotherapy when their CRCs lacked Bax expression; in contrast, patients with high Bax expression CRCs had worse survival when they received chemotherapy (logrank P=0.016). Surgically treated patients with CRCs lacked Bax expression had 5.33 times higher mortality than those with high Bax expression (HR, 5.33; CI: 1.78–15.94), when controlled for tumor stage and other confounding variables. Bcl-2 or p53nac had no predictive value in either patient group. Conclusions: These preliminary findings are the first to provide good evidence to suggest that patients with CRCs lacking Bax phenotypic expression benefit from 5-FU-based adjuvant therapies but not those with high Bax expression (Supported by NIH/NCI R01-CA98932–01).

No significant financial relationships to disclose.
Noncoding miRNAs as novel prognostic factor for 5-fluorouracil adjuvant therapy in colorectal cancer
Authors: Xi Y. , Formentini A. , Kornmann M. , Ju J.
Published: March 2020

3609

Background: The roles of non-coding miRNAs in tumorgenesis are just emerging. miRNAs regulate gene expression at post-transcriptional level by influencing translation efficiency of their target mRNAs. Previous studies from our laboratory have identified a number of miRNAs that were dis-regulated in colon cancer cell lines related to the loss of p53 tumor suppressor gene. In this study, the in vivo significance of some of these miRNAs was further evaluated using clinical samples. Ten miRNAs (hsa-let-7b, hsa-let-7g, hsa-miR-15b, hsa-miR-181b, hsa-miR-191, hsa-miR-200c, hsa-miR-26a, hsa-miR-27a, hsa-miR-30a-5p and hsa-miR-30c) were evaluated for their potential prognostic value in colorectal cancer patients receiving 5-fluorouracil (5-FU) based therapy. Methods: Forty eight snap frozen clinical colorectal samples (24 normal and 24 paired colorectal cancer patient samples) were selected with detailed clinical follow-up information. RNAs were isolated from these samples using TRIzol reagent. After cDNA synthesis with miRNA specific primers, the expression levels of 10 miRNAs were quantified via qRT-PCR analysis. The statistical significance of these markers for disease prognosis was evaluated using two tailed paired T-test. Kaplan-Meier survival curve was generated and followed by Logrank test. Result: Among the ten miRNAs, hsa-miR-15b (p=0.02), hsa-miR-181b (p=0.01), hsa-miR-191 (p=0.03) and hsa-miR-200c (p=0.005) were significantly over-expressed in tumors compared to normal colorectal samples. Kaplan-Meier survival analysis indicates that hsa-miR-200c was a significant prognostic marker for predicting patient’s survival (p=0.01). The patients (n=15) with higher hsa-miR-200c expression had shorter survival interval (median survival = 26 months) compared to patients (n=9) with lower expression (median survival = 38 months). Conclusions: Some of these miRNAs may function as oncogenes due to their over-expression in tumors. Hsa-miR-200c may be a potential novel prognostic factor for 5-FU based chemotherapy in colorectal cancer.

No significant financial relationships to disclose.
Risk factors for lymph node and distant metastasis in colorectal carcinoids: An analysis of nationwide registry in Japan over 15 years
Authors: Konishi T. , Watanabe T. , Muto T. , Kotake K. , Nagawa H.
Published: March 2020

3620

Background: No global consensus has been established on the crucial determinants of metastasis in colorectal carcinoids. This study aims to determine the predictive factors for lymph node (LN) and distant metastasis, and to provide strategic model for the treatment of this uncommon disease. Methods: All patients diagnosed as carcinoids from 1984 to 1998 were extracted from the nationwide database, “Multi-Institutional Registry of Large-Bowel Cancer in Japan”, which covers almost 10% of all colorectal cancers in Japan. Risk factors for metastasis were analyzed among colorectal carcinoids undergoing surgery. Results: Among 90,057 cases of colorectal tumors registered from 1984 to 1998, a total of 345 cases of carciniods were identified. All cases were from the Asian population. The site distribution consisted of the ileum 3 (0.9%), appendix 8 (2.3%), colon 28 (8.2%) and rectum 304 (88.6%). Among colorectal carcinoids, a total of 263 cases undergoing surgery were eligible for the analysis (colon 23, rectum 240). Overall incidence of LN and distant metastasis were 29% and 7%, respectively. Univariate analysis showed that age>55, tumor size, tumor invasion≥T2, and lymphovascular invasion were associated with LN metastasis as well as distant metastasis. Multivariate analysis revealed that tumor size>10mm and lymphovascular invasion (LVI) were independently predictive of LN metastasis, while tumor size>20mm was a single risk factor for distant metastasis. Notably, tumors not larger than 10mm and without LVI exhibited no LN metastasis ( Table ). Conclusions: Tumors not larger than 10mm and without LVI could be curatively treated by endoscopic resection or transanal excision. However, tumors larger than 10mm or those with LVI should undergo radical surgery for LN dissection. Furthermore, tumors larger than 20mm carry a high risk for distant metastasis, and require close follow-up even without evident metastasis at the time of surgery.

[Table: see text]

No significant financial relationships to disclose.
Mathematization of risk and benefit for first-line treatment of metastatic colorectal cancer: A graphical decision aid for patients and physicians
Authors: Sanatani M. S. , Vincent M.
Published: March 2020

3627

Background: Advances in the treatment of metastatic colorectal cancer (mCRC) have improved median overall survival (mOS) from 1yr with 5-fluorouracil (FU) therapy to >21 mos. This may come at cost of more toxicity. As the number of tested regimens increases, the question arises how to best present palliative treatment options. We present a simple way to compare treatment options in terms of risks & benefits. Methods: The literature was surveyed for reports of 1st-line systemic therapies for mCRC. The largest recent reports with detailed toxicity data were selected as representative for a regimen; if several comparable reports existed then all were selected. Toxicity sum (TS) of a regimen was calculated as % occurences in the study cohort of severe (≥ gr. 3) adverse effects: diarrhea+mucositis+neurocutaneous (excl. alopecia)+vomiting (or vomiting/nausea if not reported separately or nausea if no vomiting rep.)+febrile neutropenia (FN)(or infection if FN not rep. or leukopenia if infection not rep.)+toxic deathrate. Benefits (OS & progression-free survival PFS in months) were divided by TS to give a benefit/toxicity (B/T) ratio & plotted as benefit vs TS. Results: 30 regimens were found.OS, PFS & TS for the various regimens ranged from 8.9–24.7 and 4.9–9.2 mos, & 12–63 respectively. B/T ratios ranged from 0.1–0.53 (PFS) & 0.22–1.19 (OS); higher values more favorable. Regimens with similar B/T ratios may still differ - longer OS & PFS but at cost of more toxicity. Graphical presentation makes this clear. Intriguing & open to interpretation was a narrow range of PFS while OS varied greatly between regimens. Weaknesses of our study incl omission of some regimen-specific toxicities, & of symptom control benefit. Conclusions: Our comparative tool helps physicians discuss the large number of available options & their clinical differences easily with patients, improving informed consent & disclosure, in order to arrive at the treatment plan most appropriate to the individual.

[Table: see text]

[Table: see text]
GW572016, gemcitabine and GW572016, gemcitabine, oxaliplatin, a two-stage, phase I study for advanced pancreaticobiliary cancer
Authors: Safran H. , Iannitti D. , Miner T. , Demel K. , Yoo D. , Joseph P. , Maia-Acuna C. , Lockridge L. , Evans D. , Teresa K.
Published: March 2020

4002

Background: GW572016 is an orally active small molecule that reversibly inhibits ErbB1 and ErbB2 tyrosine kinases. ErbB1 is commonly expressed in pancreaticobiliary cancers. ErbB2 is the preferred heterodimer partner for other ErbB receptors. Baerman et al demonstrated that GW572016 was active against pancreatic cancer cell lines (ASCO GI 2005). We have completed a two-stage, phase I evaluation of GW572016 and gemcitabine (gem), and GW572016 with the combination of gemcitabine and oxaliplatin (GEMOX). Methods: Patients with advanced adenocarcinoma of the pancreas or bile ducts were treated with GW572016 and either weekly gemcitabine (1gm/m2/week, 3 weeks on, 1 week off) or GEMOX (gemcitabine 1g/m2 over 100 minutes and oxaliplatin 100 mg/m2, every 14 days). Cohort 1: Weekly gem + GW572016, 1000mg/day. Cohort 2: Weekly gem + GW572016, 1500 mg/day. Cohort 3: GEMOX + GW572016 1000 mg/day. Cohort 4: GEMOX + GW572016 1500 mg/day. Results: Twenty-one patients have been treated; pancreatic cancer (n=15), biliary cancer (n=6). The median age was 64 (41–78). One of six patients in cohort 2 had grade 3 diarrhea. Dose limiting grade 3 nausea occurred in 2 of 5 patients in cohort 4. Two patients had a temporary decrease in cardiac ejection fraction. Five of 20 evaluable patients (25%) responded. Conclusions: GW572016 1500 mg/day can be administered will full dosage gem. The MTD of GW572016 is 1000mg/day with GEMOX. Dramatic responses have been demonstrated in patients with diffuse liver and peritoneal metastases suggesting that erbB1/erbB2 signaling is important in pancreaticobiliary cancers. Further evaluation of GW572016 in pancreaticobiliary cancer is indicated.

[Table: see text]
Increased survival using platinum analog combined with gemcitabine as compared to gemcitabine single agent in advanced pancreatic cancer (APC): Pooled analysis of two randomised trials, the GERCOR/GISCAD Intergroup Study and a German Multicenter Study
Authors: Louvet C. , Hincke A. , Labianca R. , Heinemann V.
Published: March 2020

4003

Background: Two randomized trials (GERCOR/GISCAD: gemcitabine [GEM] plus oxaliplatin versus Gem; German multicenter trial: Gem plus cisplatin versus Gem) indicated superior efficacy in terms of response rate and progression-free survival (PFS) for combined therapy. While a trend for prolonged overall survival (OS) was reported in these underpowered studies, they failed to demonstrate a significant advantage. Methods: We report a pooled analysis of both studies. Standard methods for meta-analysis based on individual patient (pt) data were used. Results: Among 503 evaluable pts, 252 received the combination therapy (GP), while 251 pts were treated with Gem single agent (G). In the GP vs G groups, an ECOG performance status = 0 was observed in 40% vs 35%, distant metastasis in 72% vs 73%, and pathological tumor grading of 3 in 34% vs 38%, respectively. A high degree of homogeneity was noted among the study groups with regard to survival data. For PFS, the pooled univariate analysis indicated a hazard ratio (HR) of 1.34 (95% CI, 1.11–1.63, p=.0030; median PFS 5.5 m vs 3.5 m) in favour of the GP-combination. The benefit of the GP-combination was greatest in the subgroup of pts with PS 0 (HR=1.56; 95% CI, 1.11–2.20, p=.013). OS was significantly superior in the GP pts (HR=1.23; 95% CI, 1.02–1.49, p=.031; median OS 8.3 m vs 6.7m). Again, pts with a PS=0 may have a greater benefit from treatment intensification (HR=1.38; 95% CI, 0.99–1.93, p=.063). Conclusions: This pooled data analysis indicates that combination of gemcitabine with a platinum analog such as oxaliplatin or cisplatin significantly improves PFS and OS as compared to single-agent gemcitabine in APC.

[Table: see text]
Cetuximab, paclitaxel, carboplatin and radiation for esophageal and gastric cancer
Authors: Suntharalingam M. , Dipetrillo T. , Akerman P. , Wanebo H. , Daly B. , Doyle L. A. , Krasna M. J. , Kennedy T. , Safran H.
Published: March 2020

4029

Background: Cetuximab is an IgG1, chimerized, monoclonal antibody that binds specifically to the epidermal growth factor receptor. Cetuximab improves survival when combined with radiation for patients with locally advanced head and neck cancer. We evaluated the safety and efficacy of the addition of cetuximab to concurrent chemoradiation for patients with esophageal and gastric cancer. Methods: Patients with adenocarcinoma or squamous cell cancer of the esophagus or stomach without distant organ metastases were eligible. Patients with locally advanced disease from mediastinal, celiac, portal and gastric lymphadenopathy were eligible. Surgical resection was not required. Clinical complete response was defined as no tumor on postreatment endoscopic biopsy. Patients received cetuximab, 400mg/m2 week #1 then 250 mg/m2/week for 5 weeks, paclitaxel, 50 mg/m2/week, and carboplatin, AUC =2 weekly for 6 weeks, with concurrent 50.4 Gy radiation. Results: Thirty-seven patients have been entered. The median age was 61 (range of 30–87). Thirty-four have esophageal cancer and 3 have gastric cancer. Of the patients with esophageal cancer, twenty-five have adenocarcinoma and nine have squamous cell cancer. Thus far, 30 patients have completed treatment and are evaluable for toxicity. There have been no grade 4 non-hematologic toxicities and 1 pt had grade 4 neutropenia (3%). Six patients (20%) had grade 3 esophagitis. Other grade 3 toxicities included dehydration (n=5), rash (n=9), and paclitaxel/cetuximab hypersensitivity reactions (n=2). Eighteen of 27 patients (67%) have had clinical complete response. Seven pts out of 16 (43%) who have gone to surgery have had a pathologic CR. Conclusions: Cetuximab can be safely administered with chemoradiation for patients with esophageal cancer. Consistent with the data in head and neck cancer, cetuximab increases cutaneous toxicity but does not increase mucositis/esophagitis when combined with chemoradiation. Further evaluation is ongoing.

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Neoadjuvant chemotherapy improves outcomes of chemoradiation therapy for locally advanced pancreatic cancer
Authors: Rana V. , Krishnan S. , Abbruzzese J. L. , Xiong H. Q. , Varadhachary G. R. , Ho L. , Janjan N. A. , Evans D. B. , Wolff R. A. , Crane C. H.
Published: March 2020

4036

Background: Two-thirds of all pancreatic cancer patients have radiographically detectable metastatic disease at the time of diagnosis. Most of the remaining patients have locally advanced, unresectable disease that is typically treated with either chemoradiation or chemotherapy alone. We explored the possible benefit of the use of consolidative chemoradiation after induction chemotherapy. Methods: Between December 1993 and October 2005, 318 patients with locally advanced, non-metastatic, pancreatic cancer were treated at our institution with concurrent chemoradiation therapy. All patients underwent CT staging and biopsy confirmed adenocarcinoma. 245 patients received chemoradiation (CR) as initial treatment while 73 patients received a median of 2.5 months of induction chemotherapy prior to chemoradiation (CCR). Radiosensitizers included 5FU (42%), gemcitabine (39%) and capecitabine (19%) and most patients (88%) received 30 Gy of radiation therapy. The most common induction chemotherapy regimens were gemcitabine and cisplatin (73%) and gemcitabine alone (15%). Results: All statistics are actuarial and calculated from date of initial treatment. Median follow-up was 5.5 months (range 1–63 months). For all patients, overall survival was 9.0 months and 2-year survival was 8%. Age, gender, histology, grade, radiation fractionation and concurrent chemotherapy regimen had no impact on outcomes on univariate analysis. However, overall survival was 8.5 months in the CR group and 11.9 months in the CCR group (p = 0.0004). Median time to local progression was 6.0 months in the CR group and 8.4 in the CCR group (p = 0.0055). Median time to distant progression was 5.8 months in the CR group and 9.5 months in the CCR group (p=0.0136). Conclusions: In one of the largest series of locally advanced pancreatic cancer patients, the use of induction chemotherapy followed by chemoradiation seems to prolong median survival over initial treatment with chemoradiation. By excluding patients who progress rapidly during induction chemotherapy, this approach presumably selects patients most likely to benefit from a local treatment modality. This strategy merits prospective evaluation.

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Phase II study of RAD001 (everolimus) and depot octreotide (Sandostatin LAR) in patients with advanced low grade neuroendocrine carcinoma (LGNET)
Authors: Yao J. C. , Phan A. T. , Chang D. Z. , Jacobs C. , Mares J. E. , Rashid A. , Meric-Bernstam F.
Published: March 2020

4042

Background: Effective systemic therapy for advanced LGNET is lacking. Patients with mutation in TSC2, an endogenous inhibitor of mTOR develop LGNET. mTOR also mediate signaling downstream of IGF1 and VEGF, pathways important in LGNET. RAD001 inhibits the serine-threonine kinase activity of mTOR. Octreotide may have cytostatic activity and has been described to inhibit VEGF and IGF1 production in solid tumors. Methods: Treatment consisted of depot octreotide 30 mg IM q28 days, and RAD001 5 or 10 mg po daily. Response evaluation is performed every 12 weeks. Results: 32 patients (18 carcinoids, 13 islet cell) were enrolled between 2/05 - 1/06. 20 had prior octreotide. 27 patients have completed 12 weeks of therapy at the 5 mg dose level and undergone response evaluation. By RECIST criteria, response rate was 15%. There were 4 PR, 19 SD (including 4 patients having 18–28% reduction), 4 PD. PR occurred in 2 carcinoids, and 2 islet cell. PFS rate at week 24 was 71%. Of 21 patients with radiological progression prior to study entry, 17 have completed 12 weeks of therapy. Among these, there were 3 PR, 10 SD, 4 PD. Of 18 patients with elevated chromogranin A at baseline, 9 (50%) patients had > 50% reduction. Treatment is generally well tolerated. The most common toxicity is mild aphthous ulceration. CTC G3/4 toxicity include: anemia (1), thrombocytopenia (1), leukopenia (1), fatigue (3), aphthous ulcer (2), diarrhea (2), hypoglycemia (2), pain (2), rash (2), hyperglycemia (1), edema (1), nausea (1). Conclusions: RAD001 5 mg po daily is well tolerated in combination with Depot Octreotide. Anti-tumor activity has been observed. An additional cohort will be treated at RAD001 10 mg daily dose. Optional blood draws and tumor biopsies will be performed to help assess biomarkers that may predict benefit.

No significant financial relationships to disclose.
Preoperative chemotherapy followed by resection vs. surgery alone for locally advanced esophageal carcinoma: Interim analysis of a randomized study
Authors: Stilidi I. , Bokhyan V. , Tryakin A. , Suleymanov E. , Kononets P. , Malikhova O. , Tjulandin S.
Published: March 2020

4055

Background: Outcome of the patients (pts) with locally advanced esophageal cancer is poor. A prospective trial was undertaken to investigate whether preoperative chemotherapy (CT) followed by surgery results in increase of disease free survival (DFS) in pts with locally advanced resectable thoracic esophageal cancer. Methods: Previously untreated pts with stage T3–4N0–1M0, T1–2N1M0 resectable esophageal cancer were eligible for the study. After clinical evaluation (incl. chest CT-scan, endosonography) they were randomized into CT (two cycles of FLEP: cisplatin 80 mg/m2, day 1; etoposide 80 mg/m2 d 1–3, leucovorine 20 mg/m2 and 5-fluorouracil 425 mg/m2, bolus, days 1–3; every 21 days) followed by surgical resection (Ch-S group), or resection alone (S group). Four weeks after completion of CT pts underwent transthoracic extended 2 or 3-field esophagectomy with intrapleural esophago-gastrostomy through I. Lewis approach. Results: From March 2001 to September 2005 78 pts (Ch-S group, n=38; S group, n=40) were treated in our center. Median f.-up for survived pts was 20 (range, 3–53) months. All pts but one had squamous cell carcinoma. Pts’ characteristics (tumor stage and histology, coexisting disorders, age and gender) were well balanced between the two treatment groups. Main toxicity of CT was hematological, with neutropenia gr. 4 was observed in 7 (18%) pts. There was no other serious toxicity as well as preoperative toxic deaths. Complete response was observed in 3 (7,9%) pts, partial response in 23 (60,5%) pts, progression of disease in 3 (7,9%) pts of Ch-S group. Rate of R0 resection was higher in Ch-S group (86,8%) compared with S group (65%, p=0,03). There was no difference in postoperative mortality between both groups. 3-year DFS was 58,3% vs. 27,7% (p=0,01) and 3-year overall survival was 62,9% vs. 39,8% (p=0,08) in Ch-S and S groups, respectively. Conclusions: Two cycles of preoperative CT improve DFS in pts with resectable locally advanced thoracic esophageal cancer. Accrual is continuing.

No significant financial relationships to disclose.
Phase II trial of preoperative irinotecan-cisplatin (IC) followed by concurrent IC and radiotherapy (IC/RT) for locally advanced gastric and esophago-gastric junction adenocarcinoma (LA-G/EGJ-A)
Authors: Vega-Villegas M. E. , Galán-Guzmán M. C. , Gallego-Plazas J. , Cervantes A. , Escudero P. , Tabernero J. , Massutí B. , Alonso-Orduña V. , Asensio D. , Rivera F.
Published: March 2020

4059

Background: Long-term survival for LA-G/EGJ-A is poor and could be improved by preoperative chemoradiotherapy. We performed a phase II trial to evaluate IC followed by IC/RT in this setting. Methods: Patients with locally advanced (stage II-IV, M0) G/EGJ-A were included. Main objective was pathological complete response (pCR). Secondary objectives were toxicity, response to preoperative treatment and resection rate. Pretreatment staging included an esophagogram, EUS and CT scan. Two courses of IC (Irinotecan 65mg/m2 and Cisplatin 30mg/m2 d 1 and 8, each 21 d) were given and pts without progression received IC/RT: daily RT (180cGy fractions, total dose: 5040cGy) with concurrent IC (Irinotecan 65mg/m2 and Cisplatin 30mg/m2 d 1, 8, 15 and 22 of RT). Response to preoperative treatment was evaluated with EUS and CT scan 3–4 weeks after the end of radiotherapy. Five to 8 weeks after RT, surgical resection was performed if feasible. Results: Between 2003 and 2005, 40 pts were included: 32 men; median age 65 (45–80); PS (ECOG): 0: 38%, 1: 59%, 2: 3%; Location and resectability: Esophago-gastric Junction: 16 pts (resectable: 11 pts), Stomach: 24 pts (resectable: 13 pts); Stage: II: 13 pts, III: 15 pts, IV: 12 pts. Grade 3–4 toxicity of IC (40 pts evaluable): neutropenia 22 % (febrile 5%), diarrhoea 8%, emesis 5%, asthenia 3%. One pt (3%) died during IC due to progression. All the 33 pts who received IC/RT were evaluable for toxicity (G-3–4): neutropenia 39% (febrile 0%), diarrhoea 0%, emesis 6%, asthenia 26%, thrombocytopenia 6%. Four pts (12%) died during IC/RT (toxicity: 2 pts, progression: 2 pts). Response to preoperative treatment: PR: 6 pts, SD: 21 pts, Prog: 6 pts, No Evaluated: 7 pts. R0 resections were performed in 12 out of 24 (50%) initially resectable pts (pCR: 2 pts) and in 4 out of 16 (25%) initially non-resectable pts (pCR: 0 pts). One pt died during the first 30 days after resection. With a median follow-up of 12 months, 16 pts (40%) are alive with disease, 10 (25%) pts are alive and disease free and 14 pts (35%) have died. Conclusions: Preoperative IC> IC/RT obtained moderate response and resection rates with mild toxicity in LA-G/EGJ-A. Supported by a grant from Prasfarma/Almirall Prodesfarma.

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Capecitabine and docetaxel for advanced gastric cancer
Authors: Thuss-Patience P. C. , Kretzschmar A. , Dogan Y. , Blau I. , Pink D. , Lebedinzew B. , Micheel S. , Dörken B. , Reichardt P.
Published: March 2020

4068

Background: Docetaxel is increasingly integrated into chemotherapy combination regimens against gastric cancer. Docetaxel and 5-FU were compared to ECF and appeared to be very active and well tolerated (Thuss-Patience et. al. JCO 2005). In the current study the dual combination capecitabine and docetaxel (CapDoc) is evaluated to develop a convenient out-patient regimen with minimal toxicity. Methods: Prospective multicenter phase II trial. Eligibility: Metastatic or locally advanced gastro-esophageal junction or gastric adenocarcinoma, ECOG PS 0–2, no prior palliative chemotherapy. Chemotherapy: Docetaxel 75 mg/m2 d1, capecitabine 2000 mg/m2 d1–14, q3w. For part I of the study (presented here) accrual is completed (40 pts). In part II we reduced the starting dose of docetaxel to 60 mg/m2 and capecitabine to 1600 mg/m2 to further improve tolerability (accrual ongoing, 8 pts included so far, presented at meeting). Results: 40 pts are included in this trial (part I). Age: 32–79 years (median 61), M/F 29/11, ECOG PS 0: 7 pts, 1: 27 pts, 2: 6 pts. Number of organs involved by metastases: 1: 9 pts, 2: 11 pts, 3: 16 pts, more than 3: 4 pts. Measurable disease (RECIST): 40 pts. 233 cycles of chemotherapy are administered so far. Toxicity: 40 pts are evaluable for toxicity (worst grade per patient; % of pts): Grade 1/2/3/4: Nausea: 53/10/3/- %, vomiting: 18/13/-/3 %, diarrhea: 23/20/13/- %, asthenia: 38/40/10/- %, stomatitis: 23/15/10/- %, alopecia: 25/53/-/- %, fever not neutropenic: 10/20/3/- %, neutropenic fever: -/-/10/3 %, nail changes: 33/28/-/- %, paresthesia: 18/18/5/- %, dizziness: 15/8/5/- %, hand-foot-syndrome: 25/18/18/- %, leuko-neutropenia: 8/13/25/28 %, thrombocytopenia: 18/-/-/- %, anemia: 40/15/5/- %, fluid retention: 13/5/-/-, pulmonary embolism or thrombosis: 3/5/3/5. Dose adjustments of docetaxel had to be made in 45% and of capecitabine in 55% of pts. Response: 26 of 37 pts with tumor related symptoms showed a subjective improvement of symptoms (70.3%). 38 pts are evaluable for objective response: CR 1 pt (2.6%), PR 20 pts (52.6%), NC 14 pts (36.8%), PD 3 pts (7.9%), (objective response rate: 55.3%). Median time to tumor progression 5.5 months, median survival 9.5 months. Conclusion: These data suggest that CapDoc is a well tolerated convenient out-patient combination with very promising efficacy.

[Table: see text]