bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic (PK) and pharmacodynamic (PD) analysis from a phase I study of PF-03446962, a fully human mab against ALK1, a TGF-beta receptor involved in tumor angiogenesis.
Authors: Goff Laura Williams , Borghaei Hossein , Cohen Roger B. , Berlin Jordan , Noberasco Cristina , Stampino Corrado Gallo , Wang Erjian , Williams James Andrew , English Patricia A , De Braud Filippo 
Published: March 2020

e13606 Background: The proangiogenic activity of Transforming Growth Factor β (TGF-β) on vasculature is exerted by selectively binding to its receptor, activin receptor like kinase 1 (ALK1). PF-03446962 is a fully human mAb against ALK1. Updated results on anti-tumor activity of PF-03446962 from a Phase 1 study in patients (pts) with solid tumors are reported along with PK and PD data. Methods: Effects of PF-03446962 on soluble proteins related to angiogenesis and the TGFβ pathway were investigated with respect to PK, PD, and antitumor activity. Results: 44 pts have been enrolled on 8 dose levels (0.5 - 15 mg/kg). PF-03446962 is administered i.v. on Day 1, 29 and then q 2 weeks. The dose of 10 mg/kg was defined as the maximum tolerated dose. 3 PRs were observed: one HCC resistant to anti-VEGF therapy, one NSCLC and one RCC who received VEGFR2 tyrosine kinase inhibitors (TKIs) as part of the whole previous systemic therapy. SD ≥16 weeks was observed in 7/44 pts. 2/5 HCC pts pre-treated with VEGFR2 TKIs showed a time-to-progression (TTP) of 5 months. Based on PK data, plasma concentrations at 4.5 -10mg/kg doses exceeded predicted efficacious concentrations over the entire dosing period. Cmax, Tmax AUC and terminal elimination half-life values following a dose of 10 mg/kg in 7 patients were 290μg/mL, 1.5hrs, 40236 μg/mL*hr and 302hrs. Mean values of the following soluble (s) plasma proteins increased at the end of cycle 1 compared to baseline (mean value, % increase, paired t-test p value): TGFβ (+77%, p=0.28), sVEGF-A (+60%, p= 0.15), and sVEGFR1 (+113%, p=0.10), whereas mean values of 10 other angiogenesis/TGFβ pathway proteins changed <20% from baseline. Conclusions: PF-03446962 is a first-in-class anti ALK1 mAb. Increases in Cmax and AUC were proportional to increases in dose in the therapeutic dose range. Preliminary assessments of PD data supports previous laboratory observations of interaction between ALK1 and VEGF signalling pathways for pericyte protection of blood vessels. Based on preliminary results, PF-0344692 appears to be a promising novel antiangiogenic agent and further investigations in pts who failed anti-VEGF/VEGFR2 TKIs are warranted.
Serum iron levels as new predictive factor in FOLFOX/FOLFIRI with or without molecularly targeted drug therapy.
Authors: Ochiai Takumi , Nishimura Kazuhiko , Watanabe Tomoo , Kitajima Masayuki , Nakatani Akinori , Inou Takashi , Sakuyama Naoki , Washio Marie , Kishine Kennji , Sato Tsuyoshi , Ochi Takanori , Okubo Satoshi , Futagawa Shunji , Nagaoka Isao 
Published: March 2020

e14004 Background: An increase in serum iron levels after administration of various anticancer drugs was reported (Follezou et al, NEOPLASMA 1985). We have also reported an increase in serum iron levels during FOLFOX and FOLFIRI therapies (ASCO 2009: #e15110) and a correlation between prognosis and transition of serum iron levels in advanced colorectal cancer (CRC) patients (ASCO 2011: #e14141). The aim of this cohort study was to evaluate the correlation between prognosis and serum iron levels in advanced CRC patients treated with FOLFOX/FOLFIRI ± molecularly targeted drugs. Methods: Serum iron levels were measured before and at 48 hr after treatment (FOLFOX/FOLFIRI ± molecularly targeted drugs) in 69 advanced CRC patients, all of whom died between December 2005 and December 2011. No patients were treated with radiotherapy. Taking the median rate of increase in serum iron levels as the cut-off value in each therapy, the patients were categorized into cohort I (increase rate over cut-off value in at least one therapy) and cohort II (increase rate under the cut-off value in all therapies). Prognosis was evaluated between the two cohorts using the Kaplan-Meier method and the log rank test. Results: No significant bias in patient characteristics was observed between the two cohorts. Serum iron levels transiently increased after treatment (p<0.001), then returning to baseline within 2 weeks. Median survival time (MST) in cohort I (n: 41) and cohort II (n: 28) was 430 and 377 days, respectively. The MST was significantly better in cohort I (p=0.0496). No significant differences were observed in the frequency of chemotherapies or number of patients treated with molecularly targeted drugs between the two cohorts. Conclusions: Cohort I showed a statistically significant better prognosis. The results suggest that serum iron levels could be used as a new predictive factor in FOLFOX/FOLFIRI ± molecularly targeted drug therapy. In Cohort II patients, molecularly targeted drugs should be used positively for further improvement in prognosis.
Circadian rest-activity rhythm as a predictor of survival in metastatic colorectal cancer.
Authors: Spiegel David , Dugué Pierre-Antoine , Innominato Pasquale F. , Karaboué Abdoulaye , Dispersyn Garance , Parganiha Arti , Giacchetti Sylvie , Moreau Thierry , Focan C. N. J. , Waterhouse Jim , Levi Francis 
Published: March 2020

e14006 Background: Experimental disruption of the Circadian Timing System (CTS) accelerates cancer progression. The relative amount of activity in-bed versus out-of-bed (I<O) was identified as a quantitative CTS estimate that predicted survival in two cohorts of patients with metastatic colorectal cancer (CI, CII). Methods: The independent prognostic value of I<O was investigated for Overall Survival (OS) and Progression-Free Survival (PFS) 1) in a new cohort of 142 patients (CIII) receiving circadian-based salvage treatment for metastatic colorectal cancer, and 2) in a pooled population of 436 patients from cohorts I-III. All patients had two-day rest-activity rhythm monitoring and then received a new treatment. Cohort-adjusted data were analyzed with log rank and multivariate Cox analyses. Results: Patients in CIII had poor prognosis disease compared to CI and CII, as assessed by prior chemotherapy (CIII, 69%; CI, 59.5%; CII, none), prior oxaliplatin (CIII, 55%; CII, none; CI, 2%) and/or irinotecan (CIII, 39.4%; CII, none; CI, 7%). The 273 male and 163 female patients in the pooled population had generally good performance status 0 (60.7%) or 1 (33.1%) and 51% had two or more metastatic sites. Following rest-activity rhythm determination, patients received a median of 8 chemotherapy courses. Median OS was 21.6 months [95% Confidence Limits, 17.8 to 25.5] in the patients with I<O above the cutoff median value of 97.5% as compared to 11.9 months [10.4 to 13.3] in those with a lower I<O (p from Log rank < 0.001). The adjusted relative risk related to I<O above cutoff was 0.587 [0.477 to 0.722] for earlier death (p<0.001) and 0.661 [0.542 to 0.807] for earlier progression (p <0.001). Conclusions: The circadian biomarker indicator I<O is a robust and independent quantitative long-term predictor of both OS and PFS in patients with metastatic colorectal cancer. Cancer patients with low I<O could potentially benefit from specific treatments for circadian disruption in order to enhance survival.
Treatment patterns among metastatic colorectal cancer patients by line of therapy and original stage of diagnosis.
Authors: Chastek Benjamin , Kulakodlu Mahesh , Valluri Satish , Seal Brian S. 
Published: March 2020

e14013 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend use of approved biologics combined with common chemotherapy agents for treatment of metastatic colorectal cancer (CRC). Five classes of chemotherapy/biologics are available for treatment of CRC. Methods: Adult patients with a diagnosis of CRC between 01/01/05 and 05/31/10 were identified from the Impact Intelligence Oncology Management (IIOM) registry. Patients with either stage 4 CRC at original diagnosis or development of a metastasis were included. Registry data included original date of diagnosis and stage information. Linked healthcare claims from a large US health insurance database affiliated with OptumInsight were used to identify lines of therapy and patient characteristics (e.g., development of metastases). Lines of therapy were based on patients’ use of chemotherapy/biologic agents after becoming metastatic. Treatment regimens were assessed and stratified by line of therapy (1st, 2nd, 3rd, 4th) and stage at diagnosis (0-2, 3, 4, unknown). Results: 16% of the 598 study patients who developed metastasis received no chemotherapy. Of those who did, 84%, 52%, 27%, and 14% received a 1st, 2nd, 3rd, and 4th line of therapy, respectively. 71% of patients who progressed from stage 0-2 or 3 received a 2nd line compared to 90% of patients who initially presented with stage 4 CRC. In the 1st line, 59% received an oxaliplatin-based regimen, 15% received an irinotecan-based regimen, and 11% received 5-FU alone. In 2nd and 3rd line therapy, percentages of patients treated with irinotecan-based regimens increased to 45% and 50%, respectively, and use of oxaliplatin-based regimens dropped to 27% and 16%, respectively. Overall, use of anti-EGFR agents increased steadily from 4% in the 1st line to 12%, 29%, and 38%, respectively in the 2nd, 3rd, and 4th lines. Conclusions: Patients who presented with stage 4 CRC had the highest rates of chemotherapy use. Despite NCCN guidelines, 11% of patients received 5-FU monotherapy as 1st line treatment.
Differences in survival for metastatic colorectal cancer patients by lines of therapy received.
Authors: Seal Brian S. , Chastek Benjamin , Kulakodlu Mahesh , Valluri Satish 
Published: March 2020

e14016 Background: Improvements in survival for advanced-stage CRC patients who receive chemotherapy have been reported. We compared survival rates for patients with 3+ vs. <3 lines of therapy. Methods: Adult patients with a diagnosis of CRC between 01/01/05 and 05/31/10 were identified from the Impact Intelligence Oncology Management (IIOM) registry. Patients with either stage 4 CRC at original diagnosis or development of metastasis were included. Registry data included original stage and date of diagnosis. Linked healthcare claims from the Life Sciences Research Database, a large US health insurance database affiliated with OptumInsight, were used to identify lines of therapy after metastases and patient characteristics. Death data were obtained from the Social Security Administration’s master death file. Patients were categorized by number of lines of therapy received (0, 1, 2, 3+) and original stage at diagnosis (0-2, 3, 4, unknown). Survival following metastases was evaluated using Cox proportional hazards models controlling for lines of therapy received, stage, and other patient characteristics. Results: 598 patients, followed for a mean of 653 days after becoming metastatic, were included. Mean unadjusted length of follow-up was lowest among patients who received no chemotherapy (516 days) or only 1 line (511 days), and increased to 627 days for those with 2 lines and 930 days for those with 3+ lines. However, multivariate analysis indicated that patients with 3+ lines had comparable survival vs. those with 0 (HR=0.79), 1 (HR=1.59), or 2 (HR=1.15) lines of therapy (p>0.05 for all comparisons). Compared to patients who presented with stage 4 CRC, those who progressed from stage 0-2 (HR=1.22), stage 3 (HR=0.83), or unknown stage (HR=1.18) had similar survival after metastases (p>0.05 for all comparisons). After excluding 94 patients who didn’t receive chemotherapy, patients treated with an oxaliplatin-based regimen (HR=1.28; p=0.24) in first line had similar survival compared to patients treated with an irinotecan-based or anti-EGFR regimen in first line. Conclusions: Lines of therapy received and initial stage were not associated with survival after development of metastases.
Mutation profiling of KRAS, BRAF, and PIK3CA genes in colorectal cancer tissue.
Authors: McKeown S. , Doherty J. E. , Beaney M. P. , Latten M. J. , Murray H. A. , Crockard M. A. , Lamont J. V. , FitzGerald S. P. 
Published: March 2020

e14022 Background: Personalised cancer medicine based on mutation profiling of individual tumours is now a reality in the treatment of metastatic colorectal cancer (CRC) since the discovery of mutant KRAS status and resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. However, up to 65% of patients with KRAS wildtype tumours are resistant to anti-EGFR therapy. Mutations in other downstream effectors of the EGFR signaling pathway may also have a negative impact on patient response to anti-EGFR therapy. This study reportsthe analytical performance of a biochip array for the rapid simultaneous detection of 20 mutations within KRAS (including codons 12, 13, 61 and 146), BRAF and PIK3CA genes in CRC tissue samples. Methods: DNA from frozen CRC tissue samples was analysed using the Evidence Investigator KRAS/BRAF/PIK3CA Array. The assay is based on a combination of multiplex PCR and biochip array hybridisation, which enables high multiplexing detection. Innovative PCR priming technology permits high discrimination between multiple wildtype and mutant DNA regions. Providing there are enough copies of DNA present, approximately 1% of mutant can readily be detected in a background of wildtype genomic DNA. Analysis can be completed, from template DNA, through PCR (single reaction) to data readout in less than 3 hours. Confirmation of assay results was performed using Sanger sequencing and pyrosequencing. Results: Mutations were detected in 56% (14/25) of CRC tissue samples assessed. 6 samples were positive for KRAS, 3 for BRAF and 6 for PIK3CA with one sample harbouring both a KRAS and PIK3CA mutation. KRAS targets detected also included much rarer codon 61 and 13 mutations. Sanger sequencing confirmed all positive results apart from two, which were assessed via pyrosequencing. Conclusions: These findings demonstrate the applicability of the KRAS/BRAF/PIK3CA Array to rapidly simultaneously detect mutations within these genes in CRC tissue. The detection of additional markers besides KRAS and extending the profile of this gene to include other codons beyond 12 and 13 may aid in the selection of candidate patients to receive anti-EGFR therapy thereby maximising drug efficacy and minimising adverse patient effects.
Second- and third-line chemotherapy regimens in elderly Medicare stage IV colon cancer patients.
Authors: Bikov Kaloyan A , Mullins C. Daniel , Onukwugha Ebere , Seal Brian S. , Hanna Nader 
Published: March 2020

e14056 Background: The NCCN guidelines for stage 4 colon cancer (CC4) patients provide general guidance on which chemotherapies and targeted therapies improve survival or quality of life but do not provide specific treatment (TX) recommendations. The guidelines suggest that TX is highly individualized and no single treatment is right for everyone. This leads to variation in both the number and types of TX lines, especially for elderly patients where there are larger evidence gaps. Methods: Elderly (65+) SEER-Medicare patients diagnosed with CC4 in 2003-2007 were followed through death or 2009 to examine variation across sub-groups in the number of TX lines. TX included 5-fluorouracil and (levo)leucovorin-based (5FU/LV); irinotecan (IRI) and/or oxaliplatin (OX) with/out 5FU/LV; bevacizumab, cetuximab, or panitumumab (MNCLA), alone or in combination with chemotherapy; and other TX. A hierarchy categorized treatments as: 1) IROX (IRI+OX); 2) IRI or OX; 3) 5FU/LV; 4) MNCLA without chemotherapy; and 5) other TX. Gaps in TX or changes from OX or IRI to 5FU/LV were not considered new lines. Results: Of 3,263 CC4 patients who received TX, 98% started with an NCCN-approved TX for colon cancer and 1,541 (47%) went on to second line TX. Among those with at least 2 lines of TX, the most common sequences of TX lines were OX to IRI (42%), IRI to OX (12%), 5FU/LV to OX (11%) and 5FU/LV to IRI (11%). Approximately 17% switched from chemotherapy to MNCLA alone and relatively few ever used IROX. Of second line patients, 570 (37%) had a third line of treatment. The most frequent sequence for 3 TX lines were OX to IRI to MNCLA alone (30%); 5FU/LV to OX to IRI (12%); and OX to MNCLA alone to IRI (11%). Conclusions: The number of TX lines and the sequence of TX regimens vary considerably across elderly CC4 patients. Almost all patients started with an NCCN-approved TX for colon cancer. OX to IRI for first and second line TX was the most common sequence.
Safety report of a phase II trial of irinotecan plus S-1 (IRIS) with cetuximab in patients with KRAS wild type of metastatic colorectal cancer: HGCSG0902.
Authors: Komatsu Yoshito , Yuki Satoshi , Kato Takashi , Hosokawa Ayumu , Iwanaga Ichiro , Muto Osamu , Hatanaka Kazuteru , Nakamura Michio , Tsuji Yasushi , Sakata Yuh 
Published: March 2020

e14062 Background: IRIS is one of the standard regimens as second line treatment in metastatic colorectal cancer since IRIS demonstrated the non-inferiority to FOLFIRI (FIRIS study) in Japan. We previously presented IRIS plus bevacizumab (ESMO 2010), however; there is still lack of combination data of IRIS plus molecular target drugs. Thus we conduct the study of IRIS plus cetuximab (HGCSG0902) and this is the planned safety analysis for first 20 patients. Methods: HGSCG0902 is a multicenter phase ll study. Eligibility includes histologically confirmed colorectal cancer, previously received oxaliplatin-contained chemotherapy, PS: 0-1, EGFR positive and KRAS wild type. Patients (pts) received S-1 80-120 mg/m2/day p.o. on days 1-14 and irinotecan 100mg/m2 on days 1 and 15 repeated 28 days. Cetuximab administrated 400mg/m2 loading dose and continued 250mg/m2 every week or 500mg/m2 bi-weekly. The primary endpoint was response rate and the secondary endpoints were disease control rate, PFS, OS and safety. Results: Demographics of the 20 enrolled pts were male/female: 13/7, median age: 64.5, colon/rectal: 13/7, PS0/1: 12/8, prior bevacizumab +/-: 15/4 pts. Cetixumab were administrated weelkly/bi-weekly: 9/11 pts. 70% of pts had adverse events (AE). The most common non-hematological AE were diarrhea (85%), acne-like rash (80%), fatigue (75%) and anorexia (60%) and hematological AE were anemia (90%), AST increase (75%) and ALT increase (70%). The main grade 3-4 AE were diarrhea (45%), acne-like rash (20%), anorexia (20%) and stomatitis (20%). These AE were as expected. Nineteen pts stopped the treatment due to progression (52.6%) and AE (36.8%). Conclusions: This safety analysis suggests that IRIS plus cetuximab is well-tolerated and easy to administer.
Elderly patients with colorectal cancer: Treatment modalities and survival in France from the ThInDiT observational cohort study.
Authors: Doat Solene , Thiébaut Anne , Samson Solene , Ricordeau Philippe , Guillemot Didier , Mitry Emmanuel 
Published: March 2020

e14065 Background: More than 40% of the colorectal cancers (CRC) occur in elderly patients. Epidemiological data suggests that treatment modalities in this population differ from younger patients. We analysed the management of CRC patients in the real life in France using the French national health insurance system database. Methods: ThInDiT (Therapeutic Innovations in Digestive Tumors) is an observational cohort of 31 665 incident CRC diagnosed between April 1st and December 31th 2009 and registered in the French national health insurance system database. Using this cohort, we compared disease characteristics and treatment modalities within the first year of diagnosis between elderly (age >= 75) and younger patients (<75 years). Results: Elderly patients (pts) represented 42% (13 255/31 665) of the cases. They had more frequently an advanced stage at diagnosis (synchronous metastases: 20.5% vs 19.5% p=0.02, occlusion: 17% vs 11% p<0.0001). Pts with a localised disease (n=25 353): Surgery was performed in more than 80% of the cases in both age groups, delay between diagnosis and surgery was significantly shorter in elderly pts (8 vs 23 days p<0.0001) suggesting that emergency surgery was more frequent in this age group. An adjuvant chemotherapy (CT) was less frequently prescribed among elderly pts (15% vs 29% p<0.0001), 50% of the elderly received a 5FU alone whereas 79% of the younger pts had an oxaliplatin-based adjuvant CT. Pts with synchronous metastases (n= 6 312): Administration of palliative CT in elderly vs younger pts: 48% vs 85%, p<0.0001. CT regimen: LV5FU2 or capecitabine (30% vs 10%), Oxaliplatin-5FU (30% vs 34%), CT + bevacizumab (20% vs 35%) respectively. Elderly pts received less frequently a second or third line of CT than younger pts. Median overall survival was 8.4 months in elderly and 22.1 months in younger pts. Conclusions: Elderly patients represent more than 40% of incident CRC in France, they have a more advanced disease at diagnosis than younger pts. Treatment modalities are different among elderly and younger pts. Elderly pts have a worse prognosis than younger pts.
A prospective phase II study of neoadjuvant FOLFOX6 plus cetuximab in patients with colorectal cancer and unresectable liver metastasis.
Authors: Ji Jun Ho , Park Young Suk , Lee Jeeyun , Kim Tae Won , Hong Yong Sang , Kim Kyu-Pyo , Kim Sun Young , Baek Ji Yeon , Kang Hye Jin , Shin Sang Joon , Shim Byoung Yong 
Published: March 2020

e14072 Background: Colorectal cancer(CRC) with liver-only metastasis is considered potentially curable when liver metastases are completely resectable, while nonresectable liver metastases(NLM) are still incurable. In the latter cases, neoadjuvant chemotherapy could render curability by achieving resectability. We assessed efficacy of neoadjuvant cetuximab combined with FOLFOX6 in colorectal patients with NLM. Methods: Between July 2008 and Dec 2009, 73 patients were enrolled from 11 centers in Korea. Newly diagnosed K-RAS wild type CRC patients with NLM were treated with FOLFOX6 plus cetuximab(provided by Merck Serono) every 2 weeks. Response was evaluated every 3 cycles by CT scan according to RECIST 1.0. Chemotherapy was continued until disease progression or maximum of 12 cycles. Liver metastasectomy was performed at physician’s discretion in patients with enough tumor shrinkage, followed by chemotherapy of same regimen to complete total 12 cycles. The primary endpoint was overall R0 resection rate. The secondary endpoints were the response rates, progression-free survival(PFS), overall survival and toxicity. Results: In total, 73 patients were enrolled and analyzed. The median follow up duration was 28.6 months (range 11.5 to 38.1). Among 53 (72.6%) patients who showed response, surgery with curative intent was attempted in 36 (49.3%) patients. With intention-to-treat analysis, R0 resection rate(RR) was 19.2% (14/73), RFA plus R0, R1 and R2 RR were 8.2% (6/73), 8.2% (6/73), 13.7% (10/73), respectively. Despite neoadjuvant chemotherapy, 37 (50.7%) patients had unresectable hepatic metastases, however. RFA was successfully performed in combination with surgery (n=7) or alone (n=1) in 8 patients of them. Chemotherapy was discontinued in 26 patients due to disease progression (n=13), death (n=2), consent withdrawal (n=10), or protocol violation (n=1). The most common grade 3 and 4 toxicity was neutropenia (10.7%). Median PFS was 14.1 months (range 1.3 - 30.8) in patients received R0 resection and RFA + R0 resection. Conclusions: Neoadjuvant chemotherapy with FOLFOX6 plus cetuximab showed high response rates and increase resection rate in CRC patients with NLM.