bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined activity of the cancer metabolism inhibitor MPC-8640 and 5-fluorouracil in xenograft models.
Authors: Baichwal Vijay R. , Bradford Chad , Patton J. Scott , Reeves Leslie , DeMie Lynn , Fotheringham Lori , Roman Orvelin , Douce Thomas B , Brown Brita , Carlson Robert O.
Published: March 2020

e13581

Background: Nicotinamide (Nam) phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step in NAD biosynthesis from Nam. Nampt inhibition causes NAD depletion, inhibition of ATP synthesis and cell death. MPI-0487316 is a selective Nampt inhibitor with potent tumoricidal activity against cancer cell lines of diverse origin. MPC-8640, an orally bioavailable prodrug of MPI-0487316, induces regressions in xenograft models. Combining Nampt inhibitors with 5-fluorouracil (5-FU) results in synergistic tumoricidal activity in cells. We have explored the combination of MPC-8640 with 5-FU in a colon carcinoma xenograft model. Methods: In vitro studies were done in HCT-116 human colon carcinoma cells. Cell viability was measured by determining ATP levels. Xenograft studies were done with cells implanted subcutaneously into athymic mice (nu/nu). MPC-8640 was dosed orally at 12 to 48 mg/kg daily on Days 1-7 and 15-21. 5-FU was dosed intraperitoneally, weekly at 100 mg/kg. Results: MPI-0487316 showed synergistic tumoricidal activity in vitro with 5-FU. In xenograft studies, the prodrug MPC-8640, at 12, 24 and 36 mg/kg, resulted in tumor growth inhibition (TGI) of 64%, 98% and 91%, respectively, at the end of dosing on Day 22 and tumor regression of 5%, when dosed at 48 mg/kg. In the 36 and 48 mg/kg group, 20% and 10% of the mice, respectively, had no detectable tumors by the end of the study on Day 42. In another study, mice were given 5-FU or MPC-8640 as single agents or in combination. Combining 5-FU with MPC-8640 at 24 mg/kg resulted in 45% tumor regression on Day 21 compared to TGI of 88% and 78% for MPC-8640 or 5-FU, respectively, dosed as single agents. Similarly, combining 5-FU and MPC-8640 at 32 mg/kg resulted in 83% tumor regression on Day 21 compared to TGI of 86% and 78% for MPC-8640 and 5-FU, respectively, dosed as single agents. The combinations of 5-FU and MPC-8640 were well-tolerated with <10% change in median body weight. Conclusions: A combination of MPC-8640 with 5-FU causes tumor regression in a colon carcinoma xenograft model and is more effective than either agent dosed alone. Thus, MPC-8640 may have potential for treating cancers as a single agent or in combination with antimetabolites.
Interim results of an open-label, single-arm trial of ultratrace I-131-iobenguane in patients with metastatic pheochromocytoma/paraganglioma (Pheo).
Authors: Pryma Daniel A. , Coleman R. Edward , Noto Richard , Goldsmith Stanley J. , Perini Rodolfo F. , Jimenez Camilo , Pampaloni Miguel H , Serafini Aldo N. , Wahl Richard L. , Kostakoglu Lale , Conley Jennifer , Ford Kathy , LaFrance Norman David , Babich John W.
Published: March 2020

e13592

Background: To evaluate the therapeutic efficacy of no carrier added (nca) I-131-MIBG in pheo as measured by > 50% reduction of all antihypertensive medication for ≥ 6 months. Secondarily, to evaluate safety (including radiation absorbed dose to normal organs) and the proportion of subjects with objective response per modified RECIST and biomarker response by change in Chromogranin A (CgA). Methods: Pts with metastatic pheo causing secondary hypertension were treated with up to two 500 mCi doses of 131I-nca-MIBG 3-6 months apart. The administered dose was limited by pretreatment organ dosimetry and normal tissue tolerance estimates of Emami (1991). Response and toxicity were evaluated for a minimum of 1 year. Results: To date, 41 pts (17-72 years) received at least one treatment (full analysis; FA); 34 pts received 2 treatments (per protocol; PP); All patients have been followed at least 1 year or until death. The primary endpoint of sustained reduction in HTN meds was achieved in 32% and 29% of PP and FA, respectively. In total, 25/41 subjects who received at least 1 treatment had ≥ 50% reduction in their HTN meds. Mean duration of the reduction was 7.7 ± 6.6 months (range 0.1 – 22.1 months). Objective PR was seen in 41% (PP) and 34% (FA). 56% of PP had at least objective MR. All subjects in PP had at least stable disease and 90% in FA had at least stable disease. At 8 months there was a 60±33% reduction in CgA from baseline in PP. Primary toxicity was myelosupression: grade 3 (17%), grade 4 (20%). Grade 3 GI disorders were 15%. There were 3 deaths during follow up, all due to disease. Biomarker response correlated well to objective response and HTN improvement. Thrombocytopenia was the most common treatment-emergent SAE (n=9) considered related to study drug. No other treatment-emergent SAE was considered related to study drug in > 2 subjects. Conclusions: 11 of 34 pts in PP in this ongoing study met the primary endpoint of a positive clinical benefit (decreased HTN meds), which correlated with objective tumor response and biomarker levels in this disease with no approved, efficacious therapies. Toxicity for all patients (n=41) was tolerable and predominantly limited to myelosupression.
Utility of the Edmonton Frail Scale (EFS) in identifying frail elderly patients during treatment of colorectal cancer (CRC).
Authors: Meyers Brandon M , Yelamanchili Radhika , Rask Sara , Al-Shamsi Humaid Obaid , Phillips Callista Maria , Papaioannou Alexandra , Zbuk Kevin M. , Gu Chu Shu , Jeyabalan Neera , Dhesy-Thind Sukhbinder K.
Published: March 2020

e14001

Background: CRC is the second leading cause of cancer-related death, and 40-50% of patients are older than 70 years. Frailty is a concept that has been proposed by geriatricians as an indicator of functional age. The EFS is a 15 point incremental scale; it is quick (<5 min), and simple to administer. We conducted a pilot study to establish if the EFS would add utility beyond clinician’s expertise. The primary objective was to determine if there was an association between the EFS and receipt of chemotherapy. Methods: The EFS was administered to stage II-IV CRC patients ≥70 years, referred to a Medical Oncologist at a tertiary care centre. The EFS was completed by one of the investigators, with the treating oncology team blinded to results and a follow up 14 month chart review. Results: Forty-six patients were enrolled with the following characteristics: average age 76, 48% male, 78% performance status (PS) 0-1, and 21 (46%) started chemotherapy. The EFS was reproducible between visits (r = 0.81 [CI 0.64-0.9, p<0.0001]). There was no correlation between the EFS and receipt of chemotherapy for the study population as a whole. As none of the 16 stage II patients had high-risk features requiring chemotherapy, the analysis was repeated excluding these patients. There was a reduced likelihood of receiving chemotherapy for stage III/IV patients with higher EFS scores (Odds ratio 0.56 [CI 0.37-0.85, p<0.01] per unit increment). A similar effect was observed after multivariable analysis (adjusting for PS, age, stage and gender, Odds ratio 0.41 [CI 0.18-0.96, p<0.05] per unit increment). No correlation existed between EFS and upfront dose reductions, choice of less toxic regimens, or hospitalization secondary to grade 3/4 toxicities. Conclusions: This pilot study suggests the EFS can identify patients that Oncologists may have thought were too frail for chemotherapy, independent of PS. Therefore, the EFS has the potential to add a reproducible, and quantifiable measure of frailty to the clinician’s decision making armamentarium. The next study phase will employ the EFS real-time, and determine if using the EFS can minimize complications and unplanned health care utilization in elderly cancer patients.
Diabetes, metformin use, and colorectal cancer survival in women: A retrospective cohort study.
Authors: Cossor Furha Iram , Adams-Campbell Lucile L. , Chlebowski Rowan T. , Gunter Marc J , Johnson Karen , Martell Robert E. , McTiernan Anne , Simon Michael S. , Rohan Thomas , Wallace Robert B , Paulus Jessica
Published: March 2020

e14005

Background: Observational studies have associated metformin use with lower colorectal cancer incidence but few studies have examined survival impact. We examined the relationship between metformin use, diabetes, and survival in postmenopausal women diagnosed with colorectal cancer while participating in the Women’s Health Initiative (WHI) Clinical Trial or Observational Study. Methods: 2,066 postmenopausal women with colorectal cancer diagnosed while enrolled in the WHI were followed for a median of 4.1 years, with 589 deaths overall and 414 colorectal cancer deaths. In this cohort, overall and colorectal cancer-specific survival were compared among women with diabetes who reported ever using metformin (n=84); those with no reported use of metformin (n=128); and women without diabetes (n=1854). Cox proportional hazard models were used to estimate the associations between metformin use, diabetes and survival outcomes from the time of colorectal cancer diagnosis. Two strategies were used to adjust for potential confounders: multivariate adjustment with known predictors of colorectal cancer survival and construction of a propensity score for the likelihood of receiving metformin, with model stratification by propensity score quintile. Results: After adjusting for age and stage at diagnosis, women with diabetes on metformin had no significant difference in colorectal-cancer specific survival compared to metformin non-users (HR 0.75; 95% CI 0.40 -1.38, p=0.67) or compared to women without diabetes (HR 1.00; 95% CI 0.61 - 1.66, p=0.99). With propensity score adjustment, the HR for colorectal cancer-specific survival in women with diabetes on metformin compared to non-users was 0.90 (95% CI 0.48 – 1.69, p=0.75). Women with diabetes reporting metformin use had no significant difference in overall survival compared to non-users (HR 0.84; 95% CI 0.51 – 1.37; p=0.48) or non-diabetics (HR 1.20; 95% CI 0.80 - 1.79; p=0.39). Conclusions: In postmenopausal women with colorectal cancer and diabetes, no statistically significant difference was seen in colon-cancer specific survival in those who used metformin. Analyses in larger populations of colorectal cancer patients are warranted.
Current practices in 1st- (1L), 2nd- (2L), and 3rd-line (3L) treatment for metastatic colorectal cancer (mCRC).
Authors: Thompson Stephen F , Iqbal Sheikh Usman , Naoshy Sarah , Ng Daniel B , Andria Michael L , Sherman Steven A , Malangone Elisabetta , Stern Lee , Gorritz-Kindu Magdaliz
Published: March 2020

e14028

Background: Up-to-date information concerning the optimal regimen assignment and sequencing of therapies is lacking for the treatment of mCRC patients. By tracking trends in treatment choice, this retrospective, observational study assesses current treatment patterns in mCRC patients by line of therapy. Methods: Using electronic medical record data from one of the largest US oncology databases (SDI), treatment regimens for 1L, 2L, and 3L were assessed for patients age ≥18 yrs diagnosed with mCRC from 1/1/04-7/31/11 who received anticancer agents. Results: 1,793 stage IV patients were identified in 1L, 1,050 in 2L, and 504 in 3L. Overall mean age was 60.4 yrs, and 54.6% were men. The most common comorbidities were hypertension (18.0%), lipid metabolism disorders (10.6%), and diabetes (8.6%). 47.8% had commercial insurance, 37.2% Medicare, 8.5% Medicaid, and 4.6% self pay. 1,026 patients received bevacizumab (B) in 1L, 583 in 2L, and 204 in 3L. Patients were more likely to receive FOLFOX (FX) + B in 1L and 2L. The top 3 regimens are shown in the table below. For patients who began treatment with B and continued B in a subsequent regimen, mean dose of B increased from 443.7 mg/kg (1L) to 567.0 mg/kg (2L) and 618.1 mg/kg (3L). Conclusions: FX is the regimen of choice in mCRC. In terms of biologics, B is more commonly used in 1L/2L than 3L. Given that approximately half the mCRC patients progressed to 2L/3L treatment, this likely reflects an unmet need for advanced therapies for the effective treatment of the disease. Furthermore, consistent dose escalation with continued B use across 2L/3L was seen despite that use of B in 3L mCRC is inconsistent with NCCN guidelines. Additional research on outcomes implications is needed, including mortality, patient toxicity, and costs. [Table: see text]
Prognostic significance of KRAS and BRAF mutations in Japanese patients with colorectal cancer.
Authors: Oki Eiji , Nakanishi Ryota , Ando Koji , Saeki Hiroshi , Ohga Takefumi , Kakeji Yoshihiro , Tsujitani Shunichi , Kohnoe Shunji , Maehara Yoshihiko
Published: March 2020

e14033

Background: Recent evidence highlights the potential prognostic and predictive value of BRAF and K-RAS gene alterations in patients with colorectal cancer. To determine whether differences exist in the molecular mechanisms driving colorectal cancer between Japanese and Western, we characterized Japanese patients with colorectal cancer by assessing genetic alterations involved in cancer progression and response to treatment. Methods: We retrospectively evaluated 254 Japanese diagnosed with colorectal cancer at our institution between 1994 and 2009. Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing. Microsatellite instability (MSI) status was determined by genotyping in the 5 loci. Associations between KRAS or BRAF mutation and clinicopathological characteristics and prognosis were evaluated. Results: KRAS and BRAF mutation were detected in 33.5% and 6.7% of all patients, respectively. KRAS mutation was correlated with poor recurrence free survival (RFS) (p = 0.03), especially in stage II patients (p = 0.007). BRAF mutation was significantly correlated with the anatomical site of tumor (p < 0.001), tumor grade (p = 0.001) and high frequency of microsatellite instability (p < 0.001). BRAF mutation was also correlated with poor overall survival in all cases of patients (p = 0.009). Overall, the background of KRAS and BRAF mutation was almost similar between CRCs of Western countries and those of Japanese. However, KRAS mutation status was considered to be helpful to predict recurrence in Japanese patients with stage II CRC. Conclusions: Our findings indicate that BRAF and K-RAS mutation plays an important role in the tumorigenesis of colorectal cancer. These results indicate that molecular analysis for BRAF and K-RAS may be a useful biomarker for identifying patients with right-sided colon cancer with poor outcome who may benefit from a more individualized course of therapy.
Recombinant adeno-viral human p53 gene combined with FOLFOX4 in the treatment of advanced colorectal cancer.
Authors: Zhang Zhong-guo
Published: March 2020

e14036

Background: Metastatic or recurrent colorectal cancers generally become unresectable and will not respond to radio- or chemo-therapy. Studies showed that p53 has a synergic effect with radio- or chemotherapy. This study is to determine the efficacy and safety of recombinant adenoviral human p53 gene (rAd-p53) combined with standard FOLFOX4 regimen in treatment of advanced colorectal cancer. Methods: From July 2008 to Dec. 2011, 56 patients with an advanced colorectal cancer or local recurrent disease were treated with rAd-p53 and standard FOLFOX4 regimen. For local tumor, 1-4×1012 viral particles (VP) of rAd-p53 diluted into 5 ml of saline solution was injected into tumor at multiple directions, once a week for 6 weeks. If tumor spreading into abdominal cavity, 4×1012 VPs diluted in 500 ml of saline solution were injected inraperitoneally, twice in 2 weeks. If having lung or liver metastasis, 2×1012 VPs diluted into 100 ml of saline solution were given intravenously twice in 2 weeks. Three days after the first gene therapy, the standard FOLFOX4 regimen was given for six cycles. Results: The follow-up time was 3~38 months with a median of 19.5 months. Among these patients, 8 (14.3%) patients were assessed as complete response, 31 (55.4%) as partial response and 11 (19.6%) as stable disease. After the combined treatment, a radical resection was successfully performed in 18 cases with local recurrent disease. All these patients were still alive at the last follow-up. Common adverse events were 38.4~40.5 oC self-limited fever, occurring in 86% patients. No serious adverse events were observed. Conclusions: rAd-p53 combined with FOLFOX4 is a safe and effective treatment for advanced colorectal cancer or local recurrent disease.
Identification of a 14-gene signature that predicts survival in colorectal cancer with liver metastasis.
Authors: Chung Jo L , Pollack Jonathan , Chua Mei-Sze , So Sam , Lin Chii-Dean , Lin Albert Y.
Published: March 2020

e14037

Background: Colorectal cancer (CRC) is the third leading cause of cancer death in men and women combined in the USA. Colorectal liver metastasis (CLM), the most common metastasis of CRC, accounts for at least two thirds of CRC deaths. The purpose of this study is to identify a gene signature that predicts patient survival in patients with CLM. Methods: We analyzed the gene expression profiles of specimens from 24 CLM patients (M:F = 14:10) who underwent metastatic liver resection and unmatched primary CRC specimens from an independent cohort of 30 patients (M:F = 14:16). The association between gene expression levels and survival outcome was evaluated using Cox proportional hazards regression. Random Forests and risk scores were used to construct a gene expression-based survival classifier. Results: Based on survival classifier of CLM patients, a 14-gene signature was developed. According to leave-one-out cross validation, all 24 CLM patients (median follow-up time of 25 months) were correctly assigned into high-risk or low-risk groups (p=0.001). This 14-gene signature was then validated in an independent cohort of 30 primary CRC patients (median follow-up time of 42.2 months; p= 0.03) and a subset of 11 patients who were diagnosed at presentation or follow-up with liver metastasis (M:F = 5:6; median follow-up time of 27.6 months; p=0.04). Conclusions: We have identified a 14-gene signature that predicts the survival of CLM patients after liver resection, with validation in an independent cohort. Although sample size is small, the significance level achieved with our survival analysis warrants further investigation of this 14-gene signature in a larger sample size.
Should bevacizumab (B) be included in the first-line treatment of elderly patients with advanced colorectal cancer (CRC)? Results from a community-based Italian observational study.
Authors: Lutrino Stefania Eufemia , Schirripa Marta , Calvetti Lorenzo , Rosati Gerardo , Giampieri Riccardo , Avallone Antonio , Cordio Stefano Sergio , Berretta Massimiliano , Rojas Llimpe Fabiola Lorena , Foltran Luisa , Loupakis Fotios , Scartozzi Mario , Lonardi Sara , Pinto Carmine , Falcone Alfredo , Cascinu Stefano , Bordonaro Roberto , Zagonel Vittorina , Fasola Gianpiero , Aprile Giuseppe
Published: March 2020

e14040

Background: Data on B for elderly patients with advanced CRC are scarce, although recent analyses demonstrated safety for its use. To investigate the efficacy and safety of treating older pts with B and chemotherapy in the clinical practice a national cohort was analyzed. Methods: In this observational cohort study 213 elderly patients from 9 Italian centers who received first-line B combined with chemotherapy were enrolled. Demographics and comorbidities were captured, along with efficacy and toxicity results. Predefined endpoints were response rate, progression-free, overall survival, and safety. Survival curves were generated with Kaplan-Maier methodology. Results: Median age was 72 (66-84), PS was 0-1 in 96%. Comorbidities at study entry were reported in 153 pts (72%): cardiovascular (including hypertension) 107, diabetes 32, respiratory 15, endocrine 10, neurological 10, renal 7, other diseases 51. Comprehensive geriatric evaluation with ADL, IADL and CIRS scores was available for only 64 pts (29%) reporting median values of 6, 8 and 20 respectively. Companion chemotherapy was 5-FU alone for 27 (12.6%), oxaliplatin-based doublet for 75 (35.2%) and irinotecan-based combination for 111 (52.1%). 81 pts had chemotherapy dose reduction, and 23 interrupted B before progression. Disease control was achieved in 86%, with median PFS/OS of 8.8/18.9 months. 76 pts were maintained on B alone or B plus 5-FU. Main toxicities were neutropenia (44%), anemia (37.5%), diarrhea (40.8%), mucositis (25.8%) and hand-foot syndrome (14.1%). Sensorial neurotoxicity was frequent among pts receiving oxaliplatin. Specific B-induced toxicities were induced or worsened hypertension in 48 pts (22.5%), proteinuria in 24 (11%), and venous or artherial thromboembolism in 16 (7.5%). Conclusions: To treat elderly CRC pts with B and chemotherapy is safe and major efficacy endpoints did not differ from expected. Geriatric evaluation is underused in the common practice and better tools are required to select elderly to be treated with antiangiogenics.
Effect and safety of FOLFOXIRI+b-mab as preoperative chemotherapy for multiple liver metastases of colorectal cancer.
Authors: Ichikawa Yasushi , Goto Ayumu , Shimamura Takeshi , Ishikawa Takashi , Watanabe Jun , Watanabe Kazuteru , Ota Mitsuyoshi , Fujii Shoichi , Akiyama Hirotoshi , Tanaka Kuniya , Endo Itaru
Published: March 2020

e14047

Background: R0 resection for liver metastases of colorectal cancer is one of the promising treatment to improve prognosis of advanced colorectal cancer. Recently, effective anti-cancer drugs and various regimens using them were created and some advanced inoperable liver metastases were converted to operable by these chemotherapy. Therefore, development of powerful regimens to shrink liver metastases strongly is an important issue. In our department phase I/II study of FOLFOXIRI+B-mab including fluoroiuracil/oxaliplatin/irinotecan/bevacizumab for advanced liver metastases of colorectal cancer as pre-operative chemotherapy has been conducted now. Methods: The study was designed as a single-arm, open-label phase I/II trial. Phase I was conducted as sequential dose escalation to define the maximum-tolerated dose (MTD) of irinotecan. Patients who are colorectal cancer with 4 or more liver metastases and no other distant metastases are included. The regimen includes bevacizumab; 5 mg/kg, oxaliplatin; 85 mg/m2, l-LV; 200 mg/m2, 5FU; 400 mg/m2 administered on day 1, followed by 5FU; 2400 mg/m2 continuously administered for 46 hours. Dose escalation of Irinotecan was planned from level 1; 150 mg/m2 , level 2; 180 mg/m2 and level 0; 125 mg/m2. In phase II, R0 resection rate of liver metastases as primary endpoint will be evaluated using MTD of irinotecan estimated in phase I. Results: Currently, 6 patients were studied. One patient showed grade 3 diarrhea as dose-limiting toxicity. For the other 5 patients, the study was accomplished. Grade 4 neutropenia was detected in 60%, however no patient showed febrile neutropenia. Excluding hematological toxicity, grade 3 or worse adverse event was only one grade 3 diarrhea described above. All 5 patients were performed R0 resection. All 5 patients showed PR and average of reduction rate was 62.7%. There was no pathological CR in the 5 patients who was performed R0 resection. There was no severe postoperative complication in them. Conclusions: This regimen is safe and shows high PR rate. So, the regimen is effective and improve R0 resection rate for multiple liver metastases of colorectal cancer. Further investigation of this study is still ongoing now.
Prevalence of BRAF gene mutation in Thai sporadic colorectal cancer patients.
Authors: Korphaisarn Krittiya , Roothumnong Ekkapong , Nimmannit Akarin , Limwongse Chanin , Manuyakorn Ananya , Klaisuban Wipawi , Akewanlop Charuwan
Published: March 2020

e14051

Background: The role of BRAF gene mutation has been studied for its association with prognosis of colorectal cancer (CRC). The prevalence was reported 10-15% in Caucasian patients. However, there is no existing data in Thai patients. This study aimed to determine the prevalence of BRAF V600E mutation, association with various clinicopathological features and outcome in Thai sporadic CRC patients. Methods: DNA was extracted from randomly selected formalin-fixed paraffin-embedded tumor blocks of CRC patients with stage I-IV receiving surgery of the primary tumors at Siriraj Hospital between 2006 and 2007. BRAF V600E mutation was performed by two-round allele-specific PCR and analysis using high sensitivity DHPLC. The association between patient characteristics and BRAF status with overall survival (OS) and disease free survival (DFS) were explored by Kaplan-Meier estimation and log-rank test together with Cox’s proportional hazard regression. Results: BRAF V600E mutation was identified in 7 out of 188 patients (3.7%). Four patients were female. There were more likely to found in tumors on the left side (n=4) compared with right side (n=2) and rectum (n=1). All patients with mutation had stage I-III diseases; one with stage I and 3 with stage II and III each. Four had moderately differentiated tumors. Six patients had neither lymphovascular nor perineural invasion. Patients with mutation seemed to have better survival. In multivariate analysis, BRAF mutation did not have major prognostic value regarding DFS or OS. Conclusions: The prevalence of BRAF V600E mutation in Thai sporadic CRC was 3.7% which was lower than what reported in Caucasian patients. Further study with larger number of patients is warranted to determine whether BRAF mutation has significant prognostic value.
miRNA expression as a predictor of survival in patients with metastatic colorectal cancer treated with EGFR inhibitors.
Authors: Imbeaud Sandrine , Manceau Gilles , Bachet Jean-Baptiste , Emile Jean-François , Bibeau Frédéric , Diebold Marie Danielle , Marcaillou Charles , Rio Frio Thomas , Le Corre Delphine , Bouche Olivier , Liebaert Francois , Laurent-Puig Pierre
Published: March 2020

e14059

Background: The epidermal growth factor receptor (EGFR) pathway is crucial in the development and progression of human epithelial cancers. EGFR inhibitors have been tested for treatment of a variety of cancers but they are generally plagued by low response rates, leading to ineffective or non-optimal chemotherapy, unnecessary drug toxicity and expense. In colorectal cancer, KRAS mutations are clearly associated with resistance to anti-EGFR antibodies. A major challenge is to identify, in non-mutated KRAS patients, markers that can predict response to this therapy. This study aimed to develop a miRNA expression-based model for evaluating the responsiveness of patients with KRAS wild-type metastatic colorectal cancer to one or more EGFR inhibitors prior to treatment. Methods: miRNA profiling of KRAS wild-type tumors was performed on a discovery set of 44 patients with metastatic colorectal cancer treated with anti-EGFR inhibitors. A miRNA expression-based predictor of survival risk group was calculated by combining a Cox proportional hazards model and a supervised principal component method. Results: miRNA profiling of the discovery set identified hsa-miRNA-31* whose expression in tumor samples was highly correlated with survival and displayed prediction prospective for disease-free and overall survivals. Parameters of the hsa-miRNA-31* expression-based prediction model were determined on a subgroup of 23 patients. Its discriminative ability was evaluated on the complementary 21 samples that included 19 events. In this validation set, 4 of the 6 patients classified as “low risk” by the model survived for more than 25 weeks as disease-free whereas 11 of the 13 patients classified as “high risk” displayed disease progression within 25 weeks, suggesting a specificity of 85% [95% CI: 54%-98%] and a sensitivity of 67% [95% CI: 22%-96%] for the prediction model. These values were associated with a PPV of 67%, [95% CI: 22%-95%] and a NPV of 85% [95% CI: 54%-98%]. Conclusions: Our findings demonstrated that a prediction model based on the level of expression of hsa-miRNA-31* could evaluate whether a patient with a KRAS wild-type metastatic colorectal cancer is likely to respond to an EGFR inhibitor.
Two decades of therapy in metastatic colorectal cancer (mCRC): An analysis to discern the contribution and progress made by chemotherapy.
Authors: Jawed Irfan , Wilkerson Julia , Duffy Austin G. , Fojo Antonio Tito
Published: March 2020

e14064

Background: The past 20 years have seen progress in mCRC with more effective agents and better medical, surgical and supportive care. Methods: Systematic review of 101 phase III and large phase II trials in mCRC to quantify benefit over time with first-line and subsequent therapies. Outcomes in the experimental (EA) and control arms (CA) included progression-free survival (PFS), overall response rate (ORR), stable disease (SD), and overall survival (OS). Data were analyzed according to dates of publication and median enrollment. Results: Significant outcomes are reported; most had R2 values > 0.6. OS of EA improved 0.83 mos/yr. Importantly OS of CA improved 0.58 mos/yr likely reflecting subsequent use of experimental regimens in CA and improvement in mCRC care over time. Chemotherapy has contributed only partly to gains in OS since (1) only modest improvements of PFS (0.33 [EA] and 0.26 [CA] mos/yr) and we have shown OS gains are proportional to PFS gains indicating other factors are as or more important than chemotherapy; and (2) lack of OS improvement in 14 second/subsequent line trials. Furthermore, to assess the contribution of each drug/drug class to improvement in OS we performed linear regression with OS the dependent variable versus time publication. We found oxaliplatin, irinotecan and bevacizumab have contributed to progress; but not cetuximab/panitumumab likely explained by inclusion of pts with tumors harboring mutant ras in studies. Not surprisingly, capecitabine in place of 5-fluorouracil had no impact on progress made. As expected PFS correlates highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD was an “adverse” outcome, OS decreasing as SD rates increase. Conclusions: OS of mCRC patients has improved gradually over the past two decades, with gains from chemotherapy and importantly gains from other factors, including lead-time bias, better loco-regional approaches and supportive care. Gains from first line therapies have been modest but consistent; gains from second line therapies have been disappointing. We believe future progress will be more fruitful if emphasis is given to improving second line therapies.
Immunological effects as a biomarker of chemotherapy in metastatic colorectal cancer.
Authors: Sasatomi Teruo , Ogata Yutaka , Yamana Hideaki , Akagi Yoshito , Shirouzu Kazuo
Published: March 2020

e14077

Background: Many multiple anti cancer drugs regimens have been established for metastatic colorectal cancer recently. We investigated cellular immunoreaction of these patients to their cancer. Methods: 26 metastatic colorectal cancer patients have been started chemotherapies. Their PBMC were harvested and investigated their character by Fac scan with fluorescent labeled antibodies (CD3, CD8, CD4, CD25, Foxp3) at before and after chemotherapy. Results: After chemotherapy, both CTLs (CD3, CD8 positive) and regulatory T cells (CD4, CD25, Foxp3 positive) were decreased in number among all patients. On the other hand, CTL/T reg ratio were significantly increased among tumor marker decreased patients and significantly decreased among tumor marker increased or stable patients. CEA levels among 85.7% of increased CTL/T reg ratio patients became to decrease less than half. CEA levels among 66.7% of decreased CTL/T reg ratio patients became to increase or to be stable, if their regimens have not been changed. The Reactive Rate of chemotherapy of CTL/T reg ratio increased patients was significantly higher than that of ratio decreased patients. (p=0.021) The Disease Control Rate of chemotherapy of CTL/T reg ratio increased patients was higher than that of ratio decreased patients. Conclusions: We found that the CTL/T reg ratio of PBMC in metastatic colorectal cancer patients were useful for prediction of the effect of chemotherapy.
Early outcome of a phase I study of interrupted pulse-dosed axitinib combined with FOLFOX or FOLFIRI in refractory metastatic colorectal cancer.
Authors: Roeland Eric , Shimabukuro Kelly Anne , Fanta Paul Timothy , Parker Bethany H. , Hwang Michael , Reid Tony R.
Published: March 2020

e14078

Background: Therapeutic inhibition of angiogenesis pathways may improve response of chemotherapy refractory malignancies. We evaluated the combination of axitinib, a multi-target VEGF receptor inhibitor, used intermittently with 5-FU based chemotherapy for refractory mCRC. We hypothesized that intermittent pulse dosed axitinib may improve response by delivering chemotherapy during tumor reperfusion after release from angiogenesis inhibition. We present preliminary data of the Phase I portion evaluating the safety and efficacy of interrupted pulse dosed axitinib + FOLFIRI. Methods: Initially, Pfizer A4061020 was a phase IB study of axitinib + bevacizumab + FOLFOX vs. FOLFIRI to evaluate potential overlapping toxicities. A4061020 was expanded to determine the MTD of 7 days of intermittent pulse dosed axitinib + FOLFIRI or FOLFOX; while secondary outcomes include TTP and OS. Enrollment was open to mCRC with progression on both oxaliplatin and irinotecan-based regimens. Results: Preliminary data of 10 mCRC subjects show intermittent pulse dosed axitinib at 14mg and 20mg in combination chemotherapy treatment is safe and tolerable (few grade 3 and one grade 4 AE). The MTD is 20mg daily. We observed a median clinical TTP of 10.1 mos (0.8 to 21.5 mos) vs. a median TTP of 5 mos on last line of chemotherapy (1 to 13 mos). Subjects treated with pulse dose axitinib appear to demonstrate a favorable OS, however these data are still immature. Conclusions: In 10 heavily pre-treated mCRC subjects, intermittent pulse dosed axitinib demonstrates safety, tolerability, and improved TTP. Subjects treated with this approach demonstrated a favorable TTP compared to the prior line of therapy and OS. Intermittent, pulse dosed axitinib warrants further study in a larger population. [Table: see text]
Mucinous histology to predict disease-free survival in microsatellite stable stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy.
Authors: Ahn Joong Bae , Kim Se Hyun , Shin Sang Joon , Lee Kang Young , Kim Tae IL , Hur Hyuk , Min Byung Soh , Kim Nam Kyu , Chung Hyun Cheol , Roh Jae Kyung
Published: March 2020

e14084

Background: The prognostic role of mucinous histology of the colon cancer has been studied for decades and remained controversial. The aim of this retrospective study was to investigate whether mucinous adenocarcinoma (MA) is associated with a worse prognosis than that of non-mucinous adenocarcinoma (NMA) in patients with stage III colon cancer. Methods: This study enrolled unselected 402 patients with stage III colorectal cancer treated with adjuvant FOLFOX after curative resection (R0). Clinicopathological information was retrospectively reviewed. Tumors were analyzed for microsatellite instability (MSI) by polymerase chain reaction (PCR) to determine MSI-high (MSI-H) or microsatellite stable (MSS). Kaplan-Meier method, log-rank test, and Cox proportional hazards regression models were used. Results: Among 402 patients, 42 patients (10.4%) were MA and 26 patients (6.5%) were MSI-H. Compared with MSS tumors, MSI-H tumors was associated with a higher rate of MA (26.9% vs 9.3%, P=0.005). In MSS tumors (n=376), 3-year disease-free survival (DFS) rate was 79% and 55% in NMA and MA, respectively (log rank, P=0.014). In MSI-H tumors (n=26), no statistically significant difference of DFS between MA and NMA was found. In multivariate analysis, MA remained an independent significant poor prognostic factor for DFS (HR=1.9; 95% CI, 1.003-3.717; P=0.049) in MSS patients. Conclusions: Mucinous histology is an independent poor prognostic factor for DFS in patients with microsatellite stable stage III colon cancer after adjuvant FOLFOX chemotherapy. [Table: see text]
Cost-effectiveness analysis of cetuximab and panitumumab as first-line metastatic colorectal cancer therapies in Spain.
Authors: Moreno Victor , Martinez-Amores Brezo , Barriuso Jorge , Mezquita Laura , Ibañez de Cáceres Inmaculada , Ayuso Sacido Angel , Peña Jose Maria , Perona Rosario , Belda-Iniesta Cristobal
Published: March 2020

e14093

Background: Current practice of clinical oncology is a challenge where increased efficacy of new-targeted therapies is counteracted by increasing costs. International financial crisis forces national health systems to optimize all therapeutic strategies maintaining clinical outcomes. Personalized medicine tries to select specific subpopulation of patients by biomarkers to refine therapeutic algorithms. We have performed a cost-effectiveness analysis to assess incremental cost-effectiveness ratio (ICER) per radiological response (RR) for cetuximab or panitumumab based scheduled as 1st line therapies for mCRC patients in Spain. Methods: Efficacy data were computed from all randomized trials (RT) that guided on-label uses of bevacizumab (K-Ras mut), panitumumab and cetuximab. Non- significant outcomes and toxicity as predictor of efficacy were excluded. Prices for drugs in Spain were assumed to represent the best-value for each drug including all possibilities to reduce pharmacy costs. For 1st line, median duration of therapy reported by RT was used to calculate the final budget. 70kg and 1.7 m were used as reference for patient dose calculations. Results: We simulated 3 main scenarios based on the possibilities of therapy for K-Ras wt patients assuming that all patients harboring a K-Ras mut. tumor received bevacizumab based chemotherapy. So, in scenario A K-Ras wt patients received weekly cetuximab combined with FOLFOX, ORR reaches 54% and global cost per RR sums €36,964. Scenario B: administering panitumumab-FOLFOX yields 51% ORR and € 38,880 per RR. Scenario C: cetuximab biweekly combined with FOLFOX yields 54% and €36,474. ICER for scenario A vs B is estimated at €4,394 per additional response. ICER for scenario C vs B yields a negative value of €4,432 per additional response. Conclusions: 1st line oxalipatin combinations of biweekly cetuximab for wt and bevacizumab for mutated patients optimize cost per additional response rate rather than panitumumab based schedules. Marginal cost differences between cetuximab and panitumumab therapies are exceeded by efficacy gap as measured by response rates in RT.
Association of marked thrombocytopenia at postoperative day 1 with incidence of liver dysfunction, morbidity, and mortality in metastatic colorectal cancer patients undergoing liver resection.
Authors: Gruenberger Thomas , Perisanidis Beata , Tamandl Dietmar , Stremitzer Stefan , Brostjan Christine , Gruenberger Birgit , Starlinger Patrick
Published: March 2020

e14095

Background: After major liver resection, the most significant factor determining postoperative morbidity and mortality is the ability of the remnant liver to regenerate. Liver regeneration is a tightly regulated process involving various different growth factors. Recently, platelets have been shown to play a pivotal role in liver regeneration after partial hepatectomy. Methods: Patients treated with liver resection for metastatic colorectal cancer (mCRC) between January 2000 and December 2010 were eligible. Liver dysfunction (LD) was defined as bilirubin > 5 mg/dL or prothrombin time <50% within the first postoperative week. The association of marked immediate postoperative thrombocytopenia with LD, morbidity and mortality was analyzed. Results: 518 patients with mCRC were treated for liver metastasis, of whom 476 underwent liver resection. 67.9% of these had received preoperative CTx. 20.1% of all patients developed LD. Postoperative complications occurred in 39%. 7 patients died within 90 days after liver resection (1.5%). Postoperative platelets < 100 x 103/ml on the first postoperative day were the only liver function parameter predicting postoperative LD in multivariate analyses (p = 0.015). Furthermore, reduced platelets were significantly associated with increased morbidity (p = 0.014) and mortality (platelets < 100 x 103/ml – 4.1%, platelets > 100 x 103/ml – 1.5%, p = n.s.). Conclusions: Platelets < 100 x 103/ml on the first postoperative day seem to be an early marker to predict postoperative LD, increased morbidity and mortality in patients after liver resection. Using this cut-off, it might be possible to identify patients at high risk for developing postoperative LD and complications already on the first day after liver resection. Furthermore, this data suggests a pivotal role of platelets in hepatic regeneration.
Prognostic value of BRAF and KRAS mutations in colorectal cancer patients.
Authors: Murata Paola , Stradella Agostina , Páez David , Tobeña Maria , Sebio Ana , Paré Laia , González Alan , Espinosa Iñigo , Targarona Eduardo , Gich Ignasi , Barnadas Agust , Baiget Montserrat , Martin-Richard Marta
Published: March 2020

e14104

Background: KRAS mutation has been established as a predictive marker of resistance to antiEGFR therapy in patients (pts) with colorectal cancer (CRC) but the role of BRAF is not yet clear. Both gene mutations have also been studied as prognostic factors but results are contradictory. AntiEGFR therapies impair evaluation of KRAS and BRAF as prognostic factors when overall survival is an endpoint. We hypothesized that if KRAS or BRAF were prognostic factors, they would influence time to relapse (TTR) after complete tumor resection. Methods: Patients who underwent surgery between 2007 and 2011 for stage II and III CRC were retrieved from our database. Codon 12 and 13 KRAS mutations and V600E BRAF mutation were analyzed. Clinical characteristics and mutation status were correlated with TTR. Results: We analyzed 170 pts with a median age of 66 (26 – 86) years. Tumors were located in the right colon in 27% of pts, in the transverse colon in 3%, in the left colon in 41%, and in the rectum in 29%. Most (55.3%) were stage III; 59% received adjuvant chemotherapy. KRAS and BRAF mutations were present in 66 (38.8%) and 5 (2.9%) pts respectively, and both were mutually exclusive. The most frequent KRAS mutations were: G12D (39.3%), G12V (27.2%), G13D (15.1%). Median TTR was 71 weeks (w) (95% CI 63-79). V600E BRAF mutation was the only factor associated with TTR. TTR was 42 w in tumors with the BRAF mutation and 74 w in wild-type tumors (p=0.041). Among KRAS mutations, KRAS G12V conferred a significantly longer TTR (100w) than the other subtype mutations (69 w; p=0.05). Conclusions: Our results suggest that V600E BRAF mutation is a negative prognostic factor in CRC, conferring a shorter time to relapse. Additionally, the KRAS G12V determines a different behavior among KRAS mutation tumors.
Differences in survival for advanced-stage colorectal cancer (CRC) patients by lines of therapy received in a U.S. local oncology practice.
Authors: Foltz Boklage Susan H , Kreilick Charles , Asche Carl V , Haislip Sally , Gilmore James W. , Szabo Stephen , Williamson Todd E. , Valluri Satish , Seal Brian S.
Published: March 2020

e14106

Background: Improvements in survival for advanced-stage colorectal cancer (CRC) patients who receive chemotherapy have been reported. We compared survival rates for patients with 3+ vs. <3 lines of therapy using electronic medical records of a local oncology practice in Georgia, USA. Methods: The Georgia Cancer Specialist (GCS) EMR Database (1/1/2005–07/ 31/2010) was used. The database contains data on patient demographics, cancer diagnostic information, chemotherapy and non-chemotherapy drugs administered written prescriptions, chemotherapy/radiation protocols, chemotherapy protocol changes, office visit information, and hospitalizations. Patients newly diagnosed with CRC between 01/01/05 and 06/31/10 treated with systemic therapy for CRC were identified. Patients were followed from initial CRC diagnosis to death, loss to follow-up, or end of study. Patients were categorized by number of lines of therapy received (1, 2, 3+) and original stage at diagnosis (III b/c, IV, unknown). Survival following initial line of therapy was evaluated using Cox proportional hazards models controlling forstage at diagnosis, type of 1st line treatment, and other patient characteristics. Results: The study included 704 patients with a median age of 63 years (age range 26-85 years) at diagnosis and 49% (n=345) female. 45% (n=317) and 42% (n=296) had stage IV and III b/c CRC at diagnosis, respectively. 53% (n=373) received only 1st line treatment, 27% (n=190) received 1st and 2nd line treatment and 20% (n=141) received 3rd line and beyond. The median follow up was 431 days and death was reported in 27%(n=190) of subjects. The multivariate Cox proportional hazard analysis indicated that there was no statistical difference in survival between patients who received 2nd line of therapy vs. 3 plus lines of therapy (HR=1.42; p<0.067). Conclusions: A non-statistical significant association between 2nd and more than 3 total lines of therapy in survival was found in subjects diagnosed with stage III B/C and IV. However the trend towards survival was present, indicating that some patients could benefit from the addition of 3rd line but it would require additional studies to confirm this.
Tolerability and toxicity profile of chemotherapy with oxaliplatin in combination with infusional fluorouracil (FOLFOX) and capecitabine (XELOX) in a community oncology setting.
Authors: Galiauskas Raimundas , Hassett Edel , Murphy Kate , Spillane Donna , Ahmed Gul , Bird Brian Richard , Murphy Conleth G.
Published: March 2020

e14111

Background: Chemotherapy regimens combining oxaliplatin with infusional fluorouracil (folfox) and capecitabine (xelox) have been found to be superior to fluoropyrimidine chemotherapy alone in colon cancer and are also useful in other gastrointestinal tumor types, including gastro-oesophageal cancers. We retrospectively assessed the tolerability and deliverability of the folfox and xelox regimens in a community oncology setting. Methods: Patients (pts) receiving folfox or xelox chemotherapy for gastrointestinal malignancies over a five year period from 2006 to 2011 were identified through a pharmacy database. Patient and tumour characteristics were recorded. For each regimen, delays in planned chemotherapy administration (>3 days) as well as dose reductions were recorded. Reasons for dose modification and/or treatment discontinuation were recorded. Regimens were compared for these outcomes using Fisher's exact test for categorical variables and unpaired t-test for continuous variables. Results: Of 138 pts with adequate information for assessment, 94 received folfox and 44 received xelox. Pts who received folfox were more likely to experience dose delays (64% vs. 36%, 2-sided p=0.003). The mean dose delays during folfox and xelox were not significantly different (12.2 vs. 10.8 days, t-test p=0.657). Pts who received folfox were less likely to require any dose reductions during therapy (31% vs. 50%, 2-sided P=0.038). Similar numbers of pts receiving folfox and xelox required dose reductions of oxaliplatin (27% vs. 32%, 2-sided p=0.548), while fewer pts receiving folfox required dose reductions of the fluoropyrimidine component (14% vs. 39%, 2-sided p=0.002). Conclusions: We found that more pts required dose delays during treatment with infusional fluorouracil-based versus capecitabine-based oxaliplatin regimens. However, the infusional regimen was associated with considerably less dose reductions, largely related to the fluoropyrimidine component. We favour infusional fluoropyrimidine-based chemotherapy unless other factors (e.g., distance to the oncology unit) support oral fluoropyrimidine use.