bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between skin toxicities and treatment outcomes in patients with pancreatic cancer (PC) receiving erlotinib (E): Memorial Sloan-Kettering Cancer Center (MSKCC) experience.
Authors: Alejandro Linh My , Adel Nelly G. , O'Reilly Eileen Mary , Riedel Elyn , Lacouture Mario E.
Published: February 2017

294

Background: Rash is a common adverse event of E, an epidermal growth factor receptor (EGFR) inhibitor approved for advanced PC. Clinical trial results have shown that E-related rash grade 2 or higher is associated with a survival benefit in PC. We examined the correlation between all grades of rash and overall survival (OS) in PC patients receiving E at MSKCC.

Methods: This was a retrospective single-institution study that included a review of all PC patients treated with E between March 1st 2005 and December 15th 2009 at MSKCC. The association of development of rash on OS was examined using a Cox proportional hazards model using development of rash as a time dependent covariate. The associations were examined univariately and after adjusting for gender, race, smoking history, prior lines of treatment for metastatic disease, and chemotherapy. An intervention was defined as a dose change, interruption, discontinuation or medical intervention for rash.

Results: N=193 constituted the cohort of analysis. The median age was 64; 116 (60%) were male and 162 (84%) were Caucasian. Most patients (N=111, 58%) did not receive any prior medical treatment for pancreatic cancer. Skin rash occurred in 113 (59%) of patients. The median OS was 6.7 months (95% confidence interval, 5.7-7.9 months). In a univariate analysis, rash was protective compared to no skin rash (Grade 1 HR 0.71; 95% CI 0.50-1.00, Grade 2+ HR 0.57; 95% CI 0.40-0.82; P=0.007). In the multivariate model, rash appeared to have a protective effect on survival, but this was not statistically significant (Grade 1 HR 0.69; 95% CI 0.49-0.97, Grade 2+ HR 0.78; 95% CI 0.48-1.27). Non-medical interventions for rash included dose adjustment (5%), dose interruption (6%) and dose discontinuation (9%). 33 (29%) patients received medical intervention for rash.

Conclusions: Our findings suggest that grade 1 or higher E-related rash may be a surrogate for survival. Appropriate symptom interventions are recommended to enhance patient comfort and avoid discontinuation of treatment.
Immediate versus delayed adjuvant chemoradiation for resected pancreatic cancer: An analysis of local control and survival.
Authors: Childs Stephanie Krejcarek , Mamon Harvey J. , Wo Jennifer Yon-Li , Blaszkowsky Lawrence Scott , Fernandez-del Castillo Carlos , Swanson Richard , Wolpin Brian M. , Kwak Eunice Lee , Allen Jill N. , Zhu Andrew X. , Clark Jeffrey W. , Wadlow Raymond Couric , Ryan David P. , Hong Theodore S.
Published: February 2017

301

Background: Patients with resected pancreatic cancer have a significant risk of both local and distant failures. Because of the importance of chemotherapy (CT) highlighted by recent trials, the ongoing RTOG 0848 delays chemoradiation (CRT) randomization to after 5 cycles of chemotherapy (CT). However, the impact of delaying CRT on LR is unknown. We evaluated the patterns of failure and outcomes for patients treated with immediate vs. delayed CRT.

Methods: 174 consecutive patients with resectable pancreas cancer who received post-operative CRT at the Massachusetts General Hospital and Brigham & Women’s Hospital/Dana-Farber Cancer Institute between 1998-2010 were retrospectively reviewed on an IRB approved protocol. CRT was delivered to 50.4 Gy with concurrent 5FU or capecitabine. Patient baseline characteristics, pathologic features, and CA19-9 were obtained. Patients were divided into immediate CRT vs. delayed CRT, defined as receiving any CT prior to CRT. LR was independently re-reviewed and confirmed. LR, PFS, and OS were calculated using the Kaplan-Meier method and groups compared using the log-rank test.

Results: Median age was 62 (range, 34-83), 75 were male, and ECOG PS was 0-1 in 95% of patients. Median tumor size was 3 cm, 67% had positive nodes, and 33% had positive margins. Mean pre-operative and post-operative CA 19-9 was 813 U/mL and 19 U/mL, respectively. 123/174 (72%) patients received immediate CRT, of whom 101 received additional chemotherapy (5FU or gemcitabine (GEM)). 51/174 (28%) received delayed CRT, and received a median of 4 cycles of GEM prior to CRT. Median follow-up was 33 months (range, 3.6-67). 6/51 (12%) delayed CRT had LR prior to initiation of CRT. 25/51 in the delayed CRT group had a LR (49%) vs. 35/124 patients (28%) in the immediate CRT group. The 1-year LR rates in the immediate and delayed CRT groups were 18% and 40%, respectively (p=0.0093). There was no difference between immediate or delayed CRT, respectively, in mPFS (12.8 mo vs. 12.2 mo, p=0.6544) or mOS (24.8 mo vs. 26.7 mo, p=0.7163).

Conclusions: Delayed radiation is associated with an increased risk of LR, though this did not appear to impact PFS or OS.
Effect of chemoradiation-related lymphopenia on survival in patients with unresectable, locally advanced pancreatic adenocarcinoma.
Authors: Wild Aaron Tyler , Balmanoukian Ani Sarkis , Laheru Dan , Zheng Lei , Tran Phuoc T. , Hacker-Prietz Amy , Yovino Susannah G. , Kumar Rachit , Ziegler Mark A. , Pawlik Timothy M. , Wolfgang Christopher Lee , Grossman Stuart A. , Herman Joseph M.
Published: February 2017

307

Background: Pancreatic ductal adenocarcinoma (PDA) has been shown to elicit antitumor cell-mediated immune responses. In high grade gliomas, treatment-related lymphopenia has been associated with shorter survival. This study was performed to determine if patients with locally advanced PDA treated with definitive chemoradiation therapy (CRT) develop significant lymphopenia and if this affects overall survival (OS).

Methods: A retrospective analysis of patients with locally advanced PDA treated at a single institution with CRT from 1997-2009 was performed. Serial lymphocyte counts were recorded and OS was analyzed as a function of lymphopenia and known prognostic factors.

Results: 99 patients met eligibility criteria (≥18 years of age, ECOG performance status 0-2, and had baseline/follow-up lab values measured at our institution). Mean age was 61.6 years (SD, 11.6), 55% were male, mean tumor size 4.1 cm (SD, 1.6), and 97 had stage III disease. Median pre/post-CRT CA19-9 values were 241.5 and 105.2 U/mL, respectively. Total lymphocyte counts were normal in 87% of patients prior to RT. Mean RT dose was 47.3 Gy (SD, 8.2) and concurrent chemotherapy was 5-FU (67%), gemcitabine (20%), taxotere (7%), or none (6%). Chemotherapy dose reduction was necessary in 9%, and 39% required a RT break. Total lymphocyte counts fell to ≤500 cells/mm3 in 51% two months after initiating CRT with a median reduction of 66% from baseline (p<0.0001). Median OS of patients with lymphocyte counts ≤500 cells/mm3 at 2 months was 7.7 months (95% CI, 6.8-8.7) versus 15.4 (95% CI, 11.9-19.0) for patients with >500 cells/mm3 (p<0.001). Univariate analysis additionally revealed that among pre-treatment patient characteristics, only age ≥65 was significantly associated with OS (8.8 vs. 11.4 months; p=0.043). Type of concurrent chemotherapy was not significantly associated with OS. Multivariate analysis revealed a significant association between survival and lymphocyte count (<500 vs. ≥500 cells/mm3) at 2 months post-CRT (HR 3.8, p<0.001).

Conclusions: Definitive CRT induced lymphopenia is frequent, severe, and appears to be an independent predictor for OS in patients with locally advanced PDA.
Is survival from resection of pancreatic adenocarcinoma with major arterial involvement any different than venous/minor arterial resection?
Authors: Miura John T. , Pappas Sam G , Gamblin T. Clark , Turaga Kiran
Published: February 2017

310

Background: Major arterial involvement is considered a contraindication to surgical resection for pancreatic adenocarcinoma (PA). We hypothesized that survival for patients (pts) with T3 or T4 disease with major arterial involvement (SMA/Celiac Axis) undergoing pancreatic resection was worse than those undergoing venous resections.

Methods: We included all pts with T3 or T4 PA in the SEER database from 2004-2007. Patients were divided into those involving the portal vein/SMV/GDA/hepatic artery and those involving the SMA and celiac axis. Non-surgical control arm (CA) included pts who were recommended surgery but did not undergo it. Multivariate survival analyses were performed using the cox-proportional hazards model.

Results: We identified 571 pts, of whom 323(56%) underwent resection. Median disease specific survival of pts undergoing surgery with SMA, Celiac involvement was 12, 8 vs. 7, 6 months respectively in the CA(p=0.01). Pts undergoing venous resection had a longer survival than those undergoing arterial resection in multivariate models (18 vs. 12 months, p=0.001)

Conclusions: Resection for pancreatic adenocarcinoma with major arterial involvement is associated with a poorer survival as compared to those with venous/minor arterial involvement. This study validates the current practice of considering major arterial involvement as a contraindication to resection.

[Table: see text]
Meta-analysis of randomized phase II and phase III trials of gemcitabine with/without S-1 in Asian patients with advanced pancreatic cancer.
Authors: Ku Geoffrey Yuyat , Haaland Benjamin , Ioka Tatsuya , Isayama Hiroyuki , Nakai Yousuke , Cheng Ann-Lii , Okusaka Takuji , Lopes Gilberto de Lima
Published: February 2017

311

Background: Advanced pancreatic cancer (PC) is a virulent disease, where gemcitabine is considered the standard-of-care. A recent phase III evaluation demonstrated superiority of FOLFIRINOX (bolus and infusional 5-fluorouracil (FU), irinotecan, oxaliplatin) in patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤1. Recently, three studies were presented in abstract form, comparing gemcitabine/S-1 (GS) to gemcitabine. S-1 is a mixture of tegafur (an oral 5-FU prodrug), a dihydropyrimidine dehydrogenase inhibitor and an agent designed to reduce the gastrointestinal toxicity of 5-FU. All three trials demonstrated significant improvements in progression-free survival (PFS) while one study also showed a statistically significant improvement in overall survival (OS).

Methods: We performed a meta-analysis of the three trials.

Results: Seven hundred and seventy patients were randomized to receive GS vs. gemcitabine; 75% had metastatic disease and 65% had an ECOG PS of 0. GS was associated with superior RR (hazard ratio (HR) 0.348, p=3.06×10-7), PFS (HR 0.64, p=7.26×10-9) and OS (HR 0.79, p=2.47×10-2) compared to gemcitabine. Patients receiving GS were more likely to experience nausea, diarrhea, rash and stomatitis (mostly grade 1/2); neutropenic fever occurred in <2% of patients. One study demonstrated superior quality-of-life for GS.

Conclusions: GS should be considered a first-line option for the treatment of advanced PC in Asian patients. This regimen should serve as the reference for future trials and comparison with FOLFIRINOX in patients with ECOG PS ≤1 is warranted.
Dosimetic parameter predicting the hepatic complication after helical tomotherapy for patients with unresectable primary hepatocellular carcinoma.
Authors: Jang HongSeok
Published: February 2017

324

Background: We evaluated the parameters of radiation-induced liver disease (RILD) and deterioration of the hepatic function in patients with advanced hepatocellular carcinoma (HCC), who were treated with helical tomotherapy.

Methods: From April 2009 to October 2010, 32 patients with unresectable primary HCC received hypofractionated radiation therapy using the TomoTherapy Hi-Art (TomoTherapy, Madison, WI, USA) at Seoul St. Mary's Hospital, the Catholic University of Korea. To assess the deterioration of hepatic function, we evaluated the Child-Pugh class (CP class). The gross tumor volume (GTV) were 178.7 ± 216.1 cm3 and the planning target volume (PTV) were 423.1 ± 399.7 cm3. The total dose administered were 50 Gy (range: 32.5-60 Gy) in 10 or 20 fractions (range: 10-24 fractions). We evaluated the clinical parameters for predicting the RILD and the deterioration of the hepatic function (gender, age, ECOG performance saretatus, pretreatment CP class, AJCC stage, pretreatment level of AFP and hepatitis, liver cirrhosis, PVTT and previous treatments) and the dosimetric parameters (GTV, PTV, the non-target liver volume (NTLV).

Results: Of 32 patients, we observed that 4 patients (13%) developed RILD after helical tomotherapy. Classical RILD was diagnosed in one patient and non-classical RILD in three patients. In the analysis evaluating the associations between the clinical/dosimetric parameters and the RILD, there was no statistically significant parameter. Of 32 patients, five patients (16%) developed the progression of CP class. In the multivariate logistic regression analysis evaluating the associations between the clinical/dosimetric parameters and the progression of CP class, The NTLV receiving <35 Gy (VBED35) was the only significant parameter associated with the risk of progression of CP class (p = 0.039).

Conclusions: The progression of CP class is a dose-limiting toxicity. VBED35 was a significant parameter predicting the risk of the progression of CP class.
Dose-escalated radiotherapy with helical tomotherapy to spine oligometastasis from intrahepatic malignancies.
Authors: Seong Jinsil , Choi Younsun , Kim Jun Won
Published: February 2017

325

Background: Traditional palliative radiotherapy of 30 Gy in 10 fractions to spine metastases often results in poor local control. This study evaluated the role of high dose helical tomotherapy (HT) to improve local control of spine oligometastasis from intrahepatic malignancies

Methods: From 2006 to 2010, 11 hepatocellular carcinoma (HCC) patients and 3 intrahepatic cholangiocellular carcinoma patients were treated with HT for oligometastsis to spine. The gross tumor volume (GTV) was the tumor evident from MRI images fused with simulation CT images. Planning target volume (PTV) encompassed involved vertebral body or 1cm margin to GTV. The spinal cord contour represented a small area within the intradural space. To the adjacent spinal cord volume, 20 Gy dose constraint was used. Mega-voltage computed tomography (MVCT) images were used to maintain setup error within 1 mm. We assessed local control rate after HT for spine metastasis in this retrospective study. Pain response was scored by using a numerical rating scale (from 0 to 10).

Results: Spine metastatic lesions were treated with median dose of 40 Gy (range 31-51 Gy) and median 5 Gy per fraction (range 3-6 Gy) to GTV and median dose of 29 Gy (range 22.5-42.5 Gy) and median 3.75 Gy per fraction( range 2.5-5 Gy) to PTV. Median biologically equivalent dose (BED, α/β=10 Gy) was 55.2 Gy (range 45.6-76.8) to GTV. Infield failure rate was 35.7% and outfield failure rate was 78.6%. Ten patients initially accompanied pain with spine metastasis (median NPIS 7.5), and all patients showed pain relief after tomotherapy. Complete relief was shown in 20% of patients and partial relief in 80 % of patients, with median NPIS reduction of 5. The patients treated with BED (α/β=10 Gy) over 56 Gy had no local failure. Median local recurrence free survival (LRFS) was 3 months. In the univariate analysis, BED (α/β=10 Gy) over 56 Gy was a prognostic factor associated with improved LRFS (p=0.008).

Conclusions: HT was capable of delivering higher BED to metastatic lesions in close proximity of the spinal cord. Spine metastases from intrahepatic tumors were sensitive to high dose radiation, and BED (α/β=10Gy) higher than 56 Gy could improve local control.
An interim evaluation of efficacy and safety of the combination of panitumumab, gemcitabine, and irinotecan in patients with advanced or metastatic cholangiocarcinoma: A phase II study.
Authors: Sun Weijing , Sohal Davendra , Mykulowycz Kristine , Teitelbaum Ursina R. , Damjanov Nevena , Giantonio Bruce J. , Carberry Mary , Wissel Paul Stephen , Jacobs-Small Mona , O'Dwyer Peter James
Published: February 2017

328

Background: Cholangiocarcinoma is an aggressive neoplasm. Current chemotherapy approaches suggest that combinations may be superior to single agents in this disease. Over-expression of epidermal growth factor receptor (EGFR) is associated with tumor stage and prognosis. This study was designed to evaluate the efficacy and tolerability of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan in patients with advanced and metastatic cholangiocarcinoma.

Methods: Pts with advanced unresectable or metastatic cholangiocarcinoma, ECOG PS 0-2, and adequate liver, kidney and bone marrow function were treated with panitumumab (9 mg/kg) on day 1, gemcitabine (1000 mg/m2/100 min) iv and irinotecan (100 mg/m2) iv on days 1 and 8 of a 21-day cycle. Tissue specimens were collected based on availability for future biomarker analyses. The primary objective was to evaluate the 5-month progression-free survival (PFS) rate. The secondary objectives include overall response rate (ORR), overall survival rate (OS) and toxicity of the combination.

Results: There have been 24 (of planned 42) pts recruited to the study. Toxicity of the combination was assessed in all enrolled pts. There were no treatment related deaths. The most common gr 3 or higher toxicity was were neutropenia (10 pts [40%]), thrombocytopenia (6 pts, [25%]), skin rash (4 pts [17%]) and diarrhea (3 pts, [12%]). One pt developed a gr 2 infusion reaction, which was considered related to panitumumab. Efficacy was evaluated in 20 pts. Among them, there were 2 CR, 6 PR, and 10 SD (with disease control rate of 90%), and 2 PD (assessed by RECIST criteria). Two pts went on to have surgical resection. Eight pts had ≥ 10 cycles of the therapy, and dose modification/interruption were needed for some of these pts.

Conclusions: The data of this on-going study showed encouraging results of the combination of panitumumab with gemcitabine and irinotecan in both tolerability and efficacy. The pre-specified efficacy criteria to continue enrollment were met. Further analysis by biomarker status (KRAS/BRAF/EGFR) is forthcoming.
Single-institution experience with FOLFIRINOX in advanced pancreatic cancer (PC).
Authors: Gunturu Krishna Soujanya , Thumar Jaykumar Ranchodbhai , Hochster Howard S. , Stein Stacey , Yao Xiaopan , Cong Xiangyu , Hahn Carol , Kaley Kristin , Lacy Jill
Published: February 2017

330

Background: FOLFIRINOX provides clinically significant benefit in advanced PC compared to gemcitabine (Conroy et al. New Engl J Med 2011;364:1817). Despite superior efficacy, toxicities have tempered enthusiasm for FOLFIRINOX and limited its use in full doses. To assess the impact of dose attenuations on toxicity and efficacy, we reviewed our experience with FOLFIRINOX in pts with advanced PC.

Methods: We performed a retrospective review of dose, toxicity, efficacy of FOLFIRINOX in all pts with locally advanced unresectable PC (LAPC) and metastatic PC (MPC) treated with FOLFIRINOX at Yale Cancer Center between 06/10 and 06/11. Dose attenuations were at the treating physician’s discretion. All pts received prophylactic pegfilgrastim. Pts were treated until progression, unacceptable toxicity, or surgical resection. Toxicities and efficacy were compared to historical data reported by Conroy.

Results: 31 pts with ECOG PS 0 or 1 were treated. Pt characteristics: LAPC 15; MPC 16; median (med) age 60 yrs (range 48-78); male 11; prior chemotherapy 5 (adjuvant 3). Med number of cycles received was 6 (range 1-18). Only 5 pts received full doses of all drugs with cycle 1. Dose reductions with cycle 1 were: IRI 26 pts, OX 10 pts, bFU 10 pts, infusional FU 1 pt. b5FU was omitted in 6 pts. Med relative dose intensities were: OX 88%, IRI 64%, b-FU 57%, infusional FU 100% (compared to OX 78%, IRI 81%, and FU 82% [Conroy]). The % of pts with grade 3 or 4 toxicities was: fatigue or mucositis, 9.6%; dehydration or neutropenia 6.4%; vomiting, thromboembolism, febrile neutropenia, thrombopenia or anemia, 3.2%. Neutropenia (p<0.0001), diarrhea (p<0.03), fatigue (p<0.02) were significantly decreased compared to historical data (Conroy). Response (CR+PR) in 30 evaluable pts was 33% (1 CR, 9 PR, 14 SD, 6 PD) and similar to historical data (31.6%; p 0.21). 2 pts with LAPC underwent resection. Evaluation for OS and PFS is ongoing.

Conclusions: Our findings suggest that dose attentuation of FOLFIRINOX, esp IRI and bFU, with prophylactic pegfilgrastim is associated with improved tolerability and equivalent response rate compared to full dose FOLFIRINOX in advanced PC. The impact of dose attenuations on toxicity and efficacy warrants further evaluation in both LAPC and MPC.
Comparing the treatment outcomes between unresectable and recurrent cases receiving gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer: Pooled analysis of two prospective studies.
Authors: Sasaki Takashi , Isayama Hiroyuki , Ito Yukiko , Yasuda Ichiro , Toda Nobuo , Yagioka Hiroshi , Matsubara Saburo , Hanada Keiji , Maguchi Hiroyuki , Kamada Hideki , Hasebe Osamu , Mukai Tsuyoshi , Okabe Sumihiro , Maetani Iruru
Published: February 2017

331

Background: We previously conducted two prospective studies (phase II study and randomized phase II study) of gemcitabine (GEM) and S-1 combination chemotherapy. The purpose of this study was to clarify the difference of treatment outcomes between unresectable and recurrent cases receiving GEM/S-1 combination chemotherapy in patients with advanced biliary tract cancer.

Methods: The data of two prospective studies were combined for the analysis. In these studies, GEM was administered intravenously at a dose of 1,000 mg/m2 over 30 min on days 1 and 15, repeated every four weeks. S-1 was administered orally at a dose of 40 mg/m2 b.i.d. on days 1-14. Tumor response was assessed every two cycles using RECIST version 1.0. The treatment was continued until disease progression, unacceptable toxicity or patient refusal occurred.

Results: Fifty-five unresectable cases and ten recurrent cases were enrolled in this analysis. Patient characteristics were similar between each group except the baseline sum of longest diameter, which was used as a measurement of tumor volume (unresectable 9.0 cm vs recurrent 2.8 cm). Response rates of unresectable and recurrent cases were 25.5% and 40.0%, respectively. Dose intensities of each group were statistically different (gemcitabine 96.8% vs 83.5%, p=0.03; S-1 91.8% vs 75.9%, p=0.03). The median time-to-progressions of unresectable and recurrent cases were 5.7 months and 8.7 months, respectively (p=0.14). The overall survivals of each group were 9.6 months and 16.1 months (p=0.10).

Conclusions: In recurrent cases, tumor volume was smaller and dose intensity was lower than that of unresectable cases. Recurrent cases showed better treatment outcome comparing to unresectable cases. Therefore, unresectable and recurrent cases should be analyzed separately in the future study.
Phase II trial of sorafenib and capecitabine for hepatocellular carcinoma in cirrhotic patients.
Authors: Patt Yehuda Z. , Fekrazad M Houman , Steinberg Kim A , Bauman Julie E. , Lee Sang-Joon , Lee Fa-Chyi
Published: February 2017

341

Background: Sorafenib (sorf.) has become the standard treatment for Hepatocellular Carcinoma (HCC), demonstrating an increase in patients (pts) median survival from 7.9 to 10.7 months (m) (Llovett, NEJM 2008). Abou-Alfa added doxorubicin to sorf. observing a median survival of 13.7 m vs 6.7 m. for doxorubicin + placebo, (JAMA. 2010). Since most of our HCC pts were cirrhotic and 8/12 HCV +, and 2/12 HBV only +, with cirrhosis and thrombopenia we chose to add capecitabine (cap) to sorf in a phase II trial, anticipating better tolerance. Primary objectives were to assess safety and tolerability of the combination while secondary objectives included estimations of PFS, OST and documentation of disease control rate (DCR = CR+PR+SD). With relaxation of eligibility criteria C-P B-7 pts and ≥ 50,000 platelets were allowed.

Methods: Sorf dose was 400 mg BID with dose adjustments for sorf related hand foot syndrome (HFS). Starting cap dose was 850mg/m2 BID x 7 Q 14 and adjusted as tolerated to 650mg/m2 BID or to 500 mg/m2 BID x 7 Q 14.. The lowest dose used was 250 mg/m2; BID (500 mg BID) for 5 days Q14. Patients: Only 12 of about 30 assessed patients met eligibility criteria, and were recruited between Nov. 2, 2009 and Sep. 13, 2011.The protocol was reviewed and approved by the WIRB and all participants signed an IRB approved consent form.

Results: Preliminary Results: Eight of 12 patients are alive, survivals ranging from 2.5 to 23 m. One patient has an unmaintained radiological CR continuing for 23 months with an AFP decrease from 139 to 2.9. Another patient had a PR and an AFP decrease from 355 to 3.2 ng/mL. She died in PR at 13 months from an UGI bleed. Grade 3 and 4 toxicities were limited to the skin, and included HFS, in 4/12, skin ulcers at sites of prior osteomyelitis (1/12); requiring treatment cessation, and fatigue in 4 /12.

Conclusions: With meticulous attention to cap dose adjustments as dictated by HFS this combination can be tolerated longitudinally in these frail pts that are not candidates for adding more aggressive agents to sorf. The objective radiological responses corroborated by AFP decreases in this very small cohort suggest that the findings are real, and warrant expansion of the trial.
Effect of octreotide LAR on quality of life of 93 Hungarian patients with neuroendocrine tumors.
Authors: Gyökeres Tibor , Pulgar Sonia , Singh Neha , Passos Vanessa Q. , Kelemen Peter
Published: February 2017

362

Background: Studies have shown that health-related quality of life (HRQoL) of patients with neuroendocrine tumors (NET) is lower compared to the general population in the US and Norway. Secretory symptoms associated with functional NET (diarrhea/flushing) contribute to worsened HRQoL but may be controlled with the somatostatin analog octreotide long-acting repeatable (LAR). To date, there have been limited assessments of specific drug effects on HRQoL in patients with NET. The purpose of this study was to assess the effect of octreotide LAR treatment on HRQoL.

Methods: 93 Hungarian patients with gastroenteropancreatic NET who were treated with octreotide LAR participated in a multicenter observational study from 2005 to 2007. At study entry and 4 quarterly follow-up visits, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire. A mixed model was used to analyze the data and confirm significance.

Results: 91 patients (mean age = 61 years) were evaluable for QoL assessments. Overall, patients reported improvements in diarrhea, global health status, emotional functioning, and financial difficulties but worsening in role functioning, pain, and insomnia. There were some differences in trends, depending on the tumor site, but diarrhea still improved in all patient categories. Women reported lower global health status compared to men, including more fatigue, nausea/vomiting, pain, dyspnea, and constipation. Elderly patients >70 years did not report any lessening of overall global health status scores compared to younger patients; older patients did experience less nausea/vomiting and pain but more constipation and diarrhea. In addition, patients diagnosed <2 years had slightly lower global health status than patients diagnosed >2 years earlier.

Conclusions: Patients with NET who were treated with octreotide LAR had improvements in global health status and diarrhea. Interesting trends were noted in different patient populations, depending on tumor site, gender, or age. Additional analysis is planned to assess changes as measured by the GI NET disease-specific module of EORTC that was also applied to patients.
Sixty-six consecutive cases of neuroendocrine tumor treated with somatostatin analogues: A 20-year single-center experience.
Authors: Savvoukidis Theodoros , Ramadori Giuliano
Published: February 2017

374

Background: Neuroendocrine tumours (NET) arise from enterochromaffine and related cells found in epithelial organs throughout the body. Hormone related symptoms in neuroendocrine tumours are well treated with somatostatin analogues. Previous experience has demonstrated some antiproliferative activity of somatostatin analogues in the treatment of NET.

Methods: In the last 20 years 66 patients with histologically proven NET were treated: primaries in small bowel (27), pancreas (16), rectum (9), appendix (5), lung (3), unknown (3), extra- adrenal abdominal paragangliomas (2) and stomach (1). The mean age of first diagnosis was 56 years. All of them received somatostatin analogues in long acting depot administration (or combination interferon/somatostatin analogues) for a minimum period of two months and a maximum of 139 months. Somatostatin therapy was started in patients with endocrine-active tumours immediately after the diagnosis and in patients with endocrine-inactive tumours after an observation time of 3 months without therapy if progress was observed. Tumor size was assessed every 3 months after begin of therapy.

Results: Best responses were a stable disease in 46 of 66 patients (70%) and a partial remission in 2 (3%). Nineteen of 66 patients (27%) showed progress. The responses achieved were in small bowel 20/27; pancreas 13/16; rectum 7/9; pancreas 7/9 and lung 2/3. The median duration of response was 34 months (range 3-139).

Conclusions: Our results document that treatment with somatostatin analogues prolongs time to progression in NET. Stabilisation of tumour mass itself is a relevant outcome for patients with NET. The benefit of somatostin analogues is indipendent to use of chemotherapy. Because of its efficacy and the good tolerability somatostatin analogues can be considered a first line treatment option.
Effect of a gastrointestinal multidisciplinary clinic on the quality of pancreatic cancer care delivery at a community cancer center.
Authors: McCahill Laurence E. , Wright Gerald P. , Konduri Sunil , May Mary , Martinez Coralyn , Taylor Wendy K. , Morrow J. Brad , Davis Alan T.
Published: February 2017

378

Background: Healthcare reform calls for measurements of value in services received. The 2002 IOM report Crossing the Quality Chasm emphasized deficits in efficiency, effectiveness, and patient centeredness. In 2009, a pancreatic cancer panel proposed 43 measures for high quality pancreatic cancer care. We incorporated these composite measures into a unique program of multidisciplinary (MD) care, nurse navigation (NN), and quality monitoring.

Methods: A MD gastrointestinal cancer program was initiated in Jan 2010. Key components included a treatment planning conference followed immediately by a MD clinic. A GI NN coordinated staging, clinical evaluation, and treatment initiation. Patients with suspected /newly diagnosed pancreatic or periampullary neoplasms were included. We evaluated our quality of cancer care and outcomes proposed by the pancreatic cancer quality expert panel.

Results: A total of 76 patients with pancreatic neoplasms were evaluated over 18 months, 55 subjects had confirmed malignancies. Of these, 20 were clinical Stage I/II, 15 stage III and 20 Stage IV. Quality measures in Table 1 focus on quality measures. 25 patients underwent resection. Mean OR time was 424 min, mean EBL 843 mL, morbidity 30%, mortality 4%, R0 resection rate 76%, mean nodes evaluated 24, and mean hospital LOS 10 days. Complete adherence with guidelines occurred in all 30 non-operative patients and 22 of 25 patients who undergoing resection. Overall compliance for all pancreatic cancer care guidelines was 99.7%.

Conclusions: Comprehensive MD pancreatic cancer evaluation and care is feasible in a community cancer. We believe this study establishes new benchmarks of quality and value assessment for pancreatic cancer programs.

[Table: see text]
Influence of intra-hepatic chemotherapy on survival of patients with colorectal liver metastasis treated with hepatic resection and systemic chemotherapy.
Authors: Kanaan Mohammed , Mozayen Mohammad , Nagpal Sunil , Wiese David , Eilender David S. , Singh T. Trevor , Arora Madan L. , Saha Sukamal
Published: February 2017

379

Background: The role of intrahepatic pump chemotherapy (HAI) in the treatment of liver metastasis is still controversial. Our study was performed to evaluate the adjunctive role of HAI in patients (pts) with colorectal liver metastasis (CLM) treated with major hepatic resection and systemic chemotherapy (Systemic Rx).

Methods: A retrospective analysis was performed on pts with histologically confirmed CLM who had major liver resection and/or radiofrequency ablation and received systemic Rx with HAI and compared with pts without HAI. Primary outcome was overall survival. Exclusion criteria included a second cancer, refusal of chemotherapy, loss of follow-up and minor resection or biopsy alone. Statistical analysis was done using Kaplan-Meyer survival curves.

Results: Consecutive 66 pts with CLM were analyzed, of which 13 pts were lost to follow-up. Out of 53 pts undergoing systemic Rx and major liver resection, 37 pts had HAI with 5-fluorouracil (gp A) and 16 pts had no HAI (gp B). Both groups received similar systemic Rx ( Table 1). There was no HAI related mortality in gp A. Pts with minimum follow-up of 3 years were included for survival analysis. The overall 3-year survival of gp A was 36% (12 pts out of 33) compared to 23 % (3 pts out of 13 pts) in gp B. Due to small sample size statistical significance was not achieved.

Conclusions: Pts with CLM who undergo systemic Rx with HAI along with major hepatic resection or ablation may survive longer than pts with systemic Rx without HAI. A larger multicenter study is warranted.

[Table: see text]
ABO blood group and survival in pancreatic cancer.
Authors: Wai Christina , Devarajan Karthik , Hoffman John Parker
Published: February 2017

380

Background: ABO blood group has been shown to be a risk factor in many gastrointestinal cancers. Recent studies have shown that patients with non-O blood groups have a higher risk of pancreatic adenocarcinoma compared to those with blood group O. Based on this finding, we were interested in seeing if a particular ABO blood group would have an impact on survival outcomes in pancreatic cancer.

Methods: A retrospective chart review of 236 pancreatic patients who underwent surgical resection at a major cancer center from January 1998 to July 2011 was performed. Data were collected for demographics, ABO blood group, Rh factor, CA 19-9 level, use of neoadjuvant therapy, pathological stage, surgical margins and peritoneal washings. Overall survival (OS) was compared amongst the different blood groups.

Results: There were 118 male and 118 female patients. The median age at diagnosis was 68. Of the 236 patients, 80 (33.9%) were blood group O, 108 (45.8%) were blood group A, 32 (13.6%) were blood group B and 16 (6.8%) were blood group AB. For all patients, there was no statistically significant association between ABO blood group and OS (log rank test p = 0.7). Furthermore, no survival difference was seen between O and non-O blood groups when the data was stratified by stage and neoadjuvant therapy.

Conclusions: Like other GI malignancies, ABO groups have been shown to be linked to the risk of pancreatic cancer. The mechanism by which this occurs is not completely clear. In our analysis of ABO blood groups, they were not shown to be prognostic indicators. There does not appear to be a difference in overall survival between patients with O blood group and those with non-O blood groups.
Mutant (MT) KRAS codon 12 and 13 alleles in patients (pts) with metastatic colorectal cancer (mCRC): Assessment as prognostic and predictive biomarkers of response to panitumumab (pmab).
Authors: Peeters Marc , Douillard Jean-Yves , Van Cutsem Eric , Siena Salvatore , Zhang Kathy , Williams Richard Thomas , Wiezorek Jeffrey S.
Published: February 2017

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Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR). Significant improvement in progression-free survival (PFS) was demonstrated in pts with wild-type (WT) KRAS mCRC treated with pmab+FOLFOX4 (1st-line; study 20050203), pmab+FOLFIRI (2nd-line; study 20050181), and pmab monotherapy (study 20020408). In mCRC, mutations in KRAS codons 12 and 13 are established biomarkers for lack of clinical benefit to anti-EGFR therapies. We retrospectively examined individual MT KRAS codon 12 and 13 alleles as prognostic and predictive biomarkers of response in three phase 3 studies.

Methods: Pts were randomized to receive FOLFOX4, FOLFIRI, or best supportive care +/- pmab 6.0 mg/kg Q2W in studies 20050203, 20050181, and 20020408, respectively. The MT KRAS codon 12 and 13 alleles (G12A, G12C, G12D, G12R, G12S, G12V, G13D) were detected using the Therascreen K-RAS Mutation Kit (Qiagen).

Results: MT KRAS codon 12 and 13 alleles were detected in 40% (440/1096), 45% (486/1083), and 43% (184/427) of pts in studies 20050203, 20050181, and 20020408, respectively. MT KRAS allele distribution was conserved across studies and balanced between treatment arms. Baseline demographic and clinical features were comparable between all MT KRAS allele subgroups. Across all studies, no single MT KRAS allele was consistently prognostic for PFS or overall survival (OS) in the control arm-treated pts. Similarly, no single MT KRAS allele was a consistent positive or negative predictive factor for PFS or OS in pmab-treated pts. Only in the pmab+FOLFOX4 arm of study 20050203 were G13D (unfavorably) and G12V (favorably) significantly associated with OS. Response rates were similar between MT KRAS allele groups in the 1st- and 2nd-line mCRC treatment setting. Finally, in analyses of pts pooled from all 3 trials, only the G12A KRAS allele emerged as a significant negative predictive factor for OS.

Conclusions: The lack of consistent results across three lines of therapy indicates pts with MT KRAS codon 12 or 13 alleles are unlikely to respond to pmab therapy. Currently, only pts with WT KRAS mCRC should be treated with pmab.
Detecting hereditary nonpolyposis colorectal cancer syndrome (HNPCC) in patients with colorectal cancer (CRC): Optimal strategies at lower costs.
Authors: Abbott Daniel Erik , Cantor Scott B. , Rodriguez-Bigas Miguel A. , Chang George J. , Lynch Patrick M , Feig Barry W. , Skibber John Michael , You Y. Nancy
Published: February 2017

396

Background: The optimal strategy to detect HNPCC in CRC pts remains controversial, and may include testing tumors for microsatellite (MSI) status and/or pts for mutations in DNA mismatch repair (MMR) genes. Costs of 6 testing strategies were compared against their risks of missing pt managed as HNPCC.

Methods: 185 consecutive CRCs were prospectively tested by both immunohistochemistry (IHC, for protein expressions of MLH1, MSH2, MSH6, PMS2) and PCR-based MSI. Secondary tests included MLH1 promoter methylation, BRAF mutation, and germline mutation, as appropriate. A decision tree compared the strategy of performing both IHC and MSI in all (Strategy 1) to five alternatives (Strategies 2-6, Table ). Costs were obtained from commercial list prices, Medicare reimbursement, and literature; probabilities were calculated from pt data. Incremental cost-effectiveness ratios (ICERs) were reported for each additional pt managed as HNPCC

Results: 20 (10.8%) pts were identified as being managed as HNPCC. Performing IHC and MSI in all (Strategy 1) or IHC first in all followed by MSI when IHC was normal (Strategy 4) detected all 20 cases. When compared to performing IHC only (Strategy 2), Strategy 4 demonstrated an ICER of $31,821 per additional case detected, while other strategies were more costly and/or less effective (Table). Between the two strategies that detected all cases of HNPCC, Strategy 4 was less costly ($1,049 vs $1,098 per patient, Table).

Conclusions: When combined with appropriate secondary and confirmatory testing, performing IHC and MSI in all or IHC in all followed by MSI when IHC were normal, both showed a zero miss rate, while the latter was slightly more cost-effective.

[Table: see text]
Risk of colorectal cancer subsite in a prostate cancer cohort.
Authors: Lu Yunxia , Ljung Rickard , Lindblad Mats , Lagergren Jesper
Published: February 2017

404

Background: Epidemiological studies imply an association between sex hormonal related factors and the risk of colorectal cancer.

Methods: A prostate cancer cohort was initiated from the Swedish Cancer Register among patients diagnosed during 1961-2008. The prostate cancer patients were followed up until a diagnosis of colorectal adenocarcinoma, death, emigration or end of study (December, 31, 2008). The cohort was stratified into a group as “estrogen exposed” who were diagnosed with prostate cancer before 1980, and a group as “estrogen less exposed” who were diagnosed after 1980. The reason for this grouping was estrogen therapy was the predominant treatment strategy in Sweden before 1980 while other treatment became more common after 1980. Standardized incidence ratios (SIRs) and 95% confidence interval (CI) were estimated as the measure of relative risk compared to the general population of the corresponding age and calendar year. SIRs were estimated for total colorectal cancer and for cancer of the proximal colon, distal colon, and rectum separately.

Results: Among a total of 190,485 of prostate cancer patients contributing 708,019 person-years at risk, we identified 1493 colorectal adenocarcinoma. For those diagnosed with prostate cancer before 1980 (estrogen exposed group),almost all age groups showed a decreased risk of colorectal cancer, except for cancer of the distal colon, compared to the general population. Increased risk of colorectal cancer was instead found in almost all age groups for those diagnosed after 1980 (estrogen less exposed group). SIRs of adenocarcinoma in the proximal colon and distal colon showed different patterns. After 1980, the SIR of adenocarcinoma in the distal colon among patients followed up for >10 years was 1.29, (95% CI 1.02-1.60).

Conclusions: This study indicates that exposure to estrogens protect against colorectal cancer, while treatment after 1980 displayed a potential increased risk of colorectal adenocarcinoma, especially in the distal colon.
A novel, cost-effective strategy for the screening of colorectal cancer with higher patient compliance.
Authors: Motamed-Khorasani Afsaneh , Small-Howard Andrea Lee
Published: February 2017

407

Background: Routine screening methods for colorectal cancer (CRC) have poor patient compliance and low sensitivity for early stages. The sensitivity rates are 19, 71, 76, and 83% for Fecal Occult Blood test (FOBT), stool DNA test, colonoscopy/sigmoidoscopy, and double-contrast barium enema; respectively. Biological markers have also been tested including CEA (sensitivity of 38.7%); however, its utility in CRC screening is limited due to low sensitivity. Onko-Sure is an FDA-cleared blood test for monitoring of CRC treatment/recurrence. It measures the accumulation of Fibrin/Fibrinogen Degradation products in the serum using anti-DR-70 antibody. The objective was to determine whether DR-70 and CEA combination can improve the sensitivity such that it can be used as a cost-effective alternative to current screening methods yet with a higher patient compliance.

Methods: A total of 564 serum samples were retrospectively obtained from a serum bank in two arms: confirmed healthy control (n=298) and biopsy-confirmed CRC (n=266) groups. The samples were tested for DR-70 and CEA.

Results: The results showed sensitivity of 58.2% and specificity of 59.83% for DR-70 and CEA combined. The sensitivity for the combined test was 55.5% higher than that of CEA alone. A consistent improvement of sensitivity for the combined usage relative to CEA alone was observed with an increase of 73%, 108%, 58% and 18% in CRC stage I, II, III and IV; respectively. The sensitivity of the combined test was 48%, 47%, 57% and 98% for stages I, II, III and IV.

Conclusions: Combining DR-70 and CEA tests showed a significant clinical advantage in CRC screening over using each marker alone. The sensitivity improvement was highest for stages I/II, which has important implications in patient treatment options, prognosis and survival rate due to this early detection. With a 3 times higher sensitivity for early stage CRC compared to using FOBT, this approach should improve the CRC early stage diagnosis. Such early stage detection is less likely using routine approaches for CRC screening because of low sensitivity and low patient compliance.
The association between smoking and LINE-1 hypomethylation (global DNA hypomethylation) in normal esophageal epithelium of patients with esophageal squamous cell carcinoma.
Authors: Iwagami Shiro , Baba Yoshifumi , Watanabe Masayuki , Shigaki Hironobu , Miyake Keisuke , Ida Satoshi , Nagai Yohei , Ishimoto Takatsugu , Iwatsuki Masaaki , Sakamoto Yasuo , Miyamoto Yuji , Baba Hideo
Published: February 2017

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Background: DNA methylation is a major epigenetic mechanism in X-chromosome inactivation, imprinting and repression of transposable elements and endogenous retroviral sequences. Global DNA hypomethylation appears to play an important role in genomic instability, leading to cancer development. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of global DNA methylation level. Smoking and alcohol is extremely important as the etiology of esophageal squamous cell carcinoma. Nonetheless, whether or not smoking and alcohol affect LINE-1 methylation level in normal esophageal epithelium of esophageal cancer patients remains uncertain.

Methods: We quantified LINE-1 methylation of normal esophageal mucosa using pyrosequencing technology in 118 resected esophageal squamous cell carcinomas. The data on smoking (Brinkman index, absence or presence) and alcohol amount are available in all cases. We excluded preoperatively treated cases.

Results: LINE-1 methylation in normal esophageal epithelium of esophageal cancer patients ranged from 57.1 to 92.8 of 0-100 scale (N=118; mean 81.2; median 80.0; standard deviation 7.2). LINE-1 methylation level (continuous variable) was significantly associated with Brickman index (continuous variable) (r=0.12, p=0.0002); heavy smoker had lower LINE-1 methylation level of normal esophageal mucosa. LINE-1 methylation level was lower in patients with smoking history (mean 79.7) than in patients without smoking history (mean 83.2) (p=0.034). Alcohol assumption was not associated with LINE-1 methylation level (r=0.003, p=0.58).

Conclusions: Smoking was associated with LINE-1 hypomethylation in esophageal normal epithelium, suggesting the possibility of epigenetic field effects caused by cigarette in esophageal tumorigenesis. Considering that DNA methylation alterations are reversible and can thus be targets for chemoprevention, our findings may have clinical implication.