bluuebunny/crossref_metadata_2025 huggingface dataset:
Collective analysis of efficacy and safety of patients with advanced hepatocellular carcinoma (HCC) enrolled into early-phase clinical trials.
Authors: Madhusudanannair Vinu , Pollock Brad H. , Ketchum Norma , Weitman Steven , Sarantopoulos John , Mahalingam Devalingam
Published: February 2017

320

Background: Sorafenib is the only approved systemic therapy in HCC. Clinical trials in HCC often exclude patients with Child-Pugh Stage (CPS) B/C cirrhosis. Furthermore, limited information on outcomes specific to HCC population are reported from early clinical trials. We evaluated the efficacy and safety of early phase clinical trial agents used to treat HCC. Methods: 42 consecutive patients with advanced HCC enrolled in one of the 53 phase I trials at our institution between 2003- 2013 were analyzed. Median progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves along with medians and groups were compared with the log rank test. The magnitude of association and survival was estimated with the hazard ratio (HR). Results: Median age 63 (33–84), males 75 %, ECOG PS 0–1 92%, CPS A 19%, B 71.7% and C 9.4%. 41.5% subjects were treated with prior Sorafenib. Class of agents used included cytotoxics such as microtubule inhibitors (26.4%), anti-folates (5.7%), alkylators (1.9%), topoisomerase inhibitors (5.7%), and non-cytotoxic agents such as pro-apoptotic therapies (15.1%), anti-VEGF (17%) mTOR/ EGFR/ IGFR (22.6%), and HDAC inhibitors (5.7%). When evaluating for efficacy for all patients, the mPFS (95% CI) =2.3 (1.9, 3.9) months and 12 month OS ± SEM = 59% ± 15%. The mPFS was 3.7 months versus 2.1 months for CPS A subjects and CPS B/C subjects respectively (HR 1.5, CI: 0.7- 3.5, p= 0.31). The 12-month OS was 80 ± 18% among pts with CPS A vs 74 ± 8% in CPS B. Grade 3-4 toxicity included hematologic (13.2%) and hepatic (20.8%), with no significant difference in toxicity between the two CPS groups. Finally, cytotoxic agents had a mPFS of 3.1 months (95% CI: 2.1- 4.4) vs 1.9 months (95% CI: 1.1- 2.3) for non-cytotoxic therapy (HR 1.56, 95% CI: 0.8–3.07, p = 0.19). The 12 month OS was 46% vs 50% between these two groups (HR 6.2, CI: 1.3–29.3, p = 0.009). Conclusions: Patients with advanced HCC have a modest survival that is compounded further by poor liver function. Our data suggests that there are no significant differences in efficacy and safety between HCC patients with varying liver dysfunction based on CPS status.
Stereotactic body radiation therapy for pancreatic cancer: Single institutional experience.
Authors: Moningi Shalini , Raman Siva P. , Dholakia Avani Satish , Hacker-Prietz Amy , Pawlik Timothy M. , Zheng Lei , Weiss Matthew , Laheru Daniel A. , Wolfgang Christopher Lee , Herman Joseph M.
Published: February 2017

328

Background: Stereotactic Body Radiation Therapy (SBRT) is emerging as a possible standard treatment for pancreatic cancer; however, there is limited data to support its efficacy. This study reviews our institution’s experience using SBRT in the treatment of pancreatic cancer (PCA). Methods: Charts of all PCA patients receiving SBRT from January 2010 to June 2013 were retrospectively reviewed. The primary end points were overall survival (OS) and tumor response assessed by RECIST criteria. 95% of the PTV (GTV + 2-3 mm) received a total dose of 20-33 Gy in five fractions (4-6.6 Gy/fraction), with up to 20% heterogeneity allowed. Pre- and post-SBRT chemotherapy regimens included gemcitabine, cisplatin, FOLFIRINOX, 5-FU or paclitaxel. Results: 84 patients received SBRT, with a median follow-up time of 15.3 months. Median age was 66.5 years, 57.1% were male and 65.5% had head tumors. 66 patients received definitive SBRT for locally advanced or borderline resectable PCA, 4 patients were treated with adjuvant SBRT, and 14 received SBRT for treatment of recurrent disease. Median OS from the date of diagnosis for patients receiving definitive radiation was 17.8 mos (95% CI 14.9-20.9).For recurrent patients the median OS from first day of SBRT was 11.8 mos (95%CI 8.3-15.3). In the definitive SBRT group, among patients who were alive and had follow-up scans, the 6 and 12 month local control rate (stable or partial response) based on RECIST criteria was 84.6% and 81.8%, respectively. Five patients underwent surgery following SBRT and all had negative resection margins. Acute toxicity was minimal with most experiencing grade 1 or 2 fatigue and no grade 3/4 acute toxicity. Late grade 3/4 GI toxicity was seen in 5% (4/84) and 1 patient had a grade 5 GI bleed due to direct tumor invasion into the duodenum. Conclusions: Our early results using SBRT in the definitive and recurrent settings show favorable local control, toxicity, and survival when compared to historical outcomes using chemoradiation. Acute and late toxicity was minimal however the optimal dose and fractionation as well as normal tissue dose constraints need to be determined. Integration of SBRT with more aggressive chemotherapy may result in improved outcomes in patients with PCA.
Recurrence of pancreatic ductal adenocarcinoma after pancreaticoduodenectomy: Is there a role for locoregional treatment?
Authors: Gangi Alexandra , Menon Vijay G. , Sheckley Marwan , Tuli Richard , Hendifar Andrew Eugene , Wachsman Ashley , Nissen Nicholas N.
Published: February 2017

329

Background: The majority of patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma (PDA) will face recurrence. While other types of metastatic tumors are often treated with loco-regional therapy, this approach is rarely applied to metastatic PDA. We examined recurrence patterns of PDA and the potential application of loco-regional treatment. Methods: Evaluation of a prospective database of patients undergoing pancreaticoduodenctomy at an academic institution by a single surgeon. Patients: Pancreaticoduodenectomy for PDA was performed in 95 patients between 2002 and 2012. Margin status was R0 in 88 (93%) and R1 in the remainder. Results: Overall median survival was 27 months and 1 and 3 year survival was 68% and 41%. Known recurrence occurred in 44 of 64 patients (69%) at a median of 20.9 months, while the status of 31 patients was unknown. The most common site of initial recurrence was liver (n=19, median 9.2 months post-surgery), followed by local recurrence (n=15; median 18.7 months) and lung (n=5; median 5.2 months). Patients with R0 margin vs R1 recurred at a median 21 vs 5 months. In our series, 6 patients (5/6 treated in the last 2 years) underwent loco-regional treatment of recurrent disease, including liver resection (n=2), stereotactic radiotherapy (n=2), hepatic ablation (n=1) or radioembolization (n=1). All 6 patients treated with loco-regional therapy are alive at a median of 15.6 months after recurrence and a median of 25.3 months since initial surgery. Conclusions: The initial site of recurrent PDA after pancreaticoduodenectomy is usually liver, and the major risk factor for recurrence is the margin status at resection. Loco-regional modalities for the treatment of recurrent PDA hold promise in select patients. The tendency to utilize loco-regional therapy for recurrent PDA is increasing and warrants continued consideration.
Outcomes of adjuvant radiotherapy and lymph node dissection in elderly patients with pancreatic cancer treated with surgery and chemotherapy.
Authors: Freilich Jessica , Mellon Eric Albert , Springett Gregory M. , Meredith Ken , Hodul Pamela Joy , Malafa Mokenge Peter , Fulp William J. , Zhao Xiuhua , Hoffe Sarah E. , Shridhar Ravi
Published: February 2017

332

Background: To determine the effects of postoperative radiation therapy (PORT) and lymph node resection (LNR) on survival in patients age ≥ 70 with pancreatic cancer treated with surgery and chemotherapy. Methods: An analysis of patients with surgically resected pancreatic cancer who received chemotherapy from the SEER database from 2004-2008 was performed to determine association of PORT and LNR on survival. Survival curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed by the Cox proportional hazard model. Results: We identified 961 patients who met inclusion criteria. The only significant difference between PORT patients and no PORT patients was age, median 75 and 76 years, respectively (p=0.007). Overall survival (OS) in PORT versus no PORT was not statistically different in the whole cohort (p=0.064), N0 (p=0.803) or N1 (p=0.0501). On univariate analysis (UVA) there was increased OS in patients with lower T stage (p<0.001), N0 status (p<0.001), lower AJCC stage (p<0.001) and lower grade (p<0.001). No OS difference was seen based on gender, location, or PORT. There was no difference in OS based on number of lymph nodes removed in all patients (p=0.74), N0 (p=0.59), and N1 (p=0.07). MVA for all patients revealed higher T stage, N1, and high grade were prognostic for worse mortality, while there was a trend for decreased mortality with PORT (p=0.052). In N0 patients, increased T-stage and grade were prognostic for worse survival, while PORT and number of lymph nodes removed were not. In N1 patients, higher T-stage and grade were prognostic for increased mortality, while increasing number of lymph nodes removed was associated with decreased mortality. PORT trended towards improved survival in N1 patients (p=0.06). Age, gender and tumor location were not prognostic for survival. Conclusions: Adjuvant radiation therapy and number of lymph nodes removed in patients age ≥70 does not seem to correlate with increased OS in surgically resected pancreatic cancer treated with chemotherapy. Future clinical trials will need to address age as a stratification factor for pancreatic cancer in the adjuvant setting.
Hapten-enhanced personalized chemoimmunotherapy by intratumoral drug delivery in advanced pancreatic cancer.
Authors: Yu Baofa , Lu Yuanfei
Published: February 2017

333

Background: Currently cancer therapy is not satisfied with the effectiveness of available treatment. Engaging the power of immune system of individual patient has been considered as a highly attractive way for cancer treatment. Sipuleucel-T is an autologous cellular vaccine and represents a significant milestone for cancer immunotherapy. To evaluate the clinical effective of hapten enhanced personalized chemoimmunotherapy by intratumoral delivery of a combined drugs solution called ChemoCancerVac (CCV) in the treatment of advance pancreatic cancer and further to analyze the effect of immune adjuvant. Methods: Introtumoral injection of CCV into late stages of pancreatic cancer (92 cases), which is a proprietary therapeutic regimen composed of three components for modulation of chemoimmunotherapy, i.e. an oxidant, a cytotoxic drug and a hapten. The patients (47 patients with effect analysis and 45 patients with complete survival data were randomly divided into two groups: introtumoral chemotherapy (ITCT) alone received the CCV without hapten and introtumoral chemoimmunotherapy (ITCIT) received the CCV with the hapten. Results: In the ITCT and ITCIT groups, the clinical response rates were 92.86% and 82.88%, the median survival time and 6-month survival rate were 6.45 months vs 4.98 months and 45% vs 64%, respectively. All of mentioned above were showed no statistical difference (p>0.05), whereas 1-year survival rate of the ITCT group was 5% while that of ITCiT group was 28%. The difference was significant (p<0.05). Conclusions: The hapten enhanced personerlized immunotherapy by intratumoral injection of CCV was effective in the pancreatic cancer, meanwhile, the hapten plays an important role in prolong the patient survival time which are valuable in the clinic application.
Prospective observational study on chemotherapy-induced nausea and vomiting (CINV) for hepatobiliary and pancreatic cancer patients who were to receive chemotherapy including cisplatin by the CINV study group of Japan.
Authors: Furuse Junji , Baba Hideo , Ohkawa Shinichi , Sugimori Kazuya , Yamamoto Kazuhide , Minami Hironobu , Kitagawa Yuko , Kuramochi Hidekazu , Kwon A-Hon , Unno Michiaki , Wakabayashi Go , Aiba Keisuke , Tamura Kazuo
Published: February 2017

341

Background: There has been no nationwide survey on CINV or validation of the guideline in Japan. The aim of the study is to investigate occurrence of CINV in hepatobiliary and pancreatic (HBP) cancer patients who are to receive chemotherapy including high and moderate emetic risk for the first time. In addition, primary care medical staffs' perception on CINV for their patients is also studied. Methods: A nationwide survey on CINV was conducted by the CINV study group of Japan. 21 institutions participated in the study. A 7-day diary for CINV was provided to the patient prior to chemotherapy to record daily occurrence and severity of CINV and an amount of food intake. Acute and delayed CINV was defined as nausea and vomiting which developed within or after 24 hours after the start of chemotherapy, respectively. The medical staffs also filled out questionnaires about their patient’s CINV. Results: A total 103 HBP cancer patients of 1,952 patients registered in this study during the period from April 2011 to December 2012 were analyzed. These patients’ diary and their medical staffs' report were sent to the central office. Underlying diseases were biliary tract cancer (70 patients), hepatocellular carcinoma (23) and pancreatic cancer (10). There were 62 males with a median age of 69 (range: 37-83) and 41 females with a median age of 63 (range: 41-80). MEC was given to 4 as was HEC to 99 patients. Acute nausea was experienced in 6 (5.8%), while was noted delayed nausea in 25 (24.3%). Acute vomiting was noted in 2 (1.9%) patients, while delayed vomiting was experienced in 6 (5.8%). The predictive factors for delayed nausea were female and motion sickness. The predictive factor for delayed vomiting was morning sickness. Medical staffs overestimated the incidence of acute and delayed nausea/vomiting. Conclusions: CINV seems to be under control with management by the guideline, but delayed nausea remained to be high and needs further investigation.
Use of gemcitabine-platinum (Gem-P) in patients with advanced gall bladder (GB) cancer: A more aggressive disease compared to the West—Tata Memorial Centre (TMC) experience.
Authors: Sirohi Bhawna , Sheth Vipul , Singh Ashish , Gupta Alok , Goel Mahesh , Ramadvar Mukta , Shrikhande Shailesh V.
Published: February 2017

349

Background: GB cancer is a common cancer in northern India. Gem-P is currently the standard of care for pts with advanced biliary tract cancers based on the ABC02 study which had 61 pts with GB cancer with a clinical benefit rate (CR+PR+SD) of 85%. Indian patients have a higher risk disease and present at a more advanced stage than in the West and data on treatment is lacking. Methods: This is retrospective analysis of the prospectively maintained database of 131 pts with advanced GB cancer treated at TMC between Jan 2012-May 2013. Aim of the study is to assess the clinical benefit rate in this group of pts with the Gem-P. Pts received cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on D1 and D8 of a 21day cycle, for gem-oxaliplatin, pts received gemcitabine 1000mg/m2 on D1 and oxaliplatin 100mg/m2 on D2 every 14 days. Response was assessed after 3-4 cycles. Results: Of the 131 patients, 110 pts were treated with Gem-P (95 oxaliplatin, 15 cisplatin; 1 received cetuximab-Gem-P) and 21 (16%) pts received best supportive care alone in view of poor performance status and deranged organ function. Median age was 53 years (range, 27-76), 82F/49 M; median CA19.9 206 (<2-2251660); median CEA 6.9 (0.8-3541); site of metastases was liver in 66 (50%), nodal in 74(56%), peritoneal in 29(22%) and bilateral ovarian in 5(3.8%) patients. Of the 110 pts treated with GEM-P, PS was 0-1 in 91% of patients; median number of cycles received was 4 (1-12); grade 3 &4 toxicities were- thrombocytpenia-12 (11%), neutropenia -2 (2%), hepatitis -2 (2%) patients, neuropathy-4 (4%) and diarrhea-8 (7.2%). 86/110 (78%) were evaluable for response out of which 4 (5%) had CR, 31(36%) had PR, 13(15%) had SD, and 38 (44%) had progressive disease. 32/110 (29%) pts received 2nd-line chemotherapy (majority capecitabine -irinotecan based). Conclusions: This is the single largest study to show tolerance and efficacy of Gem-P in Indian pts with advanced GB cancer. Compared to the ABC 02 study, the clinical benefit rate is low at 56% suggesting that the biology of advanced GB cancers in Indian pts is likely to be aggressive and needs to be studied in prospectively designed studies.
90Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: A pilot study.
Authors: Fidelman Nicholas , Kerlan Robert Keith , Hawkins Randall A. , Bergsland Emily K. , Kelley Robin Kate , Ko Andrew H. , Korn Wolfgang Michael , Venook Alan Paul
Published: February 2017

359

Background: This prospective single-institution pilot study was undertaken to document the feasibility, safety, and efficacy of treatment of liver-dominant metastatic gastrointestinal cancer using 90Y glass microspheres. Methods: Between June 2010 and November 2012, 30 adult patients (22 men, 8 women; median age 61 years) with metastatic chemotherapy-refractory unresectable colorectal (n=15), neuroendocrine (n=9), biliary tract (n=3), pancreas (n=2), and esophageal (n=1) carcinomas underwent 45 lobar or segmental administrations of 90Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for 6 months after each treatment. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors, version 1.1. Time to maximum response, response duration, progression-free survival (hepatic and extrahepatic), and overall survival were measured. Results: Median target dose and activity were 111.6Gy and 2.5GBq per treatment session, respectively. All but 3 clinical AE were grade 1 or 2 in severity. The most frequent clinical AE were fatigue (83%), anorexia (50%), nausea (50%), abdominal pain (40%), vomiting (20%), fever (17%), and sweating (17%). Common metabolic and laboratory AE included hypoalbuminemia (50%), transaminitis (63%), and hyperbilirubinemia (27%). Serious AE included an unplanned hospital admission for carcinoid crisis, grade 3 vomiting, and grade 4 gastric ulcer. Patients with colorectal cancer had hepatic objective response rate (ORR) of 27% and a disease control rate (DCR) of 73%. Median progression-free and overall survival were 1.0 and 4.9 months, respectively. Patients with neuroendocrine tumors had hepatic ORR and DCR of 78% and 100%, respectively. Median progression-free survival was 18.5 months for this cohort. Conclusions: 90Y glass microspheres device has a favorable safety profile, and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort. Clinical trial information: NCT01290536.
Embolization versus embolization and systemic therapy in patients with hepatocellular carcinoma and metastatic disease: A retrospective analysis.
Authors: Kim Sunnie , Brown Karen T. , Fong Yuman , Solomon Stephen Barnett , Chou Joanne F. , Capanu Marinela , Harding James J. , O'Reilly Eileen Mary , Saltz Leonard , Abou-Alfa Ghassan K.
Published: February 2017

363

Background: Transarterial chemoembolization (TACE) provides a survival benefit in a subset of patients with unresectable hepatocellular carcinoma (HCC). Even though data are lacking, patients with metastatic HCC (mHCC) are sometimes treated with transarterial therapies to address the hepatic disease. Sorafenib is a standard treatment for patients with mHCC. Methods: A retrospective analysis was conducted on patients diagnosed with HCC who had undergone hepatic arterial embolization (HAE) between 2006 and until 2013. Overall survival (OS) was calculated from date of HAE to date of death and estimated by Kaplan Meier Methods. Patients alive at their last follow up date were censored. Results: Of 243 patients who had undergone HAE at MSKCC during the study period, 36 patients had mHCC on initial diagnosis. Of these, 22 received HAE only, while 14 received HAE plus systemic therapy at some time during their whole treatment course. Conclusions: Patients with mHCC who underwent HAE alone had a poor OS. These data suggest that there maybe a survival benefit in patients with mHCC treated with transarterial therapies add to systemic therapy that is given at some time during their whole treatment course. These results contrast with recent data on the use of combined modality in locally advanced disease. Further studies of combined modality therapy in the setting of mHCC may be warranted. [Table: see text]
Sorafenib in hepatocellular carcinoma (HCC): Is there a role for starting patients on a total daily dose of 400mg daily?
Authors: Olowokure Olugbenga Olanrele , Singeltary Brian , Ghose, Abhimanyu , Mierzwa Michelle Lynn , Latif Tahir , Shah Shimul , Ristagno Ross , Dwivedi Alok kumar
Published: February 2017

364

Background: S at a starting daily dose of 400mg twice daily (800mg) is considered the standard systemic therapy for HCC, in pts with well preserved liver function and advanced stage HCC, based largely on data reported by the SHARP and Asia-pacific trials. Due to complaints regarding SE and reluctance to start at full dose, we decide to retrospectively look at our HCC data base. This single institution retrospective review, evaluated the impact of starting S at a 400mg daily (200mg twice daily). Methods: From 06/01/09-09/01/13, using ICD code 155, newly registered advanced HCC pts, ECOG PS 2, Childs Pugh (CP) class A or B who were started on S 400mg daily were identified : CT scans and AFP levels were followed. PFS was estimated from the date of commencing therapy to date of progression or death if this occurred first and OS was estimated from date of commencing therapy until date of death or loss to follow up. Kaplan Meier survival estimates were obtained with 95% (CI). Log rank test was used to compare the PFS according to CP class. Results: 33 pts (M:F, 21:12), mean age of 59.8y (SD: 12.40) met inclusion criteria, the median duration (MD) of follow up was 8.7 m ( 1.07-27.43). 23(69.7%) pts were CP-A. 70% had abnormal AFP and this decreased > 50% from baseline in 8 (35%). 96% of the pts received prior locoregional therapy in CP-A and 50% in CP-B. Initial dose tolerance was observed in 23 (69.7%) pts. 16 pts (48.5%) needed dose reduction (CP-A: 56.5%, CP-B: 30%) while 19 (57.6%) pts were able to escalate their dose at some point (CP-A: 60.9%, CP-B: 50%). MD of (400mg/d) was 3m prior to any adjustment (CP-A: 3, CP-B: 2). Mean duration of S use was 8.88m (A-10.04, B-6.2). During follow up, 26 pts had POD and 24 pts died. There was no difference in PFS between CP-A and B and following POD 10/19 evaluable pts continued S. OS was 79 % (95%CI: 61-89%) at 3m, 67% (95%CI: 48-80%) at 6m, 50% (95%CI: 32-66%) at 9m, and 40% (95%CI: 23-57%) at 12m. The most common reported toxicities were fatigue 87.5%, diarrhea 53.1% and HFS/rash 43.8% Conclusions: In this cohort of pts S started at 400mg/d did not seem to result in worse outcomes compared to historic controls possibly due to the ability to tolerate therapy for a longer period of time.
Impact of body mass index on postoperative complications and long-term survival in patients with esophageal squamous cell carcinoma.
Authors: Kamachi Kenichi , Ozawa Soji , Hayashi Tsutomu , Kazuno Akihito , Ito Eisuke , Chino Osamu , Shimada Hideo , Makuuchi Hiroyasu
Published: February 2017

37

Background: Chachexia and undernutrition have been suggested to be risk factors for postoperative complications and survival in cancer patients. The aim of this study was to investigate whether body mass index (BMI) is related to the short-term and long-term outcomes in patients who undergo an esophagectomy for the resection of esophageal squamous cell cancer. Methods: Three hundred forty patients who underwent an esophagectomy for the resection of esophageal squamous cell cancer between 2003 and 2008 were retrospectively reviewed. The patients were divided into two groups: an L-BMI group characterized by a BMI < 18.5 kg/m2, and an N-BMI group characterized by a BMI ≥ 18.5 kg/m2. The overall and disease-free survival curves of the two BMI groups were determined using the Kaplan-Meier method and were compared using a log-rank test. A Cox proportional hazards regression analysis was used for the univariate and multivariate analyses. Results: The study included 40 patients in the L-BMI group and 300 patients in the N-BMI group. Pulmonary complications seemed to occur more frequently in the L-BMI group (P = 0.006). A histopathological assessment showed that nodal involvement was seen more frequently in the L-BMI group (P = 0.016). The 5-year overall survival rate was higher in the N-BMI group (63.6%) than in the L-BMI group (32.3%) (P < 0.001). The 5-year disease-free survival rate was also higher in the N-BMI group (64.2%) than in the L-BMI group (32.3%) (P = 0.014). In a multivariate analysis, a lower BMI, an upper tumor location, an advanced pathological T stage, and a larger number of metastatic lymph nodes were independent prognostic factors for overall survival (P < 0.05). Conclusions: Our data suggested that a lower BMI not only increased pulmonary complications but also impaired overall and disease-free survival after an esophagectomy for the resection of esophageal squamous cell cancer.
Second-line systemic treatment for advanced cholangiocarcinoma.
Authors: Rogers Jane Elizabeth , Law Lindsey , Nguyen D. Van , Qiao Wei , Javle Milind M. , Kaseb Ahmed Omar , Shroff Rachna T.
Published: February 2017

371

Background: Five-year survival for advanced cholangiocarcinoma (aCC) is reported at 5-10%. For advanced, unresectable patients, gemcitabine plus platinum (GEM-P) combination chemotherapy is common practice as first-line treatment with progression free survival (PFS) of 8 months and overall survival (OS) of 11.7 months. Data regarding chemotherapy treatment after first-line progression is limited. Methods: We performed a retrospective chart review of patients with aCC from 1/1/2009 to 12/31/2012 who received second-line chemotherapy at M.D. Anderson Cancer Center (MDACC). Median PFS was the primary endpoint. Secondary objectives included disease control rate (complete response + partial response + stable disease) and OS. Inclusion criteria: aCC diagnosis, progression on first-line therapy, and reimaging studies at MDACC. Exclusion criteria: patients who received localized treatment for aCC prior to second-line therapy or consolidative chemoradiation, mixed histology tumors, and those with a history of another malignancy. Results: 56 patients were identified, with the majority having intrahepatic aCC (95%). 80% of patients received gemcitabine based first-line treatment (GEM-P +/- erlotinib, GEM monotherapy). Second-line systemic treatment included GEM-P (19.6%), GEM + fluoropyrmidine (GEM-FU) (28.6%), fluoropyrmidine combination (FU-combo) (37.5%), and other consisting of chemotherapy or biotherapy monotherapy or combination (14.3%). Total median PFS was 2.7 months (95% CI = 2.3 to 3.8). Disease control rate was 50% with a median OS of 13.8 months (95% CI = 12 to19.3). No significant difference in PFS or OS was identified between the four second line treatment groups. A higher CA 19-9 at the start of second line treatment correlated with a worse survival (p= <0.01). Conclusions: This retrospective study revealed a 50% disease control rate, median PFS of 2.7 months, and a potential for improvement in OS in patients who received second line systemic treatment. Agents that may be considered include GEM + FU, FU-combination therapy, or GEM-P if not given first line.
Prognosis of advanced hepatocellular carcinoma (HCC) in patients undergoing surgery combined with peri- or postoperative treatment with sorafenib.
Authors: Wu Liqun , Pang Xufeng , Cao Jingyu , Wang Zusen
Published: February 2017

377

Background: Liver resection/transplantation are effective therapies for primary hepatocellular carcinoma (HCC), but high relapse rates can significantly impact long term survival, especially for patients with advanced disease. The objective of this study was to investigate the effects of surgery plus sorafenib on the prognosis of patients with advanced HCC. Methods: 36 male and 2 female patients of mean age 52.6 (range 36-65) years and an ECOG performance status score 0-1 (n=26) or 2 (n=12), received surgical therapy (28 liver resection and 10 liver transplantation) plus sorafenib for treatment of HCC with a high risk of relapse (n=3) or had relapsed. Sorafenib was administered orally 400 mg once or twice daily, and the dose was reduced or the treatment temporarily discontinued if a grade 3 or worse adverse event occurred. Treatment duration was >3 months and patients were evaluated every 4 weeks. The main endpoints were overall survival (OS) and time to progression (TTP). Results: Median follow-up time was 12.9 (range 4-59) months. Kaplan-Meier analysis demonstrated that median OS was 17 months (95%CI: 11.6-22.4), median TTP was 15 months (95%CI: 11.6-18.4). During follow-up, 20 patients died (18 from disease progression, 1 from a lung infection, and 1 accidently). Univariate analysis demonstrated that serum ALT >60 U/L at the beginning of treatment, Child-Pugh grade B, ECOG performance status score 2, tumor cell embolism in blood vessels, tumor volume ≥3 liver segments, and a tumor involving 2 vital organs were important factors affecting OS. The median OS of patients with a tumor volume ≥3 liver segments vs. patients with tumor volume <3 liver segments was 8 vs. 28 months (log-rank test, p<0.001), and median TTP was 5 vs. 24 months (p<0.001). Conclusions: Surgical resection in combination with sorafenib helped prolong OS and TTP in patients with advanced or relapsed HCC. OS for patients treated with sorafenib peri-operatively was longer than that for patients who received therapy after a relapse had occurred. Decreasing tumor burden and administering sorafenib as early as possible are helpful strategies to improve prognosis in patients with HCC.
Neoadjuvant rectal cancer (RC) score to predict survival: Potential surrogate endpoint for early-phase trials.
Authors: Yothers Greg , George Thomas J. , Petrelli Nicholas J. , O'Connell Michael J. , Beart Robert W. , Allegra Carmen Joseph , Roh Mark S. , Lopa Samia H. , Sharif Saima , Wolmark Norman
Published: February 2017

384

Background: Valentini, et al. (J Clin Oncol 29: 2011, 3163-72) developed nomograms for predicting overall survival (OS) based on clinical factors available after neoadjuvant therapy (tx). Pathologic T-stage (pT), N-stage (pN), and clinical T (cT) were the most important independent predictors of OS. We developed a neoadjuvant RC score (NAR score) using pN and downstaging of T (cT – pT) based on relative weights suggested by the nomograms. NSABP’s R-04 trial presents an opportunity for independent validation of the NAR score. Methods: Pts with clinical stage II/III RC undergoing preoperative RT (4,500cGy in 25 fractions over 5 wks + boost of 540-1,080cGy in 3-6 daily fractions) were randomized to one of four regimens in a 2x2 design: CVI 5-FU (225mg/m2 5 days/wk), with or without oxaliplatin (Ox) (50mg/m2 /wk x 5) or oral capecitabine (825 mg/m2 BID 5 days/wk), with or without Ox. The NAR score is computed as [5 pN – 3 (cT – pT) + 12]2/ 9.61 where: cT in {1, 2, 3, 4}, pT in {0, 1, 2, 3, 4}, and pN in {0, 1, 2}. The NAR score takes values from 0 to 100; higher scores indicate poorer prognosis. Analyses based on the score should be stratified by cT. NAR score is compared to pathologic complete response (ypCR) by Akaike’s information criterion (AIC) to determine the better predictor of OS. Results: 1,479 pts had data for the NAR score and follow-up for OS. Continuous NAR score was significantly associated with OS (HR/unit 1.04 95% CI 1.03-1.05, p<0.0001). Pts were grouped into low, intermediate, and high risk of death categories based on tertiles of the NAR score. Categories were significantly associated with OS (p<0.0001) with 5yr OS values of 92, 89, and 68%, respectively. ypCR was also significantly associated with OS (HR 0.37 95% CI 0.24-0.58, p<0.0001). Continuous NAR score had a much lower AIC (2,902.49) than ypCR (2,987.08) suggesting stronger association with OS. Conclusions: The NAR score has been validated as a predictor of OS after neoadjuvant tx for RC. AIC of the continuous NAR score suggests it is a better predictor of OS than dichotomous ypCR. NAR score could be used in place of ypCR as a surrogate endpoint for OS in early phase neoadjuvant rectal trials. Support: U10-CA-12027, U10-CA-37377, U10-CA-69651, U-10-CA-69974; Sanofi; Roche. Clinical trial information: NCT00058474.
Analysis of medical expenses according to the stage of gastric cancer during the first year after diagnosis.
Authors: Kim Sung Soo , Kim Jie-Hyun , Cheung Dae Young , Park Soo-Heon
Published: February 2017

4

Background: Gastric cancer is one of the most common malignant cancer in Korea as 33,000 new patients are being diagnosed annually. Department of Health and Human Services has performed cancer screening project that recommends adults over 40 years old get mandatorily gastrointestinal endoscopy or gastrography for the detection of early gastric cancer every two years for free. This contributes to the discovery of early gastric cancer. However, the effectiveness of gastric cancer screening project is often questioned due to the lack of accurate data of the difference in the medical expenses between early gastric cancer and advanced gastric cancer. This study was aimed to investigate that the detection of early gastric cancer can lead to a reduction in health care costs. Methods: For the patients with newly diagnosed with gastric cancer in nine medical institutions during December 1, 2011 to June 30, 2012, the cost of the initial treatment, a total of one-year costs related to gastric cancer, inpatient and outpatient visits, test costs according to the tumor stage were investigated using a retrospective analysis of the medical records. Results: The cost of the initial treatment ($1,877 USD, $7,749 USD, $8,020 USD, and $6,809 USD, respectively by stage; P=0.000) and a one-year care costs ($1,441 USD, $5,142 USD, $8,444 USD, and $24,950 USD, respectively by stage; P=0.008) were significantly lower in stage I as compared with stage II, stage III, and stage IV. The numbers of hospitalizations, outpatient visits and abdominal CT and PET-CT scans were also significantly fewer in stage I as compared with more advanced stages. There was no difference in the cost of the initial treatment and one year care costs associated with gastric cancer between stage II, III, and IV. Chemotherapy had no effect on the difference in medical expenses. In the treatment of gastric cancer, medical expenses was affected significantly by early stage, whether or not endoscopic resection and complications. Conclusions: Detection of early gastric cancer is valuable not only for the possibility of a complete cure, but also for the reduction of the medical costs that are responsible for the patients and national health insurance.
Are patients with colonoscopy also more likely to undergo other cancer screening? A population-based analysis.
Authors: Cooper Gregory , Kou Tzuyung Doug
Published: February 2017

401

Background: Colonoscopy use in the United States has been increasing but remains short of target rates, especially among minorities and lower SES; these same groups are also less likely to receive breast and prostate cancer screening. However, at a population level, it is not known whether disparities are accounted for by the same individuals. Methods: Using a 5% national random sample of fee-for-service Medicare beneficiaries, we identified patients ≥ 70 years in 2009. Medicare claims from 2004-2008 were used to identify receipt of prior colonoscopy and exclude previous cancer, and claims from 2009-10 were used to identify receipt of colonoscopy, mammography in women and PSA testing in men. Differences in mammography and PSA were compared between four groups: no prior colonoscopy (2004-8)/no colonoscopy in follow up (2009-10) (group 1), no prior colonoscopy/colonoscopy in follow up (group 2), prior colonoscopy/no colonoscopy in follow up (group 3), and prior colonoscopy/colonoscopy in follow-up (group 4). Differences were also evaluated in a multivariate logistic regression model that adjusted for SES and physician supply at the level of the hospital referral region (HRR). Results: 717,334 beneficiaries (453,945 women and 263,389 men) were included in the study. During 2009-2010, the frequency of mammography was 38.0%, PSA was 41.7% and colonoscopy was 16.1%. All three procedures were less frequently performed in patients who were older, nonwhite, and with higher comorbidity scores. The presence of additional cancer risk factors was also associated with screening. Screening receipt according to colonoscopy status is shown in the Table. Conclusions: In this population-based analysis, we found that individuals with repeat colonoscopy were also more likely to undergo other screening procedures, including mammography and PSA. The findings may be accounted for by patient factors as well as physician practice patterns. [Table: see text]
Clinical significance of serum angiopoietin-like protein 2 in colorectal cancer patients.
Authors: Kitajima Takahito , Toiyama Yuji , Shimura Tadanobu , Ide Shozo , Imaoka Hiroki , Kondo Satoru , Kawamura Mikio , Okugawa Yoshinaga , Kawamoto Aya , Hiro Junichiro , Saigusa Susumu , Ohi Masaki , Tanaka Koji , Inoue Yasuhiro , Mohri Yasuhiko , Kusunoki Masato
Published: February 2017

417

Background: Angiopoietin-like protein 2 (ANGPTL2) is a secreted protein belonging to the angiopoietin family. It has been reported to act as a causative mediator of chronic inflammation and metabolic abnormalities. ANGPTL2 increases inflammatory carcinogenesis in several cancers, and its expression in tumor cells is highly correlated with the frequency of tumor cell metastasis through increased tumor angiogenesis and tumor cell epithelial-to-mesenchymal transitions. However, to our own knowledge, clinical significance of serum ANGPTL2 in cancer patients remains unknown. The aim of this study was to quantify serum ANGPTL2 level using ELISA, and to evaluate its clinical and prognostic significance in patients with colorectal cancer (CRC). Methods: We quantified serum ANGPTL2 levels from 194 CRC patients and normal 48 controls (NC) by ELISA. Next, we investigated ANGPTL2 expression in matched CRC tissues (n=194) by immunohistochemistry (IHC) to identify the source of circulating ANGPTL2. The IHC score of ANGPTL2 was determined on the basis of both staining intensity and the percentage of positive cells. Results: Serum ANGPTL2 levels were significantly higher in CRC than in NC (p<0.01) and gradually increased according to TNM stage progression. Serum ANGPTL2 levels discriminated CRC from NC with high accuracy (AUC=0.837). High serum ANGPTL2 was significantly associated with larger tumor size (p=0.03), undifferentiated adenocarcinoma (p=0.03), advanced T stage (p<0.01), peritoneal metastasis (p<0.01). In addition, Kaplan–Meier curves revealed that high serum ANGPTL2 were significantly associated with poor disease free survival (p=0.01) and overall survival (p=0.03). Interestingly, ANGPTL2 levels in serum from CRC patients closely correlated with IHC scores of cytoplasmic ANGPTL2 expression in matched CRC tissues (r=0.14, p=0.03). Conclusions: Serum ANGPTL2, which might be derived from primary CRC tumor, has strong potential to serve as a noninvasive biomarker for CRC diagnosis and prognosis.
Are immunohistochemical (IHC)/microsatellite instability (MSI) testing necessary as part of Lynch syndrome work-up in the era of multiplex genetic testing?
Authors: Idris Ahmad Fitri , Hooper Simon D. , Farrell Michael P. , Nolan Carmel , Clarke Roisin , Berkley E , Gallagher David J.
Published: February 2017

425

Background: IHC for mismatch repair proteins and MSI are commonly used to direct genetic testing for Lynch Syndrome. Abnormal results in the setting of a positive family history often lead to genetic testing for Lynch syndrome. The often cumbersome process of completing IHC/MSI requires obtaining stored tissue +/- blood from a family member affected with cancer. Upfront genetic testing is not favoured due to concerns about identifying variants of uncertain significance. We performed a review of Lynch syndrome work-up in Ireland, and propose a model that is the reverse of the current international standard, and may expedite and simplify work up of these families. Methods: Data was ascertained from three cancer genetics services in Dublin and included the following variables: date of birth, date of request and reporting results for IHC, MSI and genetic tests. Time intervals were determined for LS work-up for all patients who had the process initiated in these 3 centres. Results: Probands from 50 families referred for LS work-up were included.The median time from date of IHC request to date of IHC report (total of 50 patients) was 4 weeks (range: 4 days to 36 weeks). The median time between date of IHC request to date of MSI report (n = 32 patients) was 20 weeks (range: 4 to 56 weeks). The median time from date of genetic test request to date of result (n = 9 patients) was 9 weeks (range: 2 to 26 weeks). The median time for completion of all 3 tests in one individual (n=3 patients) was 14 weeks (range: 10 to 60 weeks). Conclusions: The diagnostic pathway for Lynch syndrome is cumbersome and often lengthy. Appropriate upfront multiplex genetic testing would expedite the identification of mismatch repair gene mutation carriers. IHC/MSI testing could be used to characterise variants of uncertain significance.
Strenghening and protecting families: How to handle the familial colorectal cancer risk—A prospective observational study in Upper Bavaria.
Authors: Mansmann Ulrich Robert , Woelke Gabriele , Engel Jutta , Stausberg Juergen
Published: February 2017

427

Background: Lynch defines patients with familial colorectal cancer (CRC) risk as those with two or more first- or second-degree relatives (or both) with CRC. They make up about 20 percent of all CRC patients. Also, first degree relatives of CRC patients have an increased CRC risk. It is our goal to create population based data on familial CRC risk in a German population. Methods: Incident CRC cases in Upper Bavaria are collected and their family trees constructed. The patient’s relatives are documented by name, address and date of birth, but without health related information. Cancer history is added to a family by a record linkage procedure combining members of the family trees with cancer histories in the Munich CancerRegistry (MCR). A specific data protection concept guarantees anonymity for families and their cancer histories. Prevalence of familial CRC risk in upper Bavaria and the posterior probability of a family to carry CRC risk can be inferred from the anonymous data. Strength of simple familial CRC risk detection tools can also be assessed. Results: Per year, 141 clinical departments and 24 oncological practices report about 1300 incident CRC cases (below 70 years) to the MTR. Recruitment of patients started in September 2012. During the first year, we recruited 456 patients in 27 clinical departments and 6 oncological practices and contacted 1,600 relatives. Participation of relatives is reluctant in spite different information sources (leaflet, call center, internet) on the study purpose are provided. Record linkage creates an anonymous collection of CRC family histories. 37 families with a CRC patient below the age of 50 are recorded. They are recruited into a psycho-oncological substudy. First risk estimates will be available end of 2013. Conclusions: For the first time, the study offers population based data on familial CRC risk in a German population of 4.6 mio. people. The results strengthen the concept of familial CRC risk for the development of appropriate preventive screening strategies.
Mutations within the EGFR signaling pathway: Influence on efficacy in FIRE-3—A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.
Authors: Stintzing Sebastian , Jung Andreas , Rossius Lisa , Modest Dominik Paul , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Al-Batran Salah-Eddin , Vehling-Kaiser Ursula , Heintges Tobias , Moehler Markus , Scheithauer Werner , Kirchner Thomas , Heinemann Volker
Published: February 2017

445

Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In a preplanned analysis, the effect of mutations within the EGFR dependent pathway were investigated. Next to mutations within KRAS (exon 2, 3, 4), NRAS (exon 2, 3, 4) and BRAF (V600E), mutations within PIK3CA (exon 9 and 20) and Akt were investigated and their impact on ORR, PFS and OS within the FIRE-3 population was evaluated. The analysis of all mutations was carried out employing pyrosequencing. Results: The ITT population consisted of 592 KRAS WT (exon 2) patients. The current analysis includes 488 cases (82.4%) with tumor tissue available. In 407 pts sequencing of all RAS mutations was possible. The ORR within the WT RAS patient group was higher in the FOLFIRI plus cet arm (65.5% vs 59.6%; Fisher´s p: 0.157). HRs (cet; bev) for pts with WT RASwere 0.93 (95% CI, 0.74-1.17; p = 0.54) for PFS and 0.70 (95% CI, 0.53-0.92; p = 0.01) for OS. PIK3CA mutation did not influence PFS nor OS when compared to the RAS wt population. Conclusions: ORR and OS were increased in patients with cet plus FOLFIRI as compared to bev plus FOLFIRI in patients without RAS mutations. Exclusion of patients with RAS mutations identifies a population which is more likely to benefit from cetuximab. Clinical trial information: NCT00433927.