bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.