bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of peri-operative systemic therapy in liver-limited metastatic colorectal cancer (mCRC).
Authors: Kellock Trenton Tyler , Renouf Daniel John , Speers Caroline , Cheung Winson Y.
Published: March 2020

e14048

Background: Treatment for liver-limited mCRC is increasingly multi-disciplinary, frequently involving systemic therapy and surgery. Our aims were to 1) explore the use and choice of systemic therapy pre- and post-liver resection and 2) examine if specific regimens were associated with improved outcomes. Methods: All patients diagnosed with liver-limited mCRC in British Columbia, Canada from 2006 to 2007 were reviewed. Summary statistics were used to describe surgical and systemic treatment patterns. Kaplan-Meier methodology was used to characterize the relationship between systemic regimen and survival. Results: Among 374 patients, 42% were aged >/=70 years, 60% were men, 24/39/37% were ECOG 0/1/2+, 80% had primary tumor surgery, and 68% received prior adjuvant chemotherapy. For liver metastases, 95 (26%) were offered hepatic resection. Compared to those who did not receive liver surgery, resected patients were younger (median 60 vs 69), had better function (ECOG 0/1 88 vs 55%), largest liver lesion was smaller (median 3 vs 4 cm), and had fewer total lesions (median 1 vs 4) (all p<0.05). Patients who underwent liver surgery also had improved median overall survival (12.0 vs 9.4 months, p<0.05) than those who did not. Among resected patients, 47% received pre-operative chemotherapy: FOLFOX (28%, median 7 cycles), FOLFIRI (18%, median 9 cycles), or capecitabine (1%, median 6 cycles) while 74% received post-operative treatment: FOLFOX (26%, median 3 cycles), FOLFIRI (37%, median 9 cycles), or capecitabine (11%, median 8 cycles). About 15% and 31% of patients also received bevacizumab as part of their pre- and post-operative regimens, respectively. Median overall survival did not differ significantly based on choice of chemotherapy backbone: FOLFOX (13.9 months), FOLFIRI (11.5 months), and capecitabine (10.9 months) (p=0.44) or receipt of bevacizumab: yes (14.5 months) vs no (11.1 months) (p=0.57) Conclusions: In this retrospective cohort of liver-limited mCRC patients, hepatic resection was associated with improved survival. Among those offered peri-operative therapy, FOLFOX, FOLFIRI, and capecitabine, either alone or in combination with bevacizumab, appear to be reasonable options.
Burden of illness in second-line colorectal cancer: A systematic literature review.
Authors: Priedane Eugenia , Xu Yingxin , Wilson David , Jasso Mosqueda Juan Guillermo , Iqbal Sheikh Usman , Naoshy Sarah
Published: March 2020

e14061

Background: Colorectal cancer (CRC) is the third and second most common cancer in males and females, respectively, worldwide. Based on cases diagnosed in 2008, the age-adjusted incidence rate of CRC was 47.2/100,000/year in the US. Approximately 15-25% of all new cases are diagnosed with metastases and half of all cases result in metastases, representing an increased health and economic burden. The objective of this study was to gain a more in-depth understanding of the epidemiology, clinical and economic burden of second-line CRC in the US, Europe big 5, BRIC-M countries, and Japan. Methods: A Cochrane standard systematic literature review was performed using EMBASE, PubMed, NHSEED databases, and data from key congresses. Searches were conducted using specifically tailored search algorithms for years 2006-2011. Results: Of the 1,377 citations reviewed, 10 studies were identified (6 were epidemiology studies). No information on the number of patients treated for second-line mCRC was found. Estimates of median overall survival were short and varied from 7-18.7 months. New chemotherapy regimens, younger patients, and patients without KRAS mutations are associated with longer overall survival. Information on clinical burden of disease was also limited. The majority of patients presented with liver metastases (73%) and cardiovascular disease (63%). Three clinical trials evaluated quality of life (QoL) with significant heterogeneities in study design, population, treatment regimens and assessment instruments used. No statistically significant results favored targeted therapy. Only 1 study conducted in the US assessed economic burden in patients treated with either bevacizumab or cetuximab. At 6 months the total health care cost was $73,712 and $81,781 respectively, with main cost drivers being outpatient and targeted therapy costs. Conclusions: A substantial evidence gap regarding knowledge of burden of illness in second-line mCRC limits informed clinical and economic decision making. Further research is required to evaluate country-specific epidemiologic and survival data, QoL, resource utilization and cost variation associated with active treatment and end of life care. Research funded by Sanofi/Regeneron.
Down-regulation of KRAS-interacting miRNA-143 to predict prognosis and response to EGFR-targeted agents in colorectal cancer.
Authors: Eisner Florian , Stotz Michael , Samonigg Hellmut , Lax Sigurd , Hoefler Gerald , Pichler Martin
Published: March 2020

e14066

Background: MicroRNA-143 is frequently down-regulated in colorectal cancer (CRC) and influence CRC cell proliferation, apoptosis and sensitivity to 5-fluorouracil. mRNA encoded by the KRAS oncogene has been identified as a target of microRNA-143. However, the prognostic significance of microRNA-143 expression and the ability to predict the patient response to EGFR-targeted agents have not been explored yet. Methods: In this study, we analyzed 77 CRC harboring wild-type KRAS and obtaining treatment with the EGFR-targeting monoclonal antibodies cetuximab or panitumumab. MicroRNA-143 expression was measured by RT-PCR in both CRC and corresponding non-neoplastic colon tissue and the expression levels were correlated with clinico-pathological characteristics. Cancer-specific survival was calculated by uni- and multivariate analyses. The progression-free survival and objective response rates on EGFR-targeted therapy were also evaluated. Results: Down-regulation of microRNA-143 was observed in 47/77 (61%) CRC. Multivariate Cox regression analysis identified low levels of microRNA-143 expression as an independent prognostic factor with respect to cancer-specific survival (HR=1.92, CI=1.1-3.4, p=0.024). A significant difference was observed with respect to progression-free survival on EGFR-targeted therapy (p=0.031, log-rank test), but there were no significant differences with regard to the objective response rate. Conclusions: Our data suggest that microRNA-143 expression levels serve as independent prognostic biomarker for KRAS wild-type CRC patients but not as predictor for EGFR-targeted therapy. In addition, we consider microRNA-143 as a potential drug target for future therapy of CRC.
Tumor microRNA-29a expression and the risk of recurrence in stage II colon cancer.
Authors: Purim Ofer , Weismann-Brenner Alina , Kushnir Michal , Lithwick-Yanai Gila , Aharonov Ranit T. , Gibori Hadas , Kundel Yulia , Morgenstern Sara , Halpern Marisa , Niv Yaron , Brenner Baruch
Published: March 2020

e14067

Background: To compare the microRNA (miRNA) profiles in the primary tumor of patients with recurrent and non-recurrent colon cancer. Methods: The study population included 110 patients, 51 (46%) with stage I and 59 (54%) with stage II disease, who underwent curative colectomies between 1995-2005 without adjuvant therapy and for whom reliable miR expression data was available. RNA was extracted from formalin-fixed paraffin-embedded tumor samples. Initial profiling, using microarrays, was done in order to identify potential biomarkers of recurrence. The miRNA expression was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 months of surgery (bad prognosis group, n=23, 21%) and those who did not (good prognosis group, n=87, 79%) in the entire group and within each stage. Results: In stage I, none of the 903 miRNAs tested showed differential expression between patients with good prognosis compared with those with bad prognosis. In stage II, one miRNA, miR-29a, showed a clear differential expression between the groups (p=0.028). High expression of miR-29a was associated with a longer disease-free survival (DFS), on both univariate and multivariate analyses. Using miR-29a, the positive predictive value for non-recurrence was 94% (2 recurrences among 31 patients). The differential expression of miR-29a was verified by qRT-PCR, showing a similar impact of this miR on DFS. Conclusions: This study demonstrated a significant impact of miR-29a on the risk of recurrence in patients with stage II but not in patients with stage I colon cancer.
Evaluation of relapse-free survival in T3N0 colon cancer: The role of chemotherapy—A multicentric retrospective analysis.
Authors: Grande Roberta , Cosimelli Maurizio , Gemma Donatello , Ciancola Fabrizio , Corsi Domenico C. , Rossi Lorena , Sperduti Isabella , Fabbri Maria Agnese , Mancini Raffaello , Ruggeri Enzo , Longo Flavia , Quadrini Silvia , Zampa Germano , Bianchetti Sara , Gamucci Teresa
Published: March 2020

e14082

Background: Use of adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients (pts) and disease characteristics. According to worldwide guidelines AC should be considered in high-risk (H) T3N0 pts. No data are available for better option in low-risk (L) pts. Aim of the study is to evaluate relapse-free survival (RFS) and disease-free survival (DFS) retrospectively in T3N0 CC pts related to treatment. Methods: RFS and DFS are evaluated with Kaplan Meier method. In order to find the optimal cut off for node number the receiver operating characteristics curve analysis and Maximally Selected Rank Statistics were performed. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15 respectively. Results: 1,000 pts with T3N0 CC were recruited. To date, data of 926 pts are available. Median age was 69 (29-93), M/F 513/413, Grading 1/2/3 46/668/158; 360 L (39%), 411 H (44%), 155 unknown (17%); 137 (15%) pts showed symptoms (S) at diagnosis: 51 pts had perforation (P) or bowel obstruction (BO). Median sampled lymph nodes (LN) were 15 (1-76); 383 (41%) pts were treated with AC. Median follow up (fu) was 5 years (yr) (range 3-24). Survival analysis was performed only for pts with a minimum fu of 3 yr and younger than 80 (80%). 5 yr RFS was 78% and 5 yr DFS was 76% At multivariate analysis S and AC were prognostic factors for RFS. AC is prognostic factor for all endpoints (data are shown in table). In L group 5 yr RFS was 88% in treated pts and 75% in non-treated pts (p 0.03); in H group was respectively 82% and 72% (p 0.006). Conclusions: Preliminary data confirmed the role of known prognostic factors and suggest the relevance of AC also in L stage II T3N0 CC pts. However, the highest risk in L subgroup should be identified to be submitted to AC. Data collection is ongoing, update results will be presented. [Table: see text]
Single center analysis of immunotherapy in mCRC patients.
Authors: Ruckser Reinhard , Hoenigschnabl Selma , Kitzweger Elvira , Tatzreiter Georg , Kier Peter , Habertheuer Karlheinz , Zelenka Peter , Buxhofer-Ausch Veronika , Reiner-Concin Angelika , Sebesta Christian
Published: March 2020

e14087

Background: Immunotherapy in real-life, unselected patients with metastatic colorectal cancer (mCRC) was analyzed retrospectively at a single center in Austria. Methods: We have treated 137 mCRC patients with at least one antibody containing therapy since 2004 at our center based at data available at that time and patient eligibility. Results: Most mCRC patients were between 55 and 75 years old. The KRAS mutation testing performed routinely from 2008 onwards shows a distribution of 55 % wildtype (wt) and 45% mutant (mut) KRAS. Median overall survival (OS) was 24 months (n=82) with a trend towards greater benefit for KRAS wt patients compared to KRAS mut (26.8 vs. 20.9 months, respectively). Most patients received between 3 and 5 treatment lines. 40% of patients were treated with 5 therapies and 8% reached treatment line 8. The median OS correlated with the number of therapy lines. Chemotherapy alone regimens are decreasing constantly due to the establishment of biomarker analysis based treatment decisions and the increase in available antibodies for immunotherapy in mCRC. Based on direct positive experience with various antibodies, we were successfully treating patients repeatedly with the same antibodies in non-consecutive treatment lines. 75.7% of all patients treated with Cetuximab received the antibody only once during 3.8 therapy lines. 13% of patients who obtained the agent in two lines received on average 5.7 treatment lines resulting in improved OS. This was even more prominent in 8.5% patients receiving Cetuximab in 3 lines with a trend towards further OS benefit. These data describe that multiple applications of the same antibody is not only feasible but also very effective. Conclusions: By taping the full potential of treatment options, optimizing their usage and expanding the number of treatment lines we could achieve a median OS in real-life patients similar to that previously described in large phase III studies. Our analysis describes the following key factors for reproducing clinical benefits reported in large trials: biomarker assessment, early and if possible multiple applications of available therapeutic antibodies, treatment until progression and use of supportive therapy to alleviate possible toxicities.
The impact of TP53 mutation on high-risk rectal cancer patients treated within the EXPERT-C trial, a randomized phase II study of neoadjuvant oxaliplatin/capecitabine (CAPOX) and chemoradiation (CRT) with or without cetuximab.
Authors: Dewdney Alice , Chau Ian , Capdevila Jaume , Glimelius Bengt , Cervantes-Ruiperez Andres , Tait Diana M. , Brown Gina , Wotherspoon Andrew , Gonzalez de Castro David , Hulkki Wilson Sanna , Chua Yu Jo , Wong Rachel , Barbachano Yolanda , Oates Jacqueline Rose , Cunningham David
Published: March 2020

e14088

Background: The EXPERT-C trial randomised 165 patients into neoadjuvant CAPOX and CRT ± cetuximab and demonstrated a significant increase in radiological response (RR) and overall survival (OS) with cetuximab in KRAS/BRAF wild type (WT) rectal cancer (Dewdney et al JCO in press). TP53 mutation has been associated with worse CRT response and survival in rectal cancer and could lead to stimulation of PI3K signalling pathway, thus potential resistance to cetuximab. This analysis evaluates the impact of TP53 mutation in the EXPERT-C trial. Methods: FFPE tissue from biopsy (n=102) and resection specimens (n=99) were analysed for TP53 mutations (exons 5-8) using a multiplex PCR method followed by direct sequencing. If discordant results were encountered on paired biopsy and resection samples, analyses were repeated. Results: 53/102 (52%) biopsy and 24/99 (24%) resection samples harboured TP53 mutation, most commonly missense in exons 5 and 7. The vast majority had single TP53 mutations, only 4/53 biopsy and 1/24 resection samples had 2 mutations. 21/55 (38%) paired samples demonstrated discordant TP53 mutation status. In both all-treated and KRAS WT populations, presence of TP53 mutation had no impact on RR to neoadjuvant chemotherapy or CRT, regardless of treatment arm. A trend towards worse progression-free (PFS) (HR: 2.68; 95% CI: 0.85 - 8.43; p=0.08) and OS (HR: 4.04; 95% CI: 0.86 - 19.11; p=0.056) was observed in patients with TP53 mutation when treated with cetuximab, independent of the KRAS status. Conclusions: TP53 mutations were common in high-risk rectal cancer patients, the lower mutation rate in the resection samples was potentially due to lower tumour volume post CRT. The presence of a TP53 mutation at baseline had no impact on RR to treatment, however a trend towards worse PFS and OS was observed with the addition of cetuximab, consistent with the perceived biology.
Multicenter matched case-control study comparing laparoscopic surgery with open surgery for elderly colon and rectal cancer patients.
Authors: Kawaguchi Yasuo , Hinoi Takao , Hattori Minoru , Okajima Masazumi , Ohdan Hideki , Yamamoto Seiichiro , Hasegawa Hirotoshi , Horie Hisanaga , Murata Kohei , Yamaguchi Shigeki , Sugihara Kenichi , Yamamoto Seiichiro , Watanabe Masahiko ,   Japan Society of Laparoscopic Colorectal Surgery
Published: March 2020

e14091

Background: Laparoscopic surgery for colon cancer has gained acceptance due to advantages, although no clear equivalent evidences exist for the elderly patients. The aim of this study was to compare outcomes of open and laparoscopic colorectal surgery in patients aged 80 and above, and estimate the feasibility of laparoscopic surgery for the elderly patients. Methods: We conducted a matched case-control study using data from 41 hospitals, the member of Japan Society of Laparoscopic Colorectal Surgery. 2014 patients aged 80 and above underwent surgery for colon or rectal cancer between 2003 and 2007. Propensity score method was used to balance covariates between the surgery groups. Covariates included age, sex, BMI, ASA class, performance status, elective or emergency, previous abdominal surgery, tumor size, tumor site, T-stage, N-stage, and TNM stage. For the prediction model, calibration was assessed by the Hosmer-Lemeshow goodness-of-fit test. The primary end point was overall survival (OS). Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), and postoperative complications. Results: 1526 and 282 patients underwent surgery for colon and rectal cancer, respectively. The distribution of covariates was significantly different between the open surgery (OP) group and the laparoscopic surgery (LAP) group, in colon and rectal cancer. After propensity score matching, all covariates were balanced and no longer had significant differences, except for tumor size in colon cancer cases. There were 804 patients in 402 pairs managed with the OP or the LAP for colon cancer, and 114 patients in 57 pairs for rectal cancer. OS, DFS and CSS did not differ between the groups for either colon cancer (p = 0.916, 0.968 and 0.799 by log-rank test) or for rectal cancer (p = 0.765, 0.519, and 0.950). Overall morbidities were significantly fewer in the LAP group than in the OP group for colon cancer (24.9% vs. 36.3%, p < 0.001), and no difference for rectal cancer (47.4% vs. 40.4%, p = 0.450). Conclusions: The laparoscopic surgery was not inferior to the open procedure, and can be an acceptable alternative to open surgery for elderly patients with colon and rectal cancer.
Liver CT evaluation using a software that automatically generates report according to RECIST 1.1 criteria.
Authors: Longo Flavia , Iafrate Franco , Adua Daniela , Baldassarri Paolo , Del Bene Gabriella , Di Marco Marco , De Filippis Lucilla , Lapadula Vittoria , Gazzaniga Paola , Frati Luigi
Published: March 2020

e14096

Background: The aim of this retrospective study is to define the usefullness of an integrated CT software that automatically generates report according to RECIST 1.1 criteria and Choi criteria, evaluating the effects of bevacizumab based chemotherapy on CRC liver metastases. Methods: 35 patients with a total of 144 CRC liver metastases underwent CT before and after treatment. Patients with peritoneal disease were excluded. Reporting time was recorded for all patients. CT images were reviewed by two radiologists in consensus, in order to correlate clinical values with CT images using a software (Median, Technologies, France) that automatically synchronizes the images and pairs lesions in repeat CT scans according to RECIST 1.1 criteria as well as lesion density variation using Choi criteria. Results: Reports showed a good correlation between CT images and laboratory values in 31/35 patients during the period of response and in 29/35 during the period of disease progression. The associated use of Choi criteria, evaluating lesion density, provided a better correlation in 33/35 patients during the period of clinical response to therapy and in 31/35 during the period of disease progression. In 6 patients with 21 lesions, lesion density difficulty matches with laboratory values due to the presence of calcifications or to lesion small size. Average reporting time ranged between 16 to 18 minutes. Serum level biomarkers correlates with history disease and circulating tumor cells number using CellSearch system, according to recent literature, always results zero. Conclusions: Using this software we provide accurate quantitative assessment of response to bevacizumab based chemotherapy in liver mCRC with a good correlation between imaging and laboratory values.
Feasibility and challenges of a biopsy-driven and biomarker discovery clinical trial in metastatic colorectal cancer to identify signatures of clinical resistance.
Authors: Diaz Zuanel ,   Quebec Clinical Research Organization in Cancer Consortium
Published: March 2020

e14108

Background: Biopsy-driven clinical trials are essential to develop personalized therapeutics, since many critical questions are best addressed in the tumor tissue being treated. In the metastatic setting, intrinsic resistance occurs even with the most advanced therapeutic agents, and even in responders, acquired resistance is inevitable. We have designed a prospective study to identify biomarkers of clinical resistance to standard first-line therapy (FOLFOX, XELOX or FOLFIRI in combination with bevacizumab in patients with metastatic CRC (NCT00984048). Methods: Eligible patients have confirmed metastatic CRC, measurable disease, and consent to three needle-core biopsies (NCBs) of a non-resectable liver metastasis before treatment and at resistance. This study is approved at several Quebec hospitals, demonstrating that Research Ethics Boards recognize the value of biopsy-driven studies without therapeutic benefit. Results: Forty patients agreed to partake in this multi-center trial and to provide NCBs. Of these, 5% were non-neoplastic, and 5% had neuroendocrine origins. Using standard operating procedures developed for this trial, we were able to both preserve morphology and obtain high-quality genomic material. We demonstrate that this material is suitable for DNA analysis (array comparative genomic, methylation profiling) and RNA analysis (gene expression profiling, splicing isoforms variants and micro RNA profiling). In parallel, we have generated resistant CRC cell lines resistant to the combination therapy to further study biomarkers of resistance. Challenges in obtaining a biopsy at time of progression include death, patient refusal, heterogeneity of tumors, metastasis at a different organ site, and time constraints for re-biopsy. No significant adverse events were reported related to the biopsy procedure. Conclusions: We conclude that obtaining serial liver NCBs are challenging, but safe and feasible in metastatic CRC patients with unresectable liver disease. This study will provide insight on the relevance of metastatic tissue in assessing signatures of clinical resistance.
Mutational status of KRAS and BRAF of an Argentinian population of colorectal tumors.
Authors: Lopez Ruitti Paula , Salanova Ruben , Nafissi Julieta , Rabossi Guillermo , Bramuglia Guillermo , Powazniak Yanina
Published: March 2020

e14109

Background: Activating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (CRC). BRAF, another component of the EGFR-MAPK signal transduction pathway, is also subject to a common activating mutation in CRC. The aim of this report is to present the mutational status of KRAS, BRAF of an Argentinian population of CR tumors. Methods: Tumor blocks were obtained from 85 consenting patients of various public and private hospitals. We analyzed the presence of KRAS point mutations in codons 12 and 13, and the BRAF-V600E from formalin paraffin fixed sections with Polymerase Chain Reaction (PCR) amplification-sequencing. Results: From a total of 85 patients, 46% F and 54% M, with a median age of 64 years (range, 28-85), 72% (61) where found to be wild type, while the other 28% (24) showed the KRAS mutation in the following amino acids: G12V 30% (7), G12D 17% (4), G12C 17% (4), G12S 9% (2), G12A 4% (1), G13D 25% (6). We analyzed in 45 patients the mutational status of BRAF-V600E, 29 patients presented BRAF and KRAS wild type, 12 had a KRAS mutation while the BRAF was wild type, and 4 patients reveled a mutation of BRAF in the presence of a KRAS wild type. Conclusions: The type of mutation observed in this study corresponds to the findings of previous studies, where the most common KRAS mutation detected was G12V in codon 12 followed by G13D in codon 13. A preliminary report based in 146 patients from Argentine (Perazzo F, et al. 2009) revealed marked differences in KRAS mutation rates compared to our findings, showing the following percentage of mutations: G12V 62% vs. 30% , G12D 26% vs. 17% and G13R 1.7% vs. 0%, G13D 0% vs. 25%, respectively. BRAF mutational status was according to international and national reports.
Mutations in NRAS codon 61, KRAS codon 146, and BRAF V600E as prognostic factors in patients who received anti-EGFR antibody for metastatic colorectal cancer.
Authors: Takahashi Naoki , Yamada Yasuhide , Taniguchi Hirokazu , Akiyoshi Kohei , Honma Yoshitaka , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro
Published: March 2020

e14126

Background: Previous studies showed that gene mutations (NRAS, BRAF, PIK3CA) are associated with a poor prognosis or resistance of anti-EGFR antibody in metastatic colorectal cancer (mCRC) patients with wild type (WT) of KRAS codon 12/13 (KRAS-WT). However the significance of these biomarkers has not been clarified. In addition, EGFR immunohistochemistry (IHC) and EGFR gene amplification to evaluate the efficacy of anti-EGFR antibody treatment has not been reported for mCRC. Methods: We evaluated tumor response and survival in patients who received anti-EGFR antibody by mutation analysis of KRAS, NRAS, BRAF, and PIK3CA in KRAS-WT patients with mCRC. Tumor DNA samples are obtained from patients treated in our hospital with anti-EGFR antibody between August 2008 and August 2011. Results: A total of 117 patients were enrolled in this analysis, including 100 KRAS-WT patients. Seventy-one patients (60.7%) were all WT for KRAS, NRAS, BRAF, and PIK3CA, and 46 patients (39.3%) had at least 1 mutation or had insufficient DNA samples to analyze. Mutations of KRAS codon 61 (2 patients), KRAS codon 146 (5), BRAF V600E (2), PIK3CA exon9 (8), NRAS codon 12/13 (2), and NRAS codon 61 (5) were detected. No patients had a mutation of PIK3CA exon 20. Patients with at least 1 mutation had no response. Mutations of NRAS codon 61, KRAS codon 146, and BRAF V600E were associated with a shorter progression free survival (PFS) compared with all WT patients (p=0.049, p=0.004, p=0.036, respectively). Twelve patients (12% of KRAS-WT patients) with a mutation of NRAS codon 61, KRAS codon146, and BRAF V600E had poor prognosis compared with the other KRAS-WT patients (PFS, 6.4 vs 2.0 months, p<0.001; overall survival (OS), 13.7 vs 7.9 months, p=0.012). In all WT patients, moderate to strong EGFR IHC was associated with a better response rate than negative and weak IHC (p=0.046). Conclusions: Mutations of NRAS codon 61, KRAS codon 146, and BRAF V600E could be a strong prognostic factor of anti-EGFR antibody in patients with mCRC. Combination of IHC and DISH of EGFR could identify patients with a tumor response to anti-EGFR antibody in patients that are all WT for KRAS, NRAS, BRAF, and PIK3CA.
A phase II trial of salvage treatment with gemcitabine and S-1 combination in heavily pretreated patients with metastatic colorectal cancer.
Authors: Sym Sun Jin , Hong Junshik , Jung Minkyu , Park Jinny , Cho Eun Kyung , Lee Jae Hoon , Lee Won-Suk , Baek Jeong-Heum , Shin Dong Bok
Published: March 2020

e14137

Background: We conducted a phase II trial of gemcitabine with S-1 to evaluate the activity and toxicity of such a combination in heavily pre-treated patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after treatment with 5-fluorouracil, oxaliplatin and irinotecan. Methods: Between Dec 2009 and Nov 2011, 23 pts were enrolled, with the following characteristics: 12 males and 11 females, median age 57 years (28-72). S-1 was given orally (30 mg/m2) b.i.d for 14 consecutive days and gemcitabine (1000 mg/m2) was given on days 1 and 8, every 21 days, until disease progression and for a maximum of 9 cycles. The primary endpoint was objective response rate (ORR). Results: The median number of cycles was four (range 1-9). OR was 8.7% (95% confidence interval [CI] 0-20.2) and disease control rate was 56.5% (95% CI 36.4-76.9) with two partial responses and eleven stable diseases. Median duration of disease control was 8.5 months (95% CI 3.8-13.2). Median progression-free survival was 3.2 months (95% CI 1.9-4.5) and median overall survival was 11.8 months (95% CI 4.0-19.5). Grade 3-4 toxicities were neutropenia (8%) and thrombocytopenia (4%). Conclusions: Combination chemotherapy with gemcitabine and S-1 was well tolerated and efficacious for refractory mCRC pts.
Influence of comorbidity and ECOG on efficacy and safety in irinotecan-refractory elderly patients (>65 years) with metastatic colorectal cancer (mCRC) treated with cetuximab plus irinotecan.
Authors: Jehn Christian , Böning L. , Kröning Hendrik , Possinger Kurt , Pezzutto Antonio , Lueftner Diana
Published: March 2020

e14140

Background: In clinical practice elderly patients (pts) with comorbidities may not be treated appropriately based on perceptions about their life expectancy and ability to tolerate potential side effects of chemotherapy. We investigated the influence of comorbidity, ECOG status and age on the efficacy and safety profile of cetuximab and irinotecan in irinotecan pretreated mCRC patients aged < 65 and > 65 years. Methods: 497 irinotecan-pretreated pts with mCRC were entered in the database of this noninterventional study. Comorbid conditions were recorded and scored according to the Charlson Comorbidity Index (CCI). Descriptive statistics, χ²-or Fishers exact test and multivariate analysis were applied. Results: A total of 247 and 250 pts aged < 65 (median:59) and > 65 (median:70) years, respectively, were documented. 79% of the pts showed a reduced ECOG status of 1–2, with no difference the age groups (p=0.65). Grade III/IV toxicities occurred in 18 % of pts without any difference between age groups although older pts had more comorbidities, with a higher CCI (p=0.002). The duration of any grade of skin reaction was in pts age < 65 significant longer (42 d), than in patients aged > 65 (31 d); (p=0.04). However, there was a trend towards higher grade (≥2) skin toxicity in pts aged > 65. A total of 71% of the pts developed skin rash, which was strongly related to response (P=0.006). Age, line of therapy, ECOG, gender, CCI had no influence on response in multiple regression analysis. The objective response rates were similar for both groups: 38.1% for age < 65 vs. 36.4% for age > 65 (p=0.57). Progression-free survival (PFS) did not differ between pts 18–65 years old (6.0 months) in comparison with pts >65 years (6.1 months) (p=0.99; log-rank test). In a multivariate analysis only ECOG status had a negative impact on PFS (HR: 0,499; 95% Cl, 0.34–0.72; p=0.002), but not CCI, age or gender. Conclusions: Only ECOG had a negative influence on PFS. There were no significant differences in response rate and safety profile for patients aged < 65 and > 65 years when treated with cetuximab and irinotecan. Comorbidities had no influence on efficacy or toxicity.
Effect of the ADAPT strategy on dormant CD133+ colon cancer stem cells (CSC) and molecular complete remission measured by peripheral blood mononuclear (PBMC) CD133 mRNA.
Authors: Lin Edward H. , Xiazhen Yu , He Xi C , Wu Xifeng , Xie Yang , Deng Yanhong , Yang Guang , Tian Qiang , Li Lingheng
Published: March 2020

e14153

Background: The median survival for patients with unresectable metastatic colorectal cancer (CRC) is ~2 years with modern chemotherapy which yields only 5-10% complete responses (CR) including metastasectomy. Recurrences after CR are very common thanks to presence of dormant CSC that are best targeted by our proposed two-step ADAPT strategy: activate from dormancy and potentiate targeting. We examine this strategy in various CRC models and reviewed the impact on stemess including CD133 mRNA, a circulating CSC marker that predict colon cancer relapse. Methods: Different CRC models (in vitro and in vivo) were interrogated similar to clinical ADAPT treatment protocol using capecitabine (or 5FU) plus celecoxib. We also conducted IRB approved retrospective review of unresectable metastatic CRC patients treated ADAPT therapy and in those who also had PBMC CD133 mRNA measured. Results: Contrary to 5FU, which eliminates proliferating CRC cells via apoptosis but also stimulates stemness, celecoxib preferentially deplete CD133+ colon cells and exert potent stemness inhibition via rapid tumor necrosis by perturbing hypoxia and energy metabolism via CA-IX. Following response to first-line chemotherapy, ADAPT strategy plus radiation improved CR or near CR rate to 49/126 (40%) in unresectable CRC patients whose median survival had reached 92.7 months (95% CI, 53.5 months - not reached). Paradoxically, none surgical CR patients (n= 16) enjoyed 100% 5-year relapse free survival compared to 42% of surgical patients (p = 0.04). The PBMC CD133 mRNA in five long-term CR patients were 0.0024, 0.29, 0.5, 0.56, 2.96 respectively, all below previously reported cutoff value of 4.79 for recurrence and far below CD133 mRNA levels (28, 375, 3997, 15662, 83240) in none CR patients. Conclusions: ADAPT plus radiation preferentially targets colon CSC via hypoxia/CA-IX and improves clinical CR rate and molecular CR as measured by PBMC CD133 mRNA. We are actively interrogating the effects of ADAPT strategies in a phase II study funded by Gateway in CRC patients and in genetic CRC animal models.
A comparative analysis of locoregional therapy (hyperthermic intraperitoneal chemotherapy [HIPEC]) and systemic chemotherapy (CT) following cytoreductive surgery in patients (pts) with disseminated mucinous appendiceal cancers (MACA).
Authors: Bekaii-Saab Tanios S. , Martin Ludmila Katherine , Vallabhaneni Geetha D. , Park Wungki , Staley Charles A. , Maithel Shishir Kumar , Wang Zhibo , Chen Zhengjia , El-Rayes Bassel F.
Published: March 2020

e14169

Background: MACA are rare neoplasms with variable prognosis depending on tumor histology. Peritoneal dissemination is frequent and cytoreductive surgery is the mainstay of treatment (tx). HIPEC and CT may provide additional benefit, but their role is not well understood. We evaluated the role of HIPEC and CT in pts with MACA following cytoreduction. Methods: Pertinent data including demographics, tx and clinical outcome were retrospectively obtained from pts treated at The Ohio State University and Emory University. Tumors were histologically classified as disseminated peritoneal adenomucinosis (DPAM) or peritoneal mucinous carcinomatosis (PMCA) and by TNM stage. Clinical outcome was evaluated according to tx, stage, and histology. Results: 124 pts (41M, 83F) with a median age of 58 years (range 21-82) were included. All pts had stage IV disease, 43 had DPAM and 71 had PMCA (10 unavailable). Following debulking surgery, 27% of pts had HIPEC, 21% had CT, 30% had both and 22% had no additional therapy. For stage IV pts, there was a significant benefit for additional tx after surgery (Table). Pts with DPAM had significantly improved mOS versus PMCA. For pts with PMCA but not DPAM a significant survival advantage was seen for any tx (CT, HIPEC, or both) versus no therapy following surgery. Conclusions: For pts with MACA, additional tx may improve survival following cytoreductive surgery. HIPEC appears to improve outcomes, while systemic CT may not provide added benefit. Prognosis for DPAM histology appears to be superior to PMCA. Pts with PMCA may benefit most from additional tx following cytoreduction. These interesting findings are limited by their retrospective nature and prospective validation is needed. [Table: see text]
Clinicopathologic feature and outcome of appendiceal goblet cell carcinoid and neuroendocrine tumor.
Authors: Park Wungki , Vallabhaneni Geetha D. , Martin Ludmila Katherine , Adsay Volkan , Staley Charles A. , Maithel Shishir Kumar , Wang Zhibo , Chen Zhengjia , El-Rayes Bassel F , Bekaii-Saab Tanios S.
Published: March 2020

e14170

Background: Goblet cell carcinoid (GCC) of the appendix is a rare tumor comprising 5% of primary appendiceal tumors. GCC shares histological features of both neuroendocrine tumor (NET) and adenocarcinoma. Clinically, GCC also has an intermediate behavior between them. The management of GCC is mostly based on small retrospective series. We report the clinicopathological features, treatments, and outcomes of patients with appendiceal GCCs and NETs from a merged database between Emory University and the Ohio State University. Methods: We identified patients with appendiceal GCCs and NETs treated at these institutions over the period of 12 years from 1999 to 2011. Chart reviews for age, gender, date of diagnosis, TNM stage, chemotherapy, intraperitoneal hyperthermic perfusion (IPHP), surgery, and survival were performed. Results: See table. In the GCC patients with stage I, II, and III, 30 received surgery alone and 1 received surgery plus IPHP. 29 out of 31 (94%) patients are alive without disease recurrence. Out of 6 GCC patients with stage IV, 5 received chemotherapy, 1 received chemotherapy plus IPHP, and 2 (33%) are alive. In the NET patients with stage I,II, and III, all 29 were treated with surgery alone. 29 out of 31 patients are alive and there was no disease-related mortality. Out of 2 NET patients with stage IV, one received chemotherapy and both are alive. Conclusions: Our data confirms the excellent prognosis of appendiceal NET regardless of stage. The outcomes of surgery for patients with stage I, II, and III in both GCCs and NETs were excellent. Patients with stage IV GCCs have higher possibility of aggressive clinical courses. Chemotherapy or IPHP should be considered in the management of stage IV GCCs. [Table: see text]
Trimodality therapy for stage II-III carcinoma of the esophagus: A dose-ranging study of concurrent capecitabine, docetaxel, and thoracic radiotherapy.
Authors: Wood Matthew D. , Zaki Bassem I. , Gordon Stuart R. , Sutton John E. , Lisovsky Mikhail , Gui Jiang , Dragnev Konstantin H. , Bubis Jeffrey Alan , Rigas James R.
Published: March 2020

e14514

Background: This dose escalation study was performed to determine the recommended phase II dose of capecitabine to be delivered concurrently with thoracic radiation therapy and weekly docetaxel in patients with locally advanced esophageal carcinoma. Methods: Patients with operable stage II or III esophageal carcinoma were staged by endoscopic ultrasonography and CT. Two cycles of docetaxel (80 mg/m2) and carboplatin (target AUC of 6) were delivered over 6 weeks, followed by concurrent weekly docetaxel (15 mg/m2), thoracic radiotherapy (50.4 Gy in 28 fractions), and increasing doses of capecitabine (500-3500 mg) given prior to each fraction of radiotherapy. After re-staging, responding patients continued to esophagectomy. Results: Forty-four patients were enrolled and 40 were evaluable for the dose-ranging component of chemoradiotherapy. The median age was 63 (range 47-87), 32 patients (80%) were male, and 36 (90%) had adenocarcinoma while 4 (10%) had squamous cell carcinoma. EUS stages at enrollment were T3N1 (29), T3N0 (4), T2N1 (6), and T4N0 (1). The maximum tolerated dose of capecitabine was 3500 mg. Common non-hematologic grade 3 or 4 toxicities were dysphagia (n=6, 15%) and nausea/vomiting (n=3, 8%). Common grade 3 or 4 hematologic toxicities were ANC and WBC abnormalities (n=10, 25% and n=9, 23% respectively). Overall, 58% of patients had no stage 3 or 4 toxicity. Thirty-six patients had surgery; 83% had R0 (curative) resection and 14% had complete pathological response (pCR). With a median follow-up time of 18.9 months, the median overall survival was 23.5 months, with 34% and 27% alive at three and five years, respectively. The three- and five-year relapse-free survival was 37%. In patients who had pCR or microscopically residual disease, 5-year survival was 74% (n=8). Conclusions: The recommended phase II dose of capecitabine is 3500 mg when given concurrently with 50.4 Gy in 28 fractions of thoracic radiotherapy with weekly docetaxel. This trimodality therapy for locally advanced esophageal carcinoma was well-tolerated and remarkably active. This regimen holds promise for treatment of esophageal carcinoma and warrants further investigation.
Biweekly cetuximab in combination with irinotecan as second-line treatment in patients with platinum-resistant gastroesophageal cancer (GEC).
Authors: Schønnemann Katrine Rahbek , Bjerregaard Jon Kroll , Yilmaz Mette K. N. , Jensen Helle Anita , Nielsen Kirsten Marie , Vestermark Lene Weber , Pfeiffer Per
Published: March 2020

e14517

Background: Inspired by the promising results seen in patients (pts) with chemo-resistant metastatic colorectal cancer we evaluated a biweekly schedule of cetuximab (cet) and irinotecan (iri) - (Cetiri) (Pfeiffer et al. Ann Oncol 2008) in platinum resistant GEC. Methods: We treated and evaluated 111 consecutive pts with histological verified GEC adenocarcinoma and documented failure to first-line platinum-based treatment. Pts received cet 500 mg/m2 and iri 180 mg/m2 day 1 every 2nd week until progression or unacceptable toxicity. Toxicity was evaluated according to NCI-CTCAE v. 3.0. Response rate (RR) was evaluated according to RECIST v. 1.0 every 8th week. Clinical parameters and blood samples at baseline were analyzed in order to find prognostic and predictive values for prolonged overall survival (OS). Results: Pts were included from December 2007 to August 2010. Median age was 63 years (range 33-81). Performance status (PS) was 0-1 in 95 % of the pts. Thirty-six (46%) pts had more than two organs involved. Median number of courses were 5 (1-46). RR was 13% (13 PR) and 48 % had stable disease for at least 2 months. Median PFS and OS were 3.3 months (CI 2-4) and 5.6 months (CI: 5-7) respectively. Seventy six (68%) pts had treatment induced skin toxicity, rash. In a univariate analysis PS 0-1, normal baseline haematology and skin rash was associated with significantly increased survival. These parameters retained significance in a multivariate analysis. One patient had a curative intended resection after 28 courses and had an overall survival at 29.5 months. Two pts are still alive. Conclusions: Biweekly Cetiri is a convenient and well-tolerated second-line (SL) regimen in pts with GEC adenocarcinoma. Good PS, normal baseline haematology and development of skin rash indicate increased survival. Based on our findings biweekly Cetiri can be recommended as SL treatment to GEC pts in a good PS. Further studies into the role of rash are warranted.
Cost-effectiveness analysis of treatment modalities for hepatocellular carcinoma in the SEER-Medicare population.
Authors: Hanna Nader , Shaya Fadia T. , Breunig Ian Michael , Chirikov Viktor , Seal Brian S. , Mullins C. Daniel
Published: March 2020

e14522

Background: Multiple treatment options for HCC exist and the treatment(s) received depend on clinical characteristics, resource availability and access to specialists. Their comparative cost effectiveness is unclear. Methods: Medicare patients with a 1st diagnosis of 1ry HCC in 2000-07 were studied through end of ‘09. Data are from the SEER with linked Medicare parts A-B. We use incremental cost effectiveness ratios (ICERs) and 95% cost intervals for transarterial chemoembolization (TACE) vs no treatment, liver transplantation (OLT), surgical resection (RS), radiofrequency ablation (AB), systemic chemotherapy (CH), and radiation therapy (RD). Using HCC-related mortality, Cox proportional hazards models were used to compute mean life years survived (LY) under each modality, adjusting for clinical (cancer stage, underlying health status, liver conditions) and demographics. Multiple propensity scores were incorporated to adjust for treatment selection bias. Average HCC-related Medicare costs (US$2011) attributed to each modality are estimated using generalized least squares methods. Results: Cancer stages 1, 2, 3, and 4 represent 24%, 9%, 14%, and 17% of the 11,047 patients: 37% unstaged, 66% male, 75% Caucasian, 10% African American, and 13% Hispanic, 61% of patients untreated, 8% TACE, 2% “liver directed therapy” (LD), 4% OLT, 8% RS, 5% AB, 8% CH, and 6% RDST. Relative to no treatment, OLT was most effective in reducing HCC mortality (HR .06, p<.01), followed by RS (HR .19, p<.01), LD (HR .25, p<.01), AB (HR .33, p<.01), TACE (HR .39, p<.01), RD (HR .44, p<.01), CH (HR .49, p<.01). All ICERs were significant; OLT cost effective ($2,951/LY), followed by RS ($5,801/LY), RD ($6,322/LY), CH ($6,748/LY), AB ($8,405/LY), TACE ($9,074/LY), then LD ($10,453/LY). Conclusions: In SEER-Medicare patients, all treatments were associated with reduction in HCC-related mortality. TACE was more effective when combined with ablative therapy, yet OLT and resection were still more effective. Though, OLT patients are more likely than others to survive. TACE alone was only more effective than radiation therapy and systemic chemotherapy.
Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: A large retrospective study.
Authors: Walter Thomas , Horgan Anne , McNamara Mairead Geraldine , McKeever Elizabeth , Min Trisha , Hedley David W , Serra Stefano , Krzyzanowska Monika K. , Chen Eric Xueyu , Mackay Helen , Feld Ronald , Moore Malcolm J. , Knox Jennifer J.
Published: March 2020

e14524

Background: Chemotherapy is effective in advanced biliary tract cancer (ABTC). The benefits of second-line chemotherapy (CT2) are unclear. Methods: We retrospectively studied all patients starting at least one line of chemotherapy for ABTC at our institution between 1991 and 2011. We analyzed patient and chemotherapy characteristics in order to: 1) characterize patients eligible for CT2; 2) evaluate the efficacy of CT2. Results: Three hundred and ninety five, 100 (25%), and 25 (6%) patients received CT1, CT2, and CT3, respectively. Primary tumor location was the gallbladder (29%), intraphepatic (19%), perihilar (17%), distal common bile duct (19%), and ampulla of Vater (14%). Ninety-one percent had a baseline performance status (PS) of 0-1 prior to CT1. Females (p=0.005), age≤60 years (p=0.009), and patients with progression free survival (PFS) >6 months following CT1 (p=0.01) were more likely to be offered CT2. Objective response rates and stable disease with CT2 were 10% and 35%, respectively. Median PFS and median overall survival (OS) from the beginning of CT2 were 2.8 and 8.0 months, respectively. Prognostic factors impacting PFS with CT2 were the regimen type (doublet versus monotherapy, p=0.004) and PS<2 (p<0.0001). Conclusions: Among patients with ABTC, 25% received CT2, typically younger patients and those with longer PFS following CT1. Disease control occurred in 45% of patients, and more often with a doublet than single agent. However, clearly more effective therapies must be found.