bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term follow-up of advanced gastric cancer patients who achieved a pathologic complete response with neoadjuvant chemotherapy.
Authors: Cho Haruhiko , Yoshikawa Takaki
Published: February 2017

133

Background: Adjuvant chemotherapy (AC) after D2 gastrectomy has become a standard treatment for stage 2/3 gastric cancer in Japan and Korea; however, the results remain unsatisfactory due to insufficient risk reduction in patients with stage 3 disease and low compliance. Although the administration of neoadjuvant chemotherapy (NAC) is a promising approach associated with a high rate of compliance and a downstage effect, the long-term survival benefits of this modality are unclear. Moreover, the impact of the pathological response on survival has not been evaluated. Based on the hypothesis that the pathological response grade is associated with survival, we conducted a search for reports of a pathological complete response (pCR) obtained with NAC. Methods: A total of 27 gastric cancer patients who achieved a pCR following NAC therapy were identified using PubMed and the Japanese medical search engine “Ichu-shi,” with the search words “gastric cancer,” “NAC,” and “pCR.” A questionnaire regarding the patients’ prognoses was posted in 23 institutions in Japan in July 2013. Results: Answers regarding 22 patients were obtained from 20 institutions. The subjects included 13 males and nine females. The mean age was 67.5 years. Tumors with stage 3/4 (95.4%: 21/22) and a diffuse-type histology (61.9%: 13/21) were dominant. S1/CDDP was the most frequently selected NAC regimen. A total of 77.2% (17/22) of the patients required combined resection of adjacent organs, and all patients underwent R0 resection and D2 lymphadenectomy. At present, 86.3% (19/22) of the patients are alive without recurrence; none of the ten patients who received postoperative AC demonstrated any recurrence, while three of twelve patients who did not receive postoperative AC developed recurrence, and two patients died of the disease after surgery (at 71 months and nine months, respectively). The overall and recurrence-free survival rates at three/five years were 95.5%/85.1% and 90.9%/75.1%, respectively. Conclusions: Patients with gastric cancer who achieve a pCR with NAC are rare; however, their prognoses are excellent. It is therefore important to develop a NAC regimen focusing on a high pCR rate.
Postoperative chemoradiation FOLFOX 4-based for R1 resected gastric cancer: A retrospective mono-institutional study.
Authors: De Vita Ferdinando , Orditura Michele , Laterza Maria Maddalena , Fabozzi Alessio , Savastano Beatrice , Ventriglia Jole , Marano Luigi , Giordano Guido , Petrillo Angelica , Martinelli Erika , Troiani Teresa , Morgillo Floriana , Di Martino Natale , Ciardiello Fortunato
Published: February 2017

143

Background: Improved DFS and OS were seen in curatively resected patients (pts.) with gastric and gastroesophageal adenocarcinoma treated with the Int0116 protocol of postoperative adjuvant chemoradiotherapy compared to surgery alone. However, there are very limited data about the efficacy of this approach in pts. with R1 resection. To evaluate the efficacy of a combined chemoradiation regimen in this setting, we reviewed our case records from 43 pts. with R1 resection treated between May 2008 and July 2012. Methods: 43 pts. with histologically confirmed gastric adenocarcinoma, received combined adjuvant chemotherapy with FOLFOX-4 for 8 cycles and concomitant radiotherapy (45 Gy in 25 daily fractions over 5 weeks). Radiotherapy was begun after 2 cycles of CT, (reduced by 20% during the period of concomitant radiotherapy). Pts. were followed at 3-month intervals for 2 years, at 6-month intervals for the next 3 years and yearly thereafter. Results: The median age was 62 years (range, 22-74) and the majority of pts. (76.7%) were males. Tumor location was equally distributed in the stomach. Most of the patients had locally advanced disease: 93% had T3-4 tumors and 74.4% had lymph node involvement. There was no treatment related death. Gastrointestinal G3 toxicity was observed in 11.6% of pts., while haematologic G3-4 toxicity was observed in 9.3%. Experienced toxicities led to chemotherapy dose reductions in 9 pts. and dose delay in 11 patients; 7 pts. had a delay in radiotherapy. With a median follow-up of 36 months (range 2-49) for the 43 R1 pts., 74.4% died of gastric cancer, 11.6% are alive with no evidence of recurrence and 13.9% are alive with disease. 66.6% of the relapses in this group occurred at distant sites and 33.3% were locoregional. The estimated 3-year OS was 19%. The median DFS was 14.5 months and the median OS was 16 months. Conclusions: These results seem to imply some benefit for the postoperative treatment, as nearly 19% of the R1 pts. in our study remained free of recurrence at 3 years from surgery. In the absence of phase III data and consequently lack of clear guidelines in this setting, our results support the common practice of adding postoperative chemoradiation after R1 gastrectomy.
Activity of gemcitabine/5-FU combination in refractory esophagogastric (EG) cancer.
Authors: Won Elizabeth , Ilson David H. , Chou Joanne F. , Capanu Marinela
Published: February 2017

147

Background: Systemic chemotherapy has been demonstrated to improve survival and palliate symptoms in metastatic EG cancer. 2ndline (or more) chemotherapy with best supportive care also improves progression free and overall survival. Single-agent gemcitabine did not show activity in EG cancers (Ann Oncol 11:1161, 2000). Addition of gemcitabine to 5-fluorouracil (5FU) has shown modest activity (Oncology 69:130, 2005). To determine the efficacy and tolerability of gemcitabine with 5FU, we reviewed our experience in patients (pts) with metastatic or advanced EG cancers treated with this regimen. Methods: Retrospective review of MSKCC database for pts with metastatic EG cancer treated with gemcitabine/5FU (or capecitabine) between 1/1/2000 - 12/31/2012. Gemcitabine given at 600-1000mg/m2 day1, day 8 of q21 day cycle or 600-1000mg/m2 q2 weeks. 5FU given at 600-1000m2/m2 IV/48 hrs, with bolus 5FU/Leucovorin (200-400mg/m2 IV) on day 1. Capecitabine most commonly given as 1500-4000mg flat dose daily, in two divided doses, 7 days on/7 days off. Results: Of 146 pts, median age was 60; KPS 70 (50-90); 84% adenocarcinoma, 6% squamous (SCC). Sites of disease: 45% liver; 22% bone, 21% peritoneum. 112(77%) had ≥ 2 sites of disease. Pts were heavily pretreated: 42(29%) 2 prior lines of treatment (tx) for metastatic disease, 37(25%) 3 lines of tx, and 7(5%) 4+ lines of tx. Prior tx: 5FU/platinum (37%); Taxanes (56%); Irinotecan (44%). With gemcitabine, 49(34%) received 5FU and 97(66%) received capecitabine. In 144 evaluable pts, partial response rate was 7%, and stable disease was seen in 33%. Median PFS 1.84 months (95% CI,1.38-2.04) and for adenocarcinoma 2.0 months (95%CI,1.2-2.2) vs 1.2 months (95%CI: 0.9-1.51) for SCC (p =0.068). In the PR group, median PFS was 5.0 months (range 3.7-16.3 mo). Grade 3 toxicity was seen in 19 (13%); 1 pt had Grade 4 toxicity. 3(2%) discontinued treatment due to toxicity. Conclusions: Combination gemcitabine/5FU or capecitabine in metastatic EG cancer may have some limited activity and is well tolerated in a previously treated population. This regimen may be an appropriate palliative option for patients with an intact performance status who have progressed on other regimens. Research supported by Foundation 14.
Compliance of MAGIC protocol in patients with resectable gastrosophageal (GO) cancer: Tata Memorial Centre (TMC) experience.
Authors: Sirohi Bhawna , Singh Ashish , Gupta Alok , Deodhar Kedar , Goel Mahesh , Shrikhande Shailesh V
Published: February 2017

154

Background: The perioperative regimen of ECF significantly improved outcome in MAGIC trial. In pts with advanced gastric cancer, oxaliplatin and capecitabine are non-inferior to cisplatin and 5-FU (Cunningham et al, NEJM 2006, 2008). We analysed the compliance, efficacy and toxicity of perioperative EOX (epirubicin, oxaliplatin, capecitabine) in pts with resectable GO cancer. Methods: This is a retrospective analysis of prospectively maintained database of pts with resectable GO cancer txed at TMC with EOX between Jan 2012 to Aug 2013. Pts were planned to receive 3# of neoadjuvant (NA) and 3# of adjuvant EOX (iv epirubicin 50 mg/m2 D1, oxaliplatin 130 mg/m2, on D1, capecitabiine 1250mg/m2D1-21 every 21 days. On completion of 3# of EOX, pts were planned to undergo gastrectomy and D2 lymphadenectomy (Shrikhande SV, WJSO 2013). Results: 67 pts (53M/14 F, median age 54 y, 32-76) were treated with NA EOX. Median CEA and Ca 19.9 were 2.76( 0.92-135) and 13.85 (<2 -6,308). 37% pts had signet ring histology and 30% poorly differentiated adenocarcinoma. Pre-operatively 92% pts completed EOX (91% in MAGIC trial); 5 pts did not complete 3# -3 due to grade 3 toxicity, 1 died of sepsis and 1 progressed. Treatment-related mortality was 1/67 (1.4%) compared to 2/237 (0.8%) in MAGIC trial. Response to NA tx was SD 22%, PR 64 %,CR 3% and PD in 6%, not assessable in 3 pts. Surgical resection done in 90% pts (88% in MAGIC); being planned in 5 pts; 6 pts did not undergo surgery—1 lost to follow up, 1 died, 2 PD, 2 inoperable. Resection was R0 in 54 pts and R1 in 2 pts. Median number of nodes dissected was 13 (0-37). 3 pts had pCR. The grade 3 and 4 toxicity was 1% intractable hiccups, 3% neuropathy, 9% diarrhea, 4% febrile neutropenia and 5% hand-foot syndrome—slightly higher than MAGIC reported results. 71% pts received adjuvant chemotherapy compared to 58% in MAGIC trial. Conclusions: In pts with operable GO adenocarcinoma, it is possible to deliver the MAGIC-type perioperative chemotherapy with comparable results in an Indian setting. Unlike MAGIC trial, majority of pts underwent D2 lymphadenectomy.
A prospective multicenter observational study for chemotherapy-induced nausea and vomiting in gastric cancer in Japan.
Authors: Iwagami Shiro , Baba Hideo , Hirabayashi Naoki , Sugiyama Yoichi , Nakajima Go , Tsuji Yasushi , Kunisaki Chikara , Tsuburaya Akira , Goto Masahiro , Maehara Yoshihiko , Takeda Koji , Yoshida Kazuhiro , Aiba Keisuke
Published: February 2017

155

Background: There has been no nationwide survey on CINV or validation of the guideline in Japan. The aim of the study was to investigate the occurrence of CINV in gastric cancer patientstreated with chemotherapy for the first time. Methods: A nationwide survey on CINV was conducted by the CINV study group of Japan. 108 institutions participated in the study. A 7-day diary for CINV was provided to the patients prior to chemotherapy to record the daily occurrence and severity of CINV and the amount of food intake. Acute and delayed CINV was defined as nausea and vomiting which developed within or later than 24 hours after the start of chemotherapy, respectively. We evaluated the frequency and the risk factors of CINV. The medical staff also filled out questionnaires about their patients’ CINV. Results: A total of 154 patients were registered during the period from April 2011 to December 2012. There were 109 males and 45 females with a median age of 65 (range: 25-82). HEC was given to 152 and MEC was administered to 2 patients. CDDPwas included in all of HEC regimens. For preventing CINV, a three-drug regimen of aprepitant, 5-TH3 receptor antagonist (5- TH3 RA ), and dexamethasone was applied in 131 cases and a two-regimen of 5- TH3 RA and dexamethasone in 23. Acute nausea (AN) was ovserved in 19 patients (12.3%), while delayed nausea (DN) was experienced by 74 patients (48%). Acute vomiting (AV) occurred in 1 case (0.6%), while delayed vomiting (DV) was observed 15 cases (9.7%). The risk factors of CINV in gastric cancer were female and motion sickness. The age, pregnancy or morning sickness didn’t show any correlation with an occurrence of CINV. The staff predicted an occurrence of AN and DN in 96 patients (62.3%) and 132 (85.7%). However only experienced 19 (12.3%) and 74 (48.1%) patients showed symptoms of AN and DV, respectively. Conclusions: CINV in patients with gastric cancer seems to be under control with a management according to the guideline, however delayed CINV remains to be high and needs to be targeted by further investigation. Clinical trial information: UMIN000005971.
Detection of multidrug-resistant, gene-related proteins for postoperative individualized chemotherapy of gastric cancer.
Authors: Yu Pengfei
Published: February 2017

156

Background: Postoperative adjuvant chemotherapy was beneficial for some patients,however, it may increase the treatment burden and reduce the immunity of other patients. Screening appropriate patients based on molecular markers for individualized adjuvant chemotherapy was necessary. Methods: Between June 2002 to June 2004, 119 patients who underwent radical gastrectomy were retrospectively analyzed. 61 patients had adjuvant chemotherapy based on platinum and 5-FU for 4 to 6 cycles. ToPo II negative, MRP positive and GST-π positive were regarded as three risk factors which may be associated with chemotherapy resistance and poor prognosis. Patients were divided into two groups: high-risk group (≥2 risk factors) and the low-risk group (<2 risk factors), and the tumor recurrence and patients’ survival time of the two groups were analyzed. Results: The average recurrence time of the low-risk group was significantly longer than that of the high-risk group (21.29 ± 11.10 VS 15.16 ± 8.05 months ,p<0.01).The 3-year and 5-year survival rate of the high-risk group was 57.4% and 42.6%, however, it had no significant difference compared to 66.2% and 58.5% of the low-risk group (P> 0.05). In the high-risk group, the 3-year survival rate of patients with/without chemotherapy were 62.1% and 52.0%, 5-year survival rates were 44.8% and 40.0%, but the difference was not statistically significant (P> 0.05). In the low-risk group, the 3-year survival rate of patients with/without chemotherapy were 81.2% and 51.5%, 5-year survival rates were 71.9% and 45.5%, and the difference was statistically significant (p<0.05). Conclusions: Combined determination of MDR-related proteins ToPo II, MRP and GST-π may be prospectively valuable for optimizing the chemotherapy regimes, and further predicting the outcomes of gastric cancer patients.
Interim safety analysis from a randomized, open-label, multicenter, phase III trial of capecitabine plus oxaliplatin (XELOX) versus capecitabine (X) as first-line chemotherapy in elderly patients with advanced gastric cancer (AGC).
Authors: Hwang In Gyu , Kang Jung Hun , Lee Soonil , Lee Hyo Rak , Lee Hui Young , Ji Jun Ho , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki
Published: February 2017

158

Background: While combination chemotherapy involving fluoropyrimidines and platinum is currently considered a standard regimen in AGC, there has been a price to pay in terms of toxicity. Since the main goal of treatment in AGC remains palliation, the current multi-center phase III trial compares efficacy and safety of XELOX combination with those of X monotherapy in elderly patients with AGC. Methods: AGC Patients aged 70 years or older were randomized 1:1 to receive X (capecitabine 1000 mg/m2 bid po on D1-D14) or XELOX (capecitabine 1000 mg/m2 bid po on D1-D14 plus oxaliplatin 110 mg/m2 iv on D1). Treatment was repeated every 21 days until disease progression, unacceptable toxicity, or patient’s refusal. Primary endpoint was overall survival, and the target sample size was 200 eligible patients. This interim safety analysis contains toxicity data from the first 27 randomized patients. Results: Among the 27 patients (X: 13, XELOX 14), median age was 77 (range, 70-84) years and 24 patients had symptomatic (ECOG PS 1-2) disease. The arms of the study were balanced with respect to baseline characteristics. No treatment-related serious adverse events (SAEs) or unexpected toxicities were observed. The most frequent toxicities were anorexia, fatigue, anemia, and hand-foot skin reactions. Fatigue and sensory neuropathy were more common in XELOX than X patients. QOL data showed no significant differences between the two arms. Conclusions: Our data indicate that the addition of oxaliplatin does not add to the toxicity of single agent capecitabine as first-line chemotherapy in elderly (age ≥70 years) AGC patients. The accrual is currently ongoing (ClinicalTrials.gov, NCT01470742). Clinical trial information: NCT01470742.
Pretreatment skeletal muscle depletion as an adverse prognostic factor in metastatic gastric cancer.
Authors: Hasegawa Hiroko , Fujitani Kazumasa , Yamaoka Yusuke , Hirao Motohiro , Nakazuru Shoichi , Sekimoto Mistugu , Mita Eiji
Published: February 2017

161

Background: Body composition has emerged as an important prognostic factor in cancer patients. Especially, skeletal mass depletion has been associated with poor performance status, toxicity of chemotherapy and shortened survival in cancer patients. However, the impact of pre-treatment skeletal muscle index on survival or toxicity in metastatic gastric cancer patients remains uncertain. Methods: In this retrospective study, we reviewed 98 metastatic gastric cancer (mGC) patients who received S-1 based combination chemotherapy as first-line treatment from April 2006 to March 2013. Pre-treatment skeletal muscle mass was quantified by CT cross sectional area at the third lumbar vertebrae and evaluated as lumbar skeletal muscle index (SMI) (cm2/m2) after normalization for stature (m2). Patients were categorized into 2 groups depending on initial SMI: 35 patients with SMI ≤ 40 and 63 patients with SMI > 40. Results: Median overall survival was significantly shorter in the SMI ≤ 40 group than in the SMI >40 group (439 days versus 565 days; p= 0.03). Progression free survival was also better in the SMI> 40 group without statistical significance (175 days versus 151 days; p= 0.17). Toxicity (grade 3 or 4) was more common in the SMI ≤ 40 group than in the SMI >40 group. (41.1% versus 11.1%; p=0.001). In multivariate analysis, performance status of 2 (HR 4.711, 95%CI 1.065 to 20.832, p=0.04), presence of primary tumor (HR 2.322, 95%CI 1.007 to 5.357, p=0.04) and pre-treatment SMI (HR 2.525, 95%CI 1.145 to 5.568, p=0.02) were independent prognostic factors for OS. Conclusions: The present study suggests that skeletal muscle depletion at the initiation of first-line chemotherapy might be an independent prognostic factor for mGC patients.
A restrospective analysis of toxicities encountered with palliative epirubicin, oxaliplatin, and capecitabine (EOX) chemotherapy for advanced esophagogastric cancer.
Authors: Khakoo Shelize Sadrudin , Georgiou Alexandros , Waters Justin S.
Published: February 2017

162

Background: Palliative chemotherapy for advanced gastric and gastro-oesophageal junctional (GEJ) carcinoma improves tumour related symptoms and overall survival compared to best supportive care alone. EOX has been established as one of the most effective regimens in randomised clinical trials, but produced significant toxicity. We wished to examine the tolerability of EOX in everyday practice. Methods: A retrospective search was conducted to identify patients with advanced gastric or GEJ cancer, treated at our institution with at least one cycle of first line palliative EOX between 2009 and 2012. Patient baseline characteristics, toxicities (graded according to CTCAEv.4), dose reductions, treatment interruptions and discontinuations were analysed. Results: We identified 60 patients, 83% were male, and the median age was 64 years (age range18-82 years). 85% had a baseline performance status (PS) of 1, 10% PS of 2 and 5% PS of 0. 75% had GEJ cancer and the remainder had gastric cancer. 82% were commenced on standard EOX (1250mg/m2 capecitabine, 130mg/m2 oxaliplatin and 50mg/m2). 80% of patients experienced grade 3 or worse toxicity. 27% discontinued treatment due to excessive toxicity and 37% due to progressive disease. Significant toxicities (at least grade 3) were: 28% neutropenia, 27% diarrhoea, 23% fatigue, 10% vomiting, 10% anaemia, 8% neutropenic sepsis, 8% nausea, 5% thrombocytopenia, 5% peripheral neuropathy, 3% mucositis and 3% chest pain. 47% of patients required a dose reduction of at least 1 drug. 66% of patients completed 3 cycles, 35% completed 6 cycles and 18% completed 8 cycles. The mean progression free survival for patients completing 8 cycles was 4.6 months. Conclusions: EOX improves tumour related symptoms and overall survival but the benefits are often short-lived and in some patients it is associated with unacceptable toxicity, given their limited life expectancy. More thought needs to be given to prophylactic measures and modification of the EOX regimen to improve tolerability without compromising efficacy.
Matched pair analysis to examine the effects of a planned preoperative exercise program in early gastric cancer patients with metabolic syndrome to reduce operative risk: The Adjuvant Exercise for General Elective Surgery (AEGES) study group.
Authors: Cho Haruhiko , Yoshikawa Takaki , Oba Mari Saito , Hirabayashi Naoki , Shirai Junya , Aoyama Toru , Hayashi Tsutomu , Yamada Takanobu , Oba Koji , Tsuburaya Akira , Sakamoto Junichi
Published: February 2017

166

Background: Since obesity is a risk factor during surgery, the effects of a preoperative exercise program to reduce the incidence of peri- and postoperative complications in patients with a high BMI (> 25) and metabolic syndrome were investigated. An assessment of the effects of prospectively planned preoperative exercise was performed in a prospective matching study comparing an exercise testing group and a usual preoperative preparation group who underwent gastrectomy for gastric cancer in Japan. Methods: Stage I gastric cancer patients with metabolic syndrome diagnosed according to the criteria of the Japanese Ministry of Health, Labour and Welfare were enrolled in a surgery after preoperative exercise group. The control group was selected from a database using an individual matching approach for surgery, sex, weight, BMI, volume of visceral fat and institution. The primary end point was the frequency of postoperative complications (cardiovascular events, pneumonia, surgery-related abdominal complications, etc.). Results: A total of 72 patients (54 in the surgery alone group, 18 in the preoperative exercise group) were analyzed. The median operative time and amount of bleeding were 208 min and 130 ml in the surgery alone group and 248 min and 105 ml in the exercise group, respectively. Postoperative complications occurred in one case (5.5%) in the exercise group and 22 (40.7%) cases in the surgery alone group. Conclusions: Preoperative exercise is safe, and its benefits in reducing postoperative complications are promising and therefore warrant further investigation.
Exploratory analysis to investigate clinical factors that may influence trastsuzumab efficacy in patients with HER2-positive gastric cancer.
Authors: Wakatsuki Takeru , Chin Keisho , Matsusaka Satoshi , Ogura Mariko , Ozaka Masato , Suenaga Mitsukuni , Shinozaki Eiji , Nakayama Izuma , Mizunuma Nobuyuki
Published: February 2017

169

Background: ToGA study showed significant survival benefit of trastuzumab in patients with HER2 positive gastric cancer (GC); however, clinical factors which can impact its efficacy prior to treatment are still unknown. Hence, we conducted this exploratory analysis whether clinical factors could influence trastuzumab efficacy in patients with HER2 positive GC. Methods: Thirty-three HER2 positive GC patients, who were treated by trastuzumab with chemotherapy in our institute from 2011 March to 2012 December, were enrolled. Clinical factors according to ToGA study and tumor markers were examined. We retrospectively analyzed whether these clinical factors were associated with progression-free survival (PFS) and overall survival (OS). These endpoints were estimated using by Kaplan-Meier methods and compared by the log-rank test. The Cox regression analysis including only clinical factors of which p-value was less than 0.02 was done. Results: Median follow-up period was 10.8 months. Median age was 63 y.o. and 64% of the patients were male. PS 0-1, GEJ cancer, visceral metastasis (lung or liver), previous gastorectomy, previous chemotherapy, number of metastatic site (1-2), and number of metastatic lesion (1-4) were found in 97%, 27%, 58%, 36%, 21%, 76%, and 27% of the patients, respectively. Sixty-seven% and 94% of the patients were differentiated type and HER2 3+ by IHC, respectively. Baseline median CEA and CA19-9 levels were 5.2 ng/ml and 109.4 U/ml, respectively. Median PFS was 9.5 months (95% CI: 5.5-13.5) and median OS was not reached. Overall response rate by RECIST was 71.4%. Lower CA19-9 levels were associated with longer PFS in univariate analysis. Patients who had lower CA 19-9 levels showed a median PFS of 12.2 months vs. 6.9 months for patients who had higher CA19-9 levels (HR: 0.41 [95%CI: 0.17-1.00], p=0.042), however this result was not conserved in multivariate analysis. No clinical factors were associated with OS. Conclusions: Lower CA19-9 levels were associated with favorable PFS in the patients with HER2 positive GC upon when treated by trastuzunab. External clinical validations and further molecular analyses are needed to validate this result.
A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: Updated results.
Authors: Le Dung T. , Wang-Gillam Andrea , Picozzi, Jr Vincent , Greten Tim F. , Crocenzi Todd S. , Springett Gregory M. , Morse Michael , Zeh Herbert , Cohen Deirdre Jill , Fine Robert Lance , Onners Beth , Uram Jennifer N. , Laheru Dan , Murphy Aimee , Skoble Justin , Lemmens Ed , Grous John J. , Dubensky Thomas , Brockstedt Dirk G. , Jaffee Elizabeth M.
Published: February 2017

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Background: Immunotherapy for pancreatic ductal adenocarcinoma (PDA) is likely to require synergistic combinations. One approach is to use heterologous prime boost vaccinations to capitalize on immunostimulatory features of distinct vectors. GVAX is irradiated, GM-CSF-secreting allogeneic pancreatic cell lines given intradermally to elicit a broad antigenic response. Low-dose cyclophosphamide (CY) is given prior to GVAX to inhibit regulatory T-cells. CRS-207 is live-attenuated Listeria monocytogenes (Lm) which expresses mesothelin and stimulates innate and adaptive immunity. In mouse tumor models, Lm/GVAX vaccines are synergistic and in the Phase 1 study of CRS-207, 3 PDA patients who had received prior GVAX lived ≥15 months (mos). Methods: Metastatic PDA patients (ECOG 0-1; adequate organ function) who received or refused ≥1 prior chemotherapy were randomized 2:1 to receive either 2 doses of CY/GVAX followed by 4 doses of CRS-207 (Arm A) or 6 doses of CY/GVAX (Arm B) every 3 weeks. Courses could be repeated. The primary endpoint was to compare overall survival (OS) between the arms. Secondary endpoints were safety, clinical and immune responses. One-sided p-values are reported. Results: 90 patients (Full Analysis Set [FAS]; A: 61, B: 29), of which 51% had received ≥2 chemotherapy regimens for metastatic PDA, were treated. After a median follow-up of 7.8 mos, median OS in FAS was 6.1 vs 3.9 mos (A vs B; HR=0.54, p=0.011). Median OS in patients who received ≥3 doses (per protocol [PP] set: 2 doses of CY/GVAX and ≥1 dose of CRS-207 in A or ≥3 doses of CY/GVAX in B) was 9.7 vs 4.6 mos (A vs B; HR=0.44, p=0.0074). The treatment effect was particularly evident in patients who received ≥2 prior regimens for metastatic PDA with median OS of 5.1 vs 3.7 mos (A vs B; HR=0.34, p=0.001). OS in the PP set was 8.2 vs 4.0 mos (A vs B; HR=0.23, p=0.0003). CA19-9 stabilization was seen in 32% vs 13% of patients (A vs B; p=0.06). Toxicities included local reactions after GVAX and transient fevers, rigors and lymphopenia after CRS-207. Conclusions: CY/GVAX followed by CRS-207 shows extended survival with manageable toxicity in previously-treated metastatic PDA and warrants further study. Clinical trial information: NCT01417000.
Pre-SBRT metabolic tumor volume and total lesion glycolysis to predict survival in patients with locally advanced pancreatic cancer receiving stereotactic body radiation therapy.
Authors: Dholakia Avani Satish , Chaudhry Muhammad Ali , Leal Jeffrey P. , Chang Daniel Tandel , Raman Siva P. , Su Zheng , Hacker-Prietz Amy , Pai Jonathan , Griffith Mary E , Wahl Richard L. , Tryggestad Erik , Pawlik Timothy M. , Laheru Daniel A. , Wolfgang Christopher Lee , Koong Albert , Herman Joseph M.
Published: February 2017

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Background: Though prior studies have demonstrated the prognostic value of pre- and post-treatment positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer is yet to be established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiotherapy (SBRT). Methods: Thirty-two patients with LAPC received up to 3 doses of gemcitabine, followed by SBRT 6.6 Gy in 5 daily fractions, 33 Gy total, on a prospective clinical trial. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUVmax and SUVpeak) on pre-SBRT PET scans were calculated using an in-house software. Disease measurability was assessed at a threshold based on the liver standard uptake value (SUV) using the equation Livermean + (2 * Liversd). Median values of PET parameters were used as cutoffs when assessing their prognostic potential through univariate and multivariate Cox regression analyses. Results: Of the 32 patients in this study, the majority were male (N=19, 59%), 65 years or older (N=21, 66%), and had tumors located in the pancreatic head (N=27, 84%). Twenty-seven patients (85%) received induction gemcitabine prior to SBRT per protocol. Median overall survival for the entire cohort was 18.8 months (95% CI, 15.7-22.0). An MTV of 26.8 cm3 or greater (HR 4.46, 95% CI 1.64 to 5.88, p < 0.003) and TLG of 70.9 cm3 or greater (HR 3.08, 95% CI 1.18 to 8.02, p < 0.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19 to 22.21, p=0.029) and TLG (HR 3.34, 95% CI 1.07 to 10.48, p=0.038) remained independent prognostic factors for overall survival in separate multivariate analyses. Conclusions: Pre-SBRT MTV and TLG yield prognostic information on overall survival in patients with LAPC and may assist in tailoring therapy. Clinical trial information: NCT01146054.
A novel method combining gene and protein platforms on one slide for the detection of HER2 in gastric cancer: Final results.
Authors: Werner Dominique , Battmann Achim , Steinmetz Kristina , Jones Tobin , Lamb Tiffany , Martinez Michele , Al-Batran Salah-Eddin
Published: February 2017

19

Background: The evaluation of gene amplification and/or protein overexpression of HER2 in gastric cancer is a prerequisite to establish an adequate treatment strategy. Gastric tumors are heterogeneous and separate evaluations lead to uncertainties in localizing distinct clones and are time consuming. The aim of this study was to evaluate the feasibility of gene-protein platform in comparison to single staining methods. Methods: Immunohistochemistry (IHC) plus silver in situ hybridization (SISH) (IHC/SISH) and the new gene-protein platform (gene/protein) method for HER2 were performed in randomly collected 100 cases of gastric carcinoma. Evaluation was performed by two observers, in discrepant cases a third observer was consulted to make a decision by consensus. Results of IHC and SISH were compared with gene/protein staining. Rüschoff criteria were applied. Tumors showing HER2 expression 3+ or amplification were considered HER2 positive. Results: 96 of 100 samples were eligible. Amplification was observed in 14.6% by both, conventional SISH and gene/protein platform. 70.8% by IHC and gene/protein had no expression (0) and 10.4%/11.5% (IHC vs. gene/protein) had weak (1+) HER2 expression. Moderate expression (2+) was observed in 9.4% by IHC and 7.3% by gene/protein. Rate of overexpression (3+) was similar in IHC (9.4%) and gene/protein (10.4%). There were complete concordances (100%; κ=1) in IHC assessment of cases with score 0 and SISH amplified tumors. High concordance are shown in score 1+ (98.96%; κ=0.947) and 3+ (96.88%; κ=0.825) cases. Concordance in cases with score 2+ was found in 95.83% (κ=0.728) of the observations. After third observation, there were 5 discordant cases with most discrepancies in assessment of IHC score 2+ or 3+. Conclusions: Gene-protein platform has been tested for first time in gastric carcinoma. Results showed that this novel platform can be a feasible alternative to single methods. Discrepancies in cases with moderate HER2 expression are a result of observer variability.
Prevalence of detectable HBV DNA in cancer patients with resolved HBV infection (HBsAg (-) HBcAb (+) and its evolution after cytotoxic chemotherapy.
Authors: Shah Taral Ramesh , Zheng Huo Xiang , Gohari Pouyan , Shulimovich Maxim , Huang Yiwu , Xu Yiqing
Published: February 2017

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Background: Reactivation of hepatitis B virus (HBV) has been widely reported in HBsAg+ cancer patients undergoing chemotherapy, mainly in patients with lymphoma and breast cancer who received Rituximab and Adriamycin based chemotherapy. Reactivation of HBV has also been reported in a few patients who had previous exposure and resolved HBV infection (HBsAg-, HBcAb+). However there is no consensus as to whether prophylactic antiviral therapy should be used for this group, or whether the presence HBsAb plays a further protective role. Methods: We retrospectively and prospectively identified cancer patients undergoing chemotherapy who have HBsAg-, HBcAb+ status. Their HBV DNA levels and serial liver functions were followed. We aimed to evaluate the prevalence of detectable HBV DNA and HBV seroconversion rate after chemotherapy. Results: Between 11/2011 to 6/2013, 124 patients were screened and 51 (41%) had pretreatment HBsAg-, HBcAb+ status. Forty two (82%) patients were of Asian descent; 18 (35%) were males and 33 (65%) were females. Median age was 60 years with a range of 28 to 84 years. Forty seven patients (92%) received chemotherapy for solid malignancies while 4 (8%) received rituximab. Only one patient (2%) had detectable HBV DNA prior to treatment and received baraclude for prophylaxis. Fifteen patients (29%) had HBsAg-, HBcAb+, HBsAb- status, 36 (71%) had HBsAg-, HBcAb+, HBsAb+ status. Serial LFTs were followed over a median chemotherapy duration of 4 months (1 to 18 months). 2 had transient increase; 13 showed persistent but stable elevation related to tumor in the liver; 4 patients were tested for HBV DNA at LFT elevation and were negative. No patient had persistent or worsening LFT related to HBV reactivation. Conclusions: The prevalence of HBsAg-,HBcAb+ cancer patients is very high in South Brooklyn, NY, predominantly in Asian patients. Prevalence of detectable baseline HBV DNA is extremely low, even in isolated HbcAb positive patients and there was no seroconversion of HBV during chemotherapy, irrespective of HBsAb status. Prophylactic antiviral therapy is unnecessary.
A California population-based study on long-term survivors of hepatocellular carcinoma.
Authors: Subramaniam Somasundaram , Yang Juan , Lichtensztajn Daphne , Clarke Christina A
Published: February 2017

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Background: Hepatocellular carcinoma (HCC) is becoming increasingly common in the United States and long-term survival remains dismal, with only 15% of patients surviving more than 5 years. Little is known about the demographic and clinical characteristics of patients who survive. Methods: Using data from the California Cancer Registry, a member of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program, we identified all patients diagnosed with hepatocellular carcinoma between 1988 and 2007. Patients were included if they had pathological, clinical, laboratory or radiological confirmation of diagnosis. Patient’s demographic information including socio-economic status, summary stage, tumor characteristics and treatment details were included in the analysis. Hazard ratios (HR) for survival were calculated using Cox proportional hazards regression modeling. Results: We identified 19,855 patients with a median age of diagnosis of 63. Patients were predominantly male (74.4%). The majority of patients were Non-Hispanic Whites (38.1%) followed by Asian and Pacific Islander (API) (30.4%) and Hispanics (23.2%). Of the entire cohort, 3546 (17.9%) survived at least 3 years. Amongst long-term survivors, when classified by summary stage, 2552 (72%) were localized, 556 (15.7%) regional, 217 (6.1%) remote and 221 (6.2%) unknown. In a multivariate model, variables associated with survival were resection or transplant (HR 0.31), liver-directed therapies (0.53), chemotherapy (0.64), academic status of treating hospital (0.74), API race (0.832), highest socio-economic status quintile (0.88), female gender (0.93) and Hispanic race (0.94). When stratified by summary stage, API race, receipt of surgery, receipt of liver-directed therapies and treatment in an academic hospital remained significantly associated with long-term survival across all stages. Conclusions: Patients who survive for 3 years after a diagnosis of HCC have distinct demographic and clinical characteristics from patients who do not survive.
Characterization of patients with high serum level of IL-6 in advanced pancreatic cancer.
Authors: Miura Tomofumi , Mitsunaga Shuichi , Shimizu Satoshi , Ohno Izumi , Takahashi Hideaki , Okuyama Hiroyuki , Kuwahara Akiko , Ikeda Masafumi
Published: February 2017

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Background: IL-6 is a key mediator of cancer cachexia. The degree of cachexia affects serum IL-6 level in pancreatic cancer (PC) and is varied according to disease progression. The study population to characterize advanced PC patients with high IL-6 level needs the homogeneity in disease status. This study was aimed to identify IL-6-related factors in patients who were scheduled to undergo first-line chemotherapy for treatment-naïve advanced PC. Methods: Patients with treatment-naïve advanced PC were eligible for inclusion in this study. Patients with obvious infection or biliary drainage were excluded. Serum IL-6 levels and clinical parameters (e.g. symptoms, body composition) were prospectively collected. A high IL-6 level was defined as a value greater than the median value in all of the analyzed patients, and analyses were performed to identify risk factors for high IL-6 levels. Results: Eighty patients were analyzed. A multivariate analysis determined that the following parameters were associated with high IL-6: the presence of liver metastasis [Odds ratio (OR): 4.8, p < 0.01], fatigue (OR 3.4, p = 0.02), high carcinoembryonic antigen (CEA) levels (OR: 6.9, p = 0.03), anemia (OR: 9.5, p = 0.01), and high C-reactive protein (CRP) levels (OR: 12.4, p = 0.02). A decreased skeletal muscle mass tended to be frequently observed in patients with high IL-6 levels. Conclusions: High serum IL-6 related the presence of liver metastasis, severe fatigue, high CEA, high CRP and anaemia. Additionally, skeletal muscle loss might be the IL-6 related factor.
Clinical features of young patients (below age 40) with pancreatic ductal adenocarcinoma.
Authors: Ohmoto Akihiro , Morizane Chigusa , Kubo Emi , Shimada Kazuaki , Okusaka Takuji , Yachida Shinichi
Published: February 2017

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Background: The median age of pancreatic ductal adenocarcinomas (PDAC) patients is approximately 70 years. We investigated clinical features of PDAC occurring in young patients (< 40 years) in order to determine if any difference exists in comparison to older patients. Methods: We reviewed a single-institution database of 785 patients with pathologically proven PDAC between 2001 and 2012. We examined the clinical features in patients with PDAC below 40 years of age and compared it to those in older patients (≥ 40 years). Results: Of these 785 patients, a total of 10 patients (1.3%) under the age of 40 were identified, with a range of 28 to 37 years. Clinical features in young and older patients have been summarized (table). There are no differences between groups in terms of sex, smoking, tumor location, UICC stage, a family history of PDAC and a family history of any cancer. In the young patients group, three of them were diagnosed with localized diseases, two others with locally advanced diseases, and five others with metastatic diseases. Two of the three patients with localized diseases underwent curative operation. The five patients with metastatic diseases received chemotherapy, and only one patient achieved a partial response treated with FOLFIRINOX regimen. Two of the patients were long-term survivors, having survived over three years. Six of the patients had a family history of other cancers in first-degree relatives. Unexpectedly and most importantly, only one patient had a family history of PDAC. Conclusions: Cases of patients with PDAC below 40 years of age are rare. The clinical features in young patients were generally similar to those in older patients. Almost all young patients had no family history of PDAC, which suggests that hereditary genetic factors have a weak relationship with cases of onset of PDAC at a young age in Japan. [Table: see text]
Pancreas cancer: Influence of gender and other demographic and clinical parameters on survival.
Authors: Blank Patricia Renee , Szucs Thomas D.
Published: February 2017

200

Background: Research suggests that lower excess mortality risk for females compared to men do exist for several cancer types. The primary aim of this study was to investigate whether gender affects pancreas cancer (PC) prognosis. In addition, the relationship of gender and survival adjusted for clinical and demographic factors was assessed. Methods: The SEER database (version 1973-2009) was used to identify patients with primary histological confirmed PC (≥18 years, 80,689 males and 82,356 females) in the United States. The analysis was stratified by five different stages according to the categories of the American Joint Committee on Cancer (in situ, locally invasive, regional, distant, unstaged). The crude effect of gender was assessed in the total sample and in age-stratified Kaplan-Meier Curves (<55 years) in all five stages, respectively. Univariate and multivariate Cox proportional hazard models were run within the local stage at diagnosis. The predictors included in the models were demographic and clinical factors based on a prior clinical and scientific knowledge. Two-sided p-values of 0.05 were assumed as statistical significant. Results: In total, 128,645 PC-related deaths were reported with a median follow-up time of 13 months (censored patients). Kaplan-Meier curves showed a significant difference in survival among men and female in the locally invasive group (median survival in male and female: 7 months; 1-year survival: 35.5% and 35.1% among female and men, respectively; Log-Rank: p=0.0072). The remaining strata had non-significant differences (p= <.0001), except the unstaged group. The local recurrence group had a 5.6% (95%CI: 1.4%, 9.9%, p=0.0081) higher rate of dying among men compared to female. Among the population <55 years, the gender difference was significant across all disease stages, except the in situ group. Histology grade, age, race, and marital status was associated with survival from PC in the multivariate analysis. Conclusions: The present study indicates that male patients with PC have a worse prognosis than female patients. However, these results need validation and further studies are needed in the research on the prognostic value of gender in PC survival.
The role of surgical resection for hepatocellular carcinoma in octogenarians: A population-based analysis.
Authors: Akinbiyi Takintope , Burnett Atuhani S. , Ernst Philip , Cevasco Marisa , McCain Donald A. , Mokashi Suyog A.
Published: February 2017

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Background: Hepatocellular carcinoma (HCC) is a significant source of morbidity and mortality amongst the elderly population. In appropriately selected patients, surgery is known to confer a survival advantage. Octagenarians, however, given their remaining life expectancy may receive limited benefit from surgery. Nevertheless, insufficient information is available in the literature on the survival benefit of surgery in octagenarians with HCC. Methods: Octogenarians with HCC were selected from the Surveillance, Epidemiology, and End Results (SEER) database between 1998 and 2009. We evaluated patients who underwent surgical resection and those that declined to assess the impact surgery has on overall survival in this population. Results: A total of 8,614 with HCC were identified in the SEER database, of which surgery was recommended for 3,529 (41%). A total of 1,002 patients (28%) underwent surgery and 2,497 (71%) declined. Although there was a trend towards improved survival in the surgery group (7.91 months) vs the non-surgical group (7.03 months), there was no statistically significant difference in survival between the two groups (p = 0.09). Conclusions: Our study demonstrates that octagenarians as a whole do not experience a survival benefit from surgical resection for HCC. Subgroup analysis, however, may ultimately identify benefit in specific disease stages or patients with fewer comorbidities.
Clinical significance of serum protein and mRNA level of insulin-like growth factor-1 (IGF-1) in patients with hepatocellular carcinoma.
Authors: Karabulut Senem , Aykan Nuri Faruk , Yildiz Ibrahim , Kilic Leyla , Sen Fatma , Vatansever Sezai
Published: February 2017

203

Background: The hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the absolute positive and negative markers for HCC are still lacking, and even those characterized by very high sensitivity and specificity do not have an universal diagnostic usefulness. The aim of this study was to assess the usefulness of serum protein and circulating mRNA of insulin-likegrowth factor-1 (IGF-1) as a diagnostic and prognostic tool in HCC. Methods: Fifty-four HCC patients were enrolled into this study. Age and sex matched 20 healthy controls were also included in the study. Serum IGF-1 levels were determined by the solid-phase sandwich ELISA method. Serum IGF-1 mRNA levels were determined by quantitative RT-PCR. Results: The median age at diagnosis was 60 years, range 16–88 years; 48 patients were men. All of patients had cirrhotic history. Fourty-six percent (n=25) of patients had Child-Pugh Score A, 30% (n=16) had Score B or C. All of the patients were preformed with local therapies but none of them treated with sorafenib. The baseline serum IGF-1 mRNA levels were significantly higher in HCC patients than in the control group (p=0.04). while for IGF-1 protein no significant difference was observed (p=0.18). History of HBV infection and untreated patients for HCC had higher serum IGF-1 mRNA levels (p=0.03, and p=0.03, respectively). Poor performance status (p<0.001), viral etiology of cirrhosis (p=0.03), large tumor size (p=0.01), lower serum hemogloblin levels (p=0.03), and not be treated for HCC (p=0.001) related to worse survival. However, neither serum IGF-1 nor serum IGF-1 mRNA had significantly adverse effect on survival (p=0.53, and p=0.42, respectively). Conclusions: Serum circulating IGF-1 mRNA had diagnostic value, both serum protein and mRNA levels of IGF-1 had no prognostic value in patients with HCC.