bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]