bluuebunny/crossref_metadata_2025 huggingface dataset:
Cryoablation compared with radiofrequency ablation and microwave coagulation therapy for the local control of primary hepatocellular carcinoma.
Authors: Ei Shigenori , Tanabe Minoru , Hibi Taizo , Itano Osamu , Shinoda Masahiro , Kitago Minoru , Abe Yuta , Yagi Hiroshi , Okabayashi Koji , Odaira Masanori , Kadota Yoshie , Fujimura Tomonori , Katsuki Yusuke , Tanaka Masayuki , Tsutsui Rina , Wakabayashi Go , Kitagawa Yuko
Published: February 2017

286

Background: Although cryoablation (Cryo) has been advocated as an effective local treatment for hepatocellular carcinoma (HCC), data are lacking regarding its outcomes in comparison with radiofrequency ablation (RFA) and microwave coagulation therapy (MCT). The aim of this study was to clarify the benefits and disadvantages of each modality for primary HCC. Methods: We reviewed outcomes of 120 patients with primary HCCs (< 5cm) who underwent local treatment (Cryo: n = 55 and RFA/MCT: n = 65) between 1998 and 2011. The primary endpoint was local recurrence free survival (LRFS). The secondary endpoints were complication rates and the length of hospital stay. Results: Age, sex, Child-Pugh score, and background liver disease were identical between both groups. The Cryo group had larger tumors (mean ± standard error tumor size: Cryo 2.55 ± 0.75 cm vs. RFA/MCT 1.96 ± 0.72cm, p < 0.001). The LRFS was higher in the Cryo group than in RFA/MCT group (2270.0 ± 240.8 days vs. 1940.7 ± 269.5 days: p = 0.116). The Cox proportional hazards multivariate analysis revealed that Cryo as the treatment of choice was an independent predictive indicator of improved LRFS (HR, 0.403 [95% CI: 0.202−0.807], P = 0.010). On the contrary, tumor size (for each 1 cm increase, HR, 1.635 [95% CI: 1.038–2.574], p = 0.034) and Child-Pugh score ≥ 6 (HR, 2.166 [95% CI: 1.179 – 3.979], p = 0.013) were negative prognostic factors for LRFS. Subgroup analysis showed that the LRFS for tumors ≤ 2 cm was similar between the 2 groups. However, if the tumor size was greater than 2 cm, the LRFS of the Cryo group was superior to RFA/MCT (2400.0 ± 287.4 days vs. 1177.9 ± 366.5 days: p = 0.004). The complication rates (Cryo 10.9% vs. RFA/MCT 10.8%: p = 0.980) and the length of hospital stay (9.45 ± 5.33 days vs. 9.52 ± 5.90 days: p = 0.947) were similar in both groups. No mortality was observed in the entire cohort. Conclusions: Cryo provides significantly higher chance of local control for primary HCCs compared with RFA/MCT, particularly if the tumor size exceeds 2 cm. Associated risks are at least equivalent to those of RFA/MCT even in patients with marginal to poor liver function. Cryo is a promising local ablative option in an era of rising incidence of HCC.
Postoperative radiotherapy for gallbladder cancer.
Authors: Park Jin-hong , Kim Jong Hoon , Yoon Sang Min , Jung Nuri Hyun , Lee Young-Joo , Park Kwang-Min , Chang Heung-Moon , Kim Kyu-Pyo
Published: February 2017

289

Background: Gallbladder cancer (GBC) is a relatively uncommon malignancy with high recurrence rate and poor prognosis, even after curative resection. Although postoperative radiotherapy (RT) has been tried to improve the poor results of surgery alone, the benefit of postoperative RT for GBC is still a matter of debate. The present study aimed to evaluate the effect of postoperative RT on locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) in patients with GBC. Methods: Between March 1998 and July 2009, 228 patients with GBC (T2-3 N0-2) underwent surgical resection with potentially curative aim (R0 or R1) at Asan Medical Center. Among the 228 patients, 86 received postoperative RT (RT group) with or without concurrent chemotherapy, and 142 did surgery alone (no-RT group). All patients with postoperative RT received three-dimensional conformal radiotherapy, and the median radiation dose was 50 Gy (range, 45-60 Gy) at 1.8 or 2.0 Gy/fraction daily. Among them, 57 patients (66.3%) had concurrent chemotherapy based on 5-fluorouracil. Results: The median follow-up time was 90 months (range, 35-96 months) for the surviving patients. Although RT group had significantly more advanced disease in overall stage (p = 0.005), T stage (p = 0.002), N stage (p = 0.010), and higher rate of R1 resection (p = 0.027), the 3-year LRC was 78% for RT group and 66% for no-RT group (p = 0.088). Also, there was no significant difference in the 3-year DFS and OS: 51% vs. 52% (p = 0.994) and 53% vs. 56% (p = 0.541), respectively. In multivariate analysis, postoperative RT was a significant predictive factor of improved LRC (p = 0.011), DFS (p = 0.016) and OS (p = 0.036). Conclusions: Although RT group had more adverse risk factors, the treatment outcomes of RT group were similar to those of no-RT group. Moreover, postoperative RT was a significant predictor of improved LRC, DFS and OS after adjusting these factors. These results suggest that postoperative RT might be effective in locoregional control and survival for patients with GBC.
A randomized, double-blind, placebo-controlled trial of trametinib, a MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.
Authors: Infante Jeffrey R. , Somer Bradley G. , Park Joon Oh , Li Chung-Pin , Scheulen Max E. , Kasubhai Saifuddin M. , Oh Do-Youn , Liu Yuan , Lahiri Soumi , Steplewski Klaudia , Le Ngocdiep T.
Published: February 2017

291

Background: Trametinib, an oral MEK1/2 inhibitor, holds promise for tumors that frequently harbor RAS activating mutations, such as pancreatic cancer. Trametinib monotherapy or in combination with gemcitabine showed preliminary activity in patients (pts) with advanced pancreatic cancer. Methods: Eligible pts with untreated metastatic pancreatic cancer were randomized (double-blind, 1:1) to receive gemcitabine 1000 mg/m2 intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks, plus either trametinib 2 mg or placebo daily. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR). OS and ORR were also analyzed based on baseline KRAS status as determined in plasma cell free DNA (cfDNA). Results: Baseline characteristics for the 160 randomized and treated pts were similar across arms. Skin related events (73% vs. 34%), diarrhea (54% vs. 28%), thrombocytopenia (40% vs. 28%), and stomatitis (36% vs. 8%) were more frequent with trametinib, as was grade 3/4 anemia (22% vs. 11%). However, rates of grade ≥ 3 thrombocytopenia, neutropenia and febrile neutropenia were similar between the arms. More pts on trametinib arm required dose reduction or interruption due to AEs (68% vs. 49% and 74% vs. 43%, respectively). Median OS was 8.4 months with trametinib compared to 6.7 months with placebo [HR 0.98 (95% CI: 0.67, 1.44, p=0.453)]. Median PFS was 16 weeks on trametinib and 15 weeks on placebo arm. ORRs and median DoRs were 22% and 23.9 weeks and 18% and 16.1 weeks on trametinib and placebo arm, respectively. The median OS and ORR in the subgroup of pts with KRAS mutations (n=143) was similar to OS and ORR for all randomized pts. Conclusions: This is first randomized, placebo-controlled trial evaluating the combination of gemcitabine with a MEK inhibitor. There was an increased incidence of skin, GI, and hematologic toxicities with trametinib compared to placebo. The addition of trametinib did not improve OS, PFS, or response rate. These outcomes remained independent of KRAS mutations based on cfDNA. Clinical trial information: NCT01231581.
Phase I/II study of E7050 (golvantinib) in combination with sorafenib in patients (pts) with advanced hepatocellular carcinoma (HCC): Phase I results.
Authors: O'Neil Bert H. , Bendell Johanna C. , Modiano Manuel R. , Machiels Jean-Pascal H. , Versola Melissa Jo , Hodge Jeff Paul , Sawarna Karen , Tse Nielson
Published: February 2017

294

Background: Golvatinib (G) is highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. G plus sorafenib (S) had an additive cell killing effect in a HepG2 hepatocellular cell viability assay, thus warranting further evaluation of the combination in HCC. Methods: The study is an ongoing open-label phase I/II study. Eligible pts have advanced HCC, Child-Pugh (CP) A or B, up to 2 prior regimens, including S. A 3+3 dose escalation design was used to determine the maximum tolerated dose (MTD) with planned doses of G (200 mg, 300 mg, 400 mg) PO qd each in combination with S 400 mg bid in 28 day cycles.The dose limiting toxicity (DLT) evaluation period was the first 28 days. Treatment continued until disease progression or development of unmanageable toxicities. Response was assessed by RECIST 1.1. Phase I is complete and preliminary data are presented. Results: 13 pts (med age: 60; M/F: 83%/17%, CP A/B: 92%/8%) were enrolled in 2 cohorts and the MTD was declared as G 200 mg qd and S 400 mg bid. Median treatment duration, 112 days. Confirmed partial responses (PRs) were observed in 2/12 (17%) pts and durable SD was observed in 4/13 (31%) pts based on investigator assessment. Conclusions: G in combination with S appeared to demonstrate manageable toxicity in advanced HCC pts. The PRs and durable SD observed in this pretreated pt population appear favourable and support continued evaluation in phase II. Clinical trial information: NCT01271504. [Table: see text]
Survivorship care patterns and late effects after cancers of the pancreas and biliary tract.
Authors: Hill-Kayser Christine E. , Vachani Carolyn , Hampshire Margaret K. , Di Lullo Gloria A. , Metz James M.
Published: February 2017

296

Background: Pancreas and biliary (PBT) cancers are generally associated with poor prognosis, despite aggressive, multimodality therapy. The population of cancer survivors after these diagnoses may be largely ignored, despite risk of late effects. This Internet-based study seeks to evaluate patient-reported toxicities and survivorship care patterns after treatment of PBT cancers.

Methods: Patient-reported data were gathered via convenience sample from PBT survivors voluntarily utilizing a publically available Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com and the OncoLink website, the tool asks survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, PBT survivors are queried regarding late effects associated with specific treatments.

Results: 89 PBT survivors utilized the tool from 2010-2012, 66% with pancreas cancer, 20% biliary, and 13% liver. Of the entire group, 59% were female and 81% Caucasian. Median diagnosis age was 59 and median current age 61. Average time since diagnosis was 2 years (range <1-8). Most reported having had multimodality therapy - 71% surgery, 78% chemotherapy, and 46% radiation – although only 30% report continued care from an oncologist and 8% having received previous survivorship information. Of 17 patients queried, 3 had metastatic disease and 3 had recurrent disease. When the entire group was queried regarding possible side effects of treatment, 44% report persistent neuropathy, 24% chronic diarrhea, 21% bowel stricture or obstruction, and 15% chronic skin changes in the radiation portal.

Conclusions: Although the prognosis after PBT cancers remains relatively poor, a small population of long-term survivors exists. Survivors using this tool have generally not received survivorship information and most are no longer followed by an oncologist despite having received multimodality treatment. Neuropathy and gastrointestinal side effects appear to be the most bothersome to this group. This tool represents a potential way to provide information to underrepresented survivorship groups such as PBT survivors in the future.
A public hospital experience with young gastric cancer patients.
Authors: Goldner Bryan S. , Velasquez Jonathan , Stabile Bruce E. , Chen Steven L. , Kim Joseph , Lin Matthew , Caton Amy , Lee Byrne
Published: February 2017

30

Background: Recent literature has reported an increased incidence in the United States of node positive and metastatic disease in young patients with gastric adenocarcinoma. The purpose of this study was to investigate the effect of age (≤40 years) on patients with gastric adenocarcinoma at a large urban public institution. Methods: A total of 520 cases of gastric adenocarcinoma treated between 1995 and 2012 were identified. Information was gathered from the medical record including age at presentation, stage at presentation, pathological type of GC, treatment received, and mortality data. Descriptive statistics were used to analyze the data. Survival was analyzed using the Kaplan-Meier method. Comparisons were made using the log-rank test. Results: The mean age at diagnosis was 56 years. 64 patients (12%) were identified as ≤40 years old. 57 of 64 (89%) of the young age group presented with stage III or IV disease, compared with 75% of patients >40 years of age (p=0.014). For patients ≤40 years old, 38% underwent an operation with curative intent, which was comparable to 39% in patients >40 years old. Of patients who underwent surgery, only 33% (10 of 30) ≤40 years old received an R0 resection compared to 110 of 184 (60%) in those >40 years old (p=0.007). The overall median survival was 5 months with one-year survival of 24% for the young patients and a median of 7.8 months with 39% one-year survival for the older patients (p=0.016). Conclusions: There is a decreased awareness and therefore suspicion of the diagnosis of gastric cancer in young patients (≤40 years of age). For this reason, young patients with gastric adenocarcinoma may present with more advanced disease than older patients. Surgical exploration was often futile, and survival was especially poor in young patients likely due to the more advanced nature of their disease at diagnosis.
Characteristics and outcomes of adenosquamous carcinoma of the pancreas.
Authors: Simone Christine G. , Zuluaga Toro Tania , Chan Ellie , George Thomas J.
Published: February 2017

311

Background: Adenosquamous carcinoma of the pancreas (ASCAP) is a rare pancreatic malignancy variant reported to have a worse prognosis than adenocarcinoma of the pancreas (ACP). Most reports demonstrate a survival rate of less than two years. This study was undertaken to characterize this subtype in the context of a contemporary ACP cohort. Methods: This retrospective analysis included all patients who underwent definitive pancreatic cancer resection at the University of Florida from 2001 to 2011. Central pathology review of suspected ASCAP cases was undertaken. Patient characteristics, tumor features, treatment, and outcomes were collected with t-test analysis for differences. Results: Eight of 237 patients (3.3%) were histologically confirmed as ASCAP. Differences between the ASCAP and ACP cohorts are listed in the Table. ASCAP patients were similar to patients with ACP with no differences in presentation, symptoms or reported tumor markers including CA19-9, CEA, or hypercalcemia. However, ASCAP patients were slightly older, smoked less, and had more involvement of the body and tail. None (0/8) of the ASCAP diagnoses were identified on fine needle aspiration, only surgical specimen review. Post-operative therapy was inconsistently provided to the ASCAP patient population. With a median f/u of 2.9 years, 31% of ACP and 37% of ASACP patients are alive with median overall survival favoring patients with ACP (0.6 vs. 1.7 years; p<0.006). Conclusions: In a contemporary cohort, ASCAP remains a rare malignancy with a relatively worse prognosis than ACP. Diagnostic biopsy may be non-confirmatory for ASCAP and may lead to under-reporting. Aggressive surgical resection is curative for a subset of ASCAP patients, but overall survival remains poor. Further investigation into the role of adjuvant therapy and risk factor modification for this variant may be valuable. [Table: see text]
Phase I/II trial of neoadjuvant chemoradiotherapy with 5-FU, cisplatin, mitomycin C, and heparin for borderline resectable pancreatic cancer.
Authors: Hibi Taizo , Kitago Minoru , Aiura Koichi , Tanabe Minoru , Itano Osamu , Shinoda Masahiro , Abe Yuta , Yagi Hiroshi , Kitagawa Yuko
Published: February 2017

315

Background: Because of the high incidence of local recurrence and liver metastasis, long-term outcomes of patients following resection of advanced pancreatic cancer are extremely poor. Facilitation of curative resection and prevention of micrometastasis are the goals of neoadjuvant therapy. We evaluated the feasibility and efficacy of our neoadjuvant chemoradiotherapy (NACRT) protocol for borderline resectable pancreatic cancer patients. Methods: During the period between 2003 and 2011, 24 patients with borderline resectable pancreatic cancers underwent NACRT comprising 5-FU (300 mg/body/day, day 1−5/week for 4 weeks), cisplatin (10mg/body day2, 9, 16, 23), mitomycin C (4mg/body/day, day 1, 8, 15, and 22), heparin (6000 IU/body/day for 4 weeks), and radiation (2 Gy/day, day 1−5/week for 4 weeks, total 40 Gy). They were reevaluated for resectability after therapy. Primary endpoints were toxicity and overall patient and disease-free survivals. Secondary endpoint was the ratio of microscopically margin negative resection. Results: All 24 patients completedNACRT. Grade 3−4 hematological adverse events were observed in 9 (38%) patients but none developed severe gastrointestinal toxicity. In 7 (29%) patients, restaging revealed distant metastasis or local disease progression not amenable to curative resection. The remaining 17 patients (71%) underwent surgery (pancreatoduodenectomy, 13 and distal pancreatectomy, 4) with zero 30-day postoperative or in-hospital mortality. The 5-year overall all patient and disease-free survival rates after pancreatectomy were 52.6% and 36.3%, respectively. Postoperative histopathological evaluation demonstrated a marked degenerative change in the specimen, achieving negative surgical margins in 15/17 (88%) patients and pathological complete response in the remaining 2 (12%) patients. Conclusions: Our NACRT protocol is feasible with a low toxicity profile and an excellent curative resection rate in the treatment of borderline resectable pancreatic cancer. It is a promising regimen associated with improved long-term prognoses than historical controls.
MET overexpression as a hallmark of the epithelial-mesenchymal transition (EMT) phenotype in colorectal cancer.
Authors: Raghav Kanwal Pratap Singh , Wang Wenting , Overman Michael J. , Kopetz Scott
Published: February 2017

334

Background: Dysregulation of the proto-oncogene MET (mesenchymal-epithelial transition factor gene) has been implicated in tumorigenesis and correlates with worse survival and chemo/radio-resistance in colorectal cancer (CRC). EMT has been identified as a dominant molecular characteristic of a subset of CRC tumors and represents a key feature in the developing colorectal taxonomy. The purpose of this study was to compare protein expression of MET with protein/gene expression of EMT markers and other clinicopathological characteristics, and to evaluate its impact on overall survival (OS). Methods: We performed an exploratory analysis of 590 CRC samples using data from The Cancer Genome Atlas. Fisher-exact test and Pearson’s method was used to determine the relationship between MET protein expression, clinicopathological characteristics and EMT marker protein expression by reverse-phase protein array (RPPA) and EMT-associated gene expression by RNA-sequencing. Regression tree method was applied to find the best cutoff point for MET using patients with available survival data. Overall survival (OS) was estimated non-parametrically using Kaplan-Meier curve and log-rank test was used to evaluate hazard ratio. Results: MET expression by RPPA did not correlate with traditional clinicopathologic characteristics. MET was overexpressed in 17% of CRC tumors and was significantly associated with OS (HR 2.92; 95% CI: 1.45 - 5.92). Correlation analysis of MET levels with gene expression of EMT markers AXL, CDH1, FGFR1, SNAIL, TWIST1/2, VIM, SLUG, ZEB1/2, FN1 demonstrated that the highest quartile of MET protein expression was associated with a 1.5 fold increase in ZEB1 (p = 0.002), a 1.4 fold increase in AXL (p = 0.005) and ZEB2 (p = 0.008), and a 1.3 fold increase in VIM (p = 0.02). MET expression also correlated strongly with protein expressions of SNAIL (transcription factor for EMT) (r = 0.96) and ERCC1 (r = 0.83) (a marker for oxaliplatin chemo-resistance). Conclusions: Increased MET protein expression is seen in 17% of CRC tumors and strongly correlates with a molecular EMT phenotype and poor survival in patients with CRC. MET protein expression may be a surrogate biomarker for this unique subset of CRC.
Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX).
Authors: Cunningham David , Lang Istvan , Lorusso Vito , Ocvirk Janja , Shin Dongbok , Jonker Derek J. , Osborne Stuart , Andre Niko Alexander , Waterkamp Daniel , Saunders Mark P.
Published: February 2017

337

Background: Elderly patients (pts) comprise the majority of pts diagnosed with mCRC, although they are in general underrepresented in clinical trials. AVEX, an open-label phase III trial, evaluated the efficacy and safety of cape ± bev in elderly pts with previously untreated mCRC. Methods: Pts ≥70 years with mCRC, for whom single-agent chemotherapy was deemed appropriate, were randomized 1:1 to receive first-line cape (1000 mg/m2 bid days 1–14) as monotherapy or in combination with bev (7.5 mg/kg) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), and safety. The study was powered to show a difference in PFS, but not OS, between treatment arms. PFS and OS estimates were calculated using Kaplan-Meier methods. Results: 280 pts across 10 countries were randomized to cape + bev (n=140) and cape alone (n=140). Median age at enrollment was 76 years (range, 70–87), and 91.1% of pts had an ECOG performance status of 0–1. Baseline pt and disease characteristics were well balanced between arms. Bev + cape was associated with significantly prolonged PFS compared with cape alone (median of 9.1 vs 5.1 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41–0.69; p<0.001). The ORR was also significantly improved in the bev + cape arm (19.3% vs 10.0%; p=0.042). OS was longer in pts treated with bev + cape vs cape alone, although this difference did not reach statistical significance (median of 20.7 vs 16.8 months; HR, 0.79; 95% CI, 0.57–1.09; p=0.182). Grade ≥3 adverse events occurred in 59.0% vs 44.1% of pts in the bev + cape and cape arm, respectively. Treatment was in general well tolerated and the safety profile consistent with previously reported data for bev + cape. Conclusions: This is the first randomized study prospectively evaluating bev specifically in elderly pts with mCRC. Based on the efficacy and safety results, bev plus cape might be an optimal treatment approach to improve outcomes in elderly pts. Clinical trial information: NCT00484939.
Regulation of HDM2 E3-ubiquitin ligase in esophageal adenocarcinoma cells by AURKA.
Authors: Sehdev Vikas , Belkhiri Abbes , Soutto Mohammed , Katsha Ahmed M. , El-Rifai Wael
Published: February 2017

35

Background: Esophageal adenocarcinomas (EAC) exhibit intrinsic resistance against chemotherapy. AURKA regulates cell cycle progression and its overexpression is associated with oncogenic transformation. We have recently reported that AURKA is significantly overexpressed in about 70% of human EAC tissue samples and EAC cell lines. We have previously shown that AURKA inhibits p53- and p73-mediated apoptotic pathways in GI adenocarcinomas. HDM2 is an E3-ubiquitin ligase which is closely involved in regulating p53 and p73 protein stability and activity. In this study we demonstrate that AURKA directly interacts with HDM2 and regulates HDM2 protein expression and phosphorylation in both FLO-1 and OE33 EAC cells. Methods and Results: Western blot analyses were done following AURKA overexpression with adenovirus, knockdown with si-RNA or inhibition with MLN 8237 (0.5µM) in FLO-1 and OE33 EAC cell lines. The data indicated that overexpression of AURKA induced both total and phospho-HDM2-(Ser166) protein levels. Knockdown or inhibition of AURKA significantly decreased expression of both total and phospho-HDM2-(Ser166) protein levels in FLO-1 and OE33 EAC cells. Additionally, following adenovirus mediated overexpression of AURKA, co-immunoprecipitaion (Co-IP) was done for AURKA and HDM2 in FLO-1 and OE33 EAC cells. The two-way Co-IP data indicated the presence of HDM2 in a complex associated with AURKA and vice-versa. The data from in vitro protein kinase assay indicated that recombinant AURKA directly phosphorylates recombinant HDM2 at Ser166 site. To confirm direct interaction between recombinant AURKA and HDM2 proteins we performed IP following the in vitro kinase assay. The in vitro kinase IP data indicates that kinase intact recombinant AURKA directly interacts and phosphorylates recombinant HDM2 protein. Conclusions: Our data indicate that AURKA regulates HDM2 expression and phosphorylation in both FLO-1 and OE33 EAC cells. Additionally, we also report for the first time that AURKA directly interacts with HDM2 and phosphorylates it at Ser166 site. Therefore, our study suggests that AURKA-mediated regulation of HDM2 could be the major underlying mechanism for induction of apoptosis in p53-negative EAC.
Incidence rates for anal cancer in the United States: 1980-2009.
Authors: Eberly Lauren A. , Wiggins Charles , Nir Itzhak , Morris Katherine T. , Russell John C. , Rajput Ashwani
Published: February 2017

357

Background: Anal squamous cell carcinoma (SCC) is rare, but results in significant morbidity and mortality. The aim of this study was to characterize the trends of anal SCC in the U.S. between 1980-2009. Methods: Subjects were identified from records in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. The study included incident malignant squamous cell cancer of the anus, anal canal, and anorectum diagnosed among nine core areas of the SEER program from 1980-2009. Average annual age-adjusted incidence rates were calculated by the direct method with the U.S. 2000 standard population. 95% confidence intervals were calculated using the Tiwari adjustment. Temporal trends were assessed by joinpoint regression. Results: Incidence rates of anal cancer in the U.S. more than doubled during this period. A linear increase in anal cancer incidence rates was observed with an Annual Percent Change (APC) of 4.6 (p<0.01) for all races and both sexes-combined. Incidence rates were consistently greater for women than men, however, the increase in incidence rates was greater for men (APC=5.4, p<0.01) than for women (APC=4.3, p<0.01). Similar trends were seen for whites and blacks. Conclusions: Anal cancer is a relatively rare disease, yet incidence rates increased dramatically in the U.S. over the last three decades. Correlation of this increased incidence with HPV infection remains to be determined. [Table: see text]
Identification of risk factors for stage II colon cancer.
Authors: Sawazaki Sho , Shiozawa Manabu , Numata Koji , Numata Masakatsu , Godai Teni , Yamamoto Naoto , Morinaga Soichiro , Rino Yasushi , Masuda Munetaka , Akaike Makoto
Published: February 2017

375

Background: The use of adjuvant chemotherapy remains controversial in Stage II colon cancer. However, patients with specific clinicopathological features are thought to have high risk for recurrence. The aim of this study was to identify the subgroup of patients at great risk, by investigating the clinicopathological features associated with poor survived in Stage II. Methods: A total of 282 patients with Stage II colon cancer who underwent curative resection from January 1990 to September 2007 at Kanagawa Cancer Center were enrolled. Then, the clinicopathological data of the patients were retrospectively evaluated. Disease-free survival rates were calculated by the Kaplan-Meier method, and survival curves were compared by the log-rank test. Cox’s regression analysis was used for multivariate analyses. P values <0.05 were considered to be statistically significant. Results: The median follow up was 62.5 months. The 5-year disease-free survival was 92.2% in the study group as a whole. Among the recurrent patients (n=23), the most recurrent site was the liver (n=11, 44%), followed by lung (n=6, 24%), and peritoneum (n=5, 20%). Univariate analysis for 5-year disease-free survival identified two factors; tumor diameter (>5cm vs…5cm, p=0.018), and lymphatic invasion (p=0.009). Multivariate analysis for 5-year disease-free survival identified two independent factors; tumor diameter (hazard ratio [HR], 4.82; 95% CI, 1.55-15.0; p=0.006), and lymphatic invasion (HR, 4.15; 95% CI, 1.68-10.2; p=0.002). The 5-year disease-free survival differed significantly among patients with neither of these prognostic factors (98.6%), those with only 1 factor (93.3%), and those with 2 factors (76.6%, p=0.000). Conclusions: Patients with stage II colon cancer who have both 5cm in diameter and lymphatic invasion are at high risk for recurrence. The use of adjuvant chemotherapy should be considered in this subgroup of patients.
Predictive value of baseline CD66e/CEA serum levels on efficacy of bevacizumab-based treatment in advanced colorectal cancer.
Authors: Prager Gerald W. , Bramswig Kira H. , Zielinski Christoph
Published: February 2017

388

Background: CD66e (Carcinoembryonic antigen, CEA) affects tumorigenesis by enhancing tumor cell survival and by inducing tumor-angiogenesis. This study aimed to evaluate baseline CD66e serum levels as response predictor to bevacizumab-based therapies in patients with metastatic colorectal cancer (mCRC). Methods: 298 patients with mCRC and first-line treatment were analyzed. 169 mCRC received bevacizumab plus chemotherapy and 129 patients with mCRC treated with cetuximab (KRAS w.t.) and identical chemotherapy (FOLFOX6 or FOLFIRI). Disease control (DC), progression-free survival (PFS) as well as overall survival (OS) were assessed and related to baseline CD66e-serum levels. Patients with basal CD66e-serum levels below the statistical median of 26.8 ng/ml (group I) were compared with patients with higher CD66e levels (group II). Results: Baseline CD66e serum levels inversely correlated with therapeutic response in patients receiving bevacizumab-based treatment (chi square i<0.005: OR=0.579, 95% C.I. 0.422, 0.795; p<0.001), inversely correlated with median PFS leading to a median PFS benefit of 2.1 month for patients in group I when compared with group II (p<0.05), as well as inversely correlated with median OS (37.5 month vs. 21.4 month, p<0.05). In an independent cohort of 129 patients treated with cetuximab-based therapy, no association of therapeutic response or PFS with CD66e serum levels was found (p>0.05). Conclusions: These data give first evidence of CD66e as a predictive biomarker for the efficacy of first-line bevacizumab-based therapy in patients with mCRC.
Molecular characteristics of complete PTEN loss in metastatic colorectal cancer.
Authors: Jiang Zhi-Qin , Deaton Laurel , Neishaboori Nastaran , Vauthey Jean-Nicolas , Overman Michael J. , Maru Dipen M , Kopetz Scott
Published: February 2017

389

Background: Loss of expression of phosphatase and tensin homolog (PTEN) is associated with activation of the PI3K/AKT pathway, and has been identified as a potential modulator of response to targeted therapies in metastatic colorectal cancer (mCRC). The association of PTEN loss with other molecular characteristics and outcomes has not been described for mCRC. Methods: Tumor from 229 mCRC patients (pts) were included for analysis of PTEN staining by IHC from whole-mounts, across two cohorts of unresectable mCRC or resectable liver-limited disease. PTEN loss was defined as complete loss of staining with preservation of expression of stromal components. Mutation status was defined using mass-spectroscopy or next-generation sequencing platforms. CpG island methylation (CIMP) status was determined using a previously defined 6-marker panel, with methylation of ≥3 markers denoting CIMP-High. Methylation findings where confirmed in 193 pts from the Cancer Genome Atlas (TCGA) database, using previously defined classifications. Results: The overall frequency of complete PTEN loss was 12% in the primary tumor and 15% when assayed from metastatic sites (P=NS). There was no difference in clinical characteristics in patients with PTEN-loss tumors. Complete PTEN loss and PIK3CA mutations were not mutually exclusive, with PIK3CA mutation rate of 24% and 14% in PTEN loss and intact, respectively (p=0.3). There was no association of PTEN loss with KRAS mutations (p=0.3), although there were non-significant trends toward higher rates of CIMP-High, BRAF mutations, and R-sided tumors (OR 3.2, 2.7, and 1.6, respectively; p<0.2), consistent with an association with the serrated adenoma pathway and epigenetic inactivation. In the TCGA, PTEN protein loss (defined by the lowest 12% of expression) was associated with increased AKT signaling (77% increase in pAKT/AKT, p<0.01) and a similar trend with CIMP-H tumors (OR 3.1, p=0.13). Conclusions: In patient samples, PTEN loss is independent of KRAS and PIK3CA mutations, associated with robust AKT pathway activation, and may be more prominent in tumors with hypermethylation and BRAF mutations.
Gene expression profiles of rectal cancers with mutant or wild-type Kras.
Authors: Garcia-Aguilar Julio , Chen Zhenbin , Warden Charles , Avila Karin , Zhou Ning , Yuan Yate-Ching , Chen Ching-Tung , Weiser Martin R.
Published: February 2017

414

Background: The Kras oncogene is one of the most common mutations in colorectal cancer. Kras mutations are associated with increased tumor aggressiveness, poor response to selected targeted therapies, and reduced patient survival. We have previously shown that rectal cancers carrying a Kras mutation were less likely to achieve a pathologic complete response to radiation compared to tumors with wild type Kras. Our objective was to compare the gene expression profiles of rectal cancers with mutant and wild type Kras to identify genes that could be related to the Kras–dependent aggressive phenotype. Methods: Pretreatment biopsy tissue was collected from 120 patients with stages I, II and III rectal cancer treated in two prospective trials (NCT00335816 and NCT00114231). DNA and total RNA were extracted from microdissected cancer cells. Mutations in codons 12, 13, and 61 of the Kras gene were detected by pCR. 50ng of total RNAs were amplified to generate cDNA libraries using Ovation FFPE WTA System (NuGEN Technologies, Inc., San Carlos, CA). The amplified cDNA was labeled using the Encore Biotin Module, and hybridized to GeneChip Human Genome U133A plus 2.0 arrays (Affymetrix, Inc., Cleveland, OH). Differences in gene expression between mutant and wild type Kras tumors were determined using T-test and Q-bound to correct for multiple testing by performing false discovery rate (FDR) analysis. Results: A total of 44 of 117 (37.6%) were mutant Kras. A total of 379 probes were upregulated and 262 were downregulated in tumors with Kras mutant compared to Kras wild type. Heatmap based on differentially expressed genes showed separation according to Kras mutant status. REG4 expression was increased 3 fold and CXCL5 was reduced 2.4 fold in tumors with mutant Kras compared to wild type Kras. The changes in expression on these genes are concordant with their known involvement in prognosis and response to therapy of colorectal cancer. Conclusions: The search for changes in gene expression in response to Kras activation led to identifying a number of genes associated with the tumor aggressive phenotype.
A cost-effectiveness analysis of bevacizumab (BV) plus chemotherapy (CT) versus aflibercept (AFLI) plus CT in patients with metastatic colorectal cancer (mCRC) previously treated with BV.
Authors: Morlock Robert , Yu Elaine , Ray Joshua
Published: February 2017

417

Background: Trial results from ML18147 and VELOUR have recently reported outcomes for BV+CT and AFLI+CT in mCRC patients previously treated with BEV. This study evaluates cost and outcomes of BV+CT vs AFLI+CT as 2L treatment for patients with mCRC who progressed after receiving a standard BEV containing regimen in the 1L setting. Methods: In the absence of head-to-head trials comparing BV+CT & AFLI+CT, an adjusted indirect comparison was conducted using the Bucher-method. Hazard ratios (HRs) from ML18147 comparing BV+CT vs CT and patients previously treated with BV in VELOUR comparing AFLI+CT vs CT were utilized. An illness-death Markov model was enhanced looking at three states (progression free, progression and death). Distributions were fit to the risks for progression (Lognormal) and mortality (Gamma) and assessed using the adjusted indirect HRs. Only direct costs were considered for patients. Costs of drugs were based on wholesale acquisition costs and costs of treating adverse events were based on Medicare reimbursement. Utilities were derived from the literature; costs and outcomes were discounted at 5%. A probabilistic sensitivity analysis (PSA) was conducted to evaluate robustness of results. Results: Results of the analysis suggest BV+CT combination is less costly compared to AFLI+CT ($39,104 less per treated patient) and similar effectiveness between BV+CT and AFLI+CT [OS 13.3 vs. 12.5 months; HR 0.94 (95% CI 0.70-1.26); 0.498 vs. 0.479 QALYs] in 2L treatment of mCRC in patients previously treated with BV. AE rates and costs were higher for the AFLI+CT arm compared to the BV+CT arm. PSA shows that BV+CT is dominant over AFLI+CT in 98% of model iterations. Increasing the efficacy of AFLI+CT by approximately 100% resulted in an incremental cost-effectiveness ratio of more than $200,000 and AFLI+CT remained dominated by BV+CT. Conclusions: Based on current available data, analysis suggest BV+CT presents lower costs and similar effectiveness outcomes than AFLI+CT in 2L treatment of mCRC in patients previously treated with BV. The higher price of AFLI and the increased rates of AEs are the primary drivers of model results.
Impact of KRAS mutational status on clinical outcomes in patients receiving capecitabine based chemotherapy.
Authors: Yarom Nirit , Gresham Gillian , Boame Nana , Jonker Derek J.
Published: February 2017

436

Background: Mutations affecting the KRAS gene are established predictive markers of outcome with anti–epithelial growth factor receptor antibodies in metastatic colorectal cancer (mCRC). The relevance of these markers for chemotherapy has not been established. This analysis was performed to assess the predictive impact of KRAS mutation status in patients receiving chemotherapy. Methods: KRAS mutational status was available for 223 patients treated for mCRC. Predictive analysis of mutational status by type of fluoropyrmidine the 1st-line regimen contained (either capecitabine [C] based chemotherapy or infusional 5Fluorouracil [I-5Fu]) for clinical outcomes: progression-free survival (PFS), time to chemotherapy resistance (TTCR) and overall survival (OS). Results: KRAS mutations were observed in 43.5% of the patients. 165 patients received I-5Fu, 44 patients received C. KRAS mutation status (wild type [WT] v mutated [MT]) had no prognostic impact for OS (hazard ratio [HR], 0.81; CI, 0.69 to 1.1 p=0.17) for PFS (hazard ratio [HR], 0.87; CI, 0.66 to 1.14 p=0.3) and TTCR (hazard ratio [HR], 0.85; CI, 0.65to 1.12 p=0.26). C based 1st-line chemotherapy vs. I- 5FU based was predictive of PFS (hazard ratio [HR], 0.52; CI, 0.37 to 0.74 p=0.0003) and TTCR (hazard ratio [HR], 0.54; CI, 0.38 to 0.75p=0.0005) and not of OS (hazard ratio [HR], 0.74; CI, 0.52 to 1.1 p=0.1). KRAS mutational status had predictive impact in patients receiving C based 1st-line chemotherapy on OS (hazard ratio [HR], 0.47; CI, 0.23 to 0.948 p<0.0001) TTCR (hazard ratio [HR], 0.49; CI, 0.25 to 0.97 p=0.0398) and was not predictive of PFS (hazard ratio [HR], 0.78; CI, 0.4 to 1.53 p=0.47) Conclusions: KRAS gene mutation status was predicitve for OS and for TTCR in patients who received C based 1st-line chemotherapy.
Class III β-tubulin as a predictive marker for taxane-based first-line palliative chemotherapy in recurrent or metastatic gastric cancer.
Authors: Hwang Jun-Eul , Kim Dae-Eun , Shim Hyun-Jeong , Bae Woo Kyun , Cho Sang-Hee , Chung Ik-Joo
Published: February 2017

44

Background: Class III β tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in advanced gastric cancer is not clearly defined yet. We analyzed the significance of TUBB3 expression along with ERCC1 in recurrent or metastatic gastric cancer patients receiving taxane based first-line palliative chemotherapy. Methods: We reviewed 146 patients with advanced gastric adenocarcinoma who received taxane based first-line palliative chemotherapy between 2004 and 2010 at Chonnam National University Hwasun hospital. Immunohistochemical stain of TUBB3 and ERCC1 was done in paraffin-embedded tumor tissue. We evaluated response to chemotherapy, progression-free survival (PFS), and overall survival (OS). Results: A total of 146 patients with advanced gastric cancer received docetaxel and cisplatin (n=15), or paclitaxel and cisplatin (n=131) with or without 5-fluorouracil (5-FU). The median PFS was significantly shorter for patients with TUBB3 high expression than patients with TUBB3 low expression (3.63 versus 6.67 months, p=0.001). OS was not associated with TUBB3 expression status (12.9 versus 13.1 months, p=0.769). In multivariate analysis, only TUBB3 was related to shorter PFS (HR 2.74, 95% CI 1.91-3.91, p=0.001). Patients with ERCC1 high expression showed lower response rate than patients with ERCC1 low expression (24% versus 63.2%, p=0.001), however ERCC1 showed no clinical influence on PFS and OS. Conclusions: TUBB3 is a strong predictive marker in recurrent or metastatic gastric cancer patients receiving taxane based first-line palliative chemotherapy. Clinical impact of ERCC1 is not evident in this setting.
A multicenter phase I study of intravenous administration of reolysin in combination with irinotecan/fluorouracil/leucovorin (FOLFIRI) in patients (pts) with oxaliplatin-refractory/intolerant KRAS-mutant metastatic colorectal cancer (mCRC).
Authors: Ocean Allyson J. , Bekaii-Saab Tanios S. , Chaudhary Imran , Palmer Romae , Christos Paul J. , Mercado Alice , Florendo Erika O. , Rosales Veronica A. , Ruggiero Joseph T. , Popa Elizabeta C. , Wilson Melissa , Ghalib Mohammad Haroon , Hou Yijuan , Shah Umang , Rajdev Lakshmi , Elrafei Tarek , Gill George M. , Coffey Matthew C. , Shah Manish A. , Goel Sanjay
Published: February 2017

450

Background: Reolysin (reovirus serotype 3) contains a naturally occurring, ubiquitous, non-enveloped human dearing strain reovirus. Reovirus replicates in KRAS-mutant cells resulting in cell lysis. In phase I evaluation, CRC pts received single agent Reolysin with tumor stabilization and CEA response without significant toxicity. Reolysin and irinotecan (IRI) are synergistic in KRAS-mutant preclinical CRC models, providing rationale for this phase I study. Methods: This was a phase I dose escalation study of FOLFIRI + Reolysin. Eligible pts were >18 yrs with histologically confirmed KRAS-mutant mCRC, measurable disease, ECOG PS 0-1, <3 metastatic regimens, and adequate organ function. Standard FOLFIRI was administered with escalating Reolysin doses (range 1x1010 TCID50 to 3x1010 TCID50) in cohorts of 3-6 pts. Reolysin was given IV over 1 hr days 1-5 every 28d (1 cycle). Primary objectives were dose-limiting toxicity (DLT) to determine MTD and pharmacokinetics. Secondary endpoints were antitumor activity, response rate, progression-free and overall survival (PFS and OS). Results: 21 pts enrolled; median age 62 (range 39-77); 5 M; 16 F; FOLFIRI-naïve: 9/21 pts. 2 pts had DLTs in cycle 1 at the highest dose of 180 mg/m2 of IRI. Common (>10%) grade 3-4 toxicity include: neutropenia (n=11), anemia (n=4), and thrombocytopenia (n=3). One patient died of acute renal failure. The DLT is neutropenia. The recommended phase II dose is IRI 150 mg/m2 and Reolysin at 3x1010 TCID50 on days 1-5, q 28 days. 18 pts evaluable for response: PR (1pt; 5%), SD (9 pts; 50%), PD (8pts; 44%). 3 pts taken off study before evaluation. Median PFS: FOLFIRI-naïve pts = 7.4 mo. (95% CI = 1.9 mo., 12.9 mo.); Median PFS FOLFIRI non-naïve pts was not reached; overall median PFS = 7.4 mo. (95% CI = 0.6 mo., 14.1 mo.) Conclusions: The combination of Reolysin and FOLFIRI in pts with KRAS-mutant mCRC was safe, well tolerated and resulted in disease control in the majority of pts, including pts who previously progressed on IRI. We are encouraged by this activity and safety profile, and are planning additional studies. Clinical trial information: NCT01274624.
SPIRITT (study 20060141): A randomized phase II study of FOLFIRI with either panitumumab (pmab) or bevacizumab (bev) as second-line treatment (tx) in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC).
Authors: Hecht J. Randolph , Cohn Allen Lee , Dakhil Shaker R. , Saleh Mansoor N. , Piperdi Bilal , Cline-Burkhardt Vivian Jean M. , Tian Ying , Go William Y.
Published: February 2017

454

Background: Pmab has demonstrated significant improvement in progression-free survival (PFS) in pts with WT KRAS mCRC as 2nd-line tx in a phase III trial comparing pmab + FOLFIRI vs FOLFIRI alone. Here, we describe the results of SPIRITT, a multicenter, randomized phase II study evaluating pmab + FOLFIRI and bev + FOLFIRI in pts with WT KRAS mCRC previously treated with a 1st-line bev + oxaliplatin (Ox)-based chemotherapy regimen. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg + FOLFIRI Q2W or to bev 5.0 or 10.0 mg/kg + FOLFIRI Q2W. Eligibility criteria included: WT KRAS mCRC, ECOG ≤ 1, no prior irinotecan or anti-EGFR tx, and tx failure of prior 1st-line bev + Ox-based therapy (≥ 4 cycles). The primary endpoint was PFS; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. No formal hypothesis was tested. Results: 182 pts with WT KRAS mCRC were randomized. All pts received tx. Efficacy results are shown (table). Worst grade of 3/4 adverse events (AE) occurred in 78% of pts in the pmab + FOLFIRI arm and 65% in the bev + FOLFIRI arm. Grade 5 AEs occurred in 7% of pts in the pmab + FOLFIRI arm and 7% in the bev + FOLFIRI arm. Tx discontinuation due to any AE was 29% in the pmab + FOLFIRI arm and 25% in the bev + FOLFIRI arm. Conclusions: In this estimation study of pts with WT KRAS mCRC that previously received bev + Ox-based tx, the PFS hazard ratio (HR) was 1.01 (95% CI: 0.68 - 1.50). The OS HR was 1.06 (95% CI: 0.75 - 1.49). The observed ORR was higher in the pmab + FOLFIRI arm. 54% of bev + FOLFIRI pts received subsequent anti-EGFR tx. The safety profile for both arms was similar to previously reported studies. Tx discontinuation rates due to AEs were similar between the arms. Clinical trial information: NCT00418938. [Table: see text]