bluuebunny/crossref_metadata_2025 huggingface dataset:
A pilot study of neoadjuvant chemoradiotherapy for unresectable locally advanced adherent colon cancer: Assessing local tumor response.
Authors: Yu Xin , Xiao WeiWei , Zhang Rong , Zhang LuNing , Qiu Bo , Zeng ZhiFan , Ding Pei-Rong , Pan Zhi-zhong , LI Li-ren , Gao Yuan-Hong
Published: February 2017

727

Background: To analyze the outcomes of neoadjuvant chemoradiotherapy (neoCRT) in the management of unresectable locally advanced adherent colon cancer (LAACC). Methods: 40 unresectable LAACC patients were identified from Sun Yat-Sen university cancer-center Database from October 2010 to December 2014. Unresectability was determined by multidisciplinary consultation (MDT) according to image examination or confirmed by exploratory laparotomy. NeoCRT followed by surgery and postoperative chemotherapy were given to these patients. There were 27 males and 13 females. Median age was 56 years old. The location of primary tumors were as sigmoid 31, descending colon 3, ascending colon 5, and cecum1, respectively. All the patients were treated with 45-50Gy/25F using 3D-CRT or IMRT, and concomitantly with capecitabine-based chemotherapy every 3 weeks. Surgery was scheduled 6-8 weeks after completion of radiotherapy. Results: A total of 40 patients completed neoCRT and 33 patients (82.5%) received radical resection for the locally diseases, with R0 and R2 resection in 30 and 3 patients, respectively. Seven patients were assessed as unresectable after neoCRT and 3 of them received only colostomy while the other 4 continued chemotherapy. Pathological complete response was documented in 8 patients (20.0%). Multivisceral resection was necessary in 15 patients (36.6%). Among the 33 patients underwent curative surgery, bladder invasion was noticed at diagnosis in 17 patient and bladder function was preserved in all these patients, with full bladder preserving approach in 6 and partial cystectomy in 11 patients. Grade-2 post-operative complications were observed in 4 patients (10.0%) with no 30-day mortality. Median follow-up was 26 months. For all the patients, the 3-year overall survival, local progression-free survival and progression-free survival were 70.8%, 88.2%, 74.5%, respectively. Conclusions: NeoCRT is an effective strategy for the treatment of unresectable LAACC, with high R0 resection rate, satisfactory organ preservation, good local control and acceptable treatment toxicity. NeoCRT in LAACC is worthy of further clinical research.
Inverse correlation between expression and methylation of RPRM, a TP53 dependent G2 arrest mediator candidate, along the gastric precancerous cascade.
Authors: Corvalan Alejandro Hernan , Maturana Maria Jose , Olivares Wilda , Roldan Nicole , Fry Jacqueline
Published: February 2017

73

Background: Gastric cancer (GC) is one of first cause of cancer death worldwide. Lesions associated with the gastric precancerous cascade include atrophic gastritis (AG), intestinal metaplasia (IM), dysplasia (DY), and early (EGC)/advanced gastric cancer (AGC). Loss of expression due to aberrant methylation of Reprimo (RPRM), TP53 dependent G2 arrest mediator candidate, has been detected in patients with GC. Here we evaluated the methylation of the promoter region of RPRM in the precursor lesions. Methods: Fresh tissue biopsies from AG (N = 8), IM (N = 6), DY (N = 4), EGC (N = 5) and AGC (N = 8) were included. Expression and methylation levels of RPRM were detected by qPCR and MethyLight, respectively. Sequencing of 30 CpG sites of the promoter of RPRM was performed by Bisulfite sequencing. Results: Relative expression levels of the mRNA of RPRM decrease as gastric precancerous cascade progress, being significant in the transitions IM/DY and EGC/ACG. Methylation of the promoter of RPRM was detected in 4/8 AG, 3/6 IM, 4/4 DY, 5/5 EGC and 8/8 AGC. Spearman correlation analysis showed a significant inverse association between methylation and expression (r = -0.99, P < 0.0001). We observed increase of methylation of the CpG site 24 in the transition EGC to AGC. Conclusions: Our results show an inverse correlation between expression and methylation of RPRM along the gastric precancerous cascade. This inverse correlation is determinant in transitions from IM to DY and EGC to AGC. The identification of specific methylation of CpG site 24 associated EGC to AGC may be critical for the regulation of the RPRM expression. Grant Support: CONICYT-Fondap#15130011 and Fondecyt#1151411 from the Government of Chile
Metastatic colorectal cancer (mCRC) treatment: A high-volume, single-center, real-life experience.
Authors: Bergamo Francesca , Lonardi Sara , Battaglin Francesca , Marsico Valentina Angela , Paladina Isabella , Crivellari Gino , Galiano Antonella , Rumano' Laura , Bellu Luisa , Carcea Elena , Bortoletto Gladis , Fiduccia Pasquale , Bertorelle Roberta , Mammano Enzo , Rugge Massimo , Cillo Umberto , Nitti Donato , Zagonel Vittorina
Published: February 2017

733

Background: Few data are available on outcome of clinical practice unselected patients (pts) with mCRC. Methods: We retrospectively collected data of pts with mCRC followed at our Institution from January 2010 to December 2013 evaluating the clinical characteristics, treatments and survival outcomes. Results: A total of 584 pts were evaluated, 461 were followed at our Center while 123 were seen for a second opinion. Median age was 66 ys (25-94), 59% were male, 63% had an ECOG PS = 0 while 11% ≥2. 33% had right colon primary, 68% synchronous metastatic (mts) disease and 70% a single mts site. 81% underwent surgery on primary and 41% on metastases. 51% were RAS mutated (mut) and 5% BRAF mut. 57 pts didn't receive any systemic treatment, 33 due to frail clinical conditions and 24 due to radical surgical approach (R0). Among 404 treated pts, 239 received all 3 available cytotoxic agents (oxaliplatin, irinotecan, 5FU), 324 bevacizumab and 98 anti-EGFR; 153 (38%) were enrolled in clinical trials. Median overall survival (OS) was 27.6 months (mo) for the entire mCRC population, 3.7 mo for untreated frail pts, 28.7 mo for treated pts while it is still not reached for untreated R0 pts. OS was significantly longer for pts receiving first line combination therapy (29 vs 17 mo, p < 0.01) while a poor prognosis was confirmed for BRAF mut pts (p < 0.001). In a multivariate analysis age < 70, PS 0 and R0 surgery on mts disease showed a positive prognostic impact on OS while a right site of primary was a negative predictor of outcome. At logistic regression older age, low PS and peritoneal disease negatively affected the possibility to receive all 3 active drugs. Conclusions: Despite being an unselected population our outcomes are comparable with results of clinical trials in the corresponding period. We feel that such positive evidence derives from a personalization of treatment and a multidisciplinary approach to mts disease.
Phase II study of the early start of chemotherapy after excision of primary colorectal cancer with distant metastases (Pearl Star 02).
Authors: Tanimura Syu , Yoshida Yoichiro , Aisu Naoya , Komono Akira , Kojima Daibo , Mera Toshiyuki , Yamashita Yuichi
Published: February 2017

746

Background: The start of chemotherapy usually requires a delay of about 4 weeks after surgical resection of colorectal cancer. However, there is no evidence for the required length of this delay interval. In addition, there is a chance that a patient may die because postoperative chemotherapy was not started soon enough and a metastatic tumor was able to develop rapidly. We have previously reported the first pilot study to determine the safety and feasibility of an early start of chemotherapy after resection of primary colorectal cancer with distant metastases. We therefore conducted a next study to determine the safety and efficacy of the early start of chemotherapy after the resection of colorectal cancer with distant metastases. Methods: The Pearl Star 02 study was a prospective and single-arm trial. They received XELOX therapy (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1–14) on the 7th postoperative day and XELOX+bevacizumab (7.5 mg/kg of bevacizumab on day 1) after the 2nd cycle of chemotherapy. Results: A total of 20 patients were enrolled from September 2011 to June 2015. Baseline characteristics included a median age of 64 years (range: 43-72) for 15 men and 5 women. The procedures included right hemicolectomy in 6 patients, sigmoidectomy in 3 patients, high anterior resection in 3 patients, low anterior resection in 2 patients, and Hartmann procedure in 6 patients. All patients started chemotherapy on postoperative day 7. Grade 3 or higher hemotoxicity and grade 3 or higher non-hematological toxicity was noted in 5.0 % and 25.0 % of patients, respectively. Postoperative complications were observed in 2 patients (superficial incisional surgical site infection and Ileus). Median progression-free survival was 14.9 months. Overall response rate was 75%. Conclusions: An early start of chemotherapy after surgery is safe and effective. These findings suggest possible changes in the start time of chemotherapy after surgery in the future. However, further studies are certainly needed to confirm these findings. Clinical trial information: UMIN000006310.
“Real world” effectiveness of different postoperative adjuvant chemotherapy regimens in stage III colon cancer patients.
Authors: Chiang Jy Ming , Hung Hsin Yuan
Published: February 2017

754

Background: In clinical practice, choosing oral chemotherapy or FOLFOX may depend to drug toxicity and patients’ age and comorbidities, in addition to heterogeneous stage III colon cancer. The benefit of oxaliplatin in the real world practice remained further clarified. Methods: 688 stage III colon cancer patients were collected. Treatment outcomes were retrospectively compared based on the type of chemotherapy in terms of OS and DFS. Multivariate Cox-regression modeling was used to adjust for the potential confounders. Results: This study included capecitabine (259 patients), fluorouracil-leucovorin plus oxaliplatin (FOLFOX) (283 patients) and Tegafur-uracil(146 patients). Comparing patients with capecitabine and tegafur regimens, patients receiving FOLFOX were significantly younger (mean age 56.5 yrs v.s. 65,1 yrs and 66,9 yrs ), more poor differentiation (15.9% v.s. 8.1% and 8.2%), deeper tumor invasion (T4 lesion 25.1% v.s. 15.8% and 17.1%), more advanced nodal involvement (N2/3 51.9% v.s. 18.1% and 20.5%) and had less comorbidity (50.2% v.s. 61.4% and 65.1%). Rate of completeness of chemotherapies (88.0% v.s. 87.6% and 81.5%) was no significant difference. Comparing treatment outcome, by univariate analysis, demonstrated significant (p = 0.0258) difference in OS for N2/3 patients but no difference in N1 patiens. However, by balancing confounding factors including co-morbidities, multivariate analysis showed that impact on overall survival in patients receiving capecitabine was statistically significant better than Tegafur (HR = 0.59, p = 0. 03) while no difference comparing with FOLFOX regimen (HR = 0.76, p = 0.3219). However, disease free survival (DFS) was no significantly different for FOLFOX comparing with capecitabine HR 0.97 and Tegafur HR 0.89 by multivariate Cox regression analyses. Conclusions: As post-operative adjuvant setting, oral chemotherapy either Capecitabine or Tegafur-uracil showed similar effectiveness as folfox in terms of DFS while in terms of OS, Capecitabine demonstrated similar effectiveness to folfox but better than Tegafur-urecil.
Role of adjuvant chemotherapy in locally advanced rectal cancer with ypT0-3N0 after neoadjuvant chemoradiation therapy.
Authors: Kim Chang-gon , Jung Minkyu , Jung Inkyung , Shin Sang Joon , Beom Seung Hoon , Kim Joo Hoon , Heo Su Jin , Kim Ji Hyung , Koom Woong Sub , Hur Hyuk , Min Byung Soh , Kim Nam Kyu , Kim Ho Geun , Ahn Joong Bae
Published: February 2017

760

Background: Clinical benefit of adjuvant chemotherapy (AC) is still controversial in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiation therapy (CRT) followed by total mesorectal excision (TME). We aim to explore the role of adjuvant chemotherapy with fluoropyrimidine for ypT0-3N0 patients. Methods: Patients with ypT0-3N0 rectal cancer after neoadjuvant CRT and TME were included using retrospective cohort of Yonsei Cancer Center. Patients were categorized according to receipt of adjuvant chemotherapy (AC vs. no AC). Disease free survival (DFS) and overall survival (OS) between treatment groups were compared using all patients’ cohort (APC) and propensity score-matched patients’ cohort (PSMPC). Results: total of 339 patients were evaluated. Of all, 87 patients (25.7%) did not receive AC. There was no difference in DFS between two groups [hazard ratio (HR) = 1.079, p-value = 0.782 in APC; HR = 1.22, p-value in PSMPC]. Also there was no difference in OS between two groups (HR = 1.140, p-value 0.717 in APC; HR = 1.366, p-value 0.472 in PSMPC). Advanced T stage and positive resection margin were associated with inferior DFS and OS by multivariate analysis. In subgroup analysis by baseline characteristics, we could not find any group with benefit of adjuvant chemotherapy. Conclusions: AC did not improve DFS and OS of patients with ypT0-3N0 rectal cancer after neoadjuvant CRT followed by TME. The role of AC in LARC with ypT0-3N0 after preoperative CRT should be evaluated in prospective randomized trials with larger sample size.
Review of efficacy and safety of the new oral anticoagulants (NOACS) in the treatment of venous thromboembolism in gastrointestinal (GI) oncology patients.
Authors: Patel Hitendra , Diri Reem , Aljabri Ahmed , Campen Christopher Jon , Elquza Emad , Malangone Steve , Abraham Ivo , McBride Ali
Published: February 2017

761

Background: The occurrence of venous thrombosis (VTE) has been reported to increase the likelihood of death for cancer patients by 2- to 6-fold. Additionally, cancer patients have both a higher rate of VTE recurrence during oral anticoagulant therapy with warfarin and a higher anticoagulation-associated hemorrhagic risk as compared with non-cancer patients. New oral anticoagulants (NOACs) have administration and monitoring advantages treatment options for patients, however, there is limited data on the use of NOACs for cancer patients. Methods: We performed a single-institution retrospective review of electronic medical records of patients with GI cancer who received rivaroxaban with an active VTE diagnosis. Data collected included patient demographics, diagnosis, previous and active chemotherapy, previous history of VTE, and clinical outcomes. Results: Thirty-two patients were identified, with 28 patients concurrently treated with chemotherapy. Rivaroxaban was given to treat DVT = 23 patient and PE = 9 patients with average length of therapy 181 days. Forty-one percent of patients started on rivaroxaban, while 25% received enoxaparin, and 22% received warfarin prior to rivaroxaban. Overall, 13/32 (41%) patients experienced a bleeding episode; 7 patients had their dose held and 6 patients were noted to have minor bleeding. Conclusions: In our retrospective study, rivaroxaban did show efficacy in secondary prophylaxis for VTE in patients with active cancer. However our results revealed a rather high rate of bleeds in patients being treated with chemotherapy and rivaroxaban as compared to previous studies. [Table: see text]
The effect of body mass index (BMI) and nutrition on morbidity and mortality in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC).
Authors: Patel Komal , Oliver Joseph B , Chokshi Ravi , Patel Jimmy S , Spiegler Kevin
Published: February 2017

765

Background: In patients with peritoneal malignancies undergoing CRS-HIPEC, their weight and nutritional factors may be affected by the presence of cachexia or obesity. With the potential morbidity of these radical operations, the selection of patients is paramount. BMI and albumin have long been utilized to predict outcomes in surgical patients. Our study evaluated whether BMI and albumin had an impact on CRS-HIPEC morbidity and mortality. Methods: Demographics, comorbidities, intraoperative variables and post-operative outcomes were analyzed using a retrospective database comprising of 28 patients undergoing CRS-HIPEC at our institution from 2012 to 2015. Median BMI of 25 and median albumin of 3.8 were used to compare the 2 groups. Primary outcome was overall survival, while secondary outcomes included complications, length of stay and intraoperative variables. Results: Patients were organized into 2 groups: < 25 BMI (n = 13) and > 25 BMI (n = 15). Albumin levels were assigned to each group and demonstrated similar values (4.0 vs 3.8, p = 0.44). Demographic data described similarly aged (54 vs 56 years, p = 0.42), gender (92% vs 93% females, p = 0.92), and peritoneal carcinomatosis index (21 vs 18, p = 0.60). The > 25 BMI group had slightly higher number of comorbidities (Charlson Comorbidity Index > 0 in 23% vs 60%, p = 0.04). Both had similar operative times (566 vs 549 minutes, p = 0.73), blood loss (700 vs 550 ml, p = 0.96) and median numbers of organs removed during cytoreduction (4 vs 3, p = 0.28). Length of stay was no different between the 2 groups (11.5 vs 10.5 days, p = 0.86). Six of the thirteen < 25 BMI individuals died during follow up (mean 5.6 months) compared to only two of the fifteen > 25 BMI individuals (mean 10.2 months) (p = 0.01). Conclusions: In our single center series, patients > 25 BMI had a better survival when compared to < 25 BMI patients. However, the analysis of the albumin levels did not demonstrate a statistically significant difference. There were no other significant differences in preoperative, intraoperative or other post-operative outcomes. Higher powered studies with longer follow-up are needed to confirm our results.
Mir-935 to suppress gastric signet ring cell carcinoma tumorigenesis by targeting Notch1 expression.
Authors: Yan Chao , Yu Jianchun , Kang Weiming
Published: February 2017

77

Background: Although the comprehensive treatment has improved outcomes in most advanced gastric cancers, these protocols have had little effect on advanced gastric signet-ring cell carcinoma (GSRCC). New biomarkers and therapeutic targets are needed to improve its outcomes. MicroRNAs have been closely linked to the carcinogenesis of gastric cancer and have been considered as powerful prognostic markers. The function of miR-935 has never been reported in cancer before. Methods: We used microarrays in six cell lines to explore which miRNAs had dysregulated expression in GSRCC, includingGES-1, SGC-7901, MGC8-03, AGS,MKN-45 and KATO-III. We selected MKN-45 and KATO-III (with down-regulated miR-935) to transfect the miR-935 mimic, and MGC8-03 and HGC-27 (with up-regulated miR-935) to transfect the miR-935 inhibitor. TargetScan 7.0 predicted that Notch1 would have a single conserved binding sequence for miR-935 in the 3′UTR. We also assessed miR-935 expression in clinical gastric carcinoma tissue samples with adjacent normal tissue samples from the same patient. Data were analyzed with SPSS v.17.0 software. Results: Over-expression of miR-935 markedly decreased proliferation, migration and invasion of MKN-45 and KATO-III cells compared with the negative control. In contrast, the inhibitor that was transfected into MGC8-03 and HGC-27 cells significantly increased proliferation, migration and invasion compared the negative control. These results indicate that ectopic miR-935 expression decreases GSRCC proliferation, migration and invasion in vitro, and acted as a tumor suppressor for GSRCC. Expression of Notch1 is negatively regulated by miR-935. Notch1 knock-down significantly inhibited GSRCC proliferation, migration and invasion. MiR-935 was downregulated in GSRCC tissues. Conclusions: The expression of miR-935 in GSRCC cell lines is lower than in non-GSRCC cell lines, and enhanced expression of miR-935 in GSRCC cell-lines inhibit cell proliferation, migration and invasion. Notch1 is a direct target of miR-935 to reduce the proliferation, migration/invasion of GSRCC cells. MiR-935 is a potential marker for GSRCC diagnosis and therapy.
Updated analysis of phase II trial of irinotecan/s-1/cetuximab (IRIS/Cet) as second-line treatment in patients with KRAS exon2 wild type metastatic colorectal cancer (mCRC): HGCSG0902—Comparison of administration interval in cetuximab treatment.
Authors: Kondo Tomohiro , Yuki Satoshi , Kawamoto Yasuyuki , Tsuji Yasushi , Hosokawa Ayumu , Nakamura Michio , Muto Osamu , Kato Takashi , Iwanaga Ichiro , Sato Atsushi , Eto Kazunori , Furukawa Kouichi , Hayashi Hideyuki , Tateyama Miki , Takahashi Yasuo , Sogabe Susumu , Honda Takuya , Sakata Yuh , Komatsu Yoshito
Published: February 2017

771

Background: HGCSG0902 is the multicenter phase II study to investigate the safety and efficacy of irinotecan, S-1 (IRIS) plus cetuximab as second line treatment in patients with KRAS exon2 wild type mCRC. Response rate (RR) was 33.3% (95%CI 20.8-45.9%), therefore primary endpoint was met (Muto O, et al. ESMO 2014). Here we report an exploratory analysis of outcomes based on administration interval of cetuximab (every week [EW] vs bi-weekly [BW]). Methods: Eligibility includes histologically confirmed mCRC, previously received oxaliplatin-contained chemotherapy, PS: 0-1, EGFR positive and KRAS exon2 wild type. Patients received S-1 80-120 mg/day p.o. on days 1-14 and irinotecan 100mg/m2 on day 1 and 15 repeated every 28 days. Cetuximab was administrated 400mg/m2 as loading dose and continued 250mg/m2 every week or 500mg/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 and OS. Results: Between Mar 2010 and Sep 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’s choice, 34 patients of EW and 23 of BW were included in the full safety analysis set. RR was 34.4% in the EW and 31.8% in the BW (p = 1.000). Median PFS was 4.2 months in the EW and 6.1 months in the BW (HR 0.752, p = 0.350). Median OS was 8.9 months in the EW and 10.7 months in the BW (HR 0.902, p = 0.737). The most common non-hematological adverse events of grade 3 or higher were diarrhea (23.5% in the EW vs 52.2% in the BW: p = 0.005) and stomatitis (2.9% in the EW vs 30.4% in the BW group: p = 0.046), these were significantly more common in the BW. Conclusions: IRIS/Cet appeared to be highly effective with RR, PFS and OS in the both treatment schedule. Diarrhea and stomatitis were significantly more common in the BW. Therefore, in case of treatment with IRIS/Cet should be administered in the EW. Clinical trial information: UMIN000004882.
Risk factors for loss of lean body mass after gastrectomy for gastric cancer.
Authors: Aoyama Toru , Sato Tsutomu , Segami Kenki , Maezawa Yukio , Kano Kazuki , Kawabe Taiichi , Fujikawa Hirohito , Hayashi Tsutomu , Yamada Takanobu , Yukawa Norio , Oshima Takashi , Rino Yasushi , Masuda Munetaka , Ogata Takashi , Cho Haruhiko , Yoshikawa Takaki
Published: February 2017

79

Background: Lean body mass loss after surgery, which decreases compliance of adjuvant chemotherapy, is frequently observed in gastric cancer patients who underwent gastrectomy for gastric cancer. However, the risk factors of lean body mass loss remain unclear. Methods: The present study retrospectively examined the patients who underwent curative gastrectomy for gastric cancer between June 2010 and March 2014 at Kanagawa Cancer Center. All patients received perioperative care of the enhanced recovery after surgery protocol. % Lean body mass loss was calculated by percentile of lean body mass at one month after surgery to preoperative lean body mass. Severe lean body mass loss was defined as % lean body mass loss over 5%. Risk factors for severe lean body mass loss were determined by both univariate and multivariate logistic regression analyses. Results: Four-hundred eighty five patients were examined. Median age was 67 years. Operative procedure was total gastrectomy in 190 patients and distal gastrectomy in 295 patients. Surgical complications of grade 2 or more defined by Clavien-Dindo classification was observed in 78 patients including pancreatic fistula in 19, anastomotic leakage in 11 and abdominal abscess in 7. Mortality was observed in one patient. Both univariate and multivariate logistic analyses demonstrated that surgical complications (odds rate 3.576, p = 0.001), total gastrectomy (odds rate 2.522, p = 0.0001), and gender (odds rate 1.928, p = 0.001) were significant independent risk factors for severe lean body mass loss. Conclusions: Male, surgical complications, and total gastrectomy were significant risk factors for 5% of lean body mass loss at first month after gastrectomy. To maintain lean body mass after gastrectomy, the physician need careful attention for the patients who had these risk factors.
The recurrence patterns and post-recurrence survivals in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with preoperative paclitaxel/cisplatin-based chemoradiotherapy.
Authors: Kuo Hung-Yang , Guo Jhe-Cyuan , Huang Ta-Chen , Lin Chia-Chi , Hsieh Min-Shu , Lee Jang-Ming , Cheng Jason C. , Wang Hsiu-Po , Yeh Kun-Huei , Hsu Chih-Hung
Published: February 2017

80

Background: More than half of patients (pts) with locally advanced ESCC would have disease recurrence after curative preoperative chemoradiation (CRT) followed by surgery. Whether recurrence pattern correlates with the post-recurrence survival remains uncertain. Methods: We included 131 pts with locally advanced ESCC (clinical T3N0-1M0 or T1-3N1M0 or M1a according to AJCC 6thedition) who were enrolled in 3 phase II clinical trials of preoperative CRT followed by surgery and had successfully completed CRT and surgery. These pts received preoperative twice weekly paclitaxel/cisplatin-based CRT with radiotherapy 40Gy given in 20 fractions followed by esophagectomy. When pts had first disease recurrence, we divided them into three groups according to their recurrence patterns: loco-regional recurrence (LRR), distant metastasis only (DM), and both LRR and DM (LRR+DM). Survival outcomes were compared using the Kaplan-Meier curves. Results: With a median follow-up of 34.8 months, 75 pts (57.3%) had disease recurrence (Table 1) and the median post-recurrence survival of these pts is 6.7 months (m). Among them, 24 pts (32.0%) had LRR, 19 (25.3%) pts had DM, and 32 pts (42.7%) had LRR+DM. There is no statistical difference of the post-recurrence survivals (Fig. 1) among 3 groups (5.4, 7.5, 4.9m, p = 0.43 in LRR, DM, and LRR+DM group respectively). It is noteworthy that 4 pts in the DM group with limited distant metastasis (1 had brain metastasis, 3 had lung metastasis) had long post-recurrence survival (56.2+, 51.6+, 13.8+, 13.1+m) after receiving metastasectomy with or without chemotherapy. Conclusions: The post-recurrencesurvival of locally advanced ESCC pts who received preoperative CRT followed by surgerywere similar regardless of recurrence pattern (loco-regional recurrence or both loco-regional and distant failure). However, in pts with limited metastasis, curative metastasectomy might provide the opportunity of achieving long-term survival. (The work was supported by the Grant of MOST 103-2314-B-002-092, MOST 104-2314-B-002-111- and HCH104-024)
Phase II study of neoadjuvant epirubicin(E), cisplatin(C) and 5-fluorouracil(F) followed by chemoradiation with selective surgical resection/salvage for carcinomas of the esophagus and esophagogastric junction.
Authors: Poen Joseph C , Poen Joseph W , Gullion David S.
Published: February 2017

84

Background: A subset of patients with local and regionally confined carcinoma of the esophagus (ES) or esophagogastric junction (EGJ) will not benefit from esophagectomy or esophagogastrectomy. Examples include medical inoperability and confined disease that is technically unresectable (T4 and/or N2-3). With that in mind we undertook to optimize the non-operative component of ES and EGJ cancer treatment, with surgery reserved for selected cases (medically fit, limited stage, suspicion of residual or recurrent disease). Methods: Eligible patients had AJCC stage T2-4,N0-3,M0 squamous or adenocarcinoma of the esophagus or esophagogastric junction. Medically inoperable patients were included if fit for ECF and chemoradiation (CRT) and regional disease could be encompassed within extended radiation fields. E (50mg/m2), C (60mg/m2) were given days 1,22 with F (200mg/m2) days 1-42 by protracted infusion. Subsequent CRT was C (100mg/m2) days 49,70 and F (200mg/m2) days 49-91 with 54 Gy in 30 fractions over 6 weeks. Complete responders by PET and biopsy received 2 additional cycles of ECF. Results: Between 2003 and 2015, 40 patients with non-metastatic squamous (n = 13) and adenocarcinoma (n = 27) signed informed consent. Most had clinical stage T3-4 (78%), positive regional lymph nodes (58%) and/or were felt to be inoperable due to medical comorbidities or advanced disease (50%). Dose reductions were allowed for grade II-III toxicity during ECF (13%) and CRT (33%). There was one treatment-related death (3%). At a median follow-up of 5 years, 10 patients (25%) have undergone esophagogastrectomy for persistent or recurrent disease. Median overall survival (OS) is 46 months. Survival at 1,3,5 and 7 years is 82%, 53%, 44% and 35% respectively. Conclusions: In local/regionally confined ES and EGJ cancer, long term survival with acceptable toxicity can be achieved with neoadjuvant ECF and CRT followed by selective surgical resection/salvage. This strategy appears to be appropriate for medically inoperable and technically unresectable cases, and can be considered for operable cases as well.
Effects of perioperative enteral EPA-enriched immunonutrition on meaningful loss of lean body mass after total gastrectomy for gastric cancer: Post hoc analysis of a phase III study.
Authors: Yoshikawa Takaki , Hiki Naoki , Sakamaki Kentaro , Ito Seiji , Fujitani Kazumasa , Takiguchi Nobuhiro , Kawashima Yoshiyuki , Nishikawa Kazuhiro , Sasako Mitsuru , Ida Satoshi , Aoyama Toru , Honda Michitaka , Sato Tsutomu , Nunobe Souya , Ogata Takashi , Cho Haruhiko
Published: February 2017

85

Background: Total gastrectomy for gastric cancer significantly reduces body weight, especially lean body mass (LBM), through surgical stress and decrease of the calorie intake. Eicosapentaenoic acid (EPA)-enriched enteral nutrition (EPA-EN) could modulate immune function and limits catabolism. In our phase III study to compare perioperative standard diet with or without EPA-EN, additional EPA-EN did not contribute to prevent weight loss or LBM. Recently, 5% or more LBM loss after surgery was reported to impair compliance of post-operative S-1 adjuvant chemotherapy. This post hoc study explored whether additional EPA-EN prevented meaningful loss of LBM for compliance of adjuvant chemotherapy after surgery. Methods: Key entry criteria of this phase III study was (1) histologically proven adenocarcinoma of the stomach, (2) clinical T1-T4a and M0, (3) R0 resection is possible by total gastrectomy, (4) sufficient oral intake, and (5) sufficient organ function. The patients were randomized to Group A: no supplementation with oral nutrients (standard diet) or Group B: standard diet with oral supplementation of ProSure including 600 kcal with 2.2 g EPA for 7 days before surgery and for 21 days after surgery. For both groups, patients underwent total gastrectomy with Roux-en Y reconstruction. Results: A total of 127 patients (Group A: 63, Group B: 64) were enrolled in the study. All background factors were well balanced between the both groups. Median relative performance of supplement in group B was 100% before surgery and 54% after surgery. 5% or more LBM loss at 1 month after surgery was observed in 44 patients (80.0%) in group A and in 37 patients (67.3%) in group B (p = 0.194), while that at 3 months after surgery was found in 51 patients (91.1%) in group A and in 43 patients (76.8%) in group B (p = 0.070). Conclusions: Perioperative standard diet with EPA-enriched enteral nutrition tended to prevent meaningful loss of LBM after total gastrectomy. Further analysis is required whether perioperative EPA enriched EN improve compliance of S-1 adjuvant chemotherapy after total gastrectomy. Clinical trial information: UMIN000006380.
Perioperative chemotherapy in locally advanced gastric cancer in Chile: From evidence to daily practice.
Authors: MÃ¼ller Bettina G. , Garcia Carlos , Sola Jose Antonio , Benavides Carlos , Werner Patrick , Buchholtz Martin , Reyes Cosmelli Felipe , Corvalan Alejandro Hernan
Published: February 2017

92

Background: Gastric cancer is the leading cause of cancer death in Chile, with mortality rate of 26.7/100.000 in men, placing the country among the highest mortality rates worldwide. For locally advanced gastric cancer, a multimodality treatment is recommended, but in Chile, the treatment covered by the public health insurance, which assists more than 70% of the patients, is surgery alone. We conducted an observational study to assess efficacy and toxicity of perioperative chemotherapy (CT) in public hospitals in Chile (NCT01633203). Methods: Patients with locally advanced, operable gastric carcinoma, defined as presence of invasion of serosa or beyond (cT > 3 AJCC 2002) and/or lymph node metastasis (cN+) without distant metastasis (M0), were offered to receive preoperative CT with Epirubicin+Cisplatin+Capecitabine (ECX) regimen for 3 cycles followed by curative surgery with D2 lymphadenectomy. Staging abdominal CT scan was mandatory, laparoscopy was recommended. Patients with gastric retention, severe dysphagia or contraindications for CT were excluded. All patients signed the IRB approved informed consent form prior to enrolment. Data were collected using the OpenClinica platform. Results: Between August 2010 and March 2013, 110 patients were screened and 61 enrolled. Median age was 62 years (23-76 years) and most patients had good performance status at baseline (ECOG 0: 42, ECOG 1: 19). Tumor site was proximal in 24 (39%), medial in 16 (26%) and distal in 10 patients (16%). All but 4 patients (n = 57, 93%) completed three cycles of preoperative CT as planned. Fifty-five patients were operated and 54 (89%) had curative R0 resection. Of these, 36 (67%) had pT0-2, and 15 (28%) had pN0 tumors. A complete pathological response was found in 2 patients. Two patients were not operated for other reasons (one patient refused surgery and one patient presented a cerebrovascular accident during preoperative CT and died), and 5 patients (8%) progressed. As of September 1, 2015, 32 patients died. Three-year survival rate was 49%. Conclusions: Perioperative CT is feasible in public hospitals in Chile and should be offered as an alternative to primary surgery for patients with locally advanced gastric cancer.
Predicting response to neoadjuvant chemoradiotherapy in esophageal cancer by textural features derived from pretreatment FDG-PET scans.
Authors: Beukinga Jorn , Hulshoff Jan-Binne , Sijtsema Marianna , van Dijk Sanne , Muijs Christina , Burgerhof Johannes , Kats-Ugurlu Gursah , Slart Riemer , Slump Kees , Mul Veronique E. , Plukker John Theodorus
Published: February 2017

93

Background: 18-F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is currently the imaging method of choice in assessing response of neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer (EC) patients. PET/CT derived texture analysis is potentially more useful than common PET/CT measurements in response assessment and might also be of predictive value in different cancer types. The aim of this study was to develop a model to predict response to nCRT in EC based on pretreatment FDG-PET derived textural features in combination with clinical parameters. Methods: We reviewed 80 locally advanced EC patients who underwent pretreatment FDG-PET/CT and radiation planning CT scans between 2009 and 2015. Patients received nCRT according to the CROSS regimen (carboplatin/paclitaxel/41.4Gy) followed by esophagectomy. We analyzed 7 clinical, 16 geometry-based, and 87 different texture features derived from pretreatment FDG-PET images of the radiotherapy gross tumor volume. Ordinal logistic regression analysis was performed to construct a prediction model for treatment response, which was pathologically classified in complete, partial and no response on the Mandard tumor regression grade (1 vs. 2-3 vs. 4-5). The performance of this model was estimated by comparison with clinical outcome. Results: Pathologic examination revealed 16 (20.0%) complete, 46 (57.5%) partial, and 18 (22.5%) non- responders. Response analysis yielded the following independent predictive textural features: SUVmin, small zone low gray level emphasis, and contrast; and the independent predictive clinical parameters: nodal stage, endoscopic tumor length, and gender. The model has a sensitivity/specificity, positive/negative predictive value, and accuracy of 69%/97%, 85%/93%, and 91% for the prediction of complete response and 61%/79%, 46%/88%, and 75% for non-response, respectively. Conclusions: The prediction model constructed in this study, shows a good overall performance level in predicting response to nCRT in EC patients, but requires further external validation and refinement before it can be used for clinical decision making.
Evaluation of preventive factors for postoperative pulmonary complications following esophagectomy for T1bN0M0 cancer using data from JCOG0502.
Authors: Nozaki Isao , Mizusawa Junki , Kato Ken , Igaki Hiroyasu , Ito Yoshinori , Daiko Hiroyuki , Yano Masahiko , Udagawa Harushi , Nakagawa Satoru , Takagi Masakazu , Tsunoda Shigeru , Abe Tetsuya , Nakamura Tetsu , Hihara Jun , Toh Yasushi , Akutsu Yasunori , Shibuya Yuichi , Katayama Hiroshi , Nakamura Kenichi , Kitagawa Yuko
Published: February 2017

98

Background: Postoperative pulmonary complications (PPCs) are the most common cause of serious morbidity following esophageal cancer resection and are associated with a poorer prognosis in esophagectomized patients (pts). We have recently reported that thoracoscopic esophagectomy (TSE) decreases PPC frequency. However, it remains unclear whether the frequency is further decreased by the combination with laparoscopic esophagectomy (LSE). This study aimed to clarify the combined effect of TSE with LSE on the prevention of PPCs and to determine the preventive factors for PPCs following esophagectomy using data from JCOG0502. Methods: JCOG0502 is a four-arm prospective study comparing esophagectomy with definitive chemoradiotherapy for T1bN0M0 cancer, with randomized and patient preference arms. The primary endpoint is overall survival, which will be analyzed in 2018. PPCs were defined as one or more of the following ≥ grade 2 postoperative morbidities per CTCAE v3.0: pneumonia, atelectasis, and acute respiratory distress syndrome. The use of TSE and/or LSE was decided at the surgeon’s discretion. Results: Totally, 379 pts (11 in the randomized and 368 in the patient preference arm) were enrolled between 2006 and 2013 from 37 institutions. Of the 210 pts who underwent esophagectomy, TSE was performed in 101 pts (TSE with laparotomy in 43 pts and TSE with LSE in 58 pts), while esophagectomy via thoracotomy was performed in 109 pts. PPCs occurred less often in pts who underwent TSE than esophagectomy via thoracotomy (15.8% vs 30.3%, p = 0.01); however, there was no difference in the frequency of PPCs between those who underwent TSE with laparotomy and TSE with LSE (16.3% vs 15.5%). In univariate analysis, both TSE (shown above) and less blood loss ( < 350 mL) were associated with the prevention of PPCs (16.3% vs 30.2%, p = 0.02). Multivariate analysis showed that TSE was associated with the prevention of PPCs [Odds ratio, 0.33; 95% confidence interval (0.12-0.88); p = 0.03]. Conclusions: This study indicated that TSE was the only independent preventive factor for PPCs following esophagectomy, and LSE had limited effectiveness in the prevention of PPCs when it is combined with TSE. Clinical trial information: UMIN000000551.
Phase II study of nivolumab (ONO-4538/BMS-936558) in patients with esophageal cancer: Preliminary report of overall survival.
Authors: Kojima Takashi , Hara Hiroki , Yamaguchi Kensei , Hironaka Shuichi , Iwasa Satoru , Kato Ken , Tsushima Takahiro , Yasui Hirofumi , Ura Takashi , Muro Kei , Satoh Taroh , Doki Yuichiro , Ohtsu Atsushi , Hamamoto Yasuo , Kitagawa Yuko
Published: February 2017

TPS175

Background: Patients with esophageal cancer refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a human monoclonal IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced esophageal cancer. We conducted phase II, single-arm, multi-center trial in JAPAN (JapicCTI-No.142422).Methods: The target population was esophageal cancer patients aged ≥ 20 years with ECOG performance status of 0 or 1, who had received one or more previous treatments and not pre-selected by PD-L1 status. Nivolumab (3 mg/kg IV Q2W) was administered to patients until observing unacceptable toxicity or disease progression assessed at 6 week intervals. The primary endpoint was the proportion of patients with a confirmed objective response assessed by independent review committee according to RECIST 1.1. Planned sample size was 60 patients (P0 = 5, P1 = 15, α = 0.025 (one-side), 1-β = 0.8). Data cutoff, 17 May 2015.Results:We enrolled 65 patients with esophageal carcinoma: median age 62.0 years (range, 49-80 years); male/female, 54/11; ECOG PS 0/1, 29/36, Histological type was squamous in all pts. The median prior regimens was 3.0 (range, 1-8); 44 patients (67.7%) were treated with prior esophagectomy and 44 patients (67.7%) with prior radiation therapy. There were 64 evaluable patients for efficacy, and 11(17.2%) of 64 patients had objective response (CR/PR, 1/10). 16 (25.0%) of 64 patients had stable disease. The median overall survival was 12.1 months in 64 evaluable patients. The incidence of drug-related Serious AEs was 11 events (9/65 patients): Lung infection(2[3.1%]), Dehydration(2[3.1%]), Interstitial lung disease (2[3.1%]), etc. The patients with grade 3 pneumonitis improved with supportive care. There was no treatment-related death. We will introduce the updated efficacy and safety data of this trial. Conclusions: Nivolumab has meaningful activity and a manageable safety profile in pretreated esophageal cancer. These data support the assessment of nivolumab in randomized, controlled, phase III studies of second-line treatment. Funding: ONO Pharmaceutical CO.,LTD. Bristol-Myers Squibb Clinical trial information: 142422.
Phase II trial of bolus 5-FU/l-LV regimen as salvage line chemotherapy for oral fluorouracil resistant unresectable gastric cancer (HGCSG1502).
Authors: Muranaka Tetsuhito , Yuki Satoshi , Sawada Kentaro , Kawamoto Yasuyuki , Nakatsumi Hiroshi , Dazai Masayoshi , Hayashi Hideyuki , Nakamura Michio , Ishiguro Atsushi , Sogabe Susumu , Kobayashi Yoshimitsu , Miyagishima Takuto , Iwanaga Ichiro , Tateyama Miki , Hatanaka Kazuteru , Kato Takashi , Sakamoto Naoya , Sakata Yuh , Komatsu Yoshito
Published: February 2017

TPS177

Background: S-1, oral fluorouracil agent compounding tegafur, 5-chloro-2, 4-dihydropyrimidine, and potassium oxonate for gastric cancer showed non-inferiority relative to a continuous infusion of fluorouracil in JCOG9912 trial. Similarly, in ISO-5FU10 trial, S-1 revealed non-inferiority effect compared with the treatment with bolus 5-FU/l-LV treatment. It is known that there is a different mechanism of anti-cancer effect between continuous 5-FU and bolus injection of 5-FU. Continuous infusion of 5-FU and oral fluorouracil inhibit DNA synthesis, however, bolus injection of 5-FU causes dysfunction of RNA in a concentration-dependent manner. So we considered bolus 5-FU/l-LV treatment might be useful for oral fluorouracil resistant patients with gastric cancer. Methods: This is a multi-centered single-arm prospective phase II study in Japanese patients with oral fluorouracil resistant gastric cancer. The key eligibility criteria are as follows: 1) Pathologically diagnosed gastric adenocarcinoma: 2) Unresectable advanced, metastatic, or recurrent disease; 3) resistance of S-1 or capecitabine; 4) resistance or intolerance of cisplatin or oxaliplatin, paclitaxel or docetaxel, and ramucirumab; 5) 20 years of age or older; 6) ECOG PS of 0, 1 or 2. Bolus 5-FU/l-LV regimen consists of l-LV 250mg/m2/2h iv and 5-FU 600mg/m2 iv bolus given intravenously once weekly followed by 2-week rest period, within a 8-week cycle. The primary endpoint is progression free survival rate after 1cycle administration. And the secondary endpoints are response rate, disease control rate, overall survival, progression free survival, time to treatment failure, adverse events, dose intensity and QOL by EORTC QLQ-C30. This study is recruiting in Hokkaido Gastrointestinal Cancer Study Group and registered as UMIN000018882. Clinical trial information: UMIN000018882.
A randomized, double-blind, placebo-controlled phase III study of cisplatin plus a fluoropyrimidine with or without ramucirumab as first-line therapy in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (RAINFALL, NCT02314117).
Authors: Fuchs Charles S. , Tabernero Josep , Al-Batran Salah-Eddin , Chau Ian , Ilson David H. , Van Cutsem Eric , Shitara Kohei , Ferry David , Emig Michael , Vanvoorden Veerle , Hsu Yanzhi , Xu Yihuan , Sashegyi Andreas , Das Mayukh , Shah Manish A.
Published: February 2017

TPS178

Background: Ramucirumab, a human IgG1 monoclonal antibody directed to the ectodomain of VEGFR-2, prevents ligand binding to the receptor, blocking activation of downstream receptor-mediated pathways. Ramucirumab has demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) in 2 phase III registration studies (REGARD, RAINBOW) in patients in second-line treatment of gastric cancer. This global phase III trial will compare PFS in patients with HER2-negative, metastatic gastric or GEJ adenocarcinoma receiving ramucirumab with cisplatin/capecitabine (or 5-FU) versus placebo with cisplatin/capecitabine (or 5-FU) as first-line treatment. The trial is conducted in 137 sites in the Americas, Europe and Japan and is currently open to enrollment. Methods: Eligible patients will be randomized to receive ramucirumab (8mg/kg on days 1 and 8, based upon population pharmacokinetic modelling) or placebo with cisplatin/capecitabine every 21-day cycle until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary endpoint is PFS; OS is the key secondary endpoint. Efficacy will be considered at 3 analysis points: futility analysis for PFS, primary analysis of PFS & final analysis of OS. A gatekeeping strategy will be used to assess PFS and OS. The OS endpoint will only be tested if the PFS test is significant to control Type I error at 5% across both endpoints. An exposure/safety analysis will be done after 60 patients have started the 3rd cycle. The study has 90% power to demonstrate a PFS advantage assuming HR = 0.70 and 80% power to demonstrate an OS advantage assuming HR = 0.77. Other secondary endpoints include PFS2 (the time from randomization to disease progression after the start of additional systemic anticancer treatment, or death from any cause, whichever occurs first), objective response rate, safety and quality of life. As of 9/11/2015, 128 patients have been enrolled in 19 countries. The 1st exposure/safety analysis is underway. Clinical trial information: NCT02314117.