bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of adjuvant chemotherapy following chemoradiation and surgery for locoregionally advanced rectal cancer: A Veterans Health Administration analysis.
Authors: Spiegel Daphna , Boyer Matthew , Hong Julian C. , Williams Christina D. , Kelley Michael J. , Rangwala Fatima A. , Salama Joseph Kamel , Palta Manisha
Published: January 2019

741

Background: Adjuvant chemotherapy (AC) following chemoradiation (CRT) and total mesorectal excision (TME) for locoregionally advanced rectal cancer (LARC) is a standard of care in the United States despite limited data. The purpose of this study was to examine the role, optimal regimen, and duration of AC in the mandatory, prospectively collected cancer registry of the largest integrated health system in the US. Methods: Using the VA Central Cancer Registry, stage II-III rectal cancer patients diagnosed between 1/2001-4/2011 were included if they received neoadjuvant CRT followed by TME with or without AC. Adequate chemotherapy was defined as at least 4 months of therapy. Kaplan-Meier and Log-Rank tests were used to assess survival. Propensity score (PS) adjustment was performed to compare survival outcomes while adjusting for baseline characteristics, including AJCC stage, age, gender, race, smoking status, and comorbidity. Results: 649 patients were identified; 323 received AC while 326 did not (OBS). Median follow-up was 66 months. Mean age was 63 years. 85.1% were white; 98.8% were male. 49.2% had stage II disease. Median overall survival (OS) for all patients was 92 months; 6-year OS was 56.8%. Median OS was 72 months for the OBS group and not reached (NR) for the AC group (p < 0.001). OS at 6 years was 49.5% for OBS and 64.1% for AC (p < 0.0001). On PS matched analysis, OS was improved favoring AC (p < 0.0001). Median disease-specific survival (DSS) was NR for the whole group and NR for the OBS and AC groups. 6-year DSS was 73.6% for the whole group and 67.9% for OBS vs. 79.2% for AC (p < 0.001). PS matched analysis for DSS favored AC (p = 0.0004). There was no significant difference in OS (p = 0.554) or DSS (p = 0.680) when comparing single versus multi-agent chemotherapy and no significant difference in OS (p = 0.766) or DSS (p = 0.271) when comparing adequate ( > / = 4 months) versus inadequate chemotherapy ( < 4 months). Conclusions: In this VA population of LARC patients treated with neoadjuvant CRT followed by TME, the addition of AC was found to improve both OS and DSS compared to OBS. There was no improvement in OS or DSS with the addition of a multi-agent over single-agent chemotherapy.
Effect and safety of proton beam therapy for locally recurrent rectal cancer.
Authors: Ogi Yusuke , Yamaguchi Tomohiro , Kinugasa Yusuke , Shiomi Akio , Kagawa Hiroyasu , Yamakawa Yushi , Furutani Akinobu , Yamaoka Yusuke , Manabe Shoichi , Hino Hitoshi , Nagasawa Yoshinobu , Suzuki Takuya , Torii Kakeru , Kato Shunichiro , Koido Kohei , Murayama Shigeyuki
Published: January 2019

743

Background: The first choice of treatment for locally recurrent rectal cancer is surgical resection. However, the operation is often difficult with high perioperative risk. For surgically unfit cases, proton beam therapy (PBT) is proposed as the treatment option. However, its efficacy for locally recurrent rectal cancer remains unclear. Therefore, this study aimed to evaluate the efficacy and safety of PBT for locally recurrent rectal cancer. Methods: A total of 23 patients with locally recurrent rectal cancer who received PBT were retrospectively evaluated, from November 2005 to July 2014. Patients with single lesion, who refuse the radical surgical therapy, or who were considered unfit for the operation were included in this study. All patients were treated with 2.8Gy relative biological effectiveness (RBE)/fraction. Twenty-five irradiations were performed, with a total irradiation of 70Gy RBE. Unfit for operation criteria include invasion to the vertebra higher than the third sacrum or lateral lymph node recurrence after a lateral lymph node dissection. To assess the safety of PBT, adverse events were evaluated by using the Common Terminology Criteria for Adverse Effects (CTCAE version4.0). To assess the efficacy, the overall and relapse-free survival rates and local control rate were evaluated. Results: Sixteen patients were unfit for operation, and seven refused surgery. Three patients experienced Grade 3 late adverse events in the CTCAE (two ileum fistula and one urinary tract obstruction). The median follow-up time was 28.9 months. The 5-year overall and relapse-free survival rates were 47.6% and 20.2%, respectively. Fifteen patients (65.2%) showed distant metastasis or regrowth at the locally recurrent site. The 5-year local control rate was 39.0%. Ten patients (43.4%) showed regrowth at the proton beam irradiation site. Conclusions: PBT was relatively effective for locally recurrent rectal cancer with manageable adverse effects. Therefore, PBT may be considered as the therapeutic option for selected locally recurrent rectal cancer patients.
The impact of indoleamine 2,3-dioxygenase (IDO) expression on stage III gastric cancer.
Authors: Kashihara Hideya , Shimada Mitsuo , Yoshikawa Kozo , Higashijima Jun , Tokunaga Takuya , Nishi Masaaki , Takasu Chie , Ishikawa Daichi
Published: January 2019

75

Background: Indoleamine 2,3-dioxygenase (IDO) downregulates T cell activation and is related to immune tolerance. The aim of this study was to clarify the significance of IDO expression and to analyze the relationships among the expression of IDO, TGF-b, and Foxp3 in gastric cancer (GC). Methods: Sixty patients who underwent curative gastrectomy for stage III gastric cancer were included in this study. The expressions of IDO, TGF-b, and Foxp3 were examined by immunohistochemistry. The patients were divided into two groups: the IDO-positive group (n = 23) and negative group (n = 37). Clinicopathological factors were compared between the two groups. Univariate analysis was used to assess overall (OS) and disease-free survival (DFS) in several prognostic factors. Multivariate analysis was used to identify the independent prognostic factors. Results: IDO expression was not positively correlated with any clinicopathological factors. IDO expression was positively correlated with TGF-b expression (p < 0.05) and TGF-b expression was positively correlated with FoxP3 expression (p < 0.05). Overall survival (OS) rates were significantly poorer in the IDO-positive group compared with the IDO-negative group (3-year OS, 78.5% vs. 90%, respectively; p < 0.05). Multivariate analysis identified IDO expression as independent prognostic factors in OS. Disease-free survival (DFS) was significantly poorer in the IDO-positive group compared with the IDO-negative group (3-year DFS, 59.3% vs. 69.3%, respectively; p < 0.05). Conclusions: IDO is associated with poor prognosis and immuno-tolerance through Treg in Stage III GC.
SIDE in metastatic colon cancer: SEER Database analysis.
Authors: Muzaffar Mahvish , Kaur Sandeep , Naqash Abdul Rafeh , Jonnalagadda Sweta , Vohra Nasreen A.
Published: January 2019

753

Background: Recent data suggests side of colon cancer is a prognostic factor and a potential predictive factor for biologic therapy. We sought to analyze SEER database to study impact of colon cancer side. Methods: The SEER database (version 8.3.4) was reviewed for patients with Stage IV colon cancer from 2004-2014. We only included patients with labeled primary site, and excluded appendiceal, rectal or unlabeled cases. Variables included were: age, race, gender, stage, grade and side of the tumor. Primary outcome was overall survival and disease specific survival. Cox proportional hazard regression model was employed to test the association between survival and side of cancer. Results: 48,306 patients met the inclusion criteria, median age was 67 years (range 20-108), 51% were male, and 77% patients were white. 19831 (41%) patients had left colon cancer (LCC). Right colon cancer (RCC) was associated with inferior OS and DSS compared to LCC. The median overall survival was 15 months (mo) for left side and 9 months for right colon cancer (p<0.0001). Estimated 3-year OS for RCC was 14% and 24% for LCC (p <0.0001). RCC was associated with poor outcome across different variables, among patients < 60 years of age median OS was 23 mo for LCC, and 16 mo for RCC (p .0001). In the age group ≥ 60 years, 10 mo for left side and 7 mo for RCC (p < 0.0001). Among male patients RCC had 10 mo median OS vs 16 mo for LCC (p <0.0001), women 15mo for LCC vs 9mo for RCC (<0.0001). Cox regression model suggested age (<0.001), race (<0.0001), year of diagnosis (<0.0001) and grade (<0.0001) correlate with outcome. Conclusions: Right side colon cancer is associated with poor outcome compared to left colon cancer. These findings are consistent with other recent reports.
Does stereotactic body radiation therapy have a role in oligoprogressive metastatic colorectal cancer?
Authors: Jin Will , Burke Aidan M. , Rashid Abdul , Marshall John , Unger Keith Robert
Published: January 2019

755

Background: Patients with metastatic colorectal cancer undergoing systemic therapy may enter an oligoprogressive state. Traditionally, local ablative therapy (LAT) has been limited to symptom palliation. We hypothesize that LAT for oligoprogressive lesions with stereotactic body radiation therapy (SBRT) is a feasible alternative to surgical interventions and may delay progression of disease. Methods: An IRB-approved retrospective review of patients with oligoprogressive, metastatic colorectal cancer who were treated with SBRT at Georgetown University Hospital from 2012-2016 was performed. Results: 40 patients with 41 metastatic lesions of the lung (n = 11), liver (n = 10), lymph nodes (n = 8), soft tissue (n = 6), and bone (n = 6) were reviewed. Median follow-up, overall survival, and freedom from distant progression were 10.6, 17.3, and 6.4 months, respectively. Crude one year local control and overall survival were 82.9% and 75%, respectively. First site of progression was distally in 63.4% of patients. Patients treated with SBRT in the liver were significantly more likely to locally progress than other treated sites (13.18 vs. 39.81 months, p = 0.007). On univariate analysis, non-lymph node treated tumors (p = 0.046), larger CEA change at 6 month follow-up (p = 0.048), and right sided primary tumors (p = 0.004) were associated with local failure within 1 year. On multivariate analysis, only right sided primary tumors were significantly more likely to locally progress (p = 0.009). Conclusions: Patients with oligoprogressive colorectal cancer can be effectively treated with SBRT to achieve acceptable rates of local control and potentially delay progression of disease.
Robotic surgery for rectal cancer: Short-term and oncological outcomes for 607 consecutive patients.
Authors: Shiomi Akio , Yamaguchi Tomohiro , Kagawa Hiroyasu , Yamakawa Yushi , Furutani Akinobu , Yamaoka Yusuke , Manabe Shoichi , Ogi Yusuke , Hino Hitoshi , Nagasawa Yoshinobu
Published: January 2019

756

Background: Conventional laparoscopic surgery (CLS) for rectal cancer has several inherent technical difficulties, including a limited range of motion of the instruments.Robot-assisted laparoscopic surgery (RALS) has some technical advantages over CLS because it improves dexterity with an increased range of movements at the tips of the instruments. The purpose of this study was to evaluate the short-term and oncological outcomes of RALS for rectal cancer, including robotic, autonomic nerve-preserving, lateral lymph node dissection (RALLD), a new, technically challenging procedure. Methods: Between December 2011 and August 2017, 607 consecutive patients underwent RALS for rectal cancer. Surgical outcomes, pathological results, and oncological results were investigated retrospectively. Results: There were 403 males and 204 females; 577 patients had adenocarcinoma, 19 had carcinoid tumor, 8 had GIST, and 2 had other malignant tumor. The types of procedures performed were: 453 anterior resections, 93 intersphincteric resections, and 61 abdominoperineal resections. RALLD was performed in 202 patients (33.3%). Preoperative chemoradiotherapy was performed in 34 patients. The overall median operative time was 257(109-683) min. In cases without RALLD, the median operative time was 217 (109-545) min, while median operative time was 420 (162-683) min with RALLD. None of the cases was converted to an open or laparoscopic procedure.There was no surgical mortality. The overall complication rate for Clavien-Dindo classification grade III-IV was 3.0%. The oncological results for 279 patients with primary rectal adenocarcinoma, operated before December 2014 was also investigated (Stage I/II/III 115/48/116). The 5-year overall survival was 96.6%, the 3-year relapse free survival was 88.3%, and 3-year local relapse free survival was 98.5%. The 3-year RFS of pStage I/II/III was 96.2/89.6/79.6% respectively. Conclusions: RALS for rectal cancer is a feasible procedure with low morbidity and a low conversion rate, and acceptable oncological results.
Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503.
Authors: Kawazoe Akihito , Kuboki Yasutoshi , Komatsu Yoshito , Nishina Tomohiro , Shinozaki Eiji , Hara Hiroki , Yuki Satoshi , Shitara Kohei , Bando Hideaki , Takahashi Koji , Mikamoto Yuichi , Hasegawa Hiromi , Hirano Nami , Nomura Shogo , Togashi Yosuke , Nishikawa Hiroyoshi , Sato Akihiro , Ohtsu Atsushi , Yoshino Takayuki
Published: January 2019

760

Background: The anti–programmed death 1 (PD-1) antibody, pembrolizumab provided an objective response rate (ORR) of 40% in patients (pts) with Mismatch Repair–Deficient (dMMR) or Microsatellite Instability–High (MSI-H) metastatic colorectal cancer (mCRC) vs 0% in pts with MMR-proficient/Microsatellite Stable (MSS) mCRC. The WNT/β-catenin signaling has been reported to prevent anti-tumor immunity and promote resistance of anti-PD-1/PD-L1 antibodies. This study investigates efficacy and safety of the combination of BBI608, which blocks phosphorylated STAT3 and downregulates WNT/β-catenin signaling, with pembrolizumab in pts with mCRC (both MSS and MSI-H). Here, we present the results of the phase I part. Methods: Phase I part was designed to determine the recommended phase II dose (RP2D) in a “3+3” cohort-based dose escalation design of BBI608 (240mg BID every day on level 1 and 480mg BID every day on level 2) with pembrolizumab (200mg/body q3w). We also conduct biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: Five pts were enrolled in level 1, and 3 pts in level 2. All pts were MSS mCRC. Seven pts were included in the safety analyses. Two pts in level 1 were excluded from dose-limiting toxicity (DLT) evaluation because of disease progression during DLT evaluation period. No DLTs were observed at either level. Grade 3 or worse treatment-related adverse events (TRAEs) were not observed. Grade 1 or 2 TRAEs included diarrhea related to BBI608 (57%), hyperthyroidism (14%), hypothyroidism (14%), and fever (14%) without unexpected safety signals. One patient in level 2 showed a tumor shrinkage lasting more than 12 weeks for lung and lymph node metastases with remarkable decline of CEA level. Analysis of repeated tumor samples from this case demonstrated that CD8+ T-cells infiltration inside the tumor on treatment was observed by immunohistochemistry and flow-cytometry. Conclusions: BBI608 480mg BID with pembrolizumab was tolerable and determined as RP2D. This combination showed a hint of activity and might evoke immunity in MSS mCRC, which will be confirmed by ongoing phase II part. Clinical trial information: NCT02851004..
M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with heavily pretreated CRC: Preliminary results from a phase I trial.
Authors: Kopetz Scott , Spira Alexander I. , Wertheim Michael , Kim Edward , Tan Benjamin R. , Lenz Heinz-Josef , Nikolinakos Petros , Rich Patricia , Smith David A. , Helwig Christoph , Dussault Isabelle , Ojalvo Laureen , Gulley James L.
Published: January 2019

764

Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in patients (pts) with heavily pretreated colorectal cancer (CRC), an area of high unmet need since these pts no longer respond to standard therapies. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02517398, pts with heavily pretreated (≥3rd line) advanced CRC receive M7824 1200 mg q2w until confirmed progressive disease (PD), unacceptable toxicity or trial withdrawal. The primary objective is best overall response (BOR) per RECIST v1.1; secondary objectives include safety/tolerability. Results: As of 28 June 2017, 32 heavily pretreated pts with advanced CRC (87.5% had ≥3 prior therapies) received M7824 for a median duration of 7.1 (range: 2-38) weeks; 2 pts remained on treatment. Among the 29 evaluable pts, 1 had a confirmed partial response (PR; ongoing at 8 months), 1 had stable disease (SD) and 27 had PD as BOR per independent read. The pt with a PR had CRC that was microsatellite stable (MSS), consensus molecular subtype (CMS) 4, KRAS mutant (mt) and PD-L1+; this pt had the highest tumor cell PD-L1 expression in our cohort (20%; PD-L1 expression was generally low among the other 24 pts with available results). 4 pts (12.5%) experienced 5 different grade 3 treatment-related adverse events (AEs; adrenal insufficiency, anemia, blood bilirubin increased, enteritis [leading to discontinuation] and fatigue); there were no grade ≥4 treatment-related AEs or treatment-related deaths. Conclusions: In heavily pretreated pts with advanced CRC, 1 pt (MSS, CMS 4, KRAS mt and PD-L1+) had a durable PR, 1 had SD and 27 had PD as BOR. M7824 showed a manageable safety profile. Updated data – including PD-L1, TGF-β and CMS results – will be presented. A study in pts with CMS 4 is in preparation. Clinical trial information: NCT02517398.
Quality-adjusted time without symptoms or toxicity (Q-TWiST) of patients with metastatic colorectal cancer (mCRC) treated with fruquintinib in a phase II clinical trial.
Authors: Li Jin , Xu Ruihua , Bai Yuxian , Xu Jianming , Liu Tianshu , Shen Lin , Wang Liwei , Pan Hongming , Han Rubing , Chen Yun , Peng Cike , Fan Songhua , Hua Ye
Published: January 2019

765

Background: In a randomized phase II trial of mCRC patients who have failed at least 2 lines of standard therapy, fruquintinib has demonstrated superior progression free survival (PFS) and overall survival (OS) benefits over placebo. We further assessed the between-treatment difference of quality of life (QoL) using a Q-TWiST analysis, to elucidate the trade-off between adverse events and treatment benefits. Methods: Mean PFS and OS were estimated using the Kaplan-Meier method. OS in Q-TWiST analysis was partitioned into 3 health states: TOX (time with toxicity before progression), TWiST (time without symptoms or toxicity) and REL (time from progression until death). The algorism of Q-TWiST is the sum of the mean durations for the 3 health states, with each state weighted by its respective utility coefficient. The 95% confidence intervals of mean are calculated with z method and the standard error is generated by bootstrap method. The relative Q-TWiST gains of > = 10% and > = 15% are considered as a clinically important and clearly clinically important, respectively (Revicki, 2006). Results: A total of 71 patients were included in this post-hoc analysis. The 47 patients of fruquintinib arm had significant longer PFS, compared with the 24 patients in the placebo arm (mean: 5.0 vs. 2.2 months, difference [95% CI]: 2.8 [1.4, 4.3]). The benefit of OS was numerically superior (mean: 8.6 vs. 6.9 months, difference [95% CI]: 1.7 [-0.5, 4.0]). Patients treated with fruquintinib showed numerically longer overall Q-TWiST (mean: 5.8 vs. 4.4 months, difference [95% CI]: 1.4 [-0.1, 2.9] than those received placebo with the relative gain of 20.3% over OS, assuming the utility during TOX/REL period is 0.5 and that during the TWiST is 1.0. Sensitivity analysis demonstrated that the Q-TWiST gain may range from -0.7% to 41.2% at various utility assignments. Conclusions: In this phase II trial, mCRC patients treated with fruquintinib had clearly clinically important QoL benefit. Further studies with larger sample size are needed to confirm this finding. Clinical trial information: NCT02196688.
18F-FDG PET-defined therapy response to predict acute hematologic toxicity for anal cancer patients treated with chemoradiation.
Authors: David John , Yue Yong , Blas Kevin , Fraass Benedick , Hendifar Andrew Eugene , Kabolizadeh Peyman , Tuli Richard
Published: January 2019

775

Background: Hematologic toxicities (HT) induced during chemoradiotherapy (CRT) for anal cancer can lead to increased infection rates, bleeding, asthenia, and unplanned breaks compromising treatment efficacy. We hypothesize that HT in anal cancer patients treated with CRT correlate with change in active bone marrow (ABM) characterized by pre- and post-CRT 18F-FDG PET/CT (PET). Methods: Twenty-eight locally advanced anal cancer patients treated with definitive CRT from 2011-2016 were identified. PET scans were obtained 0-2 weeks pre- and 6-8 weeks post-CRT. HT was evaluated by weekly white blood cell count, absolute neutrophil count (ANC), hemoglobin (Hg) and platelet nadirs. Total bone marrow (TBM) was defined on CT images, and segmented into three subregions: lumbosacral (LS), left and right iliac pelvis. PET images were normalized to bone outside of the TBM uptakes. ABM was characterized in all PET images as the volume having standard uptake value SUV > 40% of SUVmax in the TBM. Image variables (global, subregional SUVmean, SUVmax, ABMs) of pre- and post-CRT and their differential changes were evaluated as predictors of HT. Locoregional radiomics features were calculated using a 3D kernel-based approach. HT prediction was modeled by logistic regression with the Lasso algorithm with 10-fold cross-validation. HT endpoints were defined as change between baseline blood nadir and the lowest nadir values during and up to 2 weeks after CRT. Results: The lasso regression identified 5 predictors of HT (pre-SUVmax, post-LS-ABM, LS-ABM change, homogeneity texture change, and variance). Ratios of LS-ABMs to TBM were reduced from 18.9% (pre-CRT) to 16.3% (post-CRT). This reduction of LS-ABM significantly correlated with acute HT measured by ANC (p < 0.001) and Hg (p < 0.001) nadirs. Conclusions: PET-derived active BM changes between pre- and post-CRT significantly associated with HT in anal cancer patients undergoing definitive CRT. LS-ABM is a robust surrogate for evaluation of HT and can be used to develop BM-sparing radiotherapy for reduction of potential HT.
The prechemoradiotherapy/nadir ratio of white blood-cell count to predict tumor response and survival in locally advanced rectal cancer.
Authors: Lee Joo Hwan , Kim Sung Hwan , Lee Jong Hoon , Sung Soo Yoon , Jang Hong Seok
Published: January 2019

783

Background: Predicting treatment response of preoperative chemoradiotherapy (CRT) in patients with rectal cancer is important for physicians to guide a patient to the relevant treatment. We evaluate the change of white blood cell (WBC) count before and during CRT if it is associated with susceptibility to the CRT and affects tumor response. Methods: Medical records of 641 patients with rectal cancer who received preoperative CRT followed by curative surgery were retrospectively reviewed. Complete blood cell counts were measured weekly before and during the radiation therapy. We assessed the pre-CRT/nadir ratio of WBC count for the treatment response to CRT and recurrence-free survival. Results: The enrolled patients were divided into two groups of high WBC ratio (HWR) and low WBC ratio (LWR) with the cutoff value of 0.49, which was found by receiver operating characteristic curve (Sensitivity, 0.38 and 1-Specificity, 0.22; p=0.007). In 641 patients, 490 (76.4%) were HWR group and 151 (23.6%) were LWR group. Complete pathologic response rates were 12.2% in HWR group and 23.8% in LWR group, respectively (p=0.001). Downstaging rates of each group were 37.8% and 48.3%, respectively (p=0.02). In the logistic regression analysis, CEA level over 5ng/ml (Adjusted OR 0.566, 95% CI 0.351-0.912; p=0.019) and HWR (Adjusted OR 0.412, 95% CI 0.256-0.663; p=0.001) were significant adverse factors of the pathologic complete response. The 5-year recurrence-free survival rate was significantly higher in LWR group than in HWR group (67.6% and 83.3%; p=0.001). Conclusions: Low WBC ratio predicts a good tumor response to the preoperative CRT, and is significantly associated with an improved recurrence-free survival in rectal cancer.
Risk of peritoneal carcinomatosis in pT4 and perforated colorectal cancer.
Authors: Gutierrez Sanz Lourdes Gutierrez , Muñoz-Rodríguez Joaquin M , Movilla Arsenio S , Alonso Isabel , Serrano Ángel , Pérez-Viejo Estibalitz , Penacoba Cecilia , Ruiz-Casado Ana
Published: January 2019

787

Background: Peritoneal carcinomatosis has a dismal prognosis with shorter overall survival than other isolated metastases. In selected patients, HIPEC shows encouraging results. However, early diagnosis continues to be a challenge. COLOPEC trial has been designed to determine the effectiveness of HIPEC in pT4 and perforated colon cancer expecting 25% of peritoneal carcinomatosis in the control arm. A routine second-look procedure in a pilot trial addressed to high-risk patients revealed peritoneal carcinomatosis in 13.3 % in the pT4 group and 50% in the perforation group. Methods: The aim of our study is to describe the risk of clinical/radiological peritoneal relapse in a high-risk population.This is a retrospective study. 711 patients diagnosed with colorectal cancer between 2012 and 2014 according to the hospital – based registry hospital, were reviewed. Patients with stage IV at diagnosis were excluded. 95 cases were considered as high-risk patients. We categorized different classes for pT4 (only), perforation (only) and pT4 + perforation. Results: Peritoneal carcinomatosis was identified during the follow-up in 19 (20 %) of patients initially diagnosed with pT4, perforated colorectal cancer or both. Conclusions: Whereas the risk of peritoneal carcinomatosis in patients with an only risk factor (pT4 or perforation) is 0-15%, it increases up to 33% (one in three patients) when both pT4 and perforation coexist. It is important to collect this information in the clinical record and considering it for the decision-making process. Second-look procedures should not be performed out of the setting of clinical trials. Some patients considered as high-risk patients in old series could have a good prognosis nowadays. [Table: see text]
Use of FDG PET scanning to evaluate 5-FU myocardial toxicity as a global metabolic effect rather than vascular spasm.
Authors: Dean Andrew Peter , Higgs Dom , Robins Peter , Stobie Paul , Craven Philip , Daly Ciara , Carija Samantha
Published: January 2019

792

Background: This is the first ever case series which presents a series of PET images that conclusively demonstrate reversible abnormal myocardial glucose utilisation in 7 patients with normal coronary arteries occurring during 5-FU infusions. Fluoropyrimidine induced myocardial toxicity is estimated to occur in 9% of cases, with some instances proving fatal. Traditionally some hypothesised coronary artery spasm as the mechanism of action behind such events and an animal study suggesting dysfunction of the Krebs cycle, with depletion of high-energy phosphate compounds, was largely ignored. Having observed abnormal myocardial FDG uptake in a patient with chest pain undergoing FDG PET scanning, we prospectively evaluated a further 6 patients presenting with cardiac symptoms whilst receiving infusional 5-FU. Methods: Over an eighteen-month period, 7 patients experienced cardiac like chest pain during 5FU infusion. All were investigated for cardiac ischaemia as per institutional protocol (serial troponin, ECGs and coronary artery imaging), as well as FDG PET scanning to assess FDG uptake in the myocardium. Results: All 7 cases showed reduced FDG uptake throughout the myocardium, with the ventricular blood pool demonstrating a higher affinity for FDG than the myocardium itself. All 7 cases showed normal physiological uptake of FDG in the myocardium on previous and subsequent PET imaging. Imaging of the myocardium and coronary arteries in all cases showed no structural vascular disease. Conclusions: All cases demonstrated a global pattern of reduced FDG myocardial uptake that could not be isolated to a single coronary territory. Angiography or myocardial perfusion scanning demonstrated no significant coronary artery disease, and there were no features consistent with coronary artery spasm found on ECG. This supports the hypothesis that 5FU inhibits physiological myocardial glucose utilisation, thus acting as a direct myocardial toxin. We believe our findings warrant further investigation into the metabolic effects of 5FU on myocardial tissue.
Tumor bulk to predict clinical outcomes of anti-EGFR therapy in treatment refractory metastatic colorectal cancer independent of sidedness.
Authors: Kratz Jeremy D. , LoConte Noelle K. , Lubner Sam Joseph , Mulkerin Daniel , Uboha Nataliya Volodymyrivna , Deming Dustin A.
Published: January 2019

795

Background: Epidermal growth factor receptor (EGFR) antibodies, cetuximab (C) and panitumumab (P) have shown improvement in clinical outcomes for distinct molecular profiles in metastatic colorectal cancer (mCRC). In the first line setting, EGFR targeting of left-sided tumors has shown favorable clinical outcomes when compared to right-sided tumors. Here we examined the efficacy of EGFR therapy in the treatment refractory setting as well as the impact of tumor bulk on clinical outcomes. Methods: A retrospective cohort of 72 patients (pts) with KRAS wild-type mCRC were identified who received either C or P in the late-line setting. Tumor measurements were performed per RECIST v1.1. Disease bulk was defined as single lesion with longest diameter or lymph node with short axis > 3.5 cm. Right colon primary was defined proximal to splenic flexure. Results: In pts with treatment refractory right-sided disease the response rate (RR) was 16.7%, progression free survival (PFS) was 3.7 months (mo), and overall survival (OS) was 14.0 mo. This was compared to left sided disease with RR of 26.0%, PFS 6.2 mo (p < 0.05), and OS 15.0 mo. In the non-bulky cohort the RR was 32.4%, PFS 7.9 mo, and OS 18.4 mo. In the bulky cohort the RR was 5.3% (p < 0.01), PFS 4.0 mo (p < 0.02), and OS 6.6 mo. In the right-sided non-bulky cohort there was a RR of 33% v. 0% in the right-sided bulky cohort. In the left-sided non-bulky cohort there was a RR of 32.3% v. 7.7% in the bulky cohort (p < 0.05). Conclusions: These data indicate that tumor bulk can predict clinical outcomes for anti-EGFR targeting. In the late line setting, pts with left-sided cancers overall trended towards improvements in clinical outcomes, consistent with prior understanding in first line setting. Despite a limited cohort size, response was observed in pts with non-bulky right-sided disease. There was limited-to-no benefit of anti-EGFR targeting with right-sided bulky disease. Left-sided non-bulky patient received the greatest benefit from anti-EGFR targeting. Future prospective studies of targeted therapeutics should incorporate tumor bulk and sidedness when assessing clinical outcomes and tumor biology.
Results from an institutional universal reflex testing program for MSI/MMR in colorectal cancer.
Authors: Franke Aaron J , Gaffar Maira , Feely Michael , Starr Jason Scott , Parekh Hiral D. , Tan Sanda , Iqbal Atif , Allegra Carmen Joseph , George Thomas J.
Published: January 2019

796

Background: In colorectal cancer (CRC), clinical guidelines and immunotherapy treatment selection requires knowledge of tumor DNA mismatch repair gene deficiencies (dMMR) or accumulation of microsatellite repeats through genomic errors (MSI-H). Tumors harboring dMMR/MSI-H are found in 15- 20% of early stage CRC while the prevalence is ~5% in metastatic disease. Reflex testing of CRC to identify these important subsets has been proposed as a system-solution to improve identification. We present a large, single-institutional database of CRC reflexively profiled for MSI/MMR status at the University of Florida (UF). Methods: Beginning in 2009, stage IV CRC underwent reflex testing for MSI/MMR status. Earlier stage CRC testing began in subsequent years. For all new CRC diagnosed at UF, concurrent testing for dMMR by IHC (MLH1, PMS2, MSH2, MSH6), MSI by PCR (Promega MSI kit) and NGS is performed with appropriate positive and negative controls. IHC protein loss is confirmed by second GI pathologist. MSI is not performed if inadequate adjacent normal tissue. We conducted a retrospective analysis of all CRC samples analyzed between 2009 and 2017. Clinical data was collected from the EMR. This study was approved by the UF IRB. Results: A total of 388 new CRC cases were reflex tested (16% Stage I, 23% Stage II, 35% Stage III, and 25% Stage IV). Median age at diagnosis was 63 yrs (range: 17-98 yrs), 51% male and 79% white. Both MMR and MSI were performed in 244 (63%) tumors with 100% concordance when concurrently tested. dMMR/MSI-H incidence (20% in overall population) decreased with stage: I/II (31%), III (18%) and IV (~9%) and was associated with BRAF V600E mut in 36/76 cases (47%). Importantly, in pts < 50 yrs, 13% of stage IV patients were dMMR/MSI-H. Conclusions: Reflex testing of MMR/MSI status in CRC is feasible with concordant results. Routine testing results in identification of dMMR/MSI-H at or higher than published rates. Notable findings include the high prevalence in those with sporadic CRC and/or younger than 50 yrs. Continued impact analysis of this approach is warranted to maximize IO therapy offering.
CYTO-CHIP: Cytoreductive surgery versus cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis: A propensity-score analysis from BIG RENAPE and FREGAT working groups.
Authors: Bonnot Pierre Emmanuel , Piessen Guillaume , Pocard Marc , Meunier Bernard , Bereder Jean Marc , Abboud Karine , Marchal Frederic , Quenet Francois , Goere Diane , Msika Simon , Arvieux Catherine , Pirro Nicolas , Wernert Romuald , RAT Patrick , Pezet Denis , Lefevre Jérémie , Courvoisier Thomas , Kianmanesh Reza , Meeus Pierre , Glehen Olivier ,   BIG-RENAPE and FREGAT Working Groups
Published: January 2019

8

Background: Gastric cancer with peritoneal carcinomatosis (PC) is considered by most as an end-stage disease. Poor outcomes are achieved with palliative chemotherapy. Aggressive combination of cytroreductive surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are still debated in this indication. Purpose: to assess the impact of HIPEC on survival and postoperative outcomes after complete CRS compared with CRS alone (CRSa) Methods: Data from 277 consecutive patients treated for gastric cancer with PC in 19 French centers from 1989 to 2014 were collected. 180 patients who underwent CRS and HIPEC were compared to 97 treated by CRSa. Extension of PC was assessed by the Peritoneal Cancer Index (PCI). Only patients treated by complete CRS were included (CC-0 or CC-1). To assess the effect of HIPEC and to account for confounding factors, a Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used. Multivariate models and sensitivity analyses were also performed. Results: After propensity weighting, groups were similar except for the PCI that remained higher in the HIPEC group (median: 6 v 2, P = .003). However, there was no difference in the completeness of CRS (CC-0: 76.7% v 83.5 %, P = .904). HIPEC was associated with improved overall survival (OS) on both multivariate and IPTW models. On IPTW analysis, median OS was 18.8 v 12.1 months. 3- and 5-years OS were 26.21% and 19.87% v 10.82% and 6.43% (HR, 1.66; 95% CI, 1.17-2.37; P = .005). 3- and 5-years disease-free survival were 20.40% and 17.05% v 5.87% and 3.76% (P = .001). Mortality rate (7.4% v 10.1%, P = .820) and grade 3-4 morbidity (53.7% v 55.3%, P = .496) at 90 days were similar. Surgical morbidity was 37.1% v 38.8% in CRSa group. Conclusions: Compared to CRSa, HIPEC was associated with increased OS and potential disease eradication for gastric cancer with PC, without additional morbidity. This treatment, when optimal CRS can be achieved, should be considered as the gold standard since outcomes remain grim with chemotherapies. Clinical trail information: NCT03253939
Quality of life at baseline in the international open-label early-access program of trifluridine/tipiracil in previously treated metastatic colorectal cancer (phase IIIb).
Authors: Falcone Alfredo , Taieb Julien , Price Timothy Jay , Seitz Jean Francois , Wyrwicz Lucjan , Becquart Martin , Moreno Shanti , Mounedji Nadjat , Van Cutsem Eric
Published: January 2019

803

Background: Pivotal phase 3 RECOURSE trial evaluated efficacy and safety of trifluridine/tipiracil (FTD/TPI, also known TAS-102) in metastatic colorectal cancer (mCRC) without collecting quality of life (QoL) data (Mayer et al. N Engl J Med 2015;372:1909-19). We set up a phase IIIb open-label, early access program to confirm safety and to assess QoL in mCRC in real-world practice (EudraCT Number: 2016‐002311‐18). First patient (pt) was enrolled in Oct 2016; enrolment is ongoing. Methods: Eligible pts had histologically confirmed mCRC previously treated with, or not considered candidates for, available therapies. Other inclusion criteria include Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Pts planned to receive FTD/TPI (35 mg/m2 bid) orally on days 1–5 and days 8–12 of each 28-day cycle. Pts health-related QoL were measured with the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) and the EuroQol 5-dimension, 3-level (EQ-5D) questionnaires and visual analogue scale (VAS). For the EORTC QLQ-C30 global health status, EQ-5D utility values and VAS, scores could range to a maximum of 100 representing a better health-related QoL. EORTC QLQ-C30 and EQ-5D were considered non evaluable when responses were missing for one third or at least one of the dimensions, respectively. QoL was measured at baseline, every 4 weeks on treatment, and at treatment discontinuation. Results: A total of 298 pts from 7 countries had received at least 1 dose of treatment as of 7 March 2017. Among 271 patients, 39.5% and 60.1% had respectively ECOG PS 0 and 1 at baseline except 1 pt was enrolled with ECOG PS 2. Out of these 298 pts, 263, 261 and 258 were evaluable at baseline for EORTC QLQ-C30 global health status, EQ-5D utility values and VAS, respectively. These means were 62.4 (standard deviation [SD] 21.3), 73.6 (SD 20.3) and 66.1 (SD 19.1), respectively. Conclusions: Analysis of pt QoL in the real-world practice shows it may be substantially deteriorated in heavily pretreated pts with advanced mCRC in spite of having an ECOG PS of 0/1. Preliminary safety /efficacy and QoL results are expected in summer 2018. Clinical trial information: 2016-002311-18.
Adjuvant therapy use and outcomes of stage II and III colorectal cancer (CRC): Comparison of young and elderly patients (pts) in a large, contemporary, population-based Canadian database.
Authors: Samawi Haider , Tilley Derek , Cheung Winson Y.
Published: January 2019

807

Background: The incidence of CRC increases significantly with age. Despite the benefits associated with adjuvant therapy, older pts are frequently treated less aggressively due to perceived poor tolerance to treatment, comorbidity, or limited life expectancy. We aim to examine the impact of chronological age on use of perioperative therapies in a contemporary cohort of pts and determine differences in outcomes based on age. Methods: Adult pts who underwent surgical resection for stage II or III CRC in Alberta, Canada from 2004 to 2015 were analyzed. Pts were stratified based on pre-specified age sub-groups. Overall survival (OS) and cancer specific survival (CSS) were assessed using the Kaplan-Meier method and compared with the log-rank test. A Cox proportional hazards model was constructed to evaluate the impact of age on outcomes. Results: We identified 8,538 pts of whom 56% were men, 53% had stage III disease, and 26% had rectal cancer. Older pts were more likely diagnosed with right-sided tumors, earlier stage, and higher Charlson comorbidity index (CCI) (all p <.01). Chemotherapy (CT) use decreased significantly with advancing age, even in recent years (Table). Older rectal cancer pts were also less likely to receive radiation (p <.01). Elderly age was the strongest predictor for not using CT, after adjusting for sex, stage, tumor location, and CCI. On multivariate Cox regression, older age was associated with inferior OS and CSS, but CT improved outcomes. Conclusions: Despite evidence of benefit and prior studies recommending treatment of elderly, the current cohort of older pts with resected stage II and III CRC continue to undergo perioperative therapy less commonly than their younger counterparts. [Table: see text]
Facility variation in clinical staging of rectal adenocarcinoma and its contribution to underutilization of neoadjuvant therapy.
Authors: Swords Douglas S. , Skarda David E. , Stoddard Gregory J. , Kim H. Tae , Sause William T. , Scaife Courtney L.
Published: January 2019

810

Background: Studies of the National Cancer Database (NCDB) found that neoadjuvant therapy (NAT) for clinical stage II-III rectal adenocarcinoma is underutilized, but they reclassified patients without clinical staging by pathologic stage. Methods: Study of patients < 80 with resected clinically non-metastatic rectal adenocarcinoma in the 2010-2014 NCDB. Reliability-adjusted (RA) facility rates of clinical staging were calculated. Then, patients with clinical stage I, unknown clinical/pathologic stage 0-1 and NAT contraindications/refusal were excluded. Multivariable Poisson regression was used to examine predictors of NAT. Multiple imputation was used to account for missing data. RA facility NAT rates were calculated. Variance partitioning was used to examine causes of omission of NAT. Results: Of 26220 patients with clinical stage II-III or unknown clinical/pathologic stage II-III, 3634 (14%) were not clinically staged. RA facility clinical staging rates ranged from 17%-99%. NAT was delivered to 20415/22586 (90%) patients who were clinical stage II-III vs. 1372/3634 (38%) of those without clinical staging. Of 4443 patients who did not receive NAT, 2262 (51%) did not have clinical staging. Treatment at facilities with higher volume and clinical staging rates was associated with delivery of NAT. RA facility NAT rates ranged from 33%-96%. Patient factors explained 15% of variance in facility NAT rates, type/volume 16%, and facility clinical staging rates 23%. Conclusions: A single process (omission of clinical staging) is present in half of cases omitted NAT (Pareto principle). Facility NAT rates vary 3-fold, and facility clinical staging rates explain much of the variation in use of NAT. Efforts to increase utilization of clinical staging are warranted. [Table: see text]
The significance and long-term clinical outcome of preoperative chemoradiotherapy using S-1 plus Irinotecan for locally advanced rectal cancer.
Authors: Kimura Kei , Beppu Naohito , Tsukamoto Kiyoshi , Yamano Tomoki , Noda Masafumi , Ikeda Masataka , Tomita Naohiro
Published: January 2019

819

Background: Preoperative chemoradiotherapy regimen using S-1 plus Irinotecan is still under clinical investigation. The aim of this study was to investigate the significance and the long-term outcomes of this regimen for locally advanced rectal cancer. Methods: Between 2009 and 2016, 81 patients underwent radical surgery after preoperative chemoradiotherapy. Radiotherapy was administered in total 45Gy with 1.8Gy/day for 25 days. S-1 was administered orally in a fixed daily dose of 80mg/m2 on days 1 to 5, 8 to 12, 22 to 26, and 29 to 33. Irinotecan was infused with dose of 80 mg/m2 on days 1, 8, 22, and 29. 6-9 weeks after the completion of the treatment, radical surgery was performed. The median follow-up was 35.3 months. Results: Of the 81 patients, 76 (93.8%) completed treatment of chemoradiotherapy. Relative dose intensity of CPT-11 was 92.8%, S-1 was 90.1%. 79 (97.5%) patients completed the radiotherapy. 18 patients (22.2%) had ≧Grade 3 hematologic toxicity (leukopenia; 15 patients, neutropenia; 16 patients ). 23 patients (28.3%) had ≧Grade 3 nonhematologic toxicity (diarrhea). In terms of the surgical procedure, 73 of 81 patients (90.1%) underwent sphincter-preserving surgery including 42 patients intersphincteric resection, and 8 patients (9.9%) underwent abdominoperineal resection. The tumor regression grade of 1/2/3(pCR) was 30/39/12(14.8%). In terms of long-term survival, 3-year local relapse-free survival rate was 96.7%, the recurrence-free survival rate was 71.6% and 3-year overall survival rate was 94.9%. Conclusions: Preoperative chemoradiotherapy using combined with Irinotecan as secondary drugs may result safe and feasible and accomplished favorable downstaging. This regimen was considered to be effective in patients with locally advanced rectal cancer.
Clinical outcome for continuous versus intermittent chemotherapy for unresectable metastatic colorectal cancer: Comparative analysis after first-line therapy.
Authors: Abdallah Nadine , Mohamed AMR , Ismail Hibah , Chen Wei , Akhras Alaa , Jang Hyejeong , Smith Daryn W. , Tesfaye Anteneh A. , Philip Philip Agop , Shields Anthony Frank
Published: January 2019

825

Background: Colorectal cancer (CRC) is the third most common and second most lethal cancer in the U.S, with almost 50% of patients developing metastatic disease. Although survival of metastatic CRC (mCRC) has improved significantly, current treatment strategies are associated with many adverse effects. With no prospect of cure, goals of treatment should consider both quantity and quality of life. Interruption of chemotherapy after induction can represent a means to achieve this balance. Methods: The primary objective of this meta-analysis is to assess the effect of continuation vs interruption of systemic therapy in terms of survival in patients with unresectable mCRC after first line treatment. Among 15 prospective studies published from 2009-2017, 9 qualified for inclusion. Random-effect model was used for pooled effects within two main categories: continuous chemotherapy vs chemotherapy-free interval after first line induction. Studies with maintenance fluoropyrimidine and/or bevacizumab were excluded. Primary endpoint was median progression free survival (PFS) and secondary endpoint was median overall survival (OS). z statistics were used for comparing subgroups. All statistical tests were two-sided. P values < 0.05 were considered significant. Results: 1366 patients (55% males) were included in the final analysis. Induction treatment was 5-FU or capecitabine-based chemotherapy with either oxaliplatin or irinotecan with or without bevacizumab. After stratifying for induction status, there was no statistically significant difference in median PFS between continuous vs chemotherapy free interval [Median PFS 4.74-month (95% CI 3.87-5.61) vs 3.52 month (95% CI 2.97-4.07), z-test adjusted p value 0.1383]. No significant difference in median OS between both groups [Median OS 16.95-month (95% CI 15.40-18.50) vs 18.35 month (95% CI 15.17-21.54)]. Conclusions: In mCRC patients, the superiority of continuous chemotherapy was not demonstrated. Further studies should shed light on patient and tumor characteristics most likely to benefit from continuous chemotherapy to limit delivery of cytotoxic therapy to this subset of patients.