bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes of positive resection margins after endoscopic resection of early colorectal cancer.
Authors: Kim Jin-Oh
Published: March 2017

688

Background: The management of patients with a positive resection margin after endoscopic resection of early colorectal cancer (ECC) depends on various clinical factors, including the pathology. There is little information on the clinical outcomes according to the subsequent management of a positive resection margin in patients with ECC treated by endoscopic resection. We assessed the management according to the pathology of the positive margin and evaluated the clinical outcomes. Methods: Consecutive patients with ECC who underwent endoscopic resection from January 2004 to December 2014 were reviewed. This study retrospectively analyzed 363 lesions from 338 patients (mean age, 60.1 years; 68% [230/338] male). Results: The resection margin was positive in 29.2% of patients, including cancer cells in 9.9%, adenoma in 16.5%, and high-grade dysplasia (HGD) in 2.8%. Subsequent surgery was performed on 11.8% of patients, 72.2% (26/43) of whom were cancer cell–positive, while 23.3% (10/43) were resection margin–negative but had deep submucosal (SM) or lymphatic invasion. Remnant cancer cells were identified in 25.6% (11/43) of the operated group and 81.8% (9/11) of the cancer cell–positive group. On early follow-up surveillance colonoscopy (mean interval, 3.57 months) in 88.2% of patients (320/363), including 95.7% (67/70) of the adenoma and HGD-positive group, only one (0.3%, 1/320) case of remnant adenoma was found. In the multivariate analysis, deep SM invasion ( p=0.026), number of pieces of piecemeal resection (p=0.03) and cancer cell positivity ( p=0.001) predicted subsequent surgery. In the multivariate analysis, an endoscopic appearance of incomplete resection ( p=0.002) and cancer cell positivity (p=0.041) were related to the identification of remnant cancer cells after subsequent surgery. Conclusions: Patients with an adenoma-positive resection margin had favorable clinical outcomes during subsequent surveillance. The choice of subsequent surgery was related to deep SM invasion and cancer cell–positive resection margins, and subsequent surgery group showed a high rate of remnant cancer cells.
The relationship between tumor location, tumor microenvironment, systemic inflammation, and cancer-specific survival in patients undergoing surgery for colon cancer.
Authors: Patel Meera , Park James Hugh , van Wyk Hester Catharina , Edwards Joanne , Horgan Paul G. , McMillan Donald C
Published: March 2017

689

Background: Evidence from clinical trials and cohort studies suggest primary tumour location is a prognostic factor in patients with advanced colorectal cancer and that right and left colonic tumours should be considered as distinct clinical and biological entities. The aim of the present study was to examine the relationship between tumour location, tumour microenvironment, systemic inflammatory response (SIR), and cancer-specific survival (CSS) in patients undergoing surgery for colon cancer. Methods: Clinicopathological characteristics were extracted from a prospective database of patients who underwent potentially curative surgery for colon cancer between 1997 and 2016, at a single centre. The tumour microenvironment was assessed retrospectively using routine H&E pathological sections. Results: 722 patients were included. The majority of patients were over the age of 65 years (69%), were male (52%), had right-sided (RS) tumour location (63%), had TNM stage I/II disease (64%) and 25% received adjuvant chemotherapy. RS location was associated with poor tumour differentiation ( p =< 0.001) and high venous invasion ( p =0.003) but not with TNM stage (p= 0.310), perineural invasion ( p= 0.286), tumour budding ( p= 0.568), margin involvement ( p= 0.424), peritoneal involvement ( p= 0.689), tumour necrosis ( p= 0.423) or tumour cell proliferation ( p= 0.605). RS location was not associated with tumour inflammatory cell infiltrate at the margin (CD3+ p= 0.103, CD8+ p= 0.620) or in the tumour (CD3+ p= 0.540, CD8+ p= 0.713) or with tumour stroma percentage ( p= 0.843). RS location was associated with high mGPS ( p =0.007) and neutrophil:platelet score ( p =0.001) but not NLR ( p= 0.387). Finally, there was no difference between RS and left sided tumour location in the administration of adjuvant chemotherapy (p= 0.901) or CSS ( p= 0.951). Conclusions: Few clinicopathological features were associated with tumour location in patients undergoing surgery for colon cancer. However, RS tumour location was consistently associated with a higher SIR. This may account for the poor prognosis associated with RS tumours in patients with advanced colon cancer.
Racial and gender disparities in therapy and outcomes of squamous cell cancer of the anus.
Authors: Gupta Arjun , Arora Nivedita , Zhu Hong , Christie Alana , Meyer Jeffrey John , Khan Saad A. , Beg Muhammad S.
Published: March 2017

691

Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with a rising incidence in the United States. We aimed to characterize race and gender-based disparities in receipt of therapy, and overall survival (OS) of SCCA using the Surveillance, Epidemiology and End Results (SEER) database. Methods: Cases of locoregional SCCA diagnosed between 2000-2012 in the SEER database were included. Demographics, tumor characteristics, therapy and outcomes were extracted. Primary end point was OS. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HR) and 95% confidence intervals (CI). SAS version 9.4 was used for analysis. Results: We identified 7882 cases of locoregional SCCA, median age 58 years, 61.2% women, 86.3% white. A majority of patients (82.3%) received radiation therapy; with the lowest rate in black males (76.7%) and highest in white females (86.1%). The median OS was 135 months, and it was lower in the elderly, > 65 years (68 months), men (108 months), blacks (109 months) and those who did not receive radiation therapy (121 months). In multivariate analysis, increasing age (HR 1.19, 95 % CI 1.16-1.20 per 5 years increase), gender (HR 1.59, 95% CI 1.47- 1.73, men vs women), race (HR 1.51, 95% CI 1.34- 1.71, blacks vs whites), and receipt of radiation therapy (HR 0.90, 95% CI 0.82-0.99), were associated with OS (all p < 0.05). Race was a significant predictor of receiving radiation therapy on univariate analysis. Table 1 outlines the rates of receipt of radiation and the median OS of the four racial/gender groups. Conclusions: Significant race and gender-based disparities exist in the survival of patients with locoregional SCCA. Even after adjusting for baseline and treatment characteristics, blacks had poorer OS, suggesting difference in tumor biology. Further investigation into the causes, and methods to eliminate these disparities are warranted. [Table: see text]
Safety and effectiveness of regorafenib (REG) in patients with metastatic colorectal cancer (mCRC) in routine clinical practice: An interim analysis (IA) from the prospective, observational CORRELATE study.
Authors: Ducreux Michel , Öhler Leopold , Scheithauer Werner , Metges Jean-Philippe , Dourthe Louis-Marie , De Groot Jan Willem , Thaler Joseph , Yeh Kun-Huei , Lin Jen-Kou , Falcone Alfredo , Punt Cornelis J. A. , Contijoch Ann M. , Fiala-Buskies Sabine , Cervantes-Ruiperez Andres , O Connor Juan Manuel ,   On Behalf of the CORRELATE Investigators
Published: March 2017

700

Background: REG significantly improved overall survival (OS) vs placebo in patients with mCRC who progressed on available treatments in the randomized, double-blind, phase 3 trials CORRECT and CONCUR. CORRELATE aims to characterize the safety and effectiveness of REG for the treatment of mCRC in an unselected real-world patient population treated in routine clinical practice. Here we report the results of a planned IA. Methods: This global study aims to recruit 1000 patients with mCRC previously treated with approved therapies and for whom the decision to treat with REG has been made by the treating physician according to the local health authority approved label. Dose interruptions and reductions are permitted for the management of adverse events (AEs). The primary endpoint is the incidence of treatment-emergent AEs (TEAE; NCI-CTCAE v4.03). Secondary endpoints include OS, progression-free survival, and the disease control rate. The first planned interim analysis includes the first 500 patients observed for at least 3 months. Here, we report an IA of safety. Results: Median age was 65 years (range: 29–89) and 61% of patients were male. Most patients had a baseline ECOG PS 0/1 vs 2–4 (41%/43% vs 8%) and 50% had KRAS mutations. Most common metastatic sites at study entry were liver (52%) and lung (43%). The median treatment duration was 2.4 months (range: 0.1–10.6). The daily starting REG dose was 160 mg, 120 mg, and 80 mg in 53%, 34%, and 12% of patients, respectively; 26% of patients had dose reductions, 21% due to TEAEs. TEAEs of any grade occurred in 91% of patients, and in 76% TEAEs were considered REG related. Grade ≥ 3 TEAEs occurred in 55% of patients. In 31%, grade ≥ 3 TEAEs were REG related, with fatigue (7%), hand-foot skin reaction (5%), and hypertension (5%) being most common. Grade 5 TEAEs occurred in 13% of patients and were REG related in < 1%. Conclusions: In this observational study, the planned IA showed that the rate of REG-related grade ≥ 3 TEAEs appeared to be somewhat lower than rates observed in the phase 3 trials in patients with mCRC. The starting dose for approximately half the patients was less than 160 mg/day. Clinical trial information: NCT02042144.
Oncopre: A new chemotherapy benefit prediction algorithm to assist treatment decision making.
Authors: Yusuf Dimas , Ho Maria Yi , Kennecke Hagen F. , Cheung Winson Y.
Published: March 2017

705

Background: Clinical decision support tools (CDSTs) can help physicians make complex treatment decisions and inform care. For colon cancer, CDSTs such as Adjuvant! Online and Numeracy were widely used to estimate the effects of adjuvant treatment and guide conversations with patients. Existing CDSTs, however, do not consider more contemporary predictive and prognostic factors, such as microsatellite instability (MSI), BRAF mutational status, or the presence of additional high risk clinical or pathological features (HRFs), in their assessment of outcomes. Current CDSTs are also not optimized for handheld devices. Methods: We developed ONCOPRE, which is an adjuvant chemotherapy benefit calculator for colon cancer that addresses the limitations of current CDSTs. Based on a comprehensive review of epidemiological data and results of landmark trials, ONCOPRE was devised to predict 5-year colon cancer recurrence and death. To validate ONCOPRE, we compared its predictions with those generated by existing CDSTs as well as real-world data from 7 tertiary cancer centers across Canada. Results: ONCOPRE is able to predict 5-year DFS and OS of patients with colon cancer based on age, sex, TNM status, and contemporary risk factors such as MSI status, BRAF mutations, and other HRFs. ONCOPRE’s predictions compare favorably with real-world data and predictions from other CDSTs. ONCOPRE’s predictions are typically more optimistic than historical outcomes, and this likely reflects the fact that current day colon cancer patients experience better prognosis with the use of modern therapy and improved supportive care. These attributes make ONCOPRE a potentially new benchmark among CDSTs that can reliably predict colon cancer outcomes. Conclusions: ONCOPRE ( http://www.oncopre.com/beta/ ) represents a new CDST that can assist in adjuvant treatment decision-making and patient counseling. We make the case that the next generation of CDSTs in oncology must take into account more contemporary clinical, biochemical, and genetic risk factors since these elements significantly affect outcomes. The ONCOPRE platform serves as a potential model on which to develop prediction tools for other forms of cancers.
Phase 1 trial of OCV-C02, a peptide vaccine for metastatic colorectal cancer patients refractory to all standard chemotherapies.
Authors: Iwasa Satoru , Taniguchi Hiroya , Yamazaki Kentaro , Yoshino Takayuki , Kiryu Chika , Liew Ei Leen , Naka Yoshiharu , Sakata Yuh
Published: March 2017

706

Background: OCV-C02 is a peptide vaccine consisting of 2 peptide epitopes derived from ring finger protein 43 and translocase of outer mitochondrial membrane 34. In colorectal cancer (CRC), they are upregulated in approximately 80% of tumor tissues. This study was conducted to assess safety, preliminary efficacy and immunological responses to OCV-C02. Methods: Key eligibility criteria for this open label, sequential cohort, dose escalation study were patients (pts) with unresectable metastatic CRC (mCRC) refractory to all standard chemotherapies and HLA-A*24:02. Pts in cohorts 1 to 4 received OCV-C02 0.3, 1, 3 and 6 mg/body respectively, subcutaneously, on days 1, 8, 15 and 22 of the 28-day treatment cycle. Cycle was repeated in pts without progressive disease, until occurrence of unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) that was defined as treatment-related ≥ grade 3 or 4 hematological or ≥ grade 3 non-hematological adverse events (AEs) observed from days 1 to 29 of Cycle 1. Secondary endpoints were treatment emergent AEs (TEAEs), efficacy and immunological responses. Efficacy was evaluated by overall response rate, disease control rate (DCR), time to treatment failure (TTF) and overall survival (OS). Immunological responses were evaluated by cytotoxic T lymphocytes (CTL) and delayed-type hypersensitivity (DTH). Results: A total of 24 pts were treated. No DLT occurred in cycle 1 and no major safety issues throughout the trial. All pts had ≥ 1 TEAE. Frequently reported TEAEs included injection site reaction (25%), vomiting (25%), decreased appetite (20.8%) and pyrexia (16.7%). More than 50% of TEAEs were of grade 1 or 2 in severity. None achieved complete or partial response. Six pts had stable disease and DCR were 16.7%, 50% and 33.3% for cohorts 2, 3 and 4, respectively. TTF was 1.8, 0.9, 2.3 and 1.6 months and OS was 7.9, 11.6, 8.4 and 7.4 months for cohorts 1, 2, 3 and 4, respectively. CTL and DTH responses following vaccination were observed across the 4 cohorts. Conclusions: OCV-C02 at 0.3 to 6 mg/body exhibited a safe and well tolerated profile, and showed immunological responses in mCRC pts refractory to all standard chemotherapies. Clinical trial information: NCT01801930.
Response to pembrolizumab in patients with mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC).
Authors: Leal Alexis Diane , Paludo Jonas , Finnes Heidi D. , Grothey Axel
Published: March 2017

714

Background: Mismatch repair deficient (dMMR) colorectal cancer (CRC) has been shown to be responsive to blockade with anti-programmed death-1 (PD-1) antibodies. We describe a cohort of 17 patients with dMMR mCRC receiving treatment with pembrolizumab. Methods: Patients were identified through review of the Mayo Clinic electronic medical record (EMR) and chemotherapy administration records from May 2015 through September 2016. All patients with dMMR mCRC who received treatment with pembrolizumab were included. The EMR was reviewed to identify demographic, clinical, pathologic and treatment details. Overall survival (OS), progression free survival (PFS) and disease control rate (DCR=CR+PR+SD) are reported. Time to event analysis was calculated using the Kaplan-Meier method. Results: A total of 17 patients were included in this analysis; median age at diagnosis was 48.5 years (range 25-93); 59% were female. Most primary tumors were right sided (n=12; 71%), 4 (24%) were left sided and 1 (5%) was a tumor of unknown primary within the bowel. Thirteen (75%) patients received 2 or more lines of therapy prior to pembrolizumab (range 1-4). All patients received 2 mg/kg every 3 weeks, with the exception of two patients on a clinical trial; one who received 200 mg every 3 weeks, the other received 10 mg/kg every 2 weeks. The most common mutations (mut) identified were loss of MLH1 (9/12) and PMS2 (10/12), 4 patients had germline mut. KRAS mut was identified in 6/15 patients and only 1 patient had BRAF mut. Number of cycles of pembrolizumab ranged from 1 to 35, with 10 (59%) patients receiving 6 or more cycles. DCR at first assessment was 57%, with 7% CR and 50% PR. Median follow-up was 28 months (95% CI 18-55). Median OS was 103 months (95% CI NR-NR); 12-month OS was 88% and 24-month OS was 81%. Median OS post-PD-1 therapy was NR (95% CI 2-NR). Median PFS was 19 months (95% CI 5-19); 12-month PFS was 64% and 24-month PFS was 0%. At time of analysis, 11 patients remain on PD-1 therapy; 4 patients have died. Conclusions: Anti-PD1 blockade with pembrolizumab can provide long lasting benefit in dMMR mCRC, even in heavily pretreated patients.
Effect of adjuvant chemotherapy following pathologic complete response on long-term survival in rectal cancer: A propensity score matched analysis.
Authors: Mokdad Ali , Huerta Sergio , Minter Rebecca M , Mansour John C. , Choti Michael A. , Polanco Patricio
Published: March 2017

717

Background: The role of adjuvant chemotherapy following resection in patients with rectal cancer that achieve pathologic complete response (pCR) after neoadjuvant therapy is unclear. Current data have been limited by small sample size series. This study examined the impact of adjuvant chemotherapy following pCR on overall survival in a national cohort of patients. Methods: Patients with rectal adenocarcinoma were identified in the National Cancer Data Base between 2006 and 2012. Those with locally advanced tumor (clinical stage II or III) that achieved pCR (defined as ypT0N0 in surgical specimens) after neoadjuvant chemoradiotherapy (nCRT) were included in the study. We matched by propensity score patients that received adjuvant chemotherapy (ACT) and patients that did not receive postoperative treatment (no-ACT) controlling for demographic as well as perioperative patient and tumor characteristics. Overall survival was compared using a Cox proportional hazards model. Results: We identified 2,543 patients (ACT: 732, no-ACT: 1,811 patients) with resected locally advanced rectal adenocarcinoma that achieved pCR after nCRT. Among patients that received ACT, 711 were matched with 711 patients in the no-ACT group. Adjuvant chemotherapy was associated with improved overall survival compared to no-ACT (hazard ratio[HR] = 0.46, 95% confidence interval [CI] = 0.29 – 0.75). Overall survivals at 1, 3, and 5 years in the ACT and no-ACT groups were 100% vs 98% (P=0.1), 98% vs 94% (P<0.01), and 94% vs 89% (P<0.01), respectively. In subgroup analyses, adjuvant chemotherapy improved overall survival in patients with clinical stage II (HR = 0.43, 95% CI = 0.22 – 0.85) as well as stage III tumor (OR = 0.50, 95% CI = 0.26 – 0.98). Among patients that received adjuvant chemotherapy, there was no difference in overall survival between single agent and multiagent regimens (HR = 1.37, 95% CI = 0.57 – 3.29). Conclusions: Adjuvant chemotherapy may providea small long-term survival benefit in patients with resected locally advanced rectal cancer and pCR after nCRT.
Cost effectiveness of maintenance bevacizumab in patients with metastatic colorectal cancer.
Authors: Lange Joel , Rajeev Rahul , Gamblin T. Clark , Turaga Kiran
Published: March 2017

718

Background: Observation alone after initial treatment of unresectable metastatic colorectal cancer is often anxiety provoking for physician and patient alike. The CAIRO 3 trial suggested the efficacy of maintenance capecitabine and bevacizumab in improving overall survival for such patients. We hypothesized that the cost effectiveness for maintenance capecitabine and bevacizumab would be worse than accepted population thresholds. Methods: Data from the CAIRO-3 trial was used to populate a semi-markov model, in which patients transitioned between different disease and complication based states. Transition probabilities were extratcted from the trial. Costs were determined from a thirs payer persective from the Medicare part B ASP drug pricing file. Utility was converted from the global quality of life scale. Incremental cost effectiveness ratios were calculated. Results: Cost of the maintenance arm after 10 cycles was $108,848 with a gain in 14.93 quality adjusted life months, while the quality adjusted life months gained at no cost in the observation arm was 13.67. This yielded an ICER of $1,036,648/QALY. Two way sensitivity analyses demonstrated dominance of observation across a wide range of parameters unless the cost per cycle was < $6250. Conclusions: Maintenance capecitabine and bevacizumab is not cost effective and is higher than the willingness to pay threshold for any developed nation. Reducing drug pricing is the only way to financially support the argument for this treatment strategy.
Nationwide incidence, treatment, and outcomes of patients 80 years and older with rectal adenocarcinomas: Analysis of 5,076 patients.
Authors: Cassidy Richard John , Cheng En , Switchenko Jeffrey M. , Jiang Renjian , Jhaveri Jaymin , Tanenbaum Daniel G , Gillespie Theresa Wicklin , McDonald Mark William , Landry Jerome C
Published: March 2017

723

Background: Elderly patients have been underrepresented in randomized clinical trials of rectal cancer, and the value and tolerance of treatment options in this population remain unclear. We used the National Cancer Data Base (NCDB) to assess the incidence, treatment patterns, and overall survival (OS) outcomes of patients 80 years or older with newly diagnosed non-metastatic rectal adenocarcinomas. Methods: 5076 patients 80 years and older diagnosed with non-metastatic rectal adenocarcinomas from 2004 to 2013 were identified. Univariable and multivariable (MVA) analysis were performed to identify patient, tumor, and treatment characteristics associated with receipt of standard of care therapy (SOCT) and factors predictive of OS. SOCT was defined as surgical resection for Stage I patients and receipt of neoadjuvant therapy followed by surgical resection for Stage II/III patients. Kaplan-Meier curves were generated to assess the effect of stage and treatment received on overall survival. Results: At presentation, 935 (18.5%) were TXN0, 1557 (30.8%) were Stage I, 1552 (30.6%) were Stage II, and 1,032 (20.1%) were Stage III. The rates of patients receiving no therapy were: 29.6% for TXN0, 22.6% for Stage I, 16.5% for Stage II, and 12.2% for Stage III. The rates of patients not receiving SOCT were: 22.6% for Stage I, 51.4% for Stage II and 39.4% for Stage III cases. Survival was significantly worse for patients not receiving standard of care therapy: Stage I (52.1% receiving SOCT vs. 7.6% not receiving SOCT; p < 0.01), Stage II (49.8% receiving SOCT vs. 14.5% not receiving SOCT; p < 0.01), and Stage III (47.5% receiving SOCT vs. 10.2% not receiving SOCT; p < 0.01). On MVA of patient, tumor, and treatment variables, receipt of SOCT was associated with improved OS for the entire cohort (p < 0.01) and when examined by stage (p < 0.01). Conclusions: In this nationwide sample of patient’s ≥ 80 years old with rectal cancer, there was a high rate of patients receiving no therapy. Those that did receive standard therapy achieved reasonable outcomes, suggesting avoidance of guideline care in this population should not be advised.
Current alignment between the practice patterns of gastrointestinal (GI) cancer clinical investigators (CI) and general medical oncologists (MO) in the treatment of metastatic GI cancers.
Authors: Love Neil , Kelly Gloria , Miller Kirsten , Paley Douglas , Moss Jonathan , Ziel Kathryn
Published: March 2017

724

Background: CI with an interest in specific cancers amass a unique body of knowledge and relevant experiences that may make their practice patterns different from those of MO. This initiative sought to document and compare the stated management approaches of CI and MO. Methods: InMay 2016, as part of a continuing medical education (CME) project, 31 CI elected to complete a 78-item survey assessing their usual treatments for various metastatic colorectal, gastric and pancreatic cancer clinical scenarios. A stipend was provided for participation. On June 4, 2016, 13 clinical questions from the CI survey were posed to 140 MO, 103 US-based and 37 non-US-based, prior to a CME symposium on GI cancers. Responses of the groups were compared. Results: For 10 out of 13 questions, there was relative concordance between CI and MO responses. However,for 3 there was considerable variation (see Table). Conclusions: Although CI and MO approach the care of many patients with GI cancers in a similar manner, important and noteworthy variations exist. These findings indicate that the documentation and comparison of treatment recommendations could be a novel strategy to elucidate misalignment between CI and MO and impel either or both to rethink current approaches. Additional work is needed to validate these findings and understand potential implications and applications. [Table: see text]
Predictability of survival outcome by early tumor shrinkage (ETS) at 8 weeks with cutoff value of 20% in metastatic colorectal cancer (mCRC) patients treated with mFOLFOX6 plus bevacizumab (bev) or FOLFIRI plus bev as first-line chemotherapy (1st-CTx): Validation in the phase III WJOG4407G trial.
Authors: Sakamaki Kentaro , Kito Yosuke , Izawa Naoki , Tsuda Takashi , Morita Satoshi , Yamazaki Kentaro , Boku Narikazu , Muro Kei , Hyodo Ichinosuke
Published: March 2017

729

Background: We reported that ETS at 8 weeks with cutoff value of 20% is the best candidate for predicting overall survival (OS) in mCRC patients who received 1st-CTx in the retrospective study (Kito, ESMO, 2015), where ETS was estimated by the tumor growth inhibition model (Claret, JCO, 2013). The objective of the study was to validate our proposed evaluation time and cutoff value for ETS in the phase III WJOG4407G trial which showed equivalent efficacy of mFOLFOX6+bev and FOLFIRI+bev as 1st-CTx for mCRC (Yamazaki, Ann Oncol, 2016). Methods: Tumor shrinkage ratio (TSR), which is the relative change in the sum of the longest diameters of target lesions according to the RECIST between before and during 1st-CTx, was calculated using actually measured tumor size data. Cutoff values of TSR for ETS and allowance ranges for measurement time of tumor size were evaluated. The association between ETS and OS was investigated by Cox regression model. In multivariate analyses, the general prognostic factors of mCRC, such as ECOG performance status (PS), prior history of adjuvant chemotherapy (AC), baseline tumor size (bTS), serum alkaline phosphatase (ALP) and white blood cell (WBC), were adjusted. Results: Of 402 enrolled patients, 305 patients had tumor size data measured within 8 +- 2 weeks. Patient characteristics were: mFOLFOX6+bev/FOLFIRI+bev 153/152; PS 0/1 244/61; AC Yes/No 49/256; median bTS 79 mm (range 10-512); median ALP 274 IU/L (110-1,200); median WBC 6400/mm3(3,030–12,000). In multivariate analyses, ETS at 8 weeks with cutoff value of 20% was most significantly associated with OS showing hazard ratio (HR) of 0.53 (95%CI: 0.38-0.74, p < 0.001). Moreover, HR of ETS was 0.47 (95%CI: 0.33-0.67, p < 0.001) in using the data during 8 +- 1 weeks (n = 257), while HR was 1.03 (95%CI: 0.41-2.62, p = 0.95) in using the data earlier or later than 8 +- 1 weeks (6 to 7 or 9 to 10 weeks) (n = 48). Conclusions: This analysis supported that ETS with cutoff value of 20% using data within 8 +- 1 weeks is optimal for predicting OS in mCRC patients who received 1st-CTx. Clinical trial information: UMIN000001396.
Impact of cyclophilin A on survival in gastric cancer patients who received platinum-based chemotherapy.
Authors: Maeng Chi Hoon , Baek Sun Kyung , Sung Ji-Youn , Kim Si-Young
Published: March 2017

73

Background: Cyclophilin A (CypA), which is a protein that mediates protein folding and trafficking, has known to be associated with cancer progression and drug resistance such as cisplatin. However, the actual effect in cancer patients has not been elucidated. Methods: We collected clinical data from the cohort of 289 gastric cancer patients. Subjects were selected as following criteria: 1) adjuvant or first-line palliative chemotherapy containing platinum, 2) available FFPE tissue for immunohistochemical stain for CypA. We divided the population into two groups; Group A was patients who received adjuvant chemotherapy and Group P was those of palliative chemotherapy-treated group. The score of CypA immunohistochemistry was calculated depending on the intensity of stain and the percentage of stained cells. We performed survival analysis based on CypA expression. Results: 1) Group A (N = 147) Patients with lower expression of CypA ( < vs. ≥ median IHC score) showed significantly worse progression-free survival (PFS, 2.4 years vs NR, p = 0.043), and overall survival (OS, 3.4 months vs. NR, p = 0.002). In subgroup analysis, level of CypA expression discriminated PFS significantly in patients with age less than 65, poorly differentiated histology, signet ring cell type, and OS for those with use of oxaliplatin, age less than 65, stage III, poorly differentiated histology, diffuse type of Lauren classification, and signet ring cell type favoring higher expression of CypA. 2) Group P (N = 142) There was no relationship between expression level of CypA and PFS/OS in patients with palliative settings. However, in patients who were treated with oxaliplatin-containing chemotherapy, lower expression of CypA showed worse OS (8.3 vs 11.1 months, p = 0.003) Conclusions: Lower level of CypA expression was associated with worse PFS and OS in patients with adjuvant setting, especially in case of advanced stage, and high grade histology. Although CypA did not have significant effect on survivals in palliative chemotherapy-received patients, those who received oxaliplatin showed worse OS with lower CypA.
Utilization of minimally invasive versus open colectomy for colon cancer and perioperative/short-term oncologic outcomes: Are we there yet?
Authors: Smith Jillian K. , Esnaola Nestor F.
Published: March 2017

733

Background: Randomized controlled trials (RCTs) in highly-selected patient populations demonstrated equivalent outcomes following minimally invasive colectomy (MIC) versus (vs) open colectomy (OC) for colon cancer. The purpose of this study was to evaluate utilization of MIC and compare perioperative/short-term oncologic outcomes after MIC vs OC in a large, generalizable, national sample. Methods: We identified adult patients with invasive colon adenocarcinoma who underwent elective surgical resection between 2010 and 2012 using the National Cancer Data Base. Univariate associations between patient/tumor/facility/treatment characteristics and surgical approach were analyzed using chi-square tests. Multivariable logistic regression was used to identify independent predictors of receipt of MIC, as well as to evaluate independent associations between surgical approach and outcomes. Results: Among 111,372 patients identified, 48,393 (43.5%) underwent MIC; the proportion who underwent MIC increased between 2010 (37.8%) and 2012 (49%; p < 0.001). High education level (adjusted odds ratio [aOR] 1.13) and increasing income level (aOR 1.09-1.36) were independently associated with receipt of MIC, whereas black race (aOR 0.85), Medicare (aOR 0.86)/Medicaid (aOR 0.67)/uninsured status (aOR 0.57), non-metropolitan residence (aOR 0.92), and community (aOR 0.63) or other (aOR 0.58) cancer programs were independently associated with potential underuse. Mean length of stay was shorter following MIC vs OC (6.07 vs 7.68 days; p < 0.001). Use of MIC was independently associated with reduced 30-day (aOR 0.6) and 90-day (aOR 0.62) mortality, as well as lower rate of positive surgical margins (aOR 0.69) and higher rate of regional lymph nodes examined > = 12 (aOR 1.14). Conclusions: This study confirms that MIC is associated with favorable perioperative/short-term oncologic outcomes (compared to OC), as demonstrated in RCTs. Although utilization of MIC for colon cancer continues to rise, implementation studies are warranted to enhance access to optimal surgical care and eradicate persistent disparities in receipt of MIC among historically underserved populations.
Comparative analysis of survival in colon cancer undergoing sentinel lymph node mapping versus conventional surgery based on number of positive lymph nodes.
Authors: Ramanathan Sabarina , Saha Sukamal , Mukkamala Suresh , Hicks Michael , Knight Patrick , Mazzaferro Daniel , Siva Thushy , Bajaj Vinay , Hutcherson Lori , Chang Avian , Livert David , Oza Rajen
Published: March 2017

734

Background: Unlike in breast cancer or melanoma, resection during sentinel lymph node mapping (SLNM) in colon cancer (CCa) includes regional lymphadenectomy including SLNs and non SLNs. However, SLNM often identifies micrometastases which can be missed by conventional (Conv) surgery and pathologic examination. It is unknown whether this impacts survival or recurrence. Hence, a retrospective analysis was undertaken to study overall (OS) and disease -specific (DSS) survival between patients (pts) undergoing SLNM vs Conv surgery based on the number of +veLNs. Methods: SLNM was done by subserosal injection with blue dye followed by segmental resection including regional lymphadenectomy. All SLNs were ultrastaged and other nodes were examined by conv. methods with H&E. Results: There are 309 pts in SLNM (GpA) vs 499 pts in Conv surgery (GpB); with average no. of lymph nodes (LNs) and +ve LNs 17.3/1.6 vs 14.4/2.49 respectively. For GpA, success rate was 99.6% and the average no of SLN was 3. Of the pts in GpA vs GpB, 1+ve LN were found in 38% vs 27%, 2+ve LNs in 10% vs 16%, and > 2 LNs in 53% vs 57%, respectively. Comparing 5 years OS between GpA vs GpB, for 1+ve LN was 62.8% vs 52.38%, for 2 +ve LNs 72.7% vs 48.65% and for > 2 +ve LNs 35% vs 33.33%, respectively. Similarly, DSS for 1 +veLN was 54.4% vs 47.6%, 2+ve LNs 40% vs 40.54% and > 2+ve LNs, 30.4% vs 25.76%, respectively(Table1.). Conclusions: Compared to Conv surgery, SLNM identified higher no. of LNs per pt with high success rate. Five-year OS and DSS also are better in SLNM vs Conv surgery for all +ve LN gps. Hence, SLNM in CCa may have prognostic value. A larger multicenter trial needs to be done to validate such data. [Table: see text]
Efficacy and safety of regorafenib compared to TAS-102 for metastatic colorectal cancer: A systematic review and network meta-analysis.
Authors: Kinupe Abrahao Ana Beatriz , Ko Yoo-Joung , Chan Kelvin K. , Berry Scott R.
Published: March 2017

735

Background: Recent studies have shown regorafenib and TAS-102 (TAS) to be superior to placebo (P) in refractory metastatic colorectal cancer (mCRC). However, no studies have directly compared both drugs. Giving the lack of therapeutic options for these patients,, a systematic review to compare the efficacy and safety of regorafenib compared with TAS was performed, using indirect comparison methods. Methods: A systematic review using PubMed, Medline, Embase, Scopus and Cochrane database to identify published and unpublished studies up to November 2015 for randomized controlled trials (RCTs) for patients with metastatic colorectal cancer, involving regorafenib or TAS was performed. Data including overall survival (OS), progression-free survival (PFS) and toxicity were extracted. Pairwise direct meta-analyses (regorafenib versus placebo and TAS versus placebo) and indirect comparison (regorafenib versus TAS) using network meta-analyses methods (R package “netmeta”) to preserve randomization were performed using random effects. Results: 914 citations were initially identified among which 3 RCTs fulfilled eligibility criteria (CORRECT, CONCUR and RECOURSE trials) involving 1.764 patients (regorafenib: 641, TAS: 534, Placebo: 589). Subgroups of patients (1.659) who had not received prior regorafenib or TAS-102 were used to performed meta-analyses for efficacy. In indirect comparison, there were no statically differences observed between regorafenib and TAS-102 in overall survival (HR 0.96 95% CI 0.56-1.55 p = 0.082) and progression-free survival (HR HR 0.85 95% CI 0.40-1.80 p = 0.0182). In addition, there were no differences in objective response rate and disease control between both drugs. However, regorafenib has statistically more all grade toxicity (risk difference (RD) 0.31 CI 0.25-0.38 p = 0.001) and toxicity grade 3-5 (RD 0.22 CI 0.13-0.31 p < 0.001) compared to TAS. Conclusions: In this indirect comparison, regorafenib and TAS appeared to have similar efficacy. However, regorafenib has more toxicity compared to TAS. Post-approval real world data focusing on the comparative toxicity of regorafenib and TAS is warranted.
Utilization of systemic therapy options in the routine treatment of metastatic colorectal cancer.
Authors: Delahunty Rachel Lee , Lee Margaret , Wong Hui-Li , McKendrick Joseph James , Lee Belinda , Kosmider Suzanne , Cooray Prasad , Ananda Sumitra , Tran Ben , Tie Jeanne , Desai Jayesh , Gibbs Peter , Wong Rachel
Published: March 2017

738

Background: In the treatment of metastatic colorectal cancer (mCRC), exposure to all three active cytotoxic agents; 5-fluorouracil/capecitabine (FP), irinotecan (Ir) and oxaliplatin (Ox), and the biologic agents, bevacizumab (Bev) and cetuximab and panitumumab (EGFR-I) improves outcomes. The current uptake of systemic agents for mCRC in a community setting in Australia is poorly described. Methods: The ACCORD database was interrogated to determine demographics, treatments and outcomes for all patients diagnosed with mCRC between 1/01/2011 and 1/01/2015 at 6 Melbourne centres (3 public and 3 private). Results: 865 patients were identified: median age was 68 years. 68% were ECOG 0-1, 60% had de novo metastatic disease. RAS status was known in 59%, of whom 48% were RAS wild-type (WT). At the time of analysis 69% of all patients had received systemic treatment with 51% receiving treatment second line and beyond; 65% RAS WT, 57% RASm, 16% RAS-Unk. See Table. Metastasectomy was performed in 29% of patients of whom 38% remain disease-free. With a median follow-up of 31.3 months 46% of patients remain alive. The median overall survival was 25 months for all patients(unresected;17.6 months, resected: not reached). Conclusions: A high proportion of patients receiving routine clinical care in the community setting do not receive any systemic therapy and few patients receive all available active agents. Despite this, the overall survival of patients with mCRC in this community-based cohort was 25 months and in-line with clinical trial data. [Table: see text]
The Greek participitation to IDEA (International Duration Evaluation of Adjuvant Chemotherapy) study of 3 versus 6 months of adjuvant chemotherapy in stage III colon cancer: Patients’ characteristics and safety analysis.
Authors: Souglakos John , Boukovinas Ioannis , Kakolyris Stylianos , Ziras Nikolaos , Androulakis Nikolaos E. M. , Ardavanis Alexandros , Kentepozidis Nikolaos K. , Vaslamatzis Michael , Athanasiadis Athanasios , Christopoulou Athina , Makrantonakis Paris , Polyzos Aristidis , Mavroudis Dimitrios , Mala Anastasia , Kalisperi Aggeliki , Xynogalos Spyros , Varthalitis Ioannis I. , Kouroussis Charalambos , Prinarakis Efthimios , Georgoulias Vassilis
Published: March 2017

740

Background: The International Duration Evaluation of Adjuvant (IDEA) collaboration was established to prospectively analyze data from six randomized trials to assess whether a 3-month course of oxaliplatin/fluoropyrimidines (FU)-based adjuvant chemotherapy (CT) is non-inferior to the 6-month current standard treatment in stage III colon cancer (CC). The primary endpoint of IDEA was 3-year disease-free survival. The accrual goal for the Greek IDEA study was 1.000 patients. Methods: Greek IDEA randomized patients with stage III colon cancer between 3 months (arm A) and 6 months (arm B) of adjuvant CT with modified (m) FOLFOX6 or XELOX (depending on physician/patient choice). Toxicity was graded during treatment and follow-up using NCI-CTCAE v3.0. Results: From May 2009 to October 2015, 708 patients were randomized in Greek centers either to arm A (n = 354, 50%) or to arm B (n = 354, 50.%). 297 (41.9%) patients received mFOLFOX6 and 411 (58.%) XELOX. The median age was 67 years (20-75) and 579 (81.8%) of them had PS 0. The patients’ population was balanced for the major risk factor between the two arms: N1/N2 disease (68.1/31.9% vs. 68.9/31.1 for ARM A and B, respectively), obstruction (4.5% vs. 2.5 for ARM A and B, respectively) and perforation (5.1% vs. 6.2 for ARM A and B, respectively). Overall, 96.9% and 89.5% of patients completed 3 months (arm A) and 6 months (arm B) of CT, respectively. Median oxaliplatin dose was 505 mg/m2 in arm A and 738 mg/m2 in arm B. Toxicity profiles were comparable between the two arm and the two fluoropyrimidines backbones with a total incidence of Grade 3/4 adverse events 18.9/4.4% and 19.7/5.1% for mFOLFOX6 and XELOX, respectively. Grade 2/3-4 peripheral neuropathy during the study was similar between arm A (33.9/4%) and B (38.7/3.7%). Conclusions: Both mFOLFOX6 and XELOX were safe. More patients completed the scheduled treatment in the 3-arm schedule.
Prognostic impact of primary tumor location in patients with metastatic colorectal cancer (mCRC) at the salvage lines.
Authors: Nagaoka Tomoyuki , Wakatsuki Takeru , Shinozaki Eiji , Nakayama Izuma , Suenaga Mitsukuni , Fukuda Naoki , Osumi Hiroki , Matsushima Tomohiro , Ichimura Takashi , Ogura Mariko , Ozaka Masato , Takahari Daisuke , Chin Keisho , Yamaguchi Kensei
Published: March 2017

741

Background: Recently it has been suggested that primary tumor location may have a clinical impact on the front line chemotherapies; namely, right-sided tumor benefit less from cytotoxic and targeted agents compared with left-sided tumor. Regorafenib and TAS 102 have recently emerged and the prognostic impacts of tumor location on these agents are unknown. Methods: Clinical information of patients who were administrated Regorafenib and/or TAS 102 was retrospectively collected. Patients’ demographics by tumor location were compared using Fisher’s exact test. Time to treatment failure (TTF), and overall survival (OS) by tumor location were calculated using Kaplan-Meyer Methods and compared using Log-rank test. In addition, subgroup analyses were performed to see the interactions between tumor location and covariates in each agent. All tests were performed at the two-sided .05 significance level. Results: The median TTF (mTTF) and OS (mOS) were 2.0 and 8.0 months in the regorafenib group (n = 98) and were 2.4 and 7.9 months in the TAS102 group (n = 95), respectively. In the regorafenib group, 71 patients had a left-sided tumor and 27 patients had a right-sided tumor. In the TAS102 group, 64 patients had a left-sided and 31 patients had a right-sided tumor. There was no significant difference between right and left sides in both groups with the exception that a greater number of older patients was seen in right-sided in the TAS102 group. No significant difference of TTF and OS by primary site were observed in regorafenib (HR 0.92, 95% CI 0.68-1.70, P = 0.71 for TTF, HR 1.09, 95% CI 0.68-1.81, P = 0.74 for OS) and in TAS 102 (HR 0.84, 95%CI 0.53-1.36, P = 0.48 for TTF, HR 1.26, 95% CI 0.72-2.33 P = 0.43 for OS). Significant interactions were shown between presence of liver metastasis and tumor location both in TTF and OS in regorafenib (p < 0.05). On the other hand, in TAS102, significant interactions were shown between period from 1st line chemotherapy and tumor location in TTF and between time to metastasis and tumor location in OS (p < 0.05). Conclusions: In contrast to front line chemotherapy, no clinical impact of tumor location was demonstrated at the salvage lines in mCRC.
Efficacy of bevacizumab in combination with doublet chemotherapy as first-line therapy in metastatic colorectal cancer according to KRAS status.
Authors: Murai Katsuyuki , Masuishi Toshiki , Taniguchi Hiroya , Hamauchi Satoshi , Sugiyama Keiji , Tsushima Takahiro , Mitani Seiichiro , Todaka Akiko , Honda Kazunori , Yokota Tomoya , Narita Yukiya , Machida Nozomu , Kadowaki Shigenori , Fukutomi Akira , Ura Takashi , Onozawa Yusuke , Ando Masashi , Yasui Hirofumi , Muro Kei , Yamazaki Kentaro
Published: March 2017

744

Background: Bevacizumab (BV) plus fluoropyrimidine-based chemotherapy is a standard treatment as first-line therapy for metastatic colorectal cancer (mCRC). In phase 3 studies, addition of BV to doublet chemotherapy significantly improved progression-free survival (PFS), otherwise overall survival (OS) differences didn’t reach statistical significance. There are only a few reports that assess the efficacy of BV containing chemotherapy according to KRAS status. Methods: We retrospectively reviewed the data of mCRC patients who received doublet chemotherapy (FOLFOX/CapeOX/SOX/FOLFIRI/IRIS) with or without BV as first-line therapy in Aichi Cancer Center or Shizuoka Cancer Center between Apr. 2007 and Aug. 2014. Patients fulfilled following criteria: histologically proven adenocarcinoma, ECOG PS 0-1, adequate organ functions. Exclusion criteria were as follows: KRAS status unknown, adjuvant chemotherapy within less than 6 months (M) before relapse, doublet chemotherapy with other biologics. We analyzed the efficacy of doublet chemotherapy with BV (Group A) and without BV (Group B), dividing into KRAS exon 2 wild type (WT) and mutant (MT). WT-A means Group A in WT. Results: Patients met the selection criteria were 578 (WT-A/WT-B 276/55, MT-A/MT-B 202/45). Patients’ backgrounds were as follows; median age (range) 63 (20-88) years old, male/female 60/40%, ECOG PS 0/1 66/34%, tumor location right colon/left colon and rectum 29/71%, number of metastases 1/ ≥ 2 48/52%, KRAS status WT/MT 57/43%. PFS in Group A/B was 13.0/8.4 m (HR 0.49, 95%CI 0.39-0.61, p < 0.0001), and OS was 32.4/27.1 m (HR 0.70, 95%CI 0.56-0.88, p = 0.0024). PFS was 12.7/8.5 m in WT-A/WT-B (HR 0.51, 95%CI 0.38-0.69, p < 0.0001), 14.5/8.0 m in MT-A/MT-B (HR 0.46, 95%CI 0.33-0.64, p < 0.0001). OS was 32.6/29.8 m in WT-A/WT-B (HR 0.85, 95%CI 0.62-1.17, p = 0.32), 31.7/25.8 m in MT-A/MT-B (HR 0.55, 95%CI 0.39-0.77, p = 0.0005), adjusted HR (variables: age, sex, ECOG PS, tumor location, et al) was 0.74 in WT (95%CI 0.53-1.05, p = 0.089), 0.69 in MT (95%CI 0.48-1.00, p = 0.047). Conclusions: Addition of BV to doublet chemotherapy as first-line therapy might prolong OS in patients with mCRC regardless of KRAS status.