bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of comorbidity on costs and effects of second-line treatment among elderly metastatic colon cancer patients.
Authors: Woldemichael Andinet , Onukwugha Ebere , Zheng Zhiyuan , Hanna Nader , Seal Brian S. , Mullins C. Daniel 
Published: February 2017

536 Background: The Charleston Co-morbidity Index (CCI) was developed as in hospital mortality indicatory and subsequently has been used to both predict and adjust survival differences in cancer patients. We therefore sought to examine how the incremental cost effectiveness of treating elderly metastatic colon cancer (mCC) patients with second-line treatment (Tx2) will vary based upon their baseline CCI. Methods: We identified 2,897 elderly (age 66+) mCC patients who received NCCN recommended first-line treatment (Tx1) between 2003 and 2009 in the SEER-Medicare dataset. Approximately 6% and 1% of patients with missing CCI and outlier costs, respectively, were excluded. We categorized patients by their CCI for 12 months prior to diagnosis into three categories: low (CCI = 0), medium (CCI = 1) and high (CCI = 2+). We calculated 5-years cost-effectiveness of Tx2. Patients enrolled in HMOs, lost part A and/or B, and died of causes other than colon cancer are censored. Costs are inflation adjusted to January 2009 dollars using U.S. Medical Price Index (MPI). We adjusted for censoring using Inverse Probability Weighting (IPW) method and selection bias on observables using Propensity Score Bin Bootstrapping method. Results: Among patients who received Tx1, 56% (n = 1,285) proceeded to receive Tx2. Of those who received Tx2, 67% (n = 864), 23% (n = 289), and 10% (n = 132) have low, medium and high comorbidities, respectively. Compared to those who do not received Tx2, patients who received Tx2 with low, medium, and high baseline comorbidities live 18 (se = 4), 253 (se = 4), and 183 (se = 3) days longer and incur added costs of $66,693 (se = $675), $80,217 (se = $723), and $49,610 (se = $1,136), respectively. The median Incremental Cost-Effectiveness Ratios (ICERs) of Tx2 for patients with low, medium, and high comorbidity are $80,049, $114,693, and $151,627, respectively. Conclusions: Survival benefits from receiving Tx2 vary from an average of 18 days to 253 days and added costs from $49,610 to $80,217 depending on baseline comorbidity levels. The median ICERs associated with Tx2 increase as baseline comorbidity level of patients increase.
The host inflammatory responses, tumor stroma percentage, and survival in colorectal cancer.
Authors: Park James Hugh , Richards Colin H. , Mcmillan Donald C. , Horgan Paul G. , Roxburgh Campbell S. D. 
Published: February 2017

549 Background: The role of host inflammatory responses in determining colorectal cancer (CRC) outcome is increasingly recognised. In particular, a marked local inflammatory response is associated with improved survival. However, determinants of this response are not clear. A plausible factor in the density, location and type of the inflammatory cell infiltrate is the extent of tumor stroma. The aim of the present study was to examine the relationship between tumor stroma percentage (TSP), tumor inflammatory infiltrate and survival in patients undergoing elective CRC resection. Methods: 335 patients who had undergone elective resection for stage I-III CRC at a single institution between 1997-2008 were included. TSP at the invasive margin (IM) was assessed on H and E sections and grouped as low (≤50%) or high (>50%). Local inflammatory response was assessed at the IM using Klintrup-Mäkinen (K-M) score and at the IM, tumor stroma and cancer cell nests (CCNs) using the following T-cell markers: CD3, CD8, CD45R0, FOXP3. Systemic inflammatory response was assessed using modified Glasgow Prognostic Score (mGPS). Results: Eighty-three patients (25%) had high TSP. High TSP was associated with increased T stage, N stage (both p < 0.01), margin and serosal involvement (both p < 0.05), an infiltrative invasive margin (p < 0.001) and tumor necrosis (p = 0.001). TSP was associated with decreased infiltration by CD3+ and CD8+ cells at the CCNs (p < 0.01 and p < 0.05 respectively) but not at the IM or stroma. K-M score showed a trend towards an inverse association with TSP (p = 0.067). CD45R0+ and FOXP3+cell infiltration and mGPS were not associated with TSP. On multivariate analysis, TSP was associated with poorer cancer-specific survival (HR 1.93, 95% CI 1.15-3.23, p = 0.012), independent of N stage, VI (both p < 0.05), low CD8 at the IM and CCNs (both p < 0.01) and mGPS (p = 0.001). Conclusions: TSP was associated with the presence of high risk pathological characteristics and down-regulation of host intra-tumoral immune responses and was independently associated with poorer cancer survival. The extent of tumor stroma is an important factor in the nature of the tumor inflammatory cell infiltrate and outcome in patients undergoing elective surgery for CRC.
Phase I and IIa studies of simtuzumab alone and in combination with FOLFIRI in patients with advanced solid tumors.
Authors: LoRusso Patricia , Hecht J. Randolph , Thai Dung Luong , Hawkins Michael J. , Dong Hua , Tolcher Anthony W. 
Published: February 2017

554 Background: Simtuzumab (SIM) is a monoclonal antibody that inhibits lysyl oxidase like molecule 2 (LOXL2), an extracellular matrix enzyme involved in tumor growth and metastasis. Methods: A phase I dose escalation study evaluated the safety and pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Dose escalation occurred at doses up to 20 mg/kg of SIM every 2 weeks by IV infusion followed by a dose expansion of 20 pts at 10 mg/kg of SIM every 2 weeks. PK was evaluated following the first and fourth doses. In a separate Phase IIa study, 11 pts with KRAS mutant colorectal cancer (CRC) were given SIM at 700 mg IV combined with FOLFIRI every 2 weeks in the 2nd line setting. All pts continued until disease progression or unacceptable toxicity. CT or MRI was performed every 8 weeks. Results: In the phase I study, 12 pts (3 per cohort) received SIM at doses of 1, 3, 10 and 20 mg/kg. Tumor types included CRC (5), pancreatic neuroendocrine (PNE, 1), and other tumors (1 each). In the dose expansion, 20 CRC pts (11 KRAS mutant and 9 KRAS wild-type) received SIM at 10 mg/kg. Treatment-emergent AEs (TEAEs) included fatigue and constipation. No DLTs or drug-related SAEs were observed. The mean terminal T1/2 was ~20 days, and exposure was dose proportional between 1 and 20 mg/kg. Decreased tumor size (-56% for PNE and -17%, -8%, -5%, -5%, and -4% for CRC) as measured by the sum of the linear diameter of the target lesions was observed in 6 pts following treatment with SIM alone. In the Phase IIa trial of SIM/FOLFIRI, the most common TEAEs were diarrhea, fatigue, and nausea. Median PFS was 7.8 months. Conclusions: SIM was well tolerated as a single agent and when combined with FOLFIRI and showed promising efficacy in pts with CRC. A randomized, double-blind, placebo controlled phase II study in KRAS mutant CRC pts is ongoing. Clinical trial information: NCT01323933.
A multicenter exploratory study of irinotecan-based chemotherapy on UGT1A1 polymorphisms for patients with colorectal cancer.
Authors: Chikakiyo Motoya , Sato Hirohiko , Kurita Nobuhiro , Iwata Takashi , Yoshikawa Kozo , Kashihara Hideya , Mikami Chie , Matsumoto Noriko , Eto Shohei , Shimada Mitsuo , Hotchi Masanori , Okitsu Hiroshi , Sonaka Yasuhide , Yoshida Sadahiro 
Published: February 2017

563 Background: Recent pharmacogenetic studies have revealed a significant association between uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6 and toxicities such as severe diarrhea and neutropenia under treatment with irinotecan. Moreover, the latter of these two polymorphisms is specifically detected in East Asian populations. We performed a prospective study to determine the optimal dose of this drug depending on which polymorphism is present in order to maximize the effectiveness of therapy while avoiding side effects. Methods: 59 patients from 11 institutions were enrolled in this study. Patients were assigned to one of the following three groups: wild type (*1/*1), heterozygous (*28/*1, *6/*1), or homozygous (*28/*28, *6/*6*, *28/*6*). The double heterozygous state (*28/*6) was included within the homozygous group. Second-line FOLFIRI was administered, with the dose of irinotecan at 150 mg/m2, in the wild type and heterozygous groups and at 100 mg/m2 in the homozygous group. The incidences of severe toxicities according to UGT1A1 gene type, response rate, and progression-free survival were investigated. Results: 26 (44.1%) were assigned to the wild type group, 28 (47.4%) to the heterozygous group, and 5 (8.5%) to the homozygous group. Grade 3 or higher severe toxicities were observed in 8 patients (30.8%) in the wild type group, 5 (17.9%) in the heterozygous group, and 1 (20.0%) in the homozygous group. No significant difference was observed among the three groups. The most frequently observed severe toxicities were neutropenia, nausea, vomiting, and diarrhea. The overall response rate (complete response + partial response) was 2 patients (7.7%) in the wild type group, 2 (7.1%) in the heterozygous group, and none (0.0%) in the homozygous group. Conclusions: In terms of tolerability and safety, the present results suggest that irinotecan should be administered at a dose of 150mg/m2 in heterozygous patients and 100 mg/m2 in homozygous patients receiving second-line FOLFIRI.
Impact of objective response and overall survival in patients with inoperable or metastatic gastric and esophagogastric junction (EGJ) cancer: Landmark analysis of 10-year data from first-line clinical trials.
Authors: Bolt Toki Anna , Pauligk Claudia , Werner Dominique , Hofheinz Ralf Dieter , Mayer Frank , Luley Kim Barbara , Homann Nils , Schmalenberg Harald , Egger Matthias , Al-Batran Salah-Eddin 
Published: February 2017

57 Background: The aim of the study is to determine whether the achievement of an objective response to 1st line chemotherapy is prognostic of patient’s outcome in gastric/EGJ adenocarcinoma. Methods: Individual patient (pts) data from prospective 1st line trials conducted by a single study group were used. Response data, pts’ characteristics, type of chemotherapy and overall survival (OS) data were analyzed. Responses were evaluated according to WHO criteria in all trials and landmark analysis conducted. Results: Response rates were complete (CR) in 3.1%, partial (PR) in 37.7%, stable disease (SD) in 33.8% and progressive disease (PD) in 15.4% pts (9.9% were not evaluable). Overall response rate (OR= CR + PR) was 40.8%. Median OS in pts with CR vs. PR vs. SD vs. PD were 28.9 vs. 14.8 vs. 10.8 vs. 5.2 months, respectively; p= 2.6 x 10-42. OR also strongly predicted OS (16.7 vs. 8.6 months in pts with vs. no OR; p= 9.0 x 10-14). Landmark studies were established with landmarks set on 2 and 4 months. Median OS at landmark point 2 months in pts with CR vs. PR vs. SD vs. PD were 17.3 vs. 14.5 vs. 11.1 vs. 5.4 months, respectively; p= 3,7 x 10-12. Pts with OR vs. no OR had a median OS of 14.7 vs. 10.9 months, p= 0.0001. Median OS at landmark point 4 months in pts with CR vs. PR vs. SD vs. PD were 23.9 vs. 14.8 vs. 11.8 vs. 7.7 months, respectively; p= 1.2 x 10-10. Pts with OR vs. no OR had a median OS of 16.1 vs. 11.1 months, p= 7.0 x 10-6. OR remained the strongest predictor of OS in the multivariate analysis (p= 6.3 x 10-7) followed by the presence of non-regional LN as the only site of metastasis (p= 8.2 x 10-5) and ECOG (p= 0.002). Conclusions: The achievement of an objective response is the strongest predictor of survival in pts with gastric and EGJ cancer and could serve as surrogate marker if validated.
Phase I drug-interaction study of effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and acute neurotoxicity in colorectal cancer patients.
Authors: Han Catherine HyeWon , Khwaounjoo Prashannata , Kilfoyle Dean H. , Hill Andrew Graham , McKeage Mark James 
Published: February 2017

578 Background: Calcium and magnesium (Ca/Mg) infusions have been suggested as an effective intervention for preventing oxaliplatin-induced neurotoxicity, but the effects of Ca/Mg infusions on oxaliplatin pharmacokinetics, motor nerve hyperexcitability, and acute neurotoxicity symptoms are unclear. Methods: In this double-blind crossover study, colorectal cancer patients undergoing oxaliplatin-based chemotherapy were randomised to receive Ca/Mg (1g Ca Gluconate plus 1g MgSO4) on cycle 1 and placebo (vehicle alone) on cycle 2, or to receive the same treatments in the opposite sequence. Study endpoints included plasma pharmacokinetics of intact oxaliplatin and free platinum; electromyography (EMG) detection of abnormal spontaneous high-frequency motor unit action potential discharges; and patient-reported acute neurotoxicity symptoms and their preferred study treatment for reducing these symptoms. Results: The planned accrual target was achieved. Nineteen of 20 enrolled patients completed the study. Plasma pharmacokinetics of intact oxaliplatin and free platinum were similar when oxaliplatin was given with Ca/Mg or placebo (ratio of geometric means of AUC0-t with Ca/Mg or placebo: intact oxaliplatin, 0.95 (90% CI, 0.90 – 1.01); free platinum, 0.99 (90% CI, 0.94 – 1.05)). EMG motor nerve hyperexcitability scores were similar with Ca/Mg and placebo (mean difference in EMG score between Ca/Mg and placebo: -0.3 (95% CI, -2.2 – 1.6)). Patient-reported acute neurotoxicity symptoms were similar in frequency with Ca/Mg and placebo. For reducing neurotoxic symptoms, fewer patients preferred Ca/Mg than placebo or neither treatment (26% versus 74%; p < 0.01). Conclusions: Ca/Mg infusions do not alter the clinical pharmacokinetics of oxaliplatin and do not seem to reduce its acute neurotoxicity. Clinical trial information: ACTRN12611000738921.
Resection of colorectal cancer (CRC) metastases in routine practice.
Authors: Tran Ben , Wong Hui-li , Field Kathryn Maree , Tie Jeanne , Shapiro Jeremy David , Wong Rachel , Yip Desmond , Nott Louise M. , Richardson Gary Edward , McKendrick Joseph James , Gibbs Peter 
Published: February 2017

599 Background: The optimal management of metastatic colorectal cancer (mCRC) involves a multimodality approach. Complete resection of limited metastatic disease is a critical, potentially curative intervention for a minority of patients (pts). Data on resection rates and outcomes in routine clinical practice are limited. Methods: Analysis of pts prospectively entered onto the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database, a multisite Australian mCRC registry. Data collection commenced in July 2009 and is ongoing at 14 centres. Treatment intent was recorded at initial pt review as curative, potentially curative or palliative. Results: At median follow-up of 20.9 months, 213 (21%) of 1,012 pts have undergone metastasectomy, including 179 (84%) R0 resections. Liver (55.4%) and lung (20.2%) were the commonest resected disease sites. For 26 (12.2%) pts the initial treatment intent had been palliative. Pts who had metastases resected were younger (median age 63 vs. 70 years, p<0.0001), of better performance status (PS0-1: 97.7 vs. 75.5%, p<0.0001), had fewer comorbidities (Charlson Index ≤3: 75.1 vs. 55.9%, p<0.0001) and fewer sites of disease (single site: 79.8% vs. 52.5%, p<0.0001). A significantly higher proportion of pts treated in private than public hospitals underwent resections: 143/548 (26.1%) vs. 70/459 (15.3%), p<0.0001. At initial presentation, more private pts had PS0-1 (82.8% vs. 77.8%, p=0.0459) and single disease site (61.3% vs. 54.5%, p=0.0291) than public pts, but the median age of private pts was higher (70 vs. 67 years, p=0.041). Overall survival was equivalent for resected pts in both groups (median not reached, HR 0.96, 95% CI 0.45-2.06, p=0.9189). Conclusions: A substantial proportion of mCRC pts in routine practice undergo resection of distant metastases, including some pts initially considered incurable. Significant variation between sites has been noted, which may relate to differences in pt population and/or a more aggressive treatment approach. Multivariate analyses and review of individual centre data are planned to explore reasons for potential underutilization of this critical intervention.
Molecular testing guidelines for selection of colorectal cancer patients for targeted and conventional therapies.
Authors: Sepulveda Antonia R. , Hamilton Stanley R. , Grody Wayne 
Published: February 2017

600 Background: Molecular testing to enhance the response of colorectal cancers (CRC) to targeted and conventional therapies has been the center of many recent studies. While testing for KRAS mutations is generally accepted as a requirement to select patients for anti-EGFR antibody therapies, evidence-based guidelines for other markers are needed. The objective of this project is to establish evidence-based recommendations for the molecular testing of CRC tissues to guide EGFR-targeted therapies and conventional chemotherapy regimens. Methods: Three professional societies: American Society of Clinical Pathologists (ASCP), College of American Pathologists (CAP) and the Association for Molecular Pathology (AMP) have selected co-chairs, and multidisciplinary expert and advisory panels, which include specialists in pathology, GI oncology, surgery, gastroenterology and genetics. A systematic review was designed based on five overall key questions: (1) What biomarkers are useful for CRC management (selection of patients for targeted and conventional therapies)? (2) How should tissue specimens be processed for biomarker testing for CRC management?; (3) How should biomarker testing for CRC management be performed? (4) How should molecular testing of CRC be implemented and operationalized?; V: Should other genes/biomarkers be routinely tested? The expert panel will review title-abstract (TA) and full-text (FT) in DistillerSR software. Data extraction will then be performed and the panel will draft recommendations based upon evidence tables and the considered judgment process. Results: A systematic review was performed to capture published articles from January 2009 through August 2013, yielding 2,883titles to date. Currently the TA review phase is in course. Release of draft recommendations during an open comment period is anticipated in early 2014. Conclusions: The ASCP-CAP-AMP Molecular Testing Guidelines for Selection of Colorectal Cancer Patients for Targeted and Conventional Therapies will provide evidence-based guidelines for molecular testing of CRC. The final publication release is anticipated for the fall 2014.
A phase II trial of metformin and fluorouracil (MetFU) for patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard treatment.
Authors: Miranda Vanessa Costa , Faria Luiza Dib , Braghiroli Maria Ignez Freitas Melro , Jacobs Monica , Sabbaga Jorge , Hoff Paulo Marcelo , Riechelmann Rachel Pimenta 
Published: February 2017

601 Background: Pts with mCRC whose disease progressed after 5-FU, oxaliplatin, irinotecan and monoclonal antibodies have an unmet medical need. There is growing evidence suggesting an antitumoral effect of metformin in several tumor types, including CRC. Methods: Our primary objective was to evaluate the efficacy and safety of MetFU in heavily pretreated CRC pts with current progressive disease Last dose of 5-FU was administred at least 4 months prior to enrollment. Efficacy was defined as disease control rate at 8 weeks, using RECIST 1.1. Secondary endpoints were progression free survival, overall survival and tolerability. Single-arm Simon two-stage phase II trial was used. The treatment consisted of metformin 850 mg bid continuously plus 5-FU 425mg/m2 + Leucovorin (LV) 50 mg weekly for 4 weeks until disease progression, unacceptable toxicity or consent withdrawn in pts with mCRC who had progressed to conventional lines of treatment. Results: In the first stage, 22 pts were included: 12 pts (54%) were men, median age was 55 years and 59% were classified as an ECOG 1.14 pts faced treatment adverse events and 4 pts were excluded due to toxicity G3/4 - 2 pts had thrombocytopenia and 2 had limiting fatigue. Median time on treatment was 3.8 months, and 17 pts were evaluable for response: 6 pts (27%) had stable disease at 8 weeks as best response, with a median progression free survival (PFS) of 8.1 months. For the whole cohort, median overall survival was 5.6 months (IC95%: 3.1-8.2) and PFS was 2.0 months (IC95%: 1.8-2.3). Conclusions: Our results suggest that metformin may have antitumor activity when combined with 5-FU/LV in a subgroup of mCRC pts, with acceptable toxicity. It is unlikely that 5-FU alone had activity in these heavily treated pts. Clinical trial information: NCT01941953.
A phase II study of panitumumab plus irinotecan for metastatic colorectal cancer with wild KRAS, resistant to fluoropyrimidine, oxaliplatin, and irinotecan in Japanese (OGSG1001).
Authors: Taira Koichi , Yoshida Motoki , Sugimoto Naotoshi , Kii Takayuki , Kuwakado Shin , Fukunaga Mutsumi , Hasegawa Hiroko , Kato Takeshi , Miyake Yasuhiro , Hata Taishi , Tokunaga Yukihiko , Takeda Koji , Daga Haruko , Yoshinami Tetsuhiro , Shimokawa Toshio , Sakai Daisuke , Kurokawa Yukinori , Satoh Taroh , Tsujinaka Toshimasa , Furukawa Hiroshi 
Published: February 2017

607 Background: Anti-epidermal growth factor receptor (EGFR) antibody therapy showed to be effective in treatment for metastatic colorectal cancer (mCRC) with wild KRAS. Especially, combination chemotherapy with anti-EGFR antibody plus irinotecan is expected more effective than anti-EGFR antibody alone, resistant to irinotecan. We conducted a phase II trial of panitumumab plus irinotecan for mCRC with wild KRAS resistant to fluoropyrimidine, oxaliplatin, and irinotecan in Japanese. Methods: Subjects were mCRC patients with wild KRAS, who showed resistance to fluoropyrimidine, oxaliplatin, and irinotecan and had measurable disease, ECOG PS 0-2. Panitumumab (6 mg/kg) plus irinotecan (same dose as prior irinotecan) was administered every two weeks. This treatment was provided until progression. The primary endpoint was response rate (RR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), response duration, and adverse event (AE). Results: A total of 31 subjects were enrolled between July 2010 and July 2012. Median age was 64 years old (range 42-74). Nineteen patients had liver metastasis, 11 had lung metastasis, and 3 had lymph node metastasis. An independent review committee evaluated for efficacy in eligible 31 subjects in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The RR of primary endpoint was 29.0% (95% confidence interval (CI), 14.2-48.0 %). DCR was 74.2% (95%CI, 55.4-88.1%) and median PFS was 5.6 months.(95%CI: 3.4-8.7) In 31 subjects for safety evaluation, the incidence of any Grade 3 or greater adverse events was 58.1%. Major adverse events of grade 3 were diarrhea (19.4%), rash acneiform (12.9%), fatigue (9.7%), anorexia (9.7%). A sudden death and an infusion related reaction were occurred. Conclusions: Combination chemotherapy with panitumumab plus irinotecan was demonstarated to be safe and more effective than Japanese single arm phase II of panitumumab alone for mCRC, resistant to fluoropyrimidine, oxaliplatin and irinotecan. This result in Japanese is equal to other reports of panitumumab plus irinotecan. Clinical trial information: UMIN000003819.