bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of hepatic function and tumor extent on survival in patients with unresectable hepatocellular carcinoma treated with liver-directed therapies.
Authors: Hill Marisa E. , Basu Sanjib , Arslan Bulent
Published: February 2017

358

Background: Transarterial chemoembolization (TACE) has demonstrated survival advantage over best supportive care in patients with unresectable hepatocellular carcinoma (HCC), and non-randomized data suggests that survival in HCC treated with yttrium-90 radioembolization (90Y) is similar to that achieved with TACE. Eighty to 90% of patients with HCC have underlying cirrhosis, so survival analyses of liver-directed treatments (LDT) should take into account both tumor extent and liver function. Methods: We conducted a retrospective study to evaluate the effect of tumor extent and liver function on the survival of patients treated with TACE and/or 90Y for HCC. Patients with unresectable HCC treated at Rush University Medical Center between 2002 and 2014 were analyzed. Liver function parameters prior to first treatment were recorded for each patient, and survival measured from time of first treatment to death or last follow up was calculated. Statistical inference for overall survival was performed using Kaplan-Meier method, log-rank test, and Cox proportional hazards regression model. Results: The difference in overall survival between patients with unilobar disease and with bilobar disease (n=35 and 23, median survival of 19.4 and 12.8 months, respectively) was not found to be significant (p=0.838). However, the difference in overall survival among patients with Child Pugh A (n=22, median not reached), B (n=30, median= 11.4 months) and C (n=6, median=3.8 months) cirrhosis was strongly significant (p < 0.001). In a multivariate Cox proportional hazards analysis, the association of Child class (coded on an integer scale) with overall survival, adjusted by the extent of the disease, continued to be strongly significant (HR=1.93, p < 0.001). Conclusions: Liver function may be just as important a determinant of survival in patients undergoing liver directed treatments for HCC as is extent of disease. Larger, prospective studies are needed to confirm this hypothesis.
Importance of subset classification based on tumor size for patients with single hepatocellular carcinoma.
Authors: Zhong Jian-Hong , Xiang Bang-De , Ma Liang , Wang Yan-Yan , Peng Ning-Fu , Gong Wen-Feng , Lu Shi-Dong , Li Le-Qun
Published: February 2017

373

Background: Single hepatocellular carcinoma (HCC) regardless of size that without vascular invasion is classified as stage A disease in the Barcelona Clinic Liver Cancer staging system. However, patients with different tumor size may have different overall survival after hepatectomy. This study compared the prognosis of patients with single HCC after hepatectomy among groups with different tumor size. Methods: Patients with newly diagnosed single HCC from January 1, 2004 to October 31, 2013 were classified according to tumor size: group 1, ≤ 5 cm; group 2, > 5 cm and ≤ 8 cm; group 3, > 8 cm and < 10 cm; and group 4, ≥ 10 cm. Overall survival analysis was performed according to tumor size. Results: A total of 857 patients were enrolled. Among them, 814 (95.0%) were with Child-Pugh A class liver function. Blood loss was 367 ± 424 mL. Groups 1, 2, 3, and 4 consisted of 426 (49.7%), 229 (26.7%), 52 (6.1%), and 150 (17.5%) patients, respectively. The 5 years overall survival ranged from 35 to 63% in all four groups. The median survival time differed significantly according to tumor size (76, 49, 43, and 38 months in groups 1, 2, 3, and 4, respectively; P  <  0.001). Group 3 had overall similar survival to group 4. Multivariate analysis showed that group 3 and 4 had significantly worse overall survival compared to group 1 and 2. Conclusions: Patients in group 3 and 4 had significant worse prognosis than those in group 1 or group 2. Our results suggest that subset classification based on tumor size is warranted to patients’ prognosis.
Impact of concurrent medications use on outcome of pancreatic cancer: SEER Medicare analysis.
Authors: Beg Muhammad Shaalan , Stewart Tyler , Gao Ang , Ahn Chul , Berry Jarett , Mortensen Eric
Published: February 2017

378

Background: Preclinical studies have suggested concurrent non-antineoplastic medication use may impact pancreatic cancer. We performed an analysis to examine these associations on survival in pancreatic cancer. Methods: Data from the Surveillance, Epidemiology and End Results (SEER)-Medicare with available part D data between 2006 and 2009 were analyzed. Cases with non-adenocarcinoma histology, autopsy only and death certificate only data were excluded. Drug use was defined as having two prescriptions filled within 12 months of pancreatic cancer diagnosis. The following medications were analyzed: beta-blocker, statin, insulin, metformin, thiazolidinedione, warfarin and heparin. The primary end point was overall survival. Stepwise Cox proportional hazard models were employed including each medication group as well as age, gender, stage, site, grade, diabetes, race and Charlson comorbidity score. Results: There were 13,702 cases which met inclusion criteria and had available Part D data. Median age was 76 years, There were 42.5% males, 77.1% were white and 34.0%had diabetes. Head of the pancreas tumors accounted for 49.9% cases and 49.6% had stage 4 disease and at diagnosis. The results of the stepwise Cox proportional hazard models are summarized in table 1. Beta blockers, heparin, insulin, warfarin were associated were significantly with improved survival (p<0.05). Conclusions: Concurrent medication use, particularly heparin, insulin warfarin and beta-blockers are associated with improved survival in patients with pancreatic cancer. Diabetes medications (metformin, TZD) did not have an impact in the multivariable model. Additional studies are needed to examine whether these medications may improve outcomes for patients with pancreatic cancer. [Table: see text]
Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer.
Authors: Stein Stacey , James Edward Samuel , Cong Xiangyu , Deng Yanhong , Salem Ronald R , Cha Charles , Chang Bryan William , Hochster Howard S. , Doddamane Indukala , Boustani Annmarie , Patel Vatsal , Kortmansky Jeremy S. , Li Jia , Staugaard Carol , Lacy Jill
Published: February 2017

395

Background: Toxicities associated with FOLFIRINOX have prompted use of modifications, despite absence of prospective data validating comparable efficacy and improved tolerability. To determine the impact of attenuated doses of irinotecan and bolus 5FU on efficacy and tolerability, we conducted a prospective phase II study of modified FOLFIRINOX in advanced PC. The efficacy of a FOLFIRINOX regimen has not been previously examined in locally advanced PC (LAPC). Previous studies in LAPC have compared chemo vs chemoRT with median OS in the 9-12 mo range (Loehrer et al, Chauffert et al, Hammel et al). Methods: Previously untreated pts with MPC or LAPC received modified FOLFIRINOX with pegylated filgrastim. Irinotecan and bolus FU were reduced by 25%. AEs were compared to historical control (Conroy et al NEJM 2011). Objective RR in MPC was compared to historical control. PFS and OS were calculated for both cohorts. Results: 31 and 44 pts with LAPC and MPC enrolled. Treatment-related grade 3 and 4 AEs were diarrhea (16.2%), neutropenia (12.2%), fatigue (12.2%), thrombocytopenia (9.5%), anemia (5.4%). Neutropenia (p < 0.0001), vomiting (p = 0.001), and fatigue (p = 0.01) were significantly decreased compared to historical control patients. In MPC, the RR (35.1%) was similar to the historical control group (36.3%; p 0.82); median PFS and OS were 6.1 months (95% CI, 5.19 to 8.31) and10.2 months (95% CI, 7.65 to 14.32) respectively. In LAPC, the RR was 17.2% and median PFS and OS were 17.8 mo (95% CI, 11.0 to 23.9) and 26.6 mo (95% CI, 16.7, NA) respectively. 13 pts went on to surgical resection with 10 now alive and 6 without recurrence. We found no significant association between early metabolic response by FDG-PET imaging and PFS and OS. Conclusions: In this first prospective study of modified FOLFIRINOX, the regimen was well tolerated and associated with decreased incidence of AEs compared to historical control of standard FOLFIRINOX. In MPC pts, the efficacy of the modified regimen appear uncompromised. In this first prospective study of a FOLFIRINOX regimen in LAPC, the PFS and OS surpasses that of previously studied regimens in LAPC. Clinical trial information: NCT01523457.
The outcome of surgical treatment for oldest-old patients with gastric cancer.
Authors: Hikage Makoto , Makuuchi Rie , Tokunaga Masanori , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Kinugasa Yusuke , Sugiura Teiichi , Uesaka Katsuhiko , Terashima Masanori
Published: February 2017

40

Background: The number of the oldest-old patients with gastric cancer has been increasing in Japan. Selecting optimal operation for these patients is difficult because coping with both radicality and tolerability of surgery is mandatory. The aim of this study is to clarify the feasibility and effectiveness of gastrectomy for these patients. Methods: A total of 721 old patients (aged 75 years old and older) with gastric cancer who underwent curative gastrectomy at Shizuoka Cancer Center between from Oct. 2002 to Aug. 2015 were included in this study. The patients were classified into oldest-old group (OOP; aged 85 years and older) and old group (OP; aged 75 to 84 years old). Characteristics of the patients and short and long-term outcomes were compared between the groups. Results: OOP group included 57 patients, and OP group 664 patients. Though median serum albumin level in OOP group (3.8 g/dl) was significantly lower than in OP group (4.1 g/dl) (p = 0.002), the other clinicopathological characteristics including gender, BMI, co-morbidity, ASA-PS, ECOG-PS and preoperative stage were not significantly different between the groups. In terms of operative results, gastrectomy with reduced extent of lymph node dissection was frequently performed in OOP group (33.3%) than in OP group (6.0%) with significant difference (p < 0.001). Median operation time was significantly shorter in OOP group (195 minutes) than in OP group (222 minutes) (p = 0.001), and median blood loss was significantly less in OOP group (154 ml) than in OP group (227 ml) (p = 0.041). There was no significant difference of the incidence of postoperative complications between the groups. There was no significant difference of overall survival (p = 0.973) and disease-specific-survival (p = 0.549) between the groups. In multivariate analysis, preoperative BMI < 20, serum albumin < 3.8 g/dl and 15 days or more postoperative hospital stay were revealed as significant independent prognostic factors. Conclusions: Gastrectomy is safe with acceptable oncologic outcomes for OOP with optimally reducing the extent of surgery in each patient. In order to improve the outcome in OOP, preoperative nutritional management and support for home health care system should be considered.
Tolerability and clinical outcomes in elderly patients with advanced pancreatic cancer treated with FOLFIRINOX.
Authors: Yamamoto Taikan , Sunakawa Yu , Kubota Yutaro , Tagawa Teppei , Kaga Yasuhiro , Ikusue Toshikazu , Uto Yu , Kitahara Yu , Toshima Hirokazu , Kobayashi Kouji , Hisamatsu Atsushi , Ichikawa Wataru , Sekikawa Takashi , Shimada Ken , Sasaki Yasutsuna
Published: February 2017

404

Background: FOLFIRINOX, a combination chemotherapy of 5-FU, oxaliplatin, and irinotecan, has contributed to the overall survival (OS) benefit of advanced pancreatic cancer (PC), of which a major concern is severe toxicity such as neutropenia and diarrhea. Some elderly patients (pts) with PC need such an intensive chemotherapy in practical treatment; however, tolerability and efficacy for the regimen in the elderly are not well known. We report a retrospective analysis for toxicity and efficacy of FOLFIRINOX treatment in elderly pts with advanced PC. Methods: We analyzed pts with unresectable/metastatic PC, ECOG performance status 0 or 1, neutrocyte over 1500/mm3, and hemoglobin over 9g/dl, who received FOLFIRINOX as 1st- or 2nd-line therapy between November 2012 and July 2015 in 3 institutes of Showa University, Japan. All pts were divided into two groups, elderly group with pts 65 years of age or older and younger group with pts under 65 years old, then were compared in the toxicity and efficacy of FOLFIRINOX treatment. Results: Fifty-nine pts (median age: 62 years) were enrolled in this study: elderly and younger groups included 26 pts (median age: 70 years) and 33 pts (median age: 57 years), respectively. Severe neutropenia with grade 4 was numerically more frequent in the elderly group compared to the younger group (54% vs. 36%, p = 0.17). However, rate of febrile neutropenia was similar between the groups: 3 (12%) pts for the elderly group and 2 (6%) pts for the younger group. There was no difference in frequency of any grade toxicities, and no FOLFIRINOX treatment-related death was observed in both groups. Response rate was 14% (5/26) for the elderly group and 33% (11/33) for the younger group, with no significant difference (p = 0.22). Median progression-free survival (PFS) and OS were comparable between the elderly and younger groups (5.3 months vs. 5.4 months, log-rank p = 0.47 for PFS; not-reached vs. 10.7 months, long-rank p = 0.49 for OS). Conclusions: Our study suggests that FOLFIRINOX treatment is tolerable and active for the elderly pts with advanced PC, although frequency of severe neutropenia is higher in the elderly compared to the younger pts.
Local effect and gastrointestinal toxicity for carbon-ion radiotherapy in patients with unresectable locally advanced pancreatic cancer.
Authors: Shinoto Makoto , Shioyama Yoshiyuki , Suefuji Hiroaki , Matsunobu Akira , Toyama Shingo , Kudo Sho
Published: February 2017

410

Background: Carbon-ion radiotherapy (CIRT) is a unique external radiotherapy that has an excellent dose conformity and higher biological effectiveness compared to conventional radiotherapy. The sensitivity of the organs in upper abdomen has limited the radiation dose to levels that are ineffective against pancreatic cancer, which has extreme radioresisnatnce. We investigated effectiveness and gastrointestinal (GI) toxicity of CIRT. Methods: From April 2014 to June 2015, 41 patients with pancreatic cancer were treated with definitive CIRT. 26 patients who were confirmed as unresectable locally advanced pancreatic cancer pathologically and by imaging techniques were included in this retrospective analysis. 15 patients were excluded because of resectable disease (n = 3), borderline disease (n = 4), no cell evidence (n = 11). CIRT was performed with 55.2 Gy (RBE) at 12 fractions. The maximal absolute dose with covered 2cm3 of the organ (D2) was restricted under 46 Gy (RBE). All patients were followed up using CT, FDG-PET and upper gastrointestinal endoscopy at least every six months. Anti-tumor effect was evaluated using CT and FDG-PET according to RECIST. If FDG accumulation was negative or equal to normal pancreatic tissue after CIRT, it was defined CR even no decreasing in seize on CT. GI toxicity was evaluated using CTCAE. Results: Tumor location were head in 7, head-body in 2, body-tail in 16. Median tumor size was 35mm (range 21-50). In all patients, sequential and/or concurrent chemotherapy was performed. The median follow-up period was 7.7 months. Local effect using CT criteria was CR in 0, PR in 2, SD in 22, and PD in 2. The evaluation adding FDG-PET criteria was CR in 12, PR in 4, SD in 8, and PD in 2. Two patients who were SD by CT and CR by FDG-PET performed tumor resection and were revealed pCR. The actual incidence of gastric ulcer/bleeding was 15% (n = 4). Only one patient (4%) received blood transfusion because of grade 3 gastric ulcer. The other patients experienced grade 1/2 gastric ulcer. There was no duodenal ulcer. Conclusions: CIRT were effective and well tolerated under the restriction of D2 < 46 Gy (RBE). FDG-PET was useful for the evaluation of local effect after CIRT.
Nab-paclitaxel plus gemcitabine followed by radiotherapy with concurrent 5-FU in locally advanced unresectable pancreatic cancer: A Western Australian experience.
Authors: Dean Andrew Peter , Spry Nigel , McGrath Alycea
Published: February 2017

430

Background: The optimal management of patients with locally advanced unresectable pancreatic cancer is unclear. In the metastatic setting, superior response rates have been seen with nab-paclitaxel plus gemcitabine compared to gemcitabine alone. We investigate the efficacy and safety of nab-paclitaxel plus gemcitabine followed by radical radiotherapy with concurrent 5-FU in patients with locally advanced unresectable pancreatic adenocarcinoma. Methods: A retrospective review was conducted of all patients with locally advanced unresectable pancreatic cancer treated with nab-paclitaxel plus gemcitabine, the majority proceeding to radical radiotherapy with concurrent 5-FU, at two large Western Australian metropolitan hospitals from January 2009 to December 2014. Charts were reviewed to obtain patient characteristics, efficacy and tolerability. Kaplan-Meier analysis was utilised to obtain survival curves. Results: Forty-two patients were identified as having locally advanced unresectable pancreatic adenocarcinoma, receiving nab-paclitaxel plus gemcitabine to a mean number of 5 cycles, the majority requiring dose reductions. Of these, thirty proceeded to radical radiotherapy; the majority receiving 3DCRT, 54 Gy, with concurrent 5-FU. Seven had sufficient response to therapy to be offered radical resection. Six went on to radical resection, all with R0 or close resection margins (2 with complete response). Median length of stay following surgery was 18 days, and there were no perioperative deaths. The median survival for patients proceeding with surgery was 30 months. Median survival was 23 months for those treated with chemoradiotherapy, and 10 months with chemotherapy alone. Conclusions: This retrospective investigation demonstrates that nab-paclitaxel plus gemcitabine followed by radical radiotherapy with concurrent 5-FU is a tolerable treatment option with encouraging results for patients with locally advanced unresectable pancreatic cancer. The R0 resection rate in patients that had adequate response to allow for radical resection is promising. Further studies are warranted.
The effect of postoperative morbidity on long-term survival after curative resection for extra-hepatic biliary tumors: A multi-institution analysis from the U.S. Extrahepatic Biliary Malignancy Consortium.
Authors: Jin Linda , Krasnick Bradley , Davidson Jesse , Ethun Cecilia Grace , Pawlik Timothy M. , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Weber Sharon M. , Salem Ahmed I. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Maithel Shishir Kumar , Fields Ryan C.
Published: February 2017

435

Background: Surgical resection is the cornerstone of curative therapy for extrahepatic biliary tumors (EHBTs) Postoperative complications (POCs) can negatively impact survival after oncologic resection. We evaluated the impact of POCs on survival after resection of EHBTs. Methods: We analyzed 914 patients from ten institutions of the U.S. Extrahepatic Biliary Malignancy Consortium who underwent curative resection for gallbladder adenocarcinoma (n=389), hilar (n=295) and distal (n=294) cholangiocarcinoma between 1998 and 2015. POCs were graded using the modified Clavien-Dindo system. Overall survival (OS) probabilities were estimated using the method of Kaplan and Meier and analyzed using multivariate Cox regression. Results: Median follow-up was 20 months. The median age was 66 years, and the overall complication rate was 54%. Complication rates were significantly higher in patients with distal or hilar cholangiocarcinoma (62%) when compared with gallbladder cancer (41%, p<0.001). For all cancer types, patients who experienced POCs had lower 5-year OS when compared with those who did not (18% vs 28%, p<0.001). On multivariate Cox regression, POC remained an independent predictor for decreased OS (HR 1.5, 95% CI 1.3-1.9, p<0.001; Table). Among patients who experienced POCs, survival did not differ by greatest Clavien grade of complication experienced (p=0.89), however patients who had 2 or more POCs did have decreased long term survival when compared with patients with only a single POC (HR 1.5, 95% CI 1.2-1.8, p=0.001). Conclusions: POCs adversely affect long-term outcomes after curative resection for extra-hepatic biliary tumors. While any complication grade did not have a significant impact on long-term survival, increasing number of POCs did significantly worsen the prognosis for OS. [Table: see text]
Second-line chemotherapy (CTx) outcomes in advanced biliary cancers (ABC): A retrospective multicenter analysis.
Authors: Lowery Maeve Aine , Goff Laura Williams , Jordan Emmet , Wang Rui , Bocobo Andrea Grace , Chou Joanne F. , O'Reilly Eileen Mary , Harding James J. , Kemeny Nancy E. , Capanu Marinela , Griffin Ann , McGuire Joseph P. , Venook Alan P. , Abou-Alfa Ghassan K. , Kelley Robin Kate
Published: February 2017

437

Background: While gemcitabine in combination with platinum has been well established as first line systemic therapy for ABC, there remains no standard of care regimen in the second line setting. We evaluated current practice and outcomes for second line chemotherapy in patients with ABC across three geographically diverse, large US academic medical centers. Methods: 198 pts who received second line chemotherapy for ABC after 1/1/11 were identified from institutional databases following IRB approval. Records were reviewed for demographic, treatment and response data. Overall survival (OS) was calculated from start of second line chemotherapy and estimated using Kaplan-Meier methods. Results: Median follow up among survivors was 5 months and median OS for all patients from start of second line therapy was 11 months (mo) (95% CI 8.8-13.1): intrahepatic (61.1%): 13.4 mo (95%CI: 10.7-17.8); extrahepatic (14.1%): 6.8 mo (95%CI: 5-11); and gallbladder (24.8%): 9.4 mo (95%CI: 7.2-12.3). Median duration of second line chemotherapy was 2.2 mo (range 0-32.5). 103 pts (52%) received ≥ 3 lines of chemotherapy. Median OS from start of first line of gemcitabine plus cisplatin or oxaliplatin was 22.4 mo (95% CI 17.9 – 25.5). Conclusions: In highly selected pts with ABC treated at academic medical centers, survival following progression on first line chemotherapy was higher than previously reported, and patients received multiple lines of treatment. This multicenter collaboration provides a contemporary benchmark to inform the hypotheses and design of future clinical trials of second line chemotherapy in ABC. [Table: see text]
Treatment of borderline resectable (BR) and locally advanced (LA) pancreatic cancer in the era of FOLFIRINOX and gemcitabine plus nab-paclitaxel: A multi-institutional study.
Authors: Idrees Kamran , Parikh Alexander A. , Postlewait Lauren McLendon , Weber Sharon M. , Cho Clifford Suhyun , Salem Ahmed I. , Martin Robert C. G. , Scoggins Charles Raben , Kim Hong Jin , Carr Jacquelyn , Stuart Heather , Xia Brent , Ahmed Syed , Abbott Daniel Erik , Maithel Shishir Kumar , Kooby David A. , Merchant Nipun B.
Published: February 2017

451

Background: FOLFIRINOX or Gemcitabine+nab-Paclitaxel (Gem/nPac) has superior overall survival (OS) compared with gemcitabine alone in pts with Stage 4 pancreatic cancer (PC). Based on these results, FOLFIRINOX or Gem/nPac has been utilized in neoadjuvant (NA) setting for BR and LA PC. This report describes our multi-institutional experience with NA treatment with FOLFIRINOX or Gem/nPac followed by surgical resection. Methods: Pts with BR and LA PC who received NA FOLFIRINOX or Gem/nPac and underwent surgical resection between 2011 and 2015 at 7 high volume pancreas centers were reviewed. Pre-operative chemoradiation therapy (pCXRT) was administered selectively based on radiographic response (RR). Near-complete (minimal residual disease) or complete pathologic response (PR) was categorized as marked PR. Results: 86 pts received either NA FOLFIRINOX (69%) or Gem/nPac therapy (31%) for BR (67%), LA (32%) PC. pCXRT was administered in 71% of pts. Pts received a median of 4 cycles of FOLFIRINOX (range 1-28) and 3 cycles of Gem/nPac (range 2-13). No grade 4-5 toxicities were noted. The majority of pts underwent pancreaticoduodenectomy (84%) and vascular resection was performed in 53% - 40 with venous resection and 6 with arterial resection. R0 resection rate was 86% with no difference between two treatment groups (p = 0.9). Reduction in CA 19-9 or RR did not correlate with pathological response (p = 0.8). A marked PR was seen in 12 pts – 13.6% vs. 15.4% for FOLFIRINOX and Gem/nPac, respectively (p = 0.8). Adjuvant chemotherapy or CXRT was administered in 44% of pts. With a median follow up of 20 months (mo), OS was 27.4 mo with median OS in marked PR was 53 vs. 25 mo in moderate PR/non-responders (p = 0.04). Recurrence was noted in 45 pts – 49% had distant recurrence, 20% had local recurrence and 31% had both. Conclusions: Neoadjuvant FOLFIRINOX or Gem/nPac therapy in conjunction with aggressive surgical resection in BR and select LA PDAC pts result in significant long-term survival especially in marked pathologic responders. Further, optimization of treatment protocols in the neoadjuvant and adjuvant setting is warranted since recurrence rates are high.
Results of the phase Ib portion of a phase I/II trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreatic cancer.
Authors: Bahary Nathan , Garrido-Laguna Ignacio , Wang-Gillam Andrea , Nyak-Kapoor Asha , Kennedy Eugene , Vahanian Nicholas N. , Link Charles J.
Published: February 2017

452

Background: IDO is a tryptophan-catabolizing enzyme that plays a key role in the normal regulation of peripheral immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression. In cancer, IDO mediates an acquired immune tolerance towards tumors, allowing evasion of immune mediated destruction. Indoximod is a broad IDO pathway inhibitor, as it has been shown to potentially interfere with multiple targets within the IDO pathway. Pre-clinical models have demonstrated synergy between indoximod and chemotherapy. The combination of gemcitabine (Gem) and nab-paclitaxel (Nab) is a current SOC for first line treatment of metastatic pancreas cancer. This trial is designed to determine the potential for benefit of combination therapy with indoximod and Gem / Nab for to patients with metastatic pancreatic cancer. Methods: Indoximod was escalated (600mg/1000mg/1200mg PO twice daily continuous dosing) in combination with Gem / Nab (1000mg/m2 / 125mg/m2 q week x 3 per 4 week cycle) in a 3+3 design. Patients were first line metastatic pancreatic cancer or minimum 6 months from adjuvant chemo and / or radiation following previous resection. Treatment continues until progression or toxicity. Primary endpoints for Phase 1 include safety, toxicity, and determination of a Phase 2 dose. The prospective collection of tumor samples for exploration of biomarkers is built into the trial. Results: 15 patients were required to successfully dose escalate the Phase 1 study to 1200 mg twice daily. Two patients were replaced in the lowest dose cohort after rapid deterioration due to underlying disease during the regimen limiting toxicity (RLT) window. One RLT was observed during the study (ascites Grade 3) at the highest dose cohort. The most common AE’s (all Grade 1 or 2) occurring in ≥ 4 subjects, regardless of attribution, were nausea, fatigue, peripheral edema, peripheral neuropathy, alopecia. Conclusions: Indoximod and Gem / Nab were well tolerated in a clinical trial setting. The Phase 2 dose was set at 1200 mg twice daily and Phase 2 enrollment (target 80 patients) is ongoing. Updated results will be presented. Clinical trial information: NCT02077881.
Accuracy of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in predicting node positivity and metastatic disease in patients with gastrointestinal malignancies.
Authors: Doepker Matthew , Baughen Kabisa , Brown Richard H. , Kucera Steven , Lee Justin , Shridhar Ravi , Meredith Kenneth
Published: February 2017

462

Background: Accurate predictors of node positivity and metastatic disease for patients with gastrointestinal (GI) malignancies are currently lacking. Neutrophil-lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR) have been introduced as a possible prognostic scoring system. We sought to evaluate the accuracy of NLR and PLR in predicting advanced disease in patients with GI malignancies. Methods: We queried a prospective GI oncology database to identify 116 patients. NLR and PLR were calculated from complete blood counts before and after neoadjuvant therapy (NT) and pre-operatively in patients not treated with NT. The associations between NLR and PLR and the clinicopathologic parameters were assessed via χ2 or Fisher’s exact tests where appropriate. All the tests were two-sided, and p < 0.05 was considered statistically significant. Results: We identified 49(42.2%) esophageal, 34 (29.3%) pancreatic, 14 (12.1%) colorectal, 13 (11.2%) gastric, and 6(5.2%) biliary cancers. There were 36 (31%) LN-, 52 (44.8%) LN+, and 28 (24.2%) patients with metastatic disease. The median NLR for LN – patients was 1.78 (0.2-4.5) and for LN + and metastatic patients was 4.48 (2.38-24.1) p < 0.00001. The median PLR for LN– patients was 123 (66-207) and for LN+ and metastatic patients was 212 (112-2185) p < 0.00001. The sensitivity (SENS), specificity (SPEC), positive predictive value (PPV) and negative predictive value (NPV) for a NLR > 2.25 was 98.8%, 72.2%, 89%, and 96% respectively with an overall accuracy of 91%. The SENS, SPEC, PPV, and NPV for PLR > 140 was 95%, 78%, 90%, and 88% respectively with an overall accuracy of 90%. Utilizing both NLR > 2.25 and PLR > 140 the SENS, SPEC, PPV and NPV was 95%, 89%, 95%, and 89% respectively and the overall accuracy was 93%. Conclusions: NLR and PLR can be used to identify patients with node positivity and metastatic disease. Individually, NLR has a higher sensitivity and NPV while PLR has a higher specificity and PPV. However, the combination of NLR and PLR has the highest accuracy of predicting advanced disease among all gastrointestinal malignancies.
The incidence of secondary pelvic tumors after previous (chemo)radiation for rectal cancer.
Authors: Rombouts Anouk J.M. , Hugen Niek , Elferink Marloes A. G. , Feuth Ton , Poortmans Philip M. , Nagtegaal Iris D. , de Wilt Johannes H.W.
Published: February 2017

491

Background: The aim of this study was to analyze the association between radiotherapy (RT) for rectal cancer and the development of second primary tumors. Methods: Data on all surgically treated, non-metastasized primary rectal cancer patients diagnosed between 1989 and 2007 were retrieved from a population-based cancer registry and retrospectively reviewed. To estimate the cumulative incidence of a second tumor, Fine and Gray’s competing risk model was used with death as a competing event. Standardized incidence ratios (SIR’s) were calculated for comparison with the incidence of primary tumors in the general population, taking in account sex, age and calendar year. Results: The cohort consisted of 29,214 patients of which 15,454 patients had undergone (chemo)RT. Median follow-up was 6.2 years (range 0-24). 3655 patients were diagnosed with at least one second primary tumor of which 808 patients had pelvic tumors. The SIR for any second tumor was 1.14 (95% confidence interval [CI] 1.10-1.17), resulting in 23.3/10,000 excess cases per year. RT reduced the cumulative incidence of second pelvic tumors compared to patients who received no RT (SHR 0.70, 95% CI 0.61-0.81). Second pelvic tumors were more common in patients who underwent post-operative RT than in patients who underwent pre-operative RT (SHR 1.37, 95% CI 1.10-1.70). Organ-specific analyses showed that second prostate tumors were less common in patients who received RT compared to patients who received no RT (SHR = 0.51, 95% CI 0.43-0.62). RT also reduced the risk for a second primary tumor in the rectum(sigmoid) compared to patients who did not receive RT (SHR 0.59 95% CI 0.37-0.94). Patients who received post-operative RT had higher chances of developing a second rectum(sigmoid) tumor then patients who received pre-operative RT (SHR 2.25, 95% CI 1.07-4.73). Patients without RT had worse overall survival than patients who received RT (hazard ratio 1.22, 95% CI 1.19-1.26). Conclusions: In this nationwide study, patients with previous rectal cancer had a slightly increased chance of developing another primary tumor compared with the general population. We found a protective effect of RT on the development of secondary pelvic tumors, predominantly for prostate cancer.
MAVERICC, a phase 2 study of mFOLFOX6-bevacizumab (BV) vs FOLFIRI-BV with biomarker stratification as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Lenz Heinz-Josef , Lee Fa-Chyi , Yau Linda , Koh Han A. , Knost James A. , Mitchell Edith P. , Bosanac Ivan , Mancao Christoph , Parikh Aparna
Published: February 2017

493

Background: Standard 1L mCRC treatment (tx) includes a CT backbone (e.g., modified leucovorin [LV]/5-fluorouracil [5-FU]/oxaliplatin [mFOLFOX6] or LV/ 5-FU/ irinotecan [FOLFIRI]) and biologic therapy (e.g., BV). The preferred CT backbone for anti VEGF tx is unknown. MAVERICC (NCT01374425), a global, randomized, open-label, phase 2 trial, assessed tx efficacy and safety of mFOLFOX6-BV vs FOLFIRI-BV in pts with mCRC. Intratumoral ERCC1 and plasma VEGF-A were studied as biomarkers for oxaliplatin- and BV-containing tx, respectively. Methods: Pts with mCRC (≥1 measurable metastatic lesion, ECOG performance status ≤1) were randomized 1:1 to receive BV (5 mg/kg) + mFOLFOX6 or FOLFIRI every 2 weeks, stratified by ERCC1 level (low [£1.7] vs high [>1.7]) and region. VEGF-A levels were measured at baseline. Primary objectives were to evaluate: ERCC1 as a biomarker of progression-free survival (PFS) in 1L mCRC tx (mFOLFOX-BV vs FOLFIRI); and VEGF-A as a biomarker for BV and as a biomarker in combination with ERCC1 for PFS following CT + BV. Secondary objectives were to evaluate: the effect of ERCC1 and VEGF-A on overall survival (OS), objective response rate, hepatic metastases resection, and safety. PFS and OS were estimated by Kaplan–Meier methods, hazard ratios (HR) were estimated by Cox regression, and p-values were based on stratified log-rank tests. ERCC1 biomarker analyses are presented here. Results: A total of 376 pts were randomized: median age, 61 yr; white race, 83%; US region, 85%. Baseline characteristics: ERCC1 high, 35%; KRAS mutant, 34%. Efficacy results are shown (see Table). Conclusion: Consistent with previous findings, PFS and OS were comparable in pts treated with either 1L mFOLFOX6-BV or FOLFIRI-BV. Exploratory analyses within pts with high ERCC1 levels suggest consistent results. VEGF-A analyses are ongoing. Clinical trial information: NCT01374425. [Table: see text] [Table: see text]
A phase II therapeutic, open label, multi-center clinical trial of NPC-1C, a chimeric monoclonal antibody(mAb), in adults with chemotherapy refractory metastatic colorectal cancer (mCRC), initial results.
Authors: Kim Richard D. , Azad Nilofer Saba , Morse Michael , Tan Benjamin R. , Poplin Elizabeth , Beatson Melony A. , Mavroukakis Sharon , Arlen Philip M. , Beg Muhammad Shaalan
Published: February 2017

500

Background: NEO-102 is a novel chimeric mAb targeting a variant of MUC5AC with specificity to colorectal cancer. Its mechanism of action is through antibody dependent cellular cytotoxicity (ADCC). An earlier, phase I study, established the maximum tolerated dose at 3.0 mg/kg IV every 2 weeks with encouraging early signs of clinical activity. We report initial results of the subsequent phase II study. Methods: This is a single arm, open label multi-center clinical trial of NEO-102 in adults with mCRC pts who failed at least two lines of standard chemotherapy (C). An immunohistochemistry (IHC) based companion diagnostic assay was used to select eligible pts whose tumors express the target in > 20% of tumor cells. NEO-102 at 3.0 mg/kg IV was administered q 2 weeks until disease progression. The primary endpoint was OS. A minimum of 43 pts were needed assuming that treatment with NEO-102 will improve OS by 40% (7.0 months) using a one-sided significance level of 10% and 80% power for this study compared to historical control of 5 months. Additional objectives were to evaluate response rate as measured by RECIST criteria and analyze patient PBMCs for ADCC and immune cytokine profiling. Results: A total of 47 pts enrolled were evaluable. 26 pts were male and 35 pts were white. Twenty-four out of 47 pts (51%) remain alive as of September 2015 with an ongoing median OS of 7.0 months (Range 2-22 months). Of these heavily pre-treated pts, 42 were evaluable for response, 13 (31%) demonstrated stable disease by RECIST. Seven pts had more than 4 doses of treatment, maximum 13 doses. Grade 3 adverse events were anemia 1/47 (2%), hyperbilirubinemia 1/47 (2%), diarrhea 1/47 (2%), fatigue 1/47 (2%), headache 1/47 (2%), nausea 1/47 (2%) and vomiting 1/47 (2%). No grade 4 toxicities were reported. Conclusions: In the monotherapy phase 2 study of NEO 102 in patients with refractory mCRC preliminary results demonstrate excellent tolerability and encouraging OS. Updated OS and Progression Free Survival data will be presented at the ASCO 2016 GI Cancers symposium. Additional combination trials with NEO-102 and C are underway. Clinical trial information: NCT01040000.
Assessing solid tumor response with and without RECIST.
Authors: Deng Aileen , Leiby Benjamin E , Schilder Russell J. , Kelly William Kevin , Deshmukh Sandeep , Sama Ashwin Reddy
Published: February 2017

504

Background: Response Evaluation Criteria in Solid Tumors (RECIST) has become widely accepted as gold standard for response evaluation in clinical trials. It remains underutilized in routine clinical practice. We compared tumor response assessment made with and without RECIST. Methods: This study included patients with solid tumors who underwent imaging from January 2013 to December 2014 at a single academic center. Tumor response was assessed by a radiologist using RECIST and by an oncologist (Onc) and resident (Res) without using RECIST (standard report). Tumor response was classified as progressive disease (PD), stable disease (SD), partial response (PR) and complete response (CR). Agreement in assessment between RECIST and standard report was determined by percent agreement and Kappa statistic. Results: 292 imaging studies were included. Concordance between RECIST and Onc-interpreted standard report is presented in Table 1. Overall agreement between RECIST and Onc-interpreted standard report was 56% (95% CI: 46-65%) and Kappa was 0.31 (95% CI: 0.19-0.44). Similar results were seen between RECIST and Res-interpreted standard report (Table 1). Overall agreement between RECIST and Res-interpreted report was 54% (95% CI: 44%-63%) and Kappa was 0.26 (95% CI: 0.13-0.40). Conclusions: Our study found variability in tumor response assessment between clinicians and radiologists. RECIST-classified PD was often interpreted as SD and vice versa, a distinction that affect treatment decisions. Our study highlights the need to standardize tumor response assessment. [Table: see text]
Correlation of pretreatment p63-positive subtype of gastroesophageal adenocarcinoma (GEAC) with pathologic complete response (pathCR) in patients receiving preoperative chemoradiation.
Authors: Elimova Elena , Kim Soo-Mi , Wang Xuemei , Shimodaira Yusuke , Sohn Bo Hwa , Skinner Heath Devin , Lee Jeffrey H. , Weston Brian , Bhutani Manoop S. , Minsky Bruce D. , Rice David C. , Hwang Jun Eul , Swisher Stephen , Hofstetter Wayne Lewis , Blum Mariela A. , Maru Dipen M. , Ajani Jaffer A. , Lee Ju-Seog
Published: February 2017

51

Background: Biomarker or biomarker signature(s) is needed to help optimize therapy of GEAC patients undergoing multimodality therapy. p63 is a transcription factor important in the development of squamous epithelial lineage and mediating ectodermal-mesenchymal interactions. Methods: Primary objective of this study was to study the predictive value of p63-associated subtype for pathCR. Other outcomes were also studied. Results: Unsupervised cluster analysis of gene expression data from 185 GEAC patients uncovered two distinct subtypes of GEAC with differences in expression of p63 mRNA: p63-positive and p63-negative. All patients had chemoradiation and surgery. Most were men (88%), all had adenocarcinoma, and most were p63-negative (69%). 25% of patients achieved a pathCR. The median follow-up for all patients was 3.9 years (range, 0.1 – 11.5). p63-positive subtype was associated with pathCR in both a univariate and multivariate analyses (p = 0.04 and p = 0.02, respectively). Female patients with p63-positive subtype, lower no. of ypNodes, and low grade GEACs had a higher probability of pathCR. However, p63-positive subtype was not prognostic (PFS, p = 0.26 or OS, p = 0.80). The median OS for all patients was 4.8 years (95% CI, 3.3 – 6.7 years). Higher no. of ypNodes, higher histologic grade, and mid- or higher esophageal primary were associated with shorter OS (with p-values of < 0.0001, 0.0004 and 0.0001, respectively). Conclusions: Our data suggest that pretreatment p63-positive subtype of GEAC highly correlates with pathCR. Further refinement/validation and combination with other biomarkers is warranted.
Is the accuracy of preoperative MRI stage in rectal carcinoma influenced by tumor height?
Authors: Poulsen Laurids Østergaard , Yilmaz Mette K. N. , Oddershede Lars , Bøgsted Martin , Holt Gitte , Eld Mikkel , Ljungmann Ken , Falkmer Ursula
Published: February 2017

514

Background: In order to select patients with adenocarcinoma of the rectum (RC) for optimal treatment strategies, there is a need for accurate staging of the neoplastic disease. Here, magnetic resonance imaging (MRI) is considered to be the gold standard. However, some concerns have been raised about the reproducibility of earlier results. Newer treatment strategies which include organ saving in RC patients will further emphasize the need. The aim of the present study was to evaluate the degree of accuracy of the MRI staging. Methods: All patients diagnosed with RC in northern Denmark 2009-2013 (n = 1017) were screened for inclusion. All MRI were performed on 1.5 T MRI scanners and the evaluations were made by in all four expert GI-radiologists. Only patients who were offered surgery without preoperative treatment were included (n = 357). The result of the preoperative MRI staging was correlated to the postoperative histopathological stage. Results: There were 56, 131 and 190 patients respectively with low- (0-5 cm from the anal verge), mid- (5-10 cm) and high RC (10-15 cm). MRI T-staging was in accordance with the histopathology in 84 % of the cases (81% for low, 86% for mid, and 83% for high tumors, respectively) and the accuracy was not affected by tumor height. The results were consistent over time. Concerning the MRI staging of nodal-involvement, there was a sensitivity of 88% and a specificity of 30%. Data regarding tumor invasion and distance from the tumor to mesorectal fascia will be presented at the meeting. Conclusions: MRI T-stage correlated well with postoperative histopathological T-stage, whereas the correlation to nodal involvement was poor and in accordance with previous results.
Changes in non-invasive liver fibrosis indices during chemotherapy: Potential marker for oxaliplatin-induced sinusoidal obstruction syndrome.
Authors: Kim Jin-Soo , Park Sehhoon , Kim Ki Hwan , Park Jin Hyun , Kim Won , Choi In Sil , Jung Yong Jin , Kim Hwi Young
Published: February 2017

515

Background: Oxaliplatin-based regimens are standard treatments for patients with colorectal (CRC) and advanced gastric cancer (AGC). However, the use of oxaliplatin sometimes results in hepatic sinusoidal obstruction syndrome (SOS). The aim of the study was to evaluate the utility of non-invasive liver fibrosis indices for monitoring oxaliplatin-induced hepatic SOS. We have reported a preliminary data in ASCO Annual Meeting 2014. Methods: From February 2004 to April 2014, patients with CRC or AGC who received oxaliplatin-based chemotherapy were studied. Possibility of SOS development was evaluated before and after the oxaliplatin exposure with splenic volume index (SVI). Four different non-invasive liver fibrosis indices were used for risk analysis: age-platelet index (API), AST to platelet ratio index (APRI), platelet to spleen ratio (PSR), Fibrosis-4 score (FIB-4). A prospective observation with serial elastrography is also ongoing. Results: A total of 275 patients were eligible for evaluation: 200 patients had CRC, and 75 patients had AGC. Using a cutoff of SVI increase ≥ 0.3, 113 patients (41.1%) were positive for hepatic SOS. Changes of indices were significantly correlated with SVI increase. Adjusted odds ratios for those indices were as follows: API = 1.16 (95% Confidential Interval [CI], 1.01 - 1.32; P = 0.032); APRI = 2.45 (95% CI, 1.30 - 4.63; P = 0.006); PSR = 0.69 (95% CI, 0.59 - 0.80; P < 0.001); FIB-4 = 1.37 (95% CI, 1.16 - 1.63; P < 0.001). Optimal cutoff-value with statistical significance were calculated and suggested. A total of 20 patients have been enrolled into the prospective observation until now. Comparison of elastographic changes and the indices in these patients will be presented. Conclusions: Changes of non-invasive liver fibrosis indices showed good correlation with SVI increase during oxaliplatin-based chemotherapy. These indices might be useful markers for monitoring of oxaliplatin-induced hepatic SOS. Serial monitoring of hepatic elastography could also be used for non-invasive monitoring of hepatic SOS.