bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of capecitabine plus oxaliplatin for advanced colon cancer: A public hospital experience.
Authors: Luu Carrie , Velasquez Johnathan , Kaji Amy , Stabile Bruce E. , Petrie Beverley A , Kumar Ravin , Caton Amy , Kim Joseph , Chen Steven L. , Lee Byrne
Published: February 2017

570

Background: Adjuvant chemotherapy has been shown to improve disease-free survival (DFS) and overall survival (OS) in advanced colon cancer (CC). 5-fluorouracil (5-FU)/leucovorin and oxaliplatin is the first line therapy for stage II and III CC. Due to systematic and financial constraints imposed by administering infusional 5-FU, this agent is not available at our institution. Capecitabine plus oxaliplatin (CAPOX) has been studied by others as a possible alternative. We report our experience with CAPOX in the adjuvant treatment of CC patients in a large, public hospital. Methods: A retrospective study of 142 patients with CC who received CAPOX from 2005 to 2011 was performed. Data on patient demographics, treatment, disease recurrence, and survival were analyzed. Survival was assessed by the Kaplan-Meier method. The Cox regression model was used for multivariate analysis. Results: There were 60 female and 82 male patients with a mean age of 54 years (range 21-80). 57 patients were diagnosed with stage II CC and 85 with stage III CC. All patients with stage II and stage III disease underwent curative-intent surgical resection, except for one patient, who refused surgery. 14/141 operations (10%) were performed emergently. Mean follow-up was 36 months (range 2-85 months). The 3-year OS rates were 91% and 81% for stages II and III, respectively. The 3-year DFS rate was 74% for stage II and 66% for stage III. By multivariate analysis, only cancer stage was predictive of overall survival. Conclusions: CAPOX is an effective treatment for stage II and III CC in the adjuvant setting. Our study supports recent evidence demonstrating the efficacy of CAPOX in CC. Ease of administration and improved utilization of resources make it an ideal regimen for public hospital facilities.
Oxaliplatin and capecitabine initially concomitant to radiotherapy then administered in the resting period in high-risk locally advanced rectal cancer.
Authors: Ding Pei-Rong , Gao Yuan-Hong , An Xin , Chen Gong , Wang Feng-Hua , Cai Mu-Yan , Zeng Zhi-Fan , Kong Ling-Heng , Lin Jun-Zhong , Wu Xiaojun , Lu Zhen-Hai , Li Li-Ren , Wan De-Sen , Pan Zhi-Zhong
Published: February 2017

581

Background: Although neoadjuvant chemoradiotherapy (CRT) has dramatically reduced the risk of local recurrence in locally advanced rectal cancer (LARC), it fails to reduce the risk of systemic failure. To enhance systemic control, we develop an alternative approach, combining intense chemotherapy using Oxaliplatin and Capecitabine (XELOX regimen) concomitant to radiation and extending the chemotherapy regimen to the resting period (consolidation chemotherapy) for high risk LARC. The aim of the present study was to evaluate the efficacy and toxicities of this strategy. Methods: Patients with high risk LARC were treated with CRT. Two cycles of XELOX regimen was administered concomitant to radiation. Then an additional cycle of the same regimen was extended to the resting period one week after completion of chemoradiation. Tumor response, toxicities associated with CRT and consolidation chemotherapy, and surgical complications were recorded. Results: Thirty-six patients with high risk LARC were identified treated with the strategy from 2010 to 2012. All patents completed the planned dose of radiation and concurrent chemotherapy, and two patient was unable to complete the consolidation chemotherapy because of grade 3 toxicities. Grade 3 acute toxicities were 2.8% leucopenia, 2.8% diarrhea, and 2.8% radiation dermatitis. All patients underwent optimal surgery with TME, among whom sphincter-saving procedure was performed in 27 patients (75%). There was no peri-operative mortality in this cohort. Seven patients (19.4%) developed postoperative complications. Complete regression (pCR), major regression (nearly pCR), and moderate or minimal regression were achieved in 13 (36.1%), 16 patients (44.4%), and 7 patients (19.5%), respectively. Conclusions: The preliminary results suggest that XELOX regimen concomitant to radiation and extended to the “resting period” after radiation completion are well tolerated. This strategy is associated with high pCR and nearly pCR rates. The promising results warrant further investigation of the impact of consolidation chemotherapy following CRT for LARC in future clinical trials.
How do first-line treatment and other factors affect the receipt of second-line treatment for elderly metastatic colon cancer patients?
Authors: Zheng Zhiyuan , Onukwugha Ebere , Hanna Nader , Reese Emily S , Seal Brian S. , Mullins C. Daniel
Published: February 2017

592

Background: Metastatic colon cancer (mCC) patients might receive multiple lines of chemotherapy to improve survival or quality of life. However, factors associated with receipt of 1st and 2nd line treatment (TX) haven’t been fully investigated. Methods: Elderly (65+) SEER-Medicare patients diagnosed with mCC in 2003-2007 were followed until death or 12/31/2009 to examine factors for receipt of 1st and 2nd line TX. A Cox regression framework and inverse probability weighting (IPW) method were used to adjust for patients’ informative (death) and non-informative (dropout or end-of-study) censoring histories. Additionally, we controlled for patients’ 1st line TX in the IPW to determine factors for receipt of 2nd line TX. Results: Of 7,951 mCC patients, 3,266 patients received at least 1 line TX, and 1,440 went on to 2nd line TX. For 1st line TX, significant clinical factors were CCI = 2 (HR = 0.86; p = 0.02), oxygen use (HR = 0.74; p = 0.04), walking aid use (HR = 0.58; p = 0.02), and wheel chair use (HR = 0.50; p < 0.01); significant demographic characteristics were age groups 95+ (HR = 0.11; p < 0.01), 85-94 (HR = 0.24; p < 0.01), 75-84 (HR = 0.70; p < 0.01), as compared to 65+-74, female (HR = 1.12; p < 0.01), married (HR = 1.43; p < 0.01), and African American (AA) (HR = 0.80; p < 0.01); significant factors for socio-economics status were state buy-in status (SBI) (HR = 0.97; p < 0.01), and zip code level household median income (HR = 1.03; p < 0.01). For 2nd line TX, significant factors were hospital bed use (HR = 2.82; p = 0.05), oxygen use (HR = 0.68; p = 0.02), age group 85-94 (HR = 0.718; p = 0.02) as compared to 65+-74, and days delayed for 1stline TX (HR = 0.998; p < 0.01). Conclusions: Various factors were associated with receipt of 1st line TX. Conditional on the receipt of 1st line TX, many factors became insignificant for receipt of 2nd line TX, such as age, female, marriage status, AA, SBI, and zip code level household income. Hospital bed use reduced the probability of receipt of 1st line TX, but increased the probability of receipt of 2nd line TX.
Randomized phase III study of S-1 plus oxaliplatin versus S-1 plus cisplatin for first-line treatment of advanced gastric cancer.
Authors: Higuchi Katsuhiko , Koizumi Wasaburo , Yamada Yasuhide , Nishikawa Kazuhiro , Gotoh Masahiro , Fuse Nozomu , Sugimoto Naotoshi , Nishina Tomohiro , Amagai Kenji , Chin Keisho , Niwa Yasumasa , Negoro Yuji , Imamura Hiroshi , Tsuda Masahiro , Yasui Hirofumi , Fujii Hirofumi , Yamaguchi Kensei , Yasui Hisateru , Hamada Chikuma , Hyodo Ichinosuke
Published: February 2017

60

Background: S-1 plus cisplatin (SP) is the standard first-line treatment regimen for advanced gastric cancer (AGC) in Japan. S-1 plus oxaliplatin (SOX) for AGC showed promising efficacy and safety outcomes in the previous phase II study. We aimed to evaluate the non-inferiority of SOX to SP for AGC. Methods: Patients (Pts) with unresectable advanced or recurrent gastric cancer were randomly assigned to SOX (oral S-1 40 mg/m2 b.i.d. for 14 days plus oxaliplatin 100 mg/m2 iv on day 1, q3w) or SP (oral S-1 40 mg/m2 b.i.d. for 21 days plus cisplatin 60 mg/m2iv on day 8, q5w). Eligibility criteria included PS 0-2, age 20 years or older, adequate major organ functions. Primary endpoints were non-inferiority in progression-free survival (PFS) as compared with SP and relative efficacy in overall survival among the groups. Main secondary endpoints included response rate (RR), safety, and length of hospital stay (LOS) per cycle. The primary analysis for PFS was planned after 456 PFS events occurred. Results: Six hundred eighty five pts enrolled were randomly assigned to SOX (n=342) or SP (n=343) between Jan. 2010 and Oct. 2011. The evaluable pts for safety and efficacy were 673 (SOX/SP, 335/338) and 642 (SOX/SP, 318/324), respectively. The median PFS was 5.5 months for SOX vs. 5.4 months for SP (hazard ratio [HR] =1.004; 95% confidence interval [CI], 0.840-1.199). The upper limit of the 95% CI for HR was not above the margin of 1.30 and met the predefined criterion for non-inferiority. RR was 55.7% for SOX and 52.2% for SP (P=0.374). Grade 3 or 4 toxicities in SOX v. SP were neutropenia 19.5% v. 41.5%, thrombocytopenia 9.5% v. 10.4%, febrile neutropenia 0.9% v. 6.9%, hyponatremia 7.1% v. 15.2%, sensory neuropathy 4.4% v. 0%, respectively. Serious adverse events were occurred in 29.3 % for SOX and 37.9% for SP. Eight treatment-related deaths were reported in SP (2.4%) and four in SOX (1.2%). The median LOS per cycle was 0.85 day for SOX and 6.00 days for SP (P<0.0001). Conclusions: SOX showed non-inferiority to SP in PFS and the treatment was well tolerated, with benefit in terms of outpatient-based treatment in pts with AGC. SOX is considered as a new standard regimen for the first-line treatment of AGC on an outpatient basis. Clinical trial information: JapicCTI 101021.
Efficacy and safety of trastuzumab (T-mab) and paclitaxel for T-mab naïve patients with HER2 positive previously treated metastatic gastric cancer (JFMC45-1102).
Authors: Miki Akira , Nishikawa Kazuhiro , Noshiro Hirokazu , Tsuburaya Akira , Nishida Yasunori , Yamada Yasuhide , Miwa Hiroto , Sakai Yoshinori , Yoshida Kazuhiro , Kodera Yasuhiro , Boku Narikazu , Morita Satoshi , Sakamoto Junichi , Saji Shigetoyo , Kitagawa Yuko
Published: February 2017

63

Background: The global, randomized, Phase III ToGA study showed that the first-line treatment of trastuzumab (T-mab) combined with capecitabine and cisplatin a survival (OS) benefit for patients (pts) with HER2-positive metastatic gastric cancer (mGC). However, there is no report concerning about the efficacy and safety of T-mab containing second-line treatment for T-mab naïve patients with HER2-positive mGC. Therefore, we planned a phase II study of paclitaxel plus trastuzumab in this setting. Methods: JFMC45-1102 is multicentre Phase II study. Patient (pts) with HER2 positive (IHC3+ or IHC2+/FISH+), histologically confirmed gastric adenocarcinoma, age≥20, received one or more prior chemotherapy but no prior therapy with T-mab, normal left ventricular ejection fraction (LVEF ≥ 50%) were eligible. Pts received paclitaxel (80 mg/m2on days 1, 8, and, 15 q4w) plus T-mab (8 mg/kg for the initial dose, followed by 6 mg/kg q3w) until disease progression, unacceptable toxicity or patient’s refusal. The primary endpoint was overall response rate evaluated according to RECIST ver1.0 (ORR; Threshold and expected ORR would be 15% and 30%), and the secondary endpoints include progression free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. A LVEF assessment was repeated every three months. Results: Between November 2011 to March 2012, 45 pts were enrolled. Pts characteristics were: gender (M/F); 36/9, median age; 69, ECOG PS0/1/2; 34/10/1, advanced/recurrence; 25/20, number of prior treatment (1/2): 40/5. At 16 weeks, 43 pts were ORR and disease control rate (CR+PR+SD) were 37.2% (95% CI; 23.0%-53.3%) and 83.7%(95% CI; 69.3%-93.2%), respectively. The LVEF assessment was performed in 31 patients. More than 10% decrease in LVEF was observed in only one patient, although total incidence of decrease in LVEF was 56% (17/31 pts). Conclusions: Combination chemotherapy of paclitaxel plus trastuzumab is generally well tolerated and showed promising activity for T-mab native patients with HER2-positive previously treated advanced or recurrent gastric cancer. Clinical trial information: UMIN000006223.
A NSQIP comparison of modern multicenter results for transhiatial versus transthoracic esophagectomy.
Authors: Papenfuss Wesley A. , Kukar Moshim , Hochwald Steven N. , Kakarla Venkata R. , Nurkin Steven J.
Published: February 2017

68

Background: The surgical approach to esophageal cancer continues to be controversial. A transthoracic approach is often advocated for better oncologic staging and improved survival. A transhiatal approach is often preferred due to a perceived decreased operative morbidity and mortality. Methods: Using the American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) participant-use file, patients were identified who underwent esophagectomy for cancer at the 240 participating hospitals from 2005-2011. Demographic, clinical, intra-operative variables and 30-day morbidity and mortality were collected. Results: Of the 1108 patients that had esophagectomy, 649 (58.5%) had a transhiatal (TH) resection and 459 (41.4%) had a transthoracic (TT) resection. There were no significant differences in age, gender, comorbid conditions, preoperative chemotherapy or radiation, or ASA class. Operative time was greater in the TT group (360.4 vs. 298.4min, p=0.0001). Thirty day overall mortality (TH=3.4%, TT=4.5%, p=0.3) and mean hospital length of stay(TH=15.25, TT=16.76, p=0.08) were not significantly different. The TH group had a significantly higher superficial wound infection rate (13% vs. 7.4%, p=0.002). The TT group had significantly higher rate of perioperative transfusion (9% vs. 5.1%, p=0.023) and septic shock (12.2% vs. 7.1%, p=0.004). On multivariate analysis, history of congestive heart failure and pneumonia were significant predictors of 30 day mortality. Diabetes, metabolic syndrome and COPD were predictors of morbidity. There were no differences in the rates of pneumonia, need for reintubation, ventilator requirements, or need for reoperation in both groups. Conclusions: In this modern series of patients, utilizing standardized national data collection tools, there was no significant difference in mortality of esophagectomy between transthoracic and transhiatal approaches. However, morbidity rates do vary with an increased rate of substantial morbidity in the transthoracic group including septic shock.
Association of increased time from chemoradiation (CRT) to esophagectomy (E) with increased surgical complications (Cx) in esophageal cancer (EC).
Authors: Meyer Joshua E. , Thomay Alan , Ruth Karen J. , Shaikh Talha , Konski Andre A. , Cohen Steven J. , Scott Walter Joseph
Published: February 2017

77

Background: EC is often treated with CRT followed by E. E is typically performed 6 weeks after completion of CRT, but the optimal timing is unknown. Previous work has shown that a longer time interval (TI) between CRT and E resulted in a higher percentage of patients (pts) with pathologic complete response. This study was undertaken to determine whether this improved response comes at the expense of increased surgical Cx. Methods: Complete records were available for 85 pts who underwent CRT and subsequent E at a single academic center from 2001-2011. Surgical Cx were collected. Univariable and multivariable analyses were performed to investigate the association between length of TI from CRT to E and Cx, adjusting for age, gender, and surgery type. Multiple linear regression was performed to examine the association of length of stay (LOS) and estimated blood loss (EBL) with TI, adjusting for covariates. Results: Of 85 patients, 72 were male and the histology was adenocarcinoma in 72. The median age was 61 (range: 36-80), the most common clinical stage was T3N1 and 60% of pts had ECOG performance status of 1 (range 0-2). The median length of CRT (most commonly Cisplatin, 5FU and 50.4 Gy) was 37 days and median TI from initiation of CRT to E was 89 days (range: 64-242). 59 pts (69%) experienced at least 1 complication. The mean TIs for pts with and without Cx were 97 and 87 days (P=0.019). When specific Cx were examined, the mean TI for pulmonary Cx was greater (107 v. 89 days; P=0.018). Patients experiencing anastamotic leaks had shorter mean TIs (83 v. 96 days; P=0.022). Multiple linear regression showed a positive association between LOS and TI (p=0.0027) but none with EBL. On multivariable analysis, increased TI predicted for pulmonary complications (OR 1.05, P=0.0061) and LOS (OR 1.03, P=0.033). Increased TI predicted for decreased risk of anastamotic leak (OR 0.94, P=0.063). Conclusions: In this retrospective data set, we demonstrated an association between longer TI from CRT to E and pulmonary toxicity in EC pts. Longer TI was also associated with increased LOS. In contrast, anastamotic leaks were associated with shorter TIs. These data suggest TI from CRT to E may impact the risk of Cx.
Long-term oncologic outcomes of robotic gastrectomy for gastric cancer compared with laparoscopic gastrectomy.
Authors: Hyung Woo Jin , Obama Kazutaka , Kim Yu Min , Woo Yanghee , Pak Kyung Ho , Kim Hyoung-Il , Noh Sung Hoon
Published: February 2017

8

Background: Although robotic gastrectomy (RG) showed satisfactory early postoperative outcomes, the oncologic safety of RG for gastric cancer remains a concern. We aimed to evaluate the oncologic safety of RG by comparing its long term outcomes with that of laparoscopic gastrectomy (LG). Methods: From July 2005 to December 2009, we performed 313 RGs and 524 LGs to the patients with gastric cancer. We retrospectively analyzed the patients’ characteristics, operative outcomes, overall survival (OS) and relapse-free survival (RFS), then compared between RG and LG groups using a prospectively maintained database. Results: With a median follow-up of 46 (1-80) months, there was no difference in the OS (log-rank p=0.625) nor in the RFS (p=0.761) between the two groups. When we compared the two groups stage by stage, the OS and RFS also did not differ significantly. Postoperative recurrence was observed in 17 patients (5.4%) in RG and 18 (3.4%) in LG, which showed no significant difference (p=0.745). The pattern of recurrence in RG showed 5 peritoneal, 5 loco-regional, 3 hematogenous,3 distant lymph node, and 1 mixed one. The recurence pattern of the two groups did not differ significantly. Conclusions: These data suggest that robotic assistance in gastrectomy for gastric cancer is acceptable because the oncologic outcome of RG was comparable to conventional LG in our experience.
Phase I study of neoadjuvant chemoradiotherapy as an outpatient setting for patients with resectable advanced gastric cancer.
Authors: Takahashi Tsunehiro , Saikawa Yoshiro , Wada Norihito , Kawakubo Hirofumi , Takeuchi Hiroya , Takaishi Hiromasa , Kitagawa Yuko
Published: February 2017

84

Background: The prognosis for advanced gastric cancer remains poor because of a high rate of metastasis or recurrence. Therefore, treatment options that might improve the prognosis are needed. Radiation is expected to improve the rate of curable resection and local recurrence. To that end, neoadjuvant chemoradiotherapy with S-1 and cisplatin (CDDP) was investigated. Methods: Advanced gastric cancer patients with regional lymph nodes metastases enrolled in this study. The chemoradiotherapy consisted of S-1 on days 1–14 and CDDP on days 1 and 15. The dose range of CDDP in the study was 15 mg/m2 to 30 mg/m2. Radiation therapy was started concurrently with chemotherapy and repeated daily on days 1–5, 8–12, 15–19, and 22–26. After the initial chemoradiation therapy, the chemotherapy was repeated within 2 weeks after the termination of radiotherapy. Surgery was scheduled to take place within 6 weeks after completion of the second cycle of chemotherapy. Results: A total of 9 patients were recruited. There was no dose-limiting toxicity (DLT) in patients both 15 mg/m2 and 20 mg/m2. In the next three patients at 25 mg/m2, there were two cases with DLTs. Therefore, the recommended dose (RD) of CDDP was 20 mg/m2. Eight patients underwent surgery and all had an R0 resection. Postoperative complications occurred in two cases (pancreatic fistula and chylous ascites). However, there was no treatment-related death. The grades of histological therapeutic effect were Grade 1a in two patients, Grade 1b in one patient and Grade 2 in four patients. One patient had no viable cancer cells, which is classified as a Grade 3 histological therapeutic effect and represented a pathological CR. Conclusions: The recommended dose of CDDP is 20mg/m2 bi-weekly and its safety and feasibility as a preoperative therapy are supported in this study. Neoadjuvant chemoradiotherapy can provide remarkable shrinkage of tumors and increases in curability rate would be expected. Further clinical trials in a larger number of patients are recommended to evaluate the validation of neoadjuvant chemoradiotherapy with S-1 and CDDP as a standard treatment strategy for resectable advanced gastric cancer. Clinical trial information: UMIN000008941.
Long-term survival of EMR-PDT for gastric cancer.
Authors: Narahara Hiroyuki , Morita Kaori , Yasuda Kayo , Aoi Kenji , Saita Miki , Ikezoe Seriko , Yanagawa Kazunori , Masuda Eriko , Fukushima Juichi , Matsumoto Hitoshi , Yasunaga Yuichi , Inui Yoshiaki , Kawata Sumio , Higashino Koji
Published: February 2017

85

Background: Some patients and their family refuse to undergo the surgical operation because of age or complicated diseases. Endoscopic mucosal resection (EMR) technique is popular in Japan. This method has the advantage of a histologic examination, but its uses are limited to mucosal lesions and a part of submucosal lesions (sm1). For early gastric cancer, we treated patients by photodynamic therapy (PDT) in combination with EMR (that is EMR-PDT). Methods: We treated twenty-five patients with gastric cancer by EMR-PDT from April, 1997 till March, 2004. The median age was 79 (56-88) years old. All the patients were diagnosed that it is impossible to undergo a surgical operation due to their age or complicated diseases. The endoscopic ultrasonography (EUS) showed massive invasion of the submucosal layer in sixteen cancer lesions and the muscularis propria in nine cancer lesions.In order to reduce the tumor size, piecemeal snarectomy (EMR) is performed. One week later, PDT is performed. After the intravenous injection of 2 mg/kg of Photofrin, the excimer dye laser (EDL) at 630 nm is irradiated transmitted endoscopically. The energy intensity is over 60 J/cm2. Results: 1. Early gastric cancer (sm massive): as for complications, two patients showed pyloric stenosis after treatment but both of them were cured successfully by endoscopic treatment. As for local response, 15 out of 16 patients showed cure completely. From a viewpoint of long-term outcome, during the observation period of five years (from one year to 11 years), nine patients died and six patients are alive. Only one patint died of gastric cancer four years later, and other eight patients died from other causes. The longest cancer survivor is still alive after 11 years after EMR-PDT with no recurrence of cancer. Disease-specific survival is 93%. Three- year survival rate is 85%. 2. Advanced cancer: Any of the patient were not alive more than three years. 3. Regardless of their advanced age and complications, such as liver dysfunction and renal dysfunctions, both PDT and EMR-PDT showed extremely high safety. No treatment related death was observed. Conclusions: EMR-PDT is a promising method for early gastric cancer because of its safety and long-term good outcome.
Preoperative chemoradiotherapy (CRT) in gastric cancer.
Authors: Trip Anouk Kirsten , Poppema Boelo Jan , van Berge Henegouwen Mark I. , Jansen Edwin PM , Siemerink Ester , Richel Dirk , Beukema Jannet C. , Plukker John Theodorus , van Sandick Johanna W. , Hulshof Maarten C. , Cats Annemieke , Verheij Marcel , Hospers Geke
Published: February 2017

89

Background: The prognosis of gastric cancer patients remains poor even after radical surgery. Although local control and survival are significantly improved by postoperative CRT, treatment compliance is frequently compromised due to severe toxicity. On the other hand, treatment compliance is good with preoperative chemotherapy (CT) in gastric cancer and preoperative CRT in esophageal cancer. The current study was initiated to investigate the feasibility and efficacy of preoperative CRT for marginally resectable and initially irresectable gastric cancer. Methods: Patients with marginally resectable and initially irresectable gastric cancer, without signs of peritonitis carcinomatosa, stage IB-IV(M0) were treated with CRT. Treatment consisted of irradiation to a total dose of 45 Gy given in 25 fractions of 1.8 Gy combined with concurrent weekly carboplatin (AUC 2) and paclitaxel (50mg/m2) on days 1, 8, 15, 22 and 29 of irradiation, followed by standardized surgery 4-6 weeks after the last irradiation. Results: Between December 2007 and January 2012, 25 patients with stage II-IV(M0) marginally resectable (n=13) or initially irresectable gastric cancer received preoperative CRT. One patient discontinued concurrent CT in the 4th week due to toxicity, but completed radiotherapy, and another patient stopped CRT after the 3rd week due to progressive disease. During CRT, grade III gastrointestinal adverse events (AE) occurred in 3 patients (12%), grade III hematological AE in 3 (12%) and grade III other AE in 2 (8%). Twenty-four patients (96%) were operated following CRT. Surgery-related complications consisted of anastomotic leakage in 3 patients (12%) and bowel perforation in 2 (8%). Postoperative mortality was 4%. A microscopically radical resection was achieved in 18 patients (72%), 8 of whom had initially irresectable gastric cancer. The pathologic complete response rate was 16% (4/25 patients). Conclusions: In this study, preoperative CRT for marginally resectable and initially irresectable gastric cancer was associated with manageable toxicity and resulted in an encouraging pathologic response rate. A multicenter phase II study has recently been initiated.
Randomized phase II study of 6 versus 12 months of adjuvant imatinib for patients with intermediate- or high-risk GIST.
Authors: Muguruma Kazuya , Kurokawa Yukinori , Tsujinaka Toshimasa , Fujita Junya , Nakai Takuya , Takabayashi Arimichi , Hiramatsu Masako , Terashima Masanori , Iwasaki Yoshiki , Hasegawa Junichi , Kira Toshihiko , Shimokawa Toshio , Hirota Seiichi , Nishida Toshirou
Published: February 2017

9

Background: The Z9001 study revealed adjuvant imatinib for 1 year significantly improved RFS in GIST patients (pts). The SSGXVIII study compared 3 years with 1 year of adjuvant imatinib for high risk GIST pts, but there was no study to evaluate shorter period of imatinib administration than 1 year. We conducted a randomized phase II study to compare 6 months (6-mo) with 12 months (12-mo) adjuvant imatinib for intermediate or high risk GIST pts. Methods: Inclusion criteria included ECOG-PS of 0 or 1, age between 20 and 79 years, and primary KIT-positive GIST with intermediate or high risk according to the Fletcher criteria. Pts were randomized assigned to the 6-mo or 12-mo treatment of imatinib 400 mg/day after complete resection. The primary endpoint was recurrence-free survival (RFS). The study was designed as a randomized screening trial to evaluate non-inferiority with margin of hazard ratio 1.67, 1-sided alpha 0.2 and power 0.8. Results: Ninety-two pts were randomly allocated the 6-mo group (n=45) or the 12-mo group (n=47) between Dec 2007 and Aug 2011, which was well balanced for baseline characteristics. One patient was ineligible due to non-GIST (desmoid) tumor at a central review. The proportions of pts completed their assigned adjuvant treatment were 80% in the 6-mo and 70% in the 12-mo group. The first interim analysis was conducted at Sep 2012 with the median follow-up time of 33 months. The 1- and 2-year RFS were 82% and 65% in the 6-mo group and 96% and 86% in the 12-mo group, respectively. Hazard ratio of recurrence was 1.81 (95%CI: 0.84-3.91), and the 2-sided log-rank p value was 0.12. Adjuvant imatinib was well tolerated, with one patient of Gr. 4 rash and no treatment-related death. Because of the lower efficacy of the 6-mo group than expected, the Data and Safety Monitoring Committee recommended the early release of first interim analysis results. Conclusions: Adjuvant Imatinib for 6-mo was inferior in efficacy to that for 12-mo in terms of RFS. Shortening of the adjuvant imatinib duration is not recommended for intermediate or high risk GIST pts. Clinical trial information: UMIN000000950.
Post-progression survival (PPS) and improvements in progression-free survival (PFS) in randomized controlled trials (RCTs) in advanced gastric cancer (AGC).
Authors: Shitara Kohei , Buyse Marc E. , Saad Everardo D.
Published: February 2017

93

Background: Since PPS may influence overall survival (OS), studying PPS may help in understanding why gains in PFS do not always translate into gains in OS. Methods: We searched PubMed for RCTs on first-line therapy for AGC published between 01/82 and 01/12. We estimated mean PFS and OS (in months) using the area under the published Kaplan-Meier curves, computing mean PPS as mean OS minus mean PFS for each trial arm. We compared PPS between trial arms grouped according to PFS duration (longer versus shorter PFS, regardless of statistical significance) and world region (using t tests). Results: We retrieved 53 trials (25 were phase III, 24 were randomized phase II, and 4 had no explicit phase) enrolling 12,050 patients in 121 arms. We could estimate mean endpoints for 33 trials (26/6/1 with 2/3/4 arms), which were more likely to be phase III than the 20 trials with no Kaplan-Meier curves for both endpoints. The average mean PPS was almost identical between trial arms with longer or shorter PFS. Use of PPS assessed as median OS minus median PFS yielded qualitatively similar results. Conclusions: Treatments that improve PFS do not seem to influence PPS. Asian trials appear to have longer OS due to longer PPS, not PFS. Work with individual patient data collected worldwide by the GASTRIC group is under way to confirm our findings. [Table: see text]
SCALOP: Results of a randomized phase II study of induction chemotherapy followed by gemcitabine (G) or capecitabine (Cap) based chemoradiation (CRT) in locally advanced pancreatic cancer (LANPC).
Authors: Mukherjee Somnath , Hurt Chris , Griffiths Gareth , Bridgewater John A. , Crosby Thomas , Falk Stephen , Cummins Sebastian J. , Roy Rajarshi , Mangar Stephen , Mcdonald Alec , Staffurth John , Abrams Ross A. , Maughan Tim
Published: February 2017

LBA146

Background: CRT with G or 5FU (F) is used to treat LAPC. No multicenter, randomized studies have compared G-CRT vs. F-CRT or the oral fluropyrimidine, Cap-CRT. In the UK, where chemotherapy is traditionally standard of care for LAPC, a trial was conducted to assess the safety, efficacy, and deliverability of G-CRT and Cap-CRT. Methods: Eligibility: histologically proven inoperable LAPC < 7 cm in diameter. Induction chemotherapy: 3 cycles of GEMCAP (G 1,000 mg/m2 days 1, 8, 15; Cap 830 mg/m2 days 1-21 q28 days). Patients with stable/responding disease, tumor diameter ≤ 6cm, and PS 0-1 were eligible for CRT randomisation where patients received a further cycle of GEMCAP followed by either Cap (830 mg/m2 bd weekdays only) or G (300 mg/m2 weekly) with radiation (50.4 Gy/28 fractions). Treatment volume = tumour plus enlarged nodes and margins of 2 cm sup-inf and 1.5 cm radially. Prospective RT quality assurance was mandated. Primary end-point was 9-month PFS (Fleming’s design). Funder: Cancer Research UK (CR UK 07/040). Results: Between July 2009 and October 2011, 114 patients from 28 UK centres were registered of whom 74 patients were randomised. Randomised patient characteristics: median age 64.6; 55.4% male; WHO PS (0:1) 41.9%:58.1%; median tumor diameter 4cm; site (head:body) 85.1%:14.9%. During CRT, more patients in the G arm experienced grade 3/4 haematological (18.4% vs 0%, p=0.007) and non-haematological (26.3% vs 11.1%, p=0.095) toxicity. Both C and G arms passed the primary endpoint with 9-month PFS of 62.9% (80% CIs: 50.6%-73.9%) and 51.4% (80% CIs: 39.4%-63.4%) respectively. OS was significantly superior in the Cap-CRT arm (median OS 15.2 vs 13.4 months, HR=0.50, log rank p=0.025). Conclusions: SCALOP is the largest RCT comparing radio-sensitizers in pancreatic cancer and demonstrates that both G-CRT and Cap-CRT can be delivered safely and effectively. Both regimens met the pre-specified PFS criteria. Compared to G-CRT, Cap-CRT demonstrated significantly better survival and toxicity and should form the template regimen for future trials investigating RT dose escalation and combination with novel radio-sensitizers. Clinical trial information: NCT01032057.
Results of a phase III, randomized, double-blind, placebo-controlled trial of pegfilgrastim (PEG) in patients (pts) receiving first-line FOLFOX or FOLFIRI and bevacizumab (B) for colorectal cancer (CRC).
Authors: Pinter Tamas , Abella Steve , Cesas Alvydas , Croitoru Adina , Decaestecker Jochen , Gibbs Peter , Hotko Yevhen , Jassem Jacek , Kurteva Galina Petrova , Novotny Jan , O'Reilly Seamus , Salek Tomas , Mo May F. , Choi L. Mi Rim , Blanke Charles Davic
Published: February 2017

LBA445

Background: The literature reports that adding biologics to chemotherapy (ctx) may increase the incidence of clinically significant neutropenia. This trial was conducted to evaluate the efficacy of PEG in reducing the incidence of febrile neutropenia (FN) in pts with locally advanced (LA) or metastatic (m)CRC receiving first-line treatment with either FOLFOX/B or FOLFIRI/B. Methods: Key eligibility: ≥ 18 years old; measurable, nonresectable CRC per RECIST 1.1. Pts were randomly assigned 1:1 to either placebo or 6 mg PEG ~24 h after ctx/B. The study treatment period included four Q2W cycles, but pts could continue their assigned regimen until progression. Pts were stratified by region (North America vs rest of world), stage (LA vs mCRC), and ctx (FOLFOX vs FOLFIRI). Estimated sample size (N = 800) was based on the expected incidence of grade 3/4 FN (primary endpoint) across the first 4 cycles of ctx/B, powered for PEG superiority over placebo. Other endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: 845 pts were randomized (Nov 2009 to Jan 2012) and received study treatment; 783 pts completed 4 cycles of ctx/B. Median age was 61 years; 512 (61%) pts were male; 819 (97%) had mCRC; 414 (49%) received FOLFOX, and 431 (51%) received FOLFIRI. Grade 3/4 FN (first 4 cycles) for placebo vs PEG was 5.7% vs 2.4%; OR 0.41; p = 0.014. A similar incidence of other ≥ grade 3 adverse events was seen in both arms (28% placebo; 27% PEG). See Table for additional results. Conclusions: PEG significantly reduced the incidence of grade 3/4 FN in this pt population receiving standard ctx/B for CRC. Follow-up is ongoing. Clinical trial information: NCT00911170. [Table: see text]
REGARD: A phase III, randomized, double-blinded trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy.
Authors: Fuchs Charles S. , Tomasek Jiri , Cho Jae Yong , Dumitru Filip , Passalacqua Rodolfo , Goswami Chanchal , Safran Howard , dos Santos Lucas Vieira , Aprile Giuseppe , Ferry David R. , Melichar Bohuslav , Tehfe Mustapha , Topuzov Eldar , Tabernero Josep , Zalcberg John Raymond , Chau Ian , Koshiji Minori , Hsu Yanzhi , Schwartz Jonathan D. , Ajani Jaffer A.
Published: February 2017

LBA5

Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGF-receptor 2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) plus BSC or placebo (PL) plus BSC every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Eligible patients had disease progression within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. The Hazard Ratio (HR) for OS was 0.776 (95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The HR for PFS was 0.483 (95% CI, 0.376-0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent of grade ≥ 3 adverse events (AEs) were: hypertension (7.2% RAM; 2.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.1% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), fatigue (4.2% RAM; 3.5% PL), decreased appetite (3.4% RAM; 3.5% PL) and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab conferred a statistically significant benefit in OS and PFS compared to PL in metastatic gastric or GEJ adenocarcinoma following progression on 1st-line therapy with an acceptable safety profile. Clinical trial information: NCT00917384.
A phase II randomized clinical trial of samarium-153 EDTMP (Sm-153) with or without PSA-TRICOM vaccine in metastatic castration-resistant prostate cancer (mCRPC) after docetaxel.
Authors: Heery Christopher Ryan , Madan Ravi Amrit , Bilusic Marijo , Kim Joseph W. , Singh Nishith K. , Rauckhorst Myrna , Steinberg Seth M. , Dahut William L. , Chen Clara , DiPaola Robert S. , Stein Mark N. , Panicali Dennis , Hodge James W. , Schlom Jeffrey , Gulley James L.
Published: February 2017

102

Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM demonstrated survival benefit. Sm-153 is a radiopharmaceutical that targets osteoblastic lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to immune-mediated killing. This trial was intended to examine the safety and efficacy of the Sm-153 with PSA-TRICOM vs. Sm-153 alone. Methods: This phase 2 multi-center trial was designed to randomize 68 pts to Sm-153 with or without PSA-TRICOM. Eligibility included mCRPC, bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was given at 1mCi/kg IV on day 8 and then every 12 weeks. PSA-TRICOM was given on days 1, 15, 29, then every 4 weeks. The 1° endpoint was comparison of progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA criteria. A Fisher’s exact test, assuming a one-tailed alpha = 0.10, was used to compare these fractions. 2° endpoints were OS, ORR, PSA changes, immunologic, and toxicity. Results: 44 pts were enrolled, 5 were not evaluable for the 1° endpoint due to withdrawal prior to 4 mos (4 on Arm A, 1 on Arm B). PFS and PSA findings are provided below. Hematologic toxicities were most common, and were well matched. Conclusions: This final analysis suggests the combination of PSA-TRICOM and Sm-153 has a similar toxicity profile to Sm-153 alone. Despite early closure of this trial due to poor accrual, which may be related to recent approval of multiple agents for mCRPC, this analysis appears to demonstrate improvement in PFS with the combination. This may indicate synergy between PSA-TRICOM and bone-seeking radiopharmaceuticals. Based on the data presented here, we are exploring the potential to combine PSA-TRICOM with alpharadin (radium-223), a next generation bone-seeking radiopharmaceutical. Clinical trial information: NCT00450619. [Table: see text]
Effect of GTx-758, an ERα agonist, on serum-free testosterone and serum PSA in men with advanced prostate cancer.
Authors: Yu Evan Y. , Gittelman Marc , Keane Thomas E. , Tutrone Ronald , Belkoff Laurence , Given Robert , Bass Joel , Chu Franklin , Gambla Mike , Gaylis Franklin , Bailen James , Getzenberg Robert H. , Coss Christopher , Hancock Michael L. , Dalton James T. , Steiner Mitchell S.
Published: February 2017

104

Background: Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer, but patients develop castrate resistant prostate cancer (CRPC); one of the causes of which is ineffective castration. Total serum testosterone (T) does not accurately predict prostatic levels of T. Further reduction of androgens in men with CRPC can result in improvement of survival. Herein we compare the effects GTx-758 an oral, selective estrogen receptor alpha (ERα) agonist versus leuprolide on total and free (unbound) serum T levels in men with advanced prostate cancer. Methods: In Phase II studies, men with advanced prostate cancer (n=164) received 1000 mg or 2000 mg GTx-758 daily or Lupron Depot (4 month), while men with CRPC (n=9) received 2000 mg GTx-758 daily. Serum concentrations of total T, free T, SHBG and PSA were determined at baseline and during treatment. Results: In ADT naïve advanced prostate cancer patients, 28 days of 1000 mg or 2000 mg daily GTx-758 or Lupron therapy castrated (T<50ng/dL) 50, 31 and 100% of patients, reducing mean serum total T in castrated patients to 23±14, 19±9 and 14±7 ng/dL, respectively. However, treatment with 1000 mg or 2000 mg GTx-758 daily reduced mean free T levels to a greater extent (0.9±0.7 and 0.7±0.7 pg/mL, respectively) than Lupron (1.7±1.1 pg/mL). Changes in PSA at 28 days were more closely associated with the observed changes in free T, with reductions of 74, 72 and 56% for 1000 mg, 2000 mg doses of GTx-758 and Lupron, respectively. In CRPC patients, 2000 mg GTx-758 daily did not further reduce serum total T levels, but did result in free T reductions and PSA decreases from baseline following 15 days of therapy in all of the men maintained on ADT with LHRH agonists alone. Conclusions: Although GTx-758 and LHRH based ADT both reduce total serum T and PSA levels in ADT naïve advanced prostate cancer patients, free T was rapidly reduced to a greater degree in the GTx-758 treated patients. In men with CRPC, GTx-758 therapy resulted in significant reductions in free T and resultant PSA declines. The ability of GTx-758 to reduce free T provides a unique mechanism to treat men with advanced prostate cancer and CRPC. Clinical trial information: NCT01326312.
Updated analysis of radium-223 dichloride (Ra-223) impact on skeletal-related events (SRE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase III randomized trial (ALSYMPCA).
Authors: Vogelzang Nicholas J. , Parker Chris , Nilsson Sten , Coleman Robert Edward , O'Bryan-Tear C. Gillies , Shan Minghua , Sartor A. Oliver
Published: February 2017

11

Background: Ra-223 is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy, short-range (< 100 μm) alpha-particles. In the phase 3, double-blind, randomized, multinational ALSYMPCA study, Ra-223 significantly improved OS in CRPC patients (pts) with bone mets by a median increase of 3.6 months compared with placebo (median OS: 14.9 vs 11.3 mo; P < 0.001; HR = 0.69; 95% CI: 0.58-0.83). An updated analysis of the SRE secondary endpoint is presented. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving best standard of care (BSoC); and either previously received docetaxel, or did not because they were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‑223 (50 kBq/kg IV) q4wk or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. Results: 921 pts were randomized (Ra-223, n = 614; placebo, n = 307); 40% had >20 mets. Ra-223 significantly delayed time to first SRE versus placebo by a median increase of 5.8 months (median time to SRE: 15.6 vs 9.8 mo; P < 0.001; HR = 0.66; 95% CI: 0.52-0.83). Ra-223 also reduced the risk of time to first event for all 4 SRE components versus placebo. Conclusions: Ra-223 significantly delayed time to first SRE with a reduction in risk observed for all 4 SRE components. Despite the longer time at risk, Ra-223 patients had an approximately 50% reduction in risk for SCC. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets. Clinical trial information: NCT00699751. [Table: see text]
Comparison of PSA slope and nadir between hypofractionated SBRT and conventionally fractionated EBRT.
Authors: Anwar Mekhail , Weinberg Vivian K. , Chang Albert , Hsu I-Chow Joe , Roach Mack , Gottschalk Alexander
Published: February 2017

112

Background: Patients with early stage prostate cancer have a challenge in selecting from a variety of curative radiotherapy options, including external beam radiotherapy (EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Rapid post-treatment PSA decline and low PSA nadir have been associated with improved clinical outcomes. The purpose of this study was to compare the PSA measurements over time between conventionally fractionated EBRT and SBRT in newly diagnosed localized prostate cancer. Methods: 104 patients with low to low-intermediate risk prostate cancer (GS 3+3, PSA < 20 or 3+4, PSA < 15) treated with standard fractionated EBRT (> 70.2 Gy, < 76 Gy) without hormones to the prostate only were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997-2012). Patients were excluded if they failed therapy by the Phoenix definition. All included patients had at least 1 year of follow up and 3 serial PSAs. 35 patients that were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. Of these, 47 and 19 patients treated with EBRT and SBRT, respectively, had a yearly increase in PSA follow-up over 3 years. PSA nadir and rate of change in PSA over time (e.g. slope) were calculated from the completion of RT to 1, 2 and 3 years post RT. Results: The median PSA nadir and slope for patients treated with EBRT was 0.80, 0.50, 0.40 ng and ‑0.07, ‑0.02, ‑0.01 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadir and slope were 0.73, 0.50, 0.24 ng and ‑0.09, ‑0.06, ‑0.05 ng/ml/month. The PSA slope for SBRT was greater than EBRT (p = 0.001) at 2 and 3 years following RT, although similar during the first year. These results were consistent when limited to patients with more complete PSA follow-up each year, with PSA nadir significantly lower 3 years after treatment with SBRT compared with EBRT (p = 0.03). Conclusions: Patients treated with SBRT experienced a more rapid decline in PSA 2 and 3 years following completion of RT than with EBRT, and for those with continuous long term followup, a lower PSA nadir, consistent with delivery of a higher bioequivalent dose.