bluuebunny/crossref_metadata_2025 huggingface dataset:
Pelvic radiotherapy in combination with radical resection of the primary tumor improves survival in patients with metastatic rectal adenocarcinoma: A national cancer database analysis (NCDB).
Authors: Renz Paul B. , Hasan Shaakir , Wegner Rodney E , Finley Gene Grant , Monga Dulabh K. , Raj Moses S. , McCormick James , Kirichenko Alexander V.
Published: January 2019

714

Background: With recent advances in systemic therapies and increased survival of patients with metastatic rectal cancer, the role of primary tumor resection may be of increased importance and is often debated. However, the role of combining radiotherapy to surgical resection in the metastatic setting is unknown. Accordingly, we utilized the NCDB to quantify survival in metastatic rectal adenocarcinoma patients with primary tumor resection with and without pelvic radiotherapy. Methods: Of the 15,643 Stage IV rectal adenocarcinoma patients receiving chemotherapy from 2004 to 2014, 4051 patients had primary tumor resection with sufficient follow up for analysis. Patients were stratified by receipt of pelvic radiotherapy (n = 1882) or no pelvic radiotherapy (n = 2169). Univariable/multivariable analyses and propensity-adjusted Cox proportional hazard ratios for survival were performed. Results: Median age was 63 years (18-90) with median follow up of 32.3 months (3.02-151.29). There were more patients with T3/T4 disease (69.6% vs 46.5%) or N1 disease (41.5% vs 27.3%) in the surgery plus radiotherapy arm. Metastatic burden was confined to one organ in 40.5% of patients and was equally distributed between radiotherapy and non-radiotherapy groups (OR 0.92; 95%CI 0.81-1.04). Median survival was 46.3 months vs. 35.3 months in favor of adding radiotherapy (p < 0.001). The 2, 5 and 10-year overall survival were 68.4%, 24.8%, and 9.5% for surgical resection alone compared to 77.2%, 39.6%, and 22.3% for surgery + radiotherapy. On multivariable analysis radiotherapy was associated with a statistically significant reduction in the risk of death (HR 0.718; 95% CI 0.661-0.780). This benefit was upheld on propensity matched analysis (HR 0.722; 95% CI 0.0665-0.784). Conclusions: Our study indicates that adding radiotherapy to surgical management of the primary tumor in patients receiving systemic chemotherapy for metastatic rectal adenocarcinoma improves survival. Prospective investigation of the management of the rectal primary tumor with chemotherapy, pelvic radiotherapy, and surgical resection is warranted.
Patterns of care and outcomes of low-lying adenocarcinoma and squamous cell carcinoma of the rectum.
Authors: Adedoyin Paul , Lee Anna , Malakhov Nikita , Kavi Ami , Sheth Niki , Garay Elizabeth , Schreiber David
Published: January 2019

715

Background: To analyze the patterns of care and survival for stage I-III squamous cell (SCC) and adenocarcinoma (AC) of the rectum from 2004-2015 based on receipt of surgery alone (S), neoadjuvant chemoradiation followed by surgery (CRT+S), surgery followed by adjuvant chemoradiation (S+CRT) and definitive chemoradiation (CRT). Methods: The NCDB was explored to identify patients diagnosed with low-lying stage I-III AC and SCC of the rectum from 2004-2015 who received S, CRT+S, S+CRT or CRT. Frequency distributions between the categorical variables were compared using the Chi-square test. Overall survival data and Kaplan-Meier curves were compared via the log-rank test stratifying the groups (AC vs. SCC) by stage and treatment. Cox proportional hazards regression models were performed to assess for covariates that had an impact on survival. Results: There were 22,227 patients included in this study, from which 21,587 (97.1%) were AC and 640 (2.9%) were SCC. Median follow-up for the entire cohort was 54 months. The median RT dose for AC was 5040 cGy and for SCC 5400 cGy. 5-year OS of AC vs. SCC in the entire cohort was 61.6% vs. 56.1%, respectively (p<0.001). The OS for AC was 51.5% for S alone, 71.1% for CRT+S, 65.6% for S+CRT, and 36.2% for CRT (p<0.001). The OS for SCC was 49.2% for surgery alone, 54.2% for CRT+S, 67.1% for S+CRT, and 65.7% for CRT (p=0.227). On multivariable Cox regression for AC, patients who received CRT+S (HR 0.61, p<0.001) or S+CRT (HR 0.67, p<0.001) had improved survival compared to S alone while those who had definitive CRT (HR 1.55, p<0.001) had worse survival. Conclusions: This is the largest case series of rectal SCC in the literature to date. Analysis suggests that SCCs of the rectum are more often treated with definitive CRT but are associated with slightly worse survival than adenocarcinoma, suggesting that perhaps surgery may need an increased utilization in this disease. [Table: see text]
FGFR2-altered gastroesophageal adenocarcinomas (GEA) are a rare clinicopathologic entity with a distinct genomic landscape.
Authors: Klempner Samuel Jacob , Madison Russell , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj Mahamed , Schrock Alexa Betzig , Lee Jeeyun , Kim Seung Tae , Chao Joseph
Published: January 2019

72

Background: Therapies directed at receptor tyrosine kinases (RTKs) in GEA have met with limited success. The small molecule FGFR2 inhibitor AZD4547 failed in a phase II biomarker-selected trial, though activity has been seen with FGFR2-directed strategies, including monoclonal antibodies. Despite observed activity, very little is known about the genomic landscape of FGFR2-altered GEA. Using a large genomic database, we sought to examine the classes of FGFR2 alterations and frequency of co-occurring alterations in GEA. Methods: 6,667 tissue specimens from unique patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: We identified a total of 269 (4.0%) FGFR2-altered cases consisting of FGFR2 amplified (amp; 209, 78% of FGFR2-altered), FGFR2 mutated (mut; 40, 15%) and FGFR2 rearranged (re, 37, 14%). There was a female predominance in FGFR2-altered cases (M:F = 1.6:1) vs FGFR wild-type (WT) (2.8:1). Cases with FGFR2amp and FGFR2re were exclusively MS-stable. The most common fusion partner was TACC2 (22%). FGFR2amp GEA had higher rates of TP53 mutation versus either FGFR2re of FGFR2mut cases (p = 4.4E-6). Co-occurring alterations in the other GEA RTK targets including ERBB2 (10%) , EGFR (8%) and MET (3%) were observed in all types of FGFR2-altered GEA. Co-occurring downstream alterations in MYC (17%), KRAS (10%) and PIK3CA (5.6%) were observed frequently in each class of FGFR2-altered GEA. The median TMB for FGFR2-altered GEA was 3.6 mut/mb, which was not significantly different from a median of 4.3 mut/mb seen in FGFR2 WT samples (p = 0.53). Conclusions: FGFR2-altered GEA is a heterogenous subgroup with approximately 20% of FGFR2-altered samples harboring concurrent RTK alterations. Putative co-occurring modifiers of FGFR2 directed therapy including oncogenic MYC, KRAS, PIK3CA alterations were also frequent, suggesting that pre-treatment CGP and combination approaches may be needed to optimize patient selection.
Long-term outcome of laparoscopic versus open total gastrectomy for advanced gastric cancer: A propensity score-matched analysis.
Authors: Lee Hayemin , Lee Junhyun
Published: January 2019

77

Background: Laparoscopic total gastrectomy (LTG) for advanced gastric cancer (AGC) is technically and oncologically challenging procedure for surgeons. The aim of this study is to compare technical safety and long-term oncologic feasibility of LTG for AGC patients compared to open total gastrectomy (OTG) using propensity score (PS)-matched analysis. Methods: Between 2004 and 2014, 185 patients (OTG: 127, LTG: 58) underwent total gastrectomy due to advanced gastric cancer. PS-matching was done using patients’ age, sex, American Society of Anesthesiologist (ASA) physical status, extent of lymph node dissection, presence of combined resection and pathological stage of gastric cancer. Comparisons were made based on surgical outcomes and long-term survival rates. Results: After PS-matching, 102 patients, respectively 51 patients for each group, were enrolled. LTG had longer tumor-free proximal resection margin (OTG 2.5 cm vs. LTG 3.0 cm, p = 0.008). Total number of retrieved lymph node and metastasized lymph node was similar in both groups. The retrieved number of lymph nodes around splenic hilum (#10 and #11d) was similar in both groups (p = 0.105). Longer operation time was required in LTG (OTG 240 min. vs. LTG 320 min, p = 0.002) but less intraoperative bleeding was observed in LTG (OTG 390 cc vs. LTG 276 cc, p < 0.001). Patients of LTG were discharged earlier than OTG (OTG 12 days vs. LTG 10 days, p = 0.043). Overall morbidity and mortality of both group was similar. Between two groups, there was not a difference in 5-year overall survival rate (OTG 56.3% vs. LTG 56.5%, p = 0.597) or disease free survival rate (OTG 59.0% vs. LTG 67.6%, p = 0.455). Conclusions: For treating proximal AGC, LTG may be a technically and oncologically safe and feasible method.
The impact of neoadjuvant chemoradiation versus chemotherapy on short and long-term outcomes among gastric carcinoma patients.
Authors: Azab Basem , Macedo Francisco Igor , Picado Omar , Franceschi Dido , Livingstone Alan S , Yakoub Danny
Published: January 2019

78

Background: There is little consensus on the use of neoadjuvant chemoradiation (NCRT) versus neoadjuvant chemotherapy (NCT) in gastric carcinoma (GC) patients. We sought to compare the outcomes of these two approaches in a large national data base. Methods: National Cancer Data Base PUF (2004-2014) of GC patients who underwent NCRT/NCT followed by resection were included. Primary outcome was overall survival (OS), secondary outcomes were pathological complete response (pCR), R0 resection and postoperative mortality. Results: A total of 4204 GC patients with NCT were included, 62% of them had additional neoadjuvant radiotherapy (NRT). NCRT had higher pCR and R0 rates [551/2613 (21%), 2314/2561 (90%)] than NCT group [148/1573 (9%), 1242/1543 (80%)], p < 0.0001. Multivariate logistic regression showed similar higher odds of pCR (OR 2.8, 95% CI 1.65-4.60, p < 0.0001) and R0 (OR 1.5, 95% CI 1.14-1.99, p = 0.004) among NCRT versus NCT. There was no significant difference in length of hospital stay, 30-day readmission rate, 30- and 90-day postoperative mortality. Median, 3- and 5-year OS for NCRT versus NCT were: (20.4 months, 24% and 11%) versus (18.3 months, 19% and 6%), p < 0.001. Univariate cox regression analysis showed superior OS with NRT (HR 0.9, 95% CI 0.80-0.91, p < 0.001). After adjusting for confounding variables, pCR (HR 0.2, 95% CI 0.18-0.24, p < 0.001) and R0 (HR 0.7, 95% CI 0.61-0.75, p < 0.001) had better OS, while NRT was not. Conclusions: NRT improved pCR and R0 rates in GC without increase in surgical morbidity/mortality. The long-term OS benefit of NRT is likely secondary to higher pCR and R0 resection.
The value of lymphadenectomy in esophageal cancer after neoadjuvant chemoradiation.
Authors: Azab Basem , Macedo Francisco Igor , Picado Omar , Ripat Caroline , Franceschi Dido , Livingstone Alan S , Yakoub Danny
Published: January 2019

79

Background: There are conflicting reports on the value of the extent of post neoadjuvant chemoradiation (NCRT) lymphadenectomy (LND) in locally advanced esophageal adenocarcinoma (E-ADC) and squamous cell carcinoma (E-SCC). We sought to study the impact of LND variables [positive and total lymph node (LN) number and LN ratio (LNR)] on oncological outcomes in these patients. Methods: The National Cancer Data Base 2004-2014 was queried for patients with NCRT followed by esophagectomy. The median examined LN number was used to divide the patients into a higher (> 12) and lower (≤ 12) LND groups. The primary outcome was overall survival (OS) and secondary outcomes were 30- and 90-day postoperative mortality. Results: A total 4708 patients were included. The median of positive, negative LN, and LNR were and (0, 11, 0%). The median and 5-year OS for higher LND group were higher than the lower LND group (39 vs. 32 months, 38% vs. 34%), p < 0.0001. OS was not significantly different among E-SCC subset or among those who achieved pathological complete response (pCR). The higher LND group had better 30- and 90-day postoperative mortality rates (61/2335 = 2.6%, 141/2308 = 6.1%) than lower LND group (86/2262 = 3.8%, 184/2251 = 8.2%), p = 0.01 and 0.001, respectively . In multivariate Cox regression analysis, higher LND group (HR 0.88, 95% CI 0.81-0.96, p = 0.004) and LNR (per 10% increase: 1.11, 95% CI 1.09-1.13, p < 0.0001) were significant predictor of OS. Conclusions: The LND (> 12 examined LN) remains as a crucial treatment goal after NCRT with potential survival benefit, especially among E-ADC and those did not achieve pCR.
Prognostic factor analysis in third-line chemotherapy for elderly patients with metastatic gastric cancer.
Authors: Hasegawa Hiroko , Iwasaki Tetsuya , Ishihara Akio , Sakakibara Yuko , Akasaka Tomohumi , Nakazuru Shoichi , Ishida Hisashi , Hirao Motohiro , Mita Eiji
Published: January 2019

82

Background: Recently, the proportion of elderly patients (pts) with metastatic gastric cancer (mGC) has increased in Japan. Survival benefits of salvage treatment after second-line chemotherapy (CTX) for mGC were shown in several prospective studies. However, the role of salvage treatment in elderly pts remains controversial. Methods: We reviewed 185 pts with mGC who received palliative CTX aged ≥ 70 years at our institution between April 2007 and March 2018. Eligibility criteria were as follows: PS 0-2, refractory to first-line and second-line CTX. The purpose of this study was to evaluate the clinicopathologic factors that affected overall survival for elderly pts with mGC, univariate and multivariate analyses were performed on the baseline factors at the beginning of third-line CTX. Results: Of all, 71 pts were eligible. Median age was 75 years (71-85). Median progression-free survival (PFS) and overall survival (OS) for third-line CTX were 3.2 and 7.5 months, respectively and an overall response rate and disease control rate were 4.2% and 43.7%, respectively. In univariate analysis, the following four factors were identified to have prognostic significance: performance status (PS) (ECOG 0–1 or 2), serum albumin level (< 3.5 or ≥ 3.5 g/dl), serum LDH level (≤ 240 or > 240 IU/l), PFS under second-line CTX (< 3 or ≥ 3 months). Multivariate analysis found three prognostic factors affecting poor survival following third-line CTX: PS of 2 (hazard ratio (HR) 8.89, 95% confidence interval (CI) 3.99–20.2; P = 0.001), serum LDH level > 240 IU/l (HR 2.75, 95% CI 1.48–5.05; P = 0.002) and median PFS under second-line CTX of < 3 months (HR 1.89, 95% CI 1.01–3.43; P = 0.045). A prognostic index was constructed, dividing pts into low- (0 factor), intermediate- (1-2 risk factors), or high- (3 risk factors) risk groups. Median OS for each group were 12.6, 6.0 and 3.0 months, respectively ( P < 0.001). Conclusions: This analysis suggests that some clinicopathologic factors might be helpful in identifying the subgroup of elderly pts most likely to benefit from third-line CTX for metastatic gastric cancer.
Prospective evaluation of a developed S-1 dosage formula based on renal function.
Authors: Mizukami Takuro , Takeuchi Masashi , Imamura Chiyo K. , Booka Eisuke , TAKEUCHI HIROYA , Kawakami Takeshi , Funakoshi Taro , Wakuda Kazushige , Aoki Yu , Hamamoto Yasuo , Kitago Minoru , Kawakubo Hirofumi , Boku Narikazu , Tanigawara Yusuke , Kitagawa Yuko
Published: January 2019

86

Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP, inhibitor of dihydoropyrimidine dehydrogenase) and potassium oxonate. Because CDHP is excreted in urine, renal dysfunction increases incidence of severe adverse drug reactions due to higher exposure of 5-FU. As approved dose of S-1 is determined by body surface area (BSA) for patients with normal renal function, dose of S-1 is practically reduced according to renal function of creatinine clearance (CLcr) estimated by the Cockcroft-Gault equation. In a previous pharmacokinetic study (n = 16), we had developed an S-1 dosage formula based on renal function achieving the target area under the concentration-time curve (AUC) of 5-FU: Dose = target AUC x (21.9 + 0.375 x CLcr) x BSA. We conducted a prospective study to evaluate and refine this formula if necessary. Methods: Thirty patients with various renal function received S-1 at dose determined by our developed formula. A series of blood samples were obtained at predefined times after the first dose to calculate the AUC of 5-FU. Predictability of the formula was evaluated by comparison between the observed and the target AUCs. Results: The observed daily AUC was ranged from 712.6 to 2868.7 ng‧h/mL in 30 patients with BSA in the range of 1.14-1.84 m2 and CLcr in the range of 23.8-96.4 mL/min. Eighteen patients of them achieved the target AUC (1447.8 ± 545.4 ng‧h/mL). Since population pharmacokinetic analysis using combined pharmacokinetic data of 30 patients in this study and 16 patients in the previous study demonstrated that clearance of 5-FU is significantly lower in female than in male, the S-1 dosage formula was refined including gender as an additional factor: Dose = target AUC × (14.5 + 8.23 x GENDER [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms showing recommended daily dose of S-1 were proposed for males and females taking into account tablet strengths. Conclusions: The refined formula for determining S-1 dosage on the basis of renal function, BSA and gender can be applied to clinical practice to ensure efficacy and safety for cancer patients treated with S-1. Clinical trial information: UMIN 000023880.
Feasibility of endoscopic resection in early gastric cancer with lymphovascular invasion.
Authors: Lee Jun Haeng , Lee Hyuk , Kim Jae J
Published: January 2019

87

Background: Lymphovascular invasion (LVI) is associated with the risk of lymph node metastasis (LNM) and poor survival in gastric cancer patients. However, it is unclear whether LVI is a noncurative criteria component in all patients. We evaluated the risk factors of LNM in LVI-positive early gastric cancer (EGC) patients and identified a subgroup with a negligible LNM risk to assess the feasibility of endoscopic resection in these patients. Methods: The clinicopathologic and survival data of patients undergoing surgery for gastric cancer were reviewed; LVI-positive EGC patients were selected. Logistic regression analysis was used to test the associations of potential risk factors with LNM; Kaplan-Meier analysis was used to compare survival curves. Results: LVI was detected in 1,243 (15.5%) patients. In the multivariate logistic analysis, larger tumor size (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.16-1.31; P < 0.001), presence of ulcer (OR, 1.80; 95% CI, 1.15-2.82, P = 0.010), undifferentiated histology (OR, 1.64; 95% CI, 1.25-2.16; P < 0.001), submucosal invasion (OR, 2.28, 95% CI, 1.38-3.76, P = 0.001), middle (OR, 2.12; 95% CI, 1.26-3.55, P = 0.004) or lower third location (OR, 2.28; 95% CI, 1.32-3.60, P = 0.002), and younger age (OR, 0.98; 95% CI, 0.97-0.99; P = 0.002) independently predicted LNM in LVI-positive EGC patients. LVI-positive patients fulfilling the absolute endoscopic resection criteria did not have LNM, and there was no significant difference in the overall (P = 0.928) and disease-specific survival (P = 0.821) between these patients and those with LVI-negative EGC. Conclusions: Additional surgery after endoscopic resection might be unnecessary in LVI-positive patients meeting the absolute criteria for endoscopic resection.
Nutrition and exercise patterns in survivors of esophageal and gastroesophageal junction (EGEJ) cancers.
Authors: Jain Rishi , Ramamurthy Chethan , Sheng Jennifer Y. , Granina Evgenia , Lu Xiaoning , Yu Daohai , Abbas Abbas E. , Meyer Joshua E. , Dotan Efrat , Fang Carolyn Y , Denlinger Crystal S.
Published: January 2019

89

Background: While obesity is a risk factor for EGEJ, malnutrition is common at diagnosis (dx) and can be exacerbated by neoadjuvant therapy (NAT) and esophagectomy. Little is known regarding nutrition and exercise patterns of EGEJ cancer survivors. Methods: A survey of EGEJ survivors > 12 months from esophagectomy was conducted. Pts were identified using institutional tumor registry. The Dillman mailed survey method was used. Questionnaires regarding health behaviors were employed: Godin Leisure-Time Exercise [GLTQ], Cancer Appetite and Symptom [CASQ], Nutritional Self-Efficacy (NSEQ). Chart review included demographics, pt characteristics and therapy received. Spearman correlation, Wilcoxon and Fisher’s tests assessed relationships between groups or variables. Results: Forty one of 140 eligible pts (29%) returned questionnaires and had surgery between 1991-2014. Median age was 69 and 78% were male. Most (83%) had adenocarcinoma. On presentation, 73% had clinical stage II or III disease and 76% received NAT. Median time from dx was 5 years (range 2-25). Mean weight loss from dx to current was 38 lbs. Mean BMI (kg/m2) was 29.52 at dx and 24.15 at most recent clinic visit. Obesity was present in 37% of pts at dx, but only 7% of survivors. Mean health behavior scores (SD): GLTQ 22.10 (22.93), CASQ 31.74 (6.66), and NSEQ 11.39 (4.03). Age, marital status, gender, education, and income were not associated with GLTQ, CASQ or NSEQ. Sedentary lifestyle (SL) with GTLQ score < 14 was present in 46% of survivors and associated with overweight BMI (mean 26.7 for SL vs 23.7 for non-SL; p = 0.04). There was a significant positive correlation between current BMI and NSEQ score (r = 0.68; p = 0.03). Conclusions: Many EGEJ cancer pts present with obesity but subsequently lose weight after curative therapy. The mean CASQ score in our population is similar to other GI cancer populations, suggesting that residual symptoms persist years after treatment ends. There is a high prevalence of SL in survivors which is associated with being overweight. Higher levels of nutrition self-efficacy were also associated with a higher current BMI. Future studies should define strategies to optimize nutrition and exercise habits in EGEJ cancer survivors.
Multicenter prospective observational study of QoL after palliative surgery for patients with bowel obstruction caused by peritoneal dissemination of gastric cancer.
Authors: Ito Yuichi , Fujitani Kazumasa , Sakamaki Kentaro , Ando Masahiko , Kawabata Ryohei , Tanizawa Yutaka , Yoshikawa Takaki , Yamada Takanobu , Hirao Motohiro , Yamada Makoto , Hihara Jun , Fukushima Ryoji , Choda Yasuhiro , Kodera Yasuhiro , Teshima Shin , Shinohara Hisashi , Kondo Masato
Published: January 2019

90

Background: Patients with peritoneal dissemination of gastric cancer have poor oral intake caused by bowel obstruction. Palliative surgery has often been undertaken to improve quality of life (QoL), but there is no prospective study on palliative surgery. Methods: We prospectively examined the significance of palliative surgery for patients with poor oral intake caused by peritoneal dissemination of gastric cancer using a patient-reported QoL measures. Eligibility criteria included histologically proven primary gastric adenocarcinoma presenting with bowel obstruction caused by peritoneal dissemination; presence of non-curable factors; extremely poor or no oral intake requiring parenteral nutrition. Patients underwent palliative surgery by small intestine/colon resection, small intestine/colon bypass or ileostomy/colostomy for bowel obstruction. The primary endpoint was change in QoL assessed at baseline, 14 days, 1 month and 3 months following surgical palliation by means of the Euro QoL Five Dimensions (EQ-5D) questionnaire and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire gastric cancer module (QLQ-STO22). Secondary endpoints were postoperative improvement in oral intake and surgical complications. Results: Between May 2013 and March 2018, 63 patients (33 bypass and 28 stoma, 3 exploratory laparotomy) were enrolled from 14 institutions. The mean EQ-5D utility index baseline score of 0.6 remained consistent. Gastric-specific symptoms mostly showed statistically significant improvement from baseline. 42 patients (67%) were able to eat solid food 2 weeks after palliative surgery and 36 patients (57%) tolerated it for 3 months. The rate of overall morbidity of grade III or more according to the Clavien–Dindo classification was 15.8 per cent (10 patients) and the 30-day postoperative mortality rate was 3.2 per cent (2 patients). Conclusions: In patients with bowel obstruction caused by peritoneal dissemination of gastric cancer, palliative surgery maintained QoL while improving solid food intake, with acceptable operative morbidity and mortality rate. Clinical trial information: 000023495.
Long-term effects of an oral elemental nutritional supplement on post-gastrectomy body weight loss in gastric cancer patients.
Authors: Nishikawa Kazuhiro , Kimura Yutaka , Kishi Kentaro , Inoue Kentaro , Matsuyama Jin , Akamaru Yusuke , Tamura Shigeyuki , Kawabata Ryohei , Kawada Junji , Yanagimoto Yoshitomo , Kawase Tomono , Takagi Mari , Fukui Junichi , Takeno Atsushi , Fujii Chika , Yamada Takeshi , Shimokawa Toshio , Imamura Hiroshi
Published: January 2019

94

Background: Postoperative weight loss could have a negative effect on quality of life and prognosis of gastric cancer patients. We have already shown that daily nutritional intervention with an oral elemental diet (ED) attenuated the short-term postoperative percentage of body weight loss (% BWL) in post-gastrectomy patients, especially in underwent total gastrectomy (TG). This study was conducted to evaluate the postoperative long-term BWL of nutritional intervention. Methods: This study was conducted in a cohort of consecutive patients which were randomly allocated to receive the control or ED diet in the original trial. Control group received the regular diet alone after gastrectomy, while ED group received 300 kcal of ED plus their regular diet for 6–8 weeks. The primary endpoint was the % BWL from the presurgical bodyweight to that at 1 year after surgery by surgical type. Secondary endpoints were changes in nutrition-related blood parameters. Results: One hundred six of registered patients in the original trial were eligible for efficacy analyses. There was not significant difference in the % BWL between the two groups (9.13 ± 7.72 % vs. 7.09 ± 7.49 %, respectively; p = 0.171). The % BWL at one year after surgery was significantly lower in ED group than in control group among patients who underwent TG (n = 19 and 17, respectively; 9.66 ± 5.98% vs. 15.11 ± 6.78%, respectively; p = 0.015), but not in patients who underwent distal gastrectomy (DG) (n = 38 and 32, respectively; 5.81 ± 7.91% vs. 5.96 ± 6.20%, respectively; p = 0.933). A multivariate analysis revealed that only type of gastrectomy was independently associated with % BWL at 1 year after surgery. And in total gastrectomy, ED administration was independently associated with % BWL. Total lymphocyte count in ED group increased more than that in control group at 1 year after surgery. Conclusions: Nutritional intervention with ED at 300 kcal per day for 6–8 weeks reduced body weight loss at 1 year as well as 6-8 weeks after surgery in patients who underwent total gastrectomy. Clinical trial information: 000023455.
Predictors of distress among individuals with gastric cancer.
Authors: Olson Julie , McManus Shauna , Miller Melissa F. , Yuen Eva , Denlinger Crystal S. , Stein Kevin
Published: January 2019

96

Background: With improving survival, gastric cancer patients face long-term quality of life concerns, including management of persistent symptoms and maintenance of social activity. We examined psychosocial distress and areas of concern in a national sample of gastric patients. Methods: Using data from the Cancer Support Community’s Cancer Experience Registry, our sample included 72 patients with a primary diagnosis of stomach (54%), esophageal (36%), or GIST (11%) cancer. Participants reported cancer-related distress using CancerSupportSource®, a 25-item tool with a 2-item anxiety risk subscale, 2-item depression risk subscale, and four additional subscales measuring symptom burden, body/healthy lifestyle, healthcare team communication, and relationship concerns. We used logistic regression to estimate which of these subscales influence risk for clinically significant anxiety and depression controlling for demographic/clinical variables that were associated with anxiety and depression risk in bivariate analysis. Results: Our sample was 62% female, 80% White, and averaged 58 years of age ( SD = 13). 24% were diagnosed less than one year before participating. 33% were ever diagnosed as metastatic. 42% had received surgery. 60% were at risk for clinically significant anxiety and 50% for clinically significant depression. In regression models, relationship concerns were significantly associated with greater risk for anxiety ( OR = 1.5; p < .05) and depression ( OR = 1.7; p < .05). Greater concern with healthcare team communication was associated with anxiety risk in bivariate analysis ( r = .41, p < .01), but the association was only a trend in the multivariate model ( OR = 1.4; p = .06). Similarly symptom burden concern was associated with depression risk in bivariate analysis ( r = .57, p < .01) but only a trend in multivariate analysis ( OR = 1.2; p = .06). Conclusions: Relationship concerns predicted risk for clinically significant anxiety and depression among stomach, esophageal, and GIST patients. Healthcare team communication and symptom burden concerns were also associated with anxiety and depression risk. Results highlight the need for constructive patient-provider communication, particularly around relationships and symptoms. Clinical trial information: NCT02333604.
Locally advanced gastric cancer (LAGC): Does histology suggest strategy in PAN-cancer Era?
Authors: Zurlo Ina Valeria , Calegari Maria Alessandra , Orlandi Armando , Strippoli Antonia , Pozzo Carmelo , Bagalà Cinzia , Garufi Giovanna , Di Dio Carmela , Barone Carlo , Bria Emilio , Basso Michele
Published: January 2019

97

Background: Surgery is the only potentially curative treatment for LAGC. Evidences suggest that perioperative CT (pCT) plus surgery is superior to surgery alone, whereas studies on adjuvant CT (aCT) are controversial. Guidelines recommend a pCT approach in pts with stage II/III, nevertheless in real-life many pts receive immediate surgery followed by aCT. Histology influences both survival and pathological response with worse prognosis among diffuse LAGC. No trial has compared pCT and aCT or investigated the impact of histology on the outcome of these different approaches. We hypothesized that histology may predict a different benefit from CT administered in the two settings, allowing to define the optimal strategy. We performed a study comparing the two approaches according to histology. Methods: We retrospectively analyzed pts with stage II/III LAGCs treated at our Institution between Jan-09 and Jan-17. The objective of the study was to evaluate the impact of histology (intestinal and diffuse) on survival according to strategy approach (pCT vs aCT). Primary endpoints were DFS and OS. Results: 81 pts had diffuse LAGC (29 received pCT, 52 aCT) and 60 had intestinal LAGC (32 received pCT, 29 aCT). In the intestinal cohort both DFS and OS were significantly higher in pts treated with pCT compared to aCT (DFS: HR 0.3, p = 0.02; OS: HR 0.3, p = 0.03). On the contrary in the diffuse cohort both DFS and OS were significantly lower in pts receiving pCT compared to those receiving aCT (DFS: HR 2.4, p = 0.0014; OS: HR 2.6, p = 0.0012). Conclusions: Our study, although retrospective and small-sized, shows that the survival benefit of pCT is limited to intestinal LAGC, whereas in diffuse LAGC the administration of pCT appears detrimental. Indeed, diffuse LAGC is known to be chemoresistant and pCT might delay surgery allowing metastasization. Despite the arising of recent molecular classification, still far from modifying clinical practice, histotype might represent an easy factor to discriminate pts benefitting from pCT (intestinal) to those in whom upfront surgery might be recommended (diffuse). Our hypothesis needs to be confirmed in prospective trials.
Dose escalation and expansion cohort study for DS-8895a in patients with advanced solid tumors.
Authors: Satoh Taroh , Shitara Kohei , Iwasa Satoru , Yamaguchi Kensei , Muro Kei , Komatsu Yoshito , Nishina Tomohiro , Esaki Taito , Hasegawa Jun , Kakurai Yasuyuki , Kamiyama Emi , Nakata Tomoko , Nakamura Kota , Hyodo Ichinosuke
Published: January 2019

99

Background: Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface of many tumors and is associated with poor prognosis, suggesting EPHA2 as a target for cancer therapy. DS-8895a is an afucosylated, humanized anti-EPHA2 IgG1 monoclonal antibody with potent cytotoxicity. We report results from a phase I clinical trial to determine safety, tolerability, and pharmacokinetics (PK) of DS-8895a in Japanese patients with advanced solid tumors (NCT02004717). Methods: Step 1 (dose escalation cohort) had patients with advanced solid tumors and comprised of six dose levels (0.1–20 mg/mL, intravenous infusion, every 2 weeks [Q2W]) with a 28-day dose limiting toxicity (DLT) evaluation period. Step 2 (expansion cohort) patients had gastric or esophageal cancer confirmed to be EPHA2 positive by immunohistochemistry. Dose level in Step 2 was determined based on results obtained in Step 1. We evaluated safety, PK, potential biomarkers including circulating NK cells and cytokines, and tumor response. Results: Maximum tolerated dose was not reached in Step 1 (n = 22). DS-8895a was administered at 20 mg/kg Q2W in Step 2 (n = 15). Among 37 patients in the safety analysis set, adverse events (AEs) were reported in 97.3% (64.9% drug-related); 35.1% presented grade ≥ 3 AEs (8.1% drug-related). Dose delay and study discontinuation due to AEs (treatment related: grade 4 platelet decrease, hypoesthesia, hypotension, peripheral coldness, nausea, and vomiting) were observed in one and four patients (20 mg/kg), respectively. Infusion-related reactions occurred in 51.4% of patients resulting in 10 dose interruptions with one discontinuation. Serum inflammatory cytokines were transiently increased 4 h from the end of infusion drug administration. Serum DS-8895a maximum and trough concentrations increased dose-dependently. Biomarkers had no apparent relationship to best overall response. Seven patients in Step 1 achieved stable disease; in Step 2, six patients achieved stable disease and one patient achieved partial response. Conclusions: DS-8895a was safe and well tolerated up to 20 mg/kg. The PK of DS-8895a was dose-dependent as expected. Clinical trial information: NCT02004717.
Multicenter open-label phase II trial to evaluate nivolumab and ipilimumab for second line therapy in elderly patients with advanced esophageal squamous cell cancer (RAMONA).
Authors: Meindl-Beinker Nadja M , Hartel Nicolai , Maenz Martin , Betge Johannes , Ebert Matthias Philip
Published: January 2019

TPS174

Background: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients (pts) and impact of 2nd line chemotherapy is poorly defined. In line with recent data demonstrating effectiveness of checkpoint inhibitors Nivolumab (Nivo) and Ipilimumab (Ipi) in squamous cell carcinoma pts, combined Nivo/Ipi therapy will be assessed as 2nd line therapy of advanced ESCC in elderly pts. Methods: RAMONA is a multicenter open-label phase II trial (NCT03416244). Eligibility and geriatric status of the pts will be assessed by the G8 screening tool and the Deficit Accumulation Frailty Index (DAFI). Upon safety assessment after a three cycle run-in phase of Nivo (240 mg Q2W), eligible pts will be escalated to Nivo (240 mg Q2W)/Ipi (1 mg/kg Q6W) combination therapy. The other pts will remain on Nivo only. The primary objective of this trial is to demonstrate a significant survival benefit of the Nivo/Ipi combination therapy in advanced ESCC compared to historical data of standard chemotherapy regimens. Primary endpoint is overall survival (OS); secondary endpoints are tumor response, PFS, safety and quality of life (QoL). The trial has a 90% Power to detect a hazard ratio of 0.68 at a one-side significance level of alpha = 0.05 under the assumption of exponential survival. This corresponds to an increase of the 1-year OS rate by a margin of 13% compared to historical controls for standard chemotherapy (i.e. 30% vs 17%). Subjects are accrued for a period of 12 month. Follow-up continues for 24 month after the last subject is added. Including a sample size increase to compensate for uninformative drop-outs a total of n = 75 subjects will be recruited. The primary endpoint will be assessed using a one-sample log-rank test. A particular study objective is the evaluation of the tolerability of Nivo as single agent and in combination with Ipi in terms of QoL. Therefore time to QoL deterioration will be determined. 18 pts have been enrolled by mid of September 2018. RAMONA also includes translational research to identify predictive biomarkers, establish organoid cultures from tumor tissues and assess the utility of microbiome analyses for response prediction. Clinical trial information: NCT03416244.
bTMB-High Basket trial: A multicenter phase II trial of nivolumab monotherapy in patients with advanced gastrointestinal cancers with high blood tumor mutational burden (bTMB).
Authors: Nakamura Yoshiaki , Komatsu Yoshito , Kato Ken , Shinozaki Eiji , Bando Hideaki , Kato Takeshi , Nishina Tomohiro , Esaki Taito , Nomura Shogo , Ogawa Gakuto , Sugama Ayako , Fukutani Miki , Sato Akihiro , Odegaard Justin , Kuwata Takeshi , Matsushima Kouji , Nakatsura Tetsuya , Nakajima Hiromichi , Yoshino Takayuki
Published: January 2019

TPS179

Background: Tumor mutational burden (TMB) is an emerging biomarker for immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Analysis of circulating tumor DNA (ctDNA) has been reported to effectively identify patients likely to respond to ICIs by effectively and non-invasively evaluating the TMB in the tumor in NSCLC and gastric cancer. Methods: We are conducting an investigator-initiated multicenter phase II basket trial to investigate efficacy and safety of nivolumab monotherapy in patients with advanced gastrointestinal (GI) cancers with high bTMB identified by ctDNA analysis as part of the Nationwide Cancer Genome Screening Project (SCRUM-Japan GI-SCREEN). Eligibility criteria include histologically confirmed unresectable or recurrent GI malignancies; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and high bTMB identified by a 73-gene sequencing ctDNA panel (Guardant360) regardless of microsatellite instability status. Patients will be enrolled into one of four disease-specific cohorts (colorectal, gastric, esophageal, and other GI cancer cohort), and receive intravenous nivolumab monotherapy of 360 mg every 3 weeks. The bTMB score is calculated by adjustment of mutation count by tumor fraction, and tentative bTMB level cut-offs were determined according to objective response rate (ORR) reported for ICI treatment for each tumor subtype in previous trials. The trial will utilize a two-stage design with a Bayesian hierarchical model, and tentative bTMB level cut-off will be re-assessed in the first stage. Primary endpoint in each stage is the disease control rate at 6 week and the ORR assessed by investigators per RECIST v1.1, respectively. Target sample size is determined as 70 in total so that the statistical power in each disease-specific cohort calculated based on a Bayesian posterior distribution attains 70 to 80% with one-sided alpha level in each cohort of approximately 10%. For biomarker analysis, tumor tissue and ctDNA will be serially collected and analyzed by whole-exome, transcriptome, and T cell receptor sequencing. This trial was initiated since September 2018. Clinical trial information: UMIN000033182.
Phase I/II trial of perioperative avelumab in combination with chemoradiation in the treatment of stage II/III resectable esophageal cancer.
Authors: Uboha Nataliya Volodymyrivna , Maloney James D. , McCarthy Daniel , Deming Dustin A. , LoConte Noelle K. , Matkowskyj Kristina , Eickhoff Jens C. , Mulkerin Daniel , DeCamp Malcolm M. , Lubner Sam Joseph , Turk Anita Ahmed , Bassetti Michael Frederick
Published: January 2019

TPS181

Background: Neoadjuvant chemoradiation (CRT) followed by resection is the standard treatment for patients with stage II and III esophageal cancer. However, about 50% of patients develop recurrent disease after treatment completion. Patients with residual disease at the time of resection (~ 75%) and especially those with persistent lymph node involvement have the worst prognosis. Hence, novel strategies are needed to improve outcomes. A number of preclinical and clinical studies demonstrated synergism between radiation and immunotherapy. In esophageal cancers, CRT has been shown to alter tumor microenvironment with upregulation of PD-L1 expression and increase in CD8+ T lymphocyte infiltration. Immune checkpoint inhibitors have demonstrated promising activity in metastatic gastroesophageal cancer. Utilizing these agents in earlier disease stages and combining with chemoradiation may increase their efficacy by taking advantage of potential synergism with radiation. This trial will evaluate safety and efficacy of avelumab in combination with CRT in resectable esophageal cancer. Methods: This is a two-part phase I/II clinical trial evaluating safety and efficacy of perioperative avelumab plus CRT in patients with resectable esophageal cancer. This trial will enroll a total of 24 subjects with untreated resectable esophageal cancer (including gastroesophageal junction). Part 1 will be a run-in phase that enrolls 6 patients for safety evaluation. Part 2 will enroll 18 additional patients for efficacy and additional safety evaluation. The primary endpoint for the phase II component is the pathological complete response rate. Subjects will receive neoadjuvant radiation (41.4 Gy in 23 fractions) with weekly carboplatin (AUC 2) and paclitaxel (50 mg/mg2). Three doses of avelumab (10 mg/kg, every 14 days) will be administered starting on day 29 of treatment, to coincide with the last chemotherapy dose. Esophagectomy will be performed ~ 8 weeks after CRT completion. Subjects will receive 8 doses of avelumab after resection. This study is actively enrolling patients at University of Wisconsin. Clinical trial information: NCT03490292.
HGCSG 1603: Phase II study of ramucirumab and irinotecan combination therapy as second-line treatment in patients with metastatic or advanced gastric cancer.
Authors: Ishiguro Atsushi , Kawamoto Yasuyuki , Yuki Satoshi , Kobayashi Yoshimitsu , Harada Kazuaki , Sogabe Susumu , Tsuji Yasushi , Nakano Shintaro , Sawada Kentaro , Muranaka Tetsuhito , Nakatsumi Hiroshi , Dazai Masayoshi , Sasaki Takahide , Eto Kazunori , Nakamura Michio , Muto Osamu , Sakata Yuh , Sakamoto Naoya , Komatsu Yoshito
Published: January 2019

TPS183

Background: As second-line chemotherapy for gastric cancer, a survival benefit has been shown in several clinical trials. Irinotecan and taxanes are recommended as second-line regimen. However, therapeutic outcomes have remained unsatisfactory and more effective treatment are expected. Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody that prevents ligand binding of VEGF-A, VEGF-C, and VEGF-D and the receptor-mediated pathway activation in endothelial cells, subsequently inhibiting neovascularization. In the REGARD study, RAM monotherapy for previously treated advanced gastric or gastro-esophageal junction adenocarcinoma improved median overall survival (mOS) compared with placebo. Moreover, in the RAINBOW study, RAM plus paclitaxel (PTX) versus placebo plus PTX, mOS showed significantly longer in RAM plus PTX group than in placebo plus PTX group. In contrast, there are no data on the efficacy of RAM and irinotecan in the second-line treatment for gastric cancer. The WJOG 4007 study demonstrated an equivalent efficacy between irinotecan and PTX. In this study, we propose to examine the efficacy of RAM plus irinotecan. Methods: This study is carried out as a multicenter, non-randomized, single arm, prospective, phase II study. The patients with metastatic or advanced gastric cancer that is refractory or intolerance to primary chemotherapy are eligible for this study. RAM and irinotecan combination therapy is administered every two weeks, which is continued until progression or emergence of adverse events requiring discontinuation. The primary endpoint is progression-free survival rate at six months, and the secondary endpoints are OS, progression-free survival, response rate, safety, and dose intensity for each drug. A total of 35 cases areplanned for registration. This study is registered with the University Hospital Medical Information Network. Clinical trial information: UMIN000030372.
GA CPI 613: A single arm, open-label phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel for patients with locally advanced or metastatic pancreatic cancer.
Authors: Alistar Angela Tatiana , Morris Bonny , Harrison Lawrence , Bickenbach Kai , Ginder Nancy , Proulx Jonathan , McIlwain Laura , Luther Sanjeev
Published: January 2019

TPS459

Background: Pancreatic cancer is the third leading cause of cancer death in the USA. The most effective treatments for first-line metastatic pancreatic cancer are FOLFIRINOX and gemcitabine plus nab-paclitaxel, which provide a median overall survival of 11·1 months and 8·5 months with moderate toxicity. Safer and more effective treatments are needed. The glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as Nab-Paclitaxel. CPI- 613 is a novel antimitocondrial developed by Rafael Pharmaceuticals that showed preclinical activity in pancreatic cancer cell lines as well as promising clinical activity in combination with modified FOLFIRINOX in patients with stage IV pancreatic cancer. Preclinical data suggests possible synergy of CPI- 613 with nab-paclitaxel. Methods: This is a single arm, open-label, nonblinded phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer. Key eligibility criteria include: histologically or cytologically documented and measurable locally advanced or metastatic pancreatic adenocarcinoma, ECOG performance status 0-2, first line treatment for both locally advanced or metastatic. CPI-613 will be infused intravenously with a starting dose of 500 mg/m2 followed by 125 mg/m2 nab-paclitaxel and 1,000 mg/m2 gemcitabine on day 1, 8, 15 of a 28-day cycle. The study is comprised of a two-stage dose-escalation schema to evaluate the MTD of CPI-613. At least six months of treatment is planned for patients who have a response. Primary endpoint of the study is MTD of CPI 613 when combined with gemcitabine and nab-paclitaxel and secondary endpoints of the study are treatment related adverse events, CR and PR. This study was initiated in February 2018 at Atlantic Health System and within first seven months of the study, 11 out of 24 planned patients have been enrolled. Clinical trial information: NCT03435289.