bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term quality of life (QoL) for stage II/III rectal cancer survivors in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS).
Authors: Charlton Mary E. , Stitzenberg Karyn Beth , Lin Chi , Juarez Grelda Yazmin , Halfdanarson Thorvardur Ragnar , Pendergast Jane F. , Chrischilles Elizabeth A. , Wallace Robert B.
Published: February 2017

584

Background: Standard therapy for stage II/III rectal cancer includes surgery, radiation, and chemotherapy. Multiple trials demonstrated neoadjuvant chemoradiation (CRT) provides better local control and decreased morbidity compared to adjuvant CRT, though differences in overall survival and long-term QoL have not been demonstrated. We examined impact of treatment (pre-op CRT/post-op CRT/no CRT) on long-term QoL. Methods: CanCORS patients with survey/medical record data diagnosed in 2003-2005 with stage II/III rectal (non-rectosigmoid) cancer had resection and survived > 7 years were included. QoL (SF-36, EQ-5D) measures and defecation problems were derived from surveys at 14 months and 7 years post-diagnosis. Mean scores were adjusted for the following when significant: age, gender, stage, sphincter preservation, comorbidities, and baseline self-reported health status and QoL scores. Results: Of 119 patients, 53% received pre-op CRT, 23% post-op CRT, and 24% no CRT. Of 114 patients with 14-month follow-up, Pre-op CRT and No CRT groups had better EQ-5D adjusted mean scores but worse defecation scale (DS) scores compared to the Post-op CRT group. Of 49 disease-free survivors with 7 years follow-up, there were no differences among groups in QoL scores, but the No CRT group had better DS scores than other groups. Conclusions: No major differences were detected in long-term QoL based on treatment aside from the DS, though sample sizes became small. Regardless of treatment, long term (7y) mental health and vitality were generally comparable to U.S. norms, while physical health and overall health status (EQ-5D) were somewhat lower. [Table: see text]
Does up-front definitive surgical resection with delayed chemotherapy in patients with stage IV rectal cancer compromise overall survival?
Authors: Manyam Bindu V. , Koyfman Shlomo A. , Sohal Davendra , Mallick Ismail , Reddy Chandana A. , Remzi Feza H. , Kalady Matthew F. , Lavery Ian C. , Kiran Ravi P. , Abdel-Wahab May
Published: February 2017

586

Background: Definitive resection of the primary is frequently part of the management of patients (pts) with stage IV rectal cancer with good performance status and low volume of systemic metastases. It is unclear whether delaying systemic therapy for up front surgical management of the primary compromises overall survival (OS). Methods: Pts with metastatic rectal adenocarcinoma who received definitive surgical resection between 1998-2011 were identified in an IRB approved registry. The sequencing of CT and surgery, and the use of perioperative radiation therapy (RT), was at the discretion of treating physicians. Preoperative chemotherapy (Pre-CT) regimens included 5-fluorouracil (5-FU) +/- leukovorin (LV), capecitabine, 5-FU/LV/oxaliplatin +/- avastin, or 5-FU/LV/irinocetan. RT dose was typically 50.4 Gy. OS was measured from the date of diagnosis. Baseline variables were compared using the Chi-square and unpaired t-tests. OS was calculated using the Kaplan Meier method. Univariate (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazards regression to identify variables associated with OS. Results: In this study of 115 pts, 75 (65%) were treated with pre-CT, while 40 (35%) were treated with up front surgery. Of the pts who received surgery up front, 3 (8%) received RT and of the pts who received pre-CT, 62 (83%) received RT. The cohort was predominantly male (70%) with a median age of 57, median KPS of 80, and median follow-up of 24.1 months. 94% of pts had T3/T4 tumors, 80% had N+ disease, and 33% had poorly differentiated tumors. Liver directed therapy (LDT) was performed in 61% of pts. There was no significant difference in OS (32.3 vs. 32 months; p = 0.24) between pts treated with pre-CT and those who received surgery up front, respectively. UVA demonstrated that pre-CT was not associated with OS (HR 1.26; p = 0.544). MVA demonstrated that pts with poorly differentiated tumors (HR 2.04; p = 0.007) and those that did not undergo LDT (HR 2.45; p = 0.001) had inferior survival. Conclusions: Delaying systemic chemotherapy in order to achieve local control with surgical resection up front does not appear to impact OS in pts with stage IV rectal cancer.
Phase II study of 5-FU dose-adjusted mFOLFOX7 plus bevacizumab in patients with metastatic colorectal cancer (AJUST study).
Authors: Yakabe Tomomi , Denda Tadamichi , Morita Yoshitaka , Matsuda Chu , Kim Ho Min , Fujieda Shinji , Fukunaga Mutsumi , Oba Koji , Sakamoto Junichi , Mishima Hideyuki
Published: February 2017

592

Background: Individual fluorouracil dose adjustment improved efficacy and toxicity in patients with colorectal cancer receiving FOLFOX. But the usefulness has not been studied in Japan. Methods: To evaluate the efficacy and toxicity of 5-FU dose-adjusted mFOLFOX7 plus bevecizumab, we conducted a multi-center phase II study of 5-FU dose-adjusted mFOLFOX7 plus bevacizumab as first line treatment in patients with metastatic colorectal cancer (AJUST study UMIN000007194). Blood samples were collected from patients receiving 46 hours continuous infusion of 5-FU therapy ( 2400mg/m2). 5-FU measurement were performed using my 5FUR assay. 5FU dose were adjusted according to the AUC. The results were compared with previously reported data. Results: A total of 48 patients were registered between April 2012 to June 2013 from 11 institutions in Japan. They had a wide range of AUC from 14 to 37 mg.h/L . The AUC of 5FU were 22.58 ± 5.33 mg.h/L. 29 patients (60.4%) receiving mFOLFOX7 were in the AUC target range of 20-24 mg/h/L. 16 patients (33.3%) were below the target range, and only 3 patients (6.2%) were above the target range. Past reports showed the AUC of 5FU 20.35 ± 9.87 mg.h/L. Our results of AUC, patients below the target range, and within the target range did not show significant difference from previously reported data (p= 0.12, 0.76, 0.82 respectively), except patients above the target range (p=0.047). Conclusions: This is the first report of individual fluorouracil dose adjustment of mFOLFOX7 plus bevacizumab in Japan. The mean AUC and the percentage of patients below the target range were comparable with previously reported data. These results suggested that 5FU dose monitoring is also useful for Japanese patients. The efficacy and toxicity will be presented in the meeting. Clinical trial information: 000007194.
The impact of sarcopenia on survival in locally advanced rectal cancer.
Authors: Gamenthaler Andrew , Siegel Erin M. , Clark Whalen , Chen Ann , Zhao Xiuhua , Maddox Kristen , Shibata David
Published: February 2017

604

Background: The association between sarcopenia (or muscle loss) and worse oncologic outcomes has been documented in several different cancers and is thought to be a potential marker of a diminished host response to tumor. The prognostic role of sarcopenia in rectal cancer (RC) patients has yet to be elucidated. We sought to examine the impact of radiologically-defined sarcopenia on outcomes of RC patients treated by neoadjuvant chemoradiation (NCR) and radical resection. Methods: Between 1998-2010, we identified 90 patients with stage II/III RC treated by NCR and radical surgery. Sarcopenia was assessed using 3 CT-based measures derived at the L4-L5 level including mean psoas density (MPD; Hounsfield Units), total psoas area (TPA; mm2) and muscle mass index (MMI=TPA/height2; mm2/m2). Clinicopathologic data (age, gender, pretreatment and final tumor stage, treatment response and CEA level) were collected. Associations were analyzed by Wilcoxon Rank Sum while the Kaplan–Meier method, log-rank test, and Cox proportional hazards models were used to evaluate overall survival (OS) and disease-free survival (DFS). Results: Our population consisted of 50 males and 40 females with a median age at diagnosis of 61 (range 35-87). By univariate analyses, only age >61 was associated with the presence of sarcopenia by all 3 measures [MPD (p=0.0003), MMI (p=0.0001), and TPA (p=0.0008)]. Female gender was associated with increased muscle loss by MMI (p<0.0001) and TPA (p<0.0001). By Cox multivariate analysis, MPD (range 14.5-77.3 HU) was independently associated with a worse OS (AHR= 0.94; 95% CI, 0.88-0.99; p= 0.04) and marginally associated with DFS (AHR= 0.95; 95% CI, 0.89-1.00; p= 0.056) when controlling for age, gender and pathologic response. This translates to a 28.5% reduction in risk of death with every 5 HU decrease in MPD. Conclusions: We have demonstrated that pre-treatment sarcopenia as measured by MPD is associated with worse OS and possibly DFS in patients with RC treated by NCR and radical surgery. Larger scale studies of sarcopenia and RC are warranted. Strategies targeting reversal of processes associated with muscle loss may play a potential future role in the multidisciplinary management of rectal cancer.
Positron emission tomography/computed tomography for early treatment response evaluation in metastatic colon cancer.
Authors: Engelmann Bodil E. , Loft Annika , Kjær Andreas , Nielsen Hans J. , von Benzon Eric , Brünner Nils , Christensen Ib Jarle , Gerds Thomas A. , Hansson Susanne H. , Hollander Niels Henrik , Kristensen Michael Holmsgaard , Löfgren Johan , Markova Elena , Sloth Carsten , Højgaard Liselotte
Published: February 2017

614

Background: Treatment options for metastatic colon cancer (mCC) are widening. We prospectively evaluated serial 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography/ computed tomography (PET/CT) and measurements of tissue inhibitor of metalloproteinases type 1 (TIMP-1), carcinoembryonic antigen (CEA) and urokinase plasminogen activator receptor domain I [uPAR(I)] for early assessment of treatment response in mCC patients. Methods: Thirty-three mCC patients scheduled for first line chemotherapy with capecitabine, oxaliplatin (CAPOX) and bevacizumab participated; 27 were evaluated by PET/CT before treatment, after one and four treatment series. Morphological and metabolic response was independently assessed according to Response Evaluation Criteria In Solid Tumours (RECIST1.1) and EORTC PET criteria. Plasma TIMP-1, plasma uPAR(I) and serum CEA were determined. Results: Metabolic response after one treatment course predicted the ability of CAPOX and bevacizumab to induce morphological response after four treatment series with a sensitivity of 80 %, specificity of 69 % and an Odds Ratio of 13.9 [CI 1.9; 182]. Early metabolically stable or progressive disease was associated with shorter progression-free survival (PFS) (hazard ratio (HR) = 3.2 [CI 1.3; 7.8]). Biomarker levels at early evaluation were associated to shorter PFS (TIMP-1 per unit increase on a log-2 transformed ng/mL scale: HR = 2.23 [CI 1.20; 4.14]; uPAR(I) per 25 fmol/mL increase: HR = 1.36 [CI 1.03; 1.79]). Conclusions: This monocentric study demonstrated predictive value of early metabolic PET response and prognostic value of TIMP-1 and uPAR(I) levels in mCC treated with CAPOX and bevacizumab. Results support investigation of PET/CT, TIMP-1 and uPAR(I) guided early treatment adaptation in mCC.
The importance of sequence in rescheduling bevacizumab and chemotherapy administration in the first-line treatment of metastatic colorectal carcinoma (mCRC).
Authors: Chelis Leonidas , Xenidis Nikolaos , Amarantidis Kiriakos , Diamantopoulos Nikolaos , Boutis Anastasios L. , Koukaki Triantafyllia , Michailidis Prodromos , Christakidis Evagelos , Chalvatzis Athanasios , Matthaios Dimitrios , Deftereos Savas , Courcoutsakis Nikos , Prassopoulos Panagiotis , Kakolyris Stylianos
Published: February 2017

617

Background: One of the proposed mechanisms of action for bevacizumab is by reducing the interstitial fluid pressure (IFP) allowing an increased penetration and uptake of chemotherapy agents in tumors. Clinical and laboratory data suggest that the decrease of IFP occurs after a few days of bevacizumab administration and intratumoral delivery of chemotherapy increase when bevacizumab precedes chemotherapy. We hypothesized that altering the schedule of BEV/FOLFOX regimen would improve the efficacy of the regimen and increase objective response rate. Methods: Patients (pts) with mCRC or locally advanced colorectal cancer, with ECOG PS 0-2 were eligible. The treatment schedule was Bevacizumab 5mg/Kg on day 1, standard FOLFOX-4 regimen on days 8-9 at cycles repeated every 14 days. Prior 5-FU/oxaliplatin adjuvant treatment was allowed. The pts were treated for 6 months or until reaching a plateau of response. Standard RECIST v1.1 response evaluation criteria were used. Primary endpoint of the study was the percentage of objective response rate, PR+CR (ORR), secondary end points were PFS, OS and toxicity. A Simon two step, minimax, statistical design was used: the minimum accepted ORR was 45% (p0) and the estimated ORR was 65% (p1). Results: Thirty (n=30) pts were enrolled. The median age was 69.5 years, the performance status was 0 (40%), 1 (40%), 2 (20%), the median follow up was 20.75 months and the K-RAS status was wild type for 63.5% and mutant for 36.5%. Seven pts (23.3%) had received prior adjuvant chemotherapy. Five pts had convertible metastatic disease. Four CR (13.33%), 18 PR (60%), 7 SD (23.33%), and one PD (3.3%) were observed for a total ORR of 73.3% and disease control rate (CR+PR+SD) of 96.7%. Four out of five (80%) pts with convertible disease achieved a R0 resection. The PFS was 12.8 months and OS has not been reached yet. One patient experienced a grade 4 event (febrile neutropenia). The study met its primary endpoint and therefore is considered positive. Conclusions: Delivering bevacizumab before chemotherapy in the first-line treatment of mCRC represents a very effective and promising schedule which warrants further investigation in randomized clinical trials.
Adjuvant chemotherapy following neoadjuvant chemoradiotherapy and surgery for locally advanced rectal cancer.
Authors: Laws Kirsten Elizabeth Jean , Wilson Christina , McIntosh David , Harrow Stephen
Published: February 2017

626

Background: Established guidelines exist for indications of adjuvant chemotherapy in colon cancer. However, in patients receiving neoadjuvant chemoradiotherapy for locally advanced rectal cancer, the benefit of adjuvant chemotherapy remains unproven. We evaluated clinical decision making behind adjuvant chemotherapy for locally advanced rectal cancer patients in our institute. Methods: Patients treated with long course chemoradiotherapy between January 2008 and December 2009 were identified. Exclusion criteria were inoperable disease, postoperative, recurrence, or palliative intent. 231 cases were examined retrospectively for the decisions behind giving or withholding adjuvant chemotherapy. Results: 35 (15%) were ineligible for consideration of adjuvant chemotherapy due to disease progression. 38 patients (16.4%) received chemotherapy in the adjuvant setting and 158 patients (68.4%) were potentially eligible for adjuvant chemotherapy, but did not receive it. The majority of clinicians based their decisions on post operative pathology results, and the key factor in decision making was final pathological stage in 65%. Clinicians considered pre-treatment imaging a key factor in only 14% of cases, despite a considerable number of patients being downstaged from a potentially higher initial pre-treatment stage that could have warranted adjuvant treatment. A considerable number of patients (25%) were deemed unfit for adjuvant treatment following neoadjuvant chemoradiotherapy and surgery due to toxicity of combined treatment. Conclusions: This analysis highlights the difficulty in clinical decision making for adjuvant chemotherapy in rectal cancer. The accuracy of pre-treatment staging is difficult to ascertain and its use to justify post operative treatment uncertain. It appears the majority of clinicians in our institute base their decision on post operative pathology. A considerable number of patients were not fit for consideration of adjuvant treatment due to toxicity of previous treatment. Further research is warranted as to the benefits of adjuvant chemotherapy, particularly in a setting where prior treatment already causes significant toxicity.
Phase II trial of combined chemotherapy with S-1, oral leucovorin, and bevacizumab in heavily pretreated patients with metastatic colorectal cancer.
Authors: Yamaguchi Kazuhisa , Taniguchi Hiroya , Komori Azusa , Narita Yukiya , Uegaki Shiori , Nitta Sohei , Nomura Motoo , Kadowaki Shigenori , Takahari Daisuke , Ura Takashi , Andoh Masashi , Muro Kei
Published: February 2017

627

Background: Regorafenib improves survival in refractory metastatic colorectal cancer (mCRC), but alternative chemotherapy is required to avoid severe toxicity. S-1+oral leucovorin (SL) has shown promising results in untreated mCRC without severe toxicity. TML trial demonstrated that continuation of bevacizumab (Bev) after progression prolongs overall survival. Thus, we hypothesized that combination chemotherapy of SL/Bev would be beneficial; we conducted a single-center phase II trial to assess the efficacy and safety of SL/Bev as a salvage therapy in mCRC. Methods: Major eligibility criteria were: mCRC with confirmed adenocarcinoma diagnosis; age > 20 years; ECOG performance status, 0–2; and progression after administration or intolerance to approved drugs for mCRC (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80–120 mg/body) and leucovorin (25 mg) were orally administered for 1 week followed by 1 week rest. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. Primary endpoint was disease control rate (DCR). Results: Twenty-three patients were enrolled: 8 (35%) females; median age, 70 years (range, 38–78); and 14 (61%) with KRAS wild-type. DCR was 65% [95% confidence interval (CI), 41.3–82.7%] and response rate was 6% (95% CI, 1.1–27.0%). One patient experiencing partial response to SL/Bev had BRAF mutant tumor with primary resistance to XELOX+Bev as first-line and irinotecan+cetuximab as second-line chemotherapy. Median progression-free and overall survival period were 4.1 and 9.5 months, respectively. Major adverse events were mucositis, (grade 3, 12%), diarrhea (grade 3, 12%), and decreased hemoglobin (grade 3, 12%). Conclusions: SL/Bev was well tolerated and delayed progression; therefore, it can be an alternative chemotherapy for refractory mCRC. We will report the data from final analysis at the meeting. Clinical trial information: 000009083.
The impact of dose reduction and time delay in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer.
Authors: Mashita Naoki , Nakayama Goro , Hayashi Naomi , Tanaka Chie , Kobayashi Daisuke , Kanda Mitsuro , Yamada Suguru , Fujii Tsutomu , Sugimoto Hiroyuki , Koike Masahiko , Nomoto Shuji , Fujiwara Michitaka , Ando Yuichi , Kodera Yasuhiro
Published: February 2017

631

Background: This study was designed to evaluate the influence of dose reduction and schedule modification on outcomes in patients with metastatic colorectal cancer (mCRC). Methods: Pooled datasets from two previous phase II trials of FOLFIRI (CCOG-0502; n = 36) and mFOLFOX6 (CCOG-0704; n = 30) in patients with mCRC were analyzed retrospectively. The RDIs of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). To assess the effects of dose reduction and time delay, we defined ‘dose index (DI)’ as the ratio of the actual delivered total dose to the planned total dose and ‘time index (TI)’ as the ratio of the planned duration to the actual duration of therapy. Relative dose intensity (RDI) was computed by multiplying DI by TI. DI and TI of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In patients receiving FOLFIRI therapy, the median DI and TI of irinotecan were 0.92 and 0.90, respectively. RRs were 59% vs. 12% in the higher vs. lower DI groups (p < 0.01), and 35% vs. 35% in the higher vs. lower TI groups (p = 1.00), respectively. Median PFS was 10.2 vs. 5.0 months in the higher vs. lower DI groups (p < 0.01), and 6.1 vs. 6.7 months in the higher vs. lower TI groups (p = 0.48), respectively. In mFOLFOX6 therapy, the median DI and TI of oxaliplatin were 0.97 and 0.82, respectively. RRs were 44% vs. 36% in the higher vs. lower DI groups (p = 0.65), and 44% vs. 36% in the higher vs. lower TI groups (p = 0.65), respectively. Median PFS was 7.7 vs. 6.7 months in the higher vs. lower DI groups (p = 0.13), and 8.5 vs. 5.9 months in the higher vs. lower TI groups (p = 0.02), respectively. Multivariate analyses showed that DI of irinotecan (HR 8.48; 95% CI, 2.94-24.51, p < 0.01) and TI of oxaliplatin (HR 2.74; 95% CI, 1.02-7.33, p = 0.04) were the independent prognostic factors for PFS. Conclusions: Dose reductions in irinotecan and time delays in oxaliplatin could have significant impact on PFS in patients receiving FOLFIRI and FOLFOX6, respectively.
MD Anderson experience with off-study regorafenib in patients with advanced colorectal cancer.
Authors: Bugano Diniz Gomes Diogo , Hassabo Hesham M. , Al Mutar Salwan S. , Sahin Ibrahim Halil , Rogers Jane , Nguyen D. Van , Bolonesi Ryan M. , Pini Tunghi May , Dasari Arvind , Kopetz Scott , Overman Michael J. , Eng Cathy , Kee Bryan K. , Hassan Manal , Garrett Chris R.
Published: February 2017

635

Background: Regorafenib was approved by the FDA on September 27, 2012 following the CORRECT trial demonstrating an overall survival (OS) benefit compared to placebo in pts with advanced treatment-refractory CRC (Grothey A. et al: Lancet. 2013;381:303-12). Little data exists regarding patient treatment outcomes outside of reported clinical trial data. Methods: Pts seen at MD Anderson Cancer Center with a diagnosis of gastrointestinal malignancies since October 1, 2012 were evaluated for regorafenib therapy; electronic clinic records were reviewed for pt treatment data, toxicity, and survival outcomes. Results: 61 pts were identified; 4 pts were determined to have GI malignancy other than CRC [appendiceal cancer (n=3) and duodenal cancer (n=1)] and were omitted from this analysis. Median age was 58 years (range 30.5-83.3), M:F 37:20 (65%:35%), KRAS non-mutant/ KRAS mutant 26/31 (46%:54%), BRAF mutant n=3 (5%); Median time from diagnosis of metastatic disease to initiation of regorafenib therapy was 27.7 months (range 5.9-112.3); 8 pts (14%) had enrolled in clinical trials prior to starting regorafenib. The initial starting dose was 160 mg (n= 38, 66.7%), 120mg (n=18, 31.5%), and 80mg (n=1, 1.8%) respectively. Dose reductions or interruptions were required in 25 pts (43.8%); 14 patients (24.5%) discontinued therapy due to toxicity. The most common grade 3 adverse event was hand-foot reaction (n=12; 21%). One pt initiated on 120 mg was able to tolerate dose escalation to 160mg. Seven pts (12.2%) had stable disease radiographically for more than 2 months and 2 had a confirmed partial response (3.5%). Median OS was 9.1 months (95% C.I. 5.3-12.8) and median time on regorafenib therapy was 2.2 months (range 0.2-10.3). Following regorafenib discontinuation 12 pts (21%) were enrolled on phase I trials. Conclusions: In this pt population palliative regorafenib therapy was associated with modest efficacy and significant toxicity. Dose reductions or interruptions were common (43.8%) even despite a large number of pts being initiated on a dose lower than the recommended initial dose (33.3%). Further studies may be required to determine the optimal tolerable dose in pts with advanced CRC.
Clinical outcomes for patients with liver-limited metastatic colorectal cancer: Arguing the case for specialist hepatobiliary multidisciplinary assessment.
Authors: Thillai Kiruthikah , Repana Dimitra , Korantzis Ippokratis , Prachalias Andreas , Kane Pauline , Ross Paul J.
Published: February 2017

637

Background: In patients (pts) with liver-limited metastatic colorectal cancer (mCRC), surgical resection or radiofrequency ablation (RFA) can lead to a significant overall survival benefit. Specialist hepato-biliary (HPB) multidisciplinary meetings (MDMs) are currently believed to provide the best forum to discuss this cohort of pts and assess their suitability for surgery or RFA. Methods: A retrospective analysis was undertaken of pts diagnosed with liver-limited mCRC over a period of 6 months within a specified cancer network in the United Kingdom. In addition to discussed cases, pts who were diagnosed but not referred to the HPB MDM were also discussed within the MDM setting. For these pts, contributors were blinded and decisions were made regarding resectability and appropriateness for RFA based on patient imaging and clinical history. Results: In a six month period, 159 pts were diagnosed with liver-limited mCRC within our cancer network. Of these, 68 (43%) were referred at the time of initial diagnosis, with a further 38 (24%) referred after commencing systemic treatment. 35 (56%) who were discussed at the time of their original diagnosis went on to have either a hepatectomy or RFA, as did 18 (51%) patients referred after initiating systemic treatment. 81 pts (78%) referred to the HPB MDM had synchronous liver metastases. Of the remaining 53 (33%) patients who were not referred to the HPB MDM, the average age was 70.2 years and 38 (86%) had synchronous liver metastases. Imaging was available for 31 (58%) of these pts. Decisions regarding resectability or RFA were made within the MDM based solely on history and radiology findings. Of these cases, 13 (41.9%) were identified as resectable or potentially resectable and 11 (35.5%) may have been suitable for a clinical trial. None of these 31 pts (100%) had hepatic surgery or RFA. Conclusions: Whilst the majority of pts with liver-limited mCRC were referred appropriately, this study highlights that a number of pts with potentially resectable disease are not being discussed at a specialist HPB MDM. A review of all diagnosed cases would ensure that an increased number of pts are offered hepatic resection or RFA.
Tumor angiogenesis genotyping and efficacy of first-line chemotherapy in metastatic gastric cancer patients.
Authors: Scartozzi Mario , Giampieri Riccardo , Loretelli Cristian , Bittoni Alessandro , Mandolesi Alessandra , Faloppi Luca , Del Prete Michela , Bianconi Maristella , Andrikou Kalliopi , Bearzi Italo , Cascinu Stefano
Published: February 2017

64

Background: An altered expression of tumour angiogenesis-related factors has been constantly associated to a more aggressive phenotype and an increased relapse rate in several tumour types, including gastric cancer. Besides correlating with prognosis, tumour-driven angiogenesis seemed also able to influence response/resistance to chemotherapy in pre-clinical models. We examined the role of tumour angiogenesis genotyping in determining clinical outcome in metastatic gastric cancer patients receiving first-line chemotherapy. Methods: VEGF-A, VEGF-C, FLT1, KDR and FLT4 genotyping was performed on gastric tumours from 94 consecutive patients receiving platinum-based first-line chemotherapy. Results: Only theVEGF A rs25648 correlated with RR (PR = 18% among patients showing the VEGF A rs25648 CT or TT genotype vs. 44% among patients showing the VEGF A rs25648 CC genotype, p = 0.04). The VEGF A (rs2010963) and VEGF C (rs4604600 and rs7664413) correlated with mPFS and the VEGF A rs25648 and FLT4 rs307833 correlated with both mPFS and OS. Among other clinical variables tested (sex, age, ECOG performance status, gastrectomy, adjuvant chemotherapy, metastatic sites and second-line chemotherapy) only the use of second-line chemotherapy correlated with improved overall survival (10.2 months vs. 6.3 months for patients who received or did not receive second-line, p= 0.003). At multivariate the VEGF A rs25648 maintained an independent role in determining both median PFS (HR = 1.65 95% CI: 1.12-2.78, p= < 0.0001) and OS (HR = 1.58, 95% CI: 1.17-2.65, p = 0.0003). The use of second-line chemotherapy also showed an independent role in determining median OS (HR = 0.58, 95% CI: 0.38-0.87, p= 0.003). Conclusions: VEGF A rs25648 genotyping may help identifying a patients subgroup unlikely to benefit from a first-line, platinum-based combination and potentially candidate to alternative therapy choices. Our data may help designing future clinical trials with the aim to investigate the outcome of different chemotherapy regimens in different patients groups prospectively stratified according to angiogenesis profile.
Incidence of methacronous cancer after total colectomy with ileorectal anastomosis or total proctocolectomy in classical FAP patients.
Authors: Aguiar Samuel , Stevanato Paulo Roberto , Ferreira Fabio Oliveira , Santos Erika Maria Monteiro , Batista Ranyell Spencer Sobreira , Lopes Ademar
Published: February 2017

646

Background: Total proctocolectomy (TPC) with ileal pouch is considered the procedure of choice in classic familial adenomatous polyposis (FAP), but total colectomy (TC) with rectal sparing can be performed in selected cases. The objective of this study is to determine and compare the incidence of methacronous cancer in the remanescent rectum in patients submitted to TPC or TC. Methods: We performed a retrospective analysis of 55 patients operated beteween 1992 and 2011. Patients were identified from 34 FAP families, registered at the AC Camargo Hereditary Colorectal Cancer Registry. Patients with attenuated FAP were excluded. The main endpoint was the occurence of cancer at the remanescent rectum. Results: Thirty seven patients were submitted to TPC and 18 to TC with ileo-rectal anastomosis. Among patients submitted to TPC, just one (2.7%) had methacronous adenocarcinoma just above the dentate line. Among patients submitted to TC with rectal sparing, 4 (22.2%) have another cancer at the remanescente rectum. This difference was statistically significant (0.035). The stage was initial in all cases, and all patients were submitted to salvage surgery. No deaths related to rectal cancer had occured. Conclusions: Surgical treatment of classical FAP still remains proctocolectomy with ileal pouch, whenever possible. Considering that methacronous cancer uses to be detected in initial stages, rectal sparing can be considered in very selected cases of classical FAP.
Administration of chemotherapy via median cubital vein without implantable central venous access port for metastatic colorectal cancer: Port-free chemotherapy.
Authors: Yoshida Yoichiro , Aisu Naoya , Naito Masayasu , Tanimura Syu , Sasaki Takamitsu , Takeno Shinsuke , Hoshino Seiichiro , Mogi Ai , Tanaka Toshihiro , Tamura Kazuo , Yamashita Yuichi
Published: February 2017

651

Background: Repeated venous punctures are usually required in cancer patients for application of chemotherapy. Central venous catheters and implantable port systems have substantially facilitated the problem of vascular access. Safe and easy-to-handle port systems have become an integral part of daily clinical routine in oncology. However, there are several serious complications associated with central venous ports (CV-ports). With the recent development of capecitabine plus oxaliplatin (XELOX) therapy involving oral administration of drug preparations, etc., implantation of a CV-port can be avoided. The present study was undertaken to evaluate the safety of administration of chemotherapy via median cubital vein without CV port for metastatic colorectal cancer. Methods: The study included 144 patients who received XELOX + bevacizumab (BV) therapy and XELOX therapy for metastatic colorectal cancer without implantation of a CV-port. Results: Eighty-five patients experienced vascular pain, but it was transient. The drip infusion route had to be switched to the opposite side because of vascular pain in only 1 of the 144 patients. No patients required CV-port implantation or postponement of treatment due to adverse events caused by administration of the drug via the peripheral vein. Grade 3 or higher hemotoxicity was noted in 12.5%, and grade 3 or higher nonhematological toxicity was noted in 17.4%. Conclusions: We may be able to perform port-free-chemotherapy via median cubital vein for patients with colorectal cancer. We can avoid the serious complications associated with CV-port.
Molecular classification of gastric cancers by parallel examination of multiple gene amplifications.
Authors: Minarikova Petra , Benesova Lucie , Belsanova Barbora , Tuckova Inna , Belina Frantisek , Dusek Ladislav , Zavoral Miroslav , Minarik Marek
Published: February 2017

74

Background: Gastric cancer is characterized by heterogeneity in morphology as well as on the molecular level resulting in diverse response to anticancer therapy. The subtypes are currently recognized based on histology (Lauren classification). The aim of this work was to investigate an alternative approach for description of inherent molecular mechanisms resulting in its biological behavior. Methods: Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) sections from 80 patients with histologically confirmed gastric cancer. A set of 70 genes was simultaneously examined by Multiplex Ligation-dependent Probe Amplification (MLPA) technique. The obtained gene amplification patterns were processed by hierarchical data clustering and evaluated in combination with clinical patientd data by multifactorial analysis. Results: The overall success rate of DNA extraction from the gastric FFPE samples was at a level of 85%. As expected HER2, MYC, p16 and b-catenin genes were among the most frequently amplified. Both statistical approaches delivered similarities in data clustering. The resulting dendrograms revealed comparably constituted subclusters of samples. Conclusions: Presence of specific gene amplification resulting from aberrant activation of various signaling pathways indicate distinct tumor characteristics that may lead to specific tumor behavior. A correlation to monitoring parameters such as progression-free survival or overall survival is ongoing. Supported by the Czech Ministry of Health grant no. NT13640.
Efficacy and safety result of trastuzumab (T-mab) and paclitaxel for T-mab naive patients with HER2-positive previously treated advanced or recurrent gastric cancer (JFMC45-1102): Final report.
Authors: Takahashi Tsunehiro , Nishikawa Kazuhiro , Miki Akira , Noshiro Hirokazu , Yoshikawa Takaki , Nishida Yasunori , Iwasa Satoru , Miwa Hiroto , Masuishi Toshiki , Yoshida Kazuhiro , Kodera Yasuhiro , Boku Narikazu , Yamada Yasuhide , Morita Satoshi , Sasako Mitsuru , Maehara Yoshihiko , Kitajima Masaki , Sakamoto Junichi , Saji Shigetoyo , Kitagawa Yuko
Published: February 2017

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Background: The global, randomized, phase III ToGA study showed that the first-line treatment of trastuzumab (T-mab) combined with capecitabine and cisplatin a survival (OS) benefit for patients (pts) with HER2 positive advanced or recurrent gastric cancer. However, there is no report concerning about the efficacy and safety of T-mab containing second-line treatment for T-mab naïve pts with HER2 positive advanced or recurrent gastric cancer. Therefore, we planned a phase II study of paclitaxel plus T-mab in this setting. Methods: JFMC45-1102 is multicentre phase II study. Pts with HER2 positive (IHC3+ or IHC2+/FISH+), histologically confirmed gastric adenocarcinoma, age ≥ 20, received one or more prior chemotherapy but no prior therapy with T-mab, normal left ventricular ejection fraction (LVEF ≥ 50%) were eligible. Pts received paclitaxel (80 mg/m2 on days 1, 8, and, 15 q4w) plus T-mab (8 mg/kg for the initial dose, followed by 6 mg/kg q3w) until disease progression, unacceptable toxicity or patient’s refusal. The primary endpoint was overall response rate (ORR), and the secondary endpoints include progression free survival (PFS), time to treatment failure (TTF), OS and safety. Results: A total of 47 pts were enrolled from September 2011 to March 2012.The primary endpoint ORR was 37.0% (95%CI, 23 to 52).Complete response was observed in 1 case (2.2%).The PFS data was matured, and the median PFS was 5.09 months (95%CI, 3.79 to 6.49), TTF 5.09 months (95%CI, 3.72 to 6.49), OS 16.81 months (95%CI, 13.54 to 18.65). One patient died of lung pulmonary fibrosis during therapy. The most common grade 3-4 adverse events were leucopenia (17.4%), neutropenia (32.6%), anemia (15.2%). Conclusions: Combination chemotherapy of paclitaxel plus T-mab is generally well tolerated and showed promising activity for T-mab naïve patients with HER2 positive previously treated advanced or recurrent gastric cancer. Clinical trial information: UMIN000006223.
Positive margin length and Gleason grade of tumor focus at the margin predict for biochemical failure after radical prostatectomy in patients with pT2 prostate cancer.
Authors: Nguyen Jenny N. , Chapin Brian Francis , Prokhorova Ina N. , Wang Xuemei , Davis John W. , Troncoso Patricia
Published: February 2017

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Background: While three prospective trials have demonstrated benefit from adjuvant radiation (XRT) after radical prostatectomy (RP) in patients with positive surgical margins (PSM), its use varies amongst physicians. Many rely on clinical acumen to determine the optimal strategy for application of XRT post RP. We aim to determine if the length of PSM and highest Gleason grade (GG) of tumor at the PSM (hGGPSM) can be used to identify patients at greatest risk of biochemical failure (BCF) post RP. Methods: A retrospective review of all RP patients at The University of Texas MD Anderson Cancer Center from 2002 to 2010 was performed. After a single pathologist review, patients with organ confined disease (pT2), pathologic N0/Nx and a PSM were included. BCF was defined as 2 sequential PSA values of ≥0.2 or any detectable PSA prompting XRT. Patients receiving adjuvant XRT or with <12 months follow-up were excluded. Results: 205 patients met the inclusion criteria. Median PSA was 5.3 ng/mL (0.5-33) and median follow-up was 64 months (13-130). The majority were low clinical stage (cT1c: 65%), low (11%)/intermediate (82%) grade and had a single site of a PSM (90%). BCF occurred in 47 patients for a 5 yr BCF free survival (BCFFS) of 69%. PSM length was significantly associated with BCFFS (≤1mm vs >1, p=0.02). When accounting for hGGPSM, Gl 3 tumors were less likely to experience BF (5 yr BCFFS-96%) regardless of PSM length, while BCFFS for Gl >3 tumors were significantly lower dependent upon length of PSM ( ≤1mm vs >1mm, p=0.03). On multivariable analysis length of PSM (p=0.05) and hGGPSM (p=0.007) remained independent predictors of BCF (Table). Conclusions: Length of PSM and hGGPSM are independent predictors of BCF. These should be considered when evaluating patients for adjuvant XRT and in risk stratifying patients in prospective clinical trials. [Table: see text]
ARv567es as detected in circulating tumor cells: An innovative methodology for the detection of a prognostic and therapeutic biomarker.
Authors: Shah Avani Atul , Kang Zhigang , Madan Ravi Amrit , Marte Jennifer L. , Gulley James L. , Dahut William L. , Cao Liang
Published: February 2017

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Background: Increased androgen receptor (AR) expression and signaling is associated with the progression of prostate cancer. Constitutively active AR splice variants (ARVs) are thought to arise following castration and play a key role in progression. The most well studied variant, ARv567es, lacks portions of the ligand-binding domain, increasing expression of full-length AR and transcriptional activity of AR in human prostate cancer cell lines. Tumor-derived tissue can be difficult to obtain for molecular studies on patients (pts) with castration-resistant prostate cancer (CRPC), with circulating tumor cells (CTCs) representing a unique avenue to investigate changes at the molecular level. Methods: Forty-seven whole blood samples drawn from 36 pts with metastatic CRPC (mCRPC) were processed for CTC isolation followed by molecular characterization of cDNA using epithelial tumor markers and prostate cancer specific markers. Microfluidics devices used in this study for CTCs isolation and retrieval is a surface marker independent, label-free cell trap system developed to isolate CTCs based on cell size and deformability (Clearbridge Biomedics). The ARv567eswas detected by multiplex digital PCR System (BioMark HD, Fluidigm) and confirmed by Sanger sequencing. Results: Four out of 36 pts and 6 out of 47 samples had the ARv567es.. The ARv567esamplified from three pts was confirmed by Sanger sequencing in which the ligand binding domain of the receptor was absent. Metastatic disease on presentation was seen in three out of four pts with the ARVs. The ARVs were detected late in the disease course, with the survival after assessment being brief (49, 106, and 200 days) for three out of four pts. One patient is still at 343 days. Due to the nature of this analysis it is unclear when these ARVs developed since baselines samples were not available. Conclusions: This is the first report of the ARv567es found in CTC-enriched peripheral blood samples from CRPC pts. This methodology can also be employed to find other ARVs, which could serve as potential biomarkers in pts, allowing for more appropriate treatment selection based on tumor evolution. This noninvasive method could significantly impact the molecular characterization and potentially the treatment science of CRPC.
The effect of change in PSA velocity on overall survival (OS) in men with biochemically recurrent prostate cancer (BRPC) treated with nonhormonal agents: Combined analysis of four phase 2 trials.
Authors: Suzman Daniel L. , Zahurak Marianna , Carducci Michael Anthony , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: February 2017

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Background: A number of phase 2 trials in men with BRPC have assessed the impact of non-hormonal agents on PSA kinetics. We have previously demonstrated that changes in PSA kinetics are correlated with metastasis-free survival; however, it is unknown whether these changes may also correlate with overall survival (OS). Methods: We performed a combined retrospective analysis of 146 men with BRPC treated on phase 2 trials using one of four investigational drugs: lenalidomide (n=60), marimastat (n=39), ATN-224 (n=22), and imatinib (n=25). We examined factors influencing OS, including within-subject changes in PSA kinetics (PSA slope, PSA doubling time, and PSA velocity) before and 6 months after treatment initiation. Results: After a median follow up of 77 months, 47 men had died. In univariate Cox regression analysis, four factors were associated with OS: prior androgen deprivation therapy (ADT), prior local radiotherapy, baseline PSA velocity, and change in PSA velocity after therapy. In a landmark multivariable model, stratified by study, which also controlled for age and Gleason score (<7 vs ≥7): prior radiotherapy, baseline PSA velocity, and increase in PSA velocity remained independent predictors of OS (Table). Median OS for men with an increase in PSA velocity on treatment was 9.1 years vs 12.3 years for men with a decrease in PSA velocity (HR 1.95; 95%CI 1.07–3.57; P=0.03). Conclusions: This hypothesis-generating study suggests that within-subject changes in PSA velocity after initiation of non-hormonal therapy may correlate with OS in men with BRPC. If validated in prospective trials using OS as the primary endpoint, change in PSA velocity may represent a reasonable intermediate endpoint for screening new agents in these patients. [Table: see text]
The effect of image-guided radiation therapy on rectal and urinary toxicity when radiating the prostatic fossa.
Authors: Spieler Benjamin , Goldstein Jeffrey , Pail Orrin , Samueli Benzion , Saad Akram , Ben-Betzalel Guy , Ben-Nyun Maoz , Tzvang Lev , Weiss Ilana , Lawrence Yaacov Richard , Berger Raanan , Symon Zvi
Published: February 2017

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Background: The 2013 ASTRO/AUA consensus statement reports that most outcome data for patients with biochemical failure is based on the use of older treatment techniques. Studies reporting outcomes for patients treated with modern techniques are needed. Methods: Patients were treated using the EORTC guidelines for determining the prostate fossa volume and radiation dose was above 64 Gray. 3D conformal planning and 3D treatment techniques including IMRT and VMAT were used. Daily image guidance was introduced in 2008 using cone beam CT scan and KV/KV imaging using surgical clips as fiducial markers. Toxicity and side effects were recorded and compared to patients treated prior to introduction of image guidance. Results: The Table shows toxicity results prior to and after introduction of daily image guidance. χ2 analysis indicates significant differences for GI, GU and overall toxicity between pre-IGRT and post-IGRT patient groups. Conclusions: Our results are consistent with other reports showing that salvage radiation therapy to the prostatic fossa or prostatic fossa and pelvic lymph nodes is well tolerated with few significant acute or late complications. We noted a significant decrease in GI toxicity and in GU toxicity with the introduction of image guidance techniques. [Table: see text]
Impact of prior endocrine therapy on radiographic progression-free survival (rPFS) in patients (pts) with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.
Authors: Oudard Stephane , Kheoh Thian San , Yu Margaret K. , Smith Matthew R. , Small Eric Jay , Mulders Peter F.A. , Fizazi Karim , Rathkopf Dana E. , Saad Fred , Scher Howard I. , Bellmunt Joaquim , Taplin Mary-Ellen , Davis Ian D. , Schrijvers Dirk L. , Protheroe Andrew , Molina Arturo , Griffin Thomas W. , De Bono Johann Sebastian , Ryan Charles J.
Published: February 2017

14

Background: Abiraterone acetate (AA), a prodrug of abiraterone, which is a selective androgen biosynthesis inhibitor, prolongs overall survival (OS) in mCRPC pts and is approved for use in this population. An exploratory analysis was conducted to determine the impact of prior endocrine therapy on clinical benefit of AA in COU-AA-302, a randomized phase 3 study of pts with chemotherapy-naive mCRPC. Methods: 1,088 pts (testosterone < 50 ng/dL; receiving continuous gonadotropin-releasing hormone [GnRH] agonist if not orchiectomized) were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or placebo + P alone. rPFS and OS were co-primary end points. rPFS was defined as time to first occurrence of bone scan progression by PCWG2 criteria, progression by CT/MRI by modified RECIST 1.0 criteria, or death, whichever came first. Comparison of the treatment effect on rPFS (investigator review at 55% of OS events) was made for the subgroups above or below the median duration of prior endocrine therapy in 2 categories: either prior GnRH agonist or prior antiandrogens. Cox model was used to obtain the HR and associated 95% CI with statistical inference by log rank statistic. Results: Most pts received prior GnRH agonists and antiandrogens (Table). rPFS was significantly more favorable with AA than P irrespective of the median duration of prior GnRH agonist or antiandrogen therapy. Increased median rPFS was observed in pts with longer prior exposure to GnRH agonists or antiandrogens comparing within both AA and P treatment groups. Conclusions: As shown in this COU-AA-302 exploratory analysis, duration of prior endocrine therapy, as analyzed after the onset of mCRPC, does not appear to impact clinical benefit of AA in pts with chemotherapy-naive mCRPC. Clinical trial information: NCT00887198. [Table: see text]