bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of bevacizumab and systemic therapy in metastatic colorectal cancer (mCRC) patients with peritoneal disease in the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) database.
Authors: Roohullah Aflah , Wong Hui-li , Sjoquist Katrin Marie , Field Kathryn Maree , Tran Ben , Shapiro Jeremy David , McKendrick Joseph James , Yip Desmond , Nott Louise M. , Gibbs Peter , Chantrill Lorraine A.
Published: February 2017

569

Background: Patients (pts) with peritoneal metastases from CRC are considered a poor prognostic group. Data on safety and efficacy of systemic chemotherapy and bevacizumab (BEV) in these pts are limited. Of particular concern peritoneal disease has been reported to increase the risk of GI perforation in pts treated with BEV. Methods: TRACC is a prospective, multisite, mCRC registry with data collection ongoing at 14 Australian hospitals since July 2009. Data related to baseline demographics, treatment and outcomes were extracted and differences between pts with and without peritoneal disease were examined. Results: 1,012 pts were identified, median age 68 years (range 19-97), 179 (17.7%) had peritoneal disease at diagnosis; median follow up was 20.9 months (m). In pts with peritoneal disease there were a higher proportion of pts with poor ECOG (2-4) 30.2% vs. 17.1% p = 0.0002; colon primary 87.7% vs. 66.7% p < 0.0001; and multiple disease sites p < 0.0001. A similar proportion received chemotherapy in the peritoneal group 136/179 (76.0%) compared to the non-peritoneal group 619/833 (74.3%). In the peritoneal group 90/136 (66.2%) received BEV. For patients with peritoneal disease the addition of BEV to chemotherapy was associated with an improved PFS 8.6m vs. 5.1m (HR = 0.62 95%CI 0.40-0.96 p = 0.034) and OS 18.7m vs. 12.1m (HR = 0.59 95%CI 0.36-0.96 p = 0.032) compared to chemotherapy alone. On univariate analysis the proportional benefit from the addition of BEV was similar to the non-peritoneal group. GI perforation was not increased in BEV-treated pts with peritoneal disease 2/90 (2.2%) vs. 8/332 (2.4%) without peritoneal disease, p = 1.000. Conclusions: In routine clinical practice, clinicians appear comfortable prescribing BEV in the presence of peritoneal disease. The addition of BEV to chemotherapy in these pts appears to be safe, with no apparent excess risk of GI perforation, and is associated with an improved PFS and OS. Multivariate analyses are planned.
A phase I/II study of cetuximab (cet) in combination with S-1 and oxaliplatin (SOX) in first-line treatment for metastatic colorectal cancer (mCRC) (JACCRO CC-06).
Authors: Tsuji Akihito , Sunakawa Yu , Denda Tadamichi , Takinishi Yasutaka , Kotaka Masahito , Tanioka Hiroaki , Shimada Ken , Kochi Mitsugu , Watanabe Takanori , Nakamura Masato , Ueda Hiroto , Inukai Michio , Masuishi Toshiki , Tani Satoshi , Negoro Yuji , Okuno Tatsuya , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi , Nakajima Toshifusa
Published: February 2017

571

Background: Both SOX and cet are effective treatments each other in patients (pts) with mCRC. COIN trial indicated that the use of cet in combination with capacitabine and oxaliplatin should not be recommended. However, the safety and efficacy of cet plus SOX are not clear. To evaluate the safety and clinical efficacy of the combination, we conducted a multi-center phase I/II study. Methods: In this trial, we assigned pts with KRAS wild type (wt), EGFR-expressing tumor and no prior chemotherapy to receive cet (initial dose 400, and 250 mg/m2 weekly) followed by SOX (oxaliplatin on day 1 and S-1 40 mg/m2 twice daily on days 1-14). The treatment was repeated every 3 weeks. The phase I part was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) according to the dose adaptation schedule of oxaliplatin (100 mg/m2 for level 1 and 130 mg/m2 for level 2). In the following phase II part, the enrolled pts were treated with the RD. The primary endpoint was response rate (RR) evaluated by the external review board according to RECIST criteria v1.1. Secondary endpoints included PFS, OS, and safety. In addition, we prospectively evaluated early tumor shrinkage (ETS). Results: A total of 67 pts were enrolled from January 2012 to February 2013. In the phase I part, level 2 was determined to be the RD. The MTD was not determined because dose limiting toxicity was not confirmed in level 2. In the phase II part, 59 pts including 6 pts of phase I cohort were assessable for the efficacy. The median age was 64 years, 51% of pts were male, and ECOG PS 0 was observed in 85% of pts. The median course of treatment was 5 (range 1-14). The RR was 62.7% (95%CI, 50.4 to 75.1) and ETS was observed in 72% of pts. In safety analysis, grade 3 or worse adverse events were platelet count decreased (13.1%), neutropenia (8.2%), anorexia (11.7%), rash acneform (6.7%) and peripheral neuropathy (3.3%). Conclusions: We determined the RD of cet plus SOX treatment in pts with mCRC. This combination is tolerable at full doses of cet and SOX, with manageable toxicities, and demonstrates advantages in RR for pts with KRAS wt tumor. Updated safety and efficacy data will be presented. Clinical trial information: UMIN000007022.
Dietary and behavioral adjustments to control bowel function by long-term colorectal cancer survivors.
Authors: Sun Virginia , Grant Marcia , Wendel Christopher S. , McMullen Carmit K. , Bulkley Joanna E. , Altschuler Andrea , Ramirez Michelle L. , Baldwin Carol M. , Rawl Susan , Herrinton Lisa J. , Hornbrook Mark C. , Krouse Robert S.
Published: February 2017

573

Background: Bowel dysfunction is a known complication of colorectal cancer (CRC) treatment, and has a detrimental impact on survivors’ health-related quality of life (HRQOL). The prevalence of dietary and behavioral modifications in CRC survivors has been described in only a small number of studies. To better understand dietary and behavioral adjustments that long-term (≥ 5 years) CRC survivors make to regulate their bowel function, we performed a mixed methods analysis, comparing survivors with a permanent ostomy and those with anastomosis. Methods: CRC survivors with or without permanent ostomies were surveyed with the modified version of the City of Hope Quality of Life for Ostomy tool (N=919).Dietary adjustments were compared by ostomy status (ostomy versus anastomosis) and higher quartile versus lower quartile HRQOL scores.Student’s t-tests were used to compare HRQOL measures between groups. Qualitative data from 13 focus groups (N=63) and interviews with 30 female ostomates were analyzed to explore specific strategies used for regulating bowel function. Results: CRC survivors make substantial andpermanent dietary adjustments following treatment. The majority of survivors reported that they took more than one month to feel comfortable with their diet, and many (10% to 18%) never became comfortable. No significant dietary adjustment differences were noted based on ostomy status. Survivors who took less time (<1 month) to feel comfortable with their diet and for their appetite to return had better HRQOL (p < 0.001) ≥ 5 years later. Adjustments to control bowel function consisted of four overall strategies: dietary adjustments, behavioral adjustments, exercise, and medications. Conclusions: CRC survivors use a multitude of adaptive strategies to control their bowel function. Many survivors struggle with unpredictable bowel function continually for the rest of their lives, and many never find any set of management strategies to achieve regularity. Understanding the myriad of adjustments made by CRC survivors will lead to evidence-based recommendations to foster positive adjustments after cancer treatment.
A phase II clinical trial of preoperative chemoradiotherapy (CRT) with oral S-1 plus bevacizumab in patients with middle or lower rectal adenocarcinoma.
Authors: Sadahiro Sotaro , Suzuki Toshiyuki , Tanaka Akira , Okada Kazutake , Saito Gota , Kamijo Akemi
Published: February 2017

575

Background: Preoperative CRT decreases local failure and increases sphincter preservation in patients with clinical stage II or III rectal cancer. Patients with ypCR after CRT reveal better oncologic outcomes. S-1 is an oral fluoropyrimidine with radiosensitizing activity. We previously reported preoperative CRT with S-1 was effective (ypCR 22.2%) and safe (Oncology 2011). Combining bevacizumab with 5-FU- or capecitabine-based CRT had been reported to provide promising results. We evaluated the effectiveness and safety of bevacizumab plus S-1-based CRT. Methods: The subjects were 46 patients with clinical stage II or III adenocarcinoma of the mid or low rectum enrolled from Feb. 2011 through May 2013. Pelvic radiotherapy was given in a total dose of 45 Gy, delivered in 25 factions. S-1 (80 mg/m2/day) was given orally twice daily for a total of 28 days during weeks 1, 2, 4, and 5. Bevacizumab (5 mg/kg) was administered a total of 3 times at day 1, 15, and 29. Mesorectal excision was performed 6 to 8 weeks after the completion of CRT. The primary endpoint was the ypCR rate. Secondary endpoints were the degree of tumor shrinkage, sphincter-preservation rate, and safety. Results: Clinical stage was II in 13 patients and III in 33. The median interval from the completion of CRT to surgery was 8 weeks (range, 4 to 9). The ypCR rate was 21.7% (10/46), with a T downstaging rate of 54.3% and an N downstaging rate of 50.0%. The degree of tumor shrinkage was 51.8 ± 16.6% (mean ± SD) on barium enema and 77.7 ± 11.1% on a volumetric analysis based on MRI. The sphincter-preservation rate was 76.1% (35/46). Grade 3 or higher adverse event occurring during CRT was leukopenia in 1 patient (2.2%). Surgery was not postponed because of adverse events in any patient. However, 63.0% of the patients had anal pain (grade 1, 6 patients; grade 2, 23). Postoperative complications occurred in 32.6%: anastomotic leakage in 25.7% (9/35) in LAR and perineal wound dehiscence in 18.2% (2/11) in APR. Conclusions: CRT with S-1 plus bevacizumab had similar antitumor effectiveness and adverse events as CRT only with S-1, but was associated with higher incidences of perioperative complications related to wound healing. Clinical trial information: 10R-113.
Efficacy and safety of single agent (SA) or combination (CO) adjuvant chemotherapy (AC) in elderly patients with colon cancer: A Canadian cancer institute experience.
Authors: Kim Christina , Spratlin Jennifer L. , Ghosh Sunita , Armstrong Dawn Elizabeth , Mulder Karen E.
Published: February 2017

581

Background: Although AC is recommended for colon cancer, the pattern of AC use in elderly patients (pts), the toxicity profile, & survival benefit is unclear. We sought to (1)determine whether pts ≥ 65 years old with stage III colon cancer were being offered SA or CO AC; (2)evaluate the reason for selecting SA vs. CO AC; (3)evaluate the toxicity profile of SA and CO in the elderly; and (4)determine whether a survival benefit exists for elderly pts receiving CO AC. Methods: Pts ≥ 65 diagnosed with stage III colon cancer at the Cross Cancer Institute from 2004-2010 were identified from the cancer registry. A retrospective analysis of electronic and paper patient records was performed to identify baseline characteristics, AC protocols used, toxicity, dose intensity and survival. Results: 258 pts ≥ 65 years old were diagnosed and treated with AC from 2004-2010. Of these, 168 were treated with SA and 90 with CO AC. The most common reasons for choosing SA AC were patient preference (64%), comorbidities (10%), and lack of drug coverage by provincial formulary (15%). 93 pts ≥age 75 were treated with SA AC, whereas only 10 pts ≥ 75 were treated with CO AC. Multivariate analysis revealed that for each year above 65, the adjusted odds of receiving CO over SA AC decreased by 22%. The presence of cardiac comorbidities decreased the adjusted odds of receiving CO AC by 58%. 28% of pts treated with SA and 6% of those treated with CO AC had initial dose reductions, with most common reasons being comorbidities and age. 67%, 71%, and 29% received dose delays, reductions or drug discontinuation in the SA group, respectively. 72%, 58%, and 34% received dose delays, reductions or drug discontinuation in the CO group respectively, mostly due to hematologic toxicity. The 5 year OS was 73% in pts who received SA AC, compared to 84% in those who received CO AC. A competing risk analysis showed no difference in cancer-related deaths between the CO and SA AC groups. Conclusions: In elderly pts treated with AC for stage III colon cancer, SA AC is used more frequently than CO AC, based on age, comorbidities, and patient choice. Toxicity with CO AC in elderly pts is high, leading to decreased dose intensity. No survival benefit was seen with CO AC over SA AC.
Cost differential among systemic therapies for colon cancer.
Authors: Nadeem Hasan , Jayakrishnan Thejus T. , Gamblin T. Clark , Turaga Kiran
Published: February 2017

583

Background: The National Comprehensive Cancer Network (NCCN) has outlined recommendations for the treatment of various cancers that incorporates alternative chemotherapeutic strategies presumed to be of similar effectiveness. We hypothesized that there is a significant cost-differential between the therapeutically equivalent systemic therapy regimens for colon cancer. Methods: Details of chemotherapy regimens outlined in NCCN guidelines (2013) were acquired for colon cancer. Costs (US$) were calculated based on the payment allowance for Medicare part-B drugs database (2013). Dosage amounts were calculated for an average American patient and additional costs (treatment time, pumps) were added to determine total treatment costs for 6 months. Results: Total of 25 regimens were studied. The median cost for systemic treatment of metastatic colon cancer for a 6-month period was $34,840 (IQR $9,420-$68,840, n=20). The median cost for adjuvant treatment alone was $13,870 (range $2,600-$33,230, n=5). The cost-differential for a single patient between FOLFOX and Folfiri+ziv-aflibercept was $4.2 million for metastatic colon cancer. The addition of novel antineoplastics dramatically increased the price of chemotherapy (Table). Conclusions: Economically significant cost differential exist between chemotherapeutic regimens prescribed as equally effective. Hierarchical adoption of regimens based on therapeutic benefit, cost and patient-specific toxicity profile may help reduce health care costs. [Table: see text]
Bevacizumab (Bmab) in combination with uracil-tegafur (UFT) and oral leucovorin (LV) in elderly patients (≥ 75 years old) with metastatic colorectal cancer (mCRC): A multicenter phase II trial (J-BLUE study).
Authors: Shimada Mitsuo , Nishina Tomohiro , Higashijima Jun , Moriwaki Toshikazu , Masuishi Toshiki , Sakai Yoshinori , Ozeki Mitsuharu , Negoro Yuji , Indou Shunju , Denda Tadamichi , Sato Mikio , Morimoto Masamitsu , Nakajima Go , Mizuta Minoru , Takahashi Ikuo , Hiroshima Yoshinori , Ishida Hiroyasu , Maeba Takashi , Hyodo Ichinosuke ,   Shikoku Gastrointestinal Oncology Study Group (SGOSG) and Tsukuba Cancer Clinical Trial Group (TCTG)
Published: February 2017

588

Background: Now fluoropyrimidine plus Bmab is considered a recommendable option to the majority of elderly mCRC patients who are deemed inappropriate for the standard doublet chemotherapy with biologics. Our previous phase II study of UFT/ LV in elderly mCRC patients (≥75 years old) had demonstrated acceptable safety and efficacy (overall response rate [ORR] 33%, progression-free survival [PFS] 5.3 months, overall survival [OS] 18 months). The aim of the present study was to investigate the efficacy and safety of Bmab in combination with UFT/LV for elderly mCRC patients. Methods: This study was designed as a single-arm, open-label, multicenter, cooperative group (SGOSG-TCTG) clinical trial (trial registration: UMIN000003515). Key eligibility criteria included age ≥75 years, ECOG performance status (PS) 0 or 1, first-line chemotherapy, measurable lesions, and preserved organ functions. Patients received UFT 300mg/m2/day and LV 75mg/body/day on days 1-21 followed by 7 days rest, and intravenous administration of Bmab 5mg/kg on days 1 and 15. Treatment repeated every 28 days. The primary endpoint was PFS, and secondary endpoints were ORR, OS, and safety. Results: A total of 55 patients were enrolled from 15 institutions between Aug 2008 and Mar 2012. Among them, 52 eligible patients were evaluated. Median age was 80 years (range: 75-87). ECOG PS 0 was 73%. Median PFS was 8.2 months (95% confidence interval [CI], 6.2-10.3, events in 86.5%). Confirmed ORR was 40.4% (95% CI, 27.0-54.9%). Median OS was 18.7 months (95% CI, 10.3-27.0, events in 48%). The most common grade ≥3 treatment-related adverse events were hypertension (11.5%), fatigue (7.7%), nausea (5.8%), and diarrhea (5.8%). The treatment-related death occurred in 2 (3.8%) patients. Main reasons for discontinuation of treatment were disease-progression (62.5%) and toxicity (27.1%). Conclusions: Bmab in combination with UFT/LV is tolerable and effective treatment option for elderly patients (≥75 years old) with mCRC. Further trial with Bmab plus UFT/LV targeting elderly mCRC patients would be warranted. Clinical trial information: 000003515.
Response rates to hepatic arterial infusion (HAI) pump therapy in patients with metastatic colorectal cancer liver metastases (mCRC LM) after progression on all standard chemotherapies.
Authors: Cercek Andrea , Aguilo Ariel , Gluskin Jill , Chou Joanne F. , Reidy Diane Lauren , Saltz Leonard , Siegel Cara , Capanu Marinela , Jarnagin William R. , DeMatteo Ronald P. , Allen Peter J. , Kingham Peter T. , Fong Yuman , D'Angelica Michael Ian , Kemeny Nancy E.
Published: February 2017

597

Background: To evaluate the overall response rate of HAI with floxuridine (FUDR) in the refractory setting in patients with mCRC LM. Methods: After obtaining an IRB waiver a computerized search was performed for patients with mCRC treated with 5FU, oxaliplatin and irinotecan +/- EGFR and VEGF inhibitor from 2003-2012. Charts were reviewed to ensure patients (pts) had received all standard therapies prior to HAI pump placement. All pts received HAI FUDR and no new systemic targeted or cytotoxic therapies were used with HAI pump. Imaging was re-reviewed for confirmation of progression prior to HAI pump placement and for best response using RECIST 1.1 criteria. Results: 75 pts were identified; of these 23 had radiographic disease progression on all standard chemotherapies (5FU, irinotecan and oxaliplatin) prior to having a pump placed. Of the 23 evaluable pts, the median age was 53 (range 37-75). Six pts had low volume extrahepatic metastases at the time of pump placement. The overall response rate (ORR) was 8/23 (35%); 10/23 (43%) pts had stable disease (SD). The median duration of SD was 4 months (range 1-10). Median follow up, measured from the date of HAI initiation, was 24 months and median overall survival (OS) was 22 months (95% CI 13-16). The median hepatic progression free survival (hPFS) was 4.5 months [CI: 3.8-6.7]. Thirteen pts developed extrahepatic disease progression (including 5 pts with preexisting extrahepatic disease). The median overall PFS was 3.9 months [95% CI 2.24-5.33]. Median number of HAI treatments was 4 cycles (range 1-13). Six out of 23 (26%) pts required a 50-75% dose reduction by the second cycle due to elevated liver function tests and 18/23 (78%) required a dose reduction after the 3rd cycle. No pts required stents or developed long term liver or biliary toxicity. Conclusions: In a cohort of 23 patients with mCRC LM, refractory to all standard agents, treatment with HAI FUDR resulted in an ORR by RECIST 1.1 of 35% and median OS of 22 months. Further studies focusing on locoregional therapy in patients with liver predominant disease are warranted. Studies to molecularly characterize these tumors are ongoing.
Mesothelin expression in patients as a novel target in gastric cancer.
Authors: Kelly Ronan Joseph , Pastan Ira , Cowan Morgan L , Montgomery Elizabeth , Hassan Raffit , Alewine Christine Campo , Xiang Laiman , Illei Peter B.
Published: February 2017

61

Background: Novel targets and therapeutics are of profound importance if we are to improve outcomes in gastric cancer. This study assessed the incidence of mesothelin expression in tumors of Western patients with gastric cancer. In addition, gastric cancer cell lines were then tested for their sensitivity to SS1(dsFv)PE38 (SS1P), a mesothelin-targeted immunotoxin. Methods: Tissue specimens from 127 patients with gastric or gastro-esophageal junction (GEJ) tumors were examined by immuno-histochemistry (IHC) for intensity of staining for mesothelin. Expression of HER2-neu, e-cadherin and c-Met were also assessed. Tumors were considered positive for mesothelin if moderate cytoplasmic/membranous or luminal staining was present in at least 10% of the cells. Gastric cancer cell lines were assessed for surface mesothelin expression by flow cytometry and the viability of cells treated with SS1P was measured. Results: Gastric and GEJ cancers were mesothelin positive in 64/127 tumors (50%) while only 9 tumors (7%) were Her2-neu IHC +3 positive and 8 tumors (6%) were c-Met positive (c-Met low 5% and c-Met high 1%). Mesothelin expression rates changed from stage I tumors to stage IV tumors (39% to 56% respectively). We found that both the AGS and MKN28 gastric cancer cell lines express mesothelin and are sensitive to the immunotoxin with EC50 values in the low picomolar range (0.4 and 0.3 ng/mL, respectively). Conclusions: Mesothelin is a cell surface glycoprotein that is expressed in 50% of resected gastric cancers. Gastric cancer cell lines were exquisitely sensitive to SS1P. The high expression of mesothelin and its sensitivity to the immunotoxin SS1P makes it an attractive tumor associated antigen for therapeutic targeting. Based on these observations clinical trials involving novel mesothelin targeted drugs in gastric cancer are currently in development.
The degree of segmental aneuploidy measured by total copy number abnormalities to predict survival and recurrence in superficial gastroesophageal adenocarcinoma.
Authors: Davison Jon M. , Krill-Burger J. Michael , Yee Melissa K. , Foxwell Tyler J. , Lyons-Weiler Maureen A. , Luketich James D. , Nason Katie S. , Michalopoulos George K. , LaFramboise William A
Published: February 2017

62

Background: Prognostic biomarkers are needed for superficial gastroesophageal adenocarcinoma (EAC) to predict clinical outcomes and select therapy. Although recurrent mutations have been characterized in EAC, little is known about their clinical and prognostic significance. Aneuploidy is predictive of clinical outcome in many malignancies but has not been evaluated in superficial EAC. SNP arrays offer the opportunity to evaluate segmental aneuploidy at high resolution throughout the genome. Methods: We quantified copy number changes in 41 superficial EAC using Affymetrix SNP 6.0 arrays. We identified recurrent chromosomal gains and losses and calculated the total copy number abnormality (CNA) count for each tumor as a measure of aneuploidy. We correlated CNA count with overall survival and time to first recurrence in univariate and multivariate analyses. Results: Recurrent segmental gains and losses involved multiple genes, including: HER2, EGFR, MET, CDK6 , KRAS (recurrent gains); and FHIT, WWOX, CDKN2A/B, SMAD4, RUNX1 (recurrent losses). There was a 40-fold variation in CNA count across all cases. Tumors with the lowest and highest quartile CNA count had significantly better overall survival (p=0.032, log rank test) and time to first recurrence (p=0.010, log rank test) compared to those with intermediate CNA counts. In multivariate Cox analysis, there was a 3.4-fold (95% CI, 1.1–10.4) increased hazard of death among cases with intermediate CNA counts after adjusting for other predictors of survival (N stage, angiolymphatic invasion and tumor size). Similarly, there was a 7.3-fold (95% CI, 1.5-34) increased risk of recurrence for these patients. Conclusions: SNP arrays facilitate the assessment of recurrent chromosomal gain and loss and allow high resolution, quantitative assessment of segmental aneuploidy (total CNA count).The non-monotonic association of segmental aneuploidy with survival has been described in other tumors such as breast and ovarian carcinoma. The degree of segmental aneuploidy is a promising prognostic biomarker in a potentially curable form of EAC.
Acceptance of sphincter-preserving surgery for T3 lower rectal cancer after short-course radiotherapy with delayed surgery.
Authors: Beppu Naohito , Yanagi Hidenori , Yamanaka Naoki , Doi Hiroshi , Kamikonya Norihiko , Noda Masafumi , Tomita Naohiro
Published: February 2017

620

Background: One of the reasons for avoiding sphincter-preserving surgery for lower rectal cancer is difficulty in obtaining a sufficient distal margin. Short-course radiotherapy (SRT) with immediate surgery is not expected to reduce tumor volume, and currently available evidence suggests that it does not increase the sphincter-preservation rate. However, SRT with delayed surgery has been linked to downsizing of the primary tumor during the waiting period. We evaluated the feasibility of sphincter-preserving surgery for T3 lower rectal cancer after SRT with delayed surgery and examined whether a distal margin of ≤ 5 mm has an impact on oncologic outcomes. Methods: We retrospectively studied 161 consecutive patients with lower rectal cancer located below the peritoneum reflection who underwent radical surgery with total mesorectum resection (TME) 3 to 4 weeks after the completion of SRT. The median follow-up was 53.5 months. Results: Sphincter-preserving surgery was performed in 149 (92.5%) of the 161 patients. The procedures were as follows: double-stapling technique, 58 patients; intersphincteric resection, 91; abdominoperineal resection, 10; and Hartmann operation, 2. Among the patients who underwent sphincter-preserving surgery, the distal margin was ≤ 5 mm in 41 patients and > 5 mm in 108. The local recurrence rate was respectively 5.8% vs. 10.4% (p = 0.606), the recurrence-free survival 83.4% vs. 82.8% (p = 0.682), and the overall survival at 5 years 82.3% vs. 87.6% (p = 0.418). Our results suggested that there is no difference in long-term outcomes between a distal margin of ≤ 5 mm and > 5 mm. Conclusions: Sphincter-preserving surgery was performed in 92.5% of patients with T3 lower rectal cancer who received SRT with delayed surgery. Our results confirmed the long-term oncologic feasibility of sphincter-preserving surgery with a distal margin of ≤ 5 mm; there was no negative impact on long-term outcomes such as local recurrence, recurrence-free survival, and overall survival.
Exploratory randomized trial to evaluate the effect of indisetron tablets for preventing chemotherapy-induced nausea and vomiting (CINV)/acute-onset diarrhea induced by IRIS/FOLFIRI: HGCSG0704.
Authors: Kato Sosuke , Fukushima Hiraku , Kato Kanji , Yuki Satoshi , Harada Kazuaki , Kobayashi Yoshimitsu , Sasaki Takahide , Ehira Nobuyuki , Iwanaga Ichiro , Uebayashi Minoru , Dazai Masayoshi , Sogabe Susumu , Miyagishima Takuto , Kudo Mineo , Hatanaka Kazuteru , Naruse Hirohito , Tateyama Miki , Sakata Yuh , Komatsu Yoshito
Published: February 2017

624

Background: Indisetron is a 5-HT3 receptor antagonist that also antagonizes 5-HT4receptors. Indisetron tablets showed the non-inferiority to ondansetron tablets in terms of efficacy for preventing CINV. Moreover, preclinical data administered with irinotecan showed indisetron significantly reduced stool frequency in mice and inhibited the colonic peristalsis in dogs. We designed a pilot study compared with granisetron in the efficacy and tolerability of indisetron for irinotecan-induced nausea, vomiting and especially in diarrhea. Methods: Advanced colorectal cancer patients treated with FOLFIRI or IRIS (Irinotecan + S-1) with or without bevacizumab were enrolled in this study. Treatment: Arm A: indisetron tablets 8mg po day1. Arm B: granisetron 3mg iv day 1. The primary endpoints were the incidence of acute-onset diarrhea and complete protection from vomiting. Secondary endpoints were tolerability, complete protection from nausea and rate of no rescue medication. Results: Between May 2008 and July 2012, 33 patients (pts) were randomized. The study was closed prematurely due to poor accrual. Arm A: 16 pts, arm B 17 pts. Median age A: 68 y.o., B: 66 y.o.: ECOG PS 0/1: A: 12/4, B: 14/3pts. There was no significant difference of the incidence of acute-onset diarrhea between both groups (18.8% in A vs. 35.3% in B, p = 0.438). The proportion of complete protection from vomiting was 87.5% in A and 88.2% in B (p = 1.000). Similarly, complete protection from nausea, rate of no rescue medication, proportion of patients with a complete response (defined as no emetic episodes and no rescue medication) did not have a significant difference. Severity of nausea/vomiting and AE induced by 5-HT3 receptor antagonist were also similar between two groups. Conclusions: Compared with granisetron, indisetron showed effective and feasible results for preventing CINV induced by FOLFIRI or IRIS. Indisetron had also not improved the incidence of acute-onset diarrhea induced by irinotecan. Clinical trial information: UMIN000010162.
Comparison of two bidirectional hyperthermic intraperitoneal chemotherapy (HIPEC) regimens in patients with colorectal peritoneal metastasis.
Authors: Glockzin Gabriel , Gerken Michael , Lang Sven A. , Schlitt Hans J. , Piso Pompiliu
Published: February 2017

628

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) became part of many national and international treatment guidelines as an additive therapeutic option for selected patients with colorectal peritoneal metastasis. Multiple HIPEC regimens are used regarding cytotoxic agents, concentration, perfusion time an other parameters and consistent data for standardization is missing. Methods: 32 consecutive patients after complete macroscopic cytoreduction (CC-0/1) and bidirectional HIPEC for colorectal peritoneal metastasis were retrospectively analyzed. Twenty patients received oxaliplatin-based and twelve patients received irinotecan-based HIPEC. Morbidity and toxicity according to CTCAE v4, mortality and 3-year survival rates hava been determined. Results: The overall 3/4 morbidity rate was 34.4 % and the perioperative mortality rate 0 % in both groups (p = 1.000). Median survival was 26.8 months (95 % CI 15.7-33.1 months) in the IRI group and has not yet been reached in the OX group. 3-year survival rates were 65.0 % in the OX group vs. 41.7 % in the IRI group (p = 0.295). Conclusions: Both HIPEC regimens showed comparable morbidity and toxicity. Nevertheless, oxaliplatin-based HIPEC might be preferred due to the not significant positive survival trend. Prospective randomized trials are needed to compare the different HIPEC regimens and to determine the most effective therapeutic approach.
Clinical benefits of bevacizumab in metastatic colorectal cancer depending on KRAS status.
Authors: Kurimoto Keisuke , Ishigure Kiyoshi , Kato Yoshiyasu , Asai Yasuyuki , Tanaka Nobutake , Ryo Song , Matsushita Hidenobu , Tobinaga Junichi , Fukuyama Ryuichi , Kuroda Hiruhumi , Fujii Tomoo
Published: February 2017

636

Background: KRAS status is the therapeutic marker of anti-EGFR drug, and may be the prognostic marker of metastatic colorectal cancer (mCRC). However, there is no consensus whether bevacizumab (anti-VEGF drug) benefits patients with mutated KRAS in mCRC. We investigated the clinical benefits of bevacizumab treatment in mCRC depending on KRAS status, retrospectively. Methods: We investigated 49 patients who received chemotherapies with bevacizumab as first-line treatment for mCRC from May 2008 through June 2013. We evaluated response rate (RR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tumor reduction rate and the adverse events (CTCAE v4.0 - JCOG) depending on KRAS status. Results: The median age of the patients was 66 years (range; 36 - 80). Forty-five patients received oxaliplatin-based chemotherapies with bevacizumab and four patients received irinotecan-based chemotherapies with bevacizumab. KRAS status of 30 patients was wild type and that of 19 patients was mutation type. There was no difference in patient characteristics between KRAS wild type (WT) and mutation type (MT). In all 49 patients, RR was 62.5%. DCR was 91.7%. The median PFS was 10.9 months. In RR, patients with KRAS wild type tumors had better outcome than patients with mutant type tumors (WT : MT, 69.0% : 52.6%, no statistically difference). A similar tendency was seen in DCR (WT : MT, 96.6% : 84.2%, no statistically difference). The average reduction rate in KRAS WT was 42.7% and in KRAS MT was 32.3% (p = 0.309). In the KRAS wild patients, the median PFS was longer than that in the KRAS mutant patients (WT : MT, 11.8 : 8.9 months, Log Rank p = 0.583), but there is no statistically difference between two groups. In median OS, there was no difference between two groups (WT : MT, 21.0 : 20.8 months, Log Rank p = 0.393). The incidence of severe adverse events was not statistically different between KRAS WT group and MT group. Conclusions: Regardless of KRAS status, bevacizumab provides clinical benefits for patients with mCRC.
The efficacy of oxaliplatin-based adjuvant chemotherapy for stage IV colorectal cancer after R0 resection.
Authors: Nakayama Izuma , Suenaga Mitsukuni , Wakatsuki Takeru , Ogura Mariko , Ozaka Masato , Shinozaki Eiji , Matsusaka Satoshi , Chin Keisho , Mizunuma Nobuyuki , Yamaguchi Toshiharu
Published: February 2017

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Background: In previous phase III studies (MOSAIC and XELOXA trial), oxaliplatin based chemotherapy was shown to be a standard adjuvant treatment for stage III colorectal cancer (CRC). However, its efficacy for curatively resected stage IV CRC has not yet been clarified. In this retrospective study, we evaluate the efficacy of oxaliplatin based chemotherapy in adjuvant setting for curatively resected stage IV CRC. Methods: Eighty-three patients received adjuvant chemotherapy after R0 resection for Stage IV CRC in our institute between Mar 2007 and Feb 2013. Progression-free survival (PFS), overall survival (OS), completion rate of the treatment and safety were evaluated. Median follow-up time was 33.3 months. Results: Baseline characteristics were as follows (N=83): median age, 61; male/female, 46/37; ECOG PS0, all; colon/rectum, 54/29; synchronous/asynchronous, 41/42. Metastatic sites were liver in 46, lung in 11, peritoneum in 13, lymph node in 12 patients. Median PFS and OS were not reached. Three-year PFS and OS were 67.8% and 88.2%, respectively. Completion rate was 78.6% of the patients. In univariate analysis, completion of treatment, synchronous development and metastasis limited to lung were associated with better PFS, though not statistically significant. Confirmed regional lymph node metastasis of primary tumor showed a trend toward to concern with poor OS. Differences in metastatic site were not observed in both PFS and OS. Multivariate analysis revealed none as a significant prognostic factor. Conclusions: Compared the results to previous trial for stage III CRC, oxaliplatin based adjuvant chemotherapy for stage IV CRC after R0 resection was demonstrated to be consistent in tolerability and efficacy.
Value of mismatch repair deficiency for predicting complete pathologic response to preoperative chemoradiation in rectal carcinoma.
Authors: Aguiar Samuel , Taglietti Paula Mendonca , Begnami Maria D. , Mello Celso Abdon , Santos Erika Maria Monteiro , Lopes Ademar
Published: February 2017

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Background: The objective of this study is to investigate the value of mismatch repair deficiency (MMR) in rectal cancers as a predictive fator of response to chemoradiation in rectal cancer. Methods: We evaluated a consecutive cohort of 109 patients with locally advanced rectal carcinomas, treated with a total dose of 5,040 cGy of preoperative radiation therapy, concomitant with infusional 5-FU-based chemotherapy. Radical surgery (TME) was performed in all patients. MMR status was determined by imunohistochemistry in tumor tissue from biopsies prior to chemoradiation. The primary endpoint was complete pathologic response (pCR). Results: 63 patients (57.8%) were male, and the mean age was 60 years (range from 28 to 93). The rate of pCR was 18.3%. Among clinical variables (age, sex, distance to dentate line, per-treatment CEA level, and clinical assessment of response), only clinical complete response (cCR) was significant associated with cPR (p=0.009). Only two patients (1.8%) presented tumors with MMR deficiency. These 2 patients had cPR. Despite the very low rate of MMR deficiency, the association with cPR was significant (p=0.032). Conclusions: Considering the low rate of MMR deficiency found, we do not consider MMR status as a good tool for predicting pathologic response to chemoradiation in rectal cancer. Further investigation can be considered among the subgroup of Lynch syndrome patients.
Transient increase in serum CEA while on adjuvant chemotherapy for colon cancer: Is this of prognostic importance?
Authors: Mitchell Nicola Jane , Hinder Victoria , Murray Melissa , Macapagal Jerome , Thompson Paul Ivan , Sharples Katrina , Findlay Michael P. N.
Published: February 2017

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Background: Serum Carcinoembryonic Antigen (CEA) is used to monitor response to treatment in metastatic colon cancer. Transient surges in CEA can occur after initiation of chemotherapy and are not associated with worse outcome. There is little data on transient CEA surge in the adjuvant setting. We aimed to review patterns of change in CEA levels with adjuvant chemotherapy and investigate associations between transient rises and patient survival. Methods: A retrospective review of patients in Auckland with a new diagnosis of colon cancer in 2001 or 2005 was reported previously [Murray, NZMJ, 2011]. CEA results immediately pre-chemotherapy, during and up to 9 months post chemotherapy were collected and death data was updated. Increase in CEA during chemotherapy was measured as the maximum change from baseline; values more than 2 (within-person) standard deviations above baseline [Erden, Scand, J Clin Lab Inv, 2008] were classified as increased. An increase was transient if the last recorded CEA post chemotherapy was within 2 sd of baseline. Three patient groups were defined: NI (no increase in CEA); TI (transient increase in CEA); and CI (continuous increase in CEA). Kaplan-Meier methods were used to estimate 5-year survival; Cox regression and log-rank p-values were used to compare survival. Results: Of the 77 patients identified with stage II or III disease who had received adjuvant chemotherapy, 61 had sufficient CEA data to be included. The TI group were younger (median [quartiles]: TI 59 [54, 64]; NI 65 [53, 74]; CI 68 [62, 74]) but a greater proportion were stage II (TI 32%; NI 23%; CI 17%). Patients were followed up for a minimum of 7.3 years (or death). Number of deaths per group were: TI 3/19; NI 9/30; CI 7/12. The 5 year overall survival was: TI 95%; NI 83%; CI 42%. There was no significant difference between TI and NI (p = 0.1), but the confidence interval was wide (HR 0.3; 95% CI (0.07 to 1.5). For CI compared to NI, the HR was 2.8 (95% CI (1.0 to 7.6), p = 0.04). Conclusions: The observation that CEA surge does not signal poorer prognosis will be further examined as part of a separate population-based New Zealand-wide study of colorectal cancer diagnosis, treatment and outcome. Part funded by a Genesis Oncology Trust grant.
Radiosensitization by erlotinib and veliparib in esophageal squamous cell cancer.
Authors: Whitley Alexander , Cooper Tiffiny , Angajala Anusha , Trummell Hoa , Jackson Josh , Bonner James A. , Yang Eddy Shih-Hsin
Published: February 2017

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Background: Dysregulation of the HER/EGFR family is identified in esophageal cancers and confers resistance and inferior survival rates. In addition to their unique selectivity in killing DNA repair-deficient tumors, poly-ADP ribose polymerase inhibitors (PARPi) can enhance radiation-induced cytotoxicity. We and others have also previously demonstrated attenuation of DNA repair capacity in HER-inhibited cells to induce a contextual synthetic lethal interaction with PARPi. We thus hypothesized that erlotinib, a tyrosine kinase inhibitor directed against HER1/HER2, could induce a transient DNA repair deficit and subsequently increase DNA damage with the PARPi veliparib in esophageal cancer cells while increasing tumor radiation (RT) sensitivity. Methods: Esophageal SCC cell lines (KYSE-30, KYSE-410, and OE-21) were treated with combinations of vehicle, erlotinib, veliparib (a PARP1/2 inhibitor), and RT. DNA damage and repair and signaling proteins were assessed by immunofluorescence staining of cells for DNA damage and repair foci and/or western blot analysis. Cell viability and cytotoxicity were determined via cell proliferation assays and colony formation assays, respectively. Tumor growth delay was assessed in mice bearing esophageal tumor xenografts. Results: Consistent with our hypotheses, erlotinib increased γ-H2AX foci, a marker of DNA double strand breaks (DSBs), in all three esophageal SCC tumor cells. This coincided with reduced DSB-repair capacity as assessed via RAD51 foci and pDNA-PK. Triple combination with erlotinib, veliparib, and RT demonstrated enhanced cytotoxicity. A subsequent increase in Annexin positive cells was observed, indicative of activation of the apoptotic response. Importantly, the triple combination was most effective in suppressing the growth of esophageal tumor xenografts in vivo (2– to 5.5–fold lower tumor volume) relative to other treatment groups. Furthermore, we observed reductions in tumor volume from baseline with this triple combination in 3/6 mice. Conclusions: Thus, the combination of erlotinib, PARPi, and RT can be an innovative and effective treatment strategy to enhance the therapeutic ratio and improve outcomes in esophageal SCC cancer patients.
Factors associated with recurrence in lymph node-negative gastric adenocarcinoma: Results from the U.S. Gastric Cancer Collaborative.
Authors: Jin Linda X. , Squires Malcolm Hart , Poultsides George A. , Votanopoulos Konstantinos Ioannis , Weber Sharon M. , Bloomston Mark , Pawlik Timothy M. , Hawkins William G. , Linehan David , Strasberg Steven M. , Archer Alexandra W. , Cardona Kenneth , Cho Clifford Suhyun , Kooby David A. , Levine Edward Allen , Winslow Emily , Saunders Neil , Spolverato Gaya , Maithel Shishir Kumar , Fields Ryan C. ,   US Gastric Cancer Collaborative
Published: February 2017

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Background: Lymph node (LN) status is a predictor of recurrence after gastrectomy for gastric adenocarcinoma. Clinicopathologic predictors of recurrence in patients with node-negative disease are less well established. Methods: Patients who underwent surgery with curative intent for gastric adenocarcinoma from between 2000-2012 from participating institutions of the U.S. Gastric Cancer Collaborative were analyzed. Patients who died within 30 days of surgery were excluded. Univariate (UV) and multivariate (MV) analysis of clinicopathologic factors was associated with recurrence was performed. Results: Nine-hundred sixty-five patients from seven institutions were included in the analysis. Three-hundred forty-five (36%) had LN- disease, of whom 63 (18%) had disease recurrence after a median follow-up of 24 months. The most common patterns of recurrence were: peritoneal alone (44%), liver (22%), or combined liver/peritoneal (9%). This distribution did not differ significantly from LN+ disease. UV analysis identified tumor size, linitis plastica, diffuse histology, poor differentiation, signet ring histology, T stage ≥3, perineural invasion, and lymphvascular invasion as risk factors for recurrence (Table). On MV analysis, T stage≥3 (OR 3.6, 95% CI=1.7-7.5) and poorly differentiated histology (OR 2.4, 95% CI=1.2-4.9) were independent predictors of recurrence. Conclusions: Despite the presence of negative lymph nodes, patients with T stage ≥3 and poorly differentiated histology are at high risk of recurrence after gastrectomy for adenocarcinoma of the stomach. These factors, along with other patient and treatment-related variables, may be used to select patients who may benefit from more aggressive adjuvant therapy and to guide subsequent monitoring for disease recurrence. [Table: see text]
Robotic-assisted Ivor-Lewis esophagectomy in the elderly patient.
Authors: Abbott Andrea M. , Strom Tobin Joel Crill , Saeed Nadia , Shridhar Ravi , Hoffe Sarah E. , Almhanna Khaldoun , Meredith Kenneth L.
Published: February 2017

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Background: Esophageal cancer continues to increase in incidence worldwide with the age of diagnosis continuing to move towards an older onset. Robotic assisted approaches to esophagectomy have demonstrated decreased complications and length of hospitalization (LOH). We sought to examine the impact of age on outcomes in patients undergoing robotic assisted esophagectomy (RAIL). Methods: From 2009-2013, we identified patients undergoing robotic assisted Ivor Lewis esophagectomy. Patients were then stratified according to 3 age groups. Cohort 1, age less then 50, cohort 2, age 50-70, and cohort 3 >70. Statistical comparisons between LOH, operative time (OT), estimated blood loss (EBL), adverse events (AE) and mortality were made with Kruskal-Wallis and Chi-square tests. Results: We identified 134 patients who underwent RAIL and found no statistically significant difference between the three cohorts for OT, LOH, days spent in intensive care, AE or mortality. There was a difference in EBL with higher median blood loss (150 cc) seen in cohort 1 (50-600cc) and 3 (50-400cc) compared to cohort 2 (100 cc, (25-400cc)), p < 0.01. The most common AE were arrhythmia and pneumonia but this was not significantly different between the cohorts. The overall AE rate was 10% (cohort 1), 21% (cohort 2), 34% (cohort 3), p=0.14. There were 4 leaks (p =0.38) and 2 deaths (p=0.90) in the entire cohort. A separate analysis was done to compare elderly (>70) to the non-elderly (<70). Median EBL was higher in the elderly cohort (100cc (25-600) vs 150cc (50-400), p <0.01). There was a trend towards longer LOH in the elderly (9 (4-35) vs 11 (6-38) days, p =0.06). AE and mortality were not significantly different, although there was a trend toward increased AE (19.8% vs 34%, p=0.07) in the elderly, with arrhythmia being the most common AE. Conclusions: RAIL is a safe surgical technique for use in an aging patient population. We demonstrated there was no increased risk of LOH, AE or death in the elderly patients compared to their younger cohort.