bluuebunny/crossref_metadata_2025_split huggingface dataset:
Right versus left: Impact of primary location on survival and cure in patients undergoing hepatic resection for metastatic colon cancer.
Authors: Creasy John M. , Sadot Eran , Groot Koerkamp Bas , Chou Joanne F. , Gonen Mithat , Kemeny Nancy E. , Cercek Andrea , Saltz Leonard , Balachandran Vinod P. , Kingham T. Peter , Allen Peter J. , DeMatteo Ronald P. , Jarnagin William R. , D'Angelica Michael Ian 
Published: March 2017

664 Background: Recent prospective studies in metastatic colorectal cancer (mCRC) have demonstrated an association between left-sided primaries and improved overall (OS) and progression-free survival (PFS). Primary location (right vs left colon) has not been well studied in patients undergoing potentially curative hepatic resection. Methods: A single-institution database was queried for all initial hepatic resections for mCRC 1992-2004. Postoperative deaths and patients with no followup after 90 days were excluded. Primary location determined by chart review (Right = cecum to transverse; Left = splenic flexure to sigmoid). Rectal cancer (distal 16cm), multiple primaries, and unknown location were excluded. Kaplan Meier and Cox regression methods were used. Cure was defined as actual 10-year survival with no recurrence or resected recurrence with at least 3 years of disease-free followup. Results: 907 patients were included with a median followup of 11 years. 578 patients (64%) had left-sided and 329 (36%) had right-sided primary. Median OS for patients with a left-sided primary was 5.2 years (95% CI: 4.6-6.0) versus 3.6 years (95% CI: 3.2-4.2) for right-sided (p = 0.004). The hazard ratio (HR) for right-sided tumors was 1.22 (95% CI: 1.02-1.45, p = 0.028) after adjusting for age, CEA > 200, DFI < 12 months, hepatic tumor > 5cm, > 1 tumor, lymph node status, margin, and extrahepatic disease. Recurrence-free survival (RFS) was marginally different stratified by primary location (p = 0.065). Estimated cure rates were 22% for left and 20% for right-sided tumors. Conclusions: Among patients selected for hepatic resection of metastatic colon cancer, left-sided primary tumors were associated with an improved OS but not RFS. This difference in OS was independent of common prognostic variables. Estimated cure rates were not statistically different. Patients with left-sided primary tumors display a prolonged clinical course after recurrence suggestive of more indolent biology. [Table: see text]
The prognostic impact of surgical complications after combined modality treatment of rectal cancer: Long-term results of the CAO/ARO/AIO-94 trial.
Authors: Sprenger Thilo , Beissbarth Tim , Fietkau Rainer , Raab Hans-Rudolf , Hohenberger Werner , Liersch Torsten , Rödel Claus , Ghadimi Michael 
Published: March 2017

670 Background: The influence of major surgical complications on survival in patients with locally advanced rectal cancer undergoing combined modality treatment is still debatable. The aim of this study was to evaluate the impact of surgical complications on oncological outcome in 823 patients with locally advanced rectal cancer treated within the phase III CAO/ARO/AIO-94 trial. Methods: Anastomotic leakages as well as wound healing disorders were prospectively evaluated and correlated with overall survival (OS) and the cumulative incidence of distant metastasis and local recurrence after a long-term follow-up of more than 10 years. Results: Anastomotic leakage after restorative rectal resection is significantly correlated with an impaired 10-year OS (51.0% vs. 65.2%, p = 0.02). Patients with abdominal or sacral wound healing disorders had a significantly reduced OS compared to those with sufficient wound healing (45.2% vs. 62.7%, p = 0.009). Patients developing any surgical complication (anastomotic leakage or/and wound healing disorder) had an impaired OS (50.6% vs 65.3%, p = 0.0002) as well as higher rates of distant metastases (65.3% vs. 72.7%, p = 0.03) and local recurrences (6.0% vs. 12.9%, p = 0.0007). In a multivariate cox regression model the only independent factors for restricted OS were lymph node metastases (p < 0.0001) and the occurrence of surgical complications (p = 0.008). Conclusions: Surgical complications are significantly associated with an adverse oncological outcome and reduced long-term OS in patients undergoing combined modality treatment for locally advanced rectal cancer.
Primary tumor location and survival in general population with metastatic colorectal cancer (mCRC).
Authors: Ahmed Shahid , Papneja Neha , Emara Mohamed Elsayed , Alvi Riaz , Asif Tehmina , Dorie-Anna Dueck , Le Duc , Zaidi Adnan , Haider Kamal , Kanthan Selliah , Iqbal Nayyer 
Published: March 2017

674 Background: Recent evidence from clinical trials suggests that location of the primary tumor in patients with mCRC correlates with differential outcomes and patients with tumors originating in the right side of colon have inferior survival. This large population-based cohort study using individual patient data was performed to confirm this findings in general population with mCRC. Methods: A cohort of 1947 patients who were diagnosed with synchronous mCRC from 1992-2010 was studied. Ascending and transverse colon cancers were defined as right-sided tumors (RT) and remainder tumors were define as left-sided tumors (LT). Cox proportional multivariate analyses were done to determine prognostic significance of primary tumor location and to adjust other prognostic variables including age, Charlson comorbid index (CCI) and WHO performance status (PS) in patients treated with chemotherapy. Results: Median age was 70 years (IQR: 60-78) and M:F was 1.3:1. Mean CCI was 9.7±1.4 and 29% had WHO PS of > 1. 770 (39%) patients had RT and 37% had stage IVb disease. 908 (47%) received chemotherapy and of those 44% received modern chemotherapy. Significant differences were noted between the groups with RT and LT with respect to age, WHO PS, CCI, liver metastases, mucinous tumor, grade, smoking history, and primary tumor resection. Median overall survival of patients with RT was 14 (95%CI: 12.7-15.3) months compared with 20.5 (95%CI: 18.5-22.5) of patients with LT (p < 0.001). On multivariate analysis following variables were correlated with inferior survival: Right-sided tumors, hazard ratio (HR) 1.40 (95%CI: 1.20-1.60); no primary tumor resection, HR 1.60 (95%CI: 1.32-1.90); no metastasectomy, HR 2.40 (95%CI: 1.90-2.90); not using modern chemotherapy, HR 1.52 (95%CI: 1.31-1.80); leukocytosis, HR 1.44 (95%CI: 1.28-1.73); elevated CEA, HR 1.54 (95%CI: 1.30-1.90); WHO PS > 1, HR 1.30 (95%CI: 1.10-1.55); and stage IVb disease, HR 1.50 (95%CI: 1.17-1.86). Tests for interaction were negative. Conclusions: Our results confirm that patients with RT who received chemotherapy have inferior survival independent of other known prognostic variables. Future studies are required to understand underlying pathophysiology.
Neoadjuvant chemoradiation for locally advanced rectal cancer with fluoropyrimidine alone or intensified with oxaliplatin: A systematic review and meta-analysis.
Authors: Nadler Ashlie , Handorf Elizabeth , Sigurdson Elin R. , Meyer Joshua E. , Denlinger Crystal Shereen , Farma Jeffrey M. 
Published: March 2017

678 Background: Improved outcomes have been demonstrated with the use of neoadjuvant fluoropyrimidine-based chemoradiotherapy and total mesorectal excision for locally advanced rectal cancer. The addition of oxaliplatin in the adjuvant setting has also resulted in improved disease-free survival (DFS). A meta-analysis was performed to evaluate DFS and overall survival (OS) with the addition of oxaliplatin to standard neoadjuvant chemoradiation for locally advanced rectal cancer. Methods: A systematic literature review was performed. Randomized-controlled trials (RCTs) comparing the addition of oxaliplatin in the neoadjuvant setting (oxaliplatin group) to fluoropyrimidine-based chemoradiation (standard group) were included. The primary outcomes were DFS and OS; secondary outcomes were short-term surgical results, morbidity, and mortality. Results were combined using meta-analysis via linear mixed-effects models. Calculations were performed using R. Results: Of 73 studies identified, 4 reported DFS (n=3829) and 3 reported OS (n=2680). There was no difference in DFS between the standard and oxaliplatin groups amongst RCTs [HR 0.90 (0.64-1.26), p=0.5313]. There was no difference in OS [HR 0.93 (0.59-1.47), p=0.9894]. There was no significant heterogeneity between RCTs for primary outcomes. There was also no difference in pathologic complete response rate [OR 0.93 (0.77-1.14), p=0.4923), resection margin (R0) status [OR 1.01 (0.59-1.72), p=0.9846], circumferential resection margin status [OR 0.84 (0.50-1.41), p=0.5079], sphincter saving surgery rate [OR 0.87 (0.74-1.03), p=0.1103], grade 3-4 toxicity [OR 1.60 (0.88-2.92), p=0.1251], and 60-day mortality [OR 1.27 (0.50-3.25), p=0.6148]. There was significant heterogeneity between RCTs for R0 status, circumferential margin status, and grade 3-4 toxicity. Adjuvant treatment varied across studies. Conclusions: There are no short-term or long-term survival benefits with the addition of oxaliplatin to fluoropyrimidine-based chemoradiation in the neoadjuvant setting for locally advanced rectal cancer.
A multinational, randomized, phase III trial of XELIRI with or without bevacizumab versus FOLFIRI with or without bevacizumab as second-line therapy for metastatic colorectal cancer: Safety analysis of Asian XELIRI project (AXEPT).
Authors: Nakamura Masato , Kim Tae Won , Xu Rui-hua , Park Young Suk , Hong Yong Sang , Zhang Tao , Kato Takeshi , Cho Sang Hee , Wang Wei , Matsuoka Hiroshi , Han Sae-Won , Deng Yanhong , Makiyama Akitaka , Lee Keun-Wook , Ba Yi , Ota Mitsuyoshi , Iwasa Satoru , Morita Satoshi , Yamada Yasuhide , Muro Kei 
Published: March 2017

681 Background: Several studies have shown that capecitabine plus irinotecan (XELIRI) has promising efficacy and safety in patients with metastatic colorectal cancer. AXEPT is a non-inferiority, phase III comparison of XELIRI with or without bevacizumab vs 5-fluorouracil/folinic acid plus irinotecan (FOLFIRI) with or without bevacizumab as second-line therapy in patients with metastatic colorectal cancer. Methods: We undertook an open-label, non-inferiority, randomized phase III trial in South Korea, China and Japan. Patients were randomized 1:1 to XELIRI (irinotecan 200 mg/m2 on day 1 plus capecitabine 800 mg/m2 twice daily for 2 weeks in a 3-week cycle) with or without bevacizumab 7.5 mg/kg or FOLFIRI with or without bevacizumab. The primary endpoint was overall survival. Results: From December 2013 to August 2015, 650 patients were enrolled and 625 (311 in FOLFIRI and 314 in XELIRI) were included to safety analysis at the cutoff dates on August 31, 2016. Patient baseline characteristics including KRAS status and UGT1A1 gene polymorphism were similar between the two treatment arms. Prior chemotherapy with oxaliplatin was given to 97.4% in both arms. The overall incidence of grade 3-4 toxicity was 73% in FOLFIRI arm and 53.2% in XELIRI arm. Whereas FOLFIRI was associated with more grade 3-4 neutropenia (43.7% vs 16.2%), leucopenia (13.5% vs 7.3%) and all grades anemia (80.4% vs 69.4%) than XELIRI, XELIRI was associated with more all grades hand-foot syndrome (34.1% vs 14.8%) and grade 3-4 diarrhea (7.0% vs 3.2%). There was no significant difference in febrile neutropenia (4.2% in FOLFIRI and 2.9% in XELIRI). The addition of bevacizumab did not alter safety profiles between XELIRI and FOLFIRI. There was a treatment-related death in FOLFIRI arm (0.3%). Conclusions: Both FOLFIRI and XELIRI were safe and well tolerated, though there were differences in the rates and toxicity profiles at which adverse events occur. Clinical trial information: NCT01996306. UMIN000012263.
Left versus right sided colorectal cancer: Teasing out drivers of disparity in outcomes in metastatic disease.
Authors: Lee Belinda , Mendis Shehara , Lee Margaret , Wong Rachel , Kosmider Suzanne , Shapiro Jeremy David , Yip Desmond , Steel Simone Anne , Nott Louise M. , Jennens Ross , Lipton Lara Rachel , Burge Matthew E. , Ananda Sumitra , Gibbs Peter 
Published: March 2017

682 Background: Patients (pts) with metastatic colorectal cancer (mCRC) arising from a right sided colon cancer (RCC) have an inferior survival versus pts with a left sided primary (LCC). Previous analyses have suggested that multiple factors contribute. Methods: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry has prospectively collected data on consecutive mCRC pts at 32 sites (Australia and Hong Kong) from July 2009. LLC were defined as those distal to the splenic flexure. We analysed patient, tumour, treatment and outcome data. Results: Of 1763 patients, median age 67 years (range 18 – 100), 1201 patients (68.1%) had a LCC. RCC were more common in pts ≥ 70 years old (53.9% vs 38.5%, p < 0.01) and females (50.7%, p < 0.01). Where tested, KRAS (50.9% vs 41.5%, p < 0.01) and BRAF (19.1% vs 6.4%, p < 0.01) mutations were more common in RCC. Where tested, dMMR was more common in RCC (11.0% vs 3.2%, p < 0.01). Pts with a RCC more often had peritoneal metastases (25.9% vs 12.5%%, p < 0.01) and were less likely to have liver metastases (69.8% vs 77.9%, p < 0.01) or resection of metachronous metastases (31.8% vs 43.6%, p < 0.01). LCC more commonly received chemotherapy in the 1st (86.1% vs 80.3%, p = 0.02) and 2nd (49.7% vs 43.0%, p = 0.04) line setting. There was no difference in ECOG performance status or co-morbidity for LCC vs RCC. Overall survival for pts with a RCC was 20.6 months vs 27.9 months for LCC L-sided tumours (HR 1.395, p < 0. 0001). Conclusions: Our data confirms that pts with mCRC arising from a RCC have an inferior survival. This appears multifactorial due to associations with adverse clinical and molecular features, metastatic pattern, and less therapy, some of which are related. A multivariate analysis is being performed.
Impact of primary tumor location (TL) on outcomes of first-line (1L) FOLFOX-4 (F) ± cetuximab (cet) in patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the phase 3 TAILOR trial.
Authors: Qin Shukui , Xu Jian-Ming , Wang Liwei , Cheng Ying , Liu Tian Shu , Chen Jiongjie , Chen Wen-Feng , LI Jin 
Published: March 2017

683 Background: In the RAS wt population of TAILOR, adding cet to 1L F significantly improved progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). In this subgroup analysis, we evaluate the impact of TL. Methods: TAILOR is a randomized phase 3 trial that includes a modified intention-to-treat (mITT) population of 393 pts from China with RASwt mCRC treated with F ± cet. The primary endpoint of TAILOR is PFS; key secondary endpoints include OS and ORR. TL was categorized in evaluable pts in the mITT population (left-sided = splenic flexure, descending colon, sigmoid colon, and rectum; right-sided = appendix, cecum, ascending colon, hepatic flexure, ± transverse colon). Results: Efficacy data for the TL subgroups are summarized in the table. Additionally, the prognostic effect of TL (left- vs right-sided) within the treatment arms could be shown for PFS (HR = 1.72; p = .007), OS (HR = 1.84; p = .002), and ORR (OR = 0.40; p = .014) in the cet + F arm and PFS (HR = 1.97; p = .002), OS (HR = 1.43; p = .073), and ORR (OR = 0.41; p = .028) in the F arm. Regarding the potential predictive value of TL, the p values for the interaction between TL and treatment are: PFS (.676), OS (.339), and ORR (.986). Conclusions: In TAILOR, adding cet to 1L F clearly benefitted RAS wt pts with left-sided tumors in terms of PFS, OS, and ORR; for pts with right-sided tumors, the HRs for PFS and the ORs for ORR also consistently suggested a benefit showing a trend in favor of cet. Clinical trial information: NCT01228734. [Table: see text]
Phase I study of neoadjuvant 5-fluorouracil (5FU) chemoradiation (CRT) and trametinib in patients with locally advanced rectal cancers (LARC).
Authors: Wu Christina Sing-Ying , Williams Terence M , Wei Lai , Umar Hamida , Mikhail Sameh , Ciombor Kristen Keon , Noonan Anne M. , Roychowdhury Sameek , El-Dika Samer S , Krishna Somashekar , Upchurch Bennie , McCarthy Sean T , Arnold Mark , Harzman Alan , Abdel-Misih Sherif , Cirocco William , Traugott Amber , Bekaii-Saab Tanios S. , Wuthrick Evan John 
Published: March 2017

685 Background: RAS/BRAF mutations constitutively activate the MAPK pathway in colorectal cancer, and may promote resistance to CRT. We propose that trametinib, a MEK1/2 inhibitor, in combination with 5FU CRT for patients with LARC will improve outcome. Methods: Phase I study with standard 3+3 design in patients with Stage II/III rectal cancer with 3 dose levels of trametinib: 0.5, 1, and 2mg daily with 5FU 225mg/m2/day and 50.4 Gy. Trametinib was given over a 5-day lead-in and continued through the course of CRT. Patients undergo surgery 6-10 weeks after the completion of CRT. An expansion cohort at the maximum tolerated dose (MTD) with 12 patients is ongoing. Tumor tissue is collected prior to therapy, at day 4/5 of trametinib, and at surgery. The primary endpoint is to determine the MTD of trametinib with CRT. Results: 15 patients (10 males, 5 females) have been enrolled and 14 patients are evaluable for toxicities to date. Median age is 53 years (range 35-74). Patients have completed enrollment to all dose levels, with 1 dose-limiting toxicity of diarrhea attributed to 5FU CRT. No grade 4/5 toxicities, and toxicities are shown in the table. Generalized skin rash led to trametinib discontinuation after 2 weeks of therapy for 1 patient, and was held 3 days for 2 patients. At the trametinib dose level of 2mg, 3 out of 7 (43%) patients had a pathological complete response and the average neoadjuvant rectal (NAR) score is 8.1. Tumor RAS/BRAF mutation status is determined. Analysis of tumor tissue shows dose-dependent decrease in phosphorylated-ERK1/2 with increasing doses of trametinib. Conclusions: Initial evaluation shows that the combination of trametinib with 5FU CRT is tolerable and effective, and warrants further investigation in LARC. Clinical trial information: NCT01740648. [Table: see text]
Immunoscore based on PD-L1/PD-1 and CD8+ T cells as prognostic marker for stage II/III gastric cancer.
Authors: Wen Ti , Qu Xiujuan , Li Yi , Li Zhi , Che Xiaofang , Fan Yibo , Wang Shuo , Xu Ling , Song Na , Liu Yunpeng 
Published: March 2017

69 Background: PD-L1/PD-1 pathway has become an important target in tumor immunotherapy. However, the prognostic value of PD-L1/PD-1 for gastric cancer (GC) remains controversial due to the complexity of immune response. Therefore, comprehensive evaluation of PD-L1/PD-1 expression and CD8+T cells is necessary and superior to one factor in predicting survival. Methods: 166 patients with stage II-III GC were enrolled. Expression of PD-L1, PD-1, and CD8 protein in tumor tissues was examined by IHC staining, and their association with patient’s survival was analyzed by Kaplan-Meier method. Immunoscore classification was constructed using a scoring system, which was based on hazard ratios in a Cox proportional hazard analysis. Results: Expression of PD-L1 was found in 22.29% of immune cells (IC) and 38.55% of tumor cells (TC), while expression of PD-1 was found in 31.33% of IC. CD8High was detected in 41.57% patients. PD-L1+ and PD-1+ IC were both correlated with worse overall survival (OS) ( P=0.0009 and P=0.0004, respectively). In contrast, TC PD-L1+ was associated with better clinical outcomes, including Borrmann classification 0-1, lower AJCC stage, CD8High infiltration and better OS ( P<0.05). Furthermore, IC PD-L1, IC PD-1, CD8, and TC PD-L1 had independent prognostic significance after TNM stage adjustment, and we built an immunoscore system based on these immune factors. Patients with same stage could be further categorized into low-/median-/high-risk subgroups according to their immunoscores. Conclusions: Immunoscore based on comprehensive evaluation of PD-L1/PD-1 and CD8+ T cells can separate GC patients with same stage into different risk subgroups, and might provide suggestion for immunotherapy options in GC.
Effect of neoadjuvant IMRT for locally advanced rectal cancer on toxicity and pathologic response.
Authors: David John , Jabbour Salma , Gresham Gillian K. , Deek Mathew , Shant Thomassian , Robertson John M. , Kabolizadeh Peyman , Tuli Richard 
Published: March 2017

693 Background: Neoadjuvant chemoradiation (NeoCRT) is standard of care for the treatment of locally advanced rectal cancer (LARC). Contemporary radiation techniques may reduce dose to normal organs at risk. Our purpose was to compare clinical outcomes and acute toxicities between standard 3D conformal (3D) and intensity modulated radiation therapy (IMRT). Methods: LARC patients (pts) treated at 4 large academic centers in the US between 2007 and 2016 were reviewed. Pts received 5FU-based NeoCRT concurrently with IMRT or 3D. Pathologic response (PR) was used as a surrogate for clinical outcome, and common terminology for adverse events version 4 was used to grade toxicities, summarized on a 1-5 scale. Toxicity rates were compared using chi-square analysis. Multivariable models were fit adjusting for age, gender, pre-tx CT to identify independent predictors of PR and toxicity. Results: 128 pts were analyzed: 60.1% male and 39.8% female, median age 57.7 years (Range 31-85). Clinical characteristics were similar across RT groups. The outcome of partial and complete PR was similar for IMRT and 3D (48.1%, 23.1% vs 32.2%, 23.7%*), respectively. After adjusting for gender, age, and pre-RT chemotherapy type, IMRT was significantly associated with increased odds for complete and partial response (OR: 2.9, 95%CI 1.2-7.2*). Additionally, IMRT was significantly associated with reduced rates of dehydration, dermatitis, rectal pain, rectal bleeding, diverting ostomy, and trend toward significance for decreased rates of fatigue (p = 0.07) and erythema (p = 0.06) (see table). Overall rates of grade 2 and higher toxicities were significantly reduced in IMRT vs. 3D after adjusting for confounders (OR: 0.27, 95% CI 0.08-0.87*). Conclusions: Neoadjuvant 5FU-based IMRT for LARC leads to reduced acute toxicities and improved PR compared to 3D. Given the challenges associated with prospective validation of these data, IMRT should be considered standard treatment for LARC.[Table: see text]