bluuebunny/crossref_metadata_2025 huggingface dataset:
MLN9708, an investigational proteasome inhibitor, in patients (pts) with solid tumors: Updated phase I results.
Authors: Smith David C. , Sullivan Daniel , Infante Jeffrey R. , Kauh John S. , Siu Lillian L. , Vlahovic Gordana , Thompson John A. , Gupta Neeraj , Di Bacco Alessandra , Liu Guohui , Kalebic Thea
Published: March 2020

e13603

Background: MLN9708 is a potent, reversible, orally bioavailable, and specific 20S proteasome inhibitor. This study (NCT00830869) assessed the safety, MTD, PK, PD, and antitumor activity of intravenous (IV) MLN9708 in pts with solid tumors. Methods: Pts aged ≥18 yrs (ECOG PS 0–2) received increasing doses of IV MLN9708 (starting at 0.125 mg/m2) on days 1, 4, 8, and 11 of 21-day cycles, for up to 12 cycles. MTD expansion cohorts included head and neck (H&N) cancer, non-small cell lung cancer, soft tissue sarcoma, prostate cancer, and a tumor PD expansion cohort. Plasma PK and blood PD data were analyzed by a non-compartmental method using WinNonlin software v5.3. The candidate PD biomarker ATF-3 was assessed using IHC. Results: 113 pts were enrolled; 23 in dose escalation and 96 in MTD expansion (includes 6 from dose escalation) cohorts. Median age of these heavily pretreated pts was 58 yrs (range 29–80). MTD was established as 1.76 mg/m2. Pts have received a median of 2 cycles (range 1–12) to date (data cut-off Dec 1, 2011); 22 received ≥4 cycles. 88% had ≥1 drug-related AE; most common drug-related AEs included fatigue (40%), thrombocytopenia (39%), rash (high level term) (33%), and nausea (32%). 52% of pts experienced grade ≥3 drug-related AEs, including thrombocytopenia (20%) and rash (9%). Drug-related peripheral neuropathy (PN) was seen in 13% of pts; 2 pts had grade 3 PN. 25% had drug-related SAEs, 15% discontinued due to AEs; 7 pts died, all unrelated to treatment. Of 75 response-evaluable pts, 26 achieved SD. A partial response (PR) was observed in a pt in the H&N cohort; response was achieved after 4 cycles and maintained through 8 cycles. Change in ATF-3 levels in tumor tissue post treatment was seen in 6 patients with tumor biopsy samples, indicating proteasome inhibition. PK data showed three-exponential plasma disposition, half-life of ~4–8 days, and dose linearity from 0.5–2.34 mg/m2. At MTD, maximal 20S proteasome inhibition in blood was approximately 60% at 0.08 hours. Whole blood PD effect was immediate and dose dependent. Conclusions: These data suggest that twice-weekly IV MLN9708 has a generally manageable safety profile and potential clinical utility; updated results will be presented.
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.
Optimal combination therapy for advanced colorectal cancer: An examination of synergy and antagonism with EGFR inhibition.
Authors: Vora Nilesh , Evans Steven , Bernard Paula J , Francisco Federico , Nagourney Robert Alan
Published: March 2020

e14075

Background: While FOLFOX +/- Bevacizumab is the most widely used combination in colorectal cancer (CRC), the EGFr antagonists Cetuximab & Panitumumab have not further enhanced activity. On the contrary, the addition of EGFR inhibitors to Irinotecan-based regimens at 1st & 2nd line has improved response and both progression freel & overall survival (Van Cutsem. 2010; Peeters. 2010.) Methods: We applied the ex vivo analysis of programmed cell death (EVA-PCD) (Nagourney, Curr Treat Opt Onc 2006) to examine interactions between EGFr antagonists and Irinotecan or FOLFOX in 534 human tumor primary culture microspheroids isolated from CRC surgical specimens or cytologically (+) fluids. Gefitinib was used as a surrogate for Cetuxima/Panitumumab activity. Tissue samples exposed to Oxaliplatin, 5FU, Irinotecan, and Oxaliplatin & 5FU (FOLFOX) provided dose response curves with and without Gefitinib for formal synergy analysis by median effect (Chou & Talalay). Results: Shown in table below. Conclusions: Results indicate superiority for Irinotecan combination with the EGFr antagonist Gefitinib. The percentage of synergistic interactions for Irinotecan & Gefitinib (41%) is demonstrably higher than that associated with FOLFOX & Gefitinib (4%). This suggests distinct modes of interaction between these classes of agents favoring Irinotecan and could have an impact upon future clinical trial designs. Recognizing the importance of Kras mutation, additional studies are underway to examine the impact of Kras mutation upon synergy. However, as wild-type and mutant samples would be expected to be equally distributed, subset analyses may reveal quantitative (higher % synergy) rather than qualitative differences (relative activity of Irinotecan vs FOLFOX). Results of these analyses will be reported. Supported in part by the Vanguard Cancer Foundation. [Table: see text]
inSIRT trial: Single-center phase II study of yttrium-90 radioactive resin microspheres in the treatment of liver-predominant metastatic colorectal adenocarcinoma after failure of first-line combination chemotherapy.
Authors: Reid Tony R. , Roeland Eric , Dad Shakeela , Shimabukuro Kelly Anne , Fanta Paul Timothy
Published: March 2020

e14079

Background: Liver metastases develop in half of colorectal cancer (CRC) cases and once metastatic, ~90% die due to their consequences. We are evaluating the aggressive management of liver metastases through the incorporation of selective internal radiation therapy (SIRT) using Yttrium-90 (Y-90) radioactive microspheres after evidence of progressive disease following 1st-line FOLFOX ± bevacizumab. Optimal timing for microsphere treatment relative to chemotherapy is not clearly established. Methods: Subjects with predominant hepatic metastatic CRC despite 1st-line FOLFOX based therapy ± bevacizumab are eligible. Interventional radiology and nuclear medicine assess the liver lesions and the subject receives SIRT followed by 2nd-line FOLFIRI 4-6 weeks after the final SIRT. Results: To date, 9 metastatic CRC subjects have been treated and 10 subjects enrolled (goal 30 subjects). One subject was withdrawn due to progressive lung metastases. 4 of 9 subjects (45%) achieved PFS at 6 mos and average TTP is 7 months(0.7-21.3 mos). Overall treatment has been well tolerated, except one possible study related SAE of liver failure. The OS endpoint has not been achieved. Conclusions: Historically, 2nd-line FOLFIRI has achieved a 2.5 mos median PFS. Our preliminary results of 9 subjects with metastatic CRC show a PFS up to 21.3 monthsand 45% PFS at 6 mos. These encouraging results demonstrate the utility of an innovative direct approach to metastatic CRC after failure of 1st-line combination chemotherapy. Based on our promising preliminary results, our aim is to enroll 30-35 metastatic CRC patients. [Table: see text]
Treatment with bevacizumab in patients with metastatic colorectal cancer (mCRC).
Authors: Ocvirk Janja , Rebersek Martina , Boc Marko , Ebert Motara Maja , Mesti Tanja
Published: March 2020

e14083

Background: This study was designed to prospectively evaluate the safety and toxicity of bevacizumab in mCRC patients (pts) with mCRC pts in routine clinical practice as well as selection of pts. Methods: Baseline characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected from 273 mCRC pts who started bevacizumab-containing therapy between January 2008 and August 2010. Results: The data from 273 pts (median age 62) were included in the evaluation. The ECOG performance status (PS) at baseline was 0 in 60%, 1 in 37% and 2 in 3% of pts. Eighty pts (29%) received adjuvant chemotherapy, and 84 (31%) received chemotherapy ± bevacizumab or cetuximab for prior treatment of metastatic disease. Majority of the 273 pts received irinotecan-based chemotherapy (65%). Complete response (CR) was reported in 7%, partial response (PR) in 31% and stable disease (SD) in 36% of the first-line treated pts. In pts previously treated for metastatic disease CR, PR and SD were 6%, 24% and 45%, respectively. In the first-line pts median progression-free survival (PFS) was 10.9 months (95% confidence interval [CI], 9.8 - 12.0), while median overall survival (OS) was 24.3 months (95% CI, 21.4 – 30.3). PFS was 10, 9 and 8.7 months and OS was 16.7, 13.5 and 12.8 months in pts previously treated for metastatic disease with chemotherapy, chemotherapy + cetuximab or chemotherapy + bevacizumab, respectively. Two-year survival rate was 51% in the first-line pts and 32%, 14% and 38% in pts previously treated for metastatic disease with chemotherapy, chemotherapy + cetuximab and chemotherapy + bevacizumab, respectively. Metastasectomy was performed in 39 (15.5%) of the pts. One hundred and nine pts received bevacizumab with subsequent chemotherapy and CR, PR and SD were 1%, 9% and 30%. Overall rates of bevacizumab-related grade 1-2/3-4 adverse events were: proteinuria 38/9 %, hypertension 16/3 %, thromboembolic events 1/5 %, infection 2/3 %, bleeding 2/1 % and fistula 0/1 %. Conclusions: The authors concluded that bevacizumab-containing therapy and use of bevacizumab for long period of time demonstrated efficacy and good tolerability when used as a first-, second- and third-line treatment in routine clinical practice.
Phosphorylated Akt and MAPK expression in primary tumors and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab.
Authors: Giampieri Riccardo , Scartozzi Mario , Maccaroni Elena , Mandolesi Alessandra , Biagetti Simona , Alfonsi Simona , Giustini Lucio , Loretelli Cristian , Faloppi Luca , Bianconi Maristella , Bittoni Alessandro , Del Prete Michela , Cascinu Stefano , Giorgi Francesca
Published: March 2020

e14086

Background: Other than the well-known EGFR pathway activation via the Ras-Raf-MAP-kinase, a possible role of other potential biomarkers could be relevant in determining resistance to anti-EGFR treatment, such as the protein-serine/threonine kinase Akt. We tried to assess the role of Akt and MAPK expression in metastatic colorectal cancer patients and their relationship with outcome for patients receiving Irinotecan-Cetuximab. Methods: Eligible patients were metastatic colorectal cancer patients treated in 2nd or 3rd line setting with a irinotecan-cetuximab based regimen. Patients were tested for K-ras status and subsequently assessed by immunoistochemistry for pAkt and MAPK expression, both in primary tumours and metastases whenever sufficient tissue was available. The role of pAkt and MAPK expression was evaluated for K-ras wild type patients for different likelihood of response, overall survival and progression free survival. Response was evaluated by RECIST criteria. Survival analysis was performed via Kaplan-Meier method. Results: In metastases pAkt correlated with RR (9% vs. 58%, p=0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001) and pMAPK correlated with RR (10% vs, 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p=0.0004). At multivariate analysis pAkt and pMAPK in metastases were able to independently predict PFS. pAkt in metastases independently correlated with RR as well. Conclusions: pAkt and pMAPK expression in metastases may modulate the activity of EGFR-targeted antibodies. We could speculate that in patients with pAkt and pMAPK metastases expression targeting these factors may be crucial.
Preclinical activity of BC2059, a novel compound that degrades beta-catenin, in colon cancer models.
Authors: Sharma Sunil , Soldi Raffaella , Gilcrease Glynn Weldon , Horrigan Stephen
Published: March 2020

e14090

Background: BC2059 (BetaCat Pharmaceuticals) is a novel small molecule that degrades ß-catenin in a proteosomally dependent manner in cancer cells. Methods: We tested the activity of BC2059 in vitro, in patient derived colon cancers in 3-dimensional cultures and in vivo using HT-29 xenografts. We also used a novel doxycycline driven siRNA model that downregulates ß-catenin to test activity of BC2059. Results: BC2059 was highly active with IC90s in MTS assays (μM): SW480 (0.44), Colo205 (0.66), Colo201 (0.03), HT29 (0.92) and relatively inactive in SW48 (9.83) or L cells (normal) (4). In a 3-Dimensional culture system where we grew patient-derived colon cancer cells in a matrigel system and measured cell death by ethidium bromide exclusion, surprisingly, the average EC50 was 200 picomolar indicating that the compound was much more effective in patient derived samples. In matrigel tumor invasion assays, BC2059 demonstrated potent inhibition of tumor invasion. In HT-29 mouse xenografts, BC2059 series demonstrated tumor growth inhibition with no weight loss with depletion of ß-catenin. We also used chromatin immunoprecipitation (CHIP) assays to demonstrate depletion of ß-catenin on myc and axin promoters. In combination experiments, BC2059 displayed synergy in vitro with 5-fluorouracil in vitro. We used a doxycycline driven siRNA system in colon cancer cell lines and show that the compound activity is synergistic with depletion of ß-catenin. We also conducted combination of BC2059 series of compounds using a proteasome inhibitor MG132 and demonstrate reversal of activity with proteasome inhibition. Conclusions: In conclusion, BC2059 demonstrates potent activity in vitro and in vivo against colon cancer models singly or in combination. Further, it is surprisingly potent in patient derived colon cancer models. It appears to degrade ß-catenin in a proteosomally dependent manner on important effectors like myc and axin. It merits further evaluation in this tumor type.
Is systemic inflammation the result of insufficient cortisol production in patients with colorectal cancer?
Authors: Ramanathan Michelle Leana , Roxburgh Campbell SD , Horgan Paul G , Mcmillan Donald C.
Published: March 2020

e14092

Background: Patients with colorectal cancer who have a raised systemic inflammatory response have been shown to have poorer outcomes, independent of their tumour stage. In particular, the combination of C-reactive protein (CRP) and albumin, the modified Glasgow Prognostic Score (mGPS) has been shown to have consistent and superior prognostic value. However, the basis of a systemic inflammatory response in these patients is not clear. One hypothesis is that the presence of a systemic inflammatory response in patients with colorectal cancer may be due to impaired cortisol production, a potent anti-inflammatory agent. Therefore, the aim of the present study was to examine the relationship between preoperative systemic inflammatory response and endogenous cortisol production. Methods: A prospective study was performed to incorporate the assessment of adrenocortical function using synthetic ACTH, a short Synacthen test, as part of the preoperative assessment of patients undergoing potentially curative resection for colorectal cancer. Preoperative systemic inflammatory response was assessed using mGPS. Results: A total of 80 patients underwent short Synacthen testing. The majority of patients were under 75 years old (79%), were male (59%), had colon cancer (75%) and had TNM stage I/II disease (54%). Approximately 50% received adjuvant treatment. Using standard criteria (peak cortisol <450 nmol/L = inadequate) impaired cortisol response was seen in 3 (4%) patients. There were no significant associations between the baseline, 30 minute, or change in cortisol (both relative and absolute) and age (p=0.814, p=0.443, p=0.730, p=0.929), sex (p=0.714, p=0.440, p=0.324, p=0.953), site (p=0.519, p=0.255, p=0.145, p=0.222), TNM stage (p=0.115, p=0.591, p=0.492, p=0.289), mGPS (p=0.280, p=0.202, p=0.800, p=0.818), or white cell count (p=0.787, p=0.316, p=0.462, p=0.567). Conclusions: The results of the present study show that impaired cortisol production, as evidenced by the short Synacthen test, was uncommon in patients with potentially curable colorectal cancer. Moreover, they indicate that the presence of a systemic inflammatory response is not associated with impaired cortisol production.
Comparison of magnetic resonance imaging and histopathological response to neoadjuvant chemotherapy in locally advanced rectal cancer: The GEMCAD 0801 trial.
Authors: Brown Gina , Patel Uday Bharat , Santos Cores Jesus , Isabel Gil Garcia Maria , Ayuso Juan Ramón , Puchades Roman Iciar , Mas Estelles Fernando , Risueno Noelia , Salud Antonieta , Maurel Juan , Aparicio Jorge , Pericay Pijaume Carles , Alonso Vicente , Safont M. José , Gallén Manuel , Vera Ruth , Feliu Jaime , Martin-Richard Marta , Fernandez-Martos Carlos
Published: March 2020

e14097

Background: MRI methods for rectal cancer response assessment post chemoradiotherapy include post treatment T staging(ymrT), tumor regression grading(mrTRG) and length change/modified RECIST measurement. The usefulness of MRI in evaluating response to neoadjuvant chemotherapy has not been investigated. We assessed the reproducibility and agreement of these three parameters with histopathological T and TRG stage(ypT, pTRG). Methods: 28 eligible patients were enrolled in a prospective phase II trial to evaluate safety and efficacy of neoadjuvant CAPOX-B in patients with MRI defined T3 rectal adenocarcinoma. Patients received 4 cycles of Cap 2000 mg/m2(d1-14),Ox 130 mg/m2(d1) and B 7.5 mg/kg(d1) every 3 weeks(last cycle without B). Seven radiologists assessed MRIs using the following categories: ymrT (T0-T4 using T3 substaging), mrTRG (1-5), and length change(Stable disease, Complete response,Partial response). Agreement was assessed by kappa (central reviewer data verses each local centre reviewer).Agreement between central reviewer MRI results and both pathology endpoints was also assessed. Results: 24 patients had evaluable pre and post chemotherapy imaging and pathology (4 did not have post treatment MRI). Thirteen patients had good response (ypT0-3a) and 11 had poor response (>ypT3a). Sixteen patients had good pTRG(2-4) and 8 had poor pTRG(0&1). ymrTRG showed a moderate level of reproducibility;K=0.45-0.58. ymrT showed a fair to moderate level of agreement;K=0.2-0.53. Length assessment also showed a fair level of agreement; K=0.21-0.38. ymrTRG showed 75% agreement with ypT(16/22); K=0.49(0.13-0.84) and 79% agreement with pTRG(19/24); K=0.55(0.22-0.88). ymrT showed a fair level of agreement with ypT;K=0.21, pTRG;K=0.2, length assessment showed slight agreement with ypT;K=0.1, pTRG;K=0.1. Conclusions: This is the first study to show MRI can evaluate response of rectal cancer following neoadjuvant chemotherapy. As mrTRG showed best agreement with pathology, we recommend mrTRG as the preferred method of post treatment assessment in this setting.
A pilot study of the immunohistochemical pattern of neuropilin-2 (NRP2) labeling and correlation with tumor stage in colon cancer.
Authors: Sun Hongliu , Kussman Ashleigh M. , Freeman Carol , Meredith Judy , Hensley Kenneth , Gato-Weis Cara , Skeel Roland T. , Nawras Ali , De Las Casas Luis
Published: March 2020

e14098

Background: Neuropilin 2 (NRP2) is a transmembrane glycoprotein, non-associated with kinase domains, implicated in neovascularization and metastasis of colon cancer. NRP2 has been proposed as a molecular marker for targeted cancer therapy based on its multiple functions in cancer promotion. NRP2 signaling pathway and its expression have been demonstrated in many carcinomas. To the best of our knowledge, no description of the immunohistochemical staining pattern of NRP2 in colon cancer has been published in the English medical literature. The aim of this study is to investigate the NRP2 labelilng pattern in colon cancer and correlate it with tumor stage. Methods: Tumor sections from 35 randomly selected colectomy specimens with colorectal cancer collected during the last three years were retrieved from the University of Toledo Medical Center Department of Pathology archival material. Formalin fixed, paraffin embedded, 4 μm tissue sections containing invasive tumor were immunolabeled with a commercial antibody against NRP2, using a Ventana Benchmark LT automated instrument. Randomized, immunolabeled colon cancer tissue sections were blindly reviewed by two pathologists. Cytoplasmic and nuclear expression of NRP2 by tumor cells was graded as negative (no staining), focal (staining in <50% of cells), and diffuse (staining in ≥ 50% of cells). Adjacent benign colonic mucosa was used as an internal control. Results: No T1 or T2 tumor displayed diffuse nuclear labeling for the NRP2 epitope. In contrast, 13/20 T3 tumors (65%) and 4/4 T4 tumors (100%) displayed diffuse nuclear labeling. The association of diffuse nuclear NRP2 labeling with tumor grade was highly statistically significant (p=0.0055 by Chi-squared test). In contrast to nuclear labeling, cytoplasmic staining was observed in all stages and varied from negative to diffuse, but demonstrated no significant correlation with stage. Conclusions: This pilot study on colon cancer specimens suggests that diffuse nuclear immunolabeling of neuropilin-2 is indicative of a higher tumor stage. This finding suggests a potential use for this marker as a prognostic indicator for colon cancer in small biopsy samples.
Retrospective analysis of pathological response in colorectal cancer liver metastases following treatment with bevacizumab: Updated findings.
Authors: Vera Ruth , Figueras Joan , Gomez Dorronsoro Marisa , Lopez Ben Santiago , Viudez Antonio , Queralt Bernardo , Hernandez Irene , Soriano Jordi , Zazpe Cruz , Ortiz Duran Rosa Maria
Published: March 2020

e14120

Background: Recent reports have shown that pathological response predicts for better outcome (overall survival) following preoperative chemotherapy and surgical resection of colorectal cancer (CRC) liver metastases. The aim of this retrospective analysis was to evaluate the effect of adding bevacizumab (BEV) to standard chemotherapy on pathological response in patients (pts) with CRC liver metastases. Methods: Pts with stage IV CRC with liver metastases who received neoadjuvant chemotherapy (oxaliplatin-or irinotecan-based) at two Spanish centres were analysed retrospectively. Pathological response was evaluated as follows: complete pathological response (cPR), PR1 (<25% of residual viable tumour cells), PR2 (25–50% of residual tumour), PR3 (>50% of residual tumour). cPR or PR1 was considered to be a good response, and PR2 or PR3 a poor response. KRAS status was determined from tumour blocks. Results: 95 pts were evaluated. Of these, 44 received chemotherapy alone and 51 received chemotherapy + BEV. Baseline characteristics were as follows: median age 61.0 years (range 43.0–80.0 years); male/female (68%/32%); tumour location – colon (72%) / rectum (28%); hepatic metastases – synchronous (74%) / metachronous (26%); extrahepatic disease – yes (26%) / no (74%); KRAS status – mutated (37%) / wild type (29%) / not available (34%). The overall response rate (ORR) by RECIST was 51% (1 CR and 47 PRs) and 48% of pts had stable disease. ORR did not appear to vary in pts who did or did not receive BEV. In terms of pathological response, 49% of pts receiving BEV had a good response (cPR + PR1) compared with 27% of those receiving chemotherapy alone (p=0.0302). Good pathological response (cPR + PR1) was slightly lower in pts with mutant (31%) vs wild type (43%) KRAS status (difference not significant). At the end of the analysis, 45% of pts had relapsed and 67% were alive. Conclusions: Adding BEV to standard chemotherapy in the neoadjuvant setting improves pathological response of liver metastases in pts with stage IV CRC. Further studies are required to examine the potential relationship between pathological response and survival outcomes in pts with CRC and liver metastases.