bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory metastatic colorectal cancer.
Authors: Overman Michael J. , Eng Cathy , Kee Bryan K. , Fogelman David R. , Fark Christine , Hippert Rick , Holter Scott , Issa Jean-Pierre , Hamilton Stanley R. , Kopetz Scott
Published: February 2017

450

Background: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and both clinical and preclinical studies have shown the ability to restore platinum sensitivity with the reversal of hypermethylation. CIMP is implicated in the pathogenesis of a subset of colorectal cancers termed CIMP-high. We sought to explore the safety and efficacy of the hypomethylator, azacitidine, in combination with CAPOX.

Methods: We report the results of the phase I portion of a prospective phase I/II study in fluoropyrimidine and oxaliplatin refractory metastatic colorectal cancer (mCRC). The primary objectives were to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of this combination. Two dose levels were explored with a standard 3+3 design of azacitidine (75 mg/m2, SQ D1-5), oxaliplatin (90 and 110 mg/m2 IV D2), and capecitabine (1500 mg/m2/d, PO divided BID, D1-14) every 3 weeks, followed by an expansion of 6 patients at the MTD to evaluate for delayed hematological toxicity. The phase II portion is restricted to patients with CIMP-high (≥ 2/6 methylation-specific PCR markers: hMLH1, P16, P14, MINT1, MINT2, and MINT31).

Results: 15 pts [M/F 8/7, median age: 60 yrs (range: 34-73), ECOG PS 0/1: 1/14] were enrolled from 8/2010 to 4/2011. Prior progression on fluoropyrimidine/oxaliplatin-based treatment met RECIST criteria in 13 pts. All pts were evaluable for toxicity and 13 for response. Twelve pts were treated at the highest dose level with no DLTs. Common grade 3-4 treatment-related toxicities were: neutropenia in 5 (33%), diarrhea in 2 (13%), oxaliplatin hypersensitivity reaction in 2 (13%). Best response was SD in 7 pts (54%) with a median duration of SD of 3.2 months (range: 2.2-6.9 months). Two pts remain on treatment. Two of 14 tested pts had CIMP-high tumors and both had progressive disease.

Conclusions: Azacitidine and CAPOX was well tolerated in an unenriched oxaliplatin-refractory mCRC population. The recommended phase II dose of azacitidine with CAPOX is 75mg/m2, D1-5. Enrollment in the phase II cohort continues in fluoropyrimidine and oxaliplatin refractory CIMP-high metastatic colorectal cancer.
Discovery of microRNAs in tumor tissue predictive of time to progression and overall survival in patients with colorectal cancer treated with first-line capecitabine, oxaliplatin, and bevacizumab.
Authors: Boisen Mogens Karsboel , Dehlendorff Christian , Linnemann Dorte , Ranc Kristina , Jensen Benny V. , Høgdall Estrid V. , Larsen Jim S. , Nielsen Svend Erik , Andersen Klaus Kaae , Johansen Julia S.
Published: February 2017

461

Background: The aim was to identify predictive and prognostic microRNAs (miRNAs) in cancer tissue samples from patients with metastatic colorectal cancer (mCRC) treated with 1.-line capecitabine, oxaliplatin, and bevacizumab (CapOxBev).

Methods: Patients with mCRC treated with 1.-line CapOxBev were identified from 7 hospital databases and clinical and pathological data was extracted retrospectively. Formalin-fixed paraffin-embedded (FFPE) tissue samples from primary tumors were collected and RNA was purified from 3 x 10 µm sections, without micro-dissection. MiRNA expression was measured using TaqMan® Array Human MicroRNA A and B cards (Applied Biosystems) profiling 754 miRNAs. Raw miRNA expression values were checked for outliers and data was corrected using spike-in values. In a univariate selection method, each miRNA was related to time-to-progression (TTP) and overall survival (OS) using Cox proportional hazards model (threshold p < 0.001). Candidate miRNAs were tested using Akaike’s Information Criterion in a multivariate analysis corrected for age, sex, histology, number of metastatic sites, primary location, and prior adjuvant treatment.

Results: Samples from 212 patients were profiled and 205 and 192 had acceptable miRNA and outcome data available for final analysis of OS and TTP, respectively. Four miRNAs were found to be predictive for TTP and two for OS. Higher expression of miRNAs A, B, and C and lower expression of miRNA D was predictive of longer TTP, and higher expression of miRNAs E and F predicted longer OS.

Conclusions: Four miRNAs measured in archival FFPE samples of primary CRC tumors from patients treated with 1.-line CapOxBev were predictors of TTP and two others of OS. Three of the miRNAs found have reported roles in angiogenesis pathways indicating that they may be biomarkers for bevacizumab efficacy. A validation study in 500 patients is on-going.

[Table: see text]
PKM2 mRNA expression to predict disease recurrence in patients with stage II or III colon cancer treated with oxaliplatin in combination with fluoropyrimidines.
Authors: Papadaki Chara , Sfakianaki Maria , Saridaki Zacharenia , Giagas Georgios , Mpananis Kyriakos , Tzardi Maria , Tsakalaki Eleftheria , Trypaki Maria , Georgoulias Vassilis , Sougklakos Ioannis
Published: February 2017

468

Background: Tumor cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase (PKM2), which is a key enzyme that regulates aerobic glycolysis in tumor cells. Use of RNA interfering (RNAi) targeting PKM2 significantly inhibits tumor growth when combined with cisplatin in xenograft models. We evaluated the predictive significance of PKM2 in patients with “high” risk stage II or stage III colon cancer treated with oxaliplatin-fluoropyrimidines chemotherapy adjuvant treatment.

Methods: FFPE primary tumours from 261 patients with stage II or III colon cancer with colon cancer were analyzed for PKM2 mRNA expression by RT-qPCR. All patients had received adjuvant treatment with an oxaliplatin and fluoropyrimidine combination. Also, match normal mucosas from 50 of these patients have been analyzed. Finally, 50 polyps (20 with low grade dysplasia, 20 high grade dysplasia and 10 serrated adenomas) from non-colon cancer patients were included in the for PKM2 mRNA expression by RT-qPCR. The analysis was performed with a set of primers and probes which amplify only the M2 isoform.

Results: PKM2 mRNA expression was significantly higher in tumor areas in comparison with normal mucosa (p=0.001) and low-grade adenomas (p=0.001) as well as in tumors with BRAF mutations (p=0.001). Adenomas with high-grade dysplasia (p=0.002) and serrated adenomas (p=0.001) presented significantly higher PKM2 mRNA expression. Overexpression of PKM2 was associated with significantly lower Disease Free (p=0.018) and Overall Survival (p=0.031). Multivariate analysis revealed PKM2 high mRNA expression as independent prognostic factors for decreased DFS (HR: 2.1, p=0.003) and OS (HR: 1.8, p=0.019).

Conclusions: These results provide evidence that the PKM2 mRNA expression could be used as prognostic/predictive marker for disease recurrence in patients with operable colon cancer. Analysis of the PKM2 mRNA expression in patients treated with non-oxaliplatin containing adjuvant treatment is currently performed.
Tesetaxel, a novel oral taxane, as second-line therapy for advanced gastroesophageal cancer: Activity in a dose-ranging study.
Authors: Ajani Jaffer A. , Sun Weijing , Rha Sun Young , Baker Jackie S. , Mulcahy Mary Frances
Published: February 2017

47

Background: Standard taxanes require extended IV infusion and are associated with potentially severe hypersensitivity and cumulative neuropathy. Tesetaxel is a structurally novel orally active taxane with potent and superior antitumor activity relative to standard taxanes in human tumor xenografts that overexpress P-glycoprotein. Tesetaxel is not associated with hypersensitivity, thus eliminating the need for both premedication and extended medical/nursing observation. A prior study showed an overall major response rate (ORR) of 20% as 2nd-line therapy in pts with advanced gastric cancer. Since pharmacokinetic and safety data suggested that flat dosing of tesetaxel might be feasible, we evaluated both flat and weight-based dosing in a new dose-ranging study.

Methods: Eligibility: adenocarcinoma (stomach or GE junction); treatment with 1 fluoropyrimidine/platinum analog regimen; ECOG PS 0-1; and adequate organ function. Tesetaxel was administered Q3 weeks at flat starting doses (40 mg and 50 mg) in Cohorts 1 and 2, respectively. When flat dosing proved impractical, a weight-based dose was used for Cohort 3 (27 mg/m2 with escalation to 35 mg mg/m2 pending tolerability). ORR was the primary endpoint.

Results: To date, 36 pts (29 men, 7 women; median age, 58 years [range: 25-81]) have been enrolled in this ongoing study, with results as shown below. Median survival is 7.8 and 7.5 months in Cohorts 1 and 2, respectively, and is too early to estimate in Cohort 3. Uncomplicated neutropenia was the most common ≥ 3 event (13%).

Conclusions: Extreme body weight differences resulted in marked underdosing and precluded flat dosing. Our data confirm that tesetaxel is active against gastroesophageal cancers in the 2nd-line setting using the weight-based Q3 week regimen.

[Table: see text]
Using deep sequencing of formalin-fixed paraffin embedded (FFPE) rectal cancer biopsy tissue to analyze miRNA expression in patients with rectal cancer.
Authors: Chen Zhenbin , Gao Harry , Mu Bing , Wang Jinhui , Wu Xiwei , Qin Hanjun , Li Wenyan , Garcia-Aguilar Julio
Published: February 2017

487

Background: miRNAs have been shown to be involved in tumor initiation, progression and metastasis in many cancers including colorectal cancer. However, miRNA profiling specifically in rectal cancer is not well characterized. Our objective was to generate a miRNA expression profile in locally advanced rectal cancer using formalin fixed paraffin embedded (FFPE) biopsy tissue collected from patients with locally advanced rectal cancer.

Methods: We collected pre-treatment biopsy tissue and matched normal tissue from 40 rectal cancer patients treated with pre-operative chemoradiation (CRT) and total mesorectal excision (TME). We extracted 50-1000ng of total RNA from FFPE biopsies and optimized small RNA sample preparation for deep-sequencing. We then performed deep sequencing on biopsy and matched normal tissue and compared miRNA expression in biopsy and normal tissues using paired T-test and multiple testing (Q-bound <0.05) to determine significant miRNA expression changes in rectal cancer.

Results: 182 miRNAs were differentially expressed in tumor versus normal tissues (Q-bound <0.05); 15 of these miRNAs showed a greater than 2-fold change in expression in tumor tissue; mir-18a, mir-135b, mir-503, mir-584, mir-106b, mir-224, mir-92a, mir-181d were up-regulated and mir-375, mir-378, mir-378c, mir-137, mir-378, mir-147b, mir-30a were down-regulated. miRNA mir-31 showed the highest up-regulation in tumor tissue (16-fold increase) while mir-215 expression decreased 8-fold in tumor compared to normal tissue. Tumor and normal tissues were completely separated by hierarchical cluster analysis based on their distinctive miRNA profiles.

Conclusions: We optimized small RNA sample preparation for deep sequencing of miRNAs, an approach which may be useful for quantifying miRNA expression in tissues with limited starting material. We also identified a novel miRNA expression profile in rectal cancer that may be useful as a diagnostic biomarker of disease.
Efficacy of vemurafenib (V), a selective V600EBRAF inhibitor, as monotherapy or in combination with erlotinib (Erl) or erbitux (Erb) and irinotecan (Iri) doublets and triplets in a colorectal cancer (CRC) xenograft model.
Authors: Higgins Brian , Kolinsky Kenneth Daniel , Schostack Kathleen , Bollag Gideon , Lee Richard J. , Su Fei , Packman Kathryn
Published: February 2017

494

Background: B-Raf mutations, particularly at V600 occur in 10% of CRCs resulting in constitutive activation of the MAPK pathway. V (RG7204, PLX4032) is a first-in-class, V600B-Raf-selective small molecule inhibitor previously shown to potentiate anti-tumor effects in the V600E CRC xenograft model HT29 in combination (combo) with capecitabine ± bevacizumab (ASCO GI, 2008). V600E CRC respond poorly to EGFR inhibition (EGFRi) both preclinically and clinically. We aimed to determine whether antitumor activity could be potentiated by combining V with EGFRi.

Methods: The monotherapy (mono) activities of V, Erl, Erb and Iri were compared to combo of these agents in the HT29 model. V was tested as a mono at its optimal dose (OD), Erl was tested at its MTD or 2/3 MTD, and a combo of V OD + 2/3 MTD Erl were tested. V was subsequently tested as mono or combo at the OD and suboptimal-OD with OD Erb. A final study included Iri as mono, doublets of Iri + V or Erb, and triplet combo of Iri, V, and Erb.

Results: Tumor growth inhibition (TGI) and increase in life span (ILS) for combo of OD V + 2/3 MTD Erl was superior to all mono arms. TGI in mono arms was equivalent for V, Erb and Iri. ILS was better for V vs Iri and Erb mono, while Iri vs Erb ILS were equivalent. TGI and ILS for Iri + Erb doublet was equivalent to V mono. Otherwise, TGI and ILS in all other doublets and triplets were superior to mono groups. TGI in V + Erb and V + Iri were equivalent, but ILS was better for V + Iri. TGI and ILS for V + Iri was better than Iri + Erb. TGI in V + Erb was better than Iri + Erb, but ILS was equivalent. TGI in the triplet was superior to all doublets except V + Erb, however ILS was superior to all doublets tested.

Conclusions: V potentiates anti-tumor activity in a V600E CRC model when used in combo with Erl, Erb and Iri. Although a V + Erb doublet provided impressive TGI equivalent to a triplet with Iri, the triplet yielded sustained antitumor activity as demonstrated by a significant increase in survival as compared to the doublet. Combo with V may afford V600E CRC patients a differential response to what is seen traditionally with single agent EGFi and is worthy of clinical exploration.
Expression of the nuclear receptor, FXR, as CRC progresses from primary to lymph node to liver metastases.
Authors: Lai Lily L. , Ohanian Armond , Smith David D. , Liu Xiyong
Published: February 2017

497

Background: Farnesoid X Receptor (FXR) is a nuclear receptor critical for cholesterol, triglyceride and glucose metabolism. In mouse models, loss of FXR results in tumorigenesis. FXR expression decreases from normal epithelium to cancer. Clinical studies identify FXR as a novel prognostic and predictive biomarker in CRC. We sought to further characterize FXR expression with clinical CRC progression.

Methods: Under institutional approval, we reviewed the FFPE tissues from 20 St. IV CRC patients who underwent synchronous resection of previously untreated primary cancers, lymph nodes (LN), and liver metastases (Met) from 2000-2005. FXR expression, determined using immunohistochemical techniques, was scored on a 3-point scale (0 = no expression, 1 = moderate expression, 2 = high expression). Pair-wise differences were tested using two-tailed t-tests.

Results: All 20 sets included tissues from 3 sites. We found that FXR protein levels decreased along the continuum of disease from primary to LN and from LN to Met in 15 of 20 sets of tissues. In 4 sets, there was no change in FXR expression. In 1 patient, FXR increased in the LN and Met. Overall, FXR expression decreased from primary to LN (**p<0.001), from LN to Met (**p<0.001) and from primary to Met (***p<0.0001).

Conclusions: FXR expression decreases as disease advances from primary to LN to Met. Our findings suggest that FXR regulation of metabolism in the cancer cell may be lost in CRC progression. Further studies are needed to determine if upregulation of FXR activity in localized CRC can inhibit progression to metastases.
A pilot study evaluating peripheral blood lymphocyte telomere length in elderly versus young patients with colorectal cancer (CRC).
Authors: Dotan Efrat , Nicolas Emmanuelle , Devarajan Karthik , Beck Robert J , Cohen Steven J.
Published: February 2017

512

Background: Telomere length (TL) is associated with aging as well as high cancer incidence. We conducted a pilot study to assess the TL of younger versus older (≥70 years) patients with CRC and its effect on survival.

Methods: QPCR was used to analyze the relationship between telomere repeat copy number and single gene copy number (T/S ratio) on peripheral blood lymphocytes DNA of 94 CRC patients, and used as a surrogate value for relative TL. The primary aim of the study was to evaluate differences in TL between different age groups. Correlation with overall survival (OS) was the secondary aim. Samples were run in triplicate, and a standard curve was used to calculate the relative T/S ratio and account for plate to plate variability. Univariate statistical analyses were performed using the Mann-Whitney test for continuous variables and the log-rank test for OS. Multivariable analyses were performed using the Classification and Regression Trees methodology. A Type I error of 5% was used to determine statistical significance.

Results: The mean relative TL was 0.95 (range 0.64-1.84). The assay demonstrated high correlation of technical replicates between plates (Pearson correlation: 0.96 and 0.81, for sample and control). Comparing patient under and over 70 years of age revealed a borderline significant difference in TL between the groups (mean TL 0.981 versus 0.925 respectively; p=0.067). Assessment using 4 age groups (50-60, 60-70, 70-80, >80) demonstrated a statistically significant difference in TL between the youngest and the oldest age groups (mean TL 1.022 versus 0.874 respectively; p=0.02) with evidence of shorter TL with advanced age. Marginal relationship was seen between OS and age (p-value=0.066) with older patients exhibiting slightly poorer survival (hazard ratio of 1.03, 95% confidence interval (0.998, 1.065)). No correlation was noted between relative TL and OS in univariate and multivariable analysis.

Conclusions: These results validate the ability of a qPCR-based assay to differentiate between younger and older CRC patients by TL. Ongoing studies are utilizing this methodology to evaluate the relationship of TL to treatment tolerance in elderly CRC patients.
The efficacy of antiepidermal growth factor receptor monoclonal antibodies for patients with KRAS G13D mutations and chemorefractory metastatic colorectal cancer.
Authors: Akiyoshi Kohei , Yamada Yasuhide , Takahashi Naoki , Honma Yoshitaka , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro
Published: February 2017

527

Background: The treatment benefits of epidermal growth factor receptor (EGFR) monoclonal antibodies for patients with KRAS mutations have not been demonstrated. However, some studies have suggested that all KRAS mutations are not equivalent, and that KRAS G13D mutations might have some survival benefit.

Methods: We retrospectively analyzed the efficacy and toxicity of treatment with EGFR monoclonal antibody in 8 patients with KRAS G13D mutations and 5-FU/oxaliplatin/irinotecan (CPT) refractory metastatic colorectal cancer compared with 94 KRAS wild type patients at the National Cancer Center Hospital.

Results: Eight patients with KRAS G13D mutations were treated with anti-EGFR monoclonal antibodies between July, 2009 and July, 2011. The median age was 66 (42-70); male/female 6/2; PS was 0/1/2, 2/5/1; treatment regimen was cetuximab/ cetuximab+CPT/ panitumumab+CPT, 2/5/1. Response rate (RR) was 12.5% and disease control rate (DCR) was 50.0% with 1 PR, 3 SD, and 4 PD. The PR case treated with cetuximab+CPT showed marked regression of tumor and long duration of treatment (9 months). The progression free survival (PFS) of 2 SD cases was 4.2 and 3.9 months. The other SD case is now on treatment. The median PFS of the 8 patients was 2.1 months (95% confidence interval [CI]: 0.0-5.2). The median overall survival (OS) has not been reached. Grade 3/4 toxicities included 1 hypomagnesemia G4 and 1 rash acneiform G3. Meanwhile, 94 KRAS wild type patients treated with anti EGFR monoclonal antibodies had an RR of 22.3% and DCR was 66.0% with 21 PR, 41 SD, 30 PD, and 2 NE. PFS was 5.6 months (95% CI: 4.9-6.3) and OS was 8.6 months (95% CI: 6.5-10.7).

Conclusions: In this analysis, we identified one PR to anti-EGFR monoclonal antibody in a patient with KRAS G13D mutation and chemo-refractory metastatic colorectal cancer. However, we were unable to demonstrate equivalent efficacy in patients with KRAS G13D mutations and KRAS wild type patients. Further studies are needed to evaluate the efficacy and prognosis for this treatment.
Action of SDF-1/CXCR4 axis in liver metastasis of colorectal cancer.
Authors: Yamada Shinichiro , Shimada Mitsuo , Utsunomiya Toru , Imura Satoru , Morine Yuji , Ikemoto Tetsuya , Mori Hiroki , Hanaoka Jun , Saito Yu , Asanoma Michihito , Miyake Hidenori
Published: February 2017

530

Background: It has recently been suggested that the SDF-1/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival in various cancer. In this study, we investigate the possible role of SDF-1/CXCR4 axis in colorectal liver metastasis.

Methods: Both primary colorectal tumors and liver metastatic tumors were obtained from 12 patients with colorectal liver metastasis. Expression levels of CXCR4 and SDF-1 were determined using RT-PCR. In 4 patients with benign liver disease, the expression level of SDF-1 in normal liver tissues was also determined. We divided the 12 patients into two groups; high expression group (n=6) and low expression group (n=6) according to each expression level of SDF-1 and CXCR4, and compared the clinicopathological factors between the two groups.

Results: 1. CXCR4 expression levels in primary tumor: The frequency of the peritoneal dissemination in the CXCR4 high expression group was higher than in the low expression group (p=0.07). Moreover, overall survival rate in the CXCR4 high expression group was significantly lower than that in the low expression group (3 year-survival rate: 67% vs. 100%, p<0.05). 2. CXCR4 in metastatic tumor tissues and SDF-1 in non-tumor liver tissues: The expression level of SDF-1 in non-tumor liver tissues was significantly higher than that in normal liver tissues (p<0.01). A significant correlation between the CXCR4 expression levels in metastatic tumor tissues and SDF-1 expression levels of non-tumor liver tissues (p<0.05). The number of metastatic liver tumors in the SDF-1 high expression group tended to be larger than that in the low expression group (p=0.12).

Conclusions: The present data suggest that there is a significant association of the SDF-1/CXCR4 axis with enhanced liver metastasis and poor prognosis of the patients with colorectal liver metastasis. Furthermore, an enhanced expression of SDF-1 in non-tumor liver tissues may have an important role in the formation of liver metastasis.
Final skin toxicity (ST) and patient-reported outcomes (PRO) results from PRIME: A randomized phase III study of panitumumab (pmab) plus FOLFOX4 (CT) for first-line metastatic colorectal cancer (mCRC).
Authors: Douillard Jean Yves , Siena Salvatore , Tabernero Josep , Burkes Ronald L. , Barugel Mario Edmundo , Humblet Yves , Cunningham David , Xu Feng , Zhao Zhongyun , Sidhu Roger
Published: February 2017

531^

Background: Final PRIME results showed that pmab + CT significantly improved progression-free survival (PFS) and objective response rate vs CT alone for first-line wild type (WT) KRAS mCRC. Efficacy and PRO by ST severity from the final descriptive analysis of PRIME are presented.

Methods: Patients (pts) had no prior chemotherapy for mCRC, ECOG performance status ≤ 2, and tumor tissue available for biomarker testing. The final analysis occurred 30 months after the last pt was enrolled; the primary endpoint was PFS; secondary endpoints included OS, objective response, and safety. Pts who received treatment and were alive without progression at day 28 were included in the ST analysis.

Results: 1183 pts were randomized. 1057 pts with WT or MT KRAS mCRC met the criteria for inclusion in the ST analysis. Maximum grade ST was observed by day 28 in > 50% of pts. Results are shown ( table ). Overall differences in change from baseline of the least square means from a mixed effects model of the EQ-5D Overall Health Rating for pmab + CT (n = 285) minus CT alone (n = 294) and for ST gr 0-1 (n = 53) minus ST gr 2-4 (n = 232) were −1.069 (95% CI: −3.6277 to 1.4896) and 0.8971 (95% CI: ‐4.0224 to 5.8167), respectively. The overall safety profile was broadly comparable across ST groups and treatment arms.

Conclusions: Pts with WT KRAS mCRC receiving pmab with ST gr 2-4 had longer PFS and OS vs pts receiving CT alone. PRO were not adversely affected by ST severity.

[Table: see text]
Association between delays in adjuvant chemotherapy for stage III colon cancer and increased mortality.
Authors: Haynes Alex Bernard , Chiang Yj , Feig Barry W. , Xing Yan , Chang George J. , You Y. Nancy , Cormier Janice N.
Published: February 2017

541

Background: Administration of adjuvant chemotherapy is the standard of care for stage III adenocarcinoma of the colon. There are conflicting data regarding the optimum interval for the initiation of adjuvant therapy and whether this affects survival.

Methods: Patients were identified from the National Cancer Database (1998-2002) who received adjuvant chemotherapy after resection of stage III colon cancer. Multivariate analyses were performed to examine the associations between time interval from surgery to chemotherapy initiation and overall and relative survival. Relative survival was used as a surrogate for disease-specific survival.

Results: 32,327 stage III colon cancer patients who received chemotherapy after surgery were identified. The relationship between timing of adjuvant chemotherapy and survival is reported in Table 1. Delay of chemotherapy beyond 8 weeks postoperatively was associated with an increased likelihood of death in a relative survival model, with a hazard ratio for death of 1.19 (95% CI: 1.11, 1.28) in the 8 to 12 week interval. Longer delays were associated with worse outcomes, with a 7.6% absolute decrease in relative survival. Other independent factors associated with reduced survival included gender, race, type of insurance, margin status, and tumor grade.

Conclusions: Delay in the initiation of adjuvant therapy beyond eight weeks is an independent predictor of increased mortality. While other factors contribute to the risk of death from disease, chemotherapy delays may be preventable. Policy interventions should be developed to encourage the administration of chemotherapy within eight weeks of resection when indicated. Further effort should be expended to understand the etiology of and mitigate these delays.

[Table: see text]
Preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib for rectal adenocarcinoma: A phase I trial.
Authors: Das Prajnan , Eng Cathy , Rodriguez-Bigas Miguel A. , Chang George J. , Skibber John Michael , Maru Dipen , Munsell Mark F. , Clemons Marilyn V. , Kopetz Scott , Garrett Chris R. , Shureiqi Imad , Krishnan Sunil , Delclos Marc E. , Crane Christopher H.
Published: February 2017

544

Background: The goal of this phase I trial was to determine the maximal tolerated dose (MTD) of concurrent capecitabine, bevacizumab and erlotinib with preoperative radiation therapy (RT) for rectal cancer, with a secondary objective of evaluating pathologic complete response (pCR).

Methods: Eligibility criteria included patients with clinical stage II-III rectal adenocarcinoma within 12 cm from the anal verge. Exclusion criteria included uncontrolled hypertension, recent myocardial infarction or angina, coagulopathy, impaired renal function, and history of gastrointestinal perforation. Patients were treated in cohorts of 2, in 4 escalating dose levels (DL), using the continual reassessment method, as shown in the table. Patients underwent surgery at least 9 weeks after the last dose of bevacizumab.

Results: Nineteen patients were enrolled in the study: 1 withdrew early because of insurance issues and was non-evaluable. The clinical stage was T3N0 in 3, T3N1 in 13, T3N2 in 1 and T4N0 in 1 patient. No patient had grade 4-5 acute toxicity; 1 patient had grade 3 acute toxicity (hypertension, DL 2) during or within 4 weeks after RT. The MTD was not reached; the probability of dose limiting toxicity at DL 4 was 0.15. All 18 evaluable patients underwent surgery, with low anterior resection in 7 (39%), proctectomy with coloanal anastomosis in 5 (28%), and abdominoperineal resection in 6 (33%) patients. Eight patients (44%) had pCR, and an additional 8 (44%) had ≤ 10% viable tumor in the surgical specimen. Fifteen patients (83%) had T downstaging. Three patients developed grade 3 post-operative complications (ileus, small bowel obstruction and infection). After a median follow-up of 21 months (range 9-39 months), no patient had local recurrence, but 1 patient developed distant metastasis.

Conclusions: The combination of preoperative RT with concurrent capecitabine, bevacizumab and erlotinib was well tolerated. The pCR rate of 44% is promising and warrants further investigation.

[Table: see text]
The role of partial splenic embolization (PSE) in the management of chemotherapy-induced thrombocytopenia.
Authors: Ohinata Aki , Wallace Michael J. , Overman Michael J. , Phillips Jonathan , Wolff Robert A. , Eng Cathy
Published: February 2017

569

Background: Chemotherapy-induced splenomegaly is a relatively known treatment complication, where the clinical sequale of hypersplenism is persistent thrombocytopenia due to splenic sequestration. For cancer patients (pts) undergoing chemotherapy, thrombocytopenia may result in a dose delay or dose reduction, thus reducing dose intensity. The impact of refinement in technique with limited volume embolization (50-70%) of the spleen upon morbidity and mortality has not been well studied.

Methods: A retrospective review of gastrointestinal cancer pts undergoing PSE for thrombocytopenia to facilitate the initiation or resumption of systemic chemotherapy between Jan. 2008 and March 2011 was completed. Pre- and post-PSE platelet (plt) counts within 30 days were evaluated for benefit of treatment. Objectives included the re-initiation of systemic therapy and post-PSE plt count >150 (< 30 days). Periprocedural laboratory values and adverse events were recorded.

Results: PSE was performed in 79 pts. Median prior chemotherapy regimens = 2 (range 1-3). The median follow-up was 12M (range: 7-31). The mean plt count prior to PSE was 80 K/ UL (3-196). Post-PSE platelet count of > 150 was achieved in 52 (66%) pts with a mean peak plt count of 219 K/UL. Six (8%) pts underwent repeat PSE due to recurrent thrombocytopenia after initiation of systemic therapy. Re-initiation of chemotherapy was achieved in 59 (79%) pts. The median duration of chemotherapy following PSE was 8M (95% CI: 4.2-14.2); median overall survival was 33M (95% CI: 10-47). Post-procedure fever developed in 7 (9%) pts and pleural effusion, atelectasis, or consolidation was reported in 8 (10%) pts. Seventeen (21%) pts developed reversible grade 1 hyperbilirubinemia. Median length of hospital stay was 3 days (interquartile range 1-5 days). 60-day mortality rate was 9% (7 of 79).

Conclusions: Partial splenic embolization (PSE) is a safe and effective method of managing thrombocytopenia secondary to chemotherapy-induced hypersplenism to facilitate re-initiation of systemic therapy in cancer patients. PSE may be considered as a potential option in patients with good performance status to facilitate further systemic chemotherapy.
Reasons for and outcomes of adjuvant chemotherapy choices in elderly patients with resected stage III colon cancer.
Authors: Ko Jenny , Kennecke Hagen F. , Lim Howard John , Gill Sharlene , Woods Ryan , Speers Caroline , Cheung Winson Y.
Published: February 2017

571

Background: Research suggests that elderly cancer patients are commonly undertreated, but the precise reasons for this are unclear. Robust clinical data on the optimal adjuvant chemotherapy regimen for elderly colon cancer patients are also lacking. Our aims were to: 1) evaluate the impact of advanced age on choice of adjuvant chemotherapy (none vs. capecitabine vs. FOLFOX) for curatively resected colon cancer; b) determine the reasons for selecting a particular regimen; and 3) examine whether treatment effect on outcomes is modified by age.

Methods: All patients diagnosed with stage III colon cancer between 2006 and 2008, and referred to any 1 of 5 regional cancer centers in British Columbia, Canada were identified. Descriptive statistics were used to summarize treatment patterns among young patients (YPs) aged <70 years vs. elderly patients (EPs) aged >/=70 years. Multivariate logistic regression models were constructed to evaluate the association between adjuvant chemotherapy and cancer-specific survival (CSS) in YPs and EPs.

Results: In total, 810 patients were identified: 51% were male, 52% YPs and 48% EPs, and 74% received adjuvant chemotherapy. When compared to YPs, EPs had worse ECOG and more comorbidities (both p<0.001). EPs were less likely than YPs to receive adjuvant chemotherapy (57% vs. 91%, p<0.001). Frequent reasons for no treatment included age, comorbidities, and small perceived benefit from adjuvant therapy. Among treated pts, EPs were less likely to receive FOLFOX (32% vs. 74%, p<0.0001) in favor of capecitabine due to patient preference, age, and comorbidities. In multivariate analyses, receipt of either FOLFOX or capecitabine was correlated with improved CSS compared to surgery alone. The effect of adjuvant chemotherapy on CSS was not modified by age (interaction p for capecitabine and age = 0.26; interaction p for FOLFOX and age = 0.40).

Conclusions: EPs with stage III colon cancer frequently received either no adjuvant treatment or capecitabine monotherapy due to advanced age and co-morbidities. The treatment effect of adjuvant therapy on CSS is similar among EPs and YPs. Adjuvant chemotherapy should not be withheld from colon cancer patients based on advanced age alone.
BSA dosing and suboptimal 5-FU exposure among colorectal cancer patients of varying gender and age.
Authors: Haregewoin Abebe , Hamilton Stephanie A. , Grier Charles E. , Kaldate Rajesh R.
Published: February 2017

579

Background: 5-Fluorouracil (5-FU) remains the cornerstone of colorectal cancer (CRC) therapy and its dosing is based on body surface area (BSA). Although convenient, BSA dosing disregards factors that impact 5-FU PK such as genotype, age, gender, etc. Thus, patients receiving the same BSA based dose show a wide range of 5-FU plasma levels (measured as AUC in mg·h/L), resulting in ineffective or toxic doses affecting therapy outcome. An optimal therapeutic AUC target range of 20-30 mg·h/L has been proposed.

Methods: Plasma samples from the initial treatment cycle of 927 CRC patients who received 2400 mg/m2 continuous infusion of 5-FU over 44-48 hours, with or without bevacizumab, were tested for 5-FU exposure using an immune-based assay (OnDose). AUC results were analyzed to evaluate gender and age effects.

Results: There are 391 (42.2%) female and 536 (57.8%) male patients with age ranging from 17-93 years (mean/SD: 58.5/11.8). These analyses indicate that in comparison to the proposed optimal AUC target range of 20-30 mg·h/L, females receive supra-optimal doses compared to males (p=0.0083). Age also affects the 5-FU AUC (p=0.0002), with younger patients more likely to receive sub-optimal doses than older patients.

Conclusions: BSA dosing is an unreliable indicator of exposure and may lead to under dosing in males and younger patients, and overdosing in females and older patients, potentially resulting in corresponding diminished efficacy or increased toxicity. Data suggest that therapy could be optimized by 5-FU dose adjustment in subsequent cycles based on PK monitoring so that AUC values will converge towards the target range irrespective of gender or age. A large clinical trial is in progress to validate these findings.
Pathologic complete response rates after neoadjuvant chemoradiation (CRT) for rectal cancer: Do novel agents have a role?
Authors: Beg Muhammad Shaalan , Meyer Jeffrey , Balch Glen C. , Xie Xian-Jin , Singal Amit G
Published: February 2017

597

Background: Preoperative concurrent radiation with either 5-fluorouracil (5FU) or capecitabine (CAP) is considered standard of care for T3-T4 and/or node positive rectal cancers with historical pathological complete response (pCR) rates ranging from 7-29%. There is lack of randomized data on the incorporation of bevacizumab (B) and cetuximab (C) with neoadjuvant chemoradiation (CRT). The aim of our study was to quantify pCR and adverse event rates for B-CRT and C-CRT in patients with rectal cancer.

Methods: A systematic literature review using the Medline database and national meeting abstracts identified trials incorporating bevacizumab and cetuximab for neoadjuvant chemoradiation between 2000 and 2011. Pooled rates of pCR and frequency of grade 3-4 adverse events per patient with 95% confidence intervals (CI) using the adjusted Wald method, were calculated.

Results: Out of 24 trials identified, 15 trials with a total of 457 (range 8-61) patients incorporated B-CRT. Five studies used 5FU, ten used CAP. A third chemotherapeutic agent was also included in 7 trials of B-CRT. There were 9 trials incorporating C-CRT with a total of 332 (range 20-50) patients. Two studies used 5FU, 7 used CAP, while four studies also included a third therapeutic agent. The pooled pCR rate for B-CRT of 20.8% (95% CI 17.3-24.8), was significantly higher than the 9.6% (95%CI 6.92-13.2) pCR rate for C-CRT (p < 0.001). The rate of grade 3-4 adverse events was significantly lower for B-CRT at 0.38 per patient studied (95% CI 0.34-0.43) compared to C-CRT at 0.55 per patient (95%CI 0.49-0.60) (p<0.001). Surgery was performed in 92% of B-CRT and 94% of C-CRT patients.

Conclusions: The addition of either B or C to conventional neoadjuvant CRT does not appear to yield higher pCR rates than those reported with conventional CRT alone. There is insufficient evidence to support routine use of novel agents in this treatment strategy for rectal cancer. Interestingly, although surgical rates are high in both groups, C-CRT has significantly lower rates of pathologic complete response and significantly higher rates of toxicity than B-CRT.
Effect of inhibition of nuclear protein export using a novel CRM1 inhibitor on the apoptotic response to SN38 in preclinical colon cancer models.
Authors: Chung Hye Won , Salas Fragomeni Roberto A. , Shacham Sharon , Kauffman Michael , Cusack James C.
Published: February 2017

609

Background: Resistance to conventional chemotherapy remains a major challenge in Stage IV colon cancer. CRM1 inhibition leads to nuclear sequestration of proteins such as tumor suppressor p53, growth regulatory proteins, and chemotherapy targets such as topoisomerase I/II. We examined the effects of combination use of KPT185 (a novel CRM1 inhibitor) with SN38 (active metabolite of irinotecan) and the effect of drug administration sequence in human colon cancer cell lines to determine if CRM1 inhibition enhances the cytotoxic effect of chemotherapy.

Methods: We evaluated the combination effect of KPT185 with SN-38 on both Lovo (KPT-sensitive, IC50 = ∼ 500nM) and HT29 cells (KPT-resistant, IC50 = 1000 ∼ 3000nM) by the Chou-Talalay method, an MTT-based assay that interrogates response across a spectrum of drug dosages: KPT185 (0, 1, 10, 100, 1000, 10000 nM) and SN38 (0, 100, 500, 1000 nM). Cell cycle analysis by FACS with propidium iodide (PI) staining was performed. Effects on apoptosis were determined by FACS (Annexin V/PI staining) and Cell Death Detection ELISA assay.

Results: The Chou-Talalay method determined that there is a synergistic effect when KPT185 is combined with SN38 in both Lovo and HT29 cells (combination index > 1). FACS analysis demonstrated combination use of KPT185 and SN38 induced an increase in the apoptotic sub-G1 fraction and a shift toward G2/M arrest. Combination treatment also significantly increased the Annexin V/PI-positive fraction compared with SN38 alone case (P < 0.05). Treatment sequence studies demonstrated that pretreatment of SN38 followed by KPT185 (KPT-post) produced the maximum synergistic effect compared with pretreatment of KPT185 followed by SN38 (KPT-pre) or concurrent use (KPT-con); Cell Death Detection ELISA assay showed KPT-post increased apoptosis most (4.3-fold) compared with KPT-pre (4.2-fold), KPT-con (3.8-fold) and SN38 alone (1-fold).

Conclusions: Our results show KPT185, a novel CRM1 inhibitor, sensitizes the response to SN38 in KPT-sensitive as well as KPT-resistant colon cancer cells. This method of sensitizing colon cancer cells warrants further evaluation in preclinical models of colon cancer.
A phase II, single-arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with advanced esophageal carcinoma.
Authors: Chatterjee Aradeep , Bhattacharya Sudin , Chakraborty Amitava , Bhakta Radhe S. , Chatterjee Ashim Kumar , Biswas Jaydip
Published: February 2017

62

Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating advanced esophageal carcinoma (ECA).

Methods: Our study was phase- II, open level, single arm and single stage. Participants’ eligibility criteria included (1) histopathology confirmation of ECA (2) inoperable tumor (3) no prior conventional cancer treatments (4) karnofsky performance status between 40 -70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2 yrs, 3 yrs, 4 yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti- cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.02ml / kg body weight / day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares.

Results: 65 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 11 (16.92%) case and partial response occurred in 20 (30.77%) cases. 44 (67.69%) of them survived at least 1 yr, 32 (49.23%) survived at least 2 yrs, 24 (36.92%) survived at least 3 yrs, 21 (32.31%) survived at least 4 yrs and 17 (26.15%) of them survived at least 5 yrs. These participants didn’t receive conventional or any other investigational cancer treatments. According to AJCC TNM staging system, 31 (47.69%) participants diagnosed at stage IV. Among them complete response observed in 4 (12.90%) cases, partial response observed in 8 (25.81%) cases and 5 (16.13%) of them survived at least 5 yrs.

Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with advanced ECA. The investigational drug psorinum is non- toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating esophageal cancer.
Genetic polymorphisms and ethnic difference in outcome of adjuvant FOLFOX chemotherapy in Korean patients with colon cancer.
Authors: Lee Kyung-Hun , Chang Hye Jung , Han Sae-Won , Oh Do-Youn , Im Seock-Ah , Bang Yung-Jue , Kim Sun Young , Lee Keun-Wook , Kim Jee Hyun , Hong Yong Sang , Kim Tae Won , Park Young Suk , Kang Won Ki , Shin Sang Joon , Ahn Joong Bae , Kang Gyeong Hoon , Jeong Seung-Yong , Park Kyu Joo , Park Jae-Gahb , Kim Tae-You
Published: February 2017

623

Background: Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy.

Methods: A total of 292 Korean patients (183 men and 109 women) from six hospitals in Korea were prospectively enrolled. Patients had resected stage III or high-risk stage II colon cancer and were treated with 12 cycles of adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) chemotherapy. 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) were analyzed from peripheral blood. TS genotype in 5’UTR was classified as ‘high’ (2R/3G, 3C/3G, and 3G/3G) or ‘low’ (2R/2R, 2R/3C, and 3C/3C).

Results: Most patients (86.3%) received 12 complete cycles of FOLFOX chemotherapy. In contrast to previous studies in Caucasians, neutropenia (grade 3–4, 60.5%) was frequently observed in our Korean patients, whereas only 16.4% experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95% confidence interval (CI) 1.19–4.55] and ERCC1 19007TT (adjusted OR 4.58, 95% CI 1.20–17.40) genotypes. Patients harboring XRCC1 23885GG had lower risk of neuropathy (adjusted hazard ratio 0.56, 95% CI 0.32-0.99) and longer time to the onset of grade 2-4 neuropathy. MTHFR 677TT and XRCC1 23885GG genotype was also more prevalent in Koreans compared to Caucasians, and the difference of genotypic frequency could partly explain the ethnically different toxicity profile. After median 49.4 months of follow-up, there were 58 (19.9%) relapses and 19 (6.5%) deaths. TS ‘low’ genotype [adjusted hazard ratio (OR) 1.83, 95% CI 1.003–3.34] was significantly related to shorter disease-free survival. Overall survival was not significantly different according to the polymorphisms.

Conclusions: Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. These polymorphisms may explain the ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.
Retrospective cohort study on the safety and efficacy of cetuximab for metastatic colorectal cancer patients: The HGCSG0901 study—Analysis of cetuximab refractory.
Authors: Yuki Satoshi , Komatsu Yoshito , Kawamoto Yasuyuki , Tsuji Yasushi , Naruse Hirohito , Hosokawa Ayumu , Kusumi Takaya , Ishiguro Atsushi , Saitoh Soh , Sakata Yuh
Published: February 2017

639

Background: In the NCIC CTG CO.17 trial comparing in the Best Supportive Care (BSC) and cetuximab (Cmab) monotherapy for patients as third line treatment, median survival time (MST) of patients assigned to BSC was 4.8 months in the wild-type KRAS, and 4.6 months in the KRAS mutant.In contrast, MST of patients assigned to Cmab in the same trial was 6.1 months, and median progression-free survival (mPFS) was 1.9 months, so the difference (Survival Beyond Progression: SBP) between MST and mPFS was about four months. From past reports, the prognosis after 3rd line and later Cmab refractory was very poor. We performed survival analysis of after Cmab refractory.

Methods: Of 269 cases registered in the multi-institutional retrospective study (HGCSG0901) treated with Cmab, 233 patients for Cmab refractory of 3rd line or after treatment line were analyzed. Overall survival after Cmab refractory for patients for 3rd line or after treatment line were evaluated for association with prognostic factors such as presence of peritoneal dissemination, the number of metastatic organs, Albumin, ALP, CEA, CA19-9 at the time of Cmab refractory, KRAS mutational status, chemotherapy after Cmab refractory using univariate and multivariate Cox proportional hazard model.

Results: MST after refractory for patients with Cmab administration after 3rd line treatment was 4.3 months, which was comparable with SBP of previous clinical trials. Results of multivariate analysis suggested that, PS, presence of peritoneal dissemination, the number of metastatic organs, Albumin, ALP at the time of Cmab refractory and chemotherapy (both already refractory drug only and non refractory drug included) after Cmab refractory were independent prognostic factors after Cmab refractory.

Conclusions: PS, presence of peritoneal dissemination, the number of metastatic organs, Albumin, ALP at the time of Cmab refractory and chemotherapy after Cmab refractory should be regarded as an important factor for prognosis after Cmab refractory in colorectal cancers.