bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective patient (pt) survey on clinical trials.
Authors: Moorcraft Sing Yu , Marriott Cheryl , Peckitt Clare , Cunningham David , Chau Ian , Starling Naureen , Watkins David , Andreyev Jervoise , Rao Sheela
Published: February 2017

707

Background: Recruitment to clinical trials can be challenging. We conducted a patient survey to improve our understanding of pts’ views and experiences of clinical trials and what aspects could be improved. Methods: Pts who had been approached about participation in any clinical trial in the Gastrointestinal (GI) and Lymphoma Unit at the Royal Marsden were prospectively invited to complete a questionnaire about their views and experiences of cancer research. Results: Between August 2013 and July 2014, 276 pts (90% GI, 10% lymphoma) received 298 clinical trial pt information sheets (PIS) and were asked to complete a questionnaire. 263 respondents (Res) consented to a trial and 249 of these (95%) completed the questionnaire (65 for clinical trials of an investigational medicinal product (CTIMP), 156 for non-CTIMPs and 28 for molecular pre-screening trials). 25 Res declined a trial and 10 of these completed the questionnaire. Of the 249 Res who consented to a trial, 96% were glad to be approached about clinical trials. 90% of Res felt the PIS was easy to understand and rated the verbal explanation of the trial as excellent/good. 10 Res who declined a trial felt the verbal explanation was excellent/good and that the PIS was easy to understand. The mean total PIS length (including sub-studies) was 17 pages (range 3-50 pages). 9% of Res who consented to a trial felt the PIS was too long. Regarding CTIMP trials, 48-50% of Res would have liked more information on trial drugs and any additional research procedures, 28-30% were neutral and 20-24% did not want more information. 75% of Res would consider participating in studies requiring a research biopsy and 78% would donate their tissue for genetic research. 79% of pre-screening trial Res, 66% of non-CTIMP trial Res and 54% of CTIMP trial Res would have been willing to consent to the trial on the day they received the PIS. 75% of Res (including 89% of CTIMP Res) believed pts should be told trial results, even if results are not available for many years. Conclusions: The majority of pts are willing to be approached regarding clinical trials. A high proportion of pts would consider studies involving research biopsies. New strategies for tailoring additional trial information according to the patient and informing pts of trial results should be explored.
Survival impact of adjuvant chemotherapy for resected early-stage rectal adenocarcinoma.
Authors: Tay Rebecca Yin , Jamnagerwalla Murtaza , Steel Malcolm , Wong Hui-Li , McKendrick Joseph James , Faragher Ian , Kosmider Suzanne , Hastie Ian , Desai Jayesh , Gibbs Peter , Wong Rachel
Published: February 2017

712

Background: Recent data have created uncertainty regarding the benefit of the current standard of care adjuvant fluoropyrimidine-containing chemotherapy following preoperative chemoradiotherapy and surgical resection for locally advanced rectal cancer. In particular, patients with a pathologic complete response may derive no benefit from adjuvant chemotherapy. Methods: This is a retrospective analysis of patients with early stage rectal adenocarcinoma, diagnosed between 1 January 2003 and 30 June 2013 at three Melbourne health services (Eastern Health, Royal Melbourne Hospital, and Western Health). Patients were identified from a search of the ACCORD (Australian Comprehensive Cancer Outcomes and Research Database) database, where a defined data set is prospectively collected on consecutive patients. Patient demographics, pre-treatment staging, post-operative treatment, recurrence, and survival were analyed. Results: A total of 580 patients with localized rectal cancer were identified, of whom 451 had received neoadjuvant long-course chemoradiation followed by resection of the primary tumor. 369 patients (82%) subsequently received adjuvant 5-fluorouracil. At a median follow-up of 45.9 months, 63 (19%) patients in the adjuvant chemotherapy group and 21 (29%) in the surveillance only group had relapsed. Median relapse-free survival (RFS) has not been reached in either group; 3-year RFS was 81% in the adjuvant chemotherapy group compared to 71% in the surveillance only group (p=0.034). Five-year overall survival was 83% in the adjuvant chemotherapy group compared to 71% in the surveillance only group (p=0.038). The impact of age, surgical complications, treatment-related toxicity, and pathological complete response post-neoadjuvant therapy on the uptake of post-operative chemotherapy and on survival are being evaluated. Conclusions: A high proportion of patients in routine practice receive adjuvant chemotherapy following neoadjuvant treatment and surgery for early stage rectal cancer. Adjuvant chemotherapy was associated with a significant improvement in 3-year relapse-free and 5-year overall survival.
Is panitumumab monotherapy safe in metastatic colorectal cancer patients over 70 years old?
Authors: Martin-Babau Jerome , Douillard Jean-Yves , Dupuis Olivier Jean Marie , Porneuf Marc , Ramée Jean François , Raoul Jean-Luc , Deguiral Philippe , Faroux Roger , Gourlaouen Alain , Miglianico Laurent , Van Hulst Sylvie , El Hannani C. , Bassoulet James , Stampfli Claire , Riche Christian , Marhuenda Fanny , Deniel Lagadec Delphine , Jestin Le Tallec Veronique , Grude Francoise , Metges Jean-Philippe
Published: February 2017

714

Background: Metastatic Colorectal Cancer (mCRC) often occurs in patients older than 70 years old. Monoclonal antibodies targeting EGFR have improved the outcome of mCRC patients. Panitumumab in monotherapy is indicated in wild-type K-RAS mCRC progressing disease following fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. Very few data are available in elderly patients receiving panitumumab. Methods: Based on the cohort of the Observatory of Cancer B PL in France, we studied the efficacy and tolerance of panitumumab. We retrospectively collected data from patients treated between July 2008 and January 2014 and older than age 70 and compared the results between two cohorts: one contained patients ages 70 to 74; the other contained patients age 75 and older. Results: 136 patients were identified. The median age was 77. The median number of course received was 7 infusions. There was no difference in outcomes between the patients of the two cohorts. Median overall survival was 6.16 months. Median PFS was 13 weeks. The older patients received less previous chemotherapy ligns than the younger with a statistical difference (p=0.023). Tolerance was acceptable with a skin toxicity rate of 67% and 11.5% of grade 3-4. No diarrhea or hypomagnesemia were reported. Conclusions: Our study shows that panitumumab is feasible in elderly patients "in the real world" and has comparable efficacy than in younger patients.
Bowel dysfunction-related needs assessment in colorectal cancer survivors.
Authors: Sun Virginia , Smith David D. , Lai Lily L. , Chong Carrie , Grant Marcia
Published: February 2017

715

Background: Bowel dysfunction is common following treatment for colorectal cancer (CRC), with substantial impact on survivors’ quality of life (QOL). There are few evidence-based protocols to support positive adjustments to bowel function changes. The purpose of this study was to assess CRC survivors’ bowel dysfunction related information needs following surgery. Methods: CRC survivors who were within 1-3 months post-resection (n=37) completed questionnaires on bowel function, fecal incontinence specific QOL, and bowel dysfunction needs. Six randomly selected participants were interviewed to further explore unmet needs. Quantitative data were summarized using descriptive statistics for all subscales and individual items. Qualitative data were interpreted through content analysis methods. Results: The mean number of daily bowel movements was 5.5 (range 2-10). Many survivors reported incomplete bowel evacuation (66%) and increased urgency/frequency (75%). More problems were reported on the impact of diet on function (X=12, SD=3.2) and urgency/soilage (X=13.5, SD=4.5). Lower QOL scores were observed for the impact of dysfunction on lifestyle (X=2.7, SD=1.0) and coping behavior (X=2.7, SD=0.9). Survivors reported unmet information needs for the following: 1) managing bowel dysfunction in an emergency; 2) type of foods that are helpful or not helpful with bowel function; and 3) talking to others who share the same experience. The majority (75%) desired to participate in a rehabilitation program, and preferred to receive content before treatments or discharge from hospital following surgery. Conclusions: CRC survivors report unmet bowel dysfunction related needs, and desire more information and strategies to help with managing changes to their bowel patterns. Evidence-based interventions that are timely and personalized are needed to support long-term, positive adjustments following treatment.
Disparities in receipt of radiotherapy and survival by age, sex, and race among patients with nonmetastatic squamous cell carcinoma of the anus.
Authors: Baughman Doug , Ghimire Krishna Bilas , Shah Binay Kumar
Published: February 2017

721

Background: Combination chemoradiotherapy is the standard of care for treatment of non-metastatic squamous cell carcinoma of the anus (SCCA). This population-based study evaluated disparities in receipt of radiotherapy (RT) and its effect on survival in patients with localized and regional SCCA in the United States. Methods: The Surveillance, Epidemiology, and End Results (SEER) 18 database was used to identify patients with localized and regional SCCA diagnosed between 1998 and 2008. We used univariate and multivariate logistic regression to model the relationships between receipt of RT and age, sex, marital status, stage, and race. Relative survival rates were calculated and compared using two sample z-tests. A Cox proportional hazards model was used to find adjusted hazard ratios (HR). Results: A total of 3,971 patients with localized or regional SCCA as the only primary malignancy were included in the study, of which 3,278 (82.6%) received RT. After adjusting for covariates, those 65 years and older (adjusted OR 0.82, p=0.029) were less likely to receive RT. Females were more likely to receive RT compared to males (adjusted OR 1.54, p<0.001). We found no difference in receipt of RT by race. Comparisons of 1- and 5-year relative survival rates showed lower survival for blacks (p-value <0.01 at 1-year and <0.0001 at 5-years), those 65 years and older, and males. A 1-year survival disparity was found for those not receiving RT (p-value <0.0001 at 1-year), but no difference was observed at 5-years. A Cox proportional hazards model adjusting for all covariates showed greater hazard for blacks (adjusted HR 1.36, p=0.001), those not receiving RT (adjusted HR 1.23, p=0.03), patients 65 years or older, and males. Conclusions: This population based study identified older patients as less likely to receive RT and females as more likely to receive RT. Survival analysis identified blacks, males, older patients, and those not receiving RT as having lower rates of survival.
Impact of total lymph node count on staging and survival after neoadjuvant chemoradiation therapy for rectal cancer.
Authors: Hall Matthew David , Schultheiss Timothy E. , Wong Jeffrey Y.C. , Chen Yi-Jen
Published: February 2017

736

Background: Neoadjuvant chemoradiation therapy (CRT) results in fewer retrieved lymph nodes at the time of surgery for rectal cancer. The extent of optimal regional nodal dissection is based on guidelines developed before neoadjuvant CRT was commonly used. The purpose of this study is to assess the impact of the number of dissected and positive lymph nodes on overall survival (OS) for rectal cancer patients treated with neoadjuvant CRT. Methods: Treatment data were obtained by structured query on all patients with rectal adenocarcinoma (2000-2013) in the National Oncology Data Alliance, a proprietary database of merged tumor registries. Eligible patients were treated with neoadjuvant CRT followed by surgery and had complete data on the number of positive and dissected lymph nodes and dates of treatment. The relationships between number of lymph nodes examined and OS were separately analyzed in patients with 0, exactly 1, or any number of positive nodes. Results: The median number of lymph nodes examined was 11 (interquartile range 6-16). In 4,581 evaluable patients, there was a significant improvement in OS with the examination of more lymph nodes. Number of positive lymph nodes, number of lymph nodes dissected, age, gender, grade, marital status, and race were significant predictors of OS on multivariate analysis. On subset analysis, patients with 0, exactly 1, and any number of positive nodes were found to have better OS with increasing number of lymph nodes dissected up to eight. Increasing overall mortality was observed in patients with 0, 1, 2-4, 5-7, and ≥8 positive lymph nodes. The Kaplan-Meier curves showed a clear statistically significant difference in OS in patients divided into these five nodal groupings (p<0.0001). Conclusions: Patients with eight or more lymph nodes examined had the greatest improvement in OS in rectal cancer patients treated with neoadjuvant CRT. This should be considered the threshold for an adequate lymph node sampling in this population. A five-tier nodal grouping was found to best forecast prognosis based on the number of positive lymph nodes identified.
Predictive factors and prognostic significance of tumor regression grade in rectal cancer.
Authors: Ogundimu Oluwabunmi , Ramjeesingh Ravi , Ren Kevin , Qu Melody Xuan Lu , Hurlbut David , Biagi James Joseph , Mahmud Aamer
Published: February 2017

739

Background: Several systems describe tumour regression grade (TRG) after neo-adjuvant chemo-radiotherapy (nCRT) in rectal cancer; however, there is lack of literature on factors predicting TRG and its prognostic significance when comparing two TRG systems. Methods: Chart review of 187 patients (pts) diagnosed with rectal cancer managed at our institution identified clinical T3 or T4 and/ or node positive adenocarcinoma who completed nCRT between 2005-2011. Assessment of TRG post-nCRT in 104 pts was determined using College of American Pathologists (CAP) and Modified Rectal Cancer Regression Grade (mRCRG) scoring systems. Logistic regression model was used to identify factors associated with TRG. Overall survival (OS) was estimated using Kaplan-Meier method, log-rank test to compare groups and Cox proportional hazard model to estimate hazard ratio. Results: Median age of 103 eligible pts was 64 (range [r] 31-88) and 70% were male. Median pre-nCRT tumour size was 4 cm (r 0.5-12). 61% tumours were distal. Radiation dose (RD) was >54 Gy in 57%, 50.4 Gy in 40%, and 45 Gy in 3% patients. 71% received concomitant 5 FU; 12% capecitabine and 17% according to clinical trials prior to radical surgery. Median time between completion of nCRT and surgery was 49 days. CAP scoring was 0 (21%), 1 (7%), 2 (19%), and 3 (53%) whereas mRCRG scoring was 1 (31%), 2 (21%), and 3 (48%). With median follow up 5.04 years (yr), 5 yr OS was 65%. OS was 77% for CAP 0 and 1 vs. 59% for CAP 2 and 3 (p=0.0483, HR2.4); mRCRG 1 and 2 OS was 75% vs 54% for mRCRG 3 (p= 0.0060, HR2.6). >30% reduction in pre-nCRT tumour occurred in 63% of CAP 1, 2, and 3 cases. Age (≥65 yr), higher RD and higher pre-op CEA were associated with mRCRG grade 3 (p=0.0339, 0.0415, and 0.0760 respectively). Tumour size, location, grade, type of chemotherapy, or gender were not predictive of TRG. Conclusions: Favorable TRG post-nCRT is associated with a statistically significant OS advantage. Younger age and RD escalation are associated with favorable TRG. CAP and mRCRG scoring systems of TRG were comparable for prognosis. nCRT leads to a significant cytoreduction in 63% of non-complete responders. TRG may have a future role in decisions on surgery, organ sparing, adjuvant chemotherapy, surveillance and patient counseling.
Association of morphologic response with progression free survival in patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy: HGCSG0802.
Authors: Yuki Satoshi , Nakatsumi Hiroshi , Hayashi Hideyuki , Fukushima Hiraku , Kato Takashi , Meguro Takashi , Nakamura Michio , Iwanaga Ichiro , Eto Kazunori , Sato Atsushi , Okuda Hiroyuki , Oba Ayane , Miyagishima Takuto , Muto Osamu , Yabusaki Satoshi , Miyamoto Noriyuki , Kudo Kohsuke , Sakamoto Naoya , Sakata Yuh , Komatsu Yoshito
Published: February 2017

743

Background: It was reported that an optimal morphologic response to preoperative chemotherapy was associated with better overall survival (OS) in patients (pts) with colorectal liver metastases (CLM). We investigated association of morphologic response with progression free survival (PFS) in pts with unresectable CLM from HGCSG0802 observational cohort study in pts with mCRC treated with first-line bevacizumab (BV)-based chemotherapy. Methods: The objective of HGCSG0802 was to evaluate PFS, OS, time to treatment failure (TTF), response rate (RR), safety, etc. The key eligibility criteria were evaluable lesions, older than 20 years old, ECOG PS 0-2. Pts with CLM underwent contrast-enhanced CT at the start and every 8-weeks of BV-based chemotherapy. In this analysis, three blinded, independent radiologists evaluated images for morphologic response, based on metastases changing from heterogeneous masses with ill-defined margins into homogeneous hypoattenuating lesions with sharp borders. Association of morphologic response and pts characteristics, RR, and PFS were evaluated. PFS was analyzed with Kaplan-Meier method, log-rank test, and Cox proportional hazards model. Results: Of 108 pts (the full analysis set), 73 pts with CLM were evaluable for morphologic criteria. Eighteen pts (24.7%) had optimal morphologic response (OR), 31 (42.5%) had incomplete (IR), and 24 (32.9%) had no response (NR). The pts characteristics between those with OR, IR and NR were generally balanced. The median TTF was 7.2 months in NR versus 7.2 months in IR versus 6.8 months in OR (HR (OR/NR) = 0.91, HR (OR/IR) = 0.90; p = 0.93). RR was 77.8% in OR versus 64.5% in IR and 58.3% in NR (p = 0.528). The median PFS was 8.3 months in NR versus 8.5 months in IR versus 9.1 months in OR (HR (OR/NR) = 0.72, HR (OR/IR) = 1.04; p = 0.420). Conclusions: In this analysis, morphologic response might not be a prognostic marker in first-line BV-based chemotherapy in pts with CLM.
Phase II trial of irinotecan plus s-1 (IRIS) with cetuximab (IRIS/Cet) as second-line treatment in patients with KRAS wild-type metastatic colorectal cancer (mCRC): HGCSG0902—Comparison of administration interval in cetuximab treatment.
Authors: Komatsu Yoshito , Yuki Satoshi , Nakatsumi Hiroshi , Hosokawa Ayumu , Nakamura Michio , Muto Osamu , Meguro Takashi , Iwanaga Ichiro , Hatanaka Kazuteru , Tsuji Yasushi , Sato Atsushi , Eto Kazunori , Furukawa Kouichi , Onodera Manabu , Tateyama Miki , Takahashi Yasuo , Dazai Masayoshi , Yokoyama Sachio , Honda Takuya , Sakata Yuh ,   HGCSG
Published: February 2017

746

Background: HGCSG0902 is the multicenter phase II study to investigate the safety and efficacy of IRIS/Cet as second-line treatment in patients with KRAS wild type mCRC. RR was 33.3% (95% CI, 20.8%-45.9%), therefore primary endpoint was met (Muto et al. ESMO 2014 ). Here we report an exploratory analysis of outcomes based on administration interval of Cet (every week [EW] vs bi-weekly [BW]). Methods: Eligibility includes histologically confirmed colorectal cancer, previously received oxaliplatin-contained chemotherapy, PS: 0-1, EGFR positive and KRAS WT. Pts. received S-1 80-120 mg/day p.o. on days 1-14 and irinotecan 100 mg/m2 on days 1 and 15 repeated every 28 days. Cet was administrated 400 mg/m2 as loading dose and continued 250 mg/m2 every week or 500 mg/m2 bi-weekly. The primary endpoint was RR and the secondary endpoints were disease control rate, PFS, OS and safety. To compare with EW and BW, Fisher’s exact test was used in terms of patient characteristics, AE, RR, and Log-rank test was used in terms of PFS, OS, and TTF. Results: Between March 2010 and September 2013, 58 pts were enrolled. One patient was not administered (57 pts were safety analysis set), and 3 pts were ineligible (54 pts were efficacy analysis set). Based on each physician choice, 34 pts. of EW and 23 of BW were included in the full safety analysis set. RR was 34.4% in the EW group and 31.8% in the BW group (p=1.000). Median PFS was 4.2 months (95% CI 3.5−4.9) in the EW group and 6.1 months (4.1-8.1) in the BW group (HR 0.752, 95% CI 0.413−1.372, p=0.350). The most common non-hematological adverse events of grade 3 or higher were diarrhea (23.5% in the EW group vs. 52.2% in the BW group: p=0.005) and stomatitis (2.9% in the EW group vs. 30.4% in the BW group: p=0.046), these were significantly more common in the BW group. Conclusions: IRIS/Cet appeared to be highly effective with RR and PFS in the both treatment schedule, and also had met the primary endpoint. Diarrhea and stomatitis were significantly more common in the BW group. Therefore, in case of treatment with IRIS, cetuximab should be administered weekly. Clinical trial information: 000004882.
PEPCOL: A randomized noncomparative phase II study of PEP02 (MM-398) or irinotecan in combination with leucovorin and 5-fluorouracil as second-line therapy in patients with unresectable metastatic colorectal cancer—A GERCOR Study.
Authors: Chibaudel Benoist , Maindrault-Goebel Frederique , André Thierry , Bachet Jean Baptiste , Louvet Christophe , Khalil Ahmed , Dupuis Olivier Jean Marie , Hammel Pascal , Garcia Marie Line , Bennamoun Mostefa , Brusquant David , Arbaud Claire , Wang Yi-Wen , Yeh Grace , Bonnetain Franck , De Gramont Aimery ,   GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie
Published: February 2017

751

Background: PEP02 is a highly stable nanoliposomal irinotecan. This randomized non-comparative phase II (PEPCOL) study evaluated the efficacy and safety of PEP02 (MM-398) or irinotecan in combination with LV/5-FU in the second-line treatment of metastatic colorectal cancer (mCRC). (EudraCT 2010-020468-39A, NCT01375816). Methods: Patients with unresectable mCRC who had failed one prior oxaliplatin-based first-line therapy were randomly assigned to FUPEP (PEP02 80 mg/m² d1, folinic acid (FA) 400 mg/m² d1, 5-FU 2,400 mg/m² d1-2) or FOLFIRI (FOLFIRI1: irinotecan 180 mg/m² d1, FA 400 mg/m² d1, 5-FU bolus 400 mg/m² d1, 5-FU infusion 2,400 mg/m² d1-2; or modified FOLFIRI3: irinotecan 90 mg/m² d1 and 3, FA 400 mg/m² d1, 5-FU infusion 2,400 mg/m² d1-2). Bevacizumab q2w (5 mg/kg) was allowed in both arms as of June 2012 (TML study report). The primary endpoint was the objective tumor response (OR). Results: Fifty-five patients were randomized (FUPEP, n=28; FOLFIRI, n=27). In the evaluable population (n=50), OR rate were 16.7% (n=4/24) and 11.5% (n=3/26) in the FUPEP and the FOLFIRI arms, respectively. Most common grade 3-4 adverse events reported in the respective FUPEP and the FOLFIRI arms were diarrhea (21% vs 33%), neutropenia (11% vs 30%), mucositis (11% vs 11%), and alopecia (G2: 25% vs 26%). Conclusions: FUPEP regimen exhibits promising tumor response and safety profile, and can be combined with bevacizumab, for oxaliplatin-pretreated patients. Hence PEP02 (MM-398) may provide a new second-line treatment option for mCRC. Based on the safety profile of the FUPEP regimen in this PEPCOL study, it was added as the third arm to the positive phase III metastatic pancreatic cancer (NAPOLI-1) study. Clinical trial information: NCT01375816.
A prospective study of XELIRI plus bevacizumab as the first-line therapy in Japanese patients with unresectable or recurrent colorectal cancer (KSCC1101).
Authors: Hanazono Koichi , Emi Yasunori , Tsuji Akihito , Kishihara Fumiaki , Oki Eiji , Hamanoue Masahiro , Baba Hideo , Natsugoe Shoji , Ogata Yutaka , Sakai Kenji , Maehara Yoshihiko ,   Kyushu Study Group of Clinical Cancer (KSCC)
Published: February 2017

752

Background: XELIRI plus bevacizumab (Bev) might be one of the standard therapies for metastatic colorectal cancer (mCRC). However, there was no clinical practice data in Japan. This study was designed to evaluate the efficacy and safety of XELIRI plus Bev in clinical practice in Japanese mCRC patients (pts.). Methods: This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated mCRC; presence of measurable lesions; age ≥20 years; ECOG performance status (PS) of 0–2; and adequate organ function. Pts received Bev 7.5 mg/kg day 1 and XELIRI (irinotecan 200 mg/m2 day 1 plus capecitabine 800 mg/m2 bid d1-14) q3w. This schedule was repeated until unacceptable toxicity or disease progression occurred. The primary endpoint was RECIST-confirmed objective response rate (ORR). A sample size of 35 was planned for a threshold ORR of 30% and expected value of 53%, with one-sided alpha of 0.05 and beta of approximately 0.2. Results: A total of 36 pts (male/female, 23/13; median age, 65.0 years (range 44.0-80.0); PS 0/1/2, 31/5/0) were enrolled in this study from July 2011 to September 2012. One patient did not fulfill the eligibility criteria and one withdrew the informed consent before the start of protocol treatment. Thirty-four pts were assessed for response; CR 0, PR 18, SD 9, PD 4, and NE 3. The confirmed ORR was 52.9% (90% CI, 37.7-67.8%). Median PFS was 9.6 months (95% CI, 5.1-11.1 months) and mOS was 23.0 months (95% CI, 11.3-NE months). mTTF was 5.3 months (95% CI, 3.2-8.3 months). The most common grade 3/4 adverse events were neutropenia 31.4%, anemia 20.0%, thrombocytopenia 5.7%, hyponatremia 20.0%, anorexia 20.0%, diarrhea 22.8%, fatigue 0.0%, hypertension 2.9%, hand-foot syndrome 0.0%, and bleeding 0.0%. Conclusions: First-line treatment of XELIRI + Bev showed a promising response rate and an acceptable tolerability profile in the clinical practice in Japanese mCRC pts. Clinical trial information: UMIN000006070.
Exploratory analysis of a prognosis predictive formula for metastatic colorectal cancer treated with chemotherapy.
Authors: Tanaka Mamoru , Kusaba Hitoshi , Mukaide Satomi , Kishimoto Junji , Kumagai Hozumi , Makiyama Akitaka , Shirakawa Tsuyoshi , Oda Hisanobu , Komoda Masato , Mitsugi Kenji , Akashi Koichi , Baba Eishi
Published: February 2017

757

Background: Progression free survival (PFS) has been recognized as a surrogate outcome in the therapy for metastatic or recurrent colorectal cancer (mCRC). As molecular targeted therapies have become to be widely used, new surrogate outcome such as early tumor shrinkage (ETS; the relative change in the sum of longest diameters of target lesions at week 8 compared to baseline) and deepness of response (DpR; the relative change in the sum of longest diameters of target lesions at the nadir compared to baseline) are proposed. However, their validity has not been fully proven. We conducted to develop a new prognosis predictive formula consisting of the three factors, DpR, ETS and PFS, in the first-line chemotherapy of mCRC. Methods: We retrospectively evaluated mCRC patients who started any chemotherapy from 2005 to 2010. Estimated ETS (eETS), instead of ETS, was defined as the estimated relative change of target lesions at week 8 calculated from first image assessment. DpR was defined as above. Predictive formulae of prognosis were examined by single and multiple regression analysis. Results: 63 patients were enrolled. KRAS status were as follows; wild type; 33, mutant; 17, unknown; 13. Chemotherapies were performed as follows; oxaliplatin-based plus bevacizumab; 34, irinotecan-based plus bevacizumab; 6, oxaliplatin-based plus anti-EGFR antibody; 2, oxaliplatin-based; 17, irinotecan-based; 4. Median of DpR, eETS, PFS and overall survival (OS) were 26.5%, 15.4%, 236 days and 571 days, respectively. PFS showed a correlation with OS (r2= 0.434), while DpR and eETS were less correlated with OS (r2= 0.228, 0.082). PFS and eETS were thus chosen as variables for the prediction formula of prognosis. However, the present formula did not show an apparent increased R2 value compared with the formula consisted of PFS alone (adjusted R2= 0.442 vs 0.425), indicating that the present formula could not provide more accurate prediction. In the stratified subgroups according to treatment regimen and KRAS status, the formula did not show remarkable change in R2 value. Conclusions: The present formulae including DpR and eETS does not have superior predicting potential to PFS alone for prognosis of the whole mCRC patients.
The study of efficacy and safety of chemotherapy plus bevacizumab with oxaliplatin stop-and-go strategy in first-line treatment for metastatic colorectal cancer.
Authors: Takano Nao , Nakayama Goro , Kodera Yasuhiro
Published: February 2017

761

Background: In metastatic colorectal cancer (mCRC), the benefit of the molecular targeted drugs added to chemotherapy has been reported and a combination therapy of capecitabine (CAP) and oxaliplatin (CapeOX) plus bevacizumab (BEV) is an established first-line therapy for mCRC. However, the management of the cumlateve neurotoxicity of oxaliplatin still remains. We evaluated the efficacy and safety of CapeOX plus BEV with oxaliplatin stop and go strategy. Methods: Two prospective clinical trials of previously untreated unresectable mCRC were analyzed. Fifty four patients were treated with CapeOX plus BEV with oxaliplatin stop and go strategy (CCOG-0902). They were treated 4 cycles of CapeOX plus BV therapy followed by maintenance therapy of 8 cycles of Capecitabine plus BV and oxaliplatin reintroduction was scheduled after maintenance therapy or upon tumor progression. On the other group, forty seven patients were treated with mFOLFOX6 plus BEV (CCOG-0801). Progression free survival (PFS), overall survival (OS), response rate (RR), disease control rate (DCR), relative dose intensity (RDI), and frequency of peripheral sensory neuropathy (PSN) were evaluated. Results: Patient characteristics were balanced between the two groups. The median RDI of oxaliplatin in CCOG-0902 group was significantly higher, 92% than in CCOG-0801 group, 80%. RR and DCR were 61.5% and 96.3% respectively, in CCOG-0902 group, compared with 61.7% and 89.4% respectively, in CCOG-0801 group. Median PFS was 13.6 and 30.5 months, respectively, compared with 11.7 and 31.6 months, respectively, in CCOG-0801 group (p=not significant). The frequency of peripheral sensory neuropathy (PSN) was 19.0% (>Grade3: 1.9%) of patients in CCOG-0902 group compared with 72.3% (>grade 3: 17.0%) in CCOG-0801 group. Conclusions: CapeOX plus BV with oxaliplatin stop and go strategy could have same efficacy as continuing oxaliplatin with avoiding PSN. Clinical trial information: UMIN000006478.
Neoadjuvant chemoradiation (CRT) with or without panitumumab (Pan) in patients with K-ras unmutated, locally advanced rectal cancer (LARC): Final results of a randomized multicenter phase II trial (SAKK 41/07).
Authors: Helbling Daniel , Bodoky Gyorgy , Gautschi Oliver , Hayoz Stefanie , Bosman Fred , Madlung Axel , Gloor Beat , Burkhard Roger , Rauch Daniel , Winterhalder Ralph C. , Saletti Piercarlo , Widmer Lukas , Borner Markus M. , Baertschi Daniela , Yan Pu , Koeberle Dieter
Published: February 2017

762

Background: We conducted a randomized phase II multicenter trial evaluate the anti-epidermal growth factor receptor (EGFR) panitumumab (P) in combination with CRT with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS LARC. Methods: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT either with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Secondary end-points were pathological response, R0-resection, sphincter preservation, downstaging, time to local relapse, time to distant failure and disease-free survival (DFS). Results: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT either with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Secondary end-points were pathological response, R0-resection, sphincter preservation, downstaging, time to local relapse, time to distant failure and disease-free survival (DFS). Conclusions: An addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. Up to date no local recurrence occurred and DFS compared favorably to other trials. Clinical trial information: NCT00814619.
Budgetary impact of adding ziv-aflibercept to a United States health plan formulary as a post-oxaliplatin biologic option for patients with metastatic colorectal cancer (mCRC).
Authors: Huff Keith , Drea Edward , Hennessy Daniel , Thompson Stephen F. , Dhawan Ravinder
Published: February 2017

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Background: To assess the economic impact of the availability of ziv-aflibercept for patients with mCRC following disease progression after oxaliplatin, a user-adaptable budget impact model was developed for payers, based on use of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) chemotherapy alone or combined with a biologic agent, including ziv-aflibercept. Methods: A Markov-like model simulated transition from progression-free survival (PFS) to progressive disease (PD) and death. Over the model time frame of 1 year, each 90-day cycle adjusted for the probability of patients experiencing PFS, PD or death. Treatment options were FOLFIRI alone or combined with a biologic agent, ziv-aflibercept, bevacizumab, cetuximab or panitumumab. April 2013 United States utilization rates were used as baseline, with biologic agent drug costs as per July 2014 Medicare Part B Drug Average Sales Price. PFS and overall survival were calculated from clinical trial data of biologic agents combined with chemotherapy. Adverse event cost calculations used documented incidence rates and published cost sources. Other costs were for biomarker testing, drug administration/monitoring and death/terminal care. Results: The estimated number of patients receiving FOLFIRI alone or with a biologic agent for mCRC was 57 per million-member health plan. Using April 2013 utilization rates (including ziv-aflibercept at 3.4%), estimated treatment costs were $5.259M, a per-member-per-month (PMPM) cost of $0.0438. Changes in utilization rates of biologic agents, including, for example, ziv-aflibercept at 20.1%, would decrease costs by 2.1% ($108,176) to $5.151M annually, a PMPM decrease of $0.009. The model suggests cost savings primarily due to lower unit costs for ziv-aflibercept and lower death-related costs, rather than decreased adverse event management. Conclusions: The model estimates a PMPM cost saving with increased utilization of biologics, including ziv-aflibercept. Sensitivity analysis of utilization rate changes supports these findings. Including further user-defined scenarios allows plan-specific modeling of budgetary impact.
Unraveling the regulation of a putative cancer stem cell-like population in esophageal cancer.
Authors: Wang Da , Smit Justin , Chiu Roland , Plukker John Theodorus , Coppes Robert P.
Published: February 2017

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Background: Despite advances in the treatment of esophageal cancer (EC), most patients face poor outcome. Mounting evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. Whereas most cancer cells are sensitive to chemo- and/or radiotherapy (CRT), CSCs are generally resistant and ultimately have the potential to generate a new tumor. Mechanisms regulating EC CSCs are poorly understood and need to be elucidated. Previously, we identified a putative CSC-like population (CD24-/CD44+) in EC cell lines and in esophageal adenocarcinoma (EAC). Here we show that the Hedgehog signaling pathway may regulate CSC-like populations in EC. Methods: To identify up-regulated CSC related genes, qPCR arrays were performed on CD24-/CD44+ OE21 esophageal squamous cell carcinoma (ESCC) and OE33 (EAC). CD24-/CD44+ was compared to CD24+/CD44+ and solid tumors generated from the same cell lines obtained from xenografts. Immunohistochemical (IHC) staining from tumor material of microscopical residual disease (mRD) patients after CRT was compared to surgery alone patients (S). Results: From a panel of 84 CSC related genes, Ptch1 was found to be up-regulated in the OE21 CD24-/CD44+ putative CSC-like population when compared to CD24+/CD44+ population and the solid tumor (2.5 and 3.7 fold, respectively). Furthermore, in OE33 this up-regulation was 1.4 and 1.7 fold. From 6 preselected candidate CRT response markers, CD44 and Sonic Hedgehog (SHH) expression was 55% (p<0.05) and 64% (P<0.005) enhanced in mRD compared to the S group in IHC material. Moreover, SHH expression showed a positive correlation coefficient of 0.551 (P<0.005) with CD44 and 0.512 (P<0.05) with Excision Repair Cross-Complementation group 1 (ERCC1, a nucleotide excision repair gene) in mRD tissue. Conclusions: These findings indicate that the Hedgehog pathway might be involved in regulating EC CSC-like properties. Although requiring further research, an exciting prospect would be the modulation of the Hedgehog pathway in combating CSC-like populations and the potential predictive value of SHH expression on treatment outcome.
Subjective and objective assessment of oxaliplatin-induced peripheral neuropathy.
Authors: Yamada Teppei , Yoshida Yoichiro , Aisu Naoya , Matsuoka Taisuke , Kojima Daibo , Tanimura Syu , Hoshino Seiichiro , Mogi Ai , Koganemaru Tomoko , Oda Mayumi , Fukuda Mahiru , Kiyomi Fumiaki , Noda Keita , Hirata Keiji , Tamura Kazuo , Yamashita Yuichi
Published: February 2017

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Background: Oxaliplatin-induced peripheral neuropathy (PN), for which no therapy has been firmly established, is a critical factor that makes the continuation of chemotherapy difficult. Numbness and pain are currently evaluated using subjective methods such as the visual analog scale (VAS). However, because the assessment of pain can greatly vary depending on the mood and physical state of the patient at the time of assessment, it is best to objectively evaluate pain. Therefore, a method for objective assessment is also required to evaluate drugs designed to ameliorate PN. Pain Vision PS-2100 (PV) is an analytical instrument that was designed to quantitatively and objectively assess sense perception and nociception in a patient. Although it is used in the field of anesthesiology, there have been no reports concerning its use for the assessment of oxaliplatin-induced PN. Methods: The present study examined the correlation of subjective and objective assessment results using VAS and PV, respectively, for cases of oxaliplatin-induced PN. Subjects comprised 58 patients with colorectal cancer who underwent chemotherapy at the Fukuoka University. Results: Both VAS and PV assessments of PN were performed 173 times in total, and partial correlation coefficient analysis adjusted by subject and gender. The VAS and PV mean values of PN were 20.5 (0–100) and 27.9 (0–416), respectively. The partial correlation coefficient was 0.258 (p=0.0053). Conclusions: Although both assessments evaluated the same events, no strong correlation was observed between the results and a weak correlation was observed between VAS and PV. These results suggest that because VAS and PV each measure different factors, both subjective and objective assessments of drugs designed to ameliorate oxaliplatin-induced PN are necessary.
“First chemotherapy” or “first local” approach for liver-only synchronic metastasis rectal cancer? A single institution experience.
Authors: Ghanem Ismael , Higuera Gomez Oliver , Mata Alberto , Reyes Jose , Rodriguez Nuria , Castell Jose , Custodio Ana B. , Martinez Virginia , Pastrian Laura Guerra , Feliu Jaime
Published: February 2017

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Background: Approximately 10% of patients (p) with rectal cancer have synchronic liver-only metastasis (RCSLM). Although local and systemic therapies are required for this setting, there is not a well defined sequence of treatments. We analyze both, the initial systemic and local approaches at a single institution. Methods: We retrospectively reviewed the medical records of RCSLM p between Jan 2006 and Dec 2013. The “first chemotherapy” (Ch) approach and the “first local” (Lo) approach (surgery or radiotherapy) were reviewed in terms of patient characteristics, tumour features and survival. Results: Forty-five p (26 men) with a median age of 65 years old (35-88) and ECOG 0-1 (91%) were analyzed. Most (84%) of the 32 p with known K-Ras status had wild-type. Twenty-five p (56%) had bilobar liver metastasis (LM) with a median number LM of 3 and a median size of 2.6 cm for the largest lesion. Thirty-four p (75%) were treated with curative intention and, liver and rectal resections (LRR) were performed for 24 p (53%). Bilobar LM (p=0.029), basal CEA>60 (p=0.014), non-LRR (p=0.001) and non-R0 resection of LM (p=0.004) were found to be predictor of poor overall survival (OS). Twenty-five p were treated with Ch and 9 p with Lo approach”. Table 1 shows the characteristics of both groups of p. After a median follow up of 28 months there were 12 events (35%) with a median OS of 55m vs. not reached (p=0.72) for Ch and Lo respectively. Conclusions: Bilobar LM, basal CEA>60, non-LRR and non-R0 resection of LM were predictors of poor OS. The Ch approach was chosen for patients with worse prognostic. However, there were no significant differences in OS between Ch and Lo approaches. Clinical trials are needed to evaluate the best therapy strategy at this setting. [Table: see text]
Weight loss at the first month of palliative chemotherapy to predict survival outcomes in patients with advanced gastric cancer.
Authors: Ock Chan-Young , Oh Do-Youn , Kim Tae-Yong , Lee Kyung-Hun , Han Sae-Won , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue
Published: February 2017

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Background: Weight loss during chemotherapy is a significant prognostic factor for poor survival in patients advanced gastric cancer (AGC). However, in most studies, weight loss was measured at the end of chemotherapy, limiting its clinical use. In this study, we evaluated whether weight loss during the first month of chemotherapy could predict survival outcomes in patients with AGC. Methods: We analyzed 719 patients with metastatic or recurrent AGC who were receiving palliative chemotherapy. We calculated initial body mass index (BMIi), percent weight loss after one month of chemotherapy (ΔW1m), percent weight loss after last administration of chemotherapy (ΔWend), and average weight loss per month during chemotherapy (ΔW/m). We correlated these data with overall survival (OS) by receiver operating characteristic (ROC) curves and Kaplan-Meier curves, and performed a subgroup analysis using Cox regression. Results: The probabilities of longer OS had stronger correlations with ΔW/m and ΔW1m than with ΔWend or BMIi. The optimal cutoff values of ΔW/m and ΔW1m for predicting shorter survival were 1% and 3%, respectively. A significant positive correlation between ΔW1m and ΔW/m (r2 = 0.591, p < 0.001) was observed. Patients with ΔW1m more than 3% significantly younger, had worse performance status, more diffuse-type Lauren classification, more HER2-negative pathology, a higher number of involved organs, and more peritoneal seeding at initial presentation. OS of patients with ΔW1m more than 3% were significantly shorter than patients with less weight loss (ΔW1m ≥3%: 9.7, <3%: 16.3 months, p < 0.001). Patients who recovered average weight loss per month after experiencing weight loss at the first month showed prolonged OS compared with patients who did not recovered (ΔW/m < 1%: 21.3, ≥1%: 7.8 months, p < 0.001). Subgroup analysis revealed ΔW1m accompanied poor survival irrespective of other clinical characteristics. Multivariate analysis showed weight loss at the first month of chemotherapy adversely affected OS (p= 0.038). Conclusions: Weight loss at the very first month of palliative chemotherapy could predict unfavorable survival outcomes in AGC.
Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal malignancies.
Authors: Zhang Tian , Boominathan Rengasamy , Foulk Brad , Connelly Mark Carle , Rao Chandra , Kemeny Gabor , Hurwitz Herbert , Garcia-Blanco Mariano A. , Armstrong Andrew J.
Published: February 2017

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Background: Multiple GI malignancies including gastric, pancreatic, and colorectal cancers harbor genetic alterations in the MET oncogene. MET amplification is associated with poor prognosis, and c-MET targeted therapies are in development. We aimed to capture and identify c-MET CTCs using a non-invasive, rapid test. Methods: We modified the CELLSEARCH platform by using nanomagnetic particles conjugated to antibodies against the extracellular domain of c-MET to capture c-MET-expressing CTCs. The method was validated by spiking MET-amplified gastric cancer cells, c-MET-overexpressing, nonamplified cancer cells, and MET-negative cancer cells into peripheral blood from healthy volunteers. Peripheral blood samples were obtained from patients (pts) with refractory metastatic gastric, pancreatic, and colorectal cancers, prepared in duplicate, and characterized by immunofluorescence staining for intracellular c-MET-PE, DAPI, and pan-CK-FITC. CD45 + cells were excluded. CTC enumeration with c-MET capture was compared to EpCAM capture. After CTC isolation, MET DNA FISH was performed. Results: The novel c-MET CTC assay was found to be 80% sensitive for MET-amplified cells, 40-80% sensitive for c-MET-overexpressed cells, and 100% specific for c-MET negative cells and in 10 healthy volunteers. In 7/7 pts with metastatic pancreatic and 8/8 pts with metastatic colorectal cancers, we did not capture c-MET CTCs. Of 3 gastric cancer pts tested thus far, one pt had a significant number of c-MET + CTCs, with 52 CTCs and 90 CTCs in each of the duplicate samples, compared to 20 CTCs with EpCAM capture. CTC FISH demonstrated polysomy 7 and METamplification. This pt had HER2 amplification in primary tumor tissue and had progressed on FOLFOX and trastuzumab at the time of enrollment. Conclusions: We have developed a sensitive and specific c-MET CTC assay. c-MET-expressing CTCs can be detected in gastric cancer but not controls or other GI cancers to date. While not detectable in many pts, high levels in one pt support the importance of MET amplification as a resistance mechanism to HER2 therapy, and suggest that this approach may be useful to identify and follow patients who may be candidates for c-MET directed therapies.