bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term results of full-dose gemcitabine with radiation therapy compared to 5-fluorouracil with radiation therapy for locally advanced pancreatic cancer.
Authors: Huang J. , Robertson J. M. , Margolis J. H. , Balaraman S. , Gustafson G. S. , Khilanani P. V. , Nadeau L. , Jury R. P. , McIntosh B.
Published: February 2017

287

Background: To retrospectively compare the efficacy and toxicity of full-dose gemcitabine-based chemoradiotherapy (GemRT) vs. 5-fluorouracil (5-FU)-based chemoradiotherapy (5FURT) for locally advanced pancreas cancer (LAPC).

Methods: From January 1998 to December 2008, 93 patients with LAPC were treated either with 5FURT (n=38) or GemRT (n=55). 5FURT consisted of standard-field radiotherapy given concurrently with infusional 5-FU or capecitabine. GemRT consisted of involved-field radiotherapy given concurrently with full-dose gemcitabine (1000 mg/m2 weekly) with or without erlotinib. The follow-up time was calculated from the time of diagnosis to the date of death or last contact.

Results: Eighty-eight of 93 patients have died, and only one was lost to follow-up after developing DM. The median OS was 11.2 months (range 1.5-96). Patient characteristics (including Zubrod score, age, tumor stage, nodal stage, tumor location, and grade) were not significantly different between treatment groups. The OS was significantly better for GemRT compared to 5FURT (median 12.5 months vs. 10.2 months; 51% vs. 34% at 1 year; 12% vs. 0% at 3 years; 7% vs. 0% at 5 years; respectively; p=0.04), although the two groups had same DM (34% at 1 year). GemRT cohort was more likely to receive gemcitabine before or after chemoradiotherapy than 5FURT cohort (85% vs. 37%, p<0.001). Of the subset who received gemcitabine either before or after chemoradiotherapy, OS was still significantly better for GemRT without concurrent erlotinib compared to 5FURT (median 15.1 months vs. 10.7 months; 70% vs. 36% at 1 year; 21% vs. 0% at 3 years; 11% vs. 0% at 5 years; respectively; p=0.005), as was the rate of DM (23% vs. 45%; respectively; p=0.04). The subsequent hospitalization, percent of survival time spend in the hospital, acute and late grade 3-5 gastrointestinal toxicities were not significantly different between the GemRT and 5FURT groups.

Conclusions: Full-dose GemRT was associated with improved OS compared to standard 5FURT. This approach yielded a moderate number of long-term survivors and was not associated with increased hospitalization or severe gastrointestinal toxicity.

No significant financial relationships to disclose.
Resection of liver metastases from breast cancer: Effect of timing of surgery and estrogen receptor status on outcome.
Authors: Abbott D. E. , Brouquet A. , Meric-Bernstam F. , Valero V. , Green M. C. , Kuerer H. M. , Curley S. A. , Abdalla E. K. , Hunt K. , Vauthey J.
Published: February 2017

288

Background: The oncologic benefit of resecting liver metastases (LM) in breast cancer patients is unclear. Identifying predictors of improved outcome would be useful in selecting appropriate candidates for surgery.

Methods: From 1997 to 2010, 86 breast cancer patients underwent LM resection. RECIST criteria were used to define the best response to chemotherapy as the optimal response at any time during the course of metastatic disease and the preoperative response to chemotherapy as the response immediately before LM resection. Univariate and multivariate analyses were used to identify predictors of survival.

Results: Sixty-four patients (74%) had primary tumors that were either estrogen receptor (ER) or progesterone receptor (PR) positive. Fifty-three patients (62%) had solitary LM, and 73 patients (85%) had LM smaller than 5 cm. Sixty-five patients (76%) received preoperative chemotherapy, and 10 patients (12%) received 2 or more chemotherapy regimens before LM resection. Only 2 patients (3%) had progressive disease (PD) as a best response to chemotherapy, whereas 19 patients (29%) had PD as preoperative response to chemotherapy (p < 0.001). No perioperative mortality was observed. At a median follow-up of 62 months, the median durations of overall and disease-free survival were 57 and 14 months. Univariate analysis revealed that ER and PR primary tumor status, best response to chemotherapy, and preoperative response to chemotherapy were associated with overall survival after LM resection. On multivariate analysis, an ER-negative primary tumor (p=.009, hazard ratio [HR] = 3.3, 95% confidence interval [CI] =1.4-8.2) and preoperative disease progression (p=.003, HR = 3.8, 95% CI = 1.6-9.2) were independently associated with worse survival after LM resection.

Conclusions: Resection of liver metastases in breast cancer patients with ER positive disease that is responsive to chemotherapy is associated with prolonged survival. Timing of surgery is critical and resection before progression is associated with better outcome.

No significant financial relationships to disclose.
Extrapulmonary neuroendocrine tumors: An institutional experience of 337 patients at the National Cancer Center Hospital in Japan.
Authors: Terashima T. , Morizane C. , Ueno H. , Ikeda M. , Saito Y. , Shimada Y. , Kushima R. , Hiraoka N. , Kanai Y. , Okusaka T.
Published: February 2017

293

Background: Extrapulmonary neuroendocrine tumors (EPNET) are a rare and heterogeneous disease entity, and little information regarding these tumors is available. The aim of the present study was to clarify the clinical behavior, treatment strategy, and outcome of EPNET arising from various primary sites.

Methods: We retrospectively reviewed the medical records of 337 patients with pathologically confirmed NET arising from extrapulmonary site between January 2000 and December 2008 at the National Cancer Center Hospital of Japan.

Results: The major primary tumor site was the rectum followed by the pancreas and stomach. Among the gastrointestinal tract tumors, 113 patients had NET from the foregut, 92 patients from the hindgut, and only 4 patients from the midgut. The median patient age was 60 years, and 57% of the patients were male. The histologic grade was as follows: 39% were well-differentiated neuroendocrine tumors (WDNET); 20% were well-differentiated neuroendcrine carcinomas (WDNEC); 33% were poorly differentiated neuroendocrine carcinomas (PDNEC); and 8% were mixed exocrine-endocrine tumors (Mixed). Most NETs from the rectum or duodenum are WDNET, whereas the ratio of PDNEC was high among NET from the genital organs or esophagus. The treatment strategy was associated with the clinical stage or the primary organ; in particular, 94% of the localized rectal NET were resected endoscopically. The 2-year survival rate for all the patients were 70%. A multivariate analysis demonstrated that distant disease of clinical stage and PDNEC of histological grade had a stronger impact on a poor outcome than the primary tumor site. The 2-year survival rate among the patients with WDNET, WDNEC and PDNEC were 97%, 80% and 36%, respectively, and 94%, 72%, and 32% of the patients had localized, regional, and distant disease, respectively.

Conclusions: Japanese patients with EPNET have different clinicopathological features such as the primary organ or treatment procedure compared with previous reports in Western countries. Identifying the precise clinical stage and histological grade of patients with NET is essential because these factors influence the patient outcome.

No significant financial relationships to disclose.
Ethanol-induced DNA damage and the expression of repair-related molecules in human gastric carcinoma AGS cells with use of an acid pump antagonist and proton pump inhibitor.
Authors: Cho H. , Chun H. , Keum B. , Kim Y. , Jeen Y. , Seo Y. , Lee H. , Um S. , Kim C. , Ryu H.
Published: February 2017

30

Background: Proton pump inhibitor (PPI) inhibits gastric acid secretion by strongly suppressing H + / K +- ATPase of parietal cells and is a major drug for peptic ulcers and gastroesophageal reflux. Recently it was reported that PPI has antioxidant and anti- inflammatory effects as well as a powerful acid inhibitory effect. To analyze the DNA repair capacity from the antioxidant effect of acid pump antagonist (Revanex-RN) and proton pump inhibitor (Omeprazole-OP), this study examined ethanol-induced DNA damage and the expression of repair related molecules in human gastric cancer AGS cells pretreated with an acid pump antagonist and a proton pump inhibitor.

Methods: AGS, a human gastric cancer cell line was obtained from ATCC, was treated with ethanol (0, 2, 4, 6, 8, 10%) during 1hr. MTT and Comet assay were performed to evaluate ethanol-induced DNA damage. The optimum concentration of ethanol which caused DNA damage was established. And AGS cells were cultured in proper concentration of RN or OP overnight. Then, these cells were treated with 5% ethanol during 1hr. DNA damage and recovery were represented the value of Olive tail moment in comet assay. Western blot was also performed to detect expression of DNA polymerase beta, APE/ref-1, PCNA, and GADD45.

Results: The DNA damage of AGS cell depended upon ethanol concentration distinctly. Damaged cells showed up recovered tendency in the group treated with low dose RN or OP. In addition, DNA repair enzymes including DNA polymerase beta and APE/ref-1 which were associated with mechanism of base excision repair (BER) were increased. A relevant protein such as GADD45 was also increased significantly.

Conclusions: PPI has capacity to recover damaged DNA, which is associated with increased expression of GADD45 directly. Therefore, PPI offers cancer prevention by reducing the level of DNA damage in the gastric mucosa. GADD45 is also likely to suggest that it could be used a major factor on the injury mechanism and an indicator of mucosal damage in stomach. Moreover, RN, an acid pump antagonist is expected to have the higher safety compared to the existing PPIs and considered to be equal to PPIs in terms of anti-cancer effect.

No significant financial relationships to disclose.
Radioembolization of unresectable primary and secondary hepatic malignancies using yttrium-90: The University of Texas at Houston experience.
Authors: Subbiah I. M. , Cen P. , Tanikella R. , Bryant K. W. , Liaw V. J. , Fallon M. B. , Cohen A. M.
Published: February 2017

311

Background: Few effective treatments exist for unresectable hepatic malignant lesions. The objective of this study was to analyze the patient outcomes and toxicities of yttrium-90 (Y90) radioembolization in patients with unresectable primary and secondary hepatic malignancies.

Methods: A retrospective review from 3/03 to11/09 of pts with liver malignancies who received Y-90 (TheraSphere and SIR-Spheres) was conducted. Pretreatment CT scans characterized the liver lesions. Hepatic arterial Tc-99m MAA scans showed % lung shunt and liver flow. Postprocedure toxicities (including pt symptoms, lab values) were recorded. CT/MRI scans at 1-, 3-, and 6-month intervals measured tumor response as per RECIST 1.0. The Kaplan-Meier method was used for survival analyses.

Results: 50 pts were initially screened, of which 44 pts received 63 Y90 treatments. Mean age was 62y (24 male, 20 female). Of the 44 pts, 15 had hepatocellular cancer (HCC), 2 had intrahepatic cholangiocarcinoma and 27 had liver metastases (10 colorectal, 8 breast, 4 carcinoid, 1 esophagus, 1 lung, 1 gallbladder, 1 pancreas, 1 gastric). Mean tumor size was 10.6 cm (range 2.2-23.5cm), mean tumor absorbed dose was 30.8 mCi (range 7.1-63.5 mCi). Post-procedure symptoms included fatigue (n=21, 47.7%), abdominal pain (n=35, 79.5%), nausea/vomiting (n=12, 27.2%). At 1 month, 20 pts (45.5%) had SD, 14 (31.8%) had PR, and 10 (22.7%) had PD. At 3 months, 25 patients had SD, 10 had PD and 9 pts were in hospice or were deceased. At 6 months, 11 pts had SD. Per RECIST, PD at 1, 3, 6- months were significant predictors of mortality (OR 25, p<0.0002) as was the preprocedure MELD (OR 1.208, p=0.0160). Caucasian pts had a lower overall mortality (OR 1.238, p=0.0363). Survival analyses will be updated. One pt with HCC was successfully downstaged after Y90 and listed for liver transplant; 26 patients were alive at 6-month follow-up.

Conclusions: Y90 radioembolization represents a pragmatic option for hepatic lesions malignancies not amenable to resection. With an acceptable safety profile and the promising response on imaging, Y90 warrants further trials into its ideal use in the therapeutic algorithm for unresectable liver lesions.

No significant financial relationships to disclose.
Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF-1R), in Japanese patients (pts) with advanced solid tumors.
Authors: Doi T. , Fuse N. , Yoshino T. , Murakami H. , Yamamoto N. , Boku N. , Otani S. , Shibayama K. , Takubo T. , Elwyn L.
Published: February 2017

318

Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2.

Methods: Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1).

Results: Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade ≥3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented.

Conclusions: AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035).

[Table: see text]
Pilot study of neoadjuvant FOLFIRINOX in unresectable locally advanced (LA) pancreatic carcinoma (PC).
Authors: Hosein P. J. , Kawamura C. , Macintyre J. , Loaiza-Bonilla A. , Merchan J. R. , Levi J. U. , Rocha Lima C. S.
Published: February 2017

324

Background: 5-flourouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients (pts) with advanced PC who have a good performance status (Conroy et al, ACCORD 11 trial, ASCO 2010). After the initial data on FOLFIRINOX were presented at ASCO 2007, we began using it off-protocol as neoadjuvant therapy for LAPC. We report our experience herein.

Methods: In this retrospective series, we included pts with unresectable LAPC who received neoadjuvant FOLFIRINOX. The doses were identical to the ACCORD 11 trial, with G-CSF prophylaxis from cycle 1. The primary endpoint was R0 resection rate. Secondary endpoints were overall survival (OS), safety and tolerability.

Results: Between 5/2008 and 9/2010, we treated 12 pts with LAPC with neoadjuvant FOLFIRINOX. All pts met consensus criteria for unresectability after multidisciplinary review. The median age was 57.5 years and 9/12 were men. All had ECOG PS of 0 or 1. Two pts received gemcitabine prior to FOLFIRINOX and 10 were treatment-naive. Two pts are still on therapy and 10 completed a median of 6 cycles (range 3-17) and were evaluable; 6 were felt to have converted to resectability by imaging and were taken for surgery. Four had R0 resections (40% of evaluable, 33% of all patients), 1 had R1 resection, and 1 had unresectable disease at laparotomy. To date, 2 pts have died and 10 remain alive with a Kaplan-Meier estimated median OS of 20.7 months (95% CI 18.8-22.6). All 4 pts with R0 resections are alive and disease- free. Grade 3/4 chemotherapy-related toxicities were neutropenia (17%), neutropenic fever (8%) and fatigue (17%). Common grade 1/2 toxicities were neutropenia (42%), anemia (92%), thrombocytopenia (50%), fatigue (92%), nausea (58%), diarrhea (42%) and neuropathy (33%). Two of the 6 surgical pts had significant postoperative complications - 1 with C. Difficile colitis, gastroparesis and a subhepatic collection and another with an infected pancreatic bed collection requiring percutaneous drainage 3 times.

Conclusions: FOLFIRINOX is feasible as neoadjuvant therapy in patients with unresectable LAPC, with manageable toxicities. In this small series, the R0 resection rate was at least 33%. A prospective trial is warranted.

No significant financial relationships to disclose.
The feasibility, safety, and technique of endoscopic ultrasound (EUS)-guided fiducial marker placement for stereotactic body radiation therapy (SBRT) in borderline resectable pancreatic cancer.
Authors: Vignesh S. , Hoffe S. E. , Shridhar R. , Klapman J. , Barthel J. S.
Published: February 2017

327

Background: Fiducial markers implanted into tumors that move with respiration facilitate planning for SBRT. To date, there is little evidence regarding the safety and utility of EUS implanted markers for “borderline resectable” pancreatic cancer.

Methods: This is a retrospective review of 13 patients (7 men and 6 women) with “borderline resectable” pancreatic cancer as per NCCN guidelines. EUS-guided fiducial placement for stereotactic body radiation therapy was performed between January 2009 and September 2010. Gold cylindrical fiducials (0.35mmx 10mm or 0.75 mm X 10 mm; VISICOIL) were loaded into a 22g or 19 g EUS needle. With the needle in the target, the fiducial was deployed by retracting the needle and advancing the stylet. EUS confirmed fiducial position after deployment. A mean of 3 fiducials were placed (range 1-6) per patient. Fiducial position was analyzed at 4D CT simulation and daily cone beam imaging prior to SBRT.

Results: Fiducial placement was successful in all. Technical difficulty was encountered in 2 patients secondary to retained food in stomach and uncinate tumors. Smaller (10x0.35mm) fiducials were successfully placed in these 2 patients. 3 patients had abdominal pain lasting < 12 hours after fiducial placement but none had any acute complications. In 2 patients, change in fiducial position was noted on follow-up cone beam CT. This apparent change in position was related to biliary drainage, gastric distension and a pre-existing pseudocyst. Though this is not indicative of fiducial migration, it impacts radiation planning and delivery. No complications were noted at the end of a mean follow-up period of 6 months.

Conclusions: EUS fiducial placement to assist with stereotactic body radiation for “borderline resectable” pancreatic cancer is safe, feasible, and technically successful in most cases. True migration did not occur but other factors may cause an apparent change in fiducial position. Further studies are planned to optimize the best configuration of fiducial placement by virtue of tumor location for SBRT planning and treatment.

No significant financial relationships to disclose.
Single-institution experience using transarterial chemoembolization (TACE) with carboplatinum (carbo) and doxorubicin in patients (pts) with hepatocellular carcimona (HCC) awaiting liver transplantation (LTx).
Authors: Switzer B. A. , Harvey K. , Grossman S. R. , Phillips D. A. , Shah S. A. , Bozorgzadeh A. , Piperdi B.
Published: February 2017

336

Background: LTx is the best treatment option for multinodular HCC and those with advanced liver dysfunction. Tumor progression occurs in 20-50% of pts on liver transplant list. TACE is increasingly used as locoregional therapy and as a bridge to LTx. We report here our single institutional experience with TACE using carbo and doxorubicin in pts with HCC awaiting LTx.

Methods: Retrospective chart review was performed in all pts who had TACE between 2008 and June 2010. Our institutional protocol uses a fixed dose of carbo 300mg, doxorubicin 50mg, in 10ml of lipoidol solution. We analyzed pt demographics, etiologies of liver disease, Child-Pugh status, CLIP scores, size of tumor, alpha-fetoprotein (AFP), toxicity, length of stay, and transplantation statistics.

Results: 32 pts (28 men) were treated with 39 TACE procedures. The median age was 57 (32-83). 28 of 32 had cirrhosis with Child's A/B/C 36/51/18% respectively. The major etiologies of cirrhosis were hepatitis C (HCV) 8, alcohol and HCV 19, alcohol 7; portal vein thrombosis in 8 pts. The median tumor size was 6.2 cm (range 2-12 cm) and 81% were multifocal CLIP score 0,1/2,>3 were 5/62/38%. There were no mortality within 30 days of TACE procedure. The majority of the pts were discharged after 24 hr observation; 6 pts require readmissions within 30days. There was no systemic hematologic toxicity. 11 pts had elevated AFP at baseline and 6/11 (54%) had >50 % reduction in AFP value. 11pts (34%) received Ltx; 3 pts came off the LTx list due to disease progression, 2 pts are still on transplant list, and 16pts not able to be listed. 42% of pts received sorafenib in addition to TACE. The median time from last TACE to LTx was 55 days and 4 pts received transplantation within 30days. Very good pathological treatment effect was observed in 8/11 explanted liver.

Conclusions: Our regimen of TACE with carbo/doxorubicin appears to be a safe and tolerable approach for localized treatment as a bridge to liver transplantation. It has acceptable toxicity and is associated with good AFP and pathological responses. We plan to evaluate different baseline parameters for better pt selection.

No significant financial relationships to disclose.
Evaluation of obstructive jaundice as a poor prognostic factor after curative resection of advanced gallbladder cancer.
Authors: Nasu Y. , Kondo S. , Hirano S. , Tanaka E. , Tsuchikawa T. , Matsumoto J. , Kato K.
Published: February 2017

340

Background: Gallbladder cancer (GBC) is one of the most common malignancies of the biliary tract. Because of the lack of specific presentations, this condition is frequently diagnosed only at an advanced stage. Obstructive jaundice is generally regarded as an indicator of far advanced disease, unresectability, and poor prognosis. The aim of this study was to evaluate clinicopathological factors, especially jaundice, influencing outcome after radical resection of gallbladder cancer, in order to identify the patients benefiting from radical surgery.

Methods: Seventy-five patients with GBC underwent surgical resection between 1998 and 2008. A retrospective analysis was conducted on sixty-four patients with UICC T2 or more tumors. Clinicopathologic features, extents of resection, and survival rates were investigated retrospectively. Obstructive jaundice was defined that serum T-bil level was more than 2.0 mg/ml. Patients with jaundice underwent ENBD or PTBD and curative resection was performed when serum T-Bil level decreased below 2.0 mg/ml. Right after laparotomy, para-aortic lymphadenectomy and frozen section pathology were performed to convert a radical resection to a palliative procedure when a para-aortic lymph node was positive.

Results: The three and five-year disease-specific survival rates were 47% and 41%, respectively. Nine patients survived for more than five years.Univariate analysis showed that blood loss during operation, hepatic invasion, portal vein invasion, N category, M category after postoperative pathological examination and residual tumor were significant prognostic factors (p<0.05), but multivariate analysis showed that M category only was independent prognostic factor (p<0.05). Five-year disease-specific survival rates for patients with (n=37) and without (n=27) obstructive jaundice were 47% and 35%, respectively (p=0.69).

Conclusions: Obstructive jaundice had no impact on postoperative survival as long as metastatic disease was exclueded and adequate resection of the hepatic hilum was performed. Aggressive surgery might bring long-term survival in selected patients even with obstructive jaundice by advanced gallbladder cancer.

No significant financial relationships to disclose.
Hypofractionated radiotherapy for patients with locally advanced pancreatic cancer using tomotherapy Hi-Art and CyberKnife: A study of the treatment outcome and failure patterns.
Authors: Jang H.
Published: February 2017

342

Background: To evaluate the treatment outcome and pattern of failure in the patients with locally advanced pancreatic cancer, who were treated with hypofractionated radiotherapy (RT) using TomoTherapy Hi-Art and Cyberknife.

Methods: From April 2004 to May 2010, Twenty four patients with locally advanced pancreatic cancer received hypofractionated RT using TomoTherapy Hi-Art and Cyberknife at Seoul St. Mary's Hospital, the Catholic University of Korea. Eleven patients (45.8%) were treated using TomoTherapy Hi-Art and 13 patients (54.2%) using Cyberknife. The total dose delivered were 45∼55 Gy (median: 50 Gy) in 15∼22 fractions with TomoTherapy Hi-Art and 24∼40 Gy (median 30 Gy) in 3∼5 fractions with Cyberknife. The RECIST version 1.1 was used for the response evaluation. The follow-up duration was 3.0∼77.1 months (median: 34 months).

Results: In the initial response evaluation, the rates of partial response, stable disease and progressive disease were 45.8%, 54.2% and 0%, respectively. Median survival duration was 11.1 months. One year and two year survival rates were 39.4% and 21.1%, respectively. Two patients (8.3%) had local failures and 11 patients (45.8%) had distant failures. Distant failures were main cause of failures. Median time to distant failures was 7.8 months and one year distant progression-free survival rate was 35.1%. The difference of the treatment outcome between TomoTherapy Hi-Art and Cyberknife was not statistically significant. Most patients experienced abdominal discomfort and pain after RT. However, no severe gastrointestinal complication such as ulcer, bleeding, perforation and fistula were noted.

Conclusions: Hypofractionated RT for the patients with locally advanced pancreatic cancer showed excellent local control. However, overall survival still remains poor because of distant failures. Therefore, effective systemic chemotherapy should be considered with RT, either concurrently or sequentially.

No significant financial relationships to disclose.
Safety of liver resection for HCC in patients previously treated with sorafenib.
Authors: Belghiti J. , Saget A. , Fuks D. , Dokmak S. , Faivre S. J. , Ronot M. , Paradis V.
Published: February 2017

345

Background: The efficiency of sorafenib in HCC has led to its utilization in the neo-adjuvant setting in selected cases. We assessed the safety of liver surgery in patients previously treated with sorafenib.

Methods: From January 2009 to April 2010, 8 patients were resected following treatment with sorafenib. The median length of treatment was 1.5 months (range: 0.23-15). Mean size of tumors was 6.4cm (2-10). Alphafoetoprotein (AFP) was elevated in 5 patients, ranging from 45 to 100,000. Six patients had chronic liver disease. The cohort of 8 patients was cross-matched with 17 comparable patients who underwent primary resection without sorafenib during the same period.

Results: After sorafenib therapy there was a decrease of HCC size (n=4, median size decrease of 55%) and AFP level (n=4). AFP returned to normal in 3 patients. Peri-operative data showed that previous treatment with sorafenib was not associated with increased length of surgical procedure (265 vs. 293 min), blood loss (400 vs. 530cc) or blood transfusion (0 vs. 5 Units). No mortality was reported, while overall morbidity (50 vs. 61%), length of stay (10 vs. 12 days) and intensive care requirement (43 vs. 44%) were similar in both groups. Recovery of postoperative liver biochemical tests did not show significant differences between the groups. Specimen analysis showed a higher rate of tumor necrosis in the sorafenib group (100% vs 46%) while no hepatotoxicity induced by chemotherapy was found.

Conclusions: The administration of preoperative sorafenib therapy, which can improve disease control of HCC, does not increase operative risk.

No significant financial relationships to disclose.
Hepatic artery infusion for recurrent or chemoresistant hepatic malignancy.
Authors: Wanebo H. J. , Reddy Sanikommu S. , Padmaja V. , Taneja C. , Cummings F. J. , Begossi G. , Belliveau J.
Published: February 2017

351

Background: Previously treated hepatic colorectal metastases (CRC) and advanced hepatocellular cancer (HCC) are tumor challenges frequently unresponsive to systemic chemotherapy (CT). We reviewed survival outcome in chemoresistant/high-risk patients following hepatic artery infusion (HAI) in 21 CRC pts, 10 HCC pts, and 6 miscellaneous metastatic cancers.

Methods: Patient groups: 21 CRC pts (16 M, 5 F), mean age 63, 16 had metachronous (DFI-17 mos), and 5 synchronous CA; liver extent: 76% multiple (>5) mets or extensive bilateral, CEA (ng/m), >100, 8 pts > 50 (3 pts) < 5 (3 pts) and NA = 7 pts. Previous CT:FU/LV (11pts), oxaliplatin (OX) or irinotecan (IR) (10 pts). Liver surgery: partial resection/RFA = 9 pts. HCC = 9 pts, cholangio CA (1), M/F 5/5; av. age 63. Previous RX hepatic lobectomy 4 pts, RFA/TACE = 3 patients. Miscellaneous GP (therapy): hepatic lobectomy + HAI were done in metastatic lung (1), breast (1), advanced gall bladder cancer (GBCA) (T 3-4) (2 pts); HAI alone was done in Br. CA (1) carcinoid (1) treatment protocols: CRC protocol: HAI-FUDR 12-15 mg/kg/d, dexamethasone 2mg.kg/d, leucovorin 20 mg/m2 /d (14 d) plus bolus infusion (d1), oxaliplatin (OX) 130 mg/m2 (or cisplatin (CIS) 100 mg/m2 d1); systemic RX: d20-30. OX I.V. 130 mg/m2, capecitabine 750-1,000 mg/m2/d x 10 days (also used in Miscel. Grp.) HCC Protocol: HAI-14 d as in CRC Protocol. Bolus infusion d1-doxorubicin 75 mg/m2 or OX or CIS as in CRC schema.

Results: CRC:OS-CRC post start HAI = med/16mos., 2yr/5yr = 27%/6%. HCC OS = 9 mos. Median (3-12 mos in 9 evaluable pts.; 1 HCC pt, with recurrence 2 yr. post central hepatectomy was treated over 3.5 yrs. with HAI + RFA/TACE – (OS-67mo). Miscellaneous group included lung (11 mos) Br CA (23, 9 mos) adv. Carcinoid (3 mos), GBCA (2 pts > 60 mos). Major complications: pump malfunction (4 pts), misperfusion (2) pts, infected pocket (2) pts, duodenal fistula (1) pt.

Conclusions: Hepatic artery infusion alternating with systemic chemo therapy has apparent survival benefit in selected patients with persistent or progressive chemo resistant malignancy from metastatic CRC, HCC, or selected miscellaneous cancers (breast, lung, liver, gall bladder cancer) and warrants further study.

No significant financial relationships to disclose.
Gallbladder cancer: The forgotten medical oncologist.
Authors: Teo M. , O'Keeffe M. , Moylan E. , O'Reilly S. , Bird B. R. , Power D. G.
Published: February 2017

354

Background: Gallbladder cancer (GBC) is rare, is often diagnosed at an advanced stage, and survival >1 yr is uncommon. Recent randomized trials have demonstrated improved survival with well-tolerated chemotherapies. In this light, we retrospectively reviewed referral patterns to medical oncology services in our region.

Methods: Prospectively maintained departmental databases from three hospitals serving 480,000 people were reviewed. Patient demographics, disease and treatment details, and outcomes were analyzed. Regional figures were obtained from National Cancer Registry data.

Results: Between March 2003 and September 2010, 17 GBCs were referred to medical oncology, representing 25.5% of total GBC diagnosed in the region (Table). Median age at diagnosis was 63.6 years (range 47.0–72.5) and 65% (n=11) were female. The majority (n=13) initially presented with metastatic or locally advanced disease and 6 of these patients underwent cholecystectomy. Of those with early-stage disease, 2 patients were referred with relapsed disease and 2 were referred for adjuvant treatment. Sites of involvement were liver (10), lymph nodes (3), peritoneum (3), duodenum (2), gallbladder bed (1), and pancreas (1). No extra-abdominal metastases were noted. All patients were scheduled for chemotherapy, but 3 were not treated due to worsening performance score. Of the 14 patients who received chemotherapy, 7 received gemcitabine, 5 received 5FU and 2 received cisplatin/gemcitabine. Median duration of chemotherapy was 3.8 months (range 0.7–8.1) and 3 patients (21%) received second-line chemotherapy. 13 patients (76.5%) had died at the time of analysis. Median follow-up was 6.7 months (range 1.7-73.9) and median overall survival was 6 months.

Conclusions: A minority of patients with GBC were referred to medical oncology. Given the emergence of level 1 evidence reporting a survival benefit with well-tolerated combination chemotherapy and the potential for adjuvant treatment, higher referral rates may lead to improved outcome.

[Table: see text]

No significant financial relationships to disclose.
Prospective study of genetic mutations in matched tumor and plasma specimens in colorectal cancer patients.
Authors: Perkins G. , Dukes J. , Yap T. A. , Riisnaes R. , Pope L. , Cassidy A. , Denholm K. A. , Gonzalez de Castro D. , Chau I. , De Bono J. S.
Published: February 2017

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Background: Circulating free DNA (cfDNA) represents a minimally-invasive resource for detecting mutations in advanced cancer patients. The primary objective of this study was to determine if cfDNA is representative of tumor tissue for multiplex mutation detection utilizing Sequenom MassARRAY.

Methods: Samples were spiked with dilutions (10ng/μl to 0.01ng/μl) of HCT116 DNA containing KRAS G13D mutations to determine assay sensitivity and specificity. Metastatic colorectal cancer patients referred to the Drug Development Unit at the Royal Marsden Hospital between 9/09-8/10 gave their consent to provide DNA from matched archival formalin fixed paraffin-embedded (FFPE) tumor and plasma. Samples had ∼200 described gene mutations genotyped using Sequenom MassARRAY (OncoCarta Panel).

Results: Serial dilution spiking experiments revealed that the KRAS G13D mutation was reproducibly detectable to 40ng/mL of HCT116 DNA; 26 patient samples were then analyzed. KRAS, BRAF and PIK3CA mutations were detected in 8 (31%), 3 (12%) and 3 (12%) tumor specimens respectively; 100% concordance for KRAS status was observed between multiple FFPE biopsies from the same patient and analysis by Amplification Refractory Mutation System (ARMS)-Scorpion PCR. The median quantity of cfDNA was 353ng/ml (range 106-4603). Concordance between matched FFPE and cfDNA was 88% for KRAS and 100% for BRAF mutations. No patients with wildtype KRAS or BRAF tumor genotypes had mutations in their respective cfDNA confirming the high specificity of cfDNA analysis. Three patients had detectable PIK3CA mutations; 1 patient had a E346K mutation detected in both FFPE tissue and plasma; 1 patient had E545K detected only in FFPE and the other had E542K detected in a liver metastasis but not in the colorectal primary or plasma. The recently reported oncogenic AKT1 E17K mutation was detected in 1 patient in tissue and plasma. No mutations in any of the other tested oncogenes studied were detected.

Conclusions: A high concordance in detected mutations was observed between FFPE tumor and matched cfDNA. cfDNA is representative of tumor DNA and may be used for the prospective selection of cancer patients for treatment with targeted therapeutics.

No significant financial relationships to disclose.
Compliance, capacity, and quality in colonoscopy screening for CRC: A novel solution.
Authors: Lloyd S. C.
Published: February 2017

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Background: CRC is predominately preventable with high quality colonoscopy screenings. Unfortunately, less than half of Americans are “up-to-date.” When referred by primary care providers, less than half complete the process. We proposed to include the primary care provider (PCP) in a novel training program to extend skills from sigmoidoscopy to full colonoscopy in a “mentored and monitored” model. We know that quality in colonoscopy can vary widely (ten fold within a single 12-man group). The protective benefits of colonoscopy reflect the thoroughness of the removal of polyps. Unfortunately, the ACS projections for 2010 predict an increase of 4,400 deaths from CRC over 2009, an 8% rise! Furthermore the death rate for African American men has RISEN 28% since 1960. We are loosing a battle for which we posses the tools to win. To achieve victory we must successfully address all three factors: compliance, capacity and quality.

Methods: Thirty primary care physicians in two states (SC, FL) were recruited. We measured compliance rates within the practice before and after enrollment. We further evaluated quality of the colonoscopies as reflected in completion, yield and complications.

Results: Compliance more than doubled (38% to 84%). As a compliance enhancement tool, the results were outstanding. The evaluation of quality then became of paramount importance. The gross completion rate was 98.3%, the adenoma detection rate (reflecting polyp yield) was 38%. In over 20,000 cases there were only 5 perforations, substantially below published rates. The quality was consistently at the level of experienced conscientious gastroenterologists. The details of the training program and the use of the “two-man” colonoscopy technique have been reviewed elsewhere (MEDICAL CARE, Aug 2010).

Conclusions: If replicated nationally, this model has the potential for saving 25,000 lives annually. The participation of the patient's PCP is a powerful influence for improved compliance. The availability of an “expert” for mentoring and monitoring results in outstanding and consistent quality. The model has the potential to dramatically enhance compliance simultaneously increasing capacity while maintaining outstanding quality.

No significant financial relationships to disclose.
Evaluation of response after chemoradiation for rectal cancer as a predictive factor for the benefit of adjuvant chemotherapy: A pooled analysis of 2,724 individual patients.
Authors: Beets G. L. , Maas M. , Nelemans P. J. , Valentini V. , Crane C. H. , Capirci C. , Roedel C. , Kuo L. , Garcia-Aguilar J. , Glynne-Jones R.
Published: February 2017

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Background: Neoadjuvant chemoradiation (CRT) for rectal cancer increasingly results in pathologic response. It has been suggested that patients with different degrees of response might not have the same benefit of adjuvant chemotherapy. The aim was to determine whether patients with a pathologic complete response (pCR), ypT1-2 or ypT3-4 tumor after CRT for rectal cancer have different benefits of adjuvant chemotherapy for disease-free survival.

Methods: Authors from studies evaluating different degrees of response to CRT were contacted to share individual patient data. The collected individual patient data were pooled into one dataset. To evaluate the effect of adjuvant chemotherapy on disease-free survival multivariate analyses according to the Cox proportional hazards model were performed. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated for 3 subgroups: patients with pCR(ypT0N0), ypT1-2 tumor and ypT3-4 tumor after CRT. To determine benefit of adjuvant chemo for different pathologic N-stages we performed subgroup analyses.

Results: 2,724 patients were included. 811 had pCR (28%), 863 had ypT1-2 (30%) and 1050 had ypT3-4 (37%). Median follow-up was 50 months (range 0-277). 41% underwent adjuvant chemotherapy, which consisted mostly of 5-FU based chemotherapy. The HR with 95%CI for disease-free survival for adjuvant chemotherapy was 0.94 (0.50-1.78) for patients with pCR, 0.61 (0.40-0.92) for patients with ypT1-2 tumors and 0.97 (0.75-1.25) for patients with ypT3-4 tumors. ypT1-2N0 patients benefited most from adjuvant chemo: HR 0.45 (0.27-0.75) vs. 0.79 (0.31-1.95) for patients with ypT1-2N+. For ypT3-4 patients pN-stage did not alter benefit of adjuvant chemo.

Conclusions: Patients with pCR or ypT3-4 residual tumor after CRT do not seem to benefit from adjuvant chemo. This might be due to the already good prognosis of patients with pCR and less responsiveness to 5-FU based chemotherapy in the poor responders (the ypT3-4 tumors). Possibly adjuvant chemotherapy can be omitted or adapted for these patients. Patients with ypT1-2N0 benefit most from adjuvant chemo.

No significant financial relationships to disclose.
AVANT: Results from a randomized, three-arm multinational phase III study to investigate bevacizumab with either XELOX or FOLFOX4 versus FOLFOX4 alone as adjuvant treatment for colon cancer.
Authors: De Gramont A. , Van Cutsem E. , Tabernero J. , Moore M. J. , Cunningham D. , Rivera F. , Im S. , Makrutzki M. , Shang A. , Hoff P. M.
Published: February 2017

362

Background: Bevacizumab (BEV), a humanized anti-VEGF monoclonal antibody, has demonstrated clinical efficacy in combination with 5-FU-based regimens in patients with metastatic colorectal cancer. The therapeutic impact of concurrent BEV with either FOLFOX4 or XELOX chemotherapy in the adjuvant setting was evaluated in this international, controlled phase III trial.

Methods: Eligible patients had high-risk stage II or stage III colon cancer and had undergone surgical resection. Patients were randomly assigned to one of three treatment groups and stratified by geographic region and tumor stage: Arm A: FOLFOX4 on weeks 1–24; Arm B: FOLFOX4 + BEV on weeks 1–24, then BEV alone on weeks 25–48; Arm C: XELOX + BEV on weeks 1–24, then BEV alone on weeks 25–48. The primary endpoint was disease-free survival (DFS) for patients with stage III colon cancer; secondary endpoints included overall survival (OS), and safety. DFS/OS follow-up assessments were performed every 6 months after randomization for 4 years, then annually until recurrence or death.

Results: 3,451 (2,867 stage III) patients were enrolled between December 2004 and June 2007; median age was 58–59 years. Median duration of follow-up was 48 months (range 0–66 months). BEV did not prolong DFS or OS when added to either FOLFOX4 or XELOX in patients with stage III colon cancer based on the final efficacy analysis conducted in September 2010. Efficacy results favored the chemotherapy-alone control arm. Numerically more relapses and deaths occurred in both the BEV arms compared to control. The observed adverse events were consistent with those previously reported in pivotal trials of BEV across tumor types for approved indications.

Conclusions: The primary endpoint of the AVANT study was not met. BEV does not prolong DFS when added to either FOLFOX4 or XELOX in patients with stage III colon cancer. The safety profile of BEV was consistent with prior study results.

[Table: see text]
Diagnostic accuracy and value of magnetic resonance imaging (MRI) in planning exenterative pelvic surgery for advanced colorectal pelvic cancer.
Authors: Tekkis P. P. , Georgiou P. A. , Constantinides V. A. , Patel U. , Antoniou A. , Goldin R. D. , Darzi A. W. , Cunningham D. , Nicholls R. , Brown G.
Published: February 2017

370

Background: Exenterative pelvic surgery is challenging and has been used in colorectal surgery to manage patients with advanced colorectal pelvic cancer. Resection of the tumor needs to be performed en-bloc and if feasible, without exposing the tumor, since this can compromise resection margins. This can only be performed through careful pre-operative staging. This study aimed to assess the diagnostic accuracy of MRI in detecting colorectal tumor invasion into seven intrapelvic compartments and its value in planning exenterative pelvic surgery.

Methods: Sixty four consecutive patients underwent preoperative MRI planning for exenterative surgery, for locally advanced (n= 23) and recurrent (n= 41) pelvic colorectal cancer. Two radiologists reported tumor invasion for each of the seven anatomic surgical resection compartments and were blinded to histopathology and intraoperative reference standards. Sensitivity, specificity and predictive values were calculated for each compartments. Kaplan-Meier methodology was used to calculate survival rates. Interobserver agreement was assessed using Cohen's Kappa coefficient (k).

Results: The sensitivity of MRI was ≥93.3% in all except for the lateral compartment where it was 89.3%. Its specificity for the posterior (82.2%), anterior below (86.4%) the peritoneal reflection compartments was lower compared to the rest of the compartments. MRI diagnosis of lateral (OR= 11.41, p= 0.033), anterior compartment above the peritoneal reflection (OR= 3.14, p= 0.005) and multicompartmental involvement (OR= 1.99, p<0.001) was associated with higher risk of incomplete resection which was subsequently found to be significant factor in predicting overall and disease free survival (p<0.05). The agreement between the two radiologists was found to be either good or very good for all the compartments (k>0.72).

Conclusions: MRI is highly accurate in predicting tumor invasion within the intrapelvic compartments and it should be the pre-operative staging modality of choice when considering exenterative surgery for patients with locally advanced colorectal pelvic cancer.

[Table: see text]
Mucinous appendiceal tumors of uncertain malignant potential (UMP): Prognostic factors and implications for treatment and follow-up.
Authors: Fournier K. F. , Royal R. , Lambert L. A. , Taggart M. , Rafeeq S. , Mansfield P. F.
Published: February 2017

372

Background: The diagnosis of UMP is used for dysplastic mucinous tumors that are difficult to classify as clearly benign or malignant. Given the rarity of this tumor, management of these patients is unclear.

Methods: All patients with a pathologic diagnosis of an appendiceal mucinous UMP who underwent evaluation at a single institution between September 1993 and July 2009 were retrospectively reviewed. Patient demographics, operative findings, pathology, tumor markers, procedures performed, recurrence, overall survival, and disease-free survival were determined.

Results: Of 688 patients with appendiceal neoplasms, 62 (9%) patients (pts) were identified as having UMP. Initial procedures included: appendectomy - 45, colectomy - 11, cytoreduction - 2, and other - 4. Median follow-up was 43.2 months (range 2-184 mos). Median overall survival (OS) was 11.5 years (range 2-184 mos). Median disease-free survival (DFS) has not been reached. There was a trend towards improved DFS in patients who are: female, < 65 years of age, or have mucin confined to the appendix or its serosal surface. Clinicopathologic factors associated with a significantly worse overall DFS included elevated serum CEA (3.6 years, p = 0.0129) and CA-125 (4.16 years, p = 0.0288). DFS at 8 years follow-up in patients with a normal CEA was as follows: 100% if mucin confined to lumen of the appendix, 90% if mucin confined to serosa, and 69% if mucin was in an extra-appendiceal location. 15 patients developed recurrent disease and had an OS of 4.6 years after recurrence.

Conclusions: Mucinous UMP tumors of the appendix have an overall favorable prognosis. In patients with a negative margin and mucin confined to the appendix or serosa, expectant management may be sufficient. Elevation of CEA or CA-125 may warrant closer monitoring or intervention. If confirmed in a larger cohort, these findings may have substantial implications for management of these patients.

No significant financial relationships to disclose.