bluuebunny/crossref_metadata_2025 huggingface dataset:
Metronomic capecitabine (cape) and cyclophosphamide (CTX) for refractory metastatic colorectal cancer (mCRC): Results of a phase II trial.
Authors: Marmorino Federica , Cremolini Chiara , Loupakis Fotios , Salvatore Lisa , Schirripa Marta , Antoniotti Carlotta , Di Desidero Teresa , Canu Bastianina , Orlandi Paola , Fioravanti Anna , Masi Gianluca , Bocci Guido , Falcone Alfredo
Published: March 2020

e14577

Background: The protracted exposure to low doses of cytotoxics according to metronomic schedules reported encouraging results in the treatment of different malignancies. In a recent trial from our group, the association of a single standard dose of CTX followed by metronomic UFT and CTX with celecoxib showed a very favourable safety profile and promising activity in a cohort of heavily pre-treated patients (pts) with gastrointestinal tumors (Allegrini, 2012). The aim of the present trial was to prospectively evaluate the activity of metronomic cape and CTX in a population of refractory mCRC pts. Methods: Pts with documented diagnosis of CRC, progressed during or within 3 mos from the last administration of standard therapies, were eligible. They received cape 800 mg PO bid and CTX 50 mg PO once daily. Treatment was administered continuously until disease progression. Primary endpoint was 2 mos-progression free rate (2m-PFR). Hypothesizing a 2m-PFR of 10% for refractory mCRC pts with no therapeutic options, metronomic cape plus CTX would have been judged promising for an estimated increase from 10 to 35% in 2m-PFR. According to the Fleming single-stage design, setting α and β errors 0.05 and 0.10, 25 evaluable pts were required. The null hypothesis would have been rejected if at least 6 pts were progression free at 2 mos. Results: Between June 2011 and June 2012, 26 pts were enrolled. Main characteristics were: M/F 19/7; median age: 71 yrs; single/multiple sites of metastases: 2/24, KRAS wt/mut: 18/8, BRAFwt/mut 25/1. 16 (62%) pts had received at least 3 previous lines of chemotherapy. Five pts were progression free at 2 mos, for a 2m-PFR of 19%. At a median follow up of 14.4 mos, median PFS and OS were 2.1 and 6.0 mos. No chemo-related G3/4 adverse events were reported. Conclusions: Metronomic cape and CTX demonstrated low clinical activity in heavily pretreated mCRC. Ongoing pharmacokinetic and dynamic analyses might provide additional data to interpret results and further insights into the antiangiogenic properties of this metronomic combination. Clinical effects of metronomic cape and CTX are under investigation in earlier settings and in association with other antiangiogenic agents.
Is there a role for chemotherapy in metastatic colorectal cancer patients with a poor performance status?
Authors: Wong Hui-li , Field Kathryn M , Tie Jeanne , Kosmider Suzanne , Shapiro Jeremy David , McKendrick Joseph , Parente Phillip , Lipton Lara Rachel , Yip Desmond , Parakh Sagun , Nott Louise M. , Gibbs Peter
Published: March 2020

e14583

Background: The management of patients with poor performance status (PS) remains challenging in the absence of data on optimal treatment. Here we assessed the treatment and outcomes of patients with metastatic colorectal cancer (mCRC) with poor Eastern Cooperative Oncology Group (ECOG) PS (≥ 2) in routine clinical care. Methods: Analysis of patients prospectively entered onto the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database, a clinician-designed initiative to collect comprehensive data on consecutive patients with mCRC from sites across Australia. Data collection commenced in July 2009 and is ongoing at 14 participating public and private centers. Results: Of the 864 patients entered, 161 (18.6%) had an ECOG PS ≥ 2. In total, 95 (11.0%) were PS 2, 54 (6.3%) PS 3 and 12 (1.4%) PS 4. Chemotherapy was administered to 65 (68.4%) PS 2 and 17 (31.5%) PS 3 patients, with none of the PS 4 patients being treated. Overall, poor PS patients were significantly less likely to receive any chemotherapy compared to their good PS (PS 0-1) counterparts (51.6% versus 86.8%, p<0.0001) and, when chemotherapy was given, significantly less likely to receive combination chemotherapy (67.5% vs 81.1%, p=0.0057) or bevacizumab (31.3% vs 55.8%, p<0.0001). Overall survival (OS) was reduced with declining PS, with medians of 28.7, 8.9, 3.5 and 0.8 months for PS 0-1, 2, 3 and 4 patients respectively (p<0.0001). Poor PS patients treated with chemotherapy had a better OS outcome (9.0 vs 3.5 months for untreated patients, p<0.0001). At one and two years, 24 (28.9%) and 7 (8.4%) treated poor PS patients were alive. Conclusions: In routine practice many patients with a poor PS, particularly those that are PS 2, receive active treatment. Although overall survival for poor PS patients is poor, some patients appear to benefit from treatment. Further data analysis, particularly to define subsets that may benefit most from treatment, is planned as further sites around Australia contribute data to the project.
Is there any difference in overall response rate according to kras mutation in advanced colorectal cancer (aCRC)?
Authors: Rivadeneira Cabana José Antonio , Viudez Antonio , Guerrero David , Hernandez Irene , Gomez Dorronsoro Maria Luisa , Montes Marta , Verdun Juan , Tarifa Antonio , Suarez Javier , Fernandez de Lascoiti Angela , Ciga Lozano Miguel Angel , Vera Ruth
Published: March 2020

e14589

Background: Tejpar et al (JCO2012; 30(29):3570-7) showed that patients with aCRC and Gly13D kras mutation experienced worse response rate with chemotherapy alone compared to those with other kras mutations. This retrospective study analyzes differences in clinical and radiological response between patients with the two main kras mutations: Gly12Val or Gly13D. Methods: In this retrospective-observational trial, patients with aCRC and Gly12Val and Gly13D kras mutation tumours participated. Clinical and radiological responses of patients with each of the two kras mutation, detected by Therascreen technique and treated with conventional first-line chemotherapy schemes, were recorded. SPSSv17 was employed. ORR (Overall Response Rate: CR+PR) and OCR (Overall Control Rate: CR+PR+SD) were calculated. Results: From November 2005 to October 2012, 51 patients with aCRC and Gly12Val or Gly13D kras mutations were included. Median age was 66 (41-80); 52.7 % men and 49.1% with synchronous disease. Kras mutation status was: 47.3% Gly13D and 52.7% Gly12Val. The chemotherapy schedules were based on Oxaliplatin, Irinotecan and others (61.5%, 25% and 13.5% respectively). While ORR was observed in 39.22 % (38.46 % Gly12Val and 40% Gly13D; p: 0.57), OCR was 76.5% (76.9% Gly12Val and 76% Gly13D; p: 0.60). In the Kaplan-Meier analysis, OS showed no difference between both kras mutation groups (Gly12Val: 29 months; Gly13D: 28 months; p: 0.28). Conclusions: According to our results, and in contrast to other studies outcomes, there is no difference regarding ORR, OCR or OS in patients with both different kras mutation: Gly12Val or Gly13D; however, the hypothetical role of Gly13D mutation as a biomarker of chemotherapy resistance, should be evaluated in prospective studies.
Relationship of the emergence of KRAS mutations and resistance to panitumumab in second-line treatment of colorectal cancer (CRC).
Authors: Blagoev Krastan B. , Burotto Pichun Mauricio Emmanuel , Wilkerson Julia , Blanco-Codesido Montserrat , Espinal Dominguez Edward , Garcia-Alfonso Pilar , Fojo Antonio Tito
Published: March 2020

e14592

Background: Multiple analyses have concluded anti-EGFR antibodies are detrimental to a majority of patients (pts) whose CRCs harbor mutant KRAS. While panitumumab may benefit some pts with tumors harboring WT KRAS, in the majority the added benefit is small and transient. Recent studies have claimed emergence of KRAS mutations mediates acquired resistance to EGFR inhibitors. Methods: We analyzed published and unpublished data to assess this possibility, calculating growth and regression rate constants and estimating doubling times of CRC. Results: Amongst 24 pts with CRC whose tumors were initially KRAS WT, circulating mutant KRAS transcripts were detected in 9 treated in second line with panitumumab plus chemotherapy [Diaz et al, Nature 2012]. The growth rate of tumor in the 9 pts with circulating MT KRAS was 0.0019 days-1. This value is statistically indistinguishable [p = .2439] from the growth rate of 0.0021 days-1 calculated for tumors in 15 pts with no detectable circulating MT KRAS transcripts. Both values were also statistically indistinguishable [p = .3055 for MT KRAS; p = .7688 for WT KRAS] from the growth rate [0.002 days-1] of tumors in a cohort treated in second line with the same chemotherapy without an EGFR inhibitor. Similar results were observed when growth rates were calculated using CEA values [WT, 0.00087 days-1; MT, 0.0024 days-1; p = .1265] and similar regression rate constants were also calculated [WT, 0.0114 days-1; MT, 0.0117 days-1; p = .858]. Furthermore, in pts with detectable serum MT KRAS transcripts the growth rate remained constant even as MT KRAS transcripts appeared to increase. The growth rates allowed us to estimate tumor doubling times of 110 to 124 days in these pts receiving second line therapies, consistent with clinical data for disease progression in second line; and similar to the estimated doubling time of 116 days in the cohort that did not receive panitumumab. Conclusions: Resistance to panitumumab in tumors harboring WT KRAS cannot be explained by overgrowth of cells with MT KRAS. Other mechanisms must be sought to explain the limited efficacy of panitumumab. The data suggest such mechanism(s) are inherent and likely present in the majority of cells.
Worse prognosis of KRAS C.35 G > A mutant metastatic colorectal cancer (MCRC) patients treated with first-line triplet chemotherapy plus bevacizumab (FIr-B/FOx) and post-progression.
Authors: Bruera Gemma , Cannita Katia , Di Giacomo Daniela , Lamy Aude , Giordano Aldo Victor , Vicentini Roberto , Marchetti Paolo , Frébourg Thierry , Sabourin Jean-Christophe , Tosi Mario , Alesse Edoardo , Ficorella Corrado , Ricevuto Enrico
Published: March 2020

e14596

Background: Prognosis of MCRC patients (pts) treated with bevacizumab (BEV) and chemotherapy (CT) is not significantly different according to KRAS genotype. Specificmutations confer different aggressiveness. Prognostic relevance of the prevalent c.35 G > A KRAS mutation was retrospectively evaluated in pts treated with first line FIr-B/FOx, and post-progression. Methods: KRAS codon 12/13 and BRAF mutations were screened by SNaPshot and/or sequencing. FIr-B/FOx: weekly 2 days/12h-timed-flat-infusion/5-fluorouracil 900 mg/m2, weekly alternating irinotecan 160 mg/m2/BEV 5 mg/kg, or oxaliplatin 80 mg/m2. Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank. Results: At 21.5 months, 59 pts were evaluated. KRAS mutant pts: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). KRAS wild-type, 31 pts (52.7%). ORR, PFS, OS were, respectively: c.35 G > A, 71%, 9 months, 14 months; other mutants, 61%, 12 months, 39 months. OS was significantly worse in c.35 G > A pts compared to KRAS wild-type (p = 0.002), KRAS/BRAFwild-type (p = 0.03), other pts (p = 0.002), other mutants (p = 0.05), other codon 12 (p = 0.03) mutant pts; PFS was not significantly different. Post-progression, at 14 months follow-up, PFS and OS were significantly worse in c.35 G > A compared to wild-type and/or other mutant pts. ORR of second line treatments was 38%, metastasectomies 12.5%, PFS 10 months, OS 14 months. PFS and OS were significantly favourable in pts treated with triplet CT plus targeted agent compared to triplet, respectively: PFS 13 months versus 8 months; OS not reached versus 11 months. Conclusions: KRAS c.35 G > A mutation may significantly affect worse OS of MCRC pts. It does not significantly affect worse PFS of intensive first line FIr-B/FOx, while after progression significantly affect worse efficacy of second line treatments. Re-challenge of intensive regimens may affect significantly favourable PFS and OS.
Causes of urban-rural disparities in adjuvant chemotherapy (AC) for rectal cancer (RC).
Authors: Rasool Javaheri Khodadad , Moghaddamjou Ali , Speers Caroline , Cheung Winson Y.
Published: March 2020

e14603

Background: While urban-rural differences in cancer care are well described, the etiology of these disparities is unclear. Our aims were to 1) characterize differences in AC use based on community size and 2) determine if such disparities are mediated through variations in driving distance (DD) and travel time (TT) to closest cancer center. Methods: Patients diagnosed with stage 2 and 3 RC from 1999 to 2009 and referred to any 1 of 5 regional cancer centers in British Columbia were reviewed. Communities were classified as rural, small urban, moderate urban and large urban based on census data. Using zip codes and a distance matrix application interface, DD and TT to the closest cancer center were determined and categorized into quartiles. Stepwise logistic regression models were constructed to explore AC use based on urban vs rural communities, adjusting for DD and TT. Results: A total of 3,017 patients were identified: median age was 67 years (IQR 58-75), 64% were men and 58% received AC. Patients were distributed across various communities: rural 36%; small urban 12%; moderate urban 13%; and large urban 39%. There were no differences in baseline patient and disease characteristics based on community size (all p>0.05). Compared to patients in large urban centers, those living in rural, small urban and moderate urban areas were less likely to be treated with AC (62 vs 49 vs 54 vs 58%, respectively, p<0.001). Likewise, DD and TT were shortest for large urban and longest for rural residents (both p<0.001). In multivariate analyses that controlled for confounders, urban-rural disparities in receipt of AC persisted, but these differences significantly diminished after adjusting for DD, TT, or both (Table). Conclusions: Urban-rural disparities in AC use is partly mediated by commute. Strategic distribution of cancer services that reduce DD and TT to cancer centers may improve access to AC for a number of RC patients who are living in smaller communities. [Table: see text]
The efficacy of first-line IRIS with or without bevacizumab in patients with metastatic colorectal cancer: Analysis of two phase II studies.
Authors: Yuki Satoshi , Fukushima Hiraku , Amano Toraji , Nakamura Michio , Kudo Mineo , Sonoda Norikazu , Tateyama Miki , Kawamoto Yasuyuki , Hatanaka Kazuteru , Sogabe Susumu , Miyagishima Takuto , Akakura Nobuaki , Kato Takashi , Takagi Tomofumi , Iwanaga Ichiro , Miyashita Kencho , Onodera Manabu , Saitoh Soh , Sakata Yuh , Komatsu Yoshito
Published: March 2020

e14604

Background: The safety and efficacy of first-line IRIS (S-1 in combination with irinotecan; Komatsu Y, et al. Oncology, 2011) and IRIS/Bev (IRIS in combination with bevacizumab (Bev); Komatsu Y, et al. Acta Oncol, 2012/Yuki S, et al. 2013 ASCO-GI) have been evaluated in patients with metastatic colorectal cancer (mCRC). This time, no randomized studies comparing these regimens have been performed. This retrospective analysis compared efficacy and safety data for the two regimens from separate phase II studies performed at Hokkaido Gastrointestinal Cancer Study Group (HGCSG). Methods: Patients with histologically confirmed unresectable metastatic or recurrent CRC and received no prior chemotherapy were enrolled. In the first trial, patients received irinotecan 100 mg/m2 on day 1,15 and oral S-1 40 mg/m2 twice daily on days 1-14 every 4 weeks (IRIS study: HGCSG0302). In the second trial, patients received the same regimen plus Bev 5 mg/kg on day 1,15 (IRIS/Bev study). Results: A total of 40 and 52 patients were enrolled the IRIS and IRIS/Bev studies, respectively. Patient characteristics were generally similar in both groups, whereas there were more cases of good performance status and less number of metastatic organ in IRIS/Bev group. The median overall survival was 39.6 months in IRIS/Bev, as compared with 23.4 months in IRIS, corresponding to a hazard ratio for death of 0.418 (p<0.001). The median progression-free survival was 17.0 months in IRIS/Bev, as compared with 8.6 months in IRIS (hazard ratio for disease progression, 0.418; p<0.001); the corresponding response rate were 63.5 percent and 52.5 percent (p=0.393).In a multivariate analysis of PFS and OS, IRIS/Bev (n=52) was significantly associated with longer PFS and OS compared with IRIS alone (n=40). Conclusions: In this retrospective comparison of two studies, the addition of Bev to IRIS appeared to improve outcome compared with IRIS alone in the first-line treatment of patients with mCRC.
Cardiac outcomes of raltitrexed in the treatment of colorectal cancer patients with 5-fluorouracil (5-FU) cardiotoxicity.
Authors: Firouzbakht Aryan , Renouf Daniel John , Chen Leo , Cheung Winson Y.
Published: March 2020

e14607

Background: Both 5-FU and raltitrexed are thymidylate synthase inhibitors, but the latter has a toxicity profile that is distinct from 5-FU. Therefore, it is commonly used as an alternative to 5-FU in the treatment of colorectal cancer patients who have a history of cardiac problems or prior 5-FU cardiotoxicity. To date, the population-based risk of cardiac effects from raltitrexed is uncertain. Our aim was to characterize the patterns of treatment and outcomes of patients receiving raltitrexed-based chemotherapy. Methods: We conducted a retrospective study of all patients diagnosed with colorectal cancer from 1988 to 2012, evaluated at 1 of 5 regional cancer centers in British Columbia, Canada and treated with raltitrexed at any point during their disease. At the institutions in our province, raltitrexed use is limited to those in whom 5-FU is contraindicated. Using chi-squared tests and logistic regression analyses, we evaluated the associations between use of raltitrexed and various cardiovascular events, such as angina, myocardial infarction, hypertension and arrhythmias, as well as other toxicity outcomes, including nausea, vomiting and diarrhea. Results: A total of 186 patients were included: median age was 63 years (IQR 55-70), 97 (52%) were men, and 21 (11%) experienced at least one cardiovascular outcome. Only 4 (2%) patients had a documented cardiac history prior to receipt of any systemic therapy. Among the 21 cases of cardiovascular events, 10 reported angina, 1 suffered a myocardial infarction, 6 had hypertension, and 6 experienced arrhythmias. A significant number of patients also presented with other general toxicities: 25 (13%) reported fever, 11 (6%) suffered mucositis, 75 (40%) had nausea, and 51 (27%) experienced diarrhea. On regression analyses, patients with a previous history of coronary artery disease had a higher risk of cardiovascular events than those without (50 vs 11%, p=0.01). Exposure to 5-FU before raltitrexed did not increase cardiovascular outcomes (p=0.81). Conclusions: Raltitrexed is associated with a low risk of cardiovascular events, but its use should be monitored closely in those with prior coronary artery disease.
Clinical impact of histologic subtypes and somatic mutations in peritoneal carcinomatosis from colorectal cancer.
Authors: Bibeau Frederic , Gudin Amelie , Denouel Amelie , Roca Lise , Castan Florence , Lopez-Crapez Evelyne , Ho-pun-cheung Alexandre , Lamy Pierre-Jean , Saint-Aubert Bernard , Boissiere Florence , Quenet Francois
Published: March 2020

e14621

Background: Peritoneal carcinomatosis (PC) occurs in 10 to 15% of colorectal carcinoma (CRC). Strategies combining surgical resection and hyperthermic intraperitoneal chemotherapy have improved PC outcome. The morphologic, phenotypic and molecular spectrum of CRC PC and their clinical impact are still unknown. Methods: We selected 70 CRC PC cases operated in our institute (34 men, 36 women, median age: 61, median follow-up: 3.9 years.). The following investigations were performed: pathologic review; immunohistochemistry, focused on microsatellite instability (MSI) and CRC markers; mutational status of KRAS, BRAF and TP53. Results: 51 % of PC cases were pure or mixed mucinous carcinoma. Histologic types of PC and primary CRCwere concordant in 80% of cases. Lymphovascular and perineural infiltrations were only observed in 20 and 23% of cases, probably reflecting the preferential spread of PC by surface graft. 90% of cases displayed usual CRC phenotype: CK20+/CK7-/villine+/CDX2+. 96% of PC cases were microsatellite stable (MSS) and 58, 46 and 6% showed TP53, KRAS and BRAF mutations, respectively. No significant association was observed between the histologic type and sex, location, peritoneal index or molecular profile. Mucinous PC had a better relapse free survival (RFS) than conventional lieberkuhnian PC (P=0.04). KRAS/BRAF wild type PC had a better overall survival (OS) than KRAS or BRAF mutated PC, the latter group having the worst outcome (P<0.001). Conclusions: The high rate of mucinous PC suggested a propensity for peritoneal location in primary mucinous CRC. The high rate of MSS tumors, TP53 and KRAS mutations revealed that a large part of PC could be part of the chromosomic instability molecular group. Poor RFS with lieberkuhnian PC raises the question of greater aggressiveness for this histologic type. Consistent with previous reports in metastatic CRC, poor OS was associated with KRAS and particularly BRAF mutations. These preliminary and original results may indicate a peritoneal tropism and a particular behavior for mucinous CRC and need to be prospectively confirmed to determine whether mucinous CRC and PC could benefit from particular therapeutic approaches.
Comparison of efficacy and toxicity of bevacizumab in combination with chemotherapy in the first, second, and third or higher line of treatment for metastatic colorectal carcinoma (mCRC): Data from the Czech multi-institutional registry.
Authors: Kiss Igor , Bortlicek Zbynek , Melichar Bohuslav , Poprach Alexandr , Halamkova Jana , Vyzula Rostislav , Dusek Ladislav , Buchler Tomas
Published: March 2020

e14622

Background: Data from the Czech national registry of patients treated with targeted therapies for mCRC were analyzed retrospectively to compare treatment outcomes for bevacizumab in combination with chemotherapy in the 1st, 2nd and 3rd line of treatment. Methods: The database was launched in 2005 as a clinical registry of patients with mCRC treated with bevacizumab. Epidemiological and clinical data are entered by all Czech comprehensive cancer centers administering targeted therapy. In total, 4487 mCRC patients who received bevacizumab combined with chemotherapy in either 1st line (n=3990, 88.9%), 2nd line (n=386, 8.6%), or 3rd and higher line (n=111, 2.5%) had evaluable data and were included in the present analysis. Survival was calculated using the Kaplan-Meier method, and the differences were assessed using the log-rank test. Results: Statistically significant differences were observed in the efficacy of combination chemotherapy with bevacizumab between the treatment lines. The objective response rate (ORR) in the 1st, 2nd, and 3rd/higher line was 42.9%, 34.0% and 8.3%; (p<0.001) respectively. Similarly, in the 1st, 2nd, and 3rd/higher line median progression free survival (mPFS) was 11.3 months (95% CI 11.0-11.7 months), 9.5 months (95% CI 8.2-10.9 months) , and 7.3 months (95% CI 5.9-8.7 months; p<0.001), and median overall survival (mOS) was 28.4 months (95% CI 27.1-29.8 months), 25.9 months (95% CI 19.4-32.4 months), and 15.0 months (95% CI 10.7-19.3 months; p<0.001), respectively. The spectrum of the most common adverse events was comparable in the 1st, 2nd, or 3rd/higher line, and incidence of adverse events was similar at 11.6%, 8.8% and 8.1%, respectively. Conclusions: The efficacy of bevacizumab in combination with chemotherapy decreased when administered in later lines of treatment for mCRC while the incidence and spectrum of toxicities remains unchanged.
Differences in colon cancer incidence rates by latitude.
Authors: Shah Binay Kumar , Ghimire Krishna Bilas , Nepal Barsha
Published: March 2020

e14627

Background: There is significant decrease in the ultraviolet B photons reaching the earth’s surface during November to February (Holick MF Am J Clin Nutr. 2004 Dec; 80(6 Suppl):1678S-88S). This results in little if any vitamin D3 production in the skin during this period. This study was conducted to evaluate difference in colon cancer age adjusted incidence rates in the northern (latitude ≥37o N) and the southern (latitude < 37oN) regions in the contiguous United States during 1973-2008. Methods: Patients, aged 20 years and older, who had been diagnosed with colong cancer during January 1973 and December 2008, were selected from the Surveillance, Epidemiology, and End Results (SEER) 13 database. Based on the counties’ centroid, northern (latitude ≥37o N) and southern (latitude < 37oN) regions were determined. We compared age adjusted incidence rates (AAIR) of colon cancer in the southern and northern regions among cohorts of patients categorized by age (≥20, 20-64, ≥65 years), gender (Men, Women) and Race (Caucasians, Blacks, Others). The AAIR was calculated per 100,000 population. We used SEER*Stat software to calculate age adjusted incidence rate, incidence ratio, confidence interval (CI, 95%) and P value. Results: There were 314,975 cases of colon cancer diagnosed among 608,245,557 US population during 1973-2008. The overall colon cancer AAIR was 57.1 per 100,000 population studied. The incidence rates were 49.1 in the south and 58.7 in the north of 37oN latitude, (95% CI 1.18-1.20, p<0.05). The AAIRs for patients in the age group 20-64 years were 17.9 and 18.8 in the southern and northern regions, (CI 95%, 1.0346-1.0697), p<0.0005 respectively. The incidence rates for patients aged ≥65 years were 194.3 and 243.9 in the southern and northern regions, (CI 95%, 1.0346-1.0697) p<0.0005. Similarly, the AAIRs were significantly higher in the northern region compared to southern region for both sexes and all ethnic groups. Conclusions: Colon cancer age-adjusted incidence rate is significantly higher in the Northern compared to the Southern region of the US. The higher incidence of colon cancer in the North may be related to lack of sunlight exposure and relative vitamin D deficiency.
Effect of diet-induced obesity on the efficacy of colon cancer treatment in mice.
Authors: Greene Michael W , Ammannagari Nischala , Gillaspie Erin , Burrington Christine M. , Horsman Melissa J , Patel Anush V.
Published: March 2020

e14632

Background: Obesity has reached epidemic proportions globally. Colon cancer is one of the leading causes of cancer related deaths in United States and obesity is associated with one-third of incidence of colon cancer. Obesity is also associated with a worse prognosis of colon cancer. However, the mechanistic details are unknown and animal models to investigate human colon cancer in the setting of obesity are lacking. Therefore, we developed a diet-induced animal model of obesity to determine whether obesity alters the efficacy of a standard colon cancer therapeutic, 5-Fluorouracil, in mice with human colon cancer xenografts. Methods: Male Rag1 mice were placed on a High Fat Western Diet (HFWD) or a Low Fat Western Diet (LFWD) for up to 12 weeks. Body weight, biochemical parameters, and glucose and insulin tolerance were measured. To determine the efficacy of 5-Fluorouracil on human colon cancer xenograft growth, Rag1 mice were fed a LFWD or HFWD for 8 weeks and then implanted with tissue-isolated HT-29 human colon cancer tumors. After 3 weeks of tumor growth, the mice were randomly assigned to a drug (5-Flurouracil 40 mg/kg) or control (normal saline) treatment group. Tumor growth was monitored for 14 days. Results: Significant differences in body weight, and glucose and insulin tolerance were observed in the four week HFWD fed mice. Obesity, glucose intolerance, and insulin resistance were more pronounced in 8 and 12 week fed HFWD mice. Estimated HT-29 human colon cancer tumor growth was significantly greater in obese HFWD fed mice compared to lean LFWD fed mice. Treatment with 5-Fluorouracil significantly reduced HT-29 human colon cancer tumor growth in lean LFWD fed mice but was without effect in obese HFWD fed mice. Conclusions: In conclusion, our findings demonstrate that diet induced obesity impairs the efficacy of 5-Fluorouracil in an obese animal model of human colon cancer. Given that obesity is growing exponentially worldwide, more studies to understand the mechanistic links between obesity and various cancers are required.
Is oxaliplatin a good partner for EGFR monoclonal antibodies as first-line treatment in KRAS wild-type metastatic colorectal cancer? A meta-analysis.
Authors: Wen Feng , Li Qiu , Tang Ruilei , Sang Yaxiong , Li Meng , Hu Qiancheng , Du Zedong , Zhou Yi , Zhang Pengfei , He Xiaofeng
Published: March 2020

e14645

Background: This meta-analysis was performed to determine whether the addition of monoclonal antibodies (mAbs) of epidermal growth factor receptor (EGFR) to oxaliplatin-based chemotherapy treatment improves efficacy in KRAS wild-type metastatic colorectal cancer (mCRC), and whether infusional 5-fluorouracil (5-FU) and oxaliplatin is a preferred combination for EGFR mAbs. Methods: Oxaliplatin (including treatment), EGFR mAbs, first-line treatment, KRAS wild-type, and mCRC were used as key words. The PRIME, OPUS, COIN, and NORDIC VII trials were identified by two independent authors. Time-to-event outcomes of overall survival (OS) and progression-free survival (PFS) were analyzed using HRs (Hazard Ratios) with fixed effect, and response rate (RR) using odd ratios (OR) with fixed effect. Results: A total of 1,767 patients who were KRAS wild-type were included in this meta-analysis, with 866 patients in the mAbs and chemotherapy combination group and 901 patients in the chemotherapy alone group. The addition of mAbs to oxaliplatin-based chemotherapy in patients with KRAS wild-type mCRC as first-line treatment resulted in significant improvements in PFS (HR=0.88; 95% confidence interval (CI), 0.79 to 0.99; P=0.03) and response rate (RR) (OR = 1.38; 95% CI, 1.14 to 1.66; P = 0.009) compared with chemotherapy alone, but the difference in OS was not significant (HR=0.96; 95% CI, 0.85 to 1.08; P=0.48). However, the differences neither in OS nor in PFS were not significant when mAbs were added to bolus 5-FU or capecitabine-based regimens compared with chemotherapy alone, whereas PFS improved with an infusional 5-FU and oxaliplatin combination (P=0.06; PFS, HR=0.76; 95% CI, 0.65 to 0.86; P=0.0002), and even OS was marginally significant. Conclusions: Oxaliplatin and infusional 5-FU regimen tends to be a better backbone combination with EGFR mAbs as first-line treatment in KRAS wild-type mCRC.
Treatment patterns and cost for colorectal cancer by line of therapy and metastasis status.
Authors: Seal Brian S. , Kreilick Charles , Boklage Susan H. , Shermock Kenneth M. , Asche Carl V
Published: March 2020

e14658

Background: Patterns and cost of care are thought to vary substantially as patients with colorectal cancer (CRC) progress from first to third line therapy and in the presence of metastatic disease. Our aim was to compare patterns and cost of care in these patients. Methods: A retrospective analysis was performed using claims from the Optum Oncology Research Database. Patients 18 years and older, diagnosed with CRC and received chemotherapy or biologic therapy between Jul 1, 2004 and Dec 31, 2010, who were insured by a commercial health plan were included. Chemotherapy combinations were assessed in patients receiving first, second and third line of therapy for CRC; and for patients with/without metastatic disease. Inpatient, outpatient, chemotherapy, biologic-related, and total median annual costs were compared by the Kruskal-Wallis test. Results: 1039 patients were included. FOLFOX and fluorouracil monotherapy were the most common first-line therapies, each accounting for approximately 27% of patients who received any chemotherapy. Oxaliplatin-based regimens were the most common second-line therapy (45% of patients). Irinotecan-based regimens were the most common third line therapy (35% of patients). Biologic therapy was much more common in patients with metastases (39% vs. 5%; p<0.0001) and in patients receiving third line therapy (65% vs. 8%, p<0.0001). The total cost of care increased significantly for patients receiving first ($25,782), second ($36,951), and third ($86,944) line therapy (p<0.0001 for all pairwise comparisons). Costs were significantly greater (p<0.0001) for patients receiving third versus first line therapy for outpatient care ($39,952 vs. $15,521), inpatient care ($3,668 vs. $1,721), chemotherapy ($14,059 vs. $3,662) and biologic therapy ($28,824 vs. $4,899). Total costs were significantly greater for patients with metastases ($39,001) compared with those without ($8,989; p<0.0001). Conclusions: Treatment patterns vary significantly by line of therapy in patients with CRC. The total cost of care increased significantly as patients received additional lines of therapy and for patients with metastases. Biologics appear to be the most significant driver of these increased costs.
Beta-catenin and p53 expression in ampullary and small intestinal adenocarcinoma.
Authors: Hsiao Susan Jean , Remotti Helen Elaine
Published: March 2020

e14659

Background: Small intestinal adenocarcinomas are rare tumors with a worse prognosis than tumors arising from the large intestine. The majority of small intestinal adenocarcinomas arise in duodenum, most commonly around the ampulla of Vater; a smaller subset arises from the jejunum and ileum. Small intestinal adenocarcinomas remain poorly characterized due to their rarity, and limited options exist for adjuvant chemotherapy. Characterization of accumulation of the p53 tumor suppressor and aberrant expression of beta-catenin, suggestive of activation of the Wnt signaling pathway, could have important clinical implications and provide therapeutic targets. Methods: Tissue microarrays of ampullary and small intestinal adenocarcinomas were created using 2 cores of formalin-fixed tissues from 57 patients who had undergone surgical resection. Primary tumors involved the ampulla of Vater in 49% of cases, peri-ampullary duodenum in 39% of cases, and jejunum/ileum in 12% of cases.Immunohistochemical stains were performed for beta-catenin and p53. Cases with accumulation of p53 were scored as positive. Normal localization of beta-catenin is membranous; nuclear (or nuclear and cytoplasmic) accumulation of beta-catenin was scored as positive. Results: Accumulation of the p53 tumor suppressor protein was observed in 67.9% of ampullary adenocarcinomas, 86.4% of peri-ampullary/duodenal adenocarcinomas, and 57.1% of jejunal/ileal adenocarcinomas. Aberrant localization of beta-catenin was observed in 10.7% of ampullary adenocarcinomas, 0% of peri-ampullary/duodenal adenocarcinomas, and 42.9% of jejunal/ileal adenocarcinomas. Conclusions: Our initial results show accumulation of p53 in a substantial proportion of cases, similar to that which has been observed in other tumors. Abnormalities in p53 is one of the most common mutations observed in tumors. This is a clinically important result, as these tumors may respond to specific therapies targeting p53. In addition, our results implicate the Wnt signaling pathway in a subset of jejunal/ileal and ampullary adenocarcinomas offering another possible avenue for targeted therapies.
Expression of transcription factor Scratch2 in colorectal cancer.
Authors: Ivanov Krasimir , Kolev Nikola , Tonev Anton , Ghenev Peter , Zgurova Nedyalka , Ivanov Georgi , Kirilova Tanya , Ignatov Valentin , Zlatarov Aleksandar , Tonchev Anton
Published: March 2020

e14669

Background: The Scratch genes constitute an independent subgroup of the Snail superfamily of transcription factors (TFs). Vertebrates contain 2 Snail and 2 Scratch genes (Scrt1 and Scrt2). Members of the Snail/Scratch superfamilies are characterized by a having both zinc finger domains, which mediate DNA-binding and a SNAG domain that is necessary for the transcriptional repression. Under normal conditions, the Scratch genes are expressed exclusively in the nervous system, where they regulate cortical neurogenesis (Paul, Tonchev, et al. Cerebral Cortex 2012, Epub ahead of print; doi: 10.1093/cercor/bhs356). However, expression of Scrt2 under pathological conditions is poorly characterized, especially in humans. Methods: We investigated the expression of Scrt2 by immunohistochemistry in 50 primary or metastatic (hepatic metastasis) colorectal cancer biopsies acquired through routine operations at the Department of General Surgery, Medical University-Varna, Bulgaria. We also evaluated the histological type and clinical stage of the tumors. Results: We found that both the primary and the metastatic tumor strongly expressed Scrt2 protein. Interestingly, the expression was mostly in the cytoplasm, in accordance with the reported pattern in the developing cortex (Paul, Tonchev, et al. Cerebral Cortex 2012, Epub ahead of print; doi: 10.1093/cercor/bhs356). Notably, in the hepatic metastatic tumors, we found no or scarce expression in the normal hepatic parenchyma surrounding the tumor, while a strong expression in the colorectal cancer metastasis. Conclusions: Scrt2 represents a putative novel marker for colorectal cancer. Detailed correlation of the clinical parameters, such as patient survival, and the expression level of Scrt2 might yield novel prognostic value of this TF in the pathogenesis of colorectal cancer.
Inmunohistochemical expression of thymidilate synthase, ERCC1, pKDR, and LDH5 as predcitive markers of efficacy in patients with advanced colon cancer treated with XELOX or FOLFOX with or without bevacizumab.
Authors: Garde Javier , Evgenyeva Elena , Mireia Gil raga , Bernet Laia , Juarez Asuncion , Laforga Juan , Gassent Juan Manuel , Demarchi Martin , Camps Carlos , Llombart Antonio
Published: March 2020

e14671

Background: Low Thymidilate Synthase (TS) and ERCC1 expression have been related with efficacy of Fluoropirimidines and Platinum compounds respectively. High expression of angiogenic related proteins pKDR and LDH5 have been related with worse prognosis. The aim of our study is to analyze the inmunohistochemical expression of these proteins and their role as predictive markers of efficacy in advanced colorectal carcinoma. Methods: Retrospective study of patients with advanced colorectal cancer treated in first line with FOLFOX or XELOX +/- Bevacizumab between 2007 and 2011. Inmunoreactivity has been scored for staining intensity and proportion of positive cells. Staining was semiquantitative evaluated: intensity scored as none (0), to Strong (3), and percentage was categorized into five groups 0 = 0%, 1 (1-25%), 2 (26-50%), 3 (51-75%), 4 (76-100%). Staining and percentage scores were multiplied to obtain final T score (range 0-12), low expression was defined as T score <7, and high expression as T score ≥ 7. Results: 112 patients met inclusion criteria. Median age 68 years, 66 male (58.9%), 87 ECOG 0-1 (77.7%) and 58 (51,7%) with primary tumor removed before chemotherapy treatment. Seventy-five patients received bevacizumab (66.9%). Overall response rate was 56,3%, disease control rate 76.8%, and 18.8% of patients underwent surgery after treatment. Median PFS was 12 months and median OS 23 months. Preliminary results of TS expression showed 33.3% of patients with high vs 66.7% with low expression. There were not differences in response rate (60.7 vs 57.6%, p= 0.49), PFS (12 vs 13 m, p=0.48) or OS (22 vs 20 m, p= 0.6) between patients with low and high TS expression. Inmunohistochemical expression of ERCC1, LDH5 and pKDR is currently ongoing. Conclusions: Low inmunohistochemical expression of Thymidilate Synthase is not associated in our study with better outcomes in patients with advanced colon cancer treated with XELOX/FOLFOX +/- bevacizumab. Predictive value of ERCC1, LDH5 and pKDR expression is been evaluated, pending final results.
Capecitabine plus bevacizumab (Cape-Bev) as a maintenance treatment after induction treatment with FOLFIRI plus bevacizumab (FOLFIRI-Bev) in metastatic colorectal cancer (mCRC).
Authors: Tatli Ali Murat , Coskun Hasan Senol , Uysal Mukremin , Goksu Sema Sezgin , Arslan Deniz , Gunduz Seyda , Ozdogan Mustafa , Bozcuk Hakan Sat , Savas Burhan
Published: March 2020

e14683

Background: Bevacizumab is human monoclonal antibody that inhibits vascular endothelial growth factor and has been shown improvement progression-free survival and overall survival when combined with chemotherapy for treatment of mCRC in the first and second-line settings. The purpose of this study is to show the effectiveness of maintenance therapy with Cape-Bev in patients with mCRC who benefit of first-line (induction) chemotherapy with FOLFIRI-Bev. Methods: The study included patients with mCRC who received FOLFIRI-Bev as first-line chemotherapy. Maintenance therapy with Cape-Bev (Cape 1000 mg/m2 bid d1-14, Bev 7,5 mg/kg d1 q3w) was given until disease progression to patients who had achieved an objective response after 6-months FOLFIRI-Bev regimen. The time to disease progression, survival and toxic effects were analyzed from the beginning of bevacizumab-based chemotherapy. Results: We enrolled 30 patients, 16 men and 14 women. The mean age of the patients was 62 years. The patients who administered maintenance treatment received a median number of 11 cycles. The median progression-free and overall survivals were 22±4 months and 39±4 months, respectively. Significantly higher PFS and OS were seen among patients who complete or near-complete response to induction therapy with FOLFIRI-Bev (Table). Acceptable hand-foot syndrome was observed 14 patients (%51) treated with the Cape-Bev. No patient experienced severe toxicity. Conclusions: Cape-Bev regimen may be an effective maintenance treatment after response to first-line (induction) FOLFIRI plus bevacizumab treatment in selected mCRC with favorable safety profile. Further studies will be needed to demonstrate conclusively that. [Table: see text]
Sporadic rectal cancers in young adults: Experience from a tertiary cancer center in India.
Authors: Malik Monica , Adavikolanu Kesava Ramgopal , Jilla Swapna , Andra Vindhya Vasini , Lella Yugandhar , Naidu K. V. Jagannath Rao , Pamidighantam Suresh , Sunkavalli Venkata Ratnam
Published: March 2020

e14694

Background: Recent years have witnessed a trend towards an increase in incidence of rectal cancers in young adults both in western and asian populations. It has been noted that these cancers are more aggressive and associated with poorer outcomes. Methods: We conducted a retrospective analysis of young adults (age ≤ 40 years) with rectal cancers treated at our institute from 2007 to 2012. Information regarding stage, histology, treatment and outcomes were collected from patient records. Patients/family members were contacted for information regarding demographic, socioeconomic, dietary habits and occupational parameters. Disease free and overall survival was analyzed by Kaplan Meier estimates using the SPSS version 20. Results: A of total of 153 cases of rectal cancer were treated between 2007 to 2012 of which 48 patients (31%) were ≤ 40 years of age. Median age at presentation for the younger patients (≤40 years) was 30 years. There were 29 males and 19 females. None of these patients had a positive family history and no synchronous cancers were detected. Six patients were agricultural laborers and four worked in coal or cement factories. 23% of patients hailed from the coastal agricultural belt. At presentation, 41 patients had locally advanced disease and 7 had distant metastases. 25 patients received neoadjuvant chemoradiation, 17 underwent surgery and adjuvant chemoradiation and 6 were treated with palliative intent. Four patients progressed during treatment and eight had recurrent disease during follow up. Median overall survival (OS) was 21 months. 5-year OS was 37.5%. On multivariate analysis, poorly differentiated/mucinous tumors were associated with worse survival (p=0.01). Conclusions: 2-10% of colorectal cancers are reported to occur in young adults with many showing a familial association. In our series we had a higher proportion of young adults with sporadic cancers. Various occupational and environmental factors may be associated with these cancers. They are often detected in late stages and are associated with an aggressive course and unfavorable outcomes; hence early detection is of vital importance. Towards this end, identification of risk factors and screening programs need to be carried out.
Restoration of pro-death function of BAX MSI mutation for selective chemotherapy in colorectal cancer cells.
Authors: Zhang Honghong , Haferkamp Bonnie , Xiang Jialing , Wang Xin
Published: March 2020

e14707

Background: Microsatellite instability (MSI) is a common cause for a frameshift mutation in Bax the exon 3 microsatellite region leading to Bax-negative phenotype. However, we found that a unique Bax isoform (BaxΔ2) can be generated in combination of the deletion mutation (from G8 to G7) and alternative splicing. BaxΔ2 is a potent cell death inducer and specific to MSI tumors. Methods: The cell death assay, immunoblotting and immunohistochemisty are used for conducting the experiments. Results: The colon cancer cells with Bax G7, not G8, are selectively sensitive to certain chemotherapeutic drugs, such as 5-FU and Adriamycin. Unlike the parental Baxα, BaxΔ2 does not directly target to mitochondria, rather activates the caspase 8-dependent apoptotic pathway. Conclusions: Our data may provide an explanation that some colon cancer patients with “Bax negative” MSI tumor having a better prognosis and suggest that MSI colon cancer with Bax G7 mutation may potentially have a better response to selective chemotherapeutic drugs.