bluuebunny/crossref_metadata_2025 huggingface dataset:
Intensity-modulated radiation therapy versus 3D conformal radiation therapy for squamous cell carcinoma of the anal canal.
Authors: Chuong Michael , Freilich Jessica , Hoffe Sarah , Fulp William J. , Weber Jill , Almhanna Khaldoun , Dinwoodie William R. , Meredith Kenneth , Shridhar Ravi
Published: February 2017

494

Background: The emergence of intensity-modulated radiation therapy (IMRT) in the treatment of anal cancer has dramatically lowered the incidence of severe toxicity while maintaining excellent long-term outcomes. We compared our institutional experience using 3D conformal radiation therapy (3DCRT) versus IMRT for anal cancer. Methods: We performed a single-institution retrospective review of all non-metastatic squamous cell carcinoma anal cancer patients treated between 2000-2011 using definitive chemoradiation with curative intent. Results: This study included 89 consecutive anal cancer patients (37 3DCRT, 52 IMRT). Median follow-up for all patients, IMRT patients alone, and CRT patients alone was 26.5 months (range, 3.5-133.6), 20 months (range, 3.5-125.5), and 61.9 months (range, 7.6-133.6), respectively. Three-year overall survival (OS), progression free survival (PFS), locoregional control (LRC), and colostomy free survival (CFS) were 91.1%, 82.3%, 90.8%, and 91.3% in the IMRT cohort and 86.1%, 72.5%, 91.9%, and 93.7% for the 3DCRT patients (all p>0.1). More patients in the 3DCRT group required a treatment break (11 vs. 4; p=0.006), although the difference in median treatment break duration was not significant (12.2 vs. 8.0 days; p=0.35). Survival outcomes did not differ based on whether a treatment break was required (all p>0.1). Acute grade ≥3 non-hematologic toxicity was significantly decreased in the IMRT cohort (21.1 vs. 59.5%; p<0.0001). Acute grade ≥3 skin toxicity was significantly worse in the 3DCRT group (p<0.0001) while an improvement in late grade ≥3 GI toxicity was observed in the IMRT patients (p=0.012). Conclusions: This is the largest retrospective review comparing 3DCRT and IMRT for definitive treatment of anal cancer. In contrast to previously published data, this study demonstrates that while long-term outcomes do not significantly differ based on RT technique, a marked decrease in adverse effects and the need for a treatment break can be achieved using IMRT.
Predicting outcomes in locally advanced rectal cancer using pretreatment FDG-PET imaging.
Authors: Fernandes Annemarie Therese , Whaley Jonathan Taylor , Teo Kevin , Plastaras John Peter , Metz James M. , Perini Rodolfo F. , Pryma Daniel A. , Apisarnthanarax Smith
Published: February 2017

495

Background: FDG-PET/CT imaging has been shown to have clinical utility in the management of rectal cancers. The purpose of this study was to investigate multiple FDG-PET/CT parameters to predict for outcome after neoadjuvant chemoradiation (CRT) in patients (pts) with locally advanced rectal adenocarcinoma. Methods: We retrospectively evaluated pts with locally-advanced (T2-4, N0-2, M0) rectal adenocarcinoma treated with neoadjuvant CRT who received FDG-PET/CT scans for radiation therapy planning. We evaluated the impact of SUVmax and metabolic tumor volume (MTV, determined by using PET Edge MimVista), as well as dual-time point PET parameters of retention index (RI, difference in SUVmax between the two PET scans) and RI/time. Endpoints of pathologic complete response (pCR), tumor grade, margin status and pathologic downstaging were assessed using t-test, ANOVA or non-parametric analysis when appropriate. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan Meier estimates. Results: Of the 28 consecutive pts with FDG-PET/CT planning scans identified, 25 pts underwent surgical resection. All patients received a 5-FU based concurrent chemotherapy regimen with RT (median RT dose: 50.4 Gy). Median follow-up was 21 months. The median MTV was 45 cc. Compared to pts with a MTV>45 cc, pts with a MTV <45 cc had improved PFS (2-yr PFS: 86% vs. 60%, p=0.04) and improved OS (2-yr OS: 100% vs. 51%, p=0.01). The correlation between MTV and T-stage was not statistically significant (23% of pts with MTV>45 had T4 tumors vs. 0% of pts with MTV<45, p=0.17). MTV did not correlate with the other endpoints (pCR, tumor grade, margin status, pathologic downstaging). SUVmax did not correlate with any of the identified endpoints. Of the patients with dual-time point PET/CT scans (N=19), RI and RI/time did not correlate with any of the identified endpoints. Conclusions: Pretreatment MTV correlates with PFS and OS in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation. For pts with large MTVs, more aggressive treatment approaches should be considered. Dual-time point FDG-PET imaging does not appear to add clinical value in this patient population.
Phase II trial of irinotecan, S-1, and bevacizumab (IRIS/Bev) combination chemotherapy as second line for advanced colorectal cancer (NCCSG04).
Authors: Takii Yasumasa , Hurukawa Kouichi , Maruyama Satoshi , Yamazaki Toshiyuki , Nishimura Jun , Kawahara Mikako , Tomiyama Takemi , Akazawa Kohei , Hatakeyama Katsuyoshi
Published: February 2017

496

Background: The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853-860) previously demonstrated the non-inferiority of Irinotecan plus S-1 (IRIS) to FOLFIRI for metastatic colorectal cancer (mCRC), with progression-free survival as the primary endpoint. IRIS plus bevacizumab (IRIS/Bev) was reported an active and generally well-tolerated first-line treatment for mCRC (Yuki et al. ASCO 2012 #3593). We planned a Phase II trial to evaluate the efficacy and safety of IRIS/Bev as second-line therapy for patients with mCRC. Methods: The study design was multicenter, single-arm, open-label phase II study. Eligible patients had to have mCRC with confirmed diagnosis of adenocarcinoma, history of oxaliplatin containing regimen as first-line therapy, an age from 20 to 80 years, ECOG performance status (PS) of 0-1. S-1 65 mg/m2 daily p.o. was given on days 1-14 and Irinotecan 75mg/m2 and Bevacizumab 10mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall response rate (OR), overall survival (OS), time to treatment failure (TTF) and safety. Results: From 08/12 until 11/06, 35 patients were enrolled. One patient did not start therapy. Thirty-four patients were investigated. Median age was 63 years (range, 38 to 82). Twenty-five patients were male. The mean of relative dose intensity of TS-1/Irinotecan/Bev were respectively 92.1%/87.0%/86.2%. The OR was 21.1% (7/33) and disease control rate was 84.8% (28/33). Median PFS was 9.3 months, median TTF was 8.2 month and median survival time 23.1 month. On safety analysis, the incidence of grade 3 or 4 adverse reactions were as follows: neutropenia, 14.7%; fatigue, 14.7%; white blood cell decreased, 11.8%; anorexia, 8.8%; anemia, 8.8%; diarrhea, 2.9%; proteinuria, 5.9%; thromboembolic event, 2.9%. Conclusions: IRIS/Bev is an active and well-tollarated second-line treatment for patients with mCRC. Clinical trial information: UMIN000001631.
Metastatic colorectal cancer and management in public versus private hospitals: Similarities and differences.
Authors: Field Kathryn M , Shapiro Jeremy David , McKendrick Joseph J , Wong Hui-Li , Desai Jayesh , Lipton Lara Rachel , Kosmider Suzanne , Nott Louise M. , Stefanou Gregory , Parente Phillip , Zimet Allan Solomon , Lim Lionel , Jennens Ross , Yip Desmond , Burge Matthew E. , Gibbs Peter
Published: February 2017

497

Background: Potential differences between public and private cancer care in Australia include the degree of subspecialisation, multidisciplinary clinic review, access to clinical trials and continuity of care, all of which could impact treatment and outcomes. Here we compared demographics, tumour details, treatment and survival outcomes for patients (pts) with newly diagnosed metastatic colorectal cancer (mCRC) treated in the public versus private setting. Methods: This research was conducted using the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) mCRC clinical research database. Data collection began in June 2009 and is ongoing at 15 Australian centres. Here, data from four public and eight private hospitals are presented. Results: Of 671 pts, 253 (38%) were treated at public hospitals and 418 (62%) at private centres. For public versus private pts there was no significant difference in median age or percentage with good performance status. More private pts received first-line chemotherapy (89% vs 80%, p=0.002), but there were no significant difference in the use of bevacizumab (50% versus 43%, p=0.10). Similar proportions received combination therapy (72% private vs 68% public) but the use of single agent oral capecitabine was higher for private patients (9% vs 4%, p=0.03). More public pts were enrolled in a first-line clinical trial (17.3% vs 1.2%, p<0.0001). Preliminary analysis suggests improved overall survival for private pts (26 months versus 17 months, p<0.001). Conclusions: While public and private pts in this cohort were similar in age and performance status, significantly more private pts were given chemotherapy, but similar proportions were given bevacizumab and far less were enrolled on first-line clinical trials. This may relate to availability of first-line trials during this period. The superior survival outcomes achieved in private practice must be further explored, and might reflect a more intense approach to treatment, yet-to-be identified differences in patient characteristics, or differences in quality of care.
XELOX with bevacizumab in elderly patients age 75 or older with metastatic colorectal cancer: Results of a planned interim analysis for multicenter phase II ASCA study.
Authors: Ishibashi Keiichiro , Munemoto Yoshinori , Matsuoka Masaki , Hata Taishi , Kobayashi Michiya , Hasegawa Junichi , Fukunaga Mutsumi , Takagane Akinori , Otsuji Toshio , Miyake Yasuhiro , Nagase Michitaka , Oba Koji , Sakamoto Junichi , Mishima Hideyuki
Published: February 2017

502

Background: Combination chemotherapy of capecitabine plus oxaliplatin (XELOX) with bevacizumab is commonly used as standard chemotherapy for metastatic colorectal cancer (mCRC). A previous meta-analysis showed that there was no difference between two age groups of <65 years and ≥65 years on overall survival (OS) after treatment with chemotherapy with bevacizumab. However, the safety and efficacy of XELOX with bevacizumab in elderly patients (pts) ≥75 years with mCRC remain unclear. Methods: This study was an open-label multicentre phase II study to evaluate the efficacy and safety of XELOX with bevacizumab in pts ≥75 years with metastatic CRC. The primary objective was to assess progression-free survival (PFS). The secondary endpoints were the safety, response rate (RR), time to treatment-failure (TTF) and OS. Results: 36 pts were enrolled. Pts characteristics were; median age 78 (range 75-86); male/female, 21/15; ECOG performance status 0/1, 30/6; colon/rectum 24/12, creatinine clearance (CCr) 60.2 ml/min (range 32.6-84.6). Median follow-up period was 220 days. RR was 55.6% and median TTF was 209 days. The median PFS and median OS are not reached. Grade 3 or 4 adverse events (AEs) were reported in 22 pts (62.8%). Common grade 3 or 4 AEs were hypertension (11.4%), leukopenia (20.0%), peripheral sensory neuropathy (14.3%), hand foot syndrome (8.6%), and fatigue (8.6%). Examining the relationship between renal function (CCr) and AEs, the incidence of Grade 3 or 4 AEs in the lower CCr group was significantly higher than that in the higher CCr group (61.6% vs. 47.8%; p=0.013); hematological toxicities (87.5% vs. 14.8%; p=0.0003) and non-hematological toxicities (61.5% vs. 11.1%; p=0.018). Conclusions: XELOX with bevacizumab is safely administered in elderly patients ≥75 years. Renal function (CCr) could be a good predictive marker for grade 3 or 4 AEs. Clinical trial information: UMIN000003500.
Risk factors for peritoneal recurrence in stage II/III gastric cancer patients who received S-1 adjuvant chemotherapy after D2 gastrectomy.
Authors: Aoyama Toru , Yoshikawa Takaki , Shirai Junya , Fujikawa Hirohito , Hayashi Tsutomu , Ogata Takashi , Cho Haruhiko , Yukawa Norio , Oshima Takashi , Rino Yasushi , Masuda Munetaka , Tsuburaya Akira
Published: February 2017

51

Background: Peritoneum is still the most frequent site of the recurrence in stage II/III gastric cancer patients although the survival was improved by S-1 adjuvant chemotherapy. The objective of this retrospective study was to clarify the risk factors of peritoneal recurrence in patients who received S-1 adjuvant chemotherapy. Methods: Peritoneal recurrence free survival (P-RFS) was examined in 100 gastric cancer patients who underwent curative D2 surgery, were diagnosed with stage II or III pathologically, and received adjuvant S-1 between June of 2002 and March of 2011. Uni- and multi- variate analyses were performed to identify risk factors by Cox’s proportional hazard analyses. Results: P-RFS was 64.3% at 3 years and 58.8% at 5 years. A total of 18 patients were diagnosed with peritoneal recurrence. Macroscopic tumor diameter, depth of tumor invasion, and lymph node metastasis were the significant factors by univariate analysis, while tumor diameter and lymph node metastasis were the only significant independent risk factors by multivariate analysis. Conclusions: The macroscopic tumor diameter and lymph node metastasis were the most important risk factors for P-RFS. When patients had these risk factors, S-1 was not sufficient to inhibit peritoneal recurrence. When developing a novel adjuvant chemotherapy targeting peritoneal metastasis in the future, clinical trials should be limited to these patients.
Interim follow up results from a phase II study of neoadjuvant chemoembolization of resectable colorectal liver metastases (CRLM) with transcatheter hepatic therapy with irinotecan-eluting beads.
Authors: Jones Robert Peter , Malik Hassan Zakria , Fenwick Stephen W , Terlizzo Monica , O'Grady Elizabeth , Stremitzer Stefan , Gruenberger Thomas , Poston Graeme John
Published: February 2017

519

Background: 65% of patients undergoing liver resection for CRLM experience disease recurrence within 3 years. Perioperative chemotherapy improves 3-year progression free survival, and good pathologic response is associated with improved overall survival. However, systemic neoadjuvant chemotherapy increases operative morbidity. DEBIRI gives sustained delivery of drug directly to tumor, maximising response and reducing systemic exposure. This study examined the feasibility, safety and long-term outcome of patients treated with neoadjuvant DEBIRI before resection. Methods: Patients with resectable CRLM received single targeted DEBIRI (up to 200mg) 1 month pre-hepatectomy. Primary end-point: tumor resectability, secondary end-points: safety, pathologic response, disease-free (DFS) and overall survival (OS). Results: DEBIRI performed in 40 patients. Post-TACE complications: 1 acute pancreatitis (3%); 4 post-embolization syndromes (10%). 38 patients underwent hepatectomy (2 peritoneal disease, resectability rate 95%). 30-day operative mortality 5% (n=2), neither death TACE related (1 intraoperative pneumomediastinum, 1 aspiration pneumonia). Both operative deaths excluded from follow up analysis. 63 lesions (median 2 per patient) targeted with DEBIRI. Histology: no residual disease 17%; 1-49% residual disease 59%; >50% residual disease 22%; no response 2%. Median follow up 293 days. Fourteen patients (36%) had disease recurrence, median DFS 387 days (95% CI 276-498). Eight (57%) had hepatic recurrence, 2 (14%) had pulmonary recurrence and 4 (29%) had both pulmonary and hepatic recurrence. One patient died of hepatic and pulmonary recurrence after 565 days. Conclusions: Resection after neoadjuvant DEBIRI for CRLM demonstrated a good safety profile in this study population. Single DEBIRI treatment resulted in impressive pathologic response, with patterns of recurrence comparable to reported series of resection alone. Further trials assessing combination DEBIRI and systemic chemotherapy are necessary. Clinical trial information: NCT00844233.
Expression of growth and cell proliferation factors in gastric carcinomas: The association with poor overall survival on patients with intestinal type.
Authors: Begnami Maria D. , Neves Jose Ivanildo , Chaves Marcos , De Barros E Silva Milton Jose , Costa Wilson Luiz , Coimbra Felipe José Fernandez , Diniz Alessandro Landskron , Ribeiro Heber Salvador de Castro , Pinto Clovis
Published: February 2017

52

Background: Gastric carcinomas (GC) express a variety of growth factors and cell proliferation acting in the mechanisms of tumor invasion and spread. The expression of angiogenic factors such as vascular endothelial growth factor (VEGF) has been demonstrated in diffuse type GC, whereas expression of growth factors is associated with intestinal-type carcinomas. Objective: To study the immunohistochemical expression of proteins associated with growth factors and cell proliferation in GC. Methods: We studied 400 GC, arranged in duplicates in 2 blocks of tissue microarray (TMA). Immunohistochemistry was performed using antibodies: c-MET (Novocastra), TGFbetaI (Santa Cruz), TGFbetaII (Santa Cruz), c-erbB-2 (Dako) and VEGF (Santa Cruz). Cases were considered positive for TGFbetaI, TGFbetaII and VEGF when cytoplasmic staining was observed in more than 10% of tumor cells. Positive cases for c-met and c-erbB-2 were detected when strong staining on the membrane cells was observed in more than 10% of neoplastic cells. Results: Expression of TGFbetaI, TGFbetaII and VEGF were detected in 314/385 (81%), 370/382 (96%) and 333/366 (90%) of GC. 333/376 (88%) cases were positive for c-met and 54/385 (14%) for c-erbB-2. Intestinal type carcinomas were more often positive for TGFbetaII (p = 0.01), VEGF (p = 0.001), c-met (p = 0.01), and c-erbB-2 (p = 0.001). According to univariate statistical analyzes expressions of TGFbeta II, c-met and c-erbB-2 were independent factors associated with overall survival of patients with GC. Conclusions: The proteins associated with growth factors and cell proliferations are differentially expressed in intestinal type of GC. Our findings pointed them out as biological factors associated with worse prognosis and important therapeutic targets.
First-line clinical trials and metastatic colorectal cancer: How selected are clinical trial participants?
Authors: Field Kathryn M , McKendrick Joseph James , Shapiro Jeremy David , Tie Jeanne , Bae Susie , Burge Matthew E. , Yip Desmond , Nott Louise M. , Gibbs Peter
Published: February 2017

524

Background: Guidelines recommend that oncology patients have the opportunity to participate in a clinical trial wherever possible. It is purported that as trial participants are often younger and fitter, data extrapolation from trial outcomes to patients seen in routine care may be difficult. We compared characteristics of patients with metastatic colorectal cancer (mCRC) participating in a first-line clinical trial with those treated in routine care. Methods: The TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database, a clinician-designed mCRC comprehensive database, was used to identify patients treated on a first-line trial compared with those receiving combination chemotherapy; single-agent therapy; or no chemotherapy. Data collection began in June 2009 and is ongoing at 15 Australian centres to date. Results: Of 671 patients, 49 (7.3%) participated in a first-line clinical trial. Patients on trial were significantly younger, with 49% (n=24) trial participants being under 60 years, compared with 33% (n=128) receiving combination chemotherapy off study (p=0.047), 13% (n=13) single-agent therapy (p<0.0001) and 10% (n=15) no treatment (p<0.0001). All trial participants were ECOG performance status 0-1, compared with 87% (n=335) of non-trial patients receiving combination chemotherapy (p<0.0001), 80% (n=82) receiving single-agent therapy (p<0.0001) and 52% (n=76) no treatment (p<0.0001). Similarly, Charlson comorbidity score was significantly lower in trial participants, with 88% (n=43) having a score 0-3 (less comorbidity) versus 71% (n=272) receiving combination chemotherapy, 39% (n=40) receiving single-agent therapy and 25% (n=36) no treatment. Preliminary analysis suggests significant overall survival benefit for the clinical trial cohort. Conclusions: Consistent with available literature, trial participants with mCRC are significantly younger, fitter and of better performance status than those who receive similar chemotherapy off-trial or no treatment. The impact of trial participation on survival may be thus subject to multiple factors biasing for a better outcome, including the contributing benefit of younger age and less comorbidity.
Effect of trastuzumab on telomere-related proteins and the relationship to the sensitivity of HER2-amplified human gastric cancer cells to oxaliplatin and cisplatin.
Authors: Liu Yongping , Ling Yang , Qi Qiu feng , Pan Yaodong
Published: February 2017

53

Background: HER2 amplification occurs in about 20% of gastric cancers, and trastuzumab in combination with cisplatin based chemotherapy has been reported to improve oncological outcomes in gastric and gastro-oesophageal junction cancer with HER2 gene amplification. The aim of this study was to evaluate the potentially useful combined antitumor efficacy of trastuzumab and platinum agents in gastric cancer cells and to elucidate further the mechanisms possibly involved in the interaction between the trastuzumab and platinum agents. Methods: Gene expression was determined by using real-time quantitative PCR in gastric cancer cell lines. The chemosensitivity of gastric cancer cells to platinum agents and the apoptotic effect of drugs in vitro were evaluated using cellTiter 96 Aqueous One Solution Cell Proliferation Assay kit and double staining with both Annexin-V-FITC and PI, respectively. Results: Treatment with 1.0μg/ml trastuzumab for 48h could significantly increase sensitivity of oxaliplatin or cisplatin in HER2 amplified gastric cancer cells, and the IC50 of oxaliplatin and cisplatin were reduced to about 3.29 times and 6.91 times, respectively. Apoptosis analysis also indicated that trastuzumab significantly increased both oxaliplatin and cisplatin-induced apoptosis in NCI-N87 cells. Analysis of telomere-related genes revealed that trastuzumab singly and pretreatment with trastuzumab for 48h followed by oxaliplatin or cisplatin for another 48h could significantly downregulate the mRNA expression of TPP1, TRF1, TRF2, TRF2IP, POT1 and TIN2 genes. Conclusions: Our results describe the potential role of low dose trastuzumab to increase sensitivity of oxaliplatin and cisplatin in HER2 amplified gastric cancer cells, which may be partially through downregulating the expression levels of telomere-related genes.
Is there a role for chemotherapy in metastatic colorectal cancer patients with a poor performance status?
Authors: Wong Hui-li , Field Kathryn M , Tie Jeanne , Kosmider Suzanne , Shapiro Jeremy David , McKendrick Joseph J , Parente Phillip , Lipton Lara Rachel , Yip Desmond , Parakh Sagun , Nott Louise M. , Gibbs Peter
Published: February 2017

534

Background: The management of patients with poor performance status (PS) remains challenging in the absence of data on optimal treatment. Here we assessed the treatment and outcomes of patients with metastatic colorectal cancer (mCRC) with poor Eastern Cooperative Oncology Group (ECOG) PS (≥ 2) in routine clinical care. Methods: Analysis of patients prospectively entered onto the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database, a clinician-designed initiative to collect comprehensive data on consecutive patients with mCRC from sites across Australia. Data collection commenced in July 2009 and is ongoing at 14 participating public and private centres. Results: Of the 679 patients entered, 129 (19.0%) had an ECOG PS ≥ 2. In total, 77 (11.3%) were PS 2, 41 (6.0%) PS 3 and 11 (1.6%) PS 4. Chemotherapy was administered to 55 (71.4%) PS 2 and 15 (36.6%) PS 3 patients, with none of the PS 4 patients being treated. Overall, poor PS patients were significantly less likely to receive any chemotherapy compared to their good PS (PS 0-1) counterparts (55.0% versus 86.8%, p<0.0001) and, when chemotherapy was given, significantly less likely to receive combination chemotherapy (38.0% vs 71.6%, p<0.0001) or bevacizumab (15.5% vs 46.9%, p<0.0001). Overall survival (OS) was reduced with declining PS, with medians of 31.2, 9.0, 3.0 and 0.8 months for PS 0-1, 2, 3 and 4 patients respectively (p<0.0001). Poor PS patients treated with chemotherapy had a better OS outcome (9.8 vs 4.1 months for untreated patients, p<0.0001). At one and two years, 22 (31.4%) and 8 (11.4%) treated poor PS patients were alive. Conclusions: In routine practice many patients with a poor PS, particularly those that are PS 2, receive active treatment. Although overall survival for poor PS patients is poor, some patients appear to benefit from treatment. Further data analysis, particularly to define subsets that may benefit most from treatment, is planned as further sites around Australia contribute data to the project.
Phase II trial of combined chemotherapy with irinotecan, S-1, and bevacizumab (IRIS/Bev) in patients with metastatic colorectal cancer (mCRC): Hokkaido Gastrointestinal Cancer Study Group (HGCSG) trial—Comparison of the efficacy of KRAS status.
Authors: Nakamura Michio , Yuki Satoshi , Dazai Masayoshi , Kobayashi Yoshimitsu , Kato Takashi , Naruse Hirohito , Kudo Mineo , Akakura Nobuaki , Sakata Yuh , Komatsu Yoshito
Published: February 2017

536

Background: Mutations of the KRAS gene were identified as a predictive marker in mCRC for anti-EGFR antibody. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab (BV) treatment in mCRC is independent of alterations in the KRAS status. We analized efficacy of BV combined irinotecan and S-1 (IRIS/Bev) in mCRC relative to KRAS status. Methods: In the retrospective analysis (n=53) of patients who participated in the Phase II trial of IRIS/Bev, additional statistical analyses were done with data from KRAS mutational analyses. In this trial, eligible patients had to have mCRC with a confirmed diagnosis of adenocarcinoma, an age of >20 years, and no history of prior chemotherapy. S-1 40-60 mg twice daily p.o. was given on days 1-14 and irinotecan 100 mg/m2 and bevacizumab 5 mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine Progression-free survival (PFS) and OS. Log-rank test was used to compare with mutant or wild-type KRASin terms of PFS and OS. All statistical tests were performed using SPSS. Results: The target number of 53 patients was enrolled as of March 2009. KRAS status was assessed in 43 patients (wild = 27, mutant = 16). Response rate was 63.0% with wild-type and 68.8% with mutant-type KRAS, that was not significant (p=0.752). The median Progression-free survival was 17.1 months with wild-type and 22.7 months with mutant-type KRAS, that was not significant (p=0.531). And median OS was 49.0 months with wild-type and 38.0 months with mutant-type KRAS, that was not significant(p=0.906) as well. Conclusions: IRIS/Bev provides clinical benefit in patients with mCRC expressing either mutant or wild-type KRAS. Randomized control trial comparing this regimen with oxaliplatin containing regimen(XELOX or mFOLFOX6 plus bevacizumab: TRICOLORE study) is already started. Comparison of the efficacy of KRAS status is also planned in this study. Clinical trial information: NCT00569790.
Correlation of psychosocial factors (PSF) before and throughout treatment with response to chemotherapy (CTx) in patients (pts) with advanced gastrointestinal (GI) cancers: Does psychosocial status predict tumor remission?
Authors: Offergeld Anna Maria , Drabik Anna , Oechsle Karin , Mehnert Anja , Atanackovic Djordje , Arnold Dirk , Stein Alexander
Published: February 2017

542

Background: CTx has shown to have a positive impact on improving or maintaining quality of life (QoL) in patients with advanced GI cancers. The role of PSF in relation to objective tumor response (OTR) to CTx is not well described yet. We thus evaluated the predictive value of pretreatment PSF on OTR as well as the continuous evaluation of PSF in regard to OTR throughout treatment. Methods: Eligible pts had metastatic or recurrent GI cancer and were about to receive first- and second-line palliative CTx. QoL, physical symptoms and PSF were assessed by the EORTC QLQ C30, the MSKCC-Symptom Assessment Scale (MSAS), and a modified Brief-COPE before treatment start and after discussing the results of the first follow up OTR assessment. OTR was either classified according to RECIST or using a remission based approach (RA), classifying response as any decrease in size, and no change or progression as non-response. Results: 50 pts (median age 61.8 years, ECOG 0/1/2 12%/62%/26%, 21 female, 40% colorectal, 28% biliopancreatic, 24% esophagogastric, 78% 1st line CTx) were enrolled. OTR was 32% partial response, 50% stable disease and 18% progressive disease according to RECIST, and 60% response vs. 40% non-response according to RA. Interestingly, patients responding (RECIST and RA) to CTx had better role/emotional/cognitive functioning, mental state, global distress index, active coping, positive reframing, and belief in control over their lives, and less acceptance of their disease before treatment. PSF significantly predicted response (RA) to CTx, even if adjusted for age, cancer type, and line of treatment (p<0.05). During course of treatment, PSF remained largely unchanged in responders, whereas non-responders loose belief and confidence in control, safety and equity and tend to increased denial (RECIST and RA). Those findings were more pronounced using the RA classification than RECIST. Conclusions: Pretreatment PSF seem to have predictive value for response to CTx in GI cancer patients. PSF changes in non-responding patients may be an early indicator for the need for psychological support in this patient group.
Risk of arterial (ATE) and venous thromboembolism (VTE) in a population-based cohort of bevacizumab-treated metastatic colorectal cancer (mCRC) patients.
Authors: Yu Irene S. , Cheung Winson Y.
Published: February 2017

545

Background: Bevacizumab is associated with both arterial (ATE) and venous thromboembolic (VTE) events, estimated to be </=15% from clinical trials. Our objectives were to 1) characterize the incidence of ATE or VTE among mCRC patients receiving bevacizumab in a non-clinical trial setting; 2) determine patient and treatment-related factors that predispose to an increased risk of ATE or VTE; and 3) explore how thromboembolism is managed and whether bevacizumab is discontinued and/or resumed after an event. Methods: A random sample of mCRC patients diagnosed between 2008 and 2009, referred to 1 of 5 regional cancer centers in British Columbia, and who were offered bevacizumab was reviewed. Summary statistics were used to describe and compare clinical factors between those who experienced an ATE or VTE and those who did not. Results: Of the 200 mCRC patients offered bevacizumab, 10 never received the drug and 12 were lost to follow up. Among the 178 remaining patients, median age was 61 years, 103 (58%) were male, and 121 (85%) had ECOG 0 to 1. A total of 39 patients (28%) experienced at least 1 documented thromboembolic event. Compared to patients who developed a clot, those who did not had similar median age (62 vs 61), gender distribution (23% men and 20% women), ECOG 0 to 1 (84% vs 85%) and body mass index (26.4 vs 25.3). However, the mean number of bevacizumab doses was higher in the group with thromboembolism (12.6 vs 9.0), suggesting a potential dose-related effect. There were a total of 43 VTE and 5 ATE events documented, with 7 of the 39 patients (18%) experiencing more than 1 event. Bevacizumab was held or discontinued in 60% of cases, but it was continued in 25% of the cases; 4% of the events were fatal, and 10% of the VTE/ATE occurred after bevacizumab was stopped. Conclusions: The incidence of ATE and VTE in a non-study setting appears to be higher than that reported in clinical trials. There may be a dose-related effect. Bevacizumab was not consistently held or discontinued in the setting of a VTE or ATE. Development of guidelines for the management of thromboembolism with bevacizumab may be warranted.
Retrospective study to evaluate interstitial lung disease secondary to oxaliplatin-containing chemotherapy at an NCI-designated comprehensive cancer center.
Authors: Sahai Vaibhav , Nimeiri Halla Sayed , Vergo Maxwell Thomas
Published: February 2017

547

Background: Oxaliplatin-induced interstitial lung disease (ILD) in gastric and colorectal cancer (CRC) patients is rarely reported and its clinical features remain to be clarified. Methods: Using a computerized database, we retrospectively identified 621 patients with gastric or CRC treated with oxaliplatin-containing regimen from February 2003 to September 2011 at an NCCN institution. Out of 621 patients, chart review was done for 135 patients who developed lung toxicity during or post-chemotherapy. For purpose of data collection, lung toxicity was defined as pulmonary fibrosis, pneumonitis, ARDS, pneumonia-organism unspecified and acute respiratory failure. Imaging data was reviewed for all patients until death or at least 1 year after diagnosis. Results: Of 621 patients, 4 patients developed ILD (0.64%) and of those 2 died due to the toxicity (0.32%). Of the 4 patients, three were symptomatic, three had high Brinkman Index (BI) (≥600) and two showed pulmonary opacities other than lung metastases before chemotherapy. All developed ILD during or within 30 days of oxaliplatin-containing chemotherapy. Extensive work-up in 3 of 4 patients was negative for infection. Chemotherapy regimens included 5-fluorouracil/oxaliplatin (n=2; 85 mg/m2), epirubicin/5-fluorouracil/oxaliplatin (n=1; 130 mg/m2) and capecitabine/oxaliplatin (n=1; 130 mg/m2) with a median of 4.5 cycles (range 2–17 cycles) and a median dose of administered oxaliplatin of 473 mg/m2 (range 260–1445 mg/m2). Conclusions: This is the first retrospective review of patients who received oxaliplatin-containing chemotherapy to determine the incidence and significance of lung toxicity in U.S. and the first to include gastric cancer patients. ILD following oxaliplatin-containing regimen is an uncommon but life-threatening complication. The incident population is too small to infer correlation with BI but it does not seem to correlate with dose or intensity of oxaliplatin. Oncologists should consider chemotherapy-induced hypersensitivity pneumonitis in their differential diagnosis when assessing patients with new onset shortness of breath during or shortly after chemotherapy.
Reasons for delay in time to initiation of adjuvant chemotherapy (AC) for colon cancer (CC).
Authors: Wasserman David Warren , Booth Christopher M. , Hopman Wilma , Al Sharm Abdullah , Biagi James Joseph
Published: February 2017

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Background: AC improves survival among patients with colon cancer. Two meta-analyses have demonstrated a decrease in survival with increasing time to AC (TTAC). In this study, we examined individual patient charts to determine reasons for delay in AC. Methods: Medical records of patients with CC who initiated AC Aug 2005-Nov 2010 at the Cancer Centre of Southeastern Ontario were reviewed to capture patient, disease, and treatment characteristics including: medical comorbidities, post-operative complications, whether AC was or was not ordered after initial consultation, and the reasons behind the decision. Dates of surgery, referral, consult, central venous catheter (CVC) insertion, and first cycle of AC were recorded. Patients were then categorized into Group 1-medical/surgical reason for delay (MSRD), defined as presence of post-operative complications or intercurrent medical illness, and Group 2–no MSRD. In Group 2, patients were further categorized as having a non-MSRD, defined as patients in whom AC was deferred at time of consultation due to patient preference and/or further investigations required, vs none. A multivariate logistic regression model was used to determine factors associated with TTAC > 8 weeks (w). Results: For 171 patients: Mean age - 67; 52% male; 79% stage 3; IV AC – 80%, Oral AC – 20%. TTAC for all cases was 8.3 ± 2.3w. Mean intervals ± SD between surgery and TTAC in weeks were: surgery to referral 3.1 ± 2.0; referral to consult 2.5 ± 2.3; consult to oral AC 2.0 ± 2.1; for IV AC, consult to CVC 2.2 ± 1.3, and CVC to AC 0.7 ± 0.8. TTAC did not differ between patients with comorbidities (N= 89) and those without (N=82), p= 0.64, but was greater for patients in Group 1 (N=41 with MSRD) vs Group 2 (N = 130), p= 0.002. In Group 2, 43.8% (N=57) had TTAC > 8w while only 20% of cases (n=26) had a non-MSRD. Factors associated with TTAC>8w were MSRD [OR=5.6 (2.3-13.7), p = <0.001] and non-MSRD [OR=6.7 (2.3-19.5), p = <0.001]. Conclusions: Although medical/surgical complications are a strong predictor of delayed TTAC, this only applies to a small proportion of cases. Accordingly, in most patients TTAC>8w is unrelated to their post-operative medical condition and likely reflects health system and logistical issues.
Relationship between volume of bone irradiated during pelvic radiation therapy (RT) for rectal cancer and complete blood counts (CBC).
Authors: Marina Ovidiu , Ionascu Dan , McAree Daniel P , Schulze Derek , Dekhne Aamod , Wallace Michelle , Grills Inga S. , Ye Hong , Robertson John M.
Published: February 2017

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Background: CBCs decrease during standard 3D-conformal pelvic RT for rectal cancer. We evaluated RT plans and CBCs to determine if this decrease is due to RT or only concurrent chemotherapy. Methods: Pelvic bones were contoured for 69 patients who had CT-based treatment plans and CBCs 3 months pre and during RT. CBCs included white blood cells (WBC), hemoglobin (Hgb) and platelets (PLT). The pelvic bones included the bilateral femoral heads and innominate bones, sacrum and L5. Dose volume histograms (DVH) for the pelvic bones were encoded as volumes (Vol) receiving 10 (V10) to 50 Gy (V50) in cc, and percent (Perc) (P10 to P50). The paired t-test was used to compare CBCs pre and during RT. CBCs were analyzed with a repeated measures general linear model for uneven time intervals (R 2.15.1). Results: Median age was 60 y, with 40 men (58%) and preoperative RT in 32 (46%). The median RT dose was 50.4 Gy (range 25.2-60.4 Gy), with all but 2 patients receiving ≥45 Gy. Among 677 CBCs, there were 675 WBC, 677 Hgb, and 672 PLT. The average WBC pre and during RT were 7.7 vs 5.4 bil/L (p<0.001), Hgb 12.9 vs 12.5 g/dL (p=0.005), and PLT 271 vs 227 bil/L (p<0.001). A statistical model with variables for time, the 3-week chemotherapy cycle, the pre-RT average CBC, and 1st and 2nd-order interactions of time with Vol and Perc was constructed. All Vol and Perc for all bones as one structure were significant predictors of the PLT timecourse during RT, with the first-order time-dose interaction encoding a decrease over time, and the second-order time-dose interaction a recovery towards the end of RT. For WBC, V40 and P40 were most predictive (p<0.001), with P40 more so. There were no time-dependent interactions for Hgb. All models had a significant effect of pre RT average CBC and the 3-week chemo cycle. Conclusions: Whereas chemotherapy acts systemically, RT affects a circumscribed area. As such, bone marrow outside the RT field can compensate for lost hematopoiesis over time. Pelvic bone RT dose correlates with PLT and WBC (circulation half-life 1-3 d) but not Hgb (half-life 120 d) supporting an effect of RT in decreased CBC during treatment. Research of approaches that minimize bone marrow dose during pelvic radiotherapy is warranted.
Safety and efficacy during first line with cetuximab in KRAS wild-type metastatic colorectal cancer (mCRC): Results of a large prospective multicenter cohort carried out by the premium French observational study.
Authors: Mineur Laurent , Seni Gilles , Miglianico Laurent , Dourthe louis-Marie , Bonichon Nathalie , Moreau Lionel , Guimbaud Rosine , Smith Denis , Achille Emmanuel , Herve Robert , Bons Jean Michel , Remy Stephane , Daures jean Pierre
Published: February 2017

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Background: Cetuximab improves benefit in patients with kras wild type when added to CT for mCRC (Crystal, opus, celim trials). In order to assess the safety and efficacy of cetuximab in daily-practices a national prospective observational multicenter study was performed. Methods: Physicians (n=94), in health institutions (44 public and 46 private hospitals, 4 cancer centers) enrolled prospectively 502 patients. The eligibility criteria were kras wild type mCRC treated with cetuximab in combination with CT as first-line regimen and at least one measurable lesion. Data are available at 3 months, for 496 patients enrolled between september 2009 to march 2012. Results: Mean age 65,7 years old, 62.9% male, ECOG score 0-1 88.1%, 2-3 11.9%, metastases site were liver 70%, lung 26% and others unlimited 39%. Resectable mCCR 10.6%, potentially resectable metastases 33.9% and unresectable 55.5%. Primary tumor location colon: right 20.9%, transverse 6%, left 35.3%, rectum 30.5%, others 7.3%. Primary cancer was resected in 66 % (n=332), 25% (n=125) received adjuvant CT. Cetuximab was administrated respectively every week(20.2%) or two weeks (79.8% of patients). CT regimens were folfiri 51.8%, folfox 4 36.5%, others 11.7%. At 3 months response rate was complete in 4.6%, partial 44.9%, stable 34%, progression disease 16.5%. Reasons for specific cetuximab treatment discontinuation (n=207) were progressive disease 35.3%, therapeutic break 23.2%, all grade cutaneous toxicity and allergic reaction 15.9%, patient request 2.9%, surgery recruitment 20% radiotherapy, radiofrequency and others 2.7%. Adverse events in grade 2 and 3-4 were respectively neutropenia (9.4%;7.9%), anemia (8.5%;1.4%), thrombocytopenia (2.6%;1%), diarrhea (10.8%;5.3%) vomiting (5.3%;2.2%), folliculitis (17.9%;3%), xerosis (13.3%;2%), paronychia (5%;0.9%), allergy 3.4%. Conclusions: Values reported are consistent with those previously identified trials and can better understand the reasons of drug stopping. The study continues to evaluate prognostic factors influencing response, toxicity and drug discontinuation.
Intratumoral gene expression profile of genes involved in 5-FU metabolism and angiogenesis, comparison with tumor invasion depth in patients with advanced gastric cancer.
Authors: Azuma Mizutomo , Naruke Akira , Kim Myungchul , Ishido Kenji , Katada Chikatoshi , Higuchi Katsuhiko , Sasaki Tohru , Tanabe Satoshi , Koizumi Wasaburo
Published: February 2017

56

Background: The biopsy specimen by endoscopy can only show the surface of its gene profiles. We hypothesis whether the biopsy specimen can reflect all part of gene profile or not. We tested how 5-FU related genes and angiogenesis gene expressed in the invasion depth in the primary tumor of the Stage II or III advanced gastric cancer. Methods: Twenty-five patients with stage II or III advanced gastric cancer who underwent gastrectomy were analyzed.Formalin-fixed, paraffin-embedded tumor tissues were dissected from the surface section (mainly mucosa), the middle section (mainly submucossa) and the deep section (the part invaded most deeply) of the primary tumor and the normal gastric mucosa tissue by the laser-captured microdissection technique and were analyzed for target gene expressions using a quantitative real-time polymerase chain reaction.We analyzed for target genes as TS, TP, DPD, ERCC1, EGFR, VEGF and HIF1α. Results: In the primary tumor, TP and HIF1α gene expression in the surface section was significantly higher than in the deep section (p=0.021, p=0.012). These gene expression and the depth of the primary tumor had a correlation coefficient (TP; r=0.29, HIF1α; r=0.33). There was no significantly difference between surface and deep section in the primary tumor in TS, DPD, ERCC1, VEGF, EGFR except TP and HIF1α. There was no significantly difference between surface and middle section in the primary tumor in all gene expression. There was no significantly difference between middle and deep section in the primary tumor in all gene expression. Conclusions: Only TP and HIF1α had tendency that these gene expression became higher as invaded from the surface section to the deep section of primary tumor. These data suggested that biopsy specimens could be predicted gene expression profile from the surface of gastric cancer. But as you know, gastric cancer has a heterogeneity gene profile. We need at least few samples to say whole gene expression of its tumors. This is preliminary data, it will need further study to proof these result.
Relationship of oral acetaldehyde concentration and oral microflora with the development of superficial pharyngeal or esophageal squamous cell carcinoma.
Authors: Iizuka Toshiro , Kikuchi Daisuke , Hoteya Shu , Tanaka Mamoru , Kaise Mitsuru
Published: February 2017

57

Background: Acetaldehyde in alcoholic beverages is evidently carcinogenic to the pharynx and esophagus. The relationship between microflora in the gastrointestinal tract and carcinogenesis, such as that between Helicobacter pyloriand gastric cancer, has attracted attention; however, there are few reports of oral microflora influencing the developing the squamous cell carcinoma of the pharynx or esophagus. Therefore, we investigated factors that might influence the development of cancer in the pharynx and esophagus. Methods: A total of 82 patients participated in this study and consisted of 50 with pharyngeal or esophageal cancer treated by endoscopic submucosal dissection and 32 with no cancer. Chromosomal DNA was extracted from bacteria in the oral mucosa, and terminal restriction fragment length polymorphism analysis was carried out. The concentration of acetaldehyde in saliva was measured, and clinical factors were assessed by multivariable analysis. Results: The average values of clinical parameters in patients with pharyngeal or esophageal cancer were as follows: age, 68 years; acetaldehyde, 2.5 μmol/l; GOT, 30.5 IU/l; GPT, 23.5 IU/l; γGTP, 79.4 IU/l; Hb, 14.1 g/dl; MCV, 97.6 fl; alcohol consumption, 6.1 g/day; and Brinkman index, 764. In patients with no cancer, the same parameters were as follows: age, 69 years; acetaldehyde, 4.8 μmol/l; GOT, 23 IU/l; GPT, 21.9 IU/l; γGTP, 36.9 IU/l; Hb, 14.2 g/dl; MCV, 93.7 fl; alcohol consumption, 1.9 g/day, and Brinkman index, 350. Multivariable analysis showed that acetaldehyde concentration (odds ratio: 0.63; 95% CI: 0.47–0.85) and alcohol consumption (odds ratio: 1.64; 95% CI: 1.19–2.25) were significantly different between the two groups. Cluster analysis extracted 16 small clusters from the dendrogram. In 3 clusters among them, the percentage of patients with cancer was more than 80%. Conclusions: Cluster analysis revealed three clusters with a high incidence of cancer patients. Therefore, acetaldehyde concentration and alcohol consumption may be related with carcinogenesis of the pharynx and esophagus. We intend to identify the microbial flora of each cluster in a future study.