bluuebunny/crossref_metadata_2025 huggingface dataset:
The clinical significance of simple endoscopic scoring of patients with rectal cancer after concurrent chemoradiotherapy.
Authors: Kim Jae Hyun , Park Seun Ja
Published: February 2020

109

Background: Neoadjuvant concurrent chemoradiotherapy (CCRT) is an effective treatment option for patients with rectal cancer. In this study, we investigated the clinical efficacy of simple endoscopic scoring of patients with rectal cancer after CCRT. Methods: Between July 2008 and October 2015, medical records including endoscopic imaging from 41 patients with rectal cancer who received CCRT were retrospectively reviewed. Two expert gastroenterologists reviewed the endoscopic images and assigned scores from 0–3 according to post-CCRT findings. The scoring criteria were as follows: 0 = scar without marginal elevation; 1 = clean-based ulcer without marginal elevation; 2 = clean-based ulcer with marginal elevation; 3 = non-clean-based ulcer. We evaluated image scores to predict long-term outcomes using Kaplan-Meier curves and Cox regression models. Results: The median follow-up duration was 55 months (interquartile range: 35–76). Patients with a low score (≤2) had a 17.2% recurrence rate, whereas patients with a high score (3) had a 50.0% recurrence rate. Patients with a low score had longer disease-free survival (DFS) than those with a high score in log-rank test (p = 0.026). In multivariate Cox regression analysis, a high score was a significant predictor of poor DFS in patients with rectal cancer after CCRT treatment (hazard ratio = 4.89, 95% confidence interval: 1.11–21.50, p = 0.036). Conclusions: This simple endoscopic scoring approach is helpful for predicting prognosis of patients with rectal cancer after treatment with CCRT.
PD-1 blockade combined with COX inhibitor in patients with MSI-H/dMMR or high TMB, advanced or metastatic colorectal cancer (PCOX study).
Authors: Wu Zehua , Hu Huabin , Zhang Jianwei , Cai Yue , Xie Xiaoyu , Ling Jiayu , Li Weiwei , Deng Yanhong
Published: February 2020

111

Background: MSI-H/dMMR and POLE mutation had been proven to be predictive of response to PD-1 blockade in metastatic colorectal cancer. However, reported response rates are often < 50%. Several preclinical studies reported COX inhibitor improve antigen presentation and T-cell infiltration in tumors. We investigated the efficacy of PD-1 blockade combined with COX inhibitor in colorectal cancer patients with MSI-H/dMMR or POLE mutation. Methods: PCOX was a prospective, single arm, phase II study. Patients with MSI-H/dMMR or POLE mutation advanced or metastatic colorectal cancer received PD-1 blockade (pembrolizumab 200mg, q3w; or BAT 1306 100mg, q3w; or nivolumab 3mg per kilogram, q2w) plus COX inhibitor (celebrex 400mg or aspirin 200mg, p.o. qd). The primary endpoint was ORR, secondary endpoints included PFS, OS and safety. Results: Totally 24 patients were enrolled. 14(58.3%) patients were female. Median age was 41.5-years-old. Among 24 patients, 5(20.8%) patients were chemotherapy-naïve, 11(45.8%) patients had first line chemotherapy failed and 8(33.3%) patients had at least second lines chemotherapy failed. 22 patients were MSI-H/dMMR and 2 patients were with POLE mutation. At a median follow-up of 14.5 months, the ORR was 83.3% (20/24), including 5 patients achieved CR (3 pCR and 2 cCR). 3 patients achieved SD and 1 patient was PD. Median PFS and OS was not yet reached. One-year PFS rates was 80.7% (95%CI, 63.5%-97.9%). One-year survival rates was 91.3% (95%CI, 79.7%-100%). The reported treatment-related adverse events were listed in table below. Conclusions: The combination of PD-1 blockade plus COX inhibitor was associated with higher response rates in advanced or metastatic colorectal cancer patients with MSI-H/dMMR or POLE mutation than anti-PD-1 alone as historical controls. Clinical trial information: NCT03638297.

[Table: see text][Table: see text]
The treatment strategy of the second-line chemotherapy for metastatic colorectal cancer (mCRC) patients (pts) with early progression in the first-line chemotherapy with bevacizumab (BEV), BEV beyond progression (BBP), or non-BBP.
Authors: Kawakami Takeshi , Yamamoto Shun , Mitani Seiichiro , Esaki Taito , Tsuji Yasushi , Izawa Naoki , Kawakami Kentaro , Yamamoto Yoshiyuki , Makiyama Akitaka , Yamazaki Kentaro , Masuishi Toshiki , Nakajima Takako Eguchi , Okuda Hiroyuki , Moriwaki Toshikazu , Boku Narikazu
Published: February 2020

113

Background: BBP has been recognized as one of the standard 2nd-line treatment strategy for pts with mCRC based on the ML18147 trial. However, this trial excluded pts with disease progression < 3 months in the 1st-line BEV-containing chemotherapy. Methods: The subjects were mCRC pts who received the 2nd-line chemotherapy after experiencing disease progression < 100 days in the 1st-line BEV-containing chemotherapy between Apr 2010 and Dec 2016. This multi-institutional retrospective study compared the efficacy and safety between the 2nd-line chemotherapy with BEV (BBP) and without BEV (non-BBP), adjusting ECOG PS, WBC, ALP, number of metastatic sites, RAS status, and sidedness using Cox proportional hazard model. Results: 61 pts were evaluated. Patients' backgrounds were numerically different between BBP (n = 36) and non-BBP (n = 25), such as PS (0-1/2≤/unknown: 89/8/3 and 56/40/4%) and RASstatus (wild/mutant/unknown: 28/56/16 and 76/16/8%). There were no significant differences in age (median: 59 and 57), sex (male/female: 53/47 and 32/68%), tumor location (right/left: 44/56 and 40/60%), disease status (stage IV/recurrence: 67/33 and 84/16%), number of metastatic sites (1/2≤: 33/67 and 20/80%), the 1st-line regimens (oxaliplatin-based/irinotecan-based: 83/17 and 96/4%) between two arms. The 2nd-line chemotherapy regimens with EGFR antibody-containing/cytotoxic alone were 64/36% in non-BBP, respectively. The response rates were 5.9 and 8.7% in BBP and non-BBP. Median PFS were 3.7 and 2.8 months (HR 0.83, 95%CI 0.49-1.41, p = 0.486; adjusted HR 0.97, 95%CI 0.48-1.96, p = 0.932), respectively. The proportions of pts who received subsequent chemotherapy were 58 and 32% (p = 0.068). Median OS were 7.6 and 5.4 months (HR 0.70, 95%CI 0.41-1.19, p = 0.193; adjusted HR 0.65, 95%CI 0.34-1.25, p = 0.195). Common grade 3-4 adverse events (AEs) were neutropenia (11/24%) and anemia (3/16%), and other AEs were similar between two arms. Conclusions: The 2nd-line chemotherapy for pts with early progression in the 1st-line BEV-containing chemotherapy showed poor outcomes regardless of strategy.
Efficacy and safety of regorafenib in combination with chemotherapy as second-line therapy in patients with metastatic colorectal cancer: A network meta-analysis.
Authors: Xie Xiaoyu , Zhang Jianwei , Hu Huabin , Cai Yue , Wu Zehua , Ling Jiayu , Li Weiwei , Deng Yanhong
Published: February 2020

115

Background: Recent studies have shown efficacy of chemotherapy (CTX) in combination with different biological agents including regorafenib (REG) in second-line treatment of metastatic colorectal cancer (mCRC). As there is no evidence on the relative efficacy and safety of REG as compared to other biological agents in combination with CTX, we evaluated the same in this network meta-analysis (NMA). Methods: Randomized controlled trials (RCTs) comparing efficacy and safety of biological agents + CTX against CTX alone as second-line treatment of mCRC were retrieved from PubMed, EMBASE and Cochrane databases. Progression free survival (PFS) was the primary outcome, while objective response rate (ORR), overall survival (OS) and safety were secondary outcomes. Outcomes were compared by random/mixed-effects NMA using Bayesian (R software, Gemtc package) and frequentist (R software, netmeta package) approaches. Results: Twelve RCTs comparing 9 different treatment regimens with a total of 6805 patients were included for analysis. Hazard ratios (HR)/ odds ratio (OR)/ relative risk (RR) and 95% confidence intervals (CI) for PFS, ORR and grade> 3 adverse events (AE) of selected comparisons from the results of the NMA are shown in table. Conclusions: REG combined with CTX might be a potential alternative to conventional therapeutic options and could be considered as the best option for treating KRAS and BRAF mutated mCRC patients. Future RCTs are needed to confirm our results.

[Table: see text]
Regorafenib dose escalation therapy for patients with refractory metastatic colorectal cancer (RECC Study).
Authors: Nakamura Masato , Yamada Takeshi , Ishiyama Shun , Enomoto Masanobu , Yokomizo Hajime , Kosugi Chihiro , Sonoda Hiromichi , Ishimaru Kei , Ishibashi Keiichiro , Kuramochi Hidekazu , Nozawa Keijiro , Ohta Ryo , Takahashi Makoto , Yoshida Hiroshi , Hashiguchi Yojiro , Hirata Keiji , Katsumata Kenji , Ishida Hideyuki , Koda Keiji , Sakamoto Kazuhiro ,   RECC Study Group
Published: February 2020

116

Background: Regorafenib, a multi-kinase inhibitor, significantly improved overall survival in previously treated metastatic colorectal cancer (mCRC) patients in the phase 3 CORRECT trial. Despite its significant benefits, various toxicities such as hand-foot skin reaction (HFSR), fatigue, and liver dysfunction have limited regorafenib use. The toxicities occur soon after treatment initiation, typically within the first cycle, and later improve. Although the standard daily dose of regorafenib is 160 mg, physicians have adopted various dosing regimens in clinical practice, indicating the need to optimize the dosing strategy to maintain the antitumor benefits. The ReDOS study demonstrated the effectiveness of a weekly dose-escalating strategy (WDES) of regorafenib starting with a lower daily dose. We conducted the phase II RECC study to evaluate the safety and efficacy of WDES for regorafenib in an Asian population. Methods: Patients with sufficient organ function who had previously received more than two lines of chemotherapy were included. Regorafenib was started at 80 mg/day and escalated to 120 mg/day in Week 2 and 160 mg/day in Week 3 if no severe drug-related toxicities were observed. The primary endpoint was progression-free survival (PFS) and secondary endpoints were time to treatment failure (TTF), response rate (RR), overall survival (OS), and safety. Tumor response and progression were assessed radiologically every 8 weeks. Results: From March 2017 to November 2018, 57 eligible patients were enrolled and all started regorafenib at 80 mg/day. Thirty-five patients (61%) were subsequently escalated to 120 mg/day and 16 (28%) to 160 mg/day. Forty patients (70.2%) finished Cycle 2 at 8 weeks. Only 8 patients (14%) discontinued treatment because of adverse events. The median PFS was 1.9 months, RR was 0%, and disease control rate was 32%. The most frequent adverse event ≥grade 3 was hypertension (17.5%), followed by HFSR (14%). No treatment-related deaths occurred. Conclusions: Regorafenib dose escalation was well tolerated with PFS similar to that reported in the CORRECT study, indicating that WDES may represent an option for regorafenib administration. Clinical trial information: UMIN000028933.
Benefit of oxaliplatin in stage III colon cancer according to IDEA risk groups: Analysis of MOSAIC and C-07 trials.
Authors: Margalit Ofer , Boursi Ben , Rakez Manel , André Thierry , Yothers Greg , Wolmark Norman , Shmueli Einat Shacham , De Gramont Aimery
Published: February 2020

118

Background: The IDEA pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. The overarching goal was to reduce chemotherapy-related toxicity, mainly oxaliplatin-induced neuropathy. Patients were classified into low-risk and high-risk, suggesting low-risk patients may be offered only 3 months of treatment. In our previously published analysis using retrospective data from the National Cancer Database (NCDB) we showed similar benefit for oxaliplatin in both low and high IDEA risk groups. In the current study, we aimed to test our hypothesis using data from the two large clinical trials assessing the benefit of oxaliplatin in the adjuvant setting, namely, MOSAIC and C-07. Methods: Using the MOSAIC and C-07 previously published studies, we identified 1,754 low-risk and 1,302 high-risk individuals with stage III colon cancer, according to the IDEA classification. We used multivariate COX regression to evaluate the magnitude of survival differences between IDEA risk groups, according to oxaliplatin use. The analysis was adjusted for age, primary tumor sidedness, tumor stage, tumor grade and lymph node ratio. Results: Individuals with IDEA low-risk derived overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted hazard ratios (HRs) of 0.78 (0.65-0.94), 0.75 (0.63-0.89) and 0.74 (0.62-0.90). Similarly, individuals with IDEA high-risk derived OS, DFS and RFS benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted HRs of 0.84 (0.71-0.99), 0.81 (0.69-0.95) and 0.82 (0.69-0.97). Conclusions: IDEA risk classification per se does not predict benefit from addition of oxaliplatin to adjuvant chemotherapy in stage III colon cancer, according to analysis of the MOSAIC and C-07 studies. Funding: NCI U10CA-180868, NCI U10CA-180822.
Final results of multicenter phase Ib/ II study of biweekly trifluridine/tipiracil with bevacizumab combination for patients with mCRC refractory to standard therapies (BiTS study).
Authors: Nakamura Masato , Satake Hironaga , Oba Koji , Kotaka Masahito , Kagawa Yoshinori , Yasui Hisateru , Watanabe Takanori , Matsumoto Toshihiko , Kii Takayuki , Terazawa Tetsuji , Makiyama Akitaka , Takano Nao , Yokota Mitsuru , Okita Yoshihiro , Matoba Koreatsu , Hasegawa Hiroko , Tsuji Akihito , Nagata Naoki , Sakamoto Junichi , Kato Takeshi
Published: February 2020

121

Background: We have conducted the multicenter, phase Ib/II study to assess the activity and safety of biweekly Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) combination for pts with metastatic colorectal cancer (mCRC) who were refractory or intolerant to standard therapies, and the primary endpoint of investigator assessed progression-free survival rate at 16 weeks (16w-PFS) was met [Kotaka M, ASCO-GI 2018]. We show longer follow-up data from this prospective study. Methods: Patients with unresectable mCRC; refractory or intolerant to standard chemotherapies were enrolled. Phase Ib part is designed to determine the recommended phase II dose (RP2D), and the treatment was determined as biweekly FTD/TPI (70mg/m2/day on day 1-5, every 2 weeks) with BEV (5mg/kg, every 2 weeks). The primary endpoint in phase II part was a 16w-PFS with a hypothesis of 15% considered unacceptable and 38.7% deemed promising. Given a one-sided α of 0.025 and statistical power of 90%, a minimum of 40 pts were required for phase II part. This trial registered in University Hospital Medical Information Network, number UMIN000029198. Results: From October 2017 to January 2018, totally 46 pts were enrolled. Nine patients (20.5 %) received regorafenib before enrollment. Of the 44 eligible pts, 16w-PFS rate was 40.9 %. With a median follow up of 15.36 months (range, 2.79-16.93), median PFS was 4.29 months (95% CI: 2.54 to 5.83), median TTF was 4.16 months (95% CI: 2.39 to 5.82), and median OS was 10.86 months (95% CI:8.32 to 13.68), respectively. Disease control rate was 59.1 % (95%CI: 43.3 to 73.7 %). Patients received the study treatment for a median of 6.5 cycles (range, 1 to 24). The median relative dose intensity of FTD/TPI and BEV was 80.9% (range: 44.0 to 100%), 81.5% (range: 50.0 to 100%), respectively. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (11.4 %) and leucopenia (11.4 %). Conclusions: An update analysis confirmed that biweekly FTD/TPI plus BEV showed promising anti-tumor effect with acceptable less toxicities, and might be one of the treatment options for patients with heavily treated mCRC. Clinical trial information: UMIN000029198.
Efficacy and safety of the combination of aflibercept with fluorouracil, leucovorin, and irinotecan in patients aged 70 years and older with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen in Spain: A retrospective multicenter cohort study.
Authors: Gutiérrez Sainz Laura , Martínez-Recio Sergio , Higuera Oliver , Ghanem Ismael , López-Alfonso Ana , Pérez Mar , Jimenez-Gordo Ana M. , Lopez-Gomez Miriam , Molina Raquel , Ibeas Patricia , Feliu Jaime , Rodriguez-Salas Nuria
Published: February 2020

124

Background: Colorectal cancer is currently the third most common cancer worldwide. The results of the VELOUR study showed that the addition of aflibercept to Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) produced an advantage in both progression-free and overall survival (PFS and OS) in patients with metastatic colorectal cancer (mCRC) previously treated with an oxaliplatin-based regimen. The purpose of this study was to evaluate the efficacy and safety of the combination of aflibercept with FOLFIRI in patients aged 70 years and older with mCRC. Methods: We conducted a retrospective multicenter study, which included all patients aged 70 years and older with mCRC treated with Aflibercept plus FOLFIRI between May 2013 and March 2019 in 5 centers in Spain. Data regarding clinical and pathological characteristics, treatment response and survival were collected. Results: We selected 69 patients, of whom the majority (n = 48, 69.6%) were males with a median age of 75 years (range 70 to 84 years). Patients received an average of nine courses of aflibercept with FOLFIRI overall. Regarding response rates, 17 patients (24.6%) achieved a partial response, 37 (53.6%) had stable disease and 15 (21.7%) experienced disease progression. The median PFS was 6.1 months (CI 95%: 4.4–7.8), and the median OS was 13.9 months (CI 95%: 11.1–16.7). Treatment adverse events grade 3 and 4 were reported in 42 patients (60.9%). The most frequently reported treatment adverse events grade 3 and 4 were asthenia (24.6%), diarrhea (18.8%), stomatitis and ulceration (18.8%) and neutropenia (14.5%). Adverse events grade 3 and 4 typically associated with anti-VEGF therapy were infrequent. Adverse events led to permanent discontinuation of treatment in 26.1% of patients. Conclusions: In our sample the combination of aflibercept with FOLFIRI in patients aged 70 years and older with mCRC was effective and safe. Aflibercept plus FOLFIRI is a good therapeutic option for the treatment of mCRC in patients aged 70 years and older previously treated with oxaliplatin.
Phase I study of preoperative capecitabine and lenvatinib with external radiation therapy in locally advanced rectal adenocarcinoma.
Authors: Tandon Ankita , Frakes Jessica , Mehta Rutika , Hoffe Sarah E. , Martinez Jimenez Maria E , Imanirad Iman , Sanchez Julian , Malafa Mokenge Peter , Felder Seth , Dessureault Sophie , Kim Richard D.
Published: February 2020

125

Background: Neoadjuvant chemo-radiation is a standard of care for locally advanced rectal cancer. Patients with pathologic complete response (pCR) have improved outcomes with less local and systemic failure. Dual targeting with platelet derived growth factor (PDGF) and vascular endothelial growth factor receptor (VEGFR) in combination with radiation can escalate tumor response with radiation. Lenvatinib is an oral multi-kinase inhibitor and had shown potent anti-tumor activity in xenograft models cultured with human colorectal cancer (CRC) lines. Methods: Patients with stage II or III rectal cancer, confirmed by endoscopic ultrasound or MRI, were recruited in 3 cohorts of 3 patients per dose level, with an expansion cohort at the MTD. Lenvatinib oral daily dose started at 14 mg (cohort 1) and was escalated to 20 mg (cohort 2) followed by 24 mg (cohort 3). In this 3+3 design, patients received dose escalation of lenvatinib with standard doses of capecitabine (850 mg/m2 PO BID) concurrent with external beam radiation on days 1-5 weekly for 28 treatments. Following completion patients underwent surgery in 6-10 weeks. Results: Twenty patients with median age of 55 were enrolled in 3 cohorts (1 patient was ineligible). There were no dose limiting toxicity at the maximum tested dose of lenvatinib (24 mg). Two patients are still awaiting surgery. 12 patients have undergone low anterior resection and 5 patients have had abdominoperineal resection. Therefore, out of 17 patients, 29.4% (5/17) showed pCR, and downstaging was observed in 71% of the patients (12/17). The mean neoadjuvant rectal cancer score (NAR) was 11.4 and median NAR was 8.43. Six patients had grade 3 adverse events (AEs) (1 rectal pain,1 transaminitis, 2 lymphopenia, 1 HTN, 1 with both leukocytosis and hyponatremia). No grade 4 AEs were noted. Most common AEs were hypertension, rectal pain, nausea, diarrhea, fatigue and dermatitis. No peri operative complications were observed. Conclusions: The study shows that the combination of lenvatinib and capecitabine with radiation is well tolerated in locally advanced rectal cancer with promising mean NAR score. The encouraging results will need to be validated in a randomized study. Clinical trial information: NCT02935309.
Clinical significance of neutrophil-lymphocyte ratio to the patients with locally advanced rectal cancer who received preoperative chemoradiation therapy.
Authors: Lee Joo Hwan , Lee Jong Hoon , Kim Sung Hwan , Lee Hyo Chun
Published: February 2020

138

Background: Preoperative chemoradiation therapy (CRT) and total mesorectal excision have been the standard care of the patients with locally advanced rectal cancer. Response to the preop CRT varied from patient to patient, approximately 10-15% of the patients achieved complete response, on the contrary, nearly 40% of the patients still showed ypT4 disease. The aim of this study is to assess the prognostic value of NLR and suggest the optimal cut-off value to predict tumor response to the preoperative chemoradiation therapy in the patients with locally advanced rectal cancer. Methods: We analyzed the medical records of 1134 patients who diagnosed with locally advanced rectal cancer and treated with preop CRT followed by radical surgery at St. Vincent hospital, Seoul St. Mary’s hospital, Chonnam National University Hwasun Hospital, Gyeongsang National University Hospital and Dongsan Medical Center from 1998 to 2015. All patients had histologically confirmed rectal adenocarcinoma within 10 cm from anal verge. All patients received preoperative CRT to the pelvis followed by TME. Complete blood count was performed at initial workup before treatment and NLR was calculated with differential count. Results: An optimal cut-off value of the NLR was revealed as 1.98. The NLR showed average value for predicting death (AUC 0.516, p < 0.001). According to the cut-off value, patients were divided into two groups; high NLR (NLR≥2.0, n = 530) and low NLR (NLR < 2.0, n = 604). The patients with low NLR achieved pathologic complete response more frequently. 105 patients of total 604 patients (17.4%) with low NLR showed no remnant tumor cells, compared to 63 patients of the 530 patients (11.9%) with high NLR did (p = 0.012). The proportion of the patients who were downstaged to T1-2N0 was evaluated. In the low NLR group, 258 patients (42.7%) were downstaged, while 199 patients (37.5%) in the high NLR group were, which showed a tendency but did not reach statistical significance (p = 0.087). Conclusions: In this large-scale multi-center analysis, NLR was once again identified as a predictor of treatment response of preop CRT in patients with locally advanced rectal cancer.
A computed tomography-based nomogram for preoperative prediction of synchronous peritoneal carcinomatosis in colorectal cancer.
Authors: Yuan Zixu , Cao Wuteng , Wang Hui , Cai Jian , Wu Lei , Qin Xiusen
Published: February 2020

14

Background: Peritoneal carcinomatosis (PC) of colorectal cancer remain poor and is considered to be the terminal stage. Early detection of PC can bring survival benefit for chances of complete cytoreductive surgery. In this study, we have developed and validated a CT-based nomogram for preoperative prediction of synchronous PC in CRC. Methods: The CT-based nomogram optimized for image classification of PC was developed and validated in a large cohort. The specific features of synchronous PC were extracted from preoperative CT arterial stage scans by radiologists. A CT-based model was constructed by Boruta algorithm and multivariate logistic regression in the training set and validated in the test set. A CT-based nomogram was then built to predict the risk value of PC. The performance and efficacy of this nomogram to discriminate PC were assessed. Results: A total of 170 eligible CRC patients with synchronous PC were randomly divided into a training set (n = 92) and a validation set (n = 78). After processing and partition, five items of PC-related features including tumor location, cT stage, distant metastasis, thickened greater omentum and pelvic nodules were enrolled into this CT-based model. In the training set, the ROC shows AUC of CT-based model was 0.929(95% CI: 0.764-0.946). The sensitivity was 73.2% and the specificity was 98.3%. The positive predictive value (PPV) was 82.26%, while the negative predictive value (NPV) was 100%. In the test set, AUC by the ROC was 0.855(95% CI: 0.764-0.946). The sensitivity of CT-based model was 72.7% and the specificity was 93.3%. The PPV was 82.35%, while the NPV was 88.89%. These results show high predicted accuracy of CT-based model in diagnosis of synchronous PC both in the training set and test set. A nomogram based on these five preoperative predictors of PC was created. This CT-based nomogram showed good diagnostic performance by calibration curve. The decision curves analysis revealed high benefit of this CT-based nomogram in clinical decision. Conclusions: The CT-based nomogram has shown great potential in the detection and diagnosis of synchronous peritoneal metastasis in colorectal cancer.
Safety and efficacy of radiofrequency ablation for pulmonary metastases in metastatic colorectal cancer patients: A single center experience.
Authors: Koo Dong-Hoe , Hong Hyun Pyo , Oh Sukjoong , Lee Yun-Gyoo , Kang Kyung A. , Kwon Heon-Ju , Kim Mi Sung , Ham Soo Youn , Lee Hyebin , Jung Kyung Uk , Kim Hyung Ook , Kim Hungdai , Chun Ho-Kyung , Kang Du-Young , Oh Tae Yun
Published: February 2020

141

Background: Radiofrequency ablation (RFA) has been increasingly used for the treatment of pulmonary metastases from several types of malignancies. Methods: A retrospective analysis was performed for the safety and efficacy of percutaneous RFA in patients with metastatic colorectal cancer between October 2016 and June 2019 as well as assessing prognostic factors of local tumor control. Results: RFA was carried out for 48 lung metastases in 31 consecutive colorectal cancer patients. Male was 17 patients (55%), and the median age at RFA was 61 years (range, 42-81). The mean diameter of metastases targeted for RFA was 12 mm (range, 4-32), and 17 tumors (35%) were located in a sub-pleural or deep position. Although five cases (10%) were failed due to immediate complications, there was no procedure-related death. In terms of immediate complication, a total of 12 cases (25%) had events including nine pneumothorax (percutaneous drain in four), one pleural effusion, and two hemoptysis (ICU care in one). Delayed complications were lung abscess and diaphragm injury in each one patient, respectively. At the time of analysis, the median follow-up duration from RFA was 12.0 months (interquartile range, 6.5-23.1). Only two patients (6%) died of disease progression, and 3-year overall survival rate was 85.5% (95% CI, 75.5-95.5). RFA site progression was observed in 11 patients (23%), and 1-year and 2-year progression-free survival rates were 71.5% (95% CI, 58.7-84.3) and 56.6% (95% CI, 42.6-70.6), respectively. Multivariate analysis showed that extra-pulmonary progression (hazard ratio 17.49; p = 0.023) was only one independent prognostic factor associated with RFA site progression after adjusting for confounding factors including sex, age, performance, tumor size, location, contact with the vessel, last chemotherapy response, and duration. Conclusions: RFA is a comparatively safe and effective option for the treatment of small-sized lung metastases; however, the control of extra-pulmonary metastases should be accompanied for effective local control.
Comparison of doublet chemotherapy with monotherapy for vulnerable advanced colorectal cancer patients.
Authors: Furuta Mitsuhiro , Yamazaki Kentaro , Kawakami Takeshi , Shirasu Hiromichi , Tsushima Takahiro , Machida Nozomu , Hamauchi Satoshi , Yokota Tomoya , Todaka Akiko , Fukutomi Akira , Onozawa Yusuke , Yasui Hirofumi
Published: February 2020

143

Background: The efficacy of doublet chemotherapy (fluoropyrimidine + oxaliplatin/irinotecan) for vulnerable colorectal cancer patients is controversial. Some prospective trials have not shown the benefit of doublet chemotherapy for vulnerable patients compared to fluoropyrimidine monotherapy. On the other hand, one trial did show an advantage for doublet chemotherapy in PFS. Moreover, although these trials are designed for vulnerable patients, inclusion was limited by trial criteria, and patient conditions might have been better than those of vulnerable patients in clinical practice. Therefore, the advantage of doublet chemotherapy over monotherapy for vulnerable patients in clinical practice remains unclear. Chemotherapy toxicity and frailty are increased in high modified Glasgow score (mGPS = 2) patients. Therefore, we examined the efficacy of doublet chemotherapy for vulnerable patients, using mGPS. Methods: We retrospectively examined vulnerable advanced colorectal cancer patients who received monotherapy (n = 52) or doublet chemotherapy (n = 195) as 1st line treatment between 2005 and 2016. We defined vulnerable as fulfilling one of the following conditions; age ≥75, ECOG PS = 2, or mGPS = 2. Results: Patient characteristics in the monotherapy group vs the doublet group were as follows; median age (range), 80 (63-88) vs 66 (29-87); gender male/female, 28/24 vs 111/84; ECOG PS 0/1/2, 15/25/12 vs 76/79/40; mGPS = 2, 13 (25%) vs 134 (68%); median metastatic sites (range), 1 (1-3) vs 2 (1-5); presence of ascites, 9 (17%) vs 59 (30%), primary tumor location left, 35 (67%) vs 125 (64%); KRAS mutation 18 (35%) vs 52 (27%); bevacizumab/anti-EGFR antibody, 30/0 vs 79/19. The median PFS was 6.9 months in the monotherapy group and 7.7 months in the doublet group (HR = 1.129, p = 0.480). The median OS was 13.3 months in the monotherapy group and 14.8 months in the doublet group (HR = 0.999, p = 0.994). Multivariate analysis did not show the benefit of doublet chemotherapy in PFS (HR = 0.908, p = 0.615) or OS (HR = 0.764, p = 0.176). Conclusions: This study suggests that doublet chemotherapy may not be beneficial for vulnerable advanced colorectal cancer patients in clinical practice.
Pilot study of the safety and feasibility of immediate adjuvant chemotherapy (IAC) in nonmetastatic colonic adenocarcinoma (nmCC).
Authors: Jafari Mehraneh D. , Sujatha-Bhaskar Sarath , Brady Mathew , Mills Steven D. , Carmichael Joseph C. , Dayyani Farshid , Lee Fa Chyi , Zell Jason A. , Pigazzi Alessio
Published: February 2020

150

Background: The optimal timing of adjuvant chemotherapy (AC) in nmCC is poorly defined. Delays in AC result in decreased survivalbut fear of postoperative complications often causes long intervals between surgery and AC initiation. Given the transient immune suppression, inflammatory changes and increase in circulating tumor cells occurring in the perioperative period, effective cytotoxic treatments should be considered at this time to limit metastatic spread. The immediate adjuvant chemotherapy concept intends to capitalize on the therapeutic benefits that can be achieved in the perioperative period (intraoperative and early postoperative). We aim to demonstrate that IAC is safe and tolerable for patients with nmCC. Methods: Patients with nmCC microsatellite stable invasive adenocarcinomas were treated with intravenous Leucovorin 20mg/m2 followed by a single dose of 5-Flurouracil 400mg/m2 at the time of minimally invasive surgical resection. High risk stage II and stage III received the first dose of standard AC at 14 days after surgery. Serial measurements of blood-based biomarkers (circulating tumor cells, cell free DNA, and neutrophil lymphocyte ratio were measured. Quality of life (QOL) was measured using EORTC QLQ-C30. Results: Of the 20 patients recruited, 40% had final pathology of stage III, 40% stage II and 20% stage I. All patients received intra-operative chemotherapy with no associated morbidity. Median length of stay was 2 days (range of 2-4). Grade 1 complications were reported in 2 (10%) of patients. No grade 2 or higher adverse events were reported. There was no mortality. Early postoperative AC was administered to 65% of patients. The median time to AC was 14 days (range 14-36). Overall quality of life and health scores were similar before surgery and at 30-day postoperatively (p < 0.05). Conclusions: A protocol based on immediate adjuvant chemotherapy starting at the time of surgical resection was found to be safe and feasible in nmCC with no adverse effects on surgical morbidity or quality of life. Further prospective studies are needed to explore the oncologic benefit of this novel systemic treatment approach.
Long-term oncologic safety of self-expandable metal stent as a bridge to surgery for malignant colorectal obstruction: Our experience.
Authors: Jang Se Hyun , Keum Bora , Kim Sanghyun , Lee Kang Won , Jeon Han Jo , Kim Sang Hoon , Choi Seong Ji , Lee Jae Min , Choi Hyuk Soon , Kim Eun Sun , Jeen Yoon Tae , Lee Hong Sik , Chun Hoon Jai , Kim Chang Duck
Published: February 2020

153

Background: About 10-25% patients of colorectal cancer suffer from acute colonic obstruction. Traditional management of acute malignant bowel obstruction has focused on emergency resection but showed high mortality and morbidity rates. Recently, placement of a self-expanding metal stent(SEMS) was widely used and SEMS seems to be as a safe and effective “bridge to surgery” and to offer good palliation. But there is concern about long-term survival after the use of SEMS. Theoretically, tumor cell seeding can occur due to mechanical force during the stent insertion. To identify this theoretical validity, we surveyed long-term survival of malignant colonic obstruction using SEMS placement. Methods: This retrospective study included 303 patients who presented in Korea University Anam Hospital between 2006 and 2014 with obstructing CRC, and underwent surgical resection. Patients were devided into two group: the “SEMS” group included 148 patients who underwent endoscopic stent as a bridge to surgery, and the surgery group included 155 patients who underwent emergency or elective surgery without stenting. In addition, candidates for curative resection were identified (98 patients in “SEMS” group vs 101 patients in “surgery” group). The clinicopathologic characteristics, overall survival(OS), and recurrence-free survival (RFS) were compared between the two groups. Results: There was no significant difference in demographics, tumor stage between the two group. The median follow-up times were 48.5 months (IQR, 19.1-73.1 months) for the SEMS group and 39.4 months (IQR, 15.1-39.4 months) for the surgery group. There was no significant difference in 5-year OS rate between two groups (59.6% vs 56.8%; p = 0.3). The 5-year RFS rate did not significantly differ between two groups (71.0% vs. 61.3%; p = 0.221). The long-term oncologic safety did not significantly differ between two groups in either the 5-year OS rate (79.5% vs 74.5%; P= 0.6). or the 5-year RFS rate (95.8% vs 95.8%; P = 0.3). Conclusions: SEMS as bridge to surgery in obstructive CRC did not worsen the long-term oncologic outcomes compared to those of the primary surgery.
The impact of biologic agents in patients with metastatic colorectal cancer by race/ethnicity.
Authors: Tolu Seda Serra , Chergui Adel , Rao Devika , Kaumaya Meghan , Acuna-Villaorduna Ana , Kaubisch Andreas , Chuy Jennifer W. , Rajdev Lakshmi , Elrafei Tarek N. , Goel Sanjay
Published: February 2020

156

Background: Biologic agents have shown to improve overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, minority racial/ethnic groups were underrepresented in clinical trials. A retrospective study in a racially-diverse population diagnosed between 2000 - 2011, done by our group, reported a survival benefit with biologics; but, a subgroup analysis suggested that it was restricted to Non-Hispanic whites (NHW) only. This study aims to compare OS in patients with mCRC treated with chemotherapy and biologic agents (CBT) among racial/ethnic groups. Methods: Patients diagnosed with mCRC between 2012-2018 and treated with CBT at 3 cancer centers in the Bronx, NY were identified. Clinical data was collected by retrospective review for demographics (age at metastasis, gender and race/ethnicity categorized as Non-hispanic Black (NHB), NHW or Hispanic), pathological/ treatment characteristics (tumor grade, primary location, chemotherapy regimen, biologic agent). Cases without available race/ethnicity were excluded. OS was measured as time from mCRC diagnosis to death (verified from the National Death Index) and was compared among racial/ethnic groups using Kaplan-Meier curves. Results: A total of 278 patients; of whom 84 (42.4%) were Hispanic, 70 (35.4%) NHB and 44 (22.2%) NHW were included. The median age at diagnosis was 60 years and did not differ among racial/ethnic groups (62.5 vs 55.5 vs 56 years, p=0.07). There was a female predominance in NHB and Hispanics. Bevacizumab was more frequently used in Hispanics and NHB compared to NHW (95.2% vs. 92.9% vs. 77.3%, p=0.003, respectively). There were no differences in the frequency of cetuximab and panitumumab use. Median OS did not differ by racial/ethnic groups (21 in NHW vs. 22.8 in Hispanics and 28.6 months in NHB, p=0.40). Conclusions: Minority groups attain a similar survival benefit from the addition of biologics compared to NHW. Population-based studies are required to confirm these results.
The impact of mismatch repair status to the preoperative staging of local colon cancer: Implications for clinical management.
Authors: Hansen Torben , Erbs Emilie , Trabjerg Natacha D. , Rafaelsen Soeren Rafael , Lindebjerg Jan , Jensen Lars Henrik
Published: February 2020

16

Background: Computed tomography (CT) scan is standard in preoperative local staging of colon cancer. Tumours with a deficient mismatch repair (dMMR) system are characterised by unique clinical and pathophysiologic aspects that may impact on the accuracy of the preoperative CT staging. Methods: Data from the Danish Colorectal Cancer Group national clinical database addressing a cohort of patients operated for stage I-III colon cancer in 2010-15 was analysed. The analyses of MMR status had been conducted consecutively through means of immunohistochemistry. All CT scans were blindly assessed by a certified radiologist. Results: Data from 590 patients, operated at a specialised cancer centre were available for analyses. A dMMR phenotype was detected in 135 (22.9%) of the patients. The overall correlation of the clinical and pathological T-category was significant for both groups. There was inferior correlation between cN and pN (p > 0.05) in pMMR cancers with a higher degree of over-staging assessed by CT-scan, compared to a significant correlation between cN and pN stage in pMMR cancers (p < 0.01). Of the 91 dMMR tumours judged node-positive by the preoperative CT scan, 59 (64.8%) showed no sign of metastatic involvement at the postoperative assessment. Conclusions: The accuracy of preoperative CT lymph node staging in colon cancer seems to differ depending on MMR status and may impact the clinical management including the neoadjuvant setting.
Quantification of immune response after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer.
Authors: Kamp William M. , Park Hong-Jai , Slovak Ryan J. , Ludwig Johannes M. , Kang Insoo , Kim Hyun S.
Published: February 2020

160

Background: Checkpoint inhibitors have demonstrated significant clinical impact in colorectal cancer with deficient mismatch repair (MMR) and high microsatellite instability. However, most patients have disease with stable microsatellites and typically respond poorly to most immunotherapies. The purpose of this study was to quantify the immune responses induced by mono versus dual immune checkpoint blockade (DICB) in a MMR proficient model of colorectal cancer. Methods: A MMR proficient model of colorectal cancer was established in 30 BALB/c mice via bilateral subcutaneous flank injections of 0.5x106 CT26.WT murine colorectal cancer cells (CRL- 2638; ATCC, Manassas, VA). Mice were assigned to receive either sham antibodies (InVivoMAb IgG controls), monotherapy with anti-PD-1 antibodies (Clone J43; BioXcell, West Lebanon, NH, USA), or DICB with anti-PD-1 and anti-CTLA-1 antibodies (Clone 9D9; BioXcell). Tumor growth was monitored over time and mice were sacrificed at either 7 or 14 days post-treatment. Single cell suspensions of harvested tumors and spleens were analyzed using FACS. The number of CD8+ and CD4+ T cells as well as the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3 was quantified in each sample. Results: DICB was associated with a reduction in tumor volume as compared to either mono PD-1 inhibition or control (p < 0.05). Neither monotherapy nor DICB significantly affected tumor infiltration by lymphocytes. Tumor infiltrating CD8+ T cells in the DICB treatment group demonstrated less expression of PD-1 and LAG3 compared to the control and monotherapy groups (PD-1: 1723±90.5 [Mean fluorescence intensity ± SEM] vs 2489±119.9 & 2404±117.9; p < 0.05) (LAG3: 453.8±21.58 vs 664.1±53.21 & 719.7±14.25; p < 0.05). The DICB group also showed increased expression of TIM3 (11,779±1271 vs 2832±380.9 & 4081±426.6; p < 0.05). Conclusions: These results suggest dual therapy with anti-CTLA and anti-PD-1 antibodies inhibits the growth of stable microsatellite colorectal cancer by suppressing key immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism that could be a target for future combination immunotherapies.
A single-arm, phase II study of intrahepatic chemotherapy in patients with unresectable colorectal liver metastases.
Authors: Besel Kate Elenna , Ko Yoo-Joung , Karanicolas Paul Jack , Kim Christina Yiyoung
Published: February 2020

162

Background: In Canada, the standard of care for patients with unresectable colorectal liver metastases (uCRLM) is systemic chemotherapy and/or best supportive care. Intrahepatic chemotherapy using floxuridine (FUDR), in addition to systemic chemotherapy, is available in the United States but its adoption outside major centers has been limited. Methods: A single-center, prospective study of intrahepatic chemotherapy for the treatment of patients with uCRLM was initiated at Sunnybrook Health Sciences Centre in 2014. Patients underwent implantation of a hepatic infusion pump with resection of their primary tumor (if in place). Patients were treated with FUDR in addition to systemic chemotherapy (FOLFIRI or FOLFOX). Study objectives include the rate of conversion to complete resection, time to progression (TTP), disease-free survival (DFS), time to progression in liver, overall survival (OS), andresponse rate (RR). Results: From 2014 to present, 46 patients have been enrolled. Median age at the time of HAIP placement was 51 years (30-72 years). Males accounted for 61% (28/46). All patients received at least one cycle of systemic chemotherapy prior to surgery. 44 patients received a minimum of one cycle of FUDR, with the median number of cycles of FUDR received being 7.5 (0-28 cycles). Only one patient was unable to receive any FUDR after surgery. Response rate was 80% (n = 37/46). Three patients are too early for assessment. Eight (17.4%) patients have undergone liver resection. Median number of cycles of FUDR prior to resection was 7 (4-13 cycles). TTP, DFS, time to progression in liver, OS, and safety will be presented. Conclusions: The addition of intrahepatic chemotherapy to best systemic therapy may provide an increase in the rate of conversion to complete hepatic resection in patients with uCRLM. Clinical trial information: ON1233.
Lateral lymph node dissection after neoadjuvant (chemo)radiotherapy may improve oncological outcomes in Western patients with low rectal cancer.
Authors: Kroon Hidde Maarten , Malakorn Songphol , Dudi-Venkata Nagendra N , Bedrikovetski Sergei , Liu Jianliang , Bednarski Brian K. , Ogura Atsushi , Van De Velde Cornelis J. H. , Rutten Harm , Beets Geerard , Thomas Michelle , Kusters Miranda , Chang George J. , Sammour Tarik
Published: February 2020

163

Background: In the West, rectal cancer patients with pre-treatment abnormal lateral lymph nodes (LLN) are commonly treated with neoadjuvant (chemo)radiotherapy (n(C)RT) followed by total mesorectal excision (TME). Few centers perform lateral lymph node dissection (LLND) in addition to this, with the aim of improving oncological outcomes. To date, no comparative data are available in Western patients. Methods: An international multi-center cohort study was conducted comparing six centers from the Netherlands and Australia treating patients with abnormal LLN (≥5mm short-axis) with n(C)RT and TME (LLND- group) versus similarly staged patients from a dedicated cancer center in the USA who underwent a LLND in addition to n(C)RT and TME (LLND+ group). Results: Data were available on 169 patients. LLND+ patients (n = 44) consisted of significantly younger and more female patients with higher ASA-scores and ypN-stages compared to LLND- patients (n = 115). LLND+ patients also had a larger median LLN short-axis and were more likely to receive adjuvant chemotherapy (100 vs. 30%; p < 0.0001). Between groups, the lateral local recurrence rate (LLRR) was 0% for LLND+ vs. 7% for LLND- (p = 0.09) and the local recurrence rate (LRR) was 3% for LLND+ vs. 11% for LLND- (p = 0.13). No significant differences were observed in disease-free survival (DFS, p = 0.94) or overall survival (OS, p = 0.42). Sub-analysis of patients who underwent adjuvant chemotherapy (LLND- patients: n = 35) demonstrated clinically relevant though non-statistically significant trends towards a lower LLRR (0% for LLND+ vs. 6% for LLND-; p = 0.07), LRR (3% for LLND+ vs. 14% for LLND-; p = 0.06), DFS (p = 0.19) and OS (p = 0.17) in favour of the LLND+ group. Conclusions: Lateral lymph node dissection in addition to neoadjuvant (chemo)radiotherapy may improve oncological outcomes in Western patients with low rectal cancer and abnormal lateral lymph nodes.